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Find video protocols related to scientific articles indexed in Pubmed.
Distensibility of the Aorta and Carotid Artery and Left Ventricular Mass From Childhood to Early Adulthood.
Hypertension
PUBLISHED: 10-29-2014
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In adults, arterial distensibility decreases with age and relates to changes in cardiac left ventricular mass. Longitudinal data on changes in arterial distensibility from childhood to adulthood are lacking. Our aim was to study the effect of age and sex, and low-saturated fat dietary counseling on arterial distensibility from childhood to early adulthood. In addition, we assessed the association of arterial distensibility with left ventricular mass. Distensibility of the abdominal aorta and common carotid artery was measured repeatedly at ages 11, 13, 15, 17, and 19 years (n=395-472) in an atherosclerosis prevention trial (Special Turku Coronary Risk Factor Intervention Project [STRIP]). Aortic and carotid distensibility decreased with age (both P<0.0001). In boys, distensibility values were generally lower (P<0.0001) and showed steeper decrease by age (age and sex interaction: both P<0.01). The low-saturated fat dietary counseling given in STRIP was not significantly associated with arterial distensibility. Left ventricular mass increased with age (P<0.0001), and it was greater in boys (P<0.0001). In conclusion, a marked age-related decrease in vascular distensibility was found already at this young age, and this decrease was more pronounced in boys than girls. The longitudinal progression of aortic and carotid distensibility was related with changes in left ventricular mass.
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Prevalence and determinants of fatty liver in normal-weight and overweight young adults. The Cardiovascular Risk in Young Finns Study.
Ann. Med.
PUBLISHED: 10-22-2014
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Background and aims. Fatty liver may have different determinants in normal-weight and in obese individuals. We measured factors associated with fatty liver in 863 normal-weight (BMI < 25) and 1135 overweight/obese (BMI ? 25) young and middle-aged adults (45% male, age 34-49 years) in the population-based Cardiovascular Risk in Young Finns Study. Methods and results. The prevalence of fatty liver detected with ultrasound was 29% in overweight/obese and 5% in normal-weight participants. In overweight/obese, the independent correlates were waist circumference (odds ratio for 1 standard deviation increase = 3.78), alanine transaminase (2.11), BMI (2.00), male sex (1.74), triglycerides (1.44), systolic blood pressure (1.31), fasting insulin (1.23), and physical activity (0.76). In normal weight, the independent correlates included alanine transaminase (3.05), smoking (2.56), systolic blood pressure (1.54), and alcohol intake (1.41). In normal-weight participants, the associations with fatty liver were stronger for alcohol intake and smoking, and weaker for triglycerides, than in overweight/obese participants (P for interaction < 0.05). Conclusion. Prevalence of fatty liver was 29% in overweight/obese and 5% in normal-weight adults. Differences in factors associated with fatty liver were seen between these two groups: alcohol intake and smoking were more strongly and triglycerides more weakly associated in normal-weight than in overweight/obese participants.
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A novel common variant in DCST2 is associated with length in early life and height in adulthood.
Ralf J P van der Valk, Eskil Kreiner-Møller, Marjolein N Kooijman, Mònica Guxens, Evangelia Stergiakouli, Annika Sääf, Jonathan P Bradfield, Frank Geller, M Geoffrey Hayes, Diana L Cousminer, Antje Körner, Elisabeth Thiering, John A Curtin, Ronny Myhre, Ville Huikari, Raimo Joro, Marjan Kerkhof, Nicole M Warrington, Niina Pitkänen, Ioanna Ntalla, Momoko Horikoshi, Riitta Veijola, Rachel M Freathy, Yik-Ying Teo, Sheila J Barton, David M Evans, John P Kemp, Beate St Pourcain, Susan M Ring, George Davey Smith, Anna Bergström, Inger Kull, Hakon Hakonarson, Frank D Mentch, Hans Bisgaard, Bo Chawes, Jakob Stokholm, Johannes Waage, Patrick Eriksen, Astrid Sevelsted, Mads Melbye, , Cornelia M van Duijn, Carolina Medina-Gomez, Albert Hofman, Johan C de Jongste, H Rob Taal, André G Uitterlinden, Loren L Armstrong, Johan Eriksson, Aarno Palotie, Mariona Bustamante, Xavier Estivill, Juan R Gonzalez, Sabrina Llop, Wieland Kiess, Anubha Mahajan, Claudia Flexeder, Carla M T Tiesler, Clare S Murray, Angela Simpson, Per Magnus, Verena Sengpiel, Anna-Liisa Hartikainen, Sirkka Keinänen-Kiukaanniemi, Alexandra Lewin, Alexessander Da Silva Couto Alves, Alexandra I Blakemore, Jessica L Buxton, Marika Kaakinen, Alina Rodriguez, Sylvain Sebert, Marja Vaarasmaki, Timo Lakka, Virpi Lindi, Ulrike Gehring, Dirkje S Postma, Wei Ang, John P Newnham, Leo-Pekka Lyytikäinen, Katja Pahkala, Olli T Raitakari, Kalliope Panoutsopoulou, Eleftheria Zeggini, Dorret I Boomsma, Maria Groen-Blokhuis, Jorma Ilonen, Lude Franke, Joel N Hirschhorn, Tune H Pers, Liming Liang, Jinyan Huang, Berthold Hocher, Mikael Knip, Seang-Mei Saw, John W Holloway, Erik Melén, Struan F A Grant, Bjarke Feenstra, William L Lowe, Elisabeth Widén, Elena Sergeyev, Harald Grallert, Adnan Custovic, Bo Jacobsson, Marjo-Riitta Järvelin, Mustafa Atalay, Gerard H Koppelman, Craig E Pennell, Harri Niinikoski, George V Dedoussis, Mark I McCarthy, Timothy M Frayling, Jordi Sunyer, Nicholas J Timpson, Fernando Rivadeneira, Klaus Bønnelykke, Vincent W V Jaddoe.
Hum. Mol. Genet.
PUBLISHED: 10-03-2014
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Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; ? = 0.046, SE = 0.008, P = 2.46 × 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10(-4)) and adult height (N = 127 513; P = 1.45 × 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.
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Association of thyrotropin with arterial pulse wave velocity in young adults: The Cardiovascular Risk in Young Finns Study.
Scand. J. Clin. Lab. Invest.
PUBLISHED: 09-04-2014
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Abstract Objective. Limited data are available regarding the relationship of thyrotropin (TSH) and arterial pulse wave velocity (PWV) at population level. Therefore, we conducted the present study to determine whether TSH is related to PWV assessed in young adulthood. Methods. The study population consisted of 1598 Finnish white young adults (aged 30-45 years, 47.4% males) who had TSH, traditional cardiovascular risk factors, and PWV measured in 2007. PWV measurements were performed using a whole-body impedance cardiography device. Results. In bivariate association analyses, TSH level was significantly associated with body mass index (BMI), smoking, diastolic blood pressure, triglyceride and insulin levels (p < 0.001). In multivariable regression model, TSH (? = 0.055, p = 0.015) was associated with PWV when adjusted with age (? = 0.295, p < 0.001) and sex (? = 0.345, p < 0.001). The association of TSH with PWV was however diluted to non-significant after further adjustment with traditional risk factors (? = 0.027, p = 0.218 for TSH). Conclusion. Serum TSH was associated with PWV on population level when adjusted with age and sex. This association was diluted when cardiovascular risk factors were added in the model, suggesting that the association of thyroid hormone on arterial stiffening is not independent of changes in the traditional risk factor levels.
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Concordance of genetic risk across migraine subgroups: Impact on current and future genetic association studies.
Cephalalgia
PUBLISHED: 09-01-2014
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There has been intensive debate whether migraine with aura (MA) and migraine without aura (MO) should be considered distinct subtypes or part of the same disease spectrum. There is also discussion to what extent migraine cases collected in specialised headache clinics differ from cases from population cohorts, and how female cases differ from male cases with respect to their migraine. To assess the genetic overlap between these migraine subgroups, we examined genome-wide association (GWA) results from analysis of 23,285 migraine cases and 95,425 population-matched controls.
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Defining the role of common variation in the genomic and biological architecture of adult human height.
Andrew R Wood, Tonu Esko, Jian Yang, Sailaja Vedantam, Tune H Pers, Stefan Gustafsson, Audrey Y Chu, Karol Estrada, Jian'an Luan, Zoltan Kutalik, Najaf Amin, Martin L Buchkovich, Damien C Croteau-Chonka, Felix R Day, Yanan Duan, Tove Fall, Rudolf Fehrmann, Teresa Ferreira, Anne U Jackson, Juha Karjalainen, Ken Sin Lo, Adam E Locke, Reedik Mägi, Evelin Mihailov, Eleonora Porcu, Joshua C Randall, André Scherag, Anna A E Vinkhuyzen, Harm-Jan Westra, Thomas W Winkler, Tsegaselassie Workalemahu, Jing Hua Zhao, Devin Absher, Eva Albrecht, Denise Anderson, Jeffrey Baron, Marian Beekman, Ayse Demirkan, Georg B Ehret, Bjarke Feenstra, Mary F Feitosa, Krista Fischer, Ross M Fraser, Anuj Goel, Jian Gong, Anne E Justice, Stavroula Kanoni, Marcus E Kleber, Kati Kristiansson, Unhee Lim, Vaneet Lotay, Julian C Lui, Massimo Mangino, Irene Mateo Leach, Carolina Medina-Gomez, Michael A Nalls, Dale R Nyholt, Cameron D Palmer, Dorota Pasko, Sonali Pechlivanis, Inga Prokopenko, Janina S Ried, Stephan Ripke, Dmitry Shungin, Alena Stančáková, Rona J Strawbridge, Yun Ju Sung, Toshiko Tanaka, Alexander Teumer, Stella Trompet, Sander W van der Laan, Jessica van Setten, Jana V van Vliet-Ostaptchouk, Zhaoming Wang, Loïc Yengo, Weihua Zhang, Uzma Afzal, Johan Arnlöv, Gillian M Arscott, Stefania Bandinelli, Amy Barrett, Claire Bellis, Amanda J Bennett, Christian Berne, Matthias Blüher, Jennifer L Bolton, Yvonne Böttcher, Heather A Boyd, Marcel Bruinenberg, Brendan M Buckley, Steven Buyske, Ida H Caspersen, Peter S Chines, Robert Clarke, Simone Claudi-Boehm, Matthew Cooper, E Warwick Daw, Pim A de Jong, Joris Deelen, Graciela Delgado, Josh C Denny, Rosalie Dhonukshe-Rutten, Maria Dimitriou, Alex S F Doney, Marcus Dörr, Niina Eklund, Elodie Eury, Lasse Folkersen, Melissa E Garcia, Frank Geller, Vilmantas Giedraitis, Alan S Go, Harald Grallert, Tanja B Grammer, Jürgen Gräßler, Henrik Grönberg, Lisette C P G M de Groot, Christopher J Groves, Jeffrey Haessler, Per Hall, Toomas Haller, Göran Hallmans, Anke Hannemann, Catharina A Hartman, Maija Hassinen, Caroline Hayward, Nancy L Heard-Costa, Quinta Helmer, Gibran Hemani, Anjali K Henders, Hans L Hillege, Mark A Hlatky, Wolfgang Hoffmann, Per Hoffmann, Oddgeir Holmen, Jeanine J Houwing-Duistermaat, Thomas Illig, Aaron Isaacs, Alan L James, Janina Jeff, Berit Johansen, Asa Johansson, Jennifer Jolley, Thorhildur Juliusdottir, Juhani Junttila, Abel N Kho, Leena Kinnunen, Norman Klopp, Thomas Kocher, Wolfgang Kratzer, Peter Lichtner, Lars Lind, Jaana Lindström, Stéphane Lobbens, Mattias Lorentzon, Yingchang Lu, Valeriya Lyssenko, Patrik K E Magnusson, Anubha Mahajan, Marc Maillard, Wendy L McArdle, Colin A McKenzie, Stela McLachlan, Paul J McLaren, Cristina Menni, Sigrun Merger, Lili Milani, Alireza Moayyeri, Keri L Monda, Mario A Morken, Gabriele Müller, Martina Müller-Nurasyid, Arthur W Musk, Narisu Narisu, Matthias Nauck, Ilja M Nolte, Markus M Nöthen, Laticia Oozageer, Stefan Pilz, Nigel W Rayner, Frida Renstrom, Neil R Robertson, Lynda M Rose, Ronan Roussel, Serena Sanna, Hubert Scharnagl, Salome Scholtens, Fredrick R Schumacher, Heribert Schunkert, Robert A Scott, Joban Sehmi, Thomas Seufferlein, Jianxin Shi, Karri Silventoinen, Johannes H Smit, Albert Vernon Smith, Joanna Smolonska, Alice V Stanton, Kathleen Stirrups, David J Stott, Heather M Stringham, Johan Sundström, Morris A Swertz, Ann-Christine Syvänen, Bamidele O Tayo, Gudmar Thorleifsson, Jonathan P Tyrer, Suzanne van Dijk, Natasja M van Schoor, Nathalie van der Velde, Diana van Heemst, Floor V A van Oort, Sita H Vermeulen, Niek Verweij, Judith M Vonk, Lindsay L Waite, Melanie Waldenberger, Roman Wennauer, Lynne R Wilkens, Christina Willenborg, Tom Wilsgaard, Mary K Wojczynski, Andrew Wong, Alan F Wright, Qunyuan Zhang, Dominique Arveiler, Stephan J L Bakker, John Beilby, Richard N Bergman, Sven Bergmann, Reiner Biffar, John Blangero, Dorret I Boomsma, Stefan R Bornstein, Pascal Bovet, Paolo Brambilla, Morris J Brown, Harry Campbell, Mark J Caulfield, Aravinda Chakravarti, Rory Collins, Francis S Collins, Dana C Crawford, L Adrienne Cupples, John Danesh, Ulf de Faire, Hester M den Ruijter, Raimund Erbel, Jeanette Erdmann, Johan G Eriksson, Martin Farrall, Ele Ferrannini, Jean Ferrières, Ian Ford, Nita G Forouhi, Terrence Forrester, Ron T Gansevoort, Pablo V Gejman, Christian Gieger, Alain Golay, Omri Gottesman, Vilmundur Gudnason, Ulf Gyllensten, David W Haas, Alistair S Hall, Tamara B Harris, Andrew T Hattersley, Andrew C Heath, Christian Hengstenberg, Andrew A Hicks, Lucia A Hindorff, Aroon D Hingorani, Albert Hofman, G Kees Hovingh, Steve E Humphries, Steven C Hunt, Elina Hyppönen, Kevin B Jacobs, Marjo-Riitta Järvelin, Pekka Jousilahti, Antti M Jula, Jaakko Kaprio, John J P Kastelein, Manfred Kayser, Frank Kee, Sirkka M Keinanen-Kiukaanniemi, Lambertus A Kiemeney, Jaspal S Kooner, Charles Kooperberg, Seppo Koskinen, Peter Kovacs, Aldi T Kraja, Meena Kumari, Johanna Kuusisto, Timo A Lakka, Claudia Langenberg, Loic Le Marchand, Terho Lehtimäki, Sara Lupoli, Pamela A F Madden, Satu Mannisto, Paolo Manunta, André Marette, Tara C Matise, Barbara McKnight, Thomas Meitinger, Frans L Moll, Grant W Montgomery, Andrew D Morris, Andrew P Morris, Jeffrey C Murray, Mari Nelis, Claes Ohlsson, Albertine J Oldehinkel, Ken K Ong, Willem H Ouwehand, Gerard Pasterkamp, Annette Peters, Peter P Pramstaller, Jackie F Price, Lu Qi, Olli T Raitakari, Tuomo Rankinen, D C Rao, Treva K Rice, Marylyn Ritchie, Igor Rudan, Veikko Salomaa, Nilesh J Samani, Jouko Saramies, Mark A Sarzynski, Peter E H Schwarz, Sylvain Sebert, Peter Sever, Alan R Shuldiner, Juha Sinisalo, Valgerdur Steinthorsdottir, Ronald P Stolk, Jean-Claude Tardif, Anke Tönjes, Angelo Tremblay, Elena Tremoli, Jarmo Virtamo, Marie-Claude Vohl, , Philippe Amouyel, Folkert W Asselbergs, Themistocles L Assimes, Murielle Bochud, Bernhard O Boehm, Eric Boerwinkle, Erwin P Bottinger, Claude Bouchard, Stéphane Cauchi, John C Chambers, Stephen J Chanock, Richard S Cooper, Paul I W de Bakker, George Dedoussis, Luigi Ferrucci, Paul W Franks, Philippe Froguel, Leif C Groop, Christopher A Haiman, Anders Hamsten, M Geoffrey Hayes, Jennie Hui, David J Hunter, Kristian Hveem, J Wouter Jukema, Robert C Kaplan, Mika Kivimäki, Diana Kuh, Markku Laakso, Yongmei Liu, Nicholas G Martin, Winfried März, Mads Melbye, Susanne Moebus, Patricia B Munroe, Inger Njølstad, Ben A Oostra, Colin N A Palmer, Nancy L Pedersen, Markus Perola, Louis Pérusse, Ulrike Peters, Joseph E Powell, Chris Power, Thomas Quertermous, Rainer Rauramaa, Eva Reinmaa, Paul M Ridker, Fernando Rivadeneira, Jerome I Rotter, Timo E Saaristo, Danish Saleheen, David Schlessinger, P Eline Slagboom, Harold Snieder, Tim D Spector, Konstantin Strauch, Michael Stumvoll, Jaakko Tuomilehto, Matti Uusitupa, Pim van der Harst, Henry Völzke, Mark Walker, Nicholas J Wareham, Hugh Watkins, H-Erich Wichmann, James F Wilson, Pieter Zanen, Panos Deloukas, Iris M Heid, Cecilia M Lindgren, Karen L Mohlke, Elizabeth K Speliotes, Unnur Thorsteinsdottir, Inês Barroso, Caroline S Fox, Kari E North, David P Strachan, Jacques S Beckmann, Sonja I Berndt, Michael Boehnke, Ingrid B Borecki, Mark I McCarthy, Andres Metspalu, Kari Stefansson, André G Uitterlinden, Cornelia M van Duijn, Lude Franke, Cristen J Willer, Alkes L Price, Guillaume Lettre, Ruth J F Loos, Michael N Weedon, Erik Ingelsson, Jeffrey R O'Connell, Gonçalo R Abecasis, Daniel I Chasman, Michael E Goddard, Peter M Visscher, Joel N Hirschhorn, Timothy M Frayling.
Nat. Genet.
PUBLISHED: 08-29-2014
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Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ?2,000, ?3,700 and ?9,500 SNPs explained ?21%, ?24% and ?29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/?-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
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A metabolic view on menopause and ageing.
Nat Commun
PUBLISHED: 08-21-2014
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The ageing of the global population calls for a better understanding of age-related metabolic consequences. Here we report the effects of age, sex and menopause on serum metabolites in 26,065 individuals of Northern European ancestry. Age-specific metabolic fingerprints differ significantly by gender and, in females, a substantial atherogenic shift overlapping the time of menopausal transition is observed. In meta-analysis of 10,083 women, menopause status associates with amino acids glutamine, tyrosine and isoleucine, along with serum cholesterol measures and atherogenic lipoproteins. Among 3,204 women aged 40-55 years, menopause status associates additionally with glycine and total, monounsaturated, and omega-7 and -9 fatty acids. Our findings suggest that, in addition to lipid alterations, menopause may contribute to future metabolic and cardiovascular risk via influencing amino-acid concentrations, adding to the growing evidence of the importance of amino acids in metabolic disease progression. These observations shed light on the metabolic consequences of ageing, gender and menopause at the population level.
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Five-factor personality traits and sleep: evidence from two population-based cohort studies.
Health Psychol
PUBLISHED: 08-18-2014
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The current study examines associations between five factor personality traits and average sleep duration, sleep deficiency, and sleep problems.
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Genome-wide association study of sleep duration in the Finnish population.
J Sleep Res
PUBLISHED: 08-11-2014
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Sleep duration is genetically regulated, but the genetic variants are largely unknown. We aimed to identify such genes using a genome-wide association study (GWAS) combined with RNA expression at the population level, and with experimental verification. A GWAS was performed in a Finnish sample (n = 1941), and variants with suggestive association (P < 5 × 10(-5) ) were tested in a follow-up sample from the same population with sleep duration (n = 6834) and time in bed (n = 1720). Variants with pointwise association of P < 0.05 in the follow-up sample were analysed further. First, we correlated genotypes with transcript expression levels with sleep duration (n = 207). The expression levels of significant transcripts were further studied in experimental sleep restriction. Of the 31 variants with P < 5 × 10(-5) in the discovery sample, three variants showed nominal allelic association (P < 0.05) in the follow-up sample: rs10914351, near PTPRU (P = 0.049), rs1037079 in PCDH7-CENTD1 (P = 0.011) and rs2031573 near KLF6 (P = 0.044). The risk alleles for shorter sleep (rs2031573 and rs1037079) were also associated with higher KLF6 and PCDH7 expression levels (P < 0.05). Experimental sleep restriction increased the expression of KLF6 (P < 0.01). These data suggest that rs2031573 near KLF6 or related loci and rs1037079 between PCDH7-CENTD1 or related loci may contribute to the regulation of sleep duration via gene expression. These results illustrate the utility of combining different analytical approaches to identify genetic determinants for traits related to sleep physiology. However, additional studies are needed in order to understand the roles of KLF6 and PCDH7 in sleep regulation.
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FTO genetic variants, dietary intake and body mass index: insights from 177 330 individuals.
Qibin Qi, Tuomas O Kilpeläinen, Mary K Downer, Toshiko Tanaka, Caren E Smith, Ivonne Sluijs, Emily Sonestedt, Audrey Y Chu, Frida Renstrom, Xiaochen Lin, Lars H Angquist, Jinyan Huang, Zhonghua Liu, Yanping Li, Muhammad Asif Ali, Min Xu, Tarunveer Singh Ahluwalia, Jolanda M A Boer, Peng Chen, Makoto Daimon, Johan Eriksson, Markus Perola, Yechiel Friedlander, Yu-Tang Gao, Denise H M Heppe, John W Holloway, Denise K Houston, Stavroula Kanoni, Yu-Mi Kim, Maarit A Laaksonen, Tiina Jääskeläinen, Nanette R Lee, Terho Lehtimäki, Rozenn N Lemaitre, Wei Lu, Robert N Luben, Ani Manichaikul, Satu Mannisto, Pedro Marques-Vidal, Keri L Monda, Julius S Ngwa, Louis Pérusse, Frank J A van Rooij, Yong-Bing Xiang, Wanqing Wen, Mary K Wojczynski, Jingwen Zhu, Ingrid B Borecki, Claude Bouchard, Qiuyin Cai, Cyrus Cooper, George V Dedoussis, Panos Deloukas, Luigi Ferrucci, Nita G Forouhi, Torben Hansen, Lene Christiansen, Albert Hofman, Ingegerd Johansson, Torben Jørgensen, Shigeru Karasawa, Kay-Tee Khaw, Mi-Kyung Kim, Kati Kristiansson, Huaixing Li, Xu Lin, Yongmei Liu, Kurt K Lohman, Jirong Long, Vera Mikkilä, Dariush Mozaffarian, Kari North, Oluf Pedersen, Olli Raitakari, Harri Rissanen, Jaakko Tuomilehto, Yvonne T van der Schouw, André G Uitterlinden, M Carola Zillikens, Oscar H Franco, E Shyong Tai, Xiao Ou Shu, David S Siscovick, Ulla Toft, W M Monique Verschuren, Peter Vollenweider, Nicholas J Wareham, Jacqueline C M Witteman, Wei Zheng, Paul M Ridker, Jae H Kang, Liming Liang, Majken K Jensen, Gary C Curhan, Louis R Pasquale, David J Hunter, Karen L Mohlke, Matti Uusitupa, L Adrienne Cupples, Tuomo Rankinen, Marju Orho-Melander, Tao Wang, Daniel I Chasman, Paul W Franks, Thorkild I A Sørensen, Frank B Hu, Ruth J F Loos, Jennifer A Nettleton, Lu Qi.
Hum. Mol. Genet.
PUBLISHED: 08-07-2014
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FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177 330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.
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Role of childhood food patterns on adult cardiovascular disease risk.
Curr Atheroscler Rep
PUBLISHED: 08-06-2014
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Accumulating evidence indicates that childhood nutrition plays a role in the adulthood cardiovascular health. A lifelong tracking of dietary habits, following a long-term exposure to unhealthy dietary patterns or independent effects, is a potential effect-mediating mechanism. Dietary patterns have been studied by data-driven and hypothesis-based approaches. Typically, either data-driven healthy or prudent childhood dietary patterns have been characterized and found to be associated with lower adulthood cardiovascular disease (CVD) risk in the published cohort studies. With regard to the individual food groups or food quality indices, intakes particularly of vegetables and fruits (or fiber indicating plant food intake) and polyunsaturated fatty acids have shown protective effects. The evidence which could confirm the long-term healthiness of a hypothesis-based Mediterranean diet is limited, requiring further investigation. Overall, the recent literature strengthens the view that a healthy childhood diet is associated with lowered adulthood CVD risk.
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Cardiovascular risk factors in 2011 and secular trends since 2007: The Cardiovascular Risk in Young Finns Study.
Scand J Public Health
PUBLISHED: 07-22-2014
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Cardiovascular risk factor levels in 2011 and 4-year changes between 2007 and 2011 were examined using data collected in follow-ups of the Cardiovascular Risk in Young Finns Study.
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Preconception metabolic indicators predict gestational diabetes and offspring birthweight.
Gynecol. Endocrinol.
PUBLISHED: 07-09-2014
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Abstract Pregnancy conditions such as gestational diabetes (GDM) and macrosomia lead to an increased risk of diabetes and cardiovascular disease in the offspring, perpetuating a cycle of poor health. We hypothesized that (1) pre-pregnancy indicators of metabolism would be associated with GDM and birthweight; and (2) the lipid accumulation product (LAP; incorporating waist circumference and triglycerides) and visceral adiposity index (VAI; incorporating waist circumference, triglycerides, and HDL-c) would be better predictors of GDM and birthweight than other indicators. Data from the Cardiovascular Risk in Young Finns Study were linked to the Finnish birth registry for 349 women. BMI, triglycerides, waist circumference, insulin, HOMA-IR, LAP, and VAI at the visit prior to the pregnancy were examined as predictors of GDM and large-for-gestational-age (LGA) using logistic regression with adjustment for age, parity, and smoking. Waist circumference was the strongest predictor of GDM (adjusted odds ratio [aOR] 1.66, 95% confidence interval 1.16-2.38) and LGA (aOR 1.41, 1.00-1.99). For GDM, all markers had similar discrimination; for LGA, the area under the receiver operating curve for waist circumference was significantly higher than for BMI (p?
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Distribution and medical impact of loss-of-function variants in the Finnish founder population.
PLoS Genet.
PUBLISHED: 07-01-2014
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Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk and the presence of large numbers of neutral variants, even in phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantages for studying rare variants in complex diseases as they have deleterious variants that are present at higher frequencies as well as a substantial reduction in rare neutral variation. To explore the potential of the Finnish founder population for studying low-frequency (0.5-5%) variants in complex diseases, we compared exome sequence data on 3,000 Finns to the same number of non-Finnish Europeans and discovered that, despite having fewer variable sites overall, the average Finn has more low-frequency loss-of-function variants and complete gene knockouts. We then used several well-characterized Finnish population cohorts to study the phenotypic effects of 83 enriched loss-of-function variants across 60 phenotypes in 36,262 Finns. Using a deep set of quantitative traits collected on these cohorts, we show 5 associations (p<5×10??) including splice variants in LPA that lowered plasma lipoprotein(a) levels (P?=?1.5×10?¹¹?). Through accessing the national medical records of these participants, we evaluate the LPA finding via Mendelian randomization and confirm that these splice variants confer protection from cardiovascular disease (OR?=?0.84, P?=?3×10??), demonstrating for the first time the correlation between very low levels of LPA in humans with potential therapeutic implications for cardiovascular diseases. More generally, this study articulates substantial advantages for studying the role of rare variation in complex phenotypes in founder populations like the Finns and by combining a unique population genetic history with data from large population cohorts and centralized research access to National Health Registers.
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Genetic determinants of circulating interleukin-1 receptor antagonist levels and their association with glycemic traits.
Diabetes
PUBLISHED: 06-26-2014
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The proinflammatory cytokine interleukin (IL)-1? is implicated in the development of insulin resistance and ?-cell dysfunction, whereas higher circulating levels of IL-1 receptor antagonist (IL-1RA), an endogenous inhibitor of IL-1?, has been suggested to improve glycemia and ?-cell function in patients with type 2 diabetes. To elucidate the protective role of IL-1RA, this study aimed to identify genetic determinants of circulating IL-1RA concentration and to investigate their associations with immunological and metabolic variables related to cardiometabolic risk. In the analysis of seven discovery and four replication cohort studies, two single nucleotide polymorphisms (SNPs) were independently associated with circulating IL-1RA concentration (rs4251961 at the IL1RN locus [n = 13,955, P = 2.76 × 10(-21)] and rs6759676, closest gene locus IL1F10 [n = 13,994, P = 1.73 × 10(-17)]). The proportion of the variance in IL-1RA explained by both SNPs combined was 2.0%. IL-1RA-raising alleles of both SNPs were associated with lower circulating C-reactive protein concentration. The IL-1RA-raising allele of rs6759676 was also associated with lower fasting insulin levels and lower HOMA insulin resistance. In conclusion, we show that circulating IL-1RA levels are predicted by two independent SNPs at the IL1RN and IL1F10 loci and that genetically raised IL-1RA may be protective against the development of insulin resistance.
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Association of vitamin D status with arterial blood pressure and hypertension risk: a mendelian randomisation study.
Karani S Vimaleswaran, Alana Cavadino, Diane J Berry, , Rolf Jorde, Aida Karina Dieffenbach, Chen Lu, Alexessander Couto Alves, Hiddo J Lambers Heerspink, Emmi Tikkanen, Joel Eriksson, Andrew Wong, Massimo Mangino, Kathleen A Jablonski, Ilja M Nolte, Denise K Houston, Tarunveer Singh Ahluwalia, Peter J van der Most, Dorota Pasko, Lina Zgaga, Elisabeth Thiering, Veronique Vitart, Ross M Fraser, Jennifer E Huffman, Rudolf A de Boer, Ben Schöttker, Kai-Uwe Saum, Mark I McCarthy, Josée Dupuis, Karl-Heinz Herzig, Sylvain Sebert, Anneli Pouta, Jaana Laitinen, Marcus E Kleber, Gerjan Navis, Mattias Lorentzon, Karen Jameson, Nigel Arden, Jackie A Cooper, Jayshree Acharya, Rebecca Hardy, Olli Raitakari, Samuli Ripatti, Liana K Billings, Jari Lahti, Clive Osmond, Brenda W Penninx, Lars Rejnmark, Kurt K Lohman, Lavinia Paternoster, Ronald P Stolk, Dena G Hernandez, Liisa Byberg, Emil Hagström, Håkan Melhus, Erik Ingelsson, Dan Mellström, Osten Ljunggren, Ioanna Tzoulaki, Stela McLachlan, Evropi Theodoratou, Carla M T Tiesler, Antti Jula, Pau Navarro, Alan F Wright, Ozren Polašek, James F Wilson, Igor Rudan, Veikko Salomaa, Joachim Heinrich, Harry Campbell, Jacqueline F Price, Magnus Karlsson, Lars Lind, Karl Michaëlsson, Stefania Bandinelli, Timothy M Frayling, Catharina A Hartman, Thorkild I A Sørensen, Stephen B Kritchevsky, Bente Lomholt Langdahl, Johan G Eriksson, Jose C Florez, Tim D Spector, Terho Lehtimäki, Diana Kuh, Steve E Humphries, Cyrus Cooper, Claes Ohlsson, Winfried März, Martin H de Borst, Meena Kumari, Mika Kivimäki, Thomas J Wang, Chris Power, Hermann Brenner, Guri Grimnes, Pim van der Harst, Harold Snieder, Aroon D Hingorani, Stefan Pilz, John C Whittaker, Marjo-Riitta Järvelin, Elina Hyppönen.
Lancet Diabetes Endocrinol
PUBLISHED: 06-25-2014
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Low plasma 25-hydroxyvitamin D (25[OH]D) concentration is associated with high arterial blood pressure and hypertension risk, but whether this association is causal is unknown. We used a mendelian randomisation approach to test whether 25(OH)D concentration is causally associated with blood pressure and hypertension risk.
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Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.
Dan E Arking, Sara L Pulit, Lia Crotti, Pim van der Harst, Patricia B Munroe, Tamara T Koopmann, Nona Sotoodehnia, Elizabeth J Rossin, Michael Morley, Xinchen Wang, Andrew D Johnson, Alicia Lundby, Daniel F Gudbjartsson, Peter A Noseworthy, Mark Eijgelsheim, Yuki Bradford, Kirill V Tarasov, Marcus Dörr, Martina Müller-Nurasyid, Annukka M Lahtinen, Ilja M Nolte, Albert Vernon Smith, Joshua C Bis, Aaron Isaacs, Stephen J Newhouse, Daniel S Evans, Wendy S Post, Daryl Waggott, Leo-Pekka Lyytikäinen, Andrew A Hicks, Lewin Eisele, David Ellinghaus, Caroline Hayward, Pau Navarro, Sheila Ulivi, Toshiko Tanaka, David J Tester, Stéphanie Chatel, Stefan Gustafsson, Meena Kumari, Richard W Morris, Asa T Naluai, Sandosh Padmanabhan, Alexander Kluttig, Bernhard Strohmer, Andrie G Panayiotou, Maria Torres, Michael Knoflach, Jaroslav A Hubacek, Kamil Slowikowski, Soumya Raychaudhuri, Runjun D Kumar, Tamara B Harris, Lenore J Launer, Alan R Shuldiner, Alvaro Alonso, Joel S Bader, Georg Ehret, Hailiang Huang, W H Linda Kao, James B Strait, Peter W Macfarlane, Morris Brown, Mark J Caulfield, Nilesh J Samani, Florian Kronenberg, Johann Willeit, , J Gustav Smith, Karin H Greiser, Henriette Meyer zu Schwabedissen, Karl Werdan, Massimo Carella, Leopoldo Zelante, Susan R Heckbert, Bruce M Psaty, Jerome I Rotter, Ivana Kolčić, Ozren Polašek, Alan F Wright, Maura Griffin, Mark J Daly, David O Arnar, Hilma Holm, Unnur Thorsteinsdottir, Joshua C Denny, Dan M Roden, Rebecca L Zuvich, Valur Emilsson, Andrew S Plump, Martin G Larson, Christopher J O'Donnell, Xiaoyan Yin, Marco Bobbo, Adamo P d'Adamo, AnnaMaria Iorio, Gianfranco Sinagra, Angel Carracedo, Steven R Cummings, Michael A Nalls, Antti Jula, Kimmo K Kontula, Annukka Marjamaa, Lasse Oikarinen, Markus Perola, Kimmo Porthan, Raimund Erbel, Per Hoffmann, Karl-Heinz Jöckel, Hagen Kälsch, Markus M Nöthen, Marcel den Hoed, Ruth J F Loos, Dag S Thelle, Christian Gieger, Thomas Meitinger, Siegfried Perz, Annette Peters, Hanna Prucha, Moritz F Sinner, Melanie Waldenberger, Rudolf A de Boer, Lude Franke, Pieter A van der Vleuten, Britt Maria Beckmann, Eimo Martens, Abdennasser Bardai, Nynke Hofman, Arthur A M Wilde, Elijah R Behr, Chrysoula Dalageorgou, John R Giudicessi, Argelia Medeiros-Domingo, Julien Barc, Florence Kyndt, Vincent Probst, Alice Ghidoni, Roberto Insolia, Robert M Hamilton, Stephen W Scherer, Jeffrey Brandimarto, Kenneth Margulies, Christine E Moravec, Fabiola Del Greco M, Christian Fuchsberger, Jeffrey R O'Connell, Wai K Lee, Graham C M Watt, Harry Campbell, Sarah H Wild, Nour E El Mokhtari, Norbert Frey, Folkert W Asselbergs, Irene Mateo Leach, Gerjan Navis, Maarten P van den Berg, Dirk J van Veldhuisen, Manolis Kellis, Bouwe P Krijthe, Oscar H Franco, Albert Hofman, Jan A Kors, André G Uitterlinden, Jacqueline C M Witteman, Lyudmyla Kedenko, Claudia Lamina, Ben A Oostra, Gonçalo R Abecasis, Edward G Lakatta, Antonella Mulas, Marco Orrù, David Schlessinger, Manuela Uda, Marcello R P Markus, Uwe Völker, Harold Snieder, Timothy D Spector, Johan Arnlöv, Lars Lind, Johan Sundström, Ann-Christine Syvänen, Mika Kivimäki, Mika Kähönen, Nina Mononen, Olli T Raitakari, Jorma S Viikari, Vera Adamkova, Stefan Kiechl, María Brión, Andrew N Nicolaides, Bernhard Paulweber, Johannes Haerting, Anna F Dominiczak, Fredrik Nyberg, Peter H Whincup, Aroon D Hingorani, Jean-Jacques Schott, Connie R Bezzina, Erik Ingelsson, Luigi Ferrucci, Paolo Gasparini, James F Wilson, Igor Rudan, Andre Franke, Thomas W Mühleisen, Peter P Pramstaller, Terho J Lehtimäki, Andrew D Paterson, Afshin Parsa, Yongmei Liu, Cornelia M van Duijn, David S Siscovick, Vilmundur Gudnason, Yalda Jamshidi, Veikko Salomaa, Stephan B Felix, Serena Sanna, Marylyn D Ritchie, Bruno H Stricker, Kari Stefansson, Laurie A Boyer, Thomas P Cappola, Jesper V Olsen, Kasper Lage, Peter J Schwartz, Stefan Kääb, Aravinda Chakravarti, Michael J Ackerman, Arne Pfeufer, Paul I W de Bakker, Christopher Newton-Cheh.
Nat. Genet.
PUBLISHED: 05-29-2014
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The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ?8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
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Impact of adiposity on cardiac structure in adult life: the childhood determinants of adult health (CDAH) study.
BMC Cardiovasc Disord
PUBLISHED: 05-28-2014
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We have examined the association between adiposity and cardiac structure in adulthood, using a life course approach that takes account of the contribution of adiposity in both childhood and adulthood.
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[Prevention of cardiovascular diseases--the most recent recommendations from the United States].
Duodecim
PUBLISHED: 05-15-2014
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The origins of cardiovascular diseases reside in the childhood. The prevention of these diseases should therefore also start at an early age. The US recommendation for promoting children's cardiac health encourages to pay attention to living habits - non-smoking, healthy eating and adequate physical exercise. The recommendation also proposes the measurement of lipids from all children at the age of about 10 years. This has provoked discussion for and against - what would be the benefits and drawbacks of general screening.
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Genome-wide association study of sexual maturation in males and females highlights a role for body mass and menarche loci in male puberty.
Hum. Mol. Genet.
PUBLISHED: 04-25-2014
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Little is known about genes regulating male puberty. Further, while many identified pubertal timing variants associate with age at menarche, a late manifestation of puberty, and body mass, little is known about these variants' relationship to pubertal initiation or tempo. To address these questions, we performed genome-wide association meta-analysis in over 11 000 European samples with data on early pubertal traits, male genital and female breast development, measured by the Tanner scale. We report the first genome-wide significant locus for male sexual development upstream of myocardin-like 2 (MKL2) (P = 8.9 × 10(-9)), a menarche locus tagging a developmental pathway linking earlier puberty with reduced pubertal growth (P = 4.6 × 10(-5)) and short adult stature (p = 7.5 × 10(-6)) in both males and females. Furthermore, our results indicate that a proportion of menarche loci are important for pubertal initiation in both sexes. Consistent with epidemiological correlations between increased prepubertal body mass and earlier pubertal timing in girls, body mass index (BMI)-increasing alleles correlated with earlier breast development. In boys, some BMI-increasing alleles associated with earlier, and others with delayed, sexual development; these genetic results mimic the controversy in epidemiological studies, some of which show opposing correlations between prepubertal BMI and male puberty. Our results contribute to our understanding of the pubertal initiation program in both sexes and indicate that although mechanisms regulating pubertal onset in males and females may largely be shared, the relationship between body mass and pubertal timing in boys may be complex and requires further genetic studies.
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Association of physical activity in childhood and early adulthood with carotid artery elasticity 21 years later: the cardiovascular risk in Young Finns Study.
J Am Heart Assoc
PUBLISHED: 04-24-2014
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Decreased arterial elasticity is a risk factor for several cardiovascular outcomes. Longitudinal data on the effect of physical activity in youth on adult arterial elasticity are limited. The aim of this study was to determine the long-term effects of physical activity in children and young adults on carotid artery elasticity after 21 years of follow-up.
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Genetic variation in the hTAS2R38 taste receptor and food consumption among Finnish adults.
Genes Nutr
PUBLISHED: 04-23-2014
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Genetic variation in bitter taste receptors, such as hTAS2R38, may affect food preferences and intake. The aim of the present study was to investigate the association between bitter taste receptor haplotypes and the consumption of vegetables, fruits, berries and sweet foods among an adult Finnish population. A cross-sectional design utilizing data from the Cardiovascular Risk in Young Finns cohort from 2007, which consisted of 1,903 men and women who were 30-45 years of age from five different regions in Finland, was employed. DNA was extracted from blood samples, and hTAS2R38 polymorphisms were determined based on three SNPs (rs713598, rs1726866 and rs10246939). Food consumption was assessed with a validated food frequency questionnaire. The prevalence of the bitter taste-sensitive (PAV/PAV) haplotype was 11.3 % and that of the insensitive (AVI/AVI) haplotype was 39.5 % among this Finnish population. PAV homozygotic women consumed fewer vegetables than did the AVI homozygotic women, 269 g/day (SD 131) versus 301 g/day (SD 187), respectively, p = 0.03 (multivariate ANOVA). Furthermore, the intake of sweet foods was higher among the PAV homozygotes of both genders. Fruit and berry consumption did not differ significantly between the haplotypes in either gender. Individuals perceive foods differently, and this may influence their patterns of food consumption. This study showed that the hTAS2R38 taste receptor gene variation was associated with vegetable and sweet food consumption among adults in a Finnish population.
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Youth overweight and metabolic disturbances in predicting carotid intima-media thickness, type 2 diabetes, and metabolic syndrome in adulthood: the Cardiovascular Risk in Young Finns study.
Diabetes Care
PUBLISHED: 04-17-2014
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Our objective was to assess cardiovascular risk and metabolic complications in adulthood in subjects with or without overweight and metabolic disturbances (i.e., elevated blood pressure, glucose, triglycerides, low HDL cholesterol, and high LDL cholesterol) and their combinations as youth.
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Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium.
Hum. Genet.
PUBLISHED: 04-14-2014
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To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged <25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged <25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E-8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E-07), TOX (rs7823467, P = 3.47E-07) and LINC00340 (rs12212674, P = 1.49E-06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = -0.59, P = 2.10E-04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.
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Assessing multivariate gene-metabolome associations with rare variants using Bayesian reduced rank regression.
Bioinformatics
PUBLISHED: 03-24-2014
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A typical genome-wide association study searches for associations between single nucleotide polymorphisms (SNPs) and a univariate phenotype. However, there is a growing interest to investigate associations between genomics data and multivariate phenotypes, for example, in gene expression or metabolomics studies. A common approach is to perform a univariate test between each genotype-phenotype pair, and then to apply a stringent significance cutoff to account for the large number of tests performed. However, this approach has limited ability to uncover dependencies involving multiple variables. Another trend in the current genetics is the investigation of the impact of rare variants on the phenotype, where the standard methods often fail owing to lack of power when the minor allele is present in only a limited number of individuals.
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Harmonization of Neuroticism and Extraversion phenotypes across inventories and cohorts in the Genetics of Personality Consortium: an application of Item Response Theory.
Behav. Genet.
PUBLISHED: 03-20-2014
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Mega- or meta-analytic studies (e.g. genome-wide association studies) are increasingly used in behavior genetics. An issue in such studies is that phenotypes are often measured by different instruments across study cohorts, requiring harmonization of measures so that more powerful fixed effect meta-analyses can be employed. Within the Genetics of Personality Consortium, we demonstrate for two clinically relevant personality traits, Neuroticism and Extraversion, how Item-Response Theory (IRT) can be applied to map item data from different inventories to the same underlying constructs. Personality item data were analyzed in >160,000 individuals from 23 cohorts across Europe, USA and Australia in which Neuroticism and Extraversion were assessed by nine different personality inventories. Results showed that harmonization was very successful for most personality inventories and moderately successful for some. Neuroticism and Extraversion inventories were largely measurement invariant across cohorts, in particular when comparing cohorts from countries where the same language is spoken. The IRT-based scores for Neuroticism and Extraversion were heritable (48 and 49 %, respectively, based on a meta-analysis of six twin cohorts, total N = 29,496 and 29,501 twin pairs, respectively) with a significant part of the heritability due to non-additive genetic factors. For Extraversion, these genetic factors qualitatively differ across sexes. We showed that our IRT method can lead to a large increase in sample size and therefore statistical power. The IRT approach may be applied to any mega- or meta-analytic study in which item-based behavioral measures need to be harmonized.
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High birth weight is associated with obesity and increased carotid wall thickness in young adults: the cardiovascular risk in young Finns study.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 03-13-2014
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There is some evidence that people born with high birth weight may be at increased risk of cardiovascular disease in adulthood. Details of the underlying mechanisms remain unknown. We sought to determine whether people born large for gestational age have poor arterial health, increased adiposity, and a poor cardiovascular risk factor profile.
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Prospective relationship of change in ideal cardiovascular health status and arterial stiffness: the Cardiovascular Risk in Young Finns Study.
J Am Heart Assoc
PUBLISHED: 03-12-2014
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In 2010, the American Heart Association defined ideal cardiovascular health as the simultaneous presence of 4 favorable health behaviors (nonsmoking, ideal body mass index, physical activity at goal, and dietary pattern that promotes cardiovascular health) and 3 favorable health factors (ideal levels of total cholesterol, blood pressure, and fasting glucose). The association between a change in ideal cardiovascular health status and pulse wave velocity, a surrogate marker of cardiovascular disease, has not been reported.
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Determinants of exercise peak arterial blood pressure, circulatory power, and exercise cardiac power in a population based sample of Finnish male and female aged 30 to 47 years: the Cardiovascular Risk in Young Finns Study.
BMC Cardiovasc Disord
PUBLISHED: 03-05-2014
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Novel parameters derived from peak maximal oxygen uptake (VO2) and exercise arterial blood pressure, such as peak circulatory power (CP) and exercise cardiac power (ECP), can be used in the risk assessment of cardiovascular disease and stroke. However, the determinants of these factors are poorly characterized in the general population.
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Exposure to parental smoking in childhood or adolescence is associated with increased carotid intima-media thickness in young adults: evidence from the Cardiovascular Risk in Young Finns study and the Childhood Determinants of Adult Health Study.
Eur. Heart J.
PUBLISHED: 03-04-2014
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Recent evidence suggests that the exposure of children to their parents' smoking adversely effects endothelial function in adulthood. We investigated whether the association was also present with carotid intima-media thickness (IMT) up to 25 years later.
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Amerindian-specific regions under positive selection harbour new lipid variants in Latinos.
Nat Commun
PUBLISHED: 02-24-2014
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Dyslipidemia and obesity are especially prevalent in populations with Amerindian backgrounds, such as Mexican-Americans, which predispose these populations to cardiovascular disease. Here we design an approach, known as the cross-population allele screen (CPAS), which we conduct prior to a genome-wide association study (GWAS) in 19,273 Europeans and Mexicans, in order to identify Amerindian risk genes in Mexicans. Utilizing CPAS to restrict the GWAS input variants to only those differing in frequency between the two populations, we identify novel Amerindian lipid genes, receptor-related orphan receptor alpha (RORA) and salt-inducible kinase 3 (SIK3), and three loci previously unassociated with dyslipidemia or obesity. We also detect lipoprotein lipase (LPL) and apolipoprotein A5 (APOA5) harbouring specific Amerindian signatures of risk variants and haplotypes. Notably, we observe that SIK3 and one novel lipid locus underwent positive selection in Mexicans. Furthermore, after a high-fat meal, the SIK3 risk variant carriers display high triglyceride levels. These findings suggest that Amerindian-specific genetic architecture leads to a higher incidence of dyslipidemia and obesity in modern Mexicans.
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Gene-age interactions in blood pressure regulation: a large-scale investigation with the CHARGE, Global BPgen, and ICBP Consortia.
Jeannette Simino, Gang Shi, Joshua C Bis, Daniel I Chasman, Georg B Ehret, Xiangjun Gu, Xiuqing Guo, Shih-Jen Hwang, Eric Sijbrands, Albert V Smith, Germaine C Verwoert, Jennifer L Bragg-Gresham, Gemma Cadby, Peng Chen, Ching-Yu Cheng, Tanguy Corre, Rudolf A de Boer, Anuj Goel, Toby Johnson, Chiea-Chuen Khor, , Carla Lluis-Ganella, Jian'an Luan, Leo-Pekka Lyytikäinen, Ilja M Nolte, Xueling Sim, Siim Sõber, Peter J van der Most, Niek Verweij, Jing Hua Zhao, Najaf Amin, Eric Boerwinkle, Claude Bouchard, Abbas Dehghan, Gudny Eiriksdottir, Roberto Elosua, Oscar H Franco, Christian Gieger, Tamara B Harris, Serge Hercberg, Albert Hofman, Alan L James, Andrew D Johnson, Mika Kähönen, Kay-Tee Khaw, Zoltan Kutalik, Martin G Larson, Lenore J Launer, Guo Li, Jianjun Liu, Kiang Liu, Alanna C Morrison, Gerjan Navis, Rick Twee-Hee Ong, George J Papanicolau, Brenda W Penninx, Bruce M Psaty, Leslie J Raffel, Olli T Raitakari, Kenneth Rice, Fernando Rivadeneira, Lynda M Rose, Serena Sanna, Robert A Scott, David S Siscovick, Ronald P Stolk, André G Uitterlinden, Dhananjay Vaidya, Melanie M van der Klauw, Ramachandran S Vasan, Eranga Nishanthie Vithana, Uwe Völker, Henry Völzke, Hugh Watkins, Terri L Young, Tin Aung, Murielle Bochud, Martin Farrall, Catharina A Hartman, Maris Laan, Edward G Lakatta, Terho Lehtimäki, Ruth J F Loos, Gavin Lucas, Pierre Meneton, Lyle J Palmer, Rainer Rettig, Harold Snieder, E Shyong Tai, Yik-Ying Teo, Pim van der Harst, Nicholas J Wareham, Cisca Wijmenga, Tien Yin Wong, Myriam Fornage, Vilmundur Gudnason, Daniel Levy, Walter Palmas, Paul M Ridker, Jerome I Rotter, Cornelia M van Duijn, Jacqueline C M Witteman, Aravinda Chakravarti, Dabeeru C Rao.
Am. J. Hum. Genet.
PUBLISHED: 02-22-2014
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Although age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p ? 5 × 10(-8)) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age-dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 × 10(-4)) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations.
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Carotid artery elasticity decreases during pregnancy - the Cardiovascular Risk in Young Finns study.
BMC Pregnancy Childbirth
PUBLISHED: 02-21-2014
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The aims were to evaluate the effect of pregnancy on carotid artery elasticity and determine the associations between maternal lipids, endothelial function and arterial elasticity during pregnancy.
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Temperament and depressive symptoms: What is the direction of the association?
J Affect Disord
PUBLISHED: 02-17-2014
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Temperament characteristics have been suggested to be associated with mental health outcomes, especially depression, but the direction of the association is unknown. In this study, we tested whether temperament characteristics, as defined by the Buss-Plomin adulthood emotionality-activity-sociability (EAS) temperament model, predict depressive symptoms or whether depressive symptoms predict changes in temperament characteristics.
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Blood microRNA profile associates with the levels of serum lipids and metabolites associated with glucose metabolism and insulin resistance and pinpoints pathways underlying metabolic syndrome: the cardiovascular risk in Young Finns Study.
Mol. Cell. Endocrinol.
PUBLISHED: 01-30-2014
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Since metabolic syndrome (MetS) is a collection of cardiovascular risk factors involving multiple signaling systems, we related the metabolic abnormalities associated with MetS with circulating microRNA profiles to pinpoint the affected signaling pathways. The blood microRNA profile, genome wide gene expression and serum NMR metabolomics were analyzed from 71 participants of the Young Finns Study. We found nine microRNAs that associated significantly with metabolites connected to MetS. MicroRNA-144-5p concentration correlated with glucose levels, hsa-1207-5p with glycosylated hemoglobin and hsa-miR-484 with metabolites related to insulin resistance. Hsa-miR-625-3p correlated with cholesterol levels, hsa-miR-1237-3p and hsa-miR-331-3p expression with certain fatty acids levels and hsa-miR-129-1-3p, -129-2-3p, and -1288-3p with glycerol levels. The down-regulated targets of miR-1207-5p and -129-2-3p were enriched in PI3K and MAPK pathways and 8 out of the 12 enriched pathways were down-regulated in individuals with MetS. In conclusion microRNAs associated with several aspects of MetS, possibly regulating glucose and lipid metabolism.
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Upstream Transcription Factor 1 (USF1) allelic variants regulate lipoprotein metabolism in women and USF1 expression in atherosclerotic plaque.
Sci Rep
PUBLISHED: 01-20-2014
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Upstream transcription factor 1 (USF1) allelic variants significantly influence future risk of cardiovascular disease and overall mortality in females. We investigated sex-specific effects of USF1 gene allelic variants on serum indices of lipoprotein metabolism, early markers of asymptomatic atherosclerosis and their changes during six years of follow-up. In addition, we investigated the cis-regulatory role of these USF1 variants in artery wall tissues in Caucasians. In the Cardiovascular Risk in Young Finns Study, 1,608 participants (56% women, aged 31.9 ± 4.9) with lipids and cIMT data were included. For functional study, whole genome mRNA expression profiling was performed in 91 histologically classified atherosclerotic samples. In females, serum total, LDL cholesterol and apoB levels increased gradually according to USF1 rs2516839 genotypes TT < CT < CC and rs1556259 AA < AG < GG as well as according to USF1 H3 (GCCCGG) copy number 0 < 1 < 2. Furthermore, the carriers of minor alleles of rs2516839 (C) and rs1556259 (G) of USF1 gene had decreased USF1 expression in atherosclerotic plaques (P = 0.028 and 0.08, respectively) as compared to non-carriers. The genetic variation in USF1 influence USF1 transcript expression in advanced atherosclerosis and regulates levels and metabolism of circulating apoB and apoB-containing lipoprotein particles in sex-dependent manner, but is not a major determinant of early markers of atherosclerosis.
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Interleukin-6 gene polymorphism, chronic stress and atherosclerosis: interleukin-6-174G>C polymorphism, chronic stress and risk of early atherosclerosis in the Cardiovascular Risk in Young Finns Study.
J Psychosom Res
PUBLISHED: 01-14-2014
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Interleukin-6 protein has been suggested as a mediator connecting chronic stress and cardiovascular diseases. We investigated whether the functional G174C polymorphism (rs1800795) of interleukin-6 gene is associated with vital exhaustion, a measure of chronic stress, or with preclinical atherosclerosis.
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Exploring causality between TV viewing and weight change in young and middle-aged adults. The Cardiovascular Risk in Young Finns study.
PLoS ONE
PUBLISHED: 01-01-2014
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Television viewing time (TV time) is associated with increased weight and obesity, but it is unclear whether this relation is causal.
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Longitudinal Associations Between Changes in Physical Activity and Depressive Symptoms in Adulthood: The Young Finns Study.
Int J Behav Med
PUBLISHED: 12-24-2013
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Although previous studies have associated physical activity (PA) with lower depressive symptoms, the combined effects of the (1) frequency, (2) intensity, and (3) duration of long-term PA have not been examined in detail.
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Genome-wide association study on dimethylarginines reveals novel AGXT2 variants associated with heart rate variability but not with overall mortality.
Eur. Heart J.
PUBLISHED: 10-24-2013
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The purpose of this study was to identify novel genetic variants influencing circulating asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) levels and to evaluate whether they have a prognostic value on cardiovascular mortality.
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Genome-wide association study identifies 3 genomic loci significantly associated with serum levels of homoarginine: the AtheroRemo Consortium.
Circ Cardiovasc Genet
PUBLISHED: 09-18-2013
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Low serum levels of the amino acid derivative, homoarginine, have been associated with increased risk of total and cardiovascular mortality. Homoarginine deficiency may be related to renal and heart diseases, but the pathophysiologic role of homoarginine and the genetic regulation of its serum levels are largely unknown.
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Common variants in mendelian kidney disease genes and their association with renal function.
Afshin Parsa, Christian Fuchsberger, Anna Köttgen, Conall M O'Seaghdha, Cristian Pattaro, Mariza de Andrade, Daniel I Chasman, Alexander Teumer, Karlhans Endlich, Matthias Olden, Ming-Huei Chen, Adrienne Tin, Young J Kim, Daniel Taliun, Man Li, Mary Feitosa, Mathias Gorski, Qiong Yang, Claudia Hundertmark, Meredith C Foster, Nicole Glazer, Aaron Isaacs, Madhumathi Rao, Albert V Smith, Jeffrey R O'Connell, Maksim Struchalin, Toshiko Tanaka, Guo Li, Shih-Jen Hwang, Elizabeth J Atkinson, Kurt Lohman, Marilyn C Cornelis, Asa Johansson, Anke Tönjes, Abbas Dehghan, Vincent Couraki, Elizabeth G Holliday, Rossella Sorice, Zoltan Kutalik, Terho Lehtimäki, Tonu Esko, Harshal Deshmukh, Sheila Ulivi, Audrey Y Chu, Federico Murgia, Stella Trompet, Medea Imboden, Barbara Kollerits, Giorgio Pistis, Tamara B Harris, Lenore J Launer, Thor Aspelund, Gudny Eiriksdottir, Braxton D Mitchell, Eric Boerwinkle, Helena Schmidt, Edith Hofer, Frank Hu, Ayse Demirkan, Ben A Oostra, Stephen T Turner, Jingzhong Ding, Jeanette S Andrews, Barry I Freedman, Franco Giulianini, Wolfgang Koenig, Thomas Illig, Angela Döring, H-Erich Wichmann, Lina Zgaga, Tatijana Zemunik, Mladen Boban, Cosetta Minelli, Heather E Wheeler, Wilmar Igl, Ghazal Zaboli, Sarah H Wild, Alan F Wright, Harry Campbell, David Ellinghaus, Ute Nöthlings, Gunnar Jacobs, Reiner Biffar, Florian Ernst, Georg Homuth, Heyo K Kroemer, Matthias Nauck, Sylvia Stracke, Uwe Völker, Henry Völzke, Peter Kovacs, Michael Stumvoll, Reedik Mägi, Albert Hofman, André G Uitterlinden, Fernando Rivadeneira, Yurii S Aulchenko, Ozren Polašek, Nick Hastie, Veronique Vitart, Catherine Helmer, Jie Jin Wang, Bénédicte Stengel, Daniela Ruggiero, Sven Bergmann, Mika Kähönen, Jorma Viikari, Tiit Nikopensius, Michael Province, Helen Colhoun, Alex Doney, Antonietta Robino, Bernhard K Krämer, Laura Portas, Ian Ford, Brendan M Buckley, Martin Adam, Gian-Andri Thun, Bernhard Paulweber, Margot Haun, Cinzia Sala, Paul Mitchell, Marina Ciullo, Peter Vollenweider, Olli Raitakari, Andres Metspalu, Colin Palmer, Paolo Gasparini, Mario Pirastu, J Wouter Jukema, Nicole M Probst-Hensch, Florian Kronenberg, Daniela Toniolo, Vilmundur Gudnason, Alan R Shuldiner, Josef Coresh, Reinhold Schmidt, Luigi Ferrucci, Cornelia M van Duijn, Ingrid Borecki, Sharon L R Kardia, Yongmei Liu, Gary C Curhan, Igor Rudan, Ulf Gyllensten, James F Wilson, Andre Franke, Peter P Pramstaller, Rainer Rettig, Inga Prokopenko, Jacqueline Witteman, Caroline Hayward, Paul M Ridker, Murielle Bochud, Iris M Heid, David S Siscovick, Caroline S Fox, W Linda Kao, Carsten A Böger.
J. Am. Soc. Nephrol.
PUBLISHED: 09-12-2013
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Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.
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Resting heart rate and the association of physical fitness with carotid artery stiffness.
Am. J. Hypertens.
PUBLISHED: 09-12-2013
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Physical fitness is known to influence arterial stiffness. Resting heart rate is reduced by exercise and positively associated with arterial stiffness. This study aimed to investigate the role of resting heart rate in the relationship of physical fitness with arterial stiffness.
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Parental smoking produces long-term damage to vascular function in their children.
Curr. Opin. Cardiol.
PUBLISHED: 08-10-2013
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This review provides an overview of recent findings concerning the cardiovascular effects of childhood exposure to environmental tobacco smoke (ETS).
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The associations of oxidized high-density lipoprotein lipids with risk factors for atherosclerosis: The Cardiovascular Risk in Young Finns Study.
Free Radic. Biol. Med.
PUBLISHED: 07-26-2013
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Scavenging and reverse transport of atherogenic oxidized lipids by high-density lipoprotein (HDL) was recently suggested to contribute to atheroprotection. We investigated the associations of oxidized HDL lipids (oxHDLlipids) with known risk factors for atherosclerosis in a population-based cross-sectional study of 1395 Finnish adults ages 24-39 years (54.9% women). Analysis of oxidized lipids in isolated HDL and LDL (oxLDLlipids) was based on the determination of conjugated dienes. Oxidized LDL was measured also with a method based on antibodies against oxidized Apo-B (oxLDLprot). Serum lipids and risk factors were measured. In multivariable models, oxHDLlipids were associated inversely with age (partial R(2)=2.9% in men, 0.8% in women) and directly with oxLDLlipids (partial R(2)=3.4% in men, 4.2% in women) after adjustment for Apo-A1 (partial R(2)=9.6% in men, 25.2% in women). In men, oxHDLlipids were also associated inversely with insulin (partial R(2)=1.1%). In women, oxHDLlipids were additionally inversely associated with waist circumference (partial R(2)=1.8%) and daily smoking (partial R(2)=0.7%) and directly with C-reactive protein (CRP; partial R(2)=0.5%) and alcohol use (partial R(2)=0.5%). We conclude that an elevated risk profile characterized primarily by advanced age is associated with lower oxHDLlipid levels in a population of young Finnish men and women. Higher levels of oxHDLlipids are additionally associated with higher oxLDLlipid levels. In men, higher insulin levels are also associated with lower oxHDLlipid levels. In women, increased waist circumference and daily smoking are also associated with lower oxHDLlipid levels, and higher CRP levels and alcohol use are associated with higher oxHDLlipid levels.
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Mendelian randomization studies do not support a causal role for reduced circulating adiponectin levels in insulin resistance and type 2 diabetes.
Diabetes
PUBLISHED: 07-08-2013
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Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics-based genetic risk scores to test the associations with gold-standard measures of insulin sensitivity (2,969 individuals) and type 2 diabetes (15,960 case subjects and 64,731 control subjects). In conventional regression analyses, a 1-SD decrease in adiponectin levels was correlated with a 0.31-SD (95% CI 0.26-0.35) increase in fasting insulin, a 0.34-SD (0.30-0.38) decrease in insulin sensitivity, and a type 2 diabetes odds ratio (OR) of 1.75 (1.47-2.13). The instrumental variable analysis revealed no evidence of a causal association between genetically lower circulating adiponectin and higher fasting insulin (0.02 SD; 95% CI -0.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (-0.20 SD; 95% CI -0.38 to -0.02; N = 1,860), and no evidence of a relationship with type 2 diabetes (OR 0.94; 95% CI 0.75-1.19; N = 2,777 case subjects and 13,011 control subjects). Using the ADIPOQ summary statistics genetic risk scores, we found no evidence of an association between adiponectin-lowering alleles and insulin sensitivity (effect per weighted adiponectin-lowering allele: -0.03 SD; 95% CI -0.07 to 0.01; N = 2,969) or type 2 diabetes (OR per weighted adiponectin-lowering allele: 0.99; 95% CI 0.95-1.04; 15,960 case subjects vs. 64,731 control subjects). These results do not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes.
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Infancy-onset dietary counseling of low-saturated-fat diet improves insulin sensitivity in healthy adolescents 15-20 years of age: the Special Turku Coronary Risk Factor Intervention Project (STRIP) study.
Diabetes Care
PUBLISHED: 06-25-2013
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We reported previously that low-saturated-fat dietary counseling started in infancy improves insulin sensitivity in healthy children 9 years of age. The aim of this study was to evaluate the effect of lifelong dietary counseling on insulin sensitivity in healthy adolescents between 15 and 20 years of age. In addition, we examined dietary fiber intake and the polyunsaturated fatty acid (PUFA)+monounsaturated (MUFA)-to-saturated fatty acid (SFA) ratio in the intervention and control adolescents and the association of these dietary factors with homeostasis model of insulin resistance (HOMA-IR).
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Ideal cardiovascular health in young adult populations from the United States, Finland, and Australia and its association with cIMT: the International Childhood Cardiovascular Cohort Consortium.
J Am Heart Assoc
PUBLISHED: 06-21-2013
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Goals for cardiovascular (CV) disease prevention were set by the American Heart Association in 2010 for the concept of CV health. Ideal CV health is defined by 7 CV health metrics: blood pressure, glucose, cholesterol, body mass index, and physical activity on recommended levels; nonsmoking; and a healthy diet. We studied the prevalence of ideal CV health and its associations with ultrasonographically measured carotid intima-media thickness (cIMT) cross-sectionally in 5 international populations.
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Combined effects of child and adult elevated blood pressure on subclinical atherosclerosis: the International Childhood Cardiovascular Cohort Consortium.
Circulation
PUBLISHED: 06-18-2013
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Elevated blood pressure (BP) levels in childhood have been associated with subsequent atherosclerosis. However, it is uncertain whether this risk is attenuated in individuals who acquire normal BP by adulthood. The present study examined the effect of child and adult BP levels on carotid artery intima-media thickness (IMT) in adulthood.
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Active commuting from youth to adulthood and as a predictor of physical activity in early midlife: The Young Finns Study.
Prev Med
PUBLISHED: 06-10-2013
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The aims of the study were to describe the stability of active commuting (AC) behavior (i.e., walking and cycling) over 27years and examine the relationship between AC and physical activity (PA) from youth to early midlife.
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Association of fitness with vascular intima-media thickness and elasticity in adolescence.
Pediatrics
PUBLISHED: 06-10-2013
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Vascular intima-media thickness (IMT) and elasticity are surrogate markers of atherosclerosis. Data on the effect of cardiorespiratory fitness on these measures of vascular health in adolescence are scarce. The aim was to examine the association of fitness with aortic and carotid artery IMT and elasticity in adolescents.
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Simplified definitions of elevated pediatric blood pressure and high adult arterial stiffness.
Pediatrics
PUBLISHED: 06-10-2013
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The ability of childhood elevated blood pressure (BP) to predict high pulse wave velocity (PWV), a surrogate marker for cardiovascular disease, in adulthood has not been reported. We studied whether elevated pediatric BP could predict high PWV in adulthood and if there is a difference in the predictive ability between the standard BP definition endorsed by the National High Blood Pressure Education Program and the recently proposed 2 simplified definitions.
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Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.
Joshua C Randall, Thomas W Winkler, Zoltan Kutalik, Sonja I Berndt, Anne U Jackson, Keri L Monda, Tuomas O Kilpeläinen, Tonu Esko, Reedik Mägi, Shengxu Li, Tsegaselassie Workalemahu, Mary F Feitosa, Damien C Croteau-Chonka, Felix R Day, Tove Fall, Teresa Ferreira, Stefan Gustafsson, Adam E Locke, Iain Mathieson, André Scherag, Sailaja Vedantam, Andrew R Wood, Liming Liang, Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Emmanouil T Dermitzakis, Antigone S Dimas, Fredrik Karpe, Josine L Min, George Nicholson, Deborah J Clegg, Thomas Person, Jon P Krohn, Sabrina Bauer, Christa Buechler, Kristina Eisinger, , Amélie Bonnefond, Philippe Froguel, Jouke-Jan Hottenga, Inga Prokopenko, Lindsay L Waite, Tamara B Harris, Albert Vernon Smith, Alan R Shuldiner, Wendy L McArdle, Mark J Caulfield, Patricia B Munroe, Henrik Grönberg, Yii-Der Ida Chen, Guo Li, Jacques S Beckmann, Toby Johnson, Unnur Thorsteinsdottir, Maris Teder-Laving, Kay-Tee Khaw, Nicholas J Wareham, Jing Hua Zhao, Najaf Amin, Ben A Oostra, Aldi T Kraja, Michael A Province, L Adrienne Cupples, Nancy L Heard-Costa, Jaakko Kaprio, Samuli Ripatti, Ida Surakka, Francis S Collins, Jouko Saramies, Jaakko Tuomilehto, Antti Jula, Veikko Salomaa, Jeanette Erdmann, Christian Hengstenberg, Christina Loley, Heribert Schunkert, Claudia Lamina, H Erich Wichmann, Eva Albrecht, Christian Gieger, Andrew A Hicks, Asa Johansson, Peter P Pramstaller, Sekar Kathiresan, Elizabeth K Speliotes, Brenda Penninx, Anna-Liisa Hartikainen, Marjo-Riitta Järvelin, Ulf Gyllensten, Dorret I Boomsma, Harry Campbell, James F Wilson, Stephen J Chanock, Martin Farrall, Anuj Goel, Carolina Medina-Gomez, Fernando Rivadeneira, Karol Estrada, André G Uitterlinden, Albert Hofman, M Carola Zillikens, Martin den Heijer, Lambertus A Kiemeney, Andrea Maschio, Per Hall, Jonathan Tyrer, Alexander Teumer, Henry Völzke, Peter Kovacs, Anke Tönjes, Massimo Mangino, Tim D Spector, Caroline Hayward, Igor Rudan, Alistair S Hall, Nilesh J Samani, Antony Paul Attwood, Jennifer G Sambrook, Joseph Hung, Lyle J Palmer, Marja-Liisa Lokki, Juha Sinisalo, Gabrielle Boucher, Heikki Huikuri, Mattias Lorentzon, Claes Ohlsson, Niina Eklund, Johan G Eriksson, Cristina Barlassina, Carlo Rivolta, Ilja M Nolte, Harold Snieder, Melanie M van der Klauw, Jana V van Vliet-Ostaptchouk, Pablo V Gejman, Jianxin Shi, Kevin B Jacobs, Zhaoming Wang, Stephan J L Bakker, Irene Mateo Leach, Gerjan Navis, Pim van der Harst, Nicholas G Martin, Sarah E Medland, Grant W Montgomery, Jian Yang, Daniel I Chasman, Paul M Ridker, Lynda M Rose, Terho Lehtimäki, Olli Raitakari, Devin Absher, Carlos Iribarren, Hanneke Basart, Kees G Hovingh, Elina Hyppönen, Chris Power, Denise Anderson, John P Beilby, Jennie Hui, Jennifer Jolley, Hendrik Sager, Stefan R Bornstein, Peter E H Schwarz, Kati Kristiansson, Markus Perola, Jaana Lindström, Amy J Swift, Matti Uusitupa, Mustafa Atalay, Timo A Lakka, Rainer Rauramaa, Jennifer L Bolton, Gerry Fowkes, Ross M Fraser, Jackie F Price, Krista Fischer, Kaarel Krjutå Kov, Andres Metspalu, Evelin Mihailov, Claudia Langenberg, Jian'an Luan, Ken K Ong, Peter S Chines, Sirkka M Keinanen-Kiukaanniemi, Timo E Saaristo, Sarah Edkins, Paul W Franks, Göran Hallmans, Dmitry Shungin, Andrew David Morris, Colin N A Palmer, Raimund Erbel, Susanne Moebus, Markus M Nöthen, Sonali Pechlivanis, Kristian Hveem, Narisu Narisu, Anders Hamsten, Steve E Humphries, Rona J Strawbridge, Elena Tremoli, Harald Grallert, Barbara Thorand, Thomas Illig, Wolfgang Koenig, Martina Müller-Nurasyid, Annette Peters, Bernhard O Boehm, Marcus E Kleber, Winfried März, Bernhard R Winkelmann, Johanna Kuusisto, Markku Laakso, Dominique Arveiler, Giancarlo Cesana, Kari Kuulasmaa, Jarmo Virtamo, John W G Yarnell, Diana Kuh, Andrew Wong, Lars Lind, Ulf de Faire, Bruna Gigante, Patrik K E Magnusson, Nancy L Pedersen, George Dedoussis, Maria Dimitriou, Genovefa Kolovou, Stavroula Kanoni, Kathleen Stirrups, Lori L Bonnycastle, Inger Njølstad, Tom Wilsgaard, Andrea Ganna, Emil Rehnberg, Aroon Hingorani, Mika Kivimäki, Meena Kumari, Themistocles L Assimes, Inês Barroso, Michael Boehnke, Ingrid B Borecki, Panos Deloukas, Caroline S Fox, Timothy Frayling, Leif C Groop, Talin Haritunians, David Hunter, Erik Ingelsson, Robert Kaplan, Karen L Mohlke, Jeffrey R O'Connell, David Schlessinger, David P Strachan, Kari Stefansson, Cornelia M van Duijn, Gonçalo R Abecasis, Mark I McCarthy, Joel N Hirschhorn, Lu Qi, Ruth J F Loos, Cecilia M Lindgren, Kari E North, Iris M Heid.
PLoS Genet.
PUBLISHED: 06-01-2013
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Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.
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Genome-wide meta-analysis identifies new susceptibility loci for migraine.
Verneri Anttila, Bendik S Winsvold, Padhraig Gormley, Tobias Kurth, Francesco Bettella, George McMahon, Mikko Kallela, Rainer Malik, Boukje de Vries, Gisela Terwindt, Sarah E Medland, Unda Todt, Wendy L McArdle, Lydia Quaye, Markku Koiranen, M Arfan Ikram, Terho Lehtimäki, Anine H Stam, Lannie Ligthart, Juho Wedenoja, Ian Dunham, Benjamin M Neale, Priit Palta, Eija Hämäläinen, Markus Schürks, Lynda M Rose, Julie E Buring, Paul M Ridker, Stacy Steinberg, Hreinn Stefansson, Finnbogi Jakobsson, Debbie A Lawlor, David M Evans, Susan M Ring, Markus Färkkilä, Ville Artto, Mari A Kaunisto, Tobias Freilinger, Jean Schoenen, Rune R Frants, Nadine Pelzer, Claudia M Weller, Ronald Zielman, Andrew C Heath, Pamela A F Madden, Grant W Montgomery, Nicholas G Martin, Guntram Borck, Hartmut Göbel, Axel Heinze, Katja Heinze-Kuhn, Frances M K Williams, Anna-Liisa Hartikainen, Anneli Pouta, Joyce van den Ende, André G Uitterlinden, Albert Hofman, Najaf Amin, Jouke-Jan Hottenga, Jacqueline M Vink, Kauko Heikkilä, Michael Alexander, Bertram Müller-Myhsok, Stefan Schreiber, Thomas Meitinger, Heinz Erich Wichmann, Arpo Aromaa, Johan G Eriksson, Bryan J Traynor, Daniah Trabzuni, Elizabeth Rossin, Kasper Lage, Suzanne B R Jacobs, J Raphael Gibbs, Ewan Birney, Jaakko Kaprio, Brenda W Penninx, Dorret I Boomsma, Cornelia van Duijn, Olli Raitakari, Marjo-Riitta Järvelin, John-Anker Zwart, Lynn Cherkas, David P Strachan, Christian Kubisch, Michel D Ferrari, Arn M J M van den Maagdenberg, Martin Dichgans, Maija Wessman, George Davey Smith, Kari Stefansson, Mark J Daly, Dale R Nyholt, Daniel I Chasman, Aarno Palotie, .
Nat. Genet.
PUBLISHED: 05-30-2013
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Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood. We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) and 95,425 population-matched controls. We identified 12 loci associated with migraine susceptibility (P<5×10(-8)). Five loci are new: near AJAP1 at 1p36, near TSPAN2 at 1p13, within FHL5 at 6q16, within C7orf10 at 7p14 and near MMP16 at 8q21. Three of these loci were identified in disease subgroup analyses. Brain tissue expression quantitative trait locus analysis suggests potential functional candidate genes at four loci: APOA1BP, TBC1D7, FUT9, STAT6 and ATP5B.
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GWAS of 126,559 individuals identifies genetic variants associated with educational attainment.
Cornelius A Rietveld, Sarah E Medland, Jaime Derringer, Jian Yang, Tonu Esko, Nicolas W Martin, Harm-Jan Westra, Konstantin Shakhbazov, Abdel Abdellaoui, Arpana Agrawal, Eva Albrecht, Behrooz Z Alizadeh, Najaf Amin, John Barnard, Sebastian E Baumeister, Kelly S Benke, Lawrence F Bielak, Jeffrey A Boatman, Patricia A Boyle, Gail Davies, Christiaan de Leeuw, Niina Eklund, Daniel S Evans, Rudolf Ferhmann, Krista Fischer, Christian Gieger, Håkon K Gjessing, Sara Hägg, Jennifer R Harris, Caroline Hayward, Christina Holzapfel, Carla A Ibrahim-Verbaas, Erik Ingelsson, Bo Jacobsson, Peter K Joshi, Astanand Jugessur, Marika Kaakinen, Stavroula Kanoni, Juha Karjalainen, Ivana Kolčić, Kati Kristiansson, Zoltan Kutalik, Jari Lahti, Sang H Lee, Peng Lin, Penelope A Lind, Yongmei Liu, Kurt Lohman, Marisa Loitfelder, George McMahon, Pedro Marques Vidal, Osorio Meirelles, Lili Milani, Ronny Myhre, Marja-Liisa Nuotio, Christopher J Oldmeadow, Katja E Petrovic, Wouter J Peyrot, Ozren Polašek, Lydia Quaye, Eva Reinmaa, John P Rice, Thais S Rizzi, Helena Schmidt, Reinhold Schmidt, Albert V Smith, Jennifer A Smith, Toshiko Tanaka, Antonio Terracciano, Matthijs J H M van der Loos, Veronique Vitart, Henry Völzke, Jürgen Wellmann, Lei Yu, Wei Zhao, Jüri Allik, John R Attia, Stefania Bandinelli, François Bastardot, Jonathan Beauchamp, David A Bennett, Klaus Berger, Laura J Bierut, Dorret I Boomsma, Ute Bültmann, Harry Campbell, Christopher F Chabris, Lynn Cherkas, Mina K Chung, Francesco Cucca, Mariza de Andrade, Philip L De Jager, Jan-Emmanuel De Neve, Ian J Deary, George V Dedoussis, Panos Deloukas, Maria Dimitriou, Guðný Eiríksdóttir, Martin F Elderson, Johan G Eriksson, David M Evans, Jessica D Faul, Luigi Ferrucci, Melissa E Garcia, Henrik Grönberg, Vilmundur Guðnason, Per Hall, Juliette M Harris, Tamara B Harris, Nicholas D Hastie, Andrew C Heath, Dena G Hernandez, Wolfgang Hoffmann, Adriaan Hofman, Rolf Holle, Elizabeth G Holliday, Jouke-Jan Hottenga, William G Iacono, Thomas Illig, Marjo-Riitta Järvelin, Mika Kähönen, Jaakko Kaprio, Robert M Kirkpatrick, Matthew Kowgier, Antti Latvala, Lenore J Launer, Debbie A Lawlor, Terho Lehtimäki, Jingmei Li, Paul Lichtenstein, Peter Lichtner, David C Liewald, Pamela A Madden, Patrik K E Magnusson, Tomi E Mäkinen, Marco Masala, Matt McGue, Andres Metspalu, Andreas Mielck, Michael B Miller, Grant W Montgomery, Sutapa Mukherjee, Dale R Nyholt, Ben A Oostra, Lyle J Palmer, Aarno Palotie, Brenda W J H Penninx, Markus Perola, Patricia A Peyser, Martin Preisig, Katri Räikkönen, Olli T Raitakari, Anu Realo, Susan M Ring, Samuli Ripatti, Fernando Rivadeneira, Igor Rudan, Aldo Rustichini, Veikko Salomaa, Antti-Pekka Sarin, David Schlessinger, Rodney J Scott, Harold Snieder, Beate St Pourcain, John M Starr, Jae Hoon Sul, Ida Surakka, Rauli Svento, Alexander Teumer, , Henning Tiemeier, Frank J A van Rooij, David R Van Wagoner, Erkki Vartiainen, Jorma Viikari, Peter Vollenweider, Judith M Vonk, Gérard Waeber, David R Weir, H-Erich Wichmann, Elisabeth Widén, Gonneke Willemsen, James F Wilson, Alan F Wright, Dalton Conley, George Davey-Smith, Lude Franke, Patrick J F Groenen, Albert Hofman, Magnus Johannesson, Sharon L R Kardia, Robert F Krueger, David Laibson, Nicholas G Martin, Michelle N Meyer, Danielle Posthuma, A Roy Thurik, Nicholas J Timpson, André G Uitterlinden, Cornelia M van Duijn, Peter M Visscher, Daniel J Benjamin, David Cesarini, Philipp D Koellinger.
Science
PUBLISHED: 05-30-2013
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A genome-wide association study (GWAS) of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent single-nucleotide polymorphisms (SNPs) are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (coefficient of determination R(2) ? 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ?2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics.
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Deletion of TOP3?, a component of FMRP-containing mRNPs, contributes to neurodevelopmental disorders.
Nat. Neurosci.
PUBLISHED: 05-09-2013
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Implicating particular genes in the generation of complex brain and behavior phenotypes requires multiple lines of evidence. The rarity of most high-impact genetic variants typically precludes the possibility of accruing statistical evidence that they are associated with a given trait. We found that the enrichment of a rare chromosome 22q11.22 deletion in a recently expanded Northern Finnish sub-isolate enabled the detection of association between TOP3B and both schizophrenia and cognitive impairment. Biochemical analysis of TOP3? revealed that this topoisomerase was a component of cytosolic messenger ribonucleoproteins (mRNPs) and was catalytically active on RNA. The recruitment of TOP3? to mRNPs was independent of RNA cis-elements and was coupled to the co-recruitment of FMRP, the disease gene product in fragile X mental retardation syndrome. Our results indicate a previously unknown role for TOP3? in mRNA metabolism and suggest that it is involved in neurodevelopmental disorders.
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Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake.
Am. J. Clin. Nutr.
PUBLISHED: 05-01-2013
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Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants.
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Testosterone and temperament traits in men: Longitudinal analysis.
Psychoneuroendocrinology
PUBLISHED: 04-11-2013
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Testosterone is the main male hormone that has been associated with various behavioral traits in humans and other animals. We investigated whether levels of total testosterone, free testosterone, and sex hormone binding globulin were associated with temperament traits in a population-based sample of Finnish men at two measurement times taken 6 years apart (n=686 in year 2001, n=727 in year 2007). Temperament was assessed using the Temperament and Character Inventory that consists of four temperament traits: novelty seeking, harm avoidance, reward dependence, and persistence. Higher levels of total and free testosterone were associated with higher novelty seeking (standardized B=0.103, p<0.001). This association was also observed in a longitudinal within-person analysis (B=0.084, p=0.008), suggesting that the association is not confounded by stable between-individual differences in other characteristics. Within-individual variation in total testosterone was associated with higher reward dependence, and higher levels of free testosterone were marginally associated with higher reward dependence. Reward dependence reflects the importance of social rewards to an individual. These results provide additional evidence for the stable and time-varying associations between testosterone and temperament in humans.
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Childhood lifestyle and clinical determinants of adult ideal cardiovascular health: The Cardiovascular Risk in Young Finns Study, the Childhood Determinants of Adult Health Study, the Princeton Follow-up Study.
Int. J. Cardiol.
PUBLISHED: 03-28-2013
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The American Heart Association recently defined ideal cardiovascular health by simultaneous presence of seven health behaviors and factors. The concept is associated with cardiovascular disease incidence, and cardiovascular disease and all-cause mortality. To effectively promote ideal cardiovascular health already early in life, childhood factors predicting future ideal cardiovascular health should be investigated. Our aim was thus to comprehensively explore childhood determinants of adult ideal cardiovascular health in population based cohorts from three continents.
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Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error.
Ching-Yu Cheng, Maria Schache, M Kamran Ikram, Terri L Young, Jeremy A Guggenheim, Veronique Vitart, Stuart MacGregor, Virginie J M Verhoeven, Veluchamy A Barathi, Jiemin Liao, Pirro G Hysi, Joan E Bailey-Wilson, Beate St Pourcain, John P Kemp, George McMahon, Nicholas J Timpson, David M Evans, Grant W Montgomery, Aniket Mishra, Ya Xing Wang, Jie Jin Wang, Elena Rochtchina, Ozren Polašek, Alan F Wright, Najaf Amin, Elisabeth M van Leeuwen, James F Wilson, Craig E Pennell, Cornelia M van Duijn, Paulus T V M de Jong, Johannes R Vingerling, Xin Zhou, Peng Chen, Ruoying Li, Wan-Ting Tay, Yingfeng Zheng, Merwyn Chew, , Kathryn P Burdon, Jamie E Craig, Sudha K Iyengar, Robert P Igo, Jonathan H Lass, Emily Y Chew, Toomas Haller, Evelin Mihailov, Andres Metspalu, Juho Wedenoja, Claire L Simpson, Robert Wojciechowski, René Höhn, Alireza Mirshahi, Tanja Zeller, Norbert Pfeiffer, Karl J Lackner, Thomas Bettecken, Thomas Meitinger, Konrad Oexle, Mario Pirastu, Laura Portas, Abhishek Nag, Katie M Williams, Ekaterina Yonova-Doing, Ronald Klein, Barbara E Klein, S Mohsen Hosseini, Andrew D Paterson, Kari-Matti Mäkelä, Terho Lehtimäki, Mika Kähönen, Olli Raitakari, Nagahisa Yoshimura, Fumihiko Matsuda, Li Jia Chen, Chi Pui Pang, Shea Ping Yip, Maurice K H Yap, Akira Meguro, Nobuhisa Mizuki, Hidetoshi Inoko, Paul J Foster, Jing Hua Zhao, Eranga Vithana, E-Shyong Tai, Qiao Fan, Liang Xu, Harry Campbell, Brian Fleck, Igor Rudan, Tin Aung, Albert Hofman, André G Uitterlinden, Goran Bencic, Chiea-Chuen Khor, Hannah Forward, Olavi Pärssinen, Paul Mitchell, Fernando Rivadeneira, Alex W Hewitt, Cathy Williams, Ben A Oostra, Yik-Ying Teo, Christopher J Hammond, Dwight Stambolian, David A Mackey, Caroline C W Klaver, Tien-Yin Wong, Seang-Mei Saw, Paul N Baird.
Am. J. Hum. Genet.
PUBLISHED: 03-15-2013
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Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.
Sonja I Berndt, Stefan Gustafsson, Reedik Mägi, Andrea Ganna, Eleanor Wheeler, Mary F Feitosa, Anne E Justice, Keri L Monda, Damien C Croteau-Chonka, Felix R Day, Tonu Esko, Tove Fall, Teresa Ferreira, Davide Gentilini, Anne U Jackson, Jian'an Luan, Joshua C Randall, Sailaja Vedantam, Cristen J Willer, Thomas W Winkler, Andrew R Wood, Tsegaselassie Workalemahu, Yi-Juan Hu, Sang Hong Lee, Liming Liang, Dan-Yu Lin, Josine L Min, Benjamin M Neale, Gudmar Thorleifsson, Jian Yang, Eva Albrecht, Najaf Amin, Jennifer L Bragg-Gresham, Gemma Cadby, Martin den Heijer, Niina Eklund, Krista Fischer, Anuj Goel, Jouke-Jan Hottenga, Jennifer E Huffman, Ivonne Jarick, Asa Johansson, Toby Johnson, Stavroula Kanoni, Marcus E Kleber, Inke R König, Kati Kristiansson, Zoltan Kutalik, Claudia Lamina, Cécile Lecoeur, Guo Li, Massimo Mangino, Wendy L McArdle, Carolina Medina-Gomez, Martina Müller-Nurasyid, Julius S Ngwa, Ilja M Nolte, Lavinia Paternoster, Sonali Pechlivanis, Markus Perola, Marjolein J Peters, Michael Preuss, Lynda M Rose, Jianxin Shi, Dmitry Shungin, Albert Vernon Smith, Rona J Strawbridge, Ida Surakka, Alexander Teumer, Mieke D Trip, Jonathan Tyrer, Jana V van Vliet-Ostaptchouk, Liesbeth Vandenput, Lindsay L Waite, Jing Hua Zhao, Devin Absher, Folkert W Asselbergs, Mustafa Atalay, Antony P Attwood, Anthony J Balmforth, Hanneke Basart, John Beilby, Lori L Bonnycastle, Paolo Brambilla, Marcel Bruinenberg, Harry Campbell, Daniel I Chasman, Peter S Chines, Francis S Collins, John M Connell, William O Cookson, Ulf de Faire, Femmie de Vegt, Mariano Dei, Maria Dimitriou, Sarah Edkins, Karol Estrada, David M Evans, Martin Farrall, Marco M Ferrario, Jean Ferrières, Lude Franke, Francesca Frau, Pablo V Gejman, Harald Grallert, Henrik Grönberg, Vilmundur Gudnason, Alistair S Hall, Per Hall, Anna-Liisa Hartikainen, Caroline Hayward, Nancy L Heard-Costa, Andrew C Heath, Johannes Hebebrand, Georg Homuth, Frank B Hu, Sarah E Hunt, Elina Hyppönen, Carlos Iribarren, Kevin B Jacobs, John-Olov Jansson, Antti Jula, Mika Kähönen, Sekar Kathiresan, Frank Kee, Kay-Tee Khaw, Mika Kivimäki, Wolfgang Koenig, Aldi T Kraja, Meena Kumari, Kari Kuulasmaa, Johanna Kuusisto, Jaana H Laitinen, Timo A Lakka, Claudia Langenberg, Lenore J Launer, Lars Lind, Jaana Lindström, Jianjun Liu, Antonio Liuzzi, Marja-Liisa Lokki, Mattias Lorentzon, Pamela A Madden, Patrik K Magnusson, Paolo Manunta, Diana Marek, Winfried März, Irene Mateo Leach, Barbara McKnight, Sarah E Medland, Evelin Mihailov, Lili Milani, Grant W Montgomery, Vincent Mooser, Thomas W Mühleisen, Patricia B Munroe, Arthur W Musk, Narisu Narisu, Gerjan Navis, George Nicholson, Ellen A Nohr, Ken K Ong, Ben A Oostra, Colin N A Palmer, Aarno Palotie, John F Peden, Nancy Pedersen, Annette Peters, Ozren Polašek, Anneli Pouta, Peter P Pramstaller, Inga Prokopenko, Carolin Pütter, Aparna Radhakrishnan, Olli Raitakari, Augusto Rendon, Fernando Rivadeneira, Igor Rudan, Timo E Saaristo, Jennifer G Sambrook, Alan R Sanders, Serena Sanna, Jouko Saramies, Sabine Schipf, Stefan Schreiber, Heribert Schunkert, So-Youn Shin, Stefano Signorini, Juha Sinisalo, Boris Skrobek, Nicole Soranzo, Alena Stančáková, Klaus Stark, Jonathan C Stephens, Kathleen Stirrups, Ronald P Stolk, Michael Stumvoll, Amy J Swift, Eirini V Theodoraki, Barbara Thorand, David-Alexandre Trégouët, Elena Tremoli, Melanie M van der Klauw, Joyce B J van Meurs, Sita H Vermeulen, Jorma Viikari, Jarmo Virtamo, Veronique Vitart, Gérard Waeber, Zhaoming Wang, Elisabeth Widén, Sarah H Wild, Gonneke Willemsen, Bernhard R Winkelmann, Jacqueline C M Witteman, Bruce H R Wolffenbuttel, Andrew Wong, Alan F Wright, M Carola Zillikens, Philippe Amouyel, Bernhard O Boehm, Eric Boerwinkle, Dorret I Boomsma, Mark J Caulfield, Stephen J Chanock, L Adrienne Cupples, Daniele Cusi, George V Dedoussis, Jeanette Erdmann, Johan G Eriksson, Paul W Franks, Philippe Froguel, Christian Gieger, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Christian Hengstenberg, Andrew A Hicks, Aroon Hingorani, Anke Hinney, Albert Hofman, Kees G Hovingh, Kristian Hveem, Thomas Illig, Marjo-Riitta Järvelin, Karl-Heinz Jöckel, Sirkka M Keinanen-Kiukaanniemi, Lambertus A Kiemeney, Diana Kuh, Markku Laakso, Terho Lehtimäki, Douglas F Levinson, Nicholas G Martin, Andres Metspalu, Andrew D Morris, Markku S Nieminen, Inger Njølstad, Claes Ohlsson, Albertine J Oldehinkel, Willem H Ouwehand, Lyle J Palmer, Brenda Penninx, Chris Power, Michael A Province, Bruce M Psaty, Lu Qi, Rainer Rauramaa, Paul M Ridker, Samuli Ripatti, Veikko Salomaa, Nilesh J Samani, Harold Snieder, Thorkild I A Sørensen, Timothy D Spector, Kari Stefansson, Anke Tönjes, Jaakko Tuomilehto, André G Uitterlinden, Matti Uusitupa, Pim van der Harst, Peter Vollenweider, Henri Wallaschofski, Nicholas J Wareham, Hugh Watkins, H-Erich Wichmann, James F Wilson, Gonçalo R Abecasis, Themistocles L Assimes, Inês Barroso, Michael Boehnke, Ingrid B Borecki, Panos Deloukas, Caroline S Fox, Timothy Frayling, Leif C Groop, Talin Haritunian, Iris M Heid, David Hunter, Robert C Kaplan, Fredrik Karpe, Miriam F Moffatt, Karen L Mohlke, Jeffrey R O'Connell, Yudi Pawitan, Eric E Schadt, David Schlessinger, Valgerdur Steinthorsdottir, David P Strachan, Unnur Thorsteinsdottir, Cornelia M van Duijn, Peter M Visscher, Anna Maria Di Blasio, Joel N Hirschhorn, Cecilia M Lindgren, Andrew P Morris, David Meyre, André Scherag, Mark I McCarthy, Elizabeth K Speliotes, Kari E North, Ruth J F Loos, Erik Ingelsson.
Nat. Genet.
PUBLISHED: 03-14-2013
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Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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[Reduced sitting time improves health].
Duodecim
PUBLISHED: 02-26-2013
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The health-promoting effects of physical exercise are scientifically proven, but the health risks of sitting still remain rather poorly known. Technological development of the society will by no means cut down sitting. Should too much sitting be considered as one of the independent factors increasing the risk of metabolic diseases and its reduction as a health-promoting measure? Innovative solutions made possible by the new technology to cut down on sitting and to increase physical activity may prove to be important future tools for promoting health.
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Genetic determinants of trabecular and cortical volumetric bone mineral densities and bone microstructure.
PLoS Genet.
PUBLISHED: 02-21-2013
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Most previous genetic epidemiology studies within the field of osteoporosis have focused on the genetics of the complex trait areal bone mineral density (aBMD), not being able to differentiate genetic determinants of cortical volumetric BMD (vBMD), trabecular vBMD, and bone microstructural traits. The objective of this study was to separately identify genetic determinants of these bone traits as analysed by peripheral quantitative computed tomography (pQCT). Separate GWA meta-analyses for cortical and trabecular vBMDs were performed. The cortical vBMD GWA meta-analysis (n?=?5,878) followed by replication (n?=?1,052) identified genetic variants in four separate loci reaching genome-wide significance (RANKL, rs1021188, p?=?3.6×10?¹?; LOC285735, rs271170, p?=?2.7×10?¹²; OPG, rs7839059, p?=?1.2×10?¹?; and ESR1/C6orf97, rs6909279, p?=?1.1×10??). The trabecular vBMD GWA meta-analysis (n?=?2,500) followed by replication (n?=?1,022) identified one locus reaching genome-wide significance (FMN2/GREM2, rs9287237, p?=?1.9×10??). High-resolution pQCT analyses, giving information about bone microstructure, were available in a subset of the GOOD cohort (n?=?729). rs1021188 was significantly associated with cortical porosity while rs9287237 was significantly associated with trabecular bone fraction. The genetic variant in the FMN2/GREM2 locus was associated with fracture risk in the MrOS Sweden cohort (HR per extra T allele 0.75, 95% confidence interval 0.60-0.93) and GREM2 expression in human osteoblasts. In conclusion, five genetic loci associated with trabecular or cortical vBMD were identified. Two of these (FMN2/GREM2 and LOC285735) are novel bone-related loci, while the other three have previously been reported to be associated with aBMD. The genetic variants associated with cortical and trabecular bone parameters differed, underscoring the complexity of the genetics of bone parameters. We propose that a genetic variant in the RANKL locus influences cortical vBMD, at least partly, via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences GREM2 expression in osteoblasts and thereby trabecular number and thickness as well as fracture risk.
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Mapping neurotransmitter networks with PET: An example on serotonin and opioid systems.
Hum Brain Mapp
PUBLISHED: 01-16-2013
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All functions of the human brain are consequences of altered activity of specific neural pathways and neurotransmitter systems. Although the knowledge of "system level" connectivity in the brain is increasing rapidly, we lack "molecular level" information on brain networks and connectivity patterns. We introduce novel voxel-based positron emission tomography (PET) methods for studying internal neurotransmitter network structure and intercorrelations of different neurotransmitter systems in the human brain. We chose serotonin transporter and ?-opioid receptor for this analysis because of their functional interaction at the cellular level and similar regional distribution in the brain. Twenty-one healthy subjects underwent two consecutive PET scans using [(11) C]MADAM, a serotonin transporter tracer, and [(11) C]carfentanil, a ?-opioid receptor tracer. First, voxel-by-voxel "intracorrelations" (hub and seed analyses) were used to study the internal structure of opioid and serotonin systems. Second, voxel-level opioid-serotonin intercorrelations (between neurotransmitters) were computed. Regional ?-opioid receptor binding potentials were uniformly correlated throughout the brain. However, our analyses revealed nonuniformity in the serotonin transporter intracorrelations and identified a highly connected local network (midbrain-striatum-thalamus-amygdala). Regionally specific intercorrelations between the opioid and serotonin tracers were found in anteromedial thalamus, amygdala, anterior cingulate cortex, dorsolateral prefrontal cortex, and left parietal cortex, i.e., in areas relevant for several neuropsychiatric disorders, especially affective disorders. This methodology enables in vivo mapping of connectivity patterns within and between neurotransmitter systems. Quantification of functional neurotransmitter balances may be a useful approach in etiological studies of neuropsychiatric disorders and also in drug development as a biomarker-based rationale for targeted modulation of neurotransmitter networks. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.
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Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia.
Virginie J M Verhoeven, Pirro G Hysi, Robert Wojciechowski, Qiao Fan, Jeremy A Guggenheim, René Höhn, Stuart MacGregor, Alex W Hewitt, Abhishek Nag, Ching-Yu Cheng, Ekaterina Yonova-Doing, Xin Zhou, M Kamran Ikram, Gabriëlle H S Buitendijk, George McMahon, John P Kemp, Beate St Pourcain, Claire L Simpson, Kari-Matti Mäkelä, Terho Lehtimäki, Mika Kähönen, Andrew D Paterson, S Mohsen Hosseini, Hoi Suen Wong, Liang Xu, Jost B Jonas, Olavi Pärssinen, Juho Wedenoja, Shea Ping Yip, Daniel W H Ho, Chi Pui Pang, Li Jia Chen, Kathryn P Burdon, Jamie E Craig, Barbara E K Klein, Ronald Klein, Toomas Haller, Andres Metspalu, Chiea-Chuen Khor, E-Shyong Tai, Tin Aung, Eranga Vithana, Wan-Ting Tay, Veluchamy A Barathi, , Peng Chen, Ruoying Li, Jiemin Liao, Yingfeng Zheng, Rick T Ong, Angela Döring, David M Evans, Nicholas J Timpson, Annemieke J M H Verkerk, Thomas Meitinger, Olli Raitakari, Felicia Hawthorne, Tim D Spector, Lennart C Karssen, Mario Pirastu, Federico Murgia, Wei Ang, Aniket Mishra, Grant W Montgomery, Craig E Pennell, Phillippa M Cumberland, Ioana Cotlarciuc, Paul Mitchell, Jie Jin Wang, Maria Schache, Sarayut Janmahasatian, Sarayut Janmahasathian, Robert P Igo, Jonathan H Lass, Emily Chew, Sudha K Iyengar, Theo G M F Gorgels, Igor Rudan, Caroline Hayward, Alan F Wright, Ozren Polašek, Zoran Vatavuk, James F Wilson, Brian Fleck, Tanja Zeller, Alireza Mirshahi, Christian Müller, André G Uitterlinden, Fernando Rivadeneira, Johannes R Vingerling, Albert Hofman, Ben A Oostra, Najaf Amin, Arthur A B Bergen, Yik-Ying Teo, Jugnoo S Rahi, Veronique Vitart, Cathy Williams, Paul N Baird, Tien-Yin Wong, Konrad Oexle, Norbert Pfeiffer, David A Mackey, Terri L Young, Cornelia M van Duijn, Seang-Mei Saw, Joan E Bailey-Wilson, Dwight Stambolian, Caroline C Klaver, Christopher J Hammond.
Nat. Genet.
PUBLISHED: 01-16-2013
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Refractive error is the most common eye disorder worldwide and is a prominent cause of blindness. Myopia affects over 30% of Western populations and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses, including 37,382 individuals from 27 studies of European ancestry and 8,376 from 5 Asian cohorts. We identified 16 new loci for refractive error in individuals of European ancestry, of which 8 were shared with Asians. Combined analysis identified 8 additional associated loci. The new loci include candidate genes with functions in neurotransmission (GRIA4), ion transport (KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodeling (LAMA2 and BMP2) and eye development (SIX6 and PRSS56). We also confirmed previously reported associations with GJD2 and RASGRF1. Risk score analysis using associated SNPs showed a tenfold increased risk of myopia for individuals carrying the highest genetic load. Our results, based on a large meta-analysis across independent multiancestry studies, considerably advance understanding of the mechanisms involved in refractive error and myopia.
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Distinct loci in the CHRNA5/CHRNA3/CHRNB4 gene cluster are associated with onset of regular smoking.
Sarah H Stephens, Sarah M Hartz, Nicole R Hoft, Nancy L Saccone, Robin C Corley, John K Hewitt, Christian J Hopfer, Naomi Breslau, Hilary Coon, Xiangning Chen, Francesca Ducci, Nicole Dueker, Nora Franceschini, Josef Frank, Younghun Han, Nadia N Hansel, Chenhui Jiang, Tellervo Korhonen, Penelope A Lind, Jason Liu, Leo-Pekka Lyytikäinen, Martha Michel, John R Shaffer, Susan E Short, Juzhong Sun, Alexander Teumer, John R Thompson, Nicole Vogelzangs, Jacqueline M Vink, Angela Wenzlaff, William Wheeler, Bao-Zhu Yang, Steven H Aggen, Anthony J Balmforth, Sebastian E Baumeister, Terri H Beaty, Daniel J Benjamin, Andrew W Bergen, Ulla Broms, David Cesarini, Nilanjan Chatterjee, Jingchun Chen, Yu-Ching Cheng, Sven Cichon, David Couper, Francesco Cucca, Danielle Dick, Tatiana Foroud, Helena Furberg, Ina Giegling, Nathan A Gillespie, Fangyi Gu, Alistair S Hall, Jenni Hällfors, Shizhong Han, Annette M Hartmann, Kauko Heikkilä, Ian B Hickie, Jouke Jan Hottenga, Pekka Jousilahti, Marika Kaakinen, Mika Kähönen, Philipp D Koellinger, Stephen Kittner, Bettina Konte, Maria-Teresa Landi, Tiina Laatikainen, Mark Leppert, Steven M Levy, Rasika A Mathias, Daniel W McNeil, Sarah E Medland, Grant W Montgomery, Tanda Murray, Matthias Nauck, Kari E North, Peter D Pare, Michele Pergadia, Ingo Ruczinski, Veikko Salomaa, Jorma Viikari, Gonneke Willemsen, Kathleen C Barnes, Eric Boerwinkle, Dorret I Boomsma, Neil Caporaso, Howard J Edenberg, Clyde Francks, Joel Gelernter, Hans Jörgen Grabe, Hyman Hops, Marjo-Riitta Järvelin, Magnus Johannesson, Kenneth S Kendler, Terho Lehtimäki, Patrik K E Magnusson, Mary L Marazita, Jonathan Marchini, Braxton D Mitchell, Markus M Nöthen, Brenda W Penninx, Olli Raitakari, Marcella Rietschel, Dan Rujescu, Nilesh J Samani, Ann G Schwartz, Sanjay Shete, Margaret Spitz, Gary E Swan, Henry Völzke, Juha Veijola, Qingyi Wei, Chris Amos, Dale S Cannon, Richard Grucza, Dorothy Hatsukami, Andrew Heath, Eric O Johnson, Jaakko Kaprio, Pamela Madden, Nicholas G Martin, Victoria L Stevens, Robert B Weiss, Peter Kraft, Laura J Bierut, Marissa A Ehringer.
Genet. Epidemiol.
PUBLISHED: 01-11-2013
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Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype.
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Scrutiny of the CHRNA5-CHRNA3-CHRNB4 smoking behavior locus reveals a novel association with alcohol use in a Finnish population based study.
Int J Mol Epidemiol Genet
PUBLISHED: 01-01-2013
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The CHRNA5-CHRNA3-CHRNB4 gene cluster on chromosome 15q25.1 encoding the cholinergic nicotinic receptor subunits is robustly associated with smoking behavior and nicotine dependence. Only a few studies to date have examined the locus with alcohol related traits and found evidence of association with alcohol abuse and dependence. Our main goal was to examine the role of three intensively studied single nucleotide polymorphisms, rs16969968, rs578776 and rs588765, tagging three distinct loci, in alcohol use. Our sample was drawn from two independent Finnish population-based surveys, the National FINRISK Study and the Health 2000 (Health Examination) Survey. The combined sample included a total of 32,592 adult Finns (54% women) of whom 8,356 were assessed for cigarettes per day (CPD). Data on alcohol use were available for 31,812 individuals. We detected a novel association between rs588765 and alcohol use defined as abstainers and low-frequency drinkers versus drinkers (OR=1.15, p=0.00007). Additionally, we provide precise estimates of strength of the association between the three loci and smoking quantity in a very large population based sample. As a conclusion, our results provide further evidence for the nicotine-specific role of rs16969968 (locus 1). Further, our data suggest that the effect of rs588765 (locus 3) may be specific to alcohol use as the effect is seen also in never smokers.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.