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Find video protocols related to scientific articles indexed in Pubmed.
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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Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age.
Joris Deelen, Marian Beekman, Hae-Won Uh, Linda Broer, Kristin L Ayers, Qihua Tan, Yoichiro Kamatani, Anna M Bennet, Riin Tamm, Stella Trompet, Daníel F Guðbjartsson, Friederike Flachsbart, Giuseppina Rose, Alexander Viktorin, Krista Fischer, Marianne Nygaard, Heather J Cordell, Paolina Crocco, Erik B van den Akker, Stefan Böhringer, Quinta Helmer, Christopher P Nelson, Gary I Saunders, Maris Alver, Karen Andersen-Ranberg, Marie E Breen, Ruud van der Breggen, Amke Caliebe, Miriam Capri, Elisa Cevenini, Joanna C Collerton, Serena Dato, Karen Davies, Ian Ford, Jutta Gampe, Paolo Garagnani, Eco J C de Geus, Jennifer Harrow, Diana van Heemst, Bastiaan T Heijmans, Femke-Anouska Heinsen, Jouke-Jan Hottenga, Albert Hofman, Bernard Jeune, Palmi V Jonsson, Mark Lathrop, Doris Lechner, Carmen Martin-Ruiz, Susan E McNerlan, Evelin Mihailov, Alberto Montesanto, Simon P Mooijaart, Anne Murphy, Ellen A Nohr, Lavinia Paternoster, Iris Postmus, Fernando Rivadeneira, Owen A Ross, Stefano Salvioli, Naveed Sattar, Stefan Schreiber, Hreinn Stefansson, David J Stott, Henning Tiemeier, André G Uitterlinden, Rudi G J Westendorp, Gonneke Willemsen, Nilesh J Samani, Pilar Galán, Thorkild I A Sørensen, Dorret I Boomsma, J Wouter Jukema, Irene Maeve Rea, Giuseppe Passarino, Anton J M de Craen, Kaare Christensen, Almut Nebel, Kari Stefansson, Andres Metspalu, Patrik Magnusson, Hélène Blanché, Lene Christiansen, Thomas B L Kirkwood, Cornelia M van Duijn, Claudio Franceschi, Jeanine J Houwing-Duistermaat, P Eline Slagboom.
Hum. Mol. Genet.
PUBLISHED: 03-31-2014
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The genetic contribution to the variation in human lifespan is ? 25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (? 85 years) and 16 121 younger controls (<65 years) followed by replication in an additional set of 13 060 long-lived individuals and 61 156 controls. In addition, we performed a subset analysis in cases aged ? 90 years. We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR = 1.10, P = 1.74 × 10(-8)). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 × 10(-36)), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n = 34 103), the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR = 0.95, P = 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.
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Cohort Profile: Estonian Biobank of the Estonian Genome Center, University of Tartu.
Int J Epidemiol
PUBLISHED: 02-13-2014
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The Estonian Biobank cohort is a volunteer-based sample of the Estonian resident adult population (aged ?18 years). The current number of participants-close to 52000--represents a large proportion, 5%, of the Estonian adult population, making it ideally suited to population-based studies. General practitioners (GPs) and medical personnel in the special recruitment offices have recruited participants throughout the country. At baseline, the GPs performed a standardized health examination of the participants, who also donated blood samples for DNA, white blood cells and plasma tests and filled out a 16-module questionnaire on health-related topics such as lifestyle, diet and clinical diagnoses described in WHO ICD-10. A significant part of the cohort has whole genome sequencing (100), genome-wide single nucleotide polymorphism (SNP) array data (20 000) and/or NMR metabolome data (11 000) available (http://www.geenivaramu.ee/for-scientists/data-release/). The data are continuously updated through periodical linking to national electronic databases and registries. A part of the cohort has been re-contacted for follow-up purposes and resampling, and targeted invitations are possible for specific purposes, for example people with a specific diagnosis. The Estonian Genome Center of the University of Tartu is actively collaborating with many universities, research institutes and consortia and encourages fellow scientists worldwide to co-initiate new academic or industrial joint projects with us.
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Biomarker profiling by nuclear magnetic resonance spectroscopy for the prediction of all-cause mortality: an observational study of 17,345 persons.
PLoS Med.
PUBLISHED: 02-01-2014
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Early identification of ambulatory persons at high short-term risk of death could benefit targeted prevention. To identify biomarkers for all-cause mortality and enhance risk prediction, we conducted high-throughput profiling of blood specimens in two large population-based cohorts.
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The prevalence of metabolic syndrome and metabolically healthy obesity in Europe: a collaborative analysis of ten large cohort studies.
BMC Endocr Disord
PUBLISHED: 01-26-2014
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Not all obese subjects have an adverse metabolic profile predisposing them to developing type 2 diabetes or cardiovascular disease. The BioSHaRE-EU Healthy Obese Project aims to gain insights into the consequences of (healthy) obesity using data on risk factors and phenotypes across several large-scale cohort studies. Aim of this study was to describe the prevalence of obesity, metabolic syndrome (MetS) and metabolically healthy obesity (MHO) in ten participating studies.
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Leukocyte telomere length associates with prospective mortality independent of immune-related parameters and known genetic markers.
Int J Epidemiol
PUBLISHED: 01-14-2014
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Human leukocyte telomere length (LTL) decreases with age and shorter LTL has previously been associated with increased prospective mortality. However, it is not clear whether LTL merely marks the health status of an individual by its association with parameters of immune function, for example, or whether telomere shortening also contributes causally to lifespan variation in humans.
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Discovery and refinement of loci associated with lipid levels.
, Cristen J Willer, Ellen M Schmidt, Sebanti Sengupta, Gina M Peloso, Stefan Gustafsson, Stavroula Kanoni, Andrea Ganna, Jin Chen, Martin L Buchkovich, Samia Mora, Jacques S Beckmann, Jennifer L Bragg-Gresham, Hsing-Yi Chang, Ayse Demirkan, Heleen M den Hertog, Ron Do, Louise A Donnelly, Georg B Ehret, Tonu Esko, Mary F Feitosa, Teresa Ferreira, Krista Fischer, Pierre Fontanillas, Ross M Fraser, Daniel F Freitag, Deepti Gurdasani, Kauko Heikkilä, Elina Hyppönen, Aaron Isaacs, Anne U Jackson, Asa Johansson, Toby Johnson, Marika Kaakinen, Johannes Kettunen, Marcus E Kleber, Xiaohui Li, Jian'an Luan, Leo-Pekka Lyytikäinen, Patrik K E Magnusson, Massimo Mangino, Evelin Mihailov, May E Montasser, Martina Müller-Nurasyid, Ilja M Nolte, Jeffrey R O'Connell, Cameron D Palmer, Markus Perola, Ann-Kristin Petersen, Serena Sanna, Richa Saxena, Susan K Service, Sonia Shah, Dmitry Shungin, Carlo Sidore, Ci Song, Rona J Strawbridge, Ida Surakka, Toshiko Tanaka, Tanya M Teslovich, Gudmar Thorleifsson, Evita G van den Herik, Benjamin F Voight, Kelly A Volcik, Lindsay L Waite, Andrew Wong, Ying Wu, Weihua Zhang, Devin Absher, Gershim Asiki, Inês Barroso, Latonya F Been, Jennifer L Bolton, Lori L Bonnycastle, Paolo Brambilla, Mary S Burnett, Giancarlo Cesana, Maria Dimitriou, Alex S F Doney, Angela Döring, Paul Elliott, Stephen E Epstein, Gudmundur Ingi Eyjolfsson, Bruna Gigante, Mark O Goodarzi, Harald Grallert, Martha L Gravito, Christopher J Groves, Göran Hallmans, Anna-Liisa Hartikainen, Caroline Hayward, Dena Hernandez, Andrew A Hicks, Hilma Holm, Yi-Jen Hung, Thomas Illig, Michelle R Jones, Pontiano Kaleebu, John J P Kastelein, Kay-Tee Khaw, Eric Kim, Norman Klopp, Pirjo Komulainen, Meena Kumari, Claudia Langenberg, Terho Lehtimäki, Shih-Yi Lin, Jaana Lindström, Ruth J F Loos, François Mach, Wendy L McArdle, Christa Meisinger, Braxton D Mitchell, Gabrielle Müller, Ramaiah Nagaraja, Narisu Narisu, Tuomo V M Nieminen, Rebecca N Nsubuga, Isleifur Olafsson, Ken K Ong, Aarno Palotie, Theodore Papamarkou, Cristina Pomilla, Anneli Pouta, Daniel J Rader, Muredach P Reilly, Paul M Ridker, Fernando Rivadeneira, Igor Rudan, Aimo Ruokonen, Nilesh Samani, Hubert Scharnagl, Janet Seeley, Kaisa Silander, Alena Stančáková, Kathleen Stirrups, Amy J Swift, Laurence Tiret, André G Uitterlinden, L Joost van Pelt, Sailaja Vedantam, Nicholas Wainwright, Cisca Wijmenga, Sarah H Wild, Gonneke Willemsen, Tom Wilsgaard, James F Wilson, Elizabeth H Young, Jing Hua Zhao, Linda S Adair, Dominique Arveiler, Themistocles L Assimes, Stefania Bandinelli, Franklyn Bennett, Murielle Bochud, Bernhard O Boehm, Dorret I Boomsma, Ingrid B Borecki, Stefan R Bornstein, Pascal Bovet, Michel Burnier, Harry Campbell, Aravinda Chakravarti, John C Chambers, Yii-Der Ida Chen, Francis S Collins, Richard S Cooper, John Danesh, George Dedoussis, Ulf de Faire, Alan B Feranil, Jean Ferrières, Luigi Ferrucci, Nelson B Freimer, Christian Gieger, Leif C Groop, Vilmundur Gudnason, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Aroon Hingorani, Joel N Hirschhorn, Albert Hofman, G Kees Hovingh, Chao Agnes Hsiung, Steve E Humphries, Steven C Hunt, Kristian Hveem, Carlos Iribarren, Marjo-Riitta Järvelin, Antti Jula, Mika Kähönen, Jaakko Kaprio, Antero Kesäniemi, Mika Kivimäki, Jaspal S Kooner, Peter J Koudstaal, Ronald M Krauss, Diana Kuh, Johanna Kuusisto, Kirsten O Kyvik, Markku Laakso, Timo A Lakka, Lars Lind, Cecilia M Lindgren, Nicholas G Martin, Winfried März, Mark I McCarthy, Colin A McKenzie, Pierre Meneton, Andres Metspalu, Leena Moilanen, Andrew D Morris, Patricia B Munroe, Inger Njølstad, Nancy L Pedersen, Chris Power, Peter P Pramstaller, Jackie F Price, Bruce M Psaty, Thomas Quertermous, Rainer Rauramaa, Danish Saleheen, Veikko Salomaa, Dharambir K Sanghera, Jouko Saramies, Peter E H Schwarz, Wayne H-H Sheu, Alan R Shuldiner, Agneta Siegbahn, Tim D Spector, Kari Stefansson, David P Strachan, Bamidele O Tayo, Elena Tremoli, Jaakko Tuomilehto, Matti Uusitupa, Cornelia M van Duijn, Peter Vollenweider, Lars Wallentin, Nicholas J Wareham, John B Whitfield, Bruce H R Wolffenbuttel, José M Ordovás, Eric Boerwinkle, Colin N A Palmer, Unnur Thorsteinsdottir, Daniel I Chasman, Jerome I Rotter, Paul W Franks, Samuli Ripatti, L Adrienne Cupples, Manjinder S Sandhu, Stephen S Rich, Michael Boehnke, Panos Deloukas, Sekar Kathiresan, Karen L Mohlke, Erik Ingelsson, Gonçalo R Abecasis.
Nat. Genet.
PUBLISHED: 09-13-2013
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Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
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RegScan: a GWAS tool for quick estimation of allele effects on continuous traits and their combinations.
Brief. Bioinformatics
PUBLISHED: 09-07-2013
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Genome-wide association studies are becoming computationally more demanding with the growing amounts of data. Combinatorial traits can increase the data dimensions beyond the computational capabilities of the current tools. We addressed this issue by creating an application for quick association analysis that is ten to hundreds of times faster than the leading fast methods. Our tool (RegScan) is designed for performing basic linear regression analysis with continuous traits maximally fast on large data sets. RegScan specifically targets association analysis of combinatorial traits in metabolomics. It can both generate and analyze the combinatorial traits efficiently. RegScan is capable of analyzing any number of traits together without the need to specify each trait individually. The main goal of the article is to show that RegScan can be the preferred analytical tool when large amounts of data need to be analyzed quickly using the allele frequency test.Availability: Precompiled RegScan (all major platforms), source code, user guide and examples are freely available at www.biobank.ee/regscan.Requirements: Qt 4.4.3 or newer for dynamic compilations.
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Systematic identification of trans eQTLs as putative drivers of known disease associations.
Nat. Genet.
PUBLISHED: 08-14-2013
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Identifying the downstream effects of disease-associated SNPs is challenging. To help overcome this problem, we performed expression quantitative trait locus (eQTL) meta-analysis in non-transformed peripheral blood samples from 5,311 individuals with replication in 2,775 individuals. We identified and replicated trans eQTLs for 233 SNPs (reflecting 103 independent loci) that were previously associated with complex traits at genome-wide significance. Some of these SNPs affect multiple genes in trans that are known to be altered in individuals with disease: rs4917014, previously associated with systemic lupus erythematosus (SLE), altered gene expression of C1QB and five type I interferon response genes, both hallmarks of SLE. DeepSAGE RNA sequencing showed that rs4917014 strongly alters the 3 UTR levels of IKZF1 in cis, and chromatin immunoprecipitation and sequencing analysis of the trans-regulated genes implicated IKZF1 as the causal gene. Variants associated with cholesterol metabolism and type 1 diabetes showed similar phenomena, indicating that large-scale eQTL mapping provides insight into the downstream effects of many trait-associated variants.
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Whole-exome sequencing identifies a polymorphism in the BMP5 gene associated with SSRI treatment response in major depression.
J. Psychopharmacol. (Oxford)
PUBLISHED: 08-07-2013
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Although antidepressants are widely used in the pharmacotherapy of major depressive disorder (MDD), their efficacy is still insufficient as approximately one-third of the patients do not fully recover even after several treatment trials. Inter-individual genetic differences are thought to contribute to the variability in antidepressant response; however, current findings from pharmacogenetic studies are uncertain or not clearly replicated. Here we report the first application of full exome sequencing for the analysis of pharmacogenomics on antidepressant treatment. After 12 weeks of treatment with the selective serotonin re-uptake inhibitor escitalopram, we selected five clear responders and five clear non-responders for exome sequencing. By comparing the allele counts of previously known single nucleotide polymorphisms and novel polymorphisms we selected 38 markers for further genotyping in two independent patient samples treated with escitalopram (n=116 and n=394). The A allele, carried by approximately 30% of the patients with MDD, of rs41271330 in the bone morphogenetic protein (BMP5) gene showed strong association with worse treatment response in both sample sets (p=0.001), indicating that this is an promising pharmacogenetic marker for prediction of antidepressant therapeutic outcome.
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The role of adiposity in cardiometabolic traits: a mendelian randomization analysis.
Tove Fall, Sara Hägg, Reedik Mägi, Alexander Ploner, Krista Fischer, Momoko Horikoshi, Antti-Pekka Sarin, Gudmar Thorleifsson, Claes Ladenvall, Mart Kals, Maris Kuningas, Harmen H M Draisma, Janina S Ried, Natalie R Van Zuydam, Ville Huikari, Massimo Mangino, Emily Sonestedt, Beben Benyamin, Christopher P Nelson, Natalia V Rivera, Kati Kristiansson, Huei-Yi Shen, Aki S Havulinna, Abbas Dehghan, Louise A Donnelly, Marika Kaakinen, Marja-Liisa Nuotio, Neil Robertson, Renée F A G de Bruijn, M Arfan Ikram, Najaf Amin, Anthony J Balmforth, Peter S Braund, Alexander S F Doney, Angela Döring, Paul Elliott, Tonu Esko, Oscar H Franco, Solveig Gretarsdottir, Anna-Liisa Hartikainen, Kauko Heikkilä, Karl-Heinz Herzig, Hilma Holm, Jouke Jan Hottenga, Elina Hyppönen, Thomas Illig, Aaron Isaacs, Bo Isomaa, Lennart C Karssen, Johannes Kettunen, Wolfgang Koenig, Kari Kuulasmaa, Tiina Laatikainen, Jaana Laitinen, Cecilia Lindgren, Valeriya Lyssenko, Esa Läärä, Nigel W Rayner, Satu Mannisto, Anneli Pouta, Wolfgang Rathmann, Fernando Rivadeneira, Aimo Ruokonen, Markku J Savolainen, Eric J G Sijbrands, Kerrin S Small, Jan H Smit, Valgerdur Steinthorsdottir, Ann-Christine Syvänen, Anja Taanila, Martin D Tobin, André G Uitterlinden, Sara M Willems, Gonneke Willemsen, Jacqueline Witteman, Markus Perola, Alun Evans, Jean Ferrières, Jarmo Virtamo, Frank Kee, David-Alexandre Trégouët, Dominique Arveiler, Philippe Amouyel, Marco M Ferrario, Paolo Brambilla, Alistair S Hall, Andrew C Heath, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, John B Whitfield, Antti Jula, Paul Knekt, Ben Oostra, Cornelia M van Duijn, Brenda W J H Penninx, George Davey Smith, Jaakko Kaprio, Nilesh J Samani, Christian Gieger, Annette Peters, H Erich Wichmann, Dorret I Boomsma, Eco J C de Geus, Tiinamaija Tuomi, Chris Power, Christopher J Hammond, Tim D Spector, Lars Lind, Marju Orho-Melander, Colin Neil Alexander Palmer, Andrew D Morris, Leif Groop, Marjo-Riitta Järvelin, Veikko Salomaa, Erkki Vartiainen, Albert Hofman, Samuli Ripatti, Andres Metspalu, Unnur Thorsteinsdottir, Kari Stefansson, Nancy L Pedersen, Mark I McCarthy, Erik Ingelsson, Inga Prokopenko, .
PLoS Med.
PUBLISHED: 06-01-2013
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The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.
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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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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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Identification of seven loci affecting mean telomere length and their association with disease.
Veryan Codd, Christopher P Nelson, Eva Albrecht, Massimo Mangino, Joris Deelen, Jessica L Buxton, Jouke Jan Hottenga, Krista Fischer, Tonu Esko, Ida Surakka, Linda Broer, Dale R Nyholt, Irene Mateo Leach, Perttu Salo, Sara Hägg, Mary K Matthews, Jutta Palmen, Giuseppe D Norata, Paul F O'Reilly, Danish Saleheen, Najaf Amin, Anthony J Balmforth, Marian Beekman, Rudolf A de Boer, Stefan Böhringer, Peter S Braund, Paul R Burton, Anton J M de Craen, Matthew Denniff, Yanbin Dong, Konstantinos Douroudis, Elena Dubinina, Johan G Eriksson, Katia Garlaschelli, Dehuang Guo, Anna-Liisa Hartikainen, Anjali K Henders, Jeanine J Houwing-Duistermaat, Laura Kananen, Lennart C Karssen, Johannes Kettunen, Norman Klopp, Vasiliki Lagou, Elisabeth M van Leeuwen, Pamela A Madden, Reedik Mägi, Patrik K E Magnusson, Satu Mannisto, Mark I McCarthy, Sarah E Medland, Evelin Mihailov, Grant W Montgomery, Ben A Oostra, Aarno Palotie, Annette Peters, Helen Pollard, Anneli Pouta, Inga Prokopenko, Samuli Ripatti, Veikko Salomaa, H Eka D Suchiman, Ana M Valdes, Niek Verweij, Ana Viñuela, Xiaoling Wang, H-Erich Wichmann, Elisabeth Widén, Gonneke Willemsen, Margaret J Wright, Kai Xia, Xiangjun Xiao, Dirk J van Veldhuisen, Alberico L Catapano, Martin D Tobin, Alistair S Hall, Alexandra I F Blakemore, Wiek H van Gilst, Haidong Zhu, Cardiogram Consortium, Jeanette Erdmann, Muredach P Reilly, Sekar Kathiresan, Heribert Schunkert, Philippa J Talmud, Nancy L Pedersen, Markus Perola, Willem Ouwehand, Jaakko Kaprio, Nicholas G Martin, Cornelia M van Duijn, Iiris Hovatta, Christian Gieger, Andres Metspalu, Dorret I Boomsma, Marjo-Riitta Järvelin, P Eline Slagboom, John R Thompson, Tim D Spector, Pim van der Harst, Nilesh J Samani.
Nat. Genet.
PUBLISHED: 03-29-2013
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Interindividual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. We report here a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals. We identified seven loci, including five new loci, associated with mean LTL (P < 5 × 10(-8)). Five of the loci contain candidate genes (TERC, TERT, NAF1, OBFC1 and RTEL1) that are known to be involved in telomere biology. Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis. Moreover, a genetic risk score analysis combining lead variants at all 7 loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of coronary artery disease (21% (95% confidence interval, 5-35%) per standard deviation in LTL, P = 0.014). Our findings support a causal role of telomere-length variation in some age-related diseases.
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Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders.
Marcel den Hoed, Mark Eijgelsheim, Tonu Esko, Bianca J J M Brundel, David S Peal, David M Evans, Ilja M Nolte, Ayellet V Segrè, Hilma Holm, Robert E Handsaker, Harm-Jan Westra, Toby Johnson, Aaron Isaacs, Jian Yang, Alicia Lundby, Jing Hua Zhao, Young Jin Kim, Min Jin Go, Peter Almgren, Murielle Bochud, Gabrielle Boucher, Marilyn C Cornelis, Daniel Gudbjartsson, David Hadley, Pim van der Harst, Caroline Hayward, Martin den Heijer, Wilmar Igl, Anne U Jackson, Zoltan Kutalik, Jian'an Luan, John P Kemp, Kati Kristiansson, Claes Ladenvall, Mattias Lorentzon, May E Montasser, Omer T Njajou, Paul F O'Reilly, Sandosh Padmanabhan, Beate St Pourcain, Tuomo Rankinen, Perttu Salo, Toshiko Tanaka, Nicholas J Timpson, Veronique Vitart, Lindsay Waite, William Wheeler, Weihua Zhang, Harmen H M Draisma, Mary F Feitosa, Kathleen F Kerr, Penelope A Lind, Evelin Mihailov, N Charlotte Onland-Moret, Ci Song, Michael N Weedon, Weijia Xie, Loïc Yengo, Devin Absher, Christine M Albert, Alvaro Alonso, Dan E Arking, Paul I W de Bakker, Beverley Balkau, Cristina Barlassina, Paola Benaglio, Joshua C Bis, Nabila Bouatia-Naji, Søren Brage, Stephen J Chanock, Peter S Chines, Mina Chung, Dawood Darbar, Christian Dina, Marcus Dörr, Paul Elliott, Stephan B Felix, Krista Fischer, Christian Fuchsberger, Eco J C de Geus, Philippe Goyette, Vilmundur Gudnason, Tamara B Harris, Anna-Liisa Hartikainen, Aki S Havulinna, Susan R Heckbert, Andrew A Hicks, Albert Hofman, Suzanne Holewijn, Femke Hoogstra-Berends, Jouke-Jan Hottenga, Majken K Jensen, Asa Johansson, Juhani Junttila, Stefan Kääb, Bart Kanon, Shamika Ketkar, Kay-Tee Khaw, Joshua W Knowles, Angrad S Kooner, Jan A Kors, Meena Kumari, Lili Milani, Päivi Laiho, Edward G Lakatta, Claudia Langenberg, Maarten Leusink, Yongmei Liu, Robert N Luben, Kathryn L Lunetta, Stacey N Lynch, Marcello R P Markus, Pedro Marques-Vidal, Irene Mateo Leach, Wendy L McArdle, Steven A McCarroll, Sarah E Medland, Kathryn A Miller, Grant W Montgomery, Alanna C Morrison, Martina Müller-Nurasyid, Pau Navarro, Mari Nelis, Jeffrey R O'Connell, Christopher J O'Donnell, Ken K Ong, Anne B Newman, Annette Peters, Ozren Polašek, Anneli Pouta, Peter P Pramstaller, Bruce M Psaty, Dabeeru C Rao, Susan M Ring, Elizabeth J Rossin, Diana Rudan, Serena Sanna, Robert A Scott, Jaban S Sehmi, Stephen Sharp, Jordan T Shin, Andrew B Singleton, Albert V Smith, Nicole Soranzo, Tim D Spector, Chip Stewart, Heather M Stringham, Kirill V Tarasov, André G Uitterlinden, Liesbeth Vandenput, Shih-Jen Hwang, John B Whitfield, Cisca Wijmenga, Sarah H Wild, Gonneke Willemsen, James F Wilson, Jacqueline C M Witteman, Andrew Wong, Quenna Wong, Yalda Jamshidi, Paavo Zitting, Jolanda M A Boer, Dorret I Boomsma, Ingrid B Borecki, Cornelia M van Duijn, Ulf Ekelund, Nita G Forouhi, Philippe Froguel, Aroon Hingorani, Erik Ingelsson, Mika Kivimäki, Richard A Kronmal, Diana Kuh, Lars Lind, Nicholas G Martin, Ben A Oostra, Nancy L Pedersen, Thomas Quertermous, Jerome I Rotter, Yvonne T van der Schouw, W M Monique Verschuren, Mark Walker, Demetrius Albanes, David O Arnar, Themistocles L Assimes, Stefania Bandinelli, Michael Boehnke, Rudolf A de Boer, Claude Bouchard, W L Mark Caulfield, John C Chambers, Gary Curhan, Daniele Cusi, Johan Eriksson, Luigi Ferrucci, Wiek H van Gilst, Nicola Glorioso, Jacqueline de Graaf, Leif Groop, Ulf Gyllensten, Wen-Chi Hsueh, Frank B Hu, Heikki V Huikuri, David J Hunter, Carlos Iribarren, Bo Isomaa, Marjo-Riitta Järvelin, Antti Jula, Mika Kähönen, Lambertus A Kiemeney, Melanie M van der Klauw, Jaspal S Kooner, Peter Kraft, Licia Iacoviello, Terho Lehtimäki, Marja-Liisa L Lokki, Braxton D Mitchell, Gerjan Navis, Markku S Nieminen, Claes Ohlsson, Neil R Poulter, Lu Qi, Olli T Raitakari, Eric B Rimm, John D Rioux, Federica Rizzi, Igor Rudan, Veikko Salomaa, Peter S Sever, Denis C Shields, Alan R Shuldiner, Juha Sinisalo, Alice V Stanton, Ronald P Stolk, David P Strachan, Jean-Claude Tardif, Unnur Thorsteinsdottir, Jaako Tuomilehto, Dirk J van Veldhuisen, Jarmo Virtamo, Jorma Viikari, Peter Vollenweider, Gérard Waeber, Elisabeth Widén, Yoon Shin Cho, Jesper V Olsen, Peter M Visscher, Cristen Willer, Lude Franke, , Jeanette Erdmann, John R Thompson, Arne Pfeufer, Nona Sotoodehnia, Christopher Newton-Cheh, Patrick T Ellinor, Bruno H Ch Stricker, Andres Metspalu, Markus Perola, Jacques S Beckmann, George Davey Smith, Kari Stefansson, Nicholas J Wareham, Patricia B Munroe, Ody C M Sibon, David J Milan, Harold Snieder, Nilesh J Samani, Ruth J F Loos.
Nat. Genet.
PUBLISHED: 03-21-2013
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Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
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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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Common variants associated with plasma triglycerides and risk for coronary artery disease.
Ron Do, Cristen J Willer, Ellen M Schmidt, Sebanti Sengupta, Chi Gao, Gina M Peloso, Stefan Gustafsson, Stavroula Kanoni, Andrea Ganna, Jin Chen, Martin L Buchkovich, Samia Mora, Jacques S Beckmann, Jennifer L Bragg-Gresham, Hsing-Yi Chang, Ayse Demirkan, Heleen M den Hertog, Louise A Donnelly, Georg B Ehret, Tonu Esko, Mary F Feitosa, Teresa Ferreira, Krista Fischer, Pierre Fontanillas, Ross M Fraser, Daniel F Freitag, Deepti Gurdasani, Kauko Heikkilä, Elina Hyppönen, Aaron Isaacs, Anne U Jackson, Asa Johansson, Toby Johnson, Marika Kaakinen, Johannes Kettunen, Marcus E Kleber, Xiaohui Li, Jian'an Luan, Leo-Pekka Lyytikäinen, Patrik K E Magnusson, Massimo Mangino, Evelin Mihailov, May E Montasser, Martina Müller-Nurasyid, Ilja M Nolte, Jeffrey R O'Connell, Cameron D Palmer, Markus Perola, Ann-Kristin Petersen, Serena Sanna, Richa Saxena, Susan K Service, Sonia Shah, Dmitry Shungin, Carlo Sidore, Ci Song, Rona J Strawbridge, Ida Surakka, Toshiko Tanaka, Tanya M Teslovich, Gudmar Thorleifsson, Evita G van den Herik, Benjamin F Voight, Kelly A Volcik, Lindsay L Waite, Andrew Wong, Ying Wu, Weihua Zhang, Devin Absher, Gershim Asiki, Inês Barroso, Latonya F Been, Jennifer L Bolton, Lori L Bonnycastle, Paolo Brambilla, Mary S Burnett, Giancarlo Cesana, Maria Dimitriou, Alex S F Doney, Angela Döring, Paul Elliott, Stephen E Epstein, Gudmundur Ingi Eyjolfsson, Bruna Gigante, Mark O Goodarzi, Harald Grallert, Martha L Gravito, Christopher J Groves, Göran Hallmans, Anna-Liisa Hartikainen, Caroline Hayward, Dena Hernandez, Andrew A Hicks, Hilma Holm, Yi-Jen Hung, Thomas Illig, Michelle R Jones, Pontiano Kaleebu, John J P Kastelein, Kay-Tee Khaw, Eric Kim, Norman Klopp, Pirjo Komulainen, Meena Kumari, Claudia Langenberg, Terho Lehtimäki, Shih-Yi Lin, Jaana Lindström, Ruth J F Loos, François Mach, Wendy L McArdle, Christa Meisinger, Braxton D Mitchell, Gabrielle Müller, Ramaiah Nagaraja, Narisu Narisu, Tuomo V M Nieminen, Rebecca N Nsubuga, Isleifur Olafsson, Ken K Ong, Aarno Palotie, Theodore Papamarkou, Cristina Pomilla, Anneli Pouta, Daniel J Rader, Muredach P Reilly, Paul M Ridker, Fernando Rivadeneira, Igor Rudan, Aimo Ruokonen, Nilesh Samani, Hubert Scharnagl, Janet Seeley, Kaisa Silander, Alena Stančáková, Kathleen Stirrups, Amy J Swift, Laurence Tiret, André G Uitterlinden, L Joost van Pelt, Sailaja Vedantam, Nicholas Wainwright, Cisca Wijmenga, Sarah H Wild, Gonneke Willemsen, Tom Wilsgaard, James F Wilson, Elizabeth H Young, Jing Hua Zhao, Linda S Adair, Dominique Arveiler, Themistocles L Assimes, Stefania Bandinelli, Franklyn Bennett, Murielle Bochud, Bernhard O Boehm, Dorret I Boomsma, Ingrid B Borecki, Stefan R Bornstein, Pascal Bovet, Michel Burnier, Harry Campbell, Aravinda Chakravarti, John C Chambers, Yii-Der Ida Chen, Francis S Collins, Richard S Cooper, John Danesh, George Dedoussis, Ulf de Faire, Alan B Feranil, Jean Ferrières, Luigi Ferrucci, Nelson B Freimer, Christian Gieger, Leif C Groop, Vilmundur Gudnason, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Aroon Hingorani, Joel N Hirschhorn, Albert Hofman, G Kees Hovingh, Chao Agnes Hsiung, Steve E Humphries, Steven C Hunt, Kristian Hveem, Carlos Iribarren, Marjo-Riitta Järvelin, Antti Jula, Mika Kähönen, Jaakko Kaprio, Antero Kesäniemi, Mika Kivimäki, Jaspal S Kooner, Peter J Koudstaal, Ronald M Krauss, Diana Kuh, Johanna Kuusisto, Kirsten O Kyvik, Markku Laakso, Timo A Lakka, Lars Lind, Cecilia M Lindgren, Nicholas G Martin, Winfried März, Mark I McCarthy, Colin A McKenzie, Pierre Meneton, Andres Metspalu, Leena Moilanen, Andrew D Morris, Patricia B Munroe, Inger Njølstad, Nancy L Pedersen, Chris Power, Peter P Pramstaller, Jackie F Price, Bruce M Psaty, Thomas Quertermous, Rainer Rauramaa, Danish Saleheen, Veikko Salomaa, Dharambir K Sanghera, Jouko Saramies, Peter E H Schwarz, Wayne H-H Sheu, Alan R Shuldiner, Agneta Siegbahn, Tim D Spector, Kari Stefansson, David P Strachan, Bamidele O Tayo, Elena Tremoli, Jaakko Tuomilehto, Matti Uusitupa, Cornelia M van Duijn, Peter Vollenweider, Lars Wallentin, Nicholas J Wareham, John B Whitfield, Bruce H R Wolffenbuttel, David Altshuler, José M Ordovás, Eric Boerwinkle, Colin N A Palmer, Unnur Thorsteinsdottir, Daniel I Chasman, Jerome I Rotter, Paul W Franks, Samuli Ripatti, L Adrienne Cupples, Manjinder S Sandhu, Stephen S Rich, Michael Boehnke, Panos Deloukas, Karen L Mohlke, Erik Ingelsson, Gonçalo R Abecasis, Mark J Daly, Benjamin M Neale, Sekar Kathiresan.
Nat. Genet.
PUBLISHED: 02-20-2013
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Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphisms effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
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A genome-wide association study of early menopause and the combined impact of identified variants.
Hum. Mol. Genet.
PUBLISHED: 01-09-2013
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Early menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ?30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking.
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Identification of miR-374a as a prognostic marker for survival in patients with early-stage nonsmall cell lung cancer.
Genes Chromosomes Cancer
PUBLISHED: 06-09-2011
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Lung cancer is one of the deadliest types of cancer proven by the poor survival and high relapse rates after surgery. Recently discovered microRNAs (miRNAs), small noncoding RNA molecules, play a crucial role in modulating gene expression networks and are directly involved in the progression of a number of human cancers. In this study, we analyzed the expression profile of 858 miRNAs in 38 Estonian nonsmall cell lung cancer (NSCLC) samples (Stage I and II) and 27 adjacent nontumorous tissue samples using Illumina miRNA arrays. We found that 39 miRNAs were up-regulated and 33 down-regulated significantly in tumors compared with normal lung tissue. We observed aberrant expression of several well-characterized tumorigenesis-related miRNAs, as well as a number of miRNAs whose function is currently unknown. We show that low expression of miR-374a in early-stage NSCLC is associated with poor patient survival. The combinatorial effect of the up- and down-regulated miRNAs is predicted to most significantly affect pathways associated with cell migration, differentiation and growth, and several signaling pathways that contribute to tumorigenesis. In conclusion, our results demonstrate that expression of miR-374a at early stages of NSCLC progression can serve as a prognostic marker for patient risk stratification and may be a promising therapeutic target for the treatment of lung cancer.
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Vesicular monoamine transporter-1 (VMAT-1) mRNA and immunoreactive proteins in mouse brain.
Neuro Endocrinol. Lett.
PUBLISHED: 05-13-2011
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Vesicular monoamine transporter 1 (VMAT-1) mRNA and protein were examined (1) to determine whether adult mouse brain expresses full-length VMAT-1 mRNA that can be translated to functional transporter protein and (2) to compare immunoreactive VMAT-1 proteins in brain and adrenal.
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A structural mean model to allow for noncompliance in a randomized trial comparing 2 active treatments.
Biostatistics
PUBLISHED: 08-30-2010
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We propose a structural mean modeling approach to obtain compliance-adjusted estimates for treatment effects in a randomized-controlled trial comparing 2 active treatments. The model relates an individuals observed outcome to his or her counterfactual untreated outcome through the observed receipt of active treatments. Our proposed estimation procedure exploits baseline covariates that predict compliance levels on each arm. We give a closed-form estimator which allows for differential and unexplained selectivity (i.e. noncausal compliance-outcome association due to unobserved confounding) as well as a nonparametric error distribution. In a simple linear model for a 2-arm trial, we show that the distinct causal parameters are identified unless covariate-specific expected compliance levels are proportional on both treatment arms. In the latter case, only a linear contrast between the 2 treatment effects is estimable and may well be of key interest. We demonstrate the method in a clinical trial comparing 2 antidepressants.
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Seventy-five genetic loci influencing the human red blood cell.
Pim van der Harst, Weihua Zhang, Irene Mateo Leach, Augusto Rendon, Niek Verweij, Joban Sehmi, Dirk S Paul, Ulrich Elling, Hooman Allayee, Xinzhong Li, Aparna Radhakrishnan, Sian-Tsung Tan, Katrin Voss, Christian X Weichenberger, Cornelis A Albers, Abtehale Al-Hussani, Folkert W Asselbergs, Marina Ciullo, Fabrice Danjou, Christian Dina, Tonu Esko, David M Evans, Lude Franke, Martin Gögele, Jaana Hartiala, Micha Hersch, Hilma Holm, Jouke-Jan Hottenga, Stavroula Kanoni, Marcus E Kleber, Vasiliki Lagou, Claudia Langenberg, Lorna M Lopez, Leo-Pekka Lyytikäinen, Olle Melander, Federico Murgia, Ilja M Nolte, Paul F O'Reilly, Sandosh Padmanabhan, Afshin Parsa, Nicola Pirastu, Eleonora Porcu, Laura Portas, Inga Prokopenko, Janina S Ried, So-Youn Shin, Clara S Tang, Alexander Teumer, Michela Traglia, Sheila Ulivi, Harm-Jan Westra, Jian Yang, Jing Hua Zhao, Franco Anni, Abdel Abdellaoui, Antony Attwood, Beverley Balkau, Stefania Bandinelli, François Bastardot, Beben Benyamin, Bernhard O Boehm, William O Cookson, Debashish Das, Paul I W de Bakker, Rudolf A de Boer, Eco J C de Geus, Marleen H de Moor, Maria Dimitriou, Francisco S Domingues, Angela Döring, Gunnar Engström, Gudmundur Ingi Eyjolfsson, Luigi Ferrucci, Krista Fischer, Renzo Galanello, Stephen F Garner, Bernd Genser, Quince D Gibson, Giorgia Girotto, Daniel Fannar Gudbjartsson, Sarah E Harris, Anna-Liisa Hartikainen, Claire E Hastie, Bo Hedblad, Thomas Illig, Jennifer Jolley, Mika Kähönen, Ido P Kema, John P Kemp, Liming Liang, Heather Lloyd-Jones, Ruth J F Loos, Stuart Meacham, Sarah E Medland, Christa Meisinger, Yasin Memari, Evelin Mihailov, Kathy Miller, Miriam F Moffatt, Matthias Nauck, Maria Novatchkova, Teresa Nutile, Isleifur Olafsson, Pall T Onundarson, Debora Parracciani, Brenda W Penninx, Lucia Perseu, Antonio Piga, Giorgio Pistis, Anneli Pouta, Ursula Puc, Olli Raitakari, Susan M Ring, Antonietta Robino, Daniela Ruggiero, Aimo Ruokonen, Aude Saint-Pierre, Cinzia Sala, Andres Salumets, Jennifer Sambrook, Hein Schepers, Carsten Oliver Schmidt, Herman H W Sillje, Rob Sladek, Johannes H Smit, John M Starr, Jonathan Stephens, Patrick Sulem, Toshiko Tanaka, Unnur Thorsteinsdottir, Vinicius Tragante, Wiek H van Gilst, L Joost van Pelt, Dirk J van Veldhuisen, Uwe Völker, John B Whitfield, Gonneke Willemsen, Bernhard R Winkelmann, Gerald Wirnsberger, Ale Algra, Francesco Cucca, Adamo Pio D'adamo, John Danesh, Ian J Deary, Anna F Dominiczak, Paul Elliott, Paolo Fortina, Philippe Froguel, Paolo Gasparini, Andreas Greinacher, Stanley L Hazen, Marjo-Riitta Järvelin, Kay Tee Khaw, Terho Lehtimäki, Winfried Maerz, Nicholas G Martin, Andres Metspalu, Braxton D Mitchell, Grant W Montgomery, Carmel Moore, Gerjan Navis, Mario Pirastu, Peter P Pramstaller, Ramiro Ramirez-Solis, Eric Schadt, James Scott, Alan R Shuldiner, George Davey Smith, J Gustav Smith, Harold Snieder, Rossella Sorice, Tim D Spector, Kari Stefansson, Michael Stumvoll, W H Wilson Tang, Daniela Toniolo, Anke Tönjes, Peter M Visscher, Peter Vollenweider, Nicholas J Wareham, Bruce H R Wolffenbuttel, Dorret I Boomsma, Jacques S Beckmann, George V Dedoussis, Panos Deloukas, Manuel A Ferreira, Serena Sanna, Manuela Uda, Andrew A Hicks, Josef Martin Penninger, Christian Gieger, Jaspal S Kooner, Willem H Ouwehand, Nicole Soranzo, John C Chambers.
Nature
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Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P?
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Large-scale association analysis identifies new risk loci for coronary artery disease.
, Panos Deloukas, Stavroula Kanoni, Christina Willenborg, Martin Farrall, Themistocles L Assimes, John R Thompson, Erik Ingelsson, Danish Saleheen, Jeanette Erdmann, Benjamin A Goldstein, Kathleen Stirrups, Inke R König, Jean-Baptiste Cazier, Asa Johansson, Alistair S Hall, Jong-Young Lee, Cristen J Willer, John C Chambers, Tonu Esko, Lasse Folkersen, Anuj Goel, Elin Grundberg, Aki S Havulinna, Weang K Ho, Jemma C Hopewell, Niclas Eriksson, Marcus E Kleber, Kati Kristiansson, Per Lundmark, Leo-Pekka Lyytikäinen, Suzanne Rafelt, Dmitry Shungin, Rona J Strawbridge, Gudmar Thorleifsson, Emmi Tikkanen, Natalie Van Zuydam, Benjamin F Voight, Lindsay L Waite, Weihua Zhang, Andreas Ziegler, Devin Absher, David Altshuler, Anthony J Balmforth, Inês Barroso, Peter S Braund, Christof Burgdorf, Simone Claudi-Boehm, David Cox, Maria Dimitriou, Ron Do, Alex S F Doney, NourEddine El Mokhtari, Per Eriksson, Krista Fischer, Pierre Fontanillas, Anders Franco-Cereceda, Bruna Gigante, Leif Groop, Stefan Gustafsson, Jörg Hager, Göran Hallmans, Bok-Ghee Han, Sarah E Hunt, Hyun M Kang, Thomas Illig, Thorsten Kessler, Joshua W Knowles, Genovefa Kolovou, Johanna Kuusisto, Claudia Langenberg, Cordelia Langford, Karin Leander, Marja-Liisa Lokki, Anders Lundmark, Mark I McCarthy, Christa Meisinger, Olle Melander, Evelin Mihailov, Seraya Maouche, Andrew D Morris, Martina Müller-Nurasyid, Kjell Nikus, John F Peden, N William Rayner, Asif Rasheed, Silke Rosinger, Diana Rubin, Moritz P Rumpf, Arne Schäfer, Mohan Sivananthan, Ci Song, Alexandre F R Stewart, Sian-Tsung Tan, Gudmundur Thorgeirsson, C Ellen van der Schoot, Peter J Wagner, George A Wells, Philipp S Wild, Tsun-Po Yang, Philippe Amouyel, Dominique Arveiler, Hanneke Basart, Michael Boehnke, Eric Boerwinkle, Paolo Brambilla, Francois Cambien, Adrienne L Cupples, Ulf de Faire, Abbas Dehghan, Patrick Diemert, Stephen E Epstein, Alun Evans, Marco M Ferrario, Jean Ferrières, Dominique Gauguier, Alan S Go, Alison H Goodall, Villi Gudnason, Stanley L Hazen, Hilma Holm, Carlos Iribarren, Yangsoo Jang, Mika Kähönen, Frank Kee, Hyo-Soo Kim, Norman Klopp, Wolfgang Koenig, Wolfgang Kratzer, Kari Kuulasmaa, Markku Laakso, Reijo Laaksonen, Ji-Young Lee, Lars Lind, Willem H Ouwehand, Sarah Parish, Jeong E Park, Nancy L Pedersen, Annette Peters, Thomas Quertermous, Daniel J Rader, Veikko Salomaa, Eric Schadt, Svati H Shah, Juha Sinisalo, Klaus Stark, Kari Stefansson, David-Alexandre Trégouët, Jarmo Virtamo, Lars Wallentin, Nicholas Wareham, Martina E Zimmermann, Markku S Nieminen, Christian Hengstenberg, Manjinder S Sandhu, Tomi Pastinen, Ann-Christine Syvänen, G Kees Hovingh, George Dedoussis, Paul W Franks, Terho Lehtimäki, Andres Metspalu, Pierre A Zalloua, Agneta Siegbahn, Stefan Schreiber, Samuli Ripatti, Stefan S Blankenberg, Markus Perola, Robert Clarke, Bernhard O Boehm, Christopher O'Donnell, Muredach P Reilly, Winfried März, Rory Collins, Sekar Kathiresan, Anders Hamsten, Jaspal S Kooner, Unnur Thorsteinsdottir, John Danesh, Colin N A Palmer, Robert Roberts, Hugh Watkins, Heribert Schunkert, Nilesh J Samani.
Nat. Genet.
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Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.
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Thr136Ile polymorphism of human vesicular monoamine transporter-1 (SLC18A1 gene) influences its transport activity in vitro.
Neuro Endocrinol. Lett.
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Although single nucleotide polymorphisms of the human vesicular monoamine transporter 1 (hVMAT1) gene SLC18A1 have been associated with neuropsychiatric disorders, there is limited information on the function of naturally occurring hVMAT1 variant proteins. This study evaluated transport activity of full length hVMAT1 isoform-a (NP_003044.1) with a threonine (Thr) or isoleucine (Ile) at amino acid 136 and hVMAT1 isoform-b (NP_00135796.1) with a 136-Thr and deletion of 32 amino acids in the central region of the protein. Genetic studies have previously linked the 136-Thr to bipolar disorder.
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FTO genotype is associated with phenotypic variability of body mass index.
Jian Yang, Ruth J F Loos, Joseph E Powell, Sarah E Medland, Elizabeth K Speliotes, Daniel I Chasman, Lynda M Rose, Gudmar Thorleifsson, Valgerdur Steinthorsdottir, Reedik Mägi, Lindsay Waite, Albert Vernon Smith, Laura M Yerges-Armstrong, Keri L Monda, David Hadley, Anubha Mahajan, Guo Li, Karen Kapur, Veronique Vitart, Jennifer E Huffman, Sophie R Wang, Cameron Palmer, Tonu Esko, Krista Fischer, Jing Hua Zhao, Ayse Demirkan, Aaron Isaacs, Mary F Feitosa, Jian'an Luan, Nancy L Heard-Costa, Charles White, Anne U Jackson, Michael Preuss, Andreas Ziegler, Joel Eriksson, Zoltan Kutalik, Francesca Frau, Ilja M Nolte, Jana V van Vliet-Ostaptchouk, Jouke-Jan Hottenga, Kevin B Jacobs, Niek Verweij, Anuj Goel, Carolina Medina-Gomez, Karol Estrada, Jennifer Lynn Bragg-Gresham, Serena Sanna, Carlo Sidore, Jonathan Tyrer, Alexander Teumer, Inga Prokopenko, Massimo Mangino, Cecilia M Lindgren, Themistocles L Assimes, Alan R Shuldiner, Jennie Hui, John P Beilby, Wendy L McArdle, Per Hall, Talin Haritunians, Lina Zgaga, Ivana Kolčić, Ozren Polašek, Tatijana Zemunik, Ben A Oostra, M Juhani Junttila, Henrik Grönberg, Stefan Schreiber, Annette Peters, Andrew A Hicks, Jonathan Stephens, Nicola S Foad, Jaana Laitinen, Anneli Pouta, Marika Kaakinen, Gonneke Willemsen, Jacqueline M Vink, Sarah H Wild, Gerjan Navis, Folkert W Asselbergs, Georg Homuth, Ulrich John, Carlos Iribarren, Tamara Harris, Lenore Launer, Vilmundur Gudnason, Jeffrey R O'Connell, Eric Boerwinkle, Gemma Cadby, Lyle J Palmer, Alan L James, Arthur W Musk, Erik Ingelsson, Bruce M Psaty, Jacques S Beckmann, Gérard Waeber, Peter Vollenweider, Caroline Hayward, Alan F Wright, Igor Rudan, Leif C Groop, Andres Metspalu, Kay Tee Khaw, Cornelia M van Duijn, Ingrid B Borecki, Michael A Province, Nicholas J Wareham, Jean-Claude Tardif, Heikki V Huikuri, L Adrienne Cupples, Larry D Atwood, Caroline S Fox, Michael Boehnke, Francis S Collins, Karen L Mohlke, Jeanette Erdmann, Heribert Schunkert, Christian Hengstenberg, Klaus Stark, Mattias Lorentzon, Claes Ohlsson, Daniele Cusi, Jan A Staessen, Melanie M van der Klauw, Peter P Pramstaller, Sekar Kathiresan, Jennifer D Jolley, Samuli Ripatti, Marjo-Riitta Järvelin, Eco J C de Geus, Dorret I Boomsma, Brenda Penninx, James F Wilson, Harry Campbell, Stephen J Chanock, Pim van der Harst, Anders Hamsten, Hugh Watkins, Albert Hofman, Jacqueline C Witteman, M Carola Zillikens, André G Uitterlinden, Fernando Rivadeneira, Lambertus A Kiemeney, Sita H Vermeulen, Gonçalo R Abecasis, David Schlessinger, Sabine Schipf, Michael Stumvoll, Anke Tönjes, Tim D Spector, Kari E North, Guillaume Lettre, Mark I McCarthy, Sonja I Berndt, Andrew C Heath, Pamela A F Madden, Dale R Nyholt, Grant W Montgomery, Nicholas G Martin, Barbara McKnight, David P Strachan, William G Hill, Harold Snieder, Paul M Ridker, Unnur Thorsteinsdottir, Kari Stefansson, Timothy M Frayling, Joel N Hirschhorn, Michael E Goddard, Peter M Visscher.
Nature
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There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ?170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ?0.5?kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
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Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes.
Andrew P Morris, Benjamin F Voight, Tanya M Teslovich, Teresa Ferreira, Ayellet V Segrè, Valgerdur Steinthorsdottir, Rona J Strawbridge, Hassan Khan, Harald Grallert, Anubha Mahajan, Inga Prokopenko, Hyun Min Kang, Christian Dina, Tonu Esko, Ross M Fraser, Stavroula Kanoni, Ashish Kumar, Vasiliki Lagou, Claudia Langenberg, Jian'an Luan, Cecilia M Lindgren, Martina Müller-Nurasyid, Sonali Pechlivanis, N William Rayner, Laura J Scott, Steven Wiltshire, Loïc Yengo, Leena Kinnunen, Elizabeth J Rossin, Soumya Raychaudhuri, Andrew D Johnson, Antigone S Dimas, Ruth J F Loos, Sailaja Vedantam, Han Chen, Jose C Florez, Caroline Fox, Ching-Ti Liu, Denis Rybin, David J Couper, Wen Hong L Kao, Man Li, Marilyn C Cornelis, Peter Kraft, Qi Sun, Rob M Van Dam, Heather M Stringham, Peter S Chines, Krista Fischer, Pierre Fontanillas, Oddgeir L Holmen, Sarah E Hunt, Anne U Jackson, Augustine Kong, Robert Lawrence, Julia Meyer, John R B Perry, Carl G P Platou, Simon Potter, Emil Rehnberg, Neil Robertson, Suthesh Sivapalaratnam, Alena Stančáková, Kathleen Stirrups, Gudmar Thorleifsson, Emmi Tikkanen, Andrew R Wood, Peter Almgren, Mustafa Atalay, Rafn Benediktsson, Lori L Bonnycastle, Noel Burtt, Jason Carey, Guillaume Charpentier, Andrew T Crenshaw, Alex S F Doney, Mozhgan Dorkhan, Sarah Edkins, Valur Emilsson, Elodie Eury, Tom Forsén, Karl Gertow, Bruna Gigante, George B Grant, Christopher J Groves, Candace Guiducci, Christian Herder, Astradur B Hreidarsson, Jennie Hui, Alan James, Anna Jonsson, Wolfgang Rathmann, Norman Klopp, Jasmina Kravic, Kaarel Krjutskov, Cordelia Langford, Karin Leander, Eero Lindholm, Stéphane Lobbens, Satu Mannisto, Ghazala Mirza, Thomas W Mühleisen, Bill Musk, Melissa Parkin, Loukianos Rallidis, Jouko Saramies, Bengt Sennblad, Sonia Shah, Gunnar Sigurðsson, Angela Silveira, Gerald Steinbach, Barbara Thorand, Joseph Trakalo, Fabrizio Veglia, Roman Wennauer, Wendy Winckler, Delilah Zabaneh, Harry Campbell, Cornelia van Duijn, André G Uitterlinden, Albert Hofman, Eric Sijbrands, Gonçalo R Abecasis, Katharine R Owen, Eleftheria Zeggini, Mieke D Trip, Nita G Forouhi, Ann-Christine Syvänen, Johan G Eriksson, Leena Peltonen, Markus M Nöthen, Beverley Balkau, Colin N A Palmer, Valeriya Lyssenko, Tiinamaija Tuomi, Bo Isomaa, David J Hunter, Lu Qi, , Alan R Shuldiner, Michael Roden, Inês Barroso, Tom Wilsgaard, John Beilby, Kees Hovingh, Jackie F Price, James F Wilson, Rainer Rauramaa, Timo A Lakka, Lars Lind, George Dedoussis, Inger Njølstad, Nancy L Pedersen, Kay-Tee Khaw, Nicholas J Wareham, Sirkka M Keinanen-Kiukaanniemi, Timo E Saaristo, Eeva Korpi-Hyövälti, Juha Saltevo, Markku Laakso, Johanna Kuusisto, Andres Metspalu, Francis S Collins, Karen L Mohlke, Richard N Bergman, Jaakko Tuomilehto, Bernhard O Boehm, Christian Gieger, Kristian Hveem, Stéphane Cauchi, Philippe Froguel, Damiano Baldassarre, Elena Tremoli, Steve E Humphries, Danish Saleheen, John Danesh, Erik Ingelsson, Samuli Ripatti, Veikko Salomaa, Raimund Erbel, Karl-Heinz Jöckel, Susanne Moebus, Annette Peters, Thomas Illig, Ulf de Faire, Anders Hamsten, Andrew D Morris, Peter J Donnelly, Timothy M Frayling, Andrew T Hattersley, Eric Boerwinkle, Olle Melander, Sekar Kathiresan, Peter M Nilsson, Panos Deloukas, Unnur Thorsteinsdottir, Leif C Groop, Kari Stefansson, Frank Hu, James S Pankow, Josée Dupuis, James B Meigs, David Altshuler, Michael Boehnke, Mark I McCarthy.
Nat. Genet.
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To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis.
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Genome-wide meta-analysis of common variant differences between men and women.
Vesna Boraska, Ana Jerončić, Vincenza Colonna, Lorraine Southam, Dale R Nyholt, Nigel William Rayner, John R B Perry, Daniela Toniolo, Eva Albrecht, Wei Ang, Stefania Bandinelli, Maja Barbalic, Inês Barroso, Jacques S Beckmann, Reiner Biffar, Dorret Boomsma, Harry Campbell, Tanguy Corre, Jeanette Erdmann, Tonu Esko, Krista Fischer, Nora Franceschini, Timothy M Frayling, Giorgia Girotto, Juan R Gonzalez, Tamara B Harris, Andrew C Heath, Iris M Heid, Wolfgang Hoffmann, Albert Hofman, Momoko Horikoshi, Jing Hua Zhao, Anne U Jackson, Jouke-Jan Hottenga, Antti Jula, Mika Kähönen, Kay-Tee Khaw, Lambertus A Kiemeney, Norman Klopp, Zoltan Kutalik, Vasiliki Lagou, Lenore J Launer, Terho Lehtimäki, Mathieu Lemire, Marja-Liisa Lokki, Christina Loley, Jian'an Luan, Massimo Mangino, Irene Mateo Leach, Sarah E Medland, Evelin Mihailov, Grant W Montgomery, Gerjan Navis, John Newnham, Markku S Nieminen, Aarno Palotie, Kalliope Panoutsopoulou, Annette Peters, Nicola Pirastu, Ozren Polašek, Karola Rehnström, Samuli Ripatti, Graham R S Ritchie, Fernando Rivadeneira, Antonietta Robino, Nilesh J Samani, So-Youn Shin, Juha Sinisalo, Johannes H Smit, Nicole Soranzo, Lisette Stolk, Dorine W Swinkels, Toshiko Tanaka, Alexander Teumer, Anke Tönjes, Michela Traglia, Jaakko Tuomilehto, Armand Valsesia, Wiek H van Gilst, Joyce B J van Meurs, Albert Vernon Smith, Jorma Viikari, Jacqueline M Vink, Gérard Waeber, Nicole M Warrington, Elisabeth Widén, Gonneke Willemsen, Alan F Wright, Brent W Zanke, Lina Zgaga, , Michael Boehnke, Adamo Pio D'adamo, Eco de Geus, Ellen W Demerath, Martin den Heijer, Johan G Eriksson, Luigi Ferrucci, Christian Gieger, Vilmundur Gudnason, Caroline Hayward, Christian Hengstenberg, Thomas J Hudson, Marjo-Riitta Järvelin, Manolis Kogevinas, Ruth J F Loos, Nicholas G Martin, Andres Metspalu, Craig E Pennell, Brenda W Penninx, Markus Perola, Olli Raitakari, Veikko Salomaa, Stefan Schreiber, Heribert Schunkert, Tim D Spector, Michael Stumvoll, André G Uitterlinden, Sheila Ulivi, Pim van der Harst, Peter Vollenweider, Henry Völzke, Nicholas J Wareham, H-Erich Wichmann, James F Wilson, Igor Rudan, Yali Xue, Eleftheria Zeggini.
Hum. Mol. Genet.
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The male-to-female sex ratio at birth is constant across world populations with an average of 1.06 (106 male to 100 female live births) for populations of European descent. The sex ratio is considered to be affected by numerous biological and environmental factors and to have a heritable component. The aim of this study was to investigate the presence of common allele modest effects at autosomal and chromosome X variants that could explain the observed sex ratio at birth. We conducted a large-scale genome-wide association scan (GWAS) meta-analysis across 51 studies, comprising overall 114 863 individuals (61 094 women and 53 769 men) of European ancestry and 2 623 828 common (minor allele frequency >0.05) single-nucleotide polymorphisms (SNPs). Allele frequencies were compared between men and women for directly-typed and imputed variants within each study. Forward-time simulations for unlinked, neutral, autosomal, common loci were performed under the demographic model for European populations with a fixed sex ratio and a random mating scheme to assess the probability of detecting significant allele frequency differences. We do not detect any genome-wide significant (P < 5 × 10(-8)) common SNP differences between men and women in this well-powered meta-analysis. The simulated data provided results entirely consistent with these findings. This large-scale investigation across ~115 000 individuals shows no detectable contribution from common genetic variants to the observed skew in the sex ratio. The absence of sex-specific differences is useful in guiding genetic association study design, for example when using mixed controls for sex-biased traits.
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Evidence of inbreeding depression on human height.
Ruth McQuillan, Niina Eklund, Nicola Pirastu, Maris Kuningas, Brian P McEvoy, Tonu Esko, Tanguy Corre, Gail Davies, Marika Kaakinen, Leo-Pekka Lyytikäinen, Kati Kristiansson, Aki S Havulinna, Martin Gögele, Veronique Vitart, Albert Tenesa, Yurii Aulchenko, Caroline Hayward, Asa Johansson, Mladen Boban, Sheila Ulivi, Antonietta Robino, Vesna Boraska, Wilmar Igl, Sarah H Wild, Lina Zgaga, Najaf Amin, Evropi Theodoratou, Ozren Polašek, Giorgia Girotto, Lorna M Lopez, Cinzia Sala, Jari Lahti, Tiina Laatikainen, Inga Prokopenko, Mart Kals, Jorma Viikari, Jian Yang, Anneli Pouta, Karol Estrada, Albert Hofman, Nelson Freimer, Nicholas G Martin, Mika Kähönen, Lili Milani, Markku Heliövaara, Erkki Vartiainen, Katri Räikkönen, Corrado Masciullo, John M Starr, Andrew A Hicks, Laura Esposito, Ivana Kolčić, Susan M Farrington, Ben Oostra, Tatijana Zemunik, Harry Campbell, Mirna Kirin, Marina Pehlić, Flavio Faletra, David Porteous, Giorgio Pistis, Elisabeth Widén, Veikko Salomaa, Seppo Koskinen, Krista Fischer, Terho Lehtimäki, Andrew Heath, Mark I McCarthy, Fernando Rivadeneira, Grant W Montgomery, Henning Tiemeier, Anna-Liisa Hartikainen, Pamela A F Madden, Pio D'Adamo, Nicholas D Hastie, Ulf Gyllensten, Alan F Wright, Cornelia M van Duijn, Malcolm Dunlop, Igor Rudan, Paolo Gasparini, Peter P Pramstaller, Ian J Deary, Daniela Toniolo, Johan G Eriksson, Antti Jula, Olli T Raitakari, Andres Metspalu, Markus Perola, Marjo-Riitta Järvelin, André Uitterlinden, Peter M Visscher, James F Wilson, .
PLoS Genet.
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Stature is a classical and highly heritable complex trait, with 80%-90% of variation explained by genetic factors. In recent years, genome-wide association studies (GWAS) have successfully identified many common additive variants influencing human height; however, little attention has been given to the potential role of recessive genetic effects. Here, we investigated genome-wide recessive effects by an analysis of inbreeding depression on adult height in over 35,000 people from 21 different population samples. We found a highly significant inverse association between height and genome-wide homozygosity, equivalent to a height reduction of up to 3 cm in the offspring of first cousins compared with the offspring of unrelated individuals, an effect which remained after controlling for the effects of socio-economic status, an important confounder (?(2) = 83.89, df = 1; p = 5.2 × 10(-20)). There was, however, a high degree of heterogeneity among populations: whereas the direction of the effect was consistent across most population samples, the effect size differed significantly among populations. It is likely that this reflects true biological heterogeneity: whether or not an effect can be observed will depend on both the variance in homozygosity in the population and the chance inheritance of individual recessive genotypes. These results predict that multiple, rare, recessive variants influence human height. Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance.
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Methylation markers of early-stage non-small cell lung cancer.
PLoS ONE
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Despite of intense research in early cancer detection, there is a lack of biomarkers for the reliable detection of malignant tumors, including non-small cell lung cancer (NSCLC). DNA methylation changes are common and relatively stable in various types of cancers, and may be used as diagnostic or prognostic biomarkers.
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Results from a blind and a non-blind randomised trial run in parallel: experience from the Estonian Postmenopausal Hormone Therapy (EPHT) Trial.
BMC Med Res Methodol
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The Estonian Postmenopausal Hormone Therapy (EPHT) Trial assigned 4170 potential participants prior to recruitment to blind or non-blind hormone therapy (HT), with placebo or non-treatment the respective alternatives. Before having to decide on participation, women were told whether they had been randomised to the blind or non-blind trial. Eligible women who were still willing to join the trial were recruited. After recruitment participants in the non-blind trial (N = 1001) received open-label HT or no treatment, participants in the blind trial (N = 777) remained blinded until the end of the trial. The aim of this paper is to analyse the effect of blinding on internal and external validity of trial outcomes.
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Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways.
Lisette Stolk, John R B Perry, Daniel I Chasman, Chunyan He, Massimo Mangino, Patrick Sulem, Maja Barbalic, Linda Broer, Enda M Byrne, Florian Ernst, Tonu Esko, Nora Franceschini, Daniel F Gudbjartsson, Jouke-Jan Hottenga, Peter Kraft, Patrick F McArdle, Eleonora Porcu, So-Youn Shin, Albert V Smith, Sophie van Wingerden, Guangju Zhai, Wei V Zhuang, Eva Albrecht, Behrooz Z Alizadeh, Thor Aspelund, Stefania Bandinelli, Lovorka Barać Lauc, Jacques S Beckmann, Mladen Boban, Eric Boerwinkle, Frank J Broekmans, Andrea Burri, Harry Campbell, Stephen J Chanock, Constance Chen, Marilyn C Cornelis, Tanguy Corre, Andrea D Coviello, Pio D'Adamo, Gail Davies, Ulf de Faire, Eco J C de Geus, Ian J Deary, George V Z Dedoussis, Panagiotis Deloukas, Shah Ebrahim, Gudny Eiriksdottir, Valur Emilsson, Johan G Eriksson, Bart C J M Fauser, Liana Ferreli, Luigi Ferrucci, Krista Fischer, Aaron R Folsom, Melissa E Garcia, Paolo Gasparini, Christian Gieger, Nicole Glazer, Diederick E Grobbee, Per Hall, Toomas Haller, Susan E Hankinson, Merli Hass, Caroline Hayward, Andrew C Heath, Albert Hofman, Erik Ingelsson, A Cecile J W Janssens, Andrew D Johnson, David Karasik, Sharon L R Kardia, Jules Keyzer, Douglas P Kiel, Ivana Kolčić, Zoltan Kutalik, Jari Lahti, Sandra Lai, Triin Laisk, Joop S E Laven, Debbie A Lawlor, Jianjun Liu, Lorna M Lopez, Yvonne V Louwers, Patrik K E Magnusson, Mara Marongiu, Nicholas G Martin, Irena Martinović Klarić, Corrado Masciullo, Barbara McKnight, Sarah E Medland, David Melzer, Vincent Mooser, Pau Navarro, Anne B Newman, Dale R Nyholt, N Charlotte Onland-Moret, Aarno Palotie, Guillaume Paré, Alex N Parker, Nancy L Pedersen, Petra H M Peeters, Giorgio Pistis, Andrew S Plump, Ozren Polašek, Victor J M Pop, Bruce M Psaty, Katri Räikkönen, Emil Rehnberg, Jerome I Rotter, Igor Rudan, Cinzia Sala, Andres Salumets, Angelo Scuteri, Andrew Singleton, Jennifer A Smith, Harold Snieder, Nicole Soranzo, Simon N Stacey, John M Starr, Maria G Stathopoulou, Kathleen Stirrups, Ronald P Stolk, Unnur Styrkarsdottir, Yan V Sun, Albert Tenesa, Barbara Thorand, Daniela Toniolo, Laufey Tryggvadóttir, Kim Tsui, Sheila Ulivi, Rob M Van Dam, Yvonne T van der Schouw, Carla H van Gils, Peter van Nierop, Jacqueline M Vink, Peter M Visscher, Marlies Voorhuis, Gérard Waeber, Henri Wallaschofski, H Erich Wichmann, Elisabeth Widén, Colette J M Wijnands-van Gent, Gonneke Willemsen, James F Wilson, Bruce H R Wolffenbuttel, Alan F Wright, Laura M Yerges-Armstrong, Tatijana Zemunik, Lina Zgaga, M Carola Zillikens, Marek Zygmunt, The Lifelines Cohort Study, Alice M Arnold, Dorret I Boomsma, Julie E Buring, Laura Crisponi, Ellen W Demerath, Vilmundur Gudnason, Tamara B Harris, Frank B Hu, David J Hunter, Lenore J Launer, Andres Metspalu, Grant W Montgomery, Ben A Oostra, Paul M Ridker, Serena Sanna, David Schlessinger, Tim D Spector, Kari Stefansson, Elizabeth A Streeten, Unnur Thorsteinsdottir, Manuela Uda, André G Uitterlinden, Cornelia M van Duijn, Henry Völzke, Anna Murray, Joanne M Murabito, Jenny A Visser, Kathryn L Lunetta.
Nat. Genet.
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To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-?B signaling and mitochondrial dysfunction as biological processes related to timing of menopause.
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