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Find video protocols related to scientific articles indexed in Pubmed.
Rare mutations associating with serum creatinine and chronic kidney disease.
Hum. Mol. Genet.
PUBLISHED: 07-31-2014
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Chronic kidney disease (CKD) is a complex disorder with a strong genetic component. A number of common sequence variants have been found to associate with serum creatinine (SCr), estimated glomerular filtration rate (eGFR) and/or CKD. We imputed 24 million single-nucleotide polymorphisms and insertions/deletions identified by whole-genome sequencing of 2230 Icelanders into 81 656 chip-typed individuals and 112 630 relatives of genotyped individuals over the age of 18 with SCr measurements. The large set of sequenced individuals allowed accurate imputation of variants to a minor allele frequency (MAF) of 0.1%. We tested the imputed variants for association with SCr. In addition to replicating established loci, we discovered missense and loss-of-function variants associating with SCr in three solute carriers (SLC6A19, SLC25A45 and SLC47A1) and two E3 ubiquitin ligases (RNF186 and RNF128). All the variants are within coding sequences and all but one are rare (MAF <2%) with SCr effects between 0.085 and 0.129 standard deviations. These rare variants have a larger effect on SCr than previously reported common variants, explaining 0.5% of the variability of SCr in Icelanders in addition to the 1% already accounted for. We tested the five variants associating with SCr for association with CKD in an Icelandic sample of 15 594 cases and 291 428 controls. Three of the variants also associated with CKD. These variants may either affect kidney function or creatinine synthesis and excretion. Of note were four mutations in SLC6A19 that associate with reduced SCr, three of which have been shown to cause Hartnup disease.
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Nationwide study on hypertrophic cardiomyopathy in Iceland: evidence of a MYBPC3 founder mutation.
Circulation
PUBLISHED: 07-30-2014
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The geographic isolation and homogeneous population of Iceland are ideally suited to ascertain clinical and genetic characteristics of hypertrophic cardiomyopathy (HCM) at the population level.
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Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.
John R B Perry, Felix Day, Cathy E Elks, Patrick Sulem, Deborah J Thompson, Teresa Ferreira, Chunyan He, Daniel I Chasman, Tonu Esko, Gudmar Thorleifsson, Eva Albrecht, Wei Q Ang, Tanguy Corre, Diana L Cousminer, Bjarke Feenstra, Nora Franceschini, Andrea Ganna, Andrew D Johnson, Sanela Kjellqvist, Kathryn L Lunetta, George McMahon, Ilja M Nolte, Lavinia Paternoster, Eleonora Porcu, Albert V Smith, Lisette Stolk, Alexander Teumer, Natalia Tšernikova, Emmi Tikkanen, Sheila Ulivi, Erin K Wagner, Najaf Amin, Laura J Bierut, Enda M Byrne, Jouke-Jan Hottenga, Daniel L Koller, Massimo Mangino, Tune H Pers, Laura M Yerges-Armstrong, Jing Hua Zhao, Irene L Andrulis, Hoda Anton-Culver, Femke Atsma, Stefania Bandinelli, Matthias W Beckmann, Javier Benitez, Carl Blomqvist, Stig E Bojesen, Manjeet K Bolla, Bernardo Bonanni, Hiltrud Brauch, Hermann Brenner, Julie E Buring, Jenny Chang-Claude, Stephen Chanock, Jinhui Chen, Georgia Chenevix-Trench, J Margriet Collée, Fergus J Couch, David Couper, Andrea D Coviello, Angela Cox, Kamila Czene, Adamo Pio D'adamo, George Davey Smith, Immaculata De Vivo, Ellen W Demerath, Joe Dennis, Peter Devilee, Aida K Dieffenbach, Alison M Dunning, Gudny Eiriksdottir, Johan G Eriksson, Peter A Fasching, Luigi Ferrucci, Dieter Flesch-Janys, Henrik Flyger, Tatiana Foroud, Lude Franke, Melissa E Garcia, Montserrat Garcia-Closas, Frank Geller, Eco E J de Geus, Graham G Giles, Daniel F Gudbjartsson, Vilmundur Gudnason, Pascal Guénel, Suiqun Guo, Per Hall, Ute Hamann, Robin Haring, Catharina A Hartman, Andrew C Heath, Albert Hofman, Maartje J Hooning, John L Hopper, Frank B Hu, David J Hunter, David Karasik, Douglas P Kiel, Julia A Knight, Veli-Matti Kosma, Zoltan Kutalik, Sandra Lai, Diether Lambrechts, Annika Lindblom, Reedik Mägi, Patrik K Magnusson, Arto Mannermaa, Nicholas G Martin, Gisli Masson, Patrick F McArdle, Wendy L McArdle, Mads Melbye, Kyriaki Michailidou, Evelin Mihailov, Lili Milani, Roger L Milne, Heli Nevanlinna, Patrick Neven, Ellen A Nohr, Albertine J Oldehinkel, Ben A Oostra, Aarno Palotie, Munro Peacock, Nancy L Pedersen, Paolo Peterlongo, Julian Peto, Paul D P Pharoah, Dirkje S Postma, Anneli Pouta, Katri Pylkäs, Paolo Radice, Susan Ring, Fernando Rivadeneira, Antonietta Robino, Lynda M Rose, Anja Rudolph, Veikko Salomaa, Serena Sanna, David Schlessinger, Marjanka K Schmidt, Mellissa C Southey, Ulla Sovio, Meir J Stampfer, Doris Stöckl, Anna M Storniolo, Nicholas J Timpson, Jonathan Tyrer, Jenny A Visser, Peter Vollenweider, Henry Völzke, Gérard Waeber, Melanie Waldenberger, Henri Wallaschofski, Qin Wang, Gonneke Willemsen, Robert Winqvist, Bruce H R Wolffenbuttel, Margaret J Wright, , Dorret I Boomsma, Michael J Econs, Kay-Tee Khaw, Ruth J F Loos, Mark I McCarthy, Grant W Montgomery, John P Rice, Elizabeth A Streeten, Unnur Thorsteinsdottir, Cornelia M van Duijn, Behrooz Z Alizadeh, Sven Bergmann, Eric Boerwinkle, Heather A Boyd, Laura Crisponi, Paolo Gasparini, Christian Gieger, Tamara B Harris, Erik Ingelsson, Marjo-Riitta Järvelin, Peter Kraft, Debbie Lawlor, Andres Metspalu, Craig E Pennell, Paul M Ridker, Harold Snieder, Thorkild I A Sørensen, Tim D Spector, David P Strachan, André G Uitterlinden, Nicholas J Wareham, Elisabeth Widén, Marek Zygmunt, Anna Murray, Douglas F Easton, Kari Stefansson, Joanne M Murabito, Ken K Ong.
Nature
PUBLISHED: 05-30-2014
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Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P?
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Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.
Dan E Arking, Sara L Pulit, Lia Crotti, Pim van der Harst, Patricia B Munroe, Tamara T Koopmann, Nona Sotoodehnia, Elizabeth J Rossin, Michael Morley, Xinchen Wang, Andrew D Johnson, Alicia Lundby, Daniel F Gudbjartsson, Peter A Noseworthy, Mark Eijgelsheim, Yuki Bradford, Kirill V Tarasov, Marcus Dörr, Martina Müller-Nurasyid, Annukka M Lahtinen, Ilja M Nolte, Albert Vernon Smith, Joshua C Bis, Aaron Isaacs, Stephen J Newhouse, Daniel S Evans, Wendy S Post, Daryl Waggott, Leo-Pekka Lyytikäinen, Andrew A Hicks, Lewin Eisele, David Ellinghaus, Caroline Hayward, Pau Navarro, Sheila Ulivi, Toshiko Tanaka, David J Tester, Stéphanie Chatel, Stefan Gustafsson, Meena Kumari, Richard W Morris, Asa T Naluai, Sandosh Padmanabhan, Alexander Kluttig, Bernhard Strohmer, Andrie G Panayiotou, Maria Torres, Michael Knoflach, Jaroslav A Hubacek, Kamil Slowikowski, Soumya Raychaudhuri, Runjun D Kumar, Tamara B Harris, Lenore J Launer, Alan R Shuldiner, Alvaro Alonso, Joel S Bader, Georg Ehret, Hailiang Huang, W H Linda Kao, James B Strait, Peter W Macfarlane, Morris Brown, Mark J Caulfield, Nilesh J Samani, Florian Kronenberg, Johann Willeit, , J Gustav Smith, Karin H Greiser, Henriette Meyer zu Schwabedissen, Karl Werdan, Massimo Carella, Leopoldo Zelante, Susan R Heckbert, Bruce M Psaty, Jerome I Rotter, Ivana Kolčić, Ozren Polašek, Alan F Wright, Maura Griffin, Mark J Daly, David O Arnar, Hilma Holm, Unnur Thorsteinsdottir, Joshua C Denny, Dan M Roden, Rebecca L Zuvich, Valur Emilsson, Andrew S Plump, Martin G Larson, Christopher J O'Donnell, Xiaoyan Yin, Marco Bobbo, Adamo P d'Adamo, AnnaMaria Iorio, Gianfranco Sinagra, Angel Carracedo, Steven R Cummings, Michael A Nalls, Antti Jula, Kimmo K Kontula, Annukka Marjamaa, Lasse Oikarinen, Markus Perola, Kimmo Porthan, Raimund Erbel, Per Hoffmann, Karl-Heinz Jöckel, Hagen Kälsch, Markus M Nöthen, Marcel den Hoed, Ruth J F Loos, Dag S Thelle, Christian Gieger, Thomas Meitinger, Siegfried Perz, Annette Peters, Hanna Prucha, Moritz F Sinner, Melanie Waldenberger, Rudolf A de Boer, Lude Franke, Pieter A van der Vleuten, Britt Maria Beckmann, Eimo Martens, Abdennasser Bardai, Nynke Hofman, Arthur A M Wilde, Elijah R Behr, Chrysoula Dalageorgou, John R Giudicessi, Argelia Medeiros-Domingo, Julien Barc, Florence Kyndt, Vincent Probst, Alice Ghidoni, Roberto Insolia, Robert M Hamilton, Stephen W Scherer, Jeffrey Brandimarto, Kenneth Margulies, Christine E Moravec, Fabiola Del Greco M, Christian Fuchsberger, Jeffrey R O'Connell, Wai K Lee, Graham C M Watt, Harry Campbell, Sarah H Wild, Nour E El Mokhtari, Norbert Frey, Folkert W Asselbergs, Irene Mateo Leach, Gerjan Navis, Maarten P van den Berg, Dirk J van Veldhuisen, Manolis Kellis, Bouwe P Krijthe, Oscar H Franco, Albert Hofman, Jan A Kors, André G Uitterlinden, Jacqueline C M Witteman, Lyudmyla Kedenko, Claudia Lamina, Ben A Oostra, Gonçalo R Abecasis, Edward G Lakatta, Antonella Mulas, Marco Orrù, David Schlessinger, Manuela Uda, Marcello R P Markus, Uwe Völker, Harold Snieder, Timothy D Spector, Johan Arnlöv, Lars Lind, Johan Sundström, Ann-Christine Syvänen, Mika Kivimäki, Mika Kähönen, Nina Mononen, Olli T Raitakari, Jorma S Viikari, Vera Adamkova, Stefan Kiechl, María Brión, Andrew N Nicolaides, Bernhard Paulweber, Johannes Haerting, Anna F Dominiczak, Fredrik Nyberg, Peter H Whincup, Aroon D Hingorani, Jean-Jacques Schott, Connie R Bezzina, Erik Ingelsson, Luigi Ferrucci, Paolo Gasparini, James F Wilson, Igor Rudan, Andre Franke, Thomas W Mühleisen, Peter P Pramstaller, Terho J Lehtimäki, Andrew D Paterson, Afshin Parsa, Yongmei Liu, Cornelia M van Duijn, David S Siscovick, Vilmundur Gudnason, Yalda Jamshidi, Veikko Salomaa, Stephan B Felix, Serena Sanna, Marylyn D Ritchie, Bruno H Stricker, Kari Stefansson, Laurie A Boyer, Thomas P Cappola, Jesper V Olsen, Kasper Lage, Peter J Schwartz, Stefan Kääb, Aravinda Chakravarti, Michael J Ackerman, Arne Pfeufer, Paul I W de Bakker, Christopher Newton-Cheh.
Nat. Genet.
PUBLISHED: 05-29-2014
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The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ?8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
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Genome-wide association study yields variants at 20p12.2 that associate with urinary bladder cancer.
Hum. Mol. Genet.
PUBLISHED: 05-26-2014
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Genome-wide association studies (GWAS) of urinary bladder cancer (UBC) have yielded common variants at 12 loci that associate with risk of the disease. We report here the results of a GWAS of UBC including 1670 UBC cases and 90 180 controls, followed by replication analysis in additional 5266 UBC cases and 10 456 controls. We tested a dataset containing 34.2 million variants, generated by imputation based on whole-genome sequencing of 2230 Icelanders. Several correlated variants at 20p12, represented by rs62185668, show genome-wide significant association with UBC after combining discovery and replication results (OR = 1.19, P = 1.5 × 10(-11) for rs62185668-A, minor allele frequency = 23.6%). The variants are located in a non-coding region approximately 300 kb upstream from the JAG1 gene, an important component of the Notch signaling pathways that may be oncogenic or tumor suppressive in several forms of cancer. Our results add to the growing number of UBC risk variants discovered through GWAS.
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Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.
Nat. Genet.
PUBLISHED: 02-10-2014
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Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.
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Germline sequence variants in TGM3 and RGS22 confer risk of basal cell carcinoma.
Hum. Mol. Genet.
PUBLISHED: 01-08-2014
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To search for new sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conducted a genome-wide association study of 38.5 million single nucleotide polymorphisms (SNPs) and small indels identified through whole-genome sequencing of 2230 Icelanders. We imputed genotypes for 4208 BCC patients and 109 408 controls using Illumina SNP chip typing data, carried out association tests and replicated the findings in independent population samples. We found new BCC susceptibility loci at TGM3 (rs214782[G], P = 5.5 × 10(-17), OR = 1.29) and RGS22 (rs7006527[C], P = 8.7 × 10(-13), OR = 0.77). TGM3 encodes transglutaminase type 3, which plays a key role in production of the cornified envelope during epidermal differentiation.
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Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes.
Nat. Genet.
PUBLISHED: 01-06-2014
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Through whole-genome sequencing of 2,630 Icelanders and imputation into 11,114 Icelandic cases and 267,140 controls followed by testing in Danish and Iranian samples, we discovered 4 previously unreported variants affecting risk of type 2 diabetes (T2D). A low-frequency (1.47%) variant in intron 1 of CCND2, rs76895963[G], reduces risk of T2D by half (odds ratio (OR) = 0.53, P = 5.0 × 10(-21)) and is correlated with increased CCND2 expression. Notably, this variant is also associated with both greater height and higher body mass index (1.17 cm per allele, P = 5.5 × 10(-12) and 0.56 kg/m(2) per allele, P = 6.5 × 10(-7), respectively). In addition, two missense variants in PAM, encoding p.Asp563Gly (frequency of 4.98%) and p.Ser539Trp (frequency of 0.65%), confer moderately higher risk of T2D (OR = 1.23, P = 3.9 × 10(-10) and OR = 1.47, P = 1.7 × 10(-5), respectively), and a rare (0.20%) frameshift variant in PDX1, encoding p.Gly218Alafs*12, associates with high risk of T2D (OR = 2.27, P = 7.3 × 10(-7)).
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A method for detecting long non-coding RNAs with tiled RNA expression microarrays.
PLoS ONE
PUBLISHED: 01-01-2014
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Long non-coding ribonucleic acids (lncRNAs) have been proposed as biomarkers in prostate cancer. This paper proposes a selection method which uses data from tiled microarrays to identify relatively long regions of moderate expression independent of the microarray platform and probe design. The method is used to search for candidate long non-coding ribonucleic acids (lncRNAs) at locus 8q24 and is run on three independent experiments which all use samples from prostate cancer patients. The robustness of the method is tested by utilizing repeated copies of tiled probes. The method shows high consistency between experiments that used the same samples, but different probe layout. There also is statistically significant consistency when comparing experiments with different samples. The method selected the long non-coding ribonucleic acid PCNCR1 in all three experiments.
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A common variant at 8q24.21 is associated with renal cell cancer.
Nat Commun
PUBLISHED: 07-05-2013
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Renal cell carcinoma (RCC) represents between 80 and 90% of kidney cancers. Previous genome-wide association studies of RCC have identified five variants conferring risk of the disease. Here we report the results from a discovery RCC genome-wide association study and replication analysis, including a total of 2,411 patients and 71,497 controls. One variant, rs35252396[CG] located at 8q24.21, is significantly associated with RCC after combining discovery and replication results (OR=1.27, P(combined)=5.4 × 10(-11)) and has an average risk allele frequency in controls of 46%. rs35252396[CG] does not have any strongly correlated variants in the genome and is located within a region predicted to have regulatory functions in several cell lines, including six originating from the kidney. This is the first RCC variant reported at 8q24.21 and it is largely independent (r(2)?0.02) of the numerous previously reported cancer risk variants at this locus.
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Genetic architecture of vitamin B12 and folate levels uncovered applying deeply sequenced large datasets.
PLoS Genet.
PUBLISHED: 06-01-2013
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Genome-wide association studies have mainly relied on common HapMap sequence variations. Recently, sequencing approaches have allowed analysis of low frequency and rare variants in conjunction with common variants, thereby improving the search for functional variants and thus the understanding of the underlying biology of human traits and diseases. Here, we used a large Icelandic whole genome sequence dataset combined with Danish exome sequence data to gain insight into the genetic architecture of serum levels of vitamin B(12) (B12) and folate. Up to 22.9 million sequence variants were analyzed in combined samples of 45,576 and 37,341 individuals with serum B(12) and folate measurements, respectively. We found six novel loci associating with serum B(12) (CD320, TCN2, ABCD4, MMAA, MMACHC) or folate levels (FOLR3) and confirmed seven loci for these traits (TCN1, FUT6, FUT2, CUBN, CLYBL, MUT, MTHFR). Conditional analyses established that four loci contain additional independent signals. Interestingly, 13 of the 18 identified variants were coding and 11 of the 13 target genes have known functions related to B(12) and folate pathways. Contrary to epidemiological studies we did not find consistent association of the variants with cardiovascular diseases, cancers or Alzheimers disease although some variants demonstrated pleiotropic effects. Although to some degree impeded by low statistical power for some of these conditions, these data suggest that sequence variants that contribute to the population diversity in serum B(12) or folate levels do not modify the risk of developing these conditions. Yet, the study demonstrates the value of combining whole genome and exome sequencing approaches to ascertain the genetic and molecular architectures underlying quantitative trait associations.
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Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits.
Nature
PUBLISHED: 03-27-2013
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Low bone mineral density (BMD) is used as a parameter of osteoporosis. Genome-wide association studies of BMD have hitherto focused on BMD as a quantitative trait, yielding common variants of small effects that contribute to the population diversity in BMD. Here we use BMD as a dichotomous trait, searching for variants that may have a direct effect on the risk of pathologically low BMD rather than on the regulation of BMD in the healthy population. Through whole-genome sequencing of Icelandic individuals, we found a rare nonsense mutation within the leucine-rich-repeat-containing G-protein-coupled receptor 4 (LGR4) gene (c.376C>T) that is strongly associated with low BMD, and with osteoporotic fractures. This mutation leads to termination of LGR4 at position 126 and fully disrupts its function. The c.376C>T mutation is also associated with electrolyte imbalance, late onset of menarche and reduced testosterone levels, as well as an increased risk of squamous cell carcinoma of the skin and biliary tract cancer. Interestingly, the phenotype of carriers of the c.376C>T mutation overlaps that of Lgr4 mutant mice.
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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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Common and low-frequency variants associated with genome-wide recombination rate.
Nat. Genet.
PUBLISHED: 03-18-2013
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Meiotic recombination contributes to genetic diversity by yielding new combinations of alleles. Individuals vary with respect to the genome-wide recombination counts in their gametes. Exploiting data resources in Iceland, we compiled a data set consisting of 35,927 distinct parents and 71,929 parent-offspring pairs. Within this data set, we called over 2.2 million recombination events and imputed variants with sequence-level resolution from 2,261 whole genome-sequenced individuals into the parents to search for variants influencing recombination rate. We identified 13 variants in 8 regions that are associated with genome-wide recombination rate, 8 of which were previously unknown. Three of these variants associate with male recombination rate only, seven variants associate with female recombination rate only and three variants affect both. Two are low-frequency variants with large effects, one of which is estimated to increase the male and female genetic maps by 111 and 416 cM, respectively. This variant, located in an intron, would not be found by exome sequencing.
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A rare nonsynonymous sequence variant in C3 is associated with high risk of age-related macular degeneration.
Nat. Genet.
PUBLISHED: 01-24-2013
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Through whole-genome sequencing of 2,230 Icelanders, we detected a rare nonsynonymous SNP (minor allele frequency = 0.55%) in the C3 gene encoding a p.Lys155Gln substitution in complement factor 3, which, following imputation into a set of Icelandic cases with age-related macular degeneration (AMD) and controls, associated with disease (odds ratio (OR) = 3.45; P = 1.1 × 10(-7)). This signal is independent of the previously reported common SNPs in C3 encoding p.Pro314Leu and p.Arg102Gly that associate with AMD. The association of p.Lys155Gln was replicated in AMD case-control samples of European ancestry with OR = 4.22 and P = 1.6 × 10(-10), resulting in OR = 3.65 and P = 8.8 × 10(-16) for all studies combined. In vitro studies have suggested that the p.Lys155Gln substitution reduces C3b binding to complement factor H, potentially creating resistance to inhibition by this factor. This resistance to inhibition in turn is predicted to result in enhanced complement activation.
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Mutations in BRIP1 confer high risk of ovarian cancer.
Nat. Genet.
PUBLISHED: 08-01-2011
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Ovarian cancer causes more deaths than any other gynecologic malignancy in developed countries. Sixteen million sequence variants, identified through whole-genome sequencing of 457 Icelanders, were imputed to 41,675 Icelanders genotyped using SNP chips, as well as to their relatives. Sequence variants were tested for association with ovarian cancer (N of affected individuals = 656). We discovered a rare (0.41% allelic frequency) frameshift mutation, c.2040_2041insTT, in the BRIP1 (FANCJ) gene that confers an increase in ovarian cancer risk (odds ratio (OR) = 8.13, P = 2.8 × 10(-14)). The mutation was also associated with increased risk of cancer in general and reduced lifespan by 3.6 years. In a Spanish population, another frameshift mutation in BRIP1, c.1702_1703del, was seen in 2 out of 144 subjects with ovarian cancer and 1 out of 1,780 control subjects (P = 0.016). This allele was also associated with breast cancer (seen in 6/927 cases; P = 0.0079). Ovarian tumors from heterozygous carriers of the Icelandic mutation show loss of the wild-type allele, indicating that BRIP1 behaves like a classical tumor suppressor gene in ovarian cancer.
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European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene.
Hum. Mol. Genet.
PUBLISHED: 07-12-2011
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Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 × 10(-11). SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidneys ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the urogenous contact hypothesis that urine production and voiding frequency modify the risk of UBC.
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An algorithm for detecting high frequency copy number polymorphisms using SNP arrays.
J. Comput. Biol.
PUBLISHED: 07-05-2011
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We present a general algorithm for the detection of genomic variants using the Illumina iSelect platform. The Illumina iSelect platform is designed to detect SNPs, but our algorithm allows for the detections of more general forms of variations, including copy number polymorphisms and microsatellites. The algorithm does not rely on a priori information of the type of polymorphism being studied and is designed to genotype call a large number of individuals simultaneously. The algorithm proceeds by initially normalizing intensity and correcting for batch effects. Then each marker is clustered using a modified Gaussian mixture model where we account for variances in the expression of an individuals and the variance measured in bead level intensities of a probe/marker pair. Finally, these clusters are used to determine genotypes. The algorithm was then run on a dataset of 35,000 Icelandic individuals.
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A germline variant in the TP53 polyadenylation signal confers cancer susceptibility.
Simon N Stacey, Patrick Sulem, Aslaug Jonasdottir, Gisli Masson, Julius Gudmundsson, Daniel F Gudbjartsson, Olafur T Magnusson, Sigurjon A Gudjonsson, Bardur Sigurgeirsson, Kristin Thorisdottir, Rafn Ragnarsson, Kristrun R Benediktsdottir, Bjørn A Nexø, Anne Tjønneland, Kim Overvad, Peter Rudnai, Eugene Gurzau, Kvetoslava Koppova, Kari Hemminki, Cristina Corredera, Victoria Fuentelsaz, Pilar Grasa, Sebastian Navarrete, Fernando Fuertes, Maria D Garcia-Prats, Enrique Sanambrosio, Angeles Panadero, Ana De Juan, Almudena García, Fernando Rivera, Dolores Planelles, Virtudes Soriano, Celia Requena, Katja K Aben, Michelle M van Rossum, Ruben G H M Cremers, Inge M van Oort, Dick-Johan van Spronsen, Jack A Schalken, Wilbert H M Peters, Brian T Helfand, Jenny L Donovan, Freddie C Hamdy, Daniel Badescu, Ovidiu Codreanu, Mariana Jinga, Irma E Csiki, Vali Constantinescu, Paula Badea, Ioan N Mates, Daniela E Dinu, Adrian Constantin, Dana Mates, Sjofn Kristjansdottir, Bjarni A Agnarsson, Eirikur Jonsson, Rosa B Barkardottir, Gudmundur V Einarsson, Fridbjorn Sigurdsson, Pall H Moller, Tryggvi Stefansson, Trausti Valdimarsson, Oskar T Johannsson, Helgi Sigurdsson, Thorvaldur Jonsson, Jon G Jonasson, Laufey Tryggvadóttir, Terri Rice, Helen M Hansen, Yuanyuan Xiao, Daniel H Lachance, Brian Patrick O Neill, Matthew L Kosel, Paul A Decker, Gudmar Thorleifsson, Hrefna Johannsdottir, Hafdis T Helgadottir, Asgeir Sigurdsson, Valgerdur Steinthorsdottir, Annika Lindblom, , Robert S Sandler, Temitope O Keku, Karina Banasik, Torben Jørgensen, Daniel R Witte, Torben Hansen, Oluf Pedersen, Viorel Jinga, David E Neal, William J Catalona, Margaret Wrensch, John Wiencke, Robert B Jenkins, Eduardo Nagore, Ulla Vogel, Lambertus A Kiemeney, Rajiv Kumar, Jose I Mayordomo, Jon H Olafsson, Augustine Kong, Unnur Thorsteinsdottir, Thorunn Rafnar, Kari Stefansson.
Nat. Genet.
PUBLISHED: 05-27-2011
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To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 × 10(-17)), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 × 10(-20)). rs78378222 is in the 3 untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 × 10(-6)), glioma (OR = 2.35, P = 1.0 × 10(-5)) and colorectal adenoma (OR = 1.39, P = 1.6 × 10(-4)). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).
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Identification of low-frequency variants associated with gout and serum uric acid levels.
Nat. Genet.
PUBLISHED: 05-10-2011
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We tested 16 million SNPs, identified through whole-genome sequencing of 457 Icelanders, for association with gout and serum uric acid levels. Genotypes were imputed into 41,675 chip-genotyped Icelanders and their relatives, for effective sample sizes of 968 individuals with gout and 15,506 individuals for whom serum uric acid measurements were available. We identified a low-frequency missense variant (c.1580C>G) in ALDH16A1 associated with gout (OR = 3.12, P = 1.5 × 10(-16), at-risk allele frequency = 0.019) and serum uric acid levels (effect = 0.36 s.d., P = 4.5 × 10(-21)). We confirmed the association with gout by performing Sanger sequencing on 6,017 Icelanders. The association with gout was stronger in males relative to females. We also found a second variant on chromosome 1 associated with gout (OR = 1.92, P = 0.046, at-risk allele frequency = 0.986) and serum uric acid levels (effect = 0.48 s.d., P = 4.5 × 10(-16)). This variant is close to a common variant previously associated with serum uric acid levels. This work illustrates how whole-genome sequencing data allow the detection of associations between low-frequency variants and complex traits.
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Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption.
Gunter Schumann, Lachlan J Coin, Anbarasu Lourdusamy, Pimphen Charoen, Karen H Berger, David Stacey, Sylvane Desrivières, Fazil A Aliev, Anokhi A Khan, Najaf Amin, Yurii S Aulchenko, Georgy Bakalkin, Stephan J Bakker, Beverley Balkau, Joline W Beulens, Ainhoa Bilbao, Rudolf A de Boer, Delphine Beury, Michiel L Bots, Elemi J Breetvelt, Stéphane Cauchi, Christine Cavalcanti-Proença, John C Chambers, Toni-Kim Clarke, Norbert Dahmen, Eco J De Geus, Danielle Dick, Francesca Ducci, Alanna Easton, Howard J Edenberg, Tonu Esko, Tõnu Esk, Alberto Fernandez-Medarde, Tatiana Foroud, Nelson B Freimer, Jean-Antoine Girault, Diederick E Grobbee, Simonetta Guarrera, Daniel F Gudbjartsson, Anna-Liisa Hartikainen, Andrew C Heath, Victor Hesselbrock, Albert Hofman, Jouke-Jan Hottenga, Matti K Isohanni, Jaakko Kaprio, Kay-Tee Khaw, Brigitte Kuehnel, Jaana Laitinen, Stéphane Lobbens, Jian'an Luan, Massimo Mangino, Matthieu Maroteaux, Giuseppe Matullo, Mark I McCarthy, Christian Mueller, Gerjan Navis, Mattijs E Numans, Alejandro Núñez, Dale R Nyholt, Charlotte N Onland-Moret, Ben A Oostra, Paul F O'Reilly, Miklós Palkovits, Brenda W Penninx, Silvia Polidoro, Anneli Pouta, Inga Prokopenko, Fulvio Ricceri, Eugenio Santos, Johannes H Smit, Nicole Soranzo, Kijoung Song, Ulla Sovio, Michael Stumvoll, Ida Surakk, Thorgeir E Thorgeirsson, Unnur Thorsteinsdottir, Claire Troakes, Thorarinn Tyrfingsson, Anke Tönjes, Cuno S Uiterwaal, André G Uitterlinden, Pim van der Harst, Yvonne T van der Schouw, Oliver Staehlin, Nicole Vogelzangs, Peter Vollenweider, Gérard Waeber, Nicholas J Wareham, Dawn M Waterworth, John B Whitfield, Erich H Wichmann, Gonneke Willemsen, Jacqueline C Witteman, Xin Yuan, Guangju Zhai, Jing H Zhao, Weihua Zhang, Nicholas G Martin, Andres Metspalu, Angela Doering, James Scott, Tim D Spector, Ruth J Loos, Dorret I Boomsma, Vincent Mooser, Leena Peltonen, Kari Stefansson, Cornelia M van Duijn, Paolo Vineis, Wolfgang H Sommer, Jaspal S Kooner, Rainer Spanagel, Ulrike A Heberlein, Marjo-Riitta Järvelin, Paul Elliott.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 04-06-2011
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Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of ?2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene (AUTS2) was associated with alcohol consumption at genome-wide significance (P = 4 × 10(-8) to P = 4 × 10(-9)). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples (P = 0.026) and significant (P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Down-regulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila (P < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.
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Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma.
John C Chambers, Weihua Zhang, Joban Sehmi, Xinzhong Li, Mark N Wass, Pim van der Harst, Hilma Holm, Serena Sanna, Maryam Kavousi, Sebastian E Baumeister, Lachlan J Coin, Guohong Deng, Christian Gieger, Nancy L Heard-Costa, Jouke-Jan Hottenga, Brigitte Kühnel, Vinod Kumar, Vasiliki Lagou, Liming Liang, Jian'an Luan, Pedro Marques Vidal, Irene Mateo Leach, Paul F O'Reilly, John F Peden, Nilufer Rahmioglu, Pasi Soininen, Elizabeth K Speliotes, Xin Yuan, Gudmar Thorleifsson, Behrooz Z Alizadeh, Larry D Atwood, Ingrid B Borecki, Morris J Brown, Pimphen Charoen, Francesco Cucca, Debashish Das, Eco J C de Geus, Anna L Dixon, Angela Döring, Georg Ehret, Gudmundur I Eyjolfsson, Martin Farrall, Nita G Forouhi, Nele Friedrich, Wolfram Goessling, Daniel F Gudbjartsson, Tamara B Harris, Anna-Liisa Hartikainen, Simon Heath, Gideon M Hirschfield, Albert Hofman, Georg Homuth, Elina Hyppönen, Harry L A Janssen, Toby Johnson, Antti J Kangas, Ido P Kema, Jens P Kühn, Sandra Lai, Mark Lathrop, Markus M Lerch, Yun Li, T Jake Liang, Jing-Ping Lin, Ruth J F Loos, Nicholas G Martin, Miriam F Moffatt, Grant W Montgomery, Patricia B Munroe, Kiran Musunuru, Yusuke Nakamura, Christopher J O'Donnell, Isleifur Olafsson, Brenda W Penninx, Anneli Pouta, Bram P Prins, Inga Prokopenko, Ralf Puls, Aimo Ruokonen, Markku J Savolainen, David Schlessinger, Jeoffrey N L Schouten, Udo Seedorf, Srijita Sen-Chowdhry, Katherine A Siminovitch, Johannes H Smit, Timothy D Spector, Wenting Tan, Tanya M Teslovich, Taru Tukiainen, André G Uitterlinden, Melanie M van der Klauw, Ramachandran S Vasan, Chris Wallace, Henri Wallaschofski, H-Erich Wichmann, Gonneke Willemsen, Peter Würtz, Chun Xu, Laura M Yerges-Armstrong, , Gonçalo R Abecasis, Kourosh R Ahmadi, Dorret I Boomsma, Mark Caulfield, William O Cookson, Cornelia M van Duijn, Philippe Froguel, Koichi Matsuda, Mark I McCarthy, Christa Meisinger, Vincent Mooser, Kirsi H Pietiläinen, Gunter Schumann, Harold Snieder, Michael J E Sternberg, Ronald P Stolk, Howard C Thomas, Unnur Thorsteinsdottir, Manuela Uda, Gérard Waeber, Nicholas J Wareham, Dawn M Waterworth, Hugh Watkins, John B Whitfield, Jacqueline C M Witteman, Bruce H R Wolffenbuttel, Caroline S Fox, Mika Ala-Korpela, Kari Stefansson, Peter Vollenweider, Henry Völzke, Eric E Schadt, James Scott, Marjo-Riitta Järvelin, Paul Elliott, Jaspal S Kooner.
Nat. Genet.
PUBLISHED: 03-08-2011
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Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10(-8) to P = 10(-190)). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function.
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Sequence variants at CYP1A1-CYP1A2 and AHR associate with coffee consumption.
Hum. Mol. Genet.
PUBLISHED: 02-28-2011
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Coffee is the most commonly used stimulant and caffeine is its main psychoactive ingredient. The heritability of coffee consumption has been estimated at around 50%. We performed a meta-analysis of four genome-wide association studies of coffee consumption among coffee drinkers from Iceland (n = 2680), The Netherlands (n = 2791), the Sorbs Slavonic population isolate in Germany (n = 771) and the USA (n = 369) using both directly genotyped and imputed single nucleotide polymorphisms (SNPs) (2.5 million SNPs). SNPs at the two most significant loci were also genotyped in a sample set from Iceland (n = 2430) and a Danish sample set consisting of pregnant women (n = 1620). Combining all data, two sequence variants significantly associated with increased coffee consumption: rs2472297-T located between CYP1A1 and CYP1A2 at 15q24 (P = 5.4 · 10(-14)) and rs6968865-T near aryl hydrocarbon receptor (AHR) at 7p21 (P = 2.3 · 10(-11)). An effect of ?0.2 cups a day per allele was observed for both SNPs. CYP1A2 is the main caffeine metabolizing enzyme and is also involved in drug metabolism. AHR detects xenobiotics, such as polycyclic aryl hydrocarbons found in roasted coffee, and induces transcription of CYP1A1 and CYP1A2. The association of these SNPs with coffee consumption was present in both smokers and non-smokers.
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A rare variant in MYH6 is associated with high risk of sick sinus syndrome.
Nat. Genet.
PUBLISHED: 02-10-2011
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Through complementary application of SNP genotyping, whole-genome sequencing and imputation in 38,384 Icelanders, we have discovered a previously unidentified sick sinus syndrome susceptibility gene, MYH6, encoding the alpha heavy chain subunit of cardiac myosin. A missense variant in this gene, c.2161C>T, results in the conceptual amino acid substitution p.Arg721Trp, has an allelic frequency of 0.38% in Icelanders and associates with sick sinus syndrome with an odds ratio = 12.53 and P = 1.5 × 10?²?. We show that the lifetime risk of being diagnosed with sick sinus syndrome is around 6% for non-carriers of c.2161C>T but is approximately 50% for carriers of the c.2161C>T variant.
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Genome-wide significant association between a sequence variant at 15q15.2 and lung cancer risk.
Cancer Res.
PUBLISHED: 02-08-2011
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Genome-wide association studies (GWAS) have identified 3 genomic regions, at 15q24-25.1, 5p15.33, and 6p21.33, which associate with the risk of lung cancer. Large meta-analyses of GWA data have failed to find additional associations of genome-wide significance. In this study, we sought to confirm 7 variants with suggestive association to lung cancer (P < 10(-5)) in a recently published meta-analysis. In a GWA dataset of 1,447 lung cancer cases and 36,256 controls in Iceland, 3 correlated variants on 15q15.2 (rs504417, rs11853991, and rs748404) showed a significant association with lung cancer, whereas rs4254535 on 2p14, rs1530057 on 3p24.1, rs6438347 on 3q13.31, and rs1926203 on 10q23.31 did not. The most significant variant, rs748404, was genotyped in an additional 1,299 lung cancer cases and 4,102 controls from the Netherlands, Spain, and the United States and the results combined with published GWAS data. In this analysis, the T allele of rs748404 reached genome-wide significance (OR = 1.15, P = 1.1 × 10(-9)). Another variant at the same locus, rs12050604, showed association with lung cancer (OR = 1.09, 3.6 × 10(-6)) and remained significant after adjustment for rs748404 and vice versa. rs748404 is located 140 kb centromeric of the TP53BP1 gene that has been implicated in lung cancer risk. Two fully correlated, nonsynonymous coding variants in TP53BP1, rs2602141 (Q1136K) and rs560191 (E353D) showed association with lung cancer in our sample set; however, this association did not remain significant after adjustment for rs748404. Our data show that 1 or more lung cancer risk variants of genome-wide significance and distinct from the coding variants in TP53BP1 are located at 15q15.2.
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Genetic correction of PSA values using sequence variants associated with PSA levels.
Sci Transl Med
PUBLISHED: 12-17-2010
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Measuring serum levels of the prostate-specific antigen (PSA) is the most common screening method for prostate cancer. However, PSA levels are affected by a number of factors apart from neoplasia. Notably, around 40% of the variability of PSA levels in the general population is accounted for by inherited factors, suggesting that it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects. To search for sequence variants that associate with PSA levels, we performed a genome-wide association study and follow-up analysis using PSA information from 15,757 Icelandic and 454 British men not diagnosed with prostate cancer. Overall, we detected a genome-wide significant association between PSA levels and single-nucleotide polymorphisms (SNPs) at six loci: 5p15.33 (rs2736098), 10q11 (rs10993994), 10q26 (rs10788160), 12q24 (rs11067228), 17q12 (rs4430796), and 19q13.33 [rs17632542 (KLK3: I179T)], each with P(combined) <3 × 10(-10). Among 3834 men who underwent a biopsy of the prostate, the 10q26, 12q24, and 19q13.33 alleles that associate with high PSA levels are associated with higher probability of a negative biopsy (odds ratio between 1.15 and 1.27). Assessment of association between the six loci and prostate cancer risk in 5325 cases and 41,417 controls from Iceland, the Netherlands, Spain, Romania, and the United States showed that the SNPs at 10q26 and 12q24 were exclusively associated with PSA levels, whereas the other four loci also were associated with prostate cancer risk. We propose that a personalized PSA cutoff value, based on genotype, should be used when deciding to perform a prostate biopsy.
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European bone mineral density loci are also associated with BMD in East-Asian populations.
PLoS ONE
PUBLISHED: 07-09-2010
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Most genome-wide association (GWA) studies have focused on populations of European ancestry with limited assessment of the influence of the sequence variants on populations of other ethnicities. To determine whether markers that we have recently shown to associate with Bone Mineral Density (BMD) in Europeans also associate with BMD in East-Asians we analysed 50 markers from 23 genomic loci in samples from Korea (n?=?1,397) and two Chinese Hong Kong sample sets (n?=?3,869 and n?=?785). Through this effort we identified fourteen loci that associated with BMD in East-Asian samples using a false discovery rate (FDR) of 0.05; 1p36 (ZBTB40, P?=?4.3×10(-9)), 1p31 (GPR177, P?=?0.00012), 3p22 (CTNNB1, P?=?0.00013), 4q22 (MEPE, P?=?0.0026), 5q14 (MEF2C, P?=?1.3×10(-5)), 6q25 (ESR1, P?=?0.0011), 7p14 (STARD3NL, P?=?0.00025), 7q21 (FLJ42280, P?=?0.00017), 8q24 (TNFRSF11B, P?=?3.4×10(-5)), 11p15 (SOX6, P?=?0.00033), 11q13 (LRP5, P?=?0.0033), 13q14 (TNFSF11, P?=?7.5×10(-5)), 16q24 (FOXL1, P?=?0.0010) and 17q21 (SOST, P?=?0.015). Our study marks an early effort towards the challenge of cataloguing bone density variants shared by many ethnicities by testing BMD variants that have been established in Europeans, in East-Asians.
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Association of variants at UMOD with chronic kidney disease and kidney stones-role of age and comorbid diseases.
PLoS Genet.
PUBLISHED: 06-23-2010
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Chronic kidney disease (CKD) is a worldwide public health problem that is associated with substantial morbidity and mortality. To search for sequence variants that associate with CKD, we conducted a genome-wide association study (GWAS) that included a total of 3,203 Icelandic cases and 38,782 controls. We observed an association between CKD and a variant with 80% population frequency, rs4293393-T, positioned next to the UMOD gene (GeneID: 7369) on chromosome 16p12 (OR = 1.25, P = 4.1x10(-10)). This gene encodes uromodulin (Tamm-Horsfall protein), the most abundant protein in mammalian urine. The variant also associates significantly with serum creatinine concentration (SCr) in Icelandic subjects (N = 24,635, P = 1.3 x 10(-23)) but not in a smaller set of healthy Dutch controls (N = 1,819, P = 0.39). Our findings validate the association between the UMOD variant and both CKD and SCr recently discovered in a large GWAS. In the Icelandic dataset, we demonstrate that the effect on SCr increases substantially with both age (P = 3.0 x 10(-17)) and number of comorbid diseases (P = 0.008). The association with CKD is also stronger in the older age groups. These results suggest that the UMOD variant may influence the adaptation of the kidney to age-related risk factors of kidney disease such as hypertension and diabetes. The variant also associates with serum urea (P = 1.0 x 10(-6)), uric acid (P = 0.0064), and suggestively with gout. In contrast to CKD, the UMOD variant confers protection against kidney stones when studied in 3,617 Icelandic and Dutch kidney stone cases and 43,201 controls (OR = 0.88, P = 5.7 x 10(-5)).
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Genome-wide meta-analysis for serum calcium identifies significantly associated SNPs near the calcium-sensing receptor (CASR) gene.
PLoS Genet.
PUBLISHED: 06-17-2010
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Calcium has a pivotal role in biological functions, and serum calcium levels have been associated with numerous disorders of bone and mineral metabolism, as well as with cardiovascular mortality. Here we report results from a genome-wide association study of serum calcium, integrating data from four independent cohorts including a total of 12,865 individuals of European and Indian Asian descent. Our meta-analysis shows that serum calcium is associated with SNPs in or near the calcium-sensing receptor (CASR) gene on 3q13. The top hit with a p-value of 6.3 x 10(-37) is rs1801725, a missense variant, explaining 1.26% of the variance in serum calcium. This SNP had the strongest association in individuals of European descent, while for individuals of Indian Asian descent the top hit was rs17251221 (p = 1.1 x 10(-21)), a SNP in strong linkage disequilibrium with rs1801725. The strongest locus in CASR was shown to replicate in an independent Icelandic cohort of 4,126 individuals (p = 1.02 x 10(-4)). This genome-wide meta-analysis shows that common CASR variants modulate serum calcium levels in the adult general population, which confirms previous results in some candidate gene studies of the CASR locus. This study highlights the key role of CASR in calcium regulation.
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Evaluating differences in linkage disequilibrium between populations.
Ann. Hum. Genet.
PUBLISHED: 06-10-2010
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We propose two methods to evaluate the statistical significance of differences in linkage disequilibrium (LD) between populations, where LD is measured by the standardised parameter D. The first method is based on bootstrapping individuals within populations in order to test LD differences for each pair of loci. Using this approach we propose a solution to the problem of testing multiple locus-pairs by means of a single test for the number of pairs that exhibit significant LD differences among populations. The second method provides the Bayesian posterior probability that one population has greater LD than the other for each locus pair. Both methods can handle genotypes with unknown phase, and are demonstrated using two data sets. For the purpose of demonstration, we apply the methods to two different sets of data from humans. First, we explore the issue of LD differences between reproductively isolated populations using a new data set of twelve Xq25 microsatellites, typed in four European populations. Second, we examine evidence for LD differences between Alzheimer cases and controls from the Icelandic population using 19 single nucleotide polymorphisms (SNPs) from a 97 kb region flanking the Apolipoprotein E (APOE) gene on chromosome 19.
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Fine-scale recombination rate differences between sexes, populations and individuals.
Nature
PUBLISHED: 05-18-2010
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Meiotic recombinations contribute to genetic diversity by yielding new combinations of alleles. Recently, high-resolution recombination maps were inferred from high-density single-nucleotide polymorphism (SNP) data using linkage disequilibrium (LD) patterns that capture historical recombination events. The use of these maps has been demonstrated by the identification of recombination hotspots and associated motifs, and the discovery that the PRDM9 gene affects the proportion of recombinations occurring at hotspots. However, these maps provide no information about individual or sex differences. Moreover, locus-specific demographic factors like natural selection can bias LD-based estimates of recombination rate. Existing genetic maps based on family data avoid these shortcomings, but their resolution is limited by relatively few meioses and a low density of markers. Here we used genome-wide SNP data from 15,257 parent-offspring pairs to construct the first recombination maps based on directly observed recombinations with a resolution that is effective down to 10 kilobases (kb). Comparing male and female maps reveals that about 15% of hotspots in one sex are specific to that sex. Although male recombinations result in more shuffling of exons within genes, female recombinations generate more new combinations of nearby genes. We discover novel associations between recombination characteristics of individuals and variants in the PRDM9 gene and we identify new recombination hotspots. Comparisons of our maps with two LD-based maps inferred from data of HapMap populations of Utah residents with ancestry from northern and western Europe (CEU) and Yoruba in Ibadan, Nigeria (YRI) reveal population differences previously masked by noise and map differences at regions previously described as targets of natural selection.
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Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies.
Cathy E Elks, John R B Perry, Patrick Sulem, Daniel I Chasman, Nora Franceschini, Chunyan He, Kathryn L Lunetta, Jenny A Visser, Enda M Byrne, Diana L Cousminer, Daniel F Gudbjartsson, Tonu Esko, Bjarke Feenstra, Jouke-Jan Hottenga, Daniel L Koller, Zoltan Kutalik, Peng Lin, Massimo Mangino, Mara Marongiu, Patrick F McArdle, Albert V Smith, Lisette Stolk, Sophie H van Wingerden, Jing Hua Zhao, Eva Albrecht, Tanguy Corre, Erik Ingelsson, Caroline Hayward, Patrik K E Magnusson, Erin N Smith, Shelia Ulivi, Nicole M Warrington, Lina Zgaga, Helen Alavere, Najaf Amin, Thor Aspelund, Stefania Bandinelli, Inês Barroso, Gerald S Berenson, Sven Bergmann, Hannah Blackburn, Eric Boerwinkle, Julie E Buring, Fabio Busonero, Harry Campbell, Stephen J Chanock, Wei Chen, Marilyn C Cornelis, David Couper, Andrea D Coviello, Pio D'Adamo, Ulf de Faire, Eco J C de Geus, Panos Deloukas, Angela Döring, George Davey Smith, Douglas F Easton, Gudny Eiriksdottir, Valur Emilsson, Johan Eriksson, Luigi Ferrucci, Aaron R Folsom, Tatiana Foroud, Melissa Garcia, Paolo Gasparini, Frank Geller, Christian Gieger, , Vilmundur Gudnason, Per Hall, Susan E Hankinson, Liana Ferreli, Andrew C Heath, Dena G Hernandez, Albert Hofman, Frank B Hu, Thomas Illig, Marjo-Riitta Järvelin, Andrew D Johnson, David Karasik, Kay-Tee Khaw, Douglas P Kiel, Tuomas O Kilpeläinen, Ivana Kolčić, Peter Kraft, Lenore J Launer, Joop S E Laven, Shengxu Li, Jianjun Liu, Daniel Levy, Nicholas G Martin, Wendy L McArdle, Mads Melbye, Vincent Mooser, Jeffrey C Murray, Sarah S Murray, Michael A Nalls, Pau Navarro, Mari Nelis, Andrew R Ness, Kate Northstone, Ben A Oostra, Munro Peacock, Lyle J Palmer, Aarno Palotie, Guillaume Paré, Alex N Parker, Nancy L Pedersen, Leena Peltonen, Craig E Pennell, Paul Pharoah, Ozren Polašek, Andrew S Plump, Anneli Pouta, Eleonora Porcu, Thorunn Rafnar, John P Rice, Susan M Ring, Fernando Rivadeneira, Igor Rudan, Cinzia Sala, Veikko Salomaa, Serena Sanna, David Schlessinger, Nicholas J Schork, Angelo Scuteri, Ayellet V Segrè, Alan R Shuldiner, Nicole Soranzo, Ulla Sovio, Sathanur R Srinivasan, David P Strachan, Mar-Liis Tammesoo, Emmi Tikkanen, Daniela Toniolo, Kim Tsui, Laufey Tryggvadóttir, Jonathon Tyrer, Manuela Uda, Rob M Van Dam, Joyce B J van Meurs, Peter Vollenweider, Gérard Waeber, Nicholas J Wareham, Dawn M Waterworth, Michael N Weedon, H Erich Wichmann, Gonneke Willemsen, James F Wilson, Alan F Wright, Lauren Young, Guangju Zhai, Wei Vivian Zhuang, Laura J Bierut, Dorret I Boomsma, Heather A Boyd, Laura Crisponi, Ellen W Demerath, Cornelia M van Duijn, Michael J Econs, Tamara B Harris, David J Hunter, Ruth J F Loos, Andres Metspalu, Grant W Montgomery, Paul M Ridker, Tim D Spector, Elizabeth A Streeten, Kari Stefansson, Unnur Thorsteinsdottir, André G Uitterlinden, Elisabeth Widén, Joanne M Murabito, Ken K Ong, Anna Murray.
Nat. Genet.
PUBLISHED: 05-10-2010
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To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10???) and 9q31.2 (P = 2.2 × 10?³³), we identified 30 new menarche loci (all P < 5 × 10??) and found suggestive evidence for a further 10 loci (P < 1.9 × 10??). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.
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Hundreds of variants clustered in genomic loci and biological pathways affect human height.
Hana Lango Allen, Karol Estrada, Guillaume Lettre, Sonja I Berndt, Michael N Weedon, Fernando Rivadeneira, Cristen J Willer, Anne U Jackson, Sailaja Vedantam, Soumya Raychaudhuri, Teresa Ferreira, Andrew R Wood, Robert J Weyant, Ayellet V Segrè, Elizabeth K Speliotes, Eleanor Wheeler, Nicole Soranzo, Ju-Hyun Park, Jian Yang, Daniel Gudbjartsson, Nancy L Heard-Costa, Joshua C Randall, Lu Qi, Albert Vernon Smith, Reedik Mägi, Tomi Pastinen, Liming Liang, Iris M Heid, Jian'an Luan, Gudmar Thorleifsson, Thomas W Winkler, Michael E Goddard, Ken Sin Lo, Cameron Palmer, Tsegaselassie Workalemahu, Yurii S Aulchenko, Asa Johansson, M Carola Zillikens, Mary F Feitosa, Tonu Esko, Toby Johnson, Shamika Ketkar, Peter Kraft, Massimo Mangino, Inga Prokopenko, Devin Absher, Eva Albrecht, Florian Ernst, Nicole L Glazer, Caroline Hayward, Jouke-Jan Hottenga, Kevin B Jacobs, Joshua W Knowles, Zoltan Kutalik, Keri L Monda, Ozren Polašek, Michael Preuss, Nigel W Rayner, Neil R Robertson, Valgerdur Steinthorsdottir, Jonathan P Tyrer, Benjamin F Voight, Fredrik Wiklund, Jianfeng Xu, Jing Hua Zhao, Dale R Nyholt, Niina Pellikka, Markus Perola, John R B Perry, Ida Surakka, Mari-Liis Tammesoo, Elizabeth L Altmaier, Najaf Amin, Thor Aspelund, Tushar Bhangale, Gabrielle Boucher, Daniel I Chasman, Constance Chen, Lachlan Coin, Matthew N Cooper, Anna L Dixon, Quince Gibson, Elin Grundberg, Ke Hao, M Juhani Junttila, Lee M Kaplan, Johannes Kettunen, Inke R König, Tony Kwan, Robert W Lawrence, Douglas F Levinson, Mattias Lorentzon, Barbara McKnight, Andrew P Morris, Martina Müller, Julius Suh Ngwa, Shaun Purcell, Suzanne Rafelt, Rany M Salem, Erika Salvi, Serena Sanna, Jianxin Shi, Ulla Sovio, John R Thompson, Michael C Turchin, Liesbeth Vandenput, Dominique J Verlaan, Veronique Vitart, Charles C White, Andreas Ziegler, Peter Almgren, Anthony J Balmforth, Harry Campbell, Lorena Citterio, Alessandro De Grandi, Anna Dominiczak, Jubao Duan, Paul Elliott, Roberto Elosua, Johan G Eriksson, Nelson B Freimer, Eco J C Geus, Nicola Glorioso, Shen Haiqing, Anna-Liisa Hartikainen, Aki S Havulinna, Andrew A Hicks, Jennie Hui, Wilmar Igl, Thomas Illig, Antti Jula, Eero Kajantie, Tuomas O Kilpeläinen, Markku Koiranen, Ivana Kolčić, Seppo Koskinen, Peter Kovacs, Jaana Laitinen, Jianjun Liu, Marja-Liisa Lokki, Ana Marušić, Andrea Maschio, Thomas Meitinger, Antonella Mulas, Guillaume Paré, Alex N Parker, John F Peden, Astrid Petersmann, Irene Pichler, Kirsi H Pietiläinen, Anneli Pouta, Martin Ridderstråle, Jerome I Rotter, Jennifer G Sambrook, Alan R Sanders, Carsten Oliver Schmidt, Juha Sinisalo, Jan H Smit, Heather M Stringham, G Bragi Walters, Elisabeth Widén, Sarah H Wild, Gonneke Willemsen, Laura Zagato, Lina Zgaga, Paavo Zitting, Helene Alavere, Martin Farrall, Wendy L McArdle, Mari Nelis, Marjolein J Peters, Samuli Ripatti, Joyce B J van Meurs, Katja K Aben, Kristin G Ardlie, Jacques S Beckmann, John P Beilby, Richard N Bergman, Sven Bergmann, Francis S Collins, Daniele Cusi, Martin den Heijer, Gudny Eiriksdottir, Pablo V Gejman, Alistair S Hall, Anders Hamsten, Heikki V Huikuri, Carlos Iribarren, Mika Kähönen, Jaakko Kaprio, Sekar Kathiresan, Lambertus Kiemeney, Thomas Kocher, Lenore J Launer, Terho Lehtimäki, Olle Melander, Tom H Mosley, Arthur W Musk, Markku S Nieminen, Christopher J O'Donnell, Claes Ohlsson, Ben Oostra, Lyle J Palmer, Olli Raitakari, Paul M Ridker, John D Rioux, Aila Rissanen, Carlo Rivolta, Heribert Schunkert, Alan R Shuldiner, David S Siscovick, Michael Stumvoll, Anke Tönjes, Jaakko Tuomilehto, Gert-Jan van Ommen, Jorma Viikari, Andrew C Heath, Nicholas G Martin, Grant W Montgomery, Michael A Province, Manfred Kayser, Alice M Arnold, Larry D Atwood, Eric Boerwinkle, Stephen J Chanock, Panos Deloukas, Christian Gieger, Henrik Grönberg, Per Hall, Andrew T Hattersley, Christian Hengstenberg, Wolfgang Hoffman, G Mark Lathrop, Veikko Salomaa, Stefan Schreiber, Manuela Uda, Dawn Waterworth, Alan F Wright, Themistocles L Assimes, Inês Barroso, Albert Hofman, Karen L Mohlke, Dorret I Boomsma, Mark J Caulfield, L Adrienne Cupples, Jeanette Erdmann, Caroline S Fox, Vilmundur Gudnason, Ulf Gyllensten, Tamara B Harris, Richard B Hayes, Marjo-Riitta Järvelin, Vincent Mooser, Patricia B Munroe, Willem H Ouwehand, Brenda W Penninx, Peter P Pramstaller, Thomas Quertermous, Igor Rudan, Nilesh J Samani, Timothy D Spector, Henry Völzke, Hugh Watkins, James F Wilson, Leif C Groop, Talin Haritunians, Frank B Hu, Robert C Kaplan, Andres Metspalu, Kari E North, David Schlessinger, Nicholas J Wareham, David J Hunter, Jeffrey R O'Connell, David P Strachan, H-Erich Wichmann, Ingrid B Borecki, Cornelia M van Duijn, Eric E Schadt, Unnur Thorsteinsdottir, Leena Peltonen, André G Uitterlinden, Peter M Visscher, Nilanjan Chatterjee, Ruth J F Loos, Michael Boehnke, Mark I McCarthy, Erik Ingelsson, Cecilia M Lindgren, Gonçalo R Abecasis, Kari Stefansson, Timothy M Frayling, Joel N Hirschhorn.
Nature
PUBLISHED: 04-23-2010
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Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P?
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A sequence variant on 17q21 is associated with age at onset and severity of asthma.
Eur. J. Hum. Genet.
PUBLISHED: 04-07-2010
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A sequence variant (rs7216389-T) near the ORMDL3 gene on chromosome 17q21 was recently found to be associated with childhood asthma. We sought to evaluate the effect of rs7216389-T on asthma subphenotypes and its correlation with expression levels of neighboring genes. The association of rs7216389-T with asthma was replicated in six European and one Asian study cohort (N=4917 cases N=34 589 controls). In addition, we found that the association of rs7216389-T was confined to cases with early onset of asthma, particularly in early childhood (age: 0-5 years OR=1.51, P=6.89.10(-9)) and adolescence (age: 14-17 years OR=1.71, P=5.47.10(-9)). A weaker association was observed for onset between 6 and 13 years of age (OR=1.17, P=0.035), but none for adult-onset asthma (OR=1.07, P=0.12). Cases were further stratified by sex, asthma severity and atopy status. An association with greater asthma severity was observed among early-onset asthma cases (P=0.0012), but no association with sex or atopy status was observed among the asthma cases. An association between sequence variants and the expression of genes in the 17q21 region was assessed in white blood cell RNA samples collected from Icelandic individuals (n=743). rs7216389 associated with the expression of GSDMB and ORMDL3 genes. However, other sequence variants showing a weaker association with asthma compared with that of rs7216389 were more strongly associated with the expression of both genes. Thus, the contribution of rs7216389-T to the development of asthma is unlikely to operate only through an impact on the expression of ORMDL3 or GSDMB genes.
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Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior.
Thorgeir E Thorgeirsson, Daniel F Gudbjartsson, Ida Surakka, Jacqueline M Vink, Najaf Amin, Frank Geller, Patrick Sulem, Thorunn Rafnar, Tonu Esko, Stefan Walter, Christian Gieger, Rajesh Rawal, Massimo Mangino, Inga Prokopenko, Reedik Mägi, Kaisu Keskitalo, Iris H Gudjonsdottir, Solveig Gretarsdottir, Hreinn Stefansson, John R Thompson, Yurii S Aulchenko, Mari Nelis, Katja K Aben, Martin den Heijer, Asger Dirksen, Haseem Ashraf, Nicole Soranzo, Ana M Valdes, Claire Steves, André G Uitterlinden, Albert Hofman, Anke Tönjes, Peter Kovacs, Jouke Jan Hottenga, Gonneke Willemsen, Nicole Vogelzangs, Angela Döring, Norbert Dahmen, Barbara Nitz, Michele L Pergadia, Berta Saez, Verónica De Diego, Victoria Lezcano, Maria D Garcia-Prats, Samuli Ripatti, Markus Perola, Johannes Kettunen, Anna-Liisa Hartikainen, Anneli Pouta, Jaana Laitinen, Matti Isohanni, Shen Huei-Yi, Maxine Allen, Maria Krestyaninova, Alistair S Hall, Gregory T Jones, Andre M van Rij, Thomas Mueller, Benjamin Dieplinger, Meinhard Haltmayer, Steinn Jonsson, Stefan E Matthiasson, Högni Oskarsson, Thorarinn Tyrfingsson, Lambertus A Kiemeney, Jose I Mayordomo, Jes S Lindholt, Jesper Holst Pedersen, Wilbur A Franklin, Holly Wolf, Grant W Montgomery, Andrew C Heath, Nicholas G Martin, Pamela A F Madden, Ina Giegling, Dan Rujescu, Marjo-Riitta Järvelin, Veikko Salomaa, Michael Stumvoll, Tim D Spector, H-Erich Wichmann, Andres Metspalu, Nilesh J Samani, Brenda W Penninx, Ben A Oostra, Dorret I Boomsma, Henning Tiemeier, Cornelia M van Duijn, Jaakko Kaprio, Jeffrey R Gulcher, , Mark I McCarthy, Leena Peltonen, Unnur Thorsteinsdottir, Kari Stefansson.
Nat. Genet.
PUBLISHED: 03-18-2010
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Smoking is a common risk factor for many diseases. We conducted genome-wide association meta-analyses for the number of cigarettes smoked per day (CPD) in smokers (n = 31,266) and smoking initiation (n = 46,481) using samples from the ENGAGE Consortium. In a second stage, we tested selected SNPs with in silico replication in the Tobacco and Genetics (TAG) and Glaxo Smith Kline (Ox-GSK) consortia cohorts (n = 45,691 smokers) and assessed some of those in a third sample of European ancestry (n = 9,040). Variants in three genomic regions associated with CPD (P < 5 x 10(-8)), including previously identified SNPs at 15q25 represented by rs1051730[A] (effect size = 0.80 CPD, P = 2.4 x 10(-69)), and SNPs at 19q13 and 8p11, represented by rs4105144[C] (effect size = 0.39 CPD, P = 2.2 x 10(-12)) and rs6474412-T (effect size = 0.29 CPD, P = 1.4 x 10(-8)), respectively. Among the genes at the two newly associated loci are genes encoding nicotine-metabolizing enzymes (CYP2A6 and CYP2B6) and nicotinic acetylcholine receptor subunits (CHRNB3 and CHRNA6), all of which have been highlighted in previous studies of smoking and nicotine dependence. Nominal associations with lung cancer were observed at both 8p11 (rs6474412[T], odds ratio (OR) = 1.09, P = 0.04) and 19q13 (rs4105144[C], OR = 1.12, P = 0.0006).
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Addictions and their familiality in Iceland.
Ann. N. Y. Acad. Sci.
PUBLISHED: 03-06-2010
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Here, we provide an overview of previous family studies of addiction and present a new family study based on clinical data for more than 19,000 individuals who have been treated for addiction in Iceland over the last three decades. Coupled with the extensive Icelandic genealogy information, this population-based sample provides a unique opportunity for family studies. The relative risk (RR) was determined for up to fifth-degree relatives of probands diagnosed with alcohol, cannabis, sedative, and amphetamine dependence. We observe highly significant RR values for all substances ranging from 2.27 for alcohol to 7.3 for amphetamine, for first-degree relatives, and RRs significantly above 1 for distant relations, where the effect of shared environmental factors is minimized. The magnitude of risk in psychostimulant dependence is particularly striking. These findings emphasize the role of genetics in the etiology of addiction and highlight the importance of substance-specific effects.
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A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer.
Nat. Genet.
PUBLISHED: 03-03-2010
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Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 x 10(-12)). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC.
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Ancestry-shift refinement mapping of the C6orf97-ESR1 breast cancer susceptibility locus.
PLoS Genet.
PUBLISHED: 01-22-2010
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We used an approach that we term ancestry-shift refinement mapping to investigate an association, originally discovered in a GWAS of a Chinese population, between rs2046210[T] and breast cancer susceptibility. The locus is on 6q25.1 in proximity to the C6orf97 and estrogen receptor alpha (ESR1) genes. We identified a panel of SNPs that are correlated with rs2046210 in Chinese, but not necessarily so in other ancestral populations, and genotyped them in breast cancer case:control samples of Asian, European, and African origin, a total of 10,176 cases and 13,286 controls. We found that rs2046210[T] does not confer substantial risk of breast cancer in Europeans and Africans (OR = 1.04, P = 0.099, and OR = 0.98, P = 0.77, respectively). Rather, in those ancestries, an association signal arises from a group of less common SNPs typified by rs9397435. The rs9397435[G] allele was found to confer risk of breast cancer in European (OR = 1.15, P = 1.2 x 10(-3)), African (OR = 1.35, P = 0.014), and Asian (OR = 1.23, P = 2.9 x 10(-4)) population samples. Combined over all ancestries, the OR was 1.19 (P = 3.9 x 10(-7)), was without significant heterogeneity between ancestries (P(het) = 0.36) and the SNP fully accounted for the association signal in each ancestry. Haplotypes bearing rs9397435[G] are well tagged by rs2046210[T] only in Asians. The rs9397435[G] allele showed associations with both estrogen receptor positive and estrogen receptor negative breast cancer. Using early-draft data from the 1,000 Genomes project, we found that the risk allele of a novel SNP (rs77275268), which is closely correlated with rs9397435, disrupts a partially methylated CpG sequence within a known CTCF binding site. These studies demonstrate that shifting the analysis among ancestral populations can provide valuable resolution in association mapping.
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Several common variants modulate heart rate, PR interval and QRS duration.
Nat. Genet.
PUBLISHED: 01-10-2010
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Electrocardiographic measures are indicative of the function of the cardiac conduction system. To search for sequence variants that modulate heart rate, PR interval and QRS duration in individuals of European descent, we performed a genome-wide association study in approximately 10,000 individuals and followed up the top signals in an additional approximately 10,000 individuals. We identified several genome-wide significant associations (with P < 1.6 x 10(-7)). We identified one locus for heart rate (MYH6), four for PR interval (TBX5, SCN10A, CAV1 and ARHGAP24) and four for QRS duration (TBX5, SCN10A, 6p21 and 10q21). We tested for association between these loci and subjects with selected arrhythmias in Icelandic and Norwegian case-control sample sets. We observed correlations between TBX5 and CAV1 and atrial fibrillation (P = 4.0 x 10(-5) and P = 0.00032, respectively), between TBX5 and advanced atrioventricular block (P = 0.0067), and between SCN10A and pacemaker implantation (P = 0.0029). We also replicated previously described associations with the QT interval.
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Parental origin of sequence variants associated with complex diseases.
Nature
PUBLISHED: 08-14-2009
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Effects of susceptibility variants may depend on from which parent they are inherited. Although many associations between sequence variants and human traits have been discovered through genome-wide associations, the impact of parental origin has largely been ignored. Here we show that for 38,167 Icelanders genotyped using single nucleotide polymorphism (SNP) chips, the parental origin of most alleles can be determined. For this we used a combination of genealogy and long-range phasing. We then focused on SNPs that associate with diseases and are within 500 kilobases of known imprinted genes. Seven independent SNP associations were examined. Five-one with breast cancer, one with basal-cell carcinoma and three with type 2 diabetes-have parental-origin-specific associations. These variants are located in two genomic regions, 11p15 and 7q32, each harbouring a cluster of imprinted genes. Furthermore, we observed a novel association between the SNP rs2334499 at 11p15 and type 2 diabetes. Here the allele that confers risk when paternally inherited is protective when maternally transmitted. We identified a differentially methylated CTCF-binding site at 11p15 and demonstrated correlation of rs2334499 with decreased methylation of that site.
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Genome-wide association study identifies sequence variants on 6q21 associated with age at menarche.
Nat. Genet.
PUBLISHED: 04-21-2009
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Earlier menarche correlates with shorter adult height and higher childhood body fat. We conducted a genome-wide association study of age at menarche (AAM) on 15,297 Icelandic women. Combined analysis with replication sets from Iceland, Denmark and the Netherlands (N = 10,040) yielded a significant association between rs314280[T] on 6q21, near the LIN28B gene, and AAM (effect = 1.2 months later per allele; P = 1.8 × 10(-14)). A second SNP within the same linkage disequilibrium (LD) block, rs314277, splits rs314280[T] into two haplotypes with different effects (0.9 months and 1.9 months per allele). These variants have been associated with greater adult height. The association with adult height did not account for the association with AAM or vice versa. Other variants, previously associated with height, did not associate significantly with AAM. Given the link between body fat and AAM, we also assessed 11 variants recently associated with higher body mass index (BMI) and 5 of those associated with earlier AAM.
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Genome-wide association and replication studies identify four variants associated with prostate cancer susceptibility.
Nat. Genet.
PUBLISHED: 03-31-2009
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We report a prostate cancer genome-wide association follow-on study. We discovered four variants associated with susceptibility to prostate cancer in several European populations: rs10934853[A] (OR = 1.12, P = 2.9 x 10(-10)) on 3q21.3; two moderately correlated (r2 = 0.07) variants, rs16902094[G] (OR = 1.21, P = 6.2 x 10(-15)) and rs445114[T] (OR = 1.14, P = 4.7 x 10(-10)), on 8q24.21; and rs8102476[C] (OR = 1.12, P = 1.6 x 10(-11)) on 19q13.2. We also refined a previous association signal on 11q13 with the SNP rs11228565[A] (OR = 1.23, P = 6.7 x 10(-12)). In a multivariate analysis using 22 prostate cancer risk variants typed in the Icelandic population, we estimated that carriers in the top 1.3% of the risk distribution are at a 2.5 times greater risk of developing the disease than members of the general population.
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A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke.
Nat. Genet.
PUBLISHED: 03-05-2009
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We expanded our genome-wide association study on atrial fibrillation (AF) in Iceland, which previously identified risk variants on 4q25, and tested the most significant associations in samples from Iceland, Norway and the United States. A variant in the ZFHX3 gene on chromosome 16q22, rs7193343-T, associated significantly with AF (odds ratio OR = 1.21, P = 1.4 x 10(-10)). This variant also associated with ischemic stroke (OR = 1.11, P = 0.00054) and cardioembolic stroke (OR = 1.22, P = 0.00021) in a combined analysis of five stroke samples.
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Sequence variants in the CLDN14 gene associate with kidney stones and bone mineral density.
Nat. Genet.
PUBLISHED: 03-04-2009
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Kidney stone disease is a common condition. To search for sequence variants conferring risk of kidney stones, we conducted a genome-wide association study in 3,773 cases and 42,510 controls from Iceland and The Netherlands. We discovered common, synonymous variants in the CLDN14 gene that associate with kidney stones (OR = 1.25 and P = 4.0 x 10(-12) for rs219780[C]). Approximately 62% of the general population is homozygous for rs219780[C] and is estimated to have 1.64 times greater risk of developing the disease compared to noncarriers. The CLDN14 gene is expressed in the kidney and regulates paracellular permeability at epithelial tight junctions. The same variants were also found to associate with reduced bone mineral density at the hip (P = 0.00039) and spine (P = 0.0077).
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New common variants affecting susceptibility to basal cell carcinoma.
Nat. Genet.
PUBLISHED: 02-03-2009
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In a follow-up to our previously reported genome-wide association study of cutaneous basal cell carcinoma (BCC), we describe here several new susceptibility variants. SNP rs11170164, encoding a G138E substitution in the keratin 5 (KRT5) gene, affects risk of BCC (OR = 1.35, P = 2.1 x 10(-9)). A variant at 9p21 near CDKN2A and CDKN2B also confers susceptibility to BCC (rs2151280[C]; OR = 1.19, P = 6.9 x 10(-9)), as does rs157935[T] at 7q32 near the imprinted gene KLF14 (OR = 1.23, P = 5.7 x 10(-10)). The effect of rs157935[T] is dependent on the parental origin of the risk allele. None of these variants were found to be associated with melanoma or fair-pigmentation traits. A melanoma- and pigmentation-associated variant in the SLC45A2 gene, L374F, is associated with risk of both BCC and squamous cell carcinoma. Finally, we report conclusive evidence that rs401681[C] in the TERT-CLPTM1L locus confers susceptibility to BCC but protects against melanoma.
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New sequence variants associated with bone mineral density.
Nat. Genet.
PUBLISHED: 01-24-2009
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In an extended genome-wide association study of bone mineral density among 6,865 Icelanders and a follow-up in 8,510 subjects of European descent, we identified four new genome-wide significant loci. These are near the SOST gene at 17q21, the MARK3 gene at 14q32, the SP7 gene at 12q13 and the TNFRSF11A (RANK) gene at 18q21. Furthermore, nonsynonymous SNPs in the C17orf53, LRP4, ADAM19 and IBSP genes were suggestively associated with bone density.
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Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity.
Nat. Genet.
PUBLISHED: 01-24-2009
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Obesity results from the interaction of genetic and environmental factors. To search for sequence variants that affect variation in two common measures of obesity, weight and body mass index (BMI), both of which are highly heritable, we performed a genome-wide association (GWA) study with 305,846 SNPs typed in 25,344 Icelandic, 2,998 Dutch, 1,890 European Americans and 1,160 African American subjects and combined the results with previously published results from the Diabetes Genetics Initiative (DGI) on 3,024 Scandinavians. We selected 43 variants in 19 regions for follow-up in 5,586 Danish individuals and compared the results to a genome-wide study on obesity-related traits from the GIANT consortium. In total, 29 variants, some correlated, in 11 chromosomal regions reached a genome-wide significance threshold of P < 1.6 x 10(-7). This includes previously identified variants close to or in the FTO, MC4R, BDNF and SH2B1 genes, in addition to variants at seven loci not previously connected with obesity.
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Sequence variants at the TERT-CLPTM1L locus associate with many cancer types.
Thorunn Rafnar, Patrick Sulem, Simon N Stacey, Frank Geller, Julius Gudmundsson, Asgeir Sigurdsson, Margret Jakobsdottir, Hafdis Helgadottir, Steinunn Thorlacius, Katja K H Aben, Thorarinn Blondal, Thorgeir E Thorgeirsson, Gudmar Thorleifsson, Kristleifur Kristjansson, Kristin Thorisdottir, Rafn Ragnarsson, Bardur Sigurgeirsson, Halla Skuladottir, Tomas Gudbjartsson, Helgi J Isaksson, Gudmundur V Einarsson, Kristrun R Benediktsdottir, Bjarni A Agnarsson, Karl Olafsson, Anna Salvarsdottir, Hjördis Bjarnason, Margret Asgeirsdottir, Kari T Kristinsson, Sigurborg Matthiasdottir, Steinunn G Sveinsdottir, Silvia Polidoro, Veronica Höiom, Rafael Botella-Estrada, Kari Hemminki, Peter Rudnai, D Timothy Bishop, Marcello Campagna, Eliane Kellen, Maurice P Zeegers, Petra de Verdier, Ana Ferrer, Dolores Isla, Maria Jesus Vidal, Raquel Andrés, Berta Saez, Pablo Juberias, Javier Banzo, Sebastian Navarrete, Alejandro Tres, Donghui Kan, Annika Lindblom, Eugene Gurzau, Kvetoslava Koppova, Femmie de Vegt, Jack A Schalken, Henricus F M van der Heijden, Hans J Smit, René A Termeer, Egbert Oosterwijk, Onno van Hooij, Eduardo Nagore, Stefano Porru, Gunnar Steineck, Johan Hansson, Frank Buntinx, William J Catalona, Giuseppe Matullo, Paolo Vineis, Anne E Kiltie, Jose I Mayordomo, Rajiv Kumar, Lambertus A Kiemeney, Michael L Frigge, Thorvaldur Jonsson, Hafsteinn Saemundsson, Rosa B Barkardottir, Eirikur Jonsson, Steinn Jonsson, Jon H Olafsson, Jeffrey R Gulcher, Gisli Masson, Daniel F Gudbjartsson, Augustine Kong, Unnur Thorsteinsdottir, Kari Stefansson.
Nat. Genet.
PUBLISHED: 01-18-2009
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The common sequence variants that have recently been associated with cancer risk are particular to a single cancer type or at most two. Following up on our genome-wide scan of basal cell carcinoma, we found that rs401681[C] on chromosome 5p15.33 satisfied our threshold for genome-wide significance (OR = 1.25, P = 3.7 x 10(-12)). We tested rs401681 for association with 16 additional cancer types in over 30,000 cancer cases and 45,000 controls and found association with lung cancer (OR = 1.15, P = 7.2 x 10(-8)) and urinary bladder, prostate and cervix cancer (ORs = 1.07-1.31, all P < 4 x 10(-4)). However, rs401681[C] seems to confer protection against cutaneous melanoma (OR = 0.88, P = 8.0 x 10(-4)). Notably, most of these cancer types have a strong environmental component to their risk. Investigation of the region led us to rs2736098[A], which showed stronger association with some cancer types. However, neither variant could fully account for the association of the other. rs2736098 corresponds to A305A in the telomerase reverse transcriptase (TERT) protein and rs401681 is in an intron of the CLPTM1L gene.
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Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations.
Nat. Genet.
PUBLISHED: 01-05-2009
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In order to search for sequence variants conferring risk of thyroid cancer we conducted a genome-wide association study in 192 and 37,196 Icelandic cases and controls, respectively, followed by a replication study in individuals of European descent. Here we show that two common variants, located on 9q22.33 and 14q13.3, are associated with the disease. Overall, the strongest association signals were observed for rs965513 on 9q22.33 (OR = 1.75; P = 1.7 x 10(-27)) and rs944289 on 14q13.3 (OR = 1.37; P = 2.0 x 10(-9)). The gene nearest to the 9q22.33 locus is FOXE1 (TTF2) and NKX2-1 (TTF1) is among the genes located at the 14q13.3 locus. Both variants contribute to an increased risk of both papillary and follicular thyroid cancer. Approximately 3.7% of individuals are homozygous for both variants, and their estimated risk of thyroid cancer is 5.7-fold greater than that of noncarriers. In a study on a large sample set from the general population, both risk alleles are associated with low concentrations of thyroid stimulating hormone (TSH), and the 9q22.33 allele is associated with low concentration of thyroxin (T(4)) and high concentration of triiodothyronine (T(3)).
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Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction.
Nat. Genet.
PUBLISHED: 01-05-2009
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Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of inflammatory responses and thus have important roles in the pathogenesis of inflammatory diseases. Here we describe a genome-wide association scan for sequence variants affecting eosinophil counts in blood of 9,392 Icelanders. The most significant SNPs were studied further in 12,118 Europeans and 5,212 East Asians. SNPs at 2q12 (rs1420101), 2q13 (rs12619285), 3q21 (rs4857855), 5q31 (rs4143832) and 12q24 (rs3184504) reached genome-wide significance (P = 5.3 x 10(-14), 5.4 x 10(-10), 8.6 x 10(-17), 1.2 x 10(-10) and 6.5 x 10(-19), respectively). A SNP at IL1RL1 associated with asthma (P = 5.5 x 10(-12)) in a collection of ten different populations (7,996 cases and 44,890 controls). SNPs at WDR36, IL33 and MYB that showed suggestive association with eosinophil counts were also associated with atopic asthma (P = 4.2 x 10(-6), 2.2 x 10(-5) and 2.4 x 10(-4), respectively). We also found that a nonsynonymous SNP at 12q24, in SH2B3, associated significantly (P = 8.6 x 10(-8)) with myocardial infarction in six different populations (6,650 cases and 40,621 controls).
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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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A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer.
Nat. Genet.
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In Western countries, prostate cancer is the most prevalent cancer of men and one of the leading causes of cancer-related death in men. Several genome-wide association studies have yielded numerous common variants conferring risk of prostate cancer. Here, we analyzed 32.5 million variants discovered by whole-genome sequencing 1,795 Icelanders. We identified a new low-frequency variant at 8q24 associated with prostate cancer in European populations, rs188140481[A] (odds ratio (OR) = 2.90; P(combined) = 6.2 × 10(-34)), with an average risk allele frequency in controls of 0.54%. This variant is only very weakly correlated (r(2) ? 0.06) with previously reported risk variants at 8q24, and its association remains significant after adjustment for all known risk-associated variants. Carriers of rs188140481[A] were diagnosed with prostate cancer 1.26 years younger than non-carriers (P = 0.0059). We also report results for a previously described HOXB13 variant (rs138213197[T]), confirming it as a prostate cancer risk variant in populations from across Europe.
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Rate of de novo mutations and the importance of fathers age to disease risk.
Nature
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Mutations generate sequence diversity and provide a substrate for selection. The rate of de novo mutations is therefore of major importance to evolution. Here we conduct a study of genome-wide mutation rates by sequencing the entire genomes of 78 Icelandic parent-offspring trios at high coverage. We show that in our samples, with an average fathers age of 29.7, the average de novo mutation rate is 1.20?×?10(-8) per nucleotide per generation. Most notably, the diversity in mutation rate of single nucleotide polymorphisms is dominated by the age of the father at conception of the child. The effect is an increase of about two mutations per year. An exponential model estimates paternal mutations doubling every 16.5?years. After accounting for random Poisson variation, fathers age is estimated to explain nearly all of the remaining variation in the de novo mutation counts. These observations shed light on the importance of the fathers age on the risk of diseases such as schizophrenia and autism.
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Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism.
J. Am. Coll. Cardiol.
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The purpose of this study is investigate the effects of variants in the apolipoprotein(a) gene (LPA) on vascular diseases with different atherosclerotic and thrombotic components.
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A mutation in APP protects against Alzheimers disease and age-related cognitive decline.
Nature
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The prevalence of dementia in the Western world in people over the age of 60 has been estimated to be greater than 5%, about two-thirds of which are due to Alzheimers disease. The age-specific prevalence of Alzheimers disease nearly doubles every 5 years after age 65, leading to a prevalence of greater than 25% in those over the age of 90 (ref. 3). Here, to search for low-frequency variants in the amyloid-? precursor protein (APP) gene with a significant effect on the risk of Alzheimers disease, we studied coding variants in APP in a set of whole-genome sequence data from 1,795 Icelanders. We found a coding mutation (A673T) in the APP gene that protects against Alzheimers disease and cognitive decline in the elderly without Alzheimers disease. This substitution is adjacent to the aspartyl protease ?-site in APP, and results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro. The strong protective effect of the A673T substitution against Alzheimers disease provides proof of principle for the hypothesis that reducing the ?-cleavage of APP may protect against the disease. Furthermore, as the A673T allele also protects against cognitive decline in the elderly without Alzheimers disease, the two may be mediated through the same or similar mechanisms.
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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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Discovery of common variants associated with low TSH levels and thyroid cancer risk.
Nat. Genet.
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To search for sequence variants conferring risk of nonmedullary thyroid cancer, we focused our analysis on 22 SNPs with a P < 5 × 10(-8) in a genome-wide association study on levels of thyroid stimulating hormone (TSH) in 27,758 Icelanders. Of those, rs965513 has previously been shown to associate with thyroid cancer. The remaining 21 SNPs were genotyped in 561 Icelandic individuals with thyroid cancer (cases) and up to 40,013 controls. Variants suggestively associated with thyroid cancer (P < 0.05) were genotyped in an additional 595 non-Icelandic cases and 2,604 controls. After combining the results, three variants were shown to associate with thyroid cancer: rs966423 on 2q35 (OR = 1.34; P(combined) = 1.3 × 10(-9)), rs2439302 on 8p12 (OR = 1.36; P(combined) = 2.0 × 10(-9)) and rs116909374 on 14q13.3 (OR = 2.09; P(combined) = 4.6 × 10(-11)), a region previously reported to contain an uncorrelated variant conferring risk of thyroid cancer. A strong association (P = 9.1 × 10(-91)) was observed between rs2439302 on 8p12 and expression of NRG1, which encodes the signaling protein neuregulin 1, in blood.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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