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1.  Rare coding variants and X-linked loci associated with age at menarche 
Lunetta, Kathryn L. | Day, Felix R. | Sulem, Patrick | Ruth, Katherine S. | Tung, Joyce Y. | Hinds, David A. | Esko, Tõnu | Elks, Cathy E. | Altmaier, Elisabeth | He, Chunyan | Huffman, Jennifer E. | Mihailov, Evelin | Porcu, Eleonora | Robino, Antonietta | Rose, Lynda M. | Schick, Ursula M. | Stolk, Lisette | Teumer, Alexander | Thompson, Deborah J. | Traglia, Michela | Wang, Carol A. | Yerges-Armstrong, Laura M. | Antoniou, Antonis C. | Barbieri, Caterina | Coviello, Andrea D. | Cucca, Francesco | Demerath, Ellen W. | Dunning, Alison M. | Gandin, Ilaria | Grove, Megan L. | Gudbjartsson, Daniel F. | Hocking, Lynne J. | Hofman, Albert | Huang, Jinyan | Jackson, Rebecca D. | Karasik, David | Kriebel, Jennifer | Lange, Ethan M. | Lange, Leslie A. | Langenberg, Claudia | Li, Xin | Luan, Jian'an | Mägi, Reedik | Morrison, Alanna C. | Padmanabhan, Sandosh | Pirie, Ailith | Polasek, Ozren | Porteous, David | Reiner, Alex P. | Rivadeneira, Fernando | Rudan, Igor | Sala, Cinzia F. | Schlessinger, David | Scott, Robert A. | Stöckl, Doris | Visser, Jenny A. | Völker, Uwe | Vozzi, Diego | Wilson, James G. | Zygmunt, Marek | Boerwinkle, Eric | Buring, Julie E. | Crisponi, Laura | Easton, Douglas F. | Hayward, Caroline | Hu, Frank B. | Liu, Simin | Metspalu, Andres | Pennell, Craig E. | Ridker, Paul M. | Strauch, Konstantin | Streeten, Elizabeth A. | Toniolo, Daniela | Uitterlinden, André G. | Ulivi, Sheila | Völzke, Henry | Wareham, Nicholas J. | Wellons, Melissa | Franceschini, Nora | Chasman, Daniel I. | Thorsteinsdottir, Unnur | Murray, Anna | Stefansson, Kari | Murabito, Joanne M. | Ong, Ken K. | Perry, John R. B.
Nature Communications  2015;6:7756.
More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08–4.6%; effect sizes 0.08–1.25 years per allele; P<5 × 10−8). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10−13) and FAAH2 (rs5914101, P=4.9 × 10−10). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10−11), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the ‘missing heritability' of this complex trait.
Previous studies have linked over 100 genomic loci to age-at-menarche but that work was restricted to common autosomal variation. Here, Lunetta et al. identify associations with rare protein-coding and X-linked variants, implicating new mechanisms that regulate puberty timing.
PMCID: PMC4538850  PMID: 26239645
2.  Common and rare variants associated with kidney stones and biochemical traits 
Nature Communications  2015;6:7975.
Kidney stone disease is a complex disorder with a strong genetic component. We conducted a genome-wide association study of 28.3 million sequence variants detected through whole-genome sequencing of 2,636 Icelanders that were imputed into 5,419 kidney stone cases, including 2,172 cases with a history of recurrent kidney stones, and 279,870 controls. We identify sequence variants associating with kidney stones at ALPL (rs1256328[T], odds ratio (OR)=1.21, P=5.8 × 10−10) and a suggestive association at CASR (rs7627468[A], OR=1.16, P=2.0 × 10−8). Focusing our analysis on coding sequence variants in 63 genes with preferential kidney expression we identify two rare missense variants SLC34A1 p.Tyr489Cys (OR=2.38, P=2.8 × 10−5) and TRPV5 p.Leu530Arg (OR=3.62, P=4.1 × 10−5) associating with recurrent kidney stones. We also observe associations of the identified kidney stone variants with biochemical traits in a large population set, indicating potential biological mechanism.
Kidney stone formation is influenced by genetic factors and recurrent stone formation places a significant burden on health care systems. Here Oddsson et al. perform a large-scale genome-wide association study and uncover new genetic variants associated with kidney stone susceptibility and associated biochemical traits.
PMCID: PMC4557269  PMID: 26272126
3.  A Variant Associated with Nicotine Dependence, Lung Cancer and Peripheral Arterial Disease 
Nature  2008;452(7187):638-642.
Smoking is a leading cause of preventable death, causing approximately five million premature deaths world-wide each year1, 2. Evidence for genetic influence on smoking behaviour and nicotine dependence (ND)3-8 has prompted a search for susceptibility genes. Furthermore, assessing the impact of sequence variants on smoking-related diseases is important for public health reasons9, 10. Smoking is the major risk factor for lung cancer (LC)11-14, and one of the main risk factors for peripheral arterial disease (PAD)15-17. We have identified a common variant in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 with an effect on smoking quantity, ND and the risk of two smoking-related diseases in populations of European descent. The variant has an effect on the number of cigarettes smoked per day in 15,771 smokers (P=6×10−20). The same variant associated with ND in a previous genome-wide association study using low quantity smokers as controls (OR=1.3, P=1×10−3)18, 19, and with a similar approach we observe a highly significant association with ND (OR =1.40, P=7×10−15). Comparison of LC (N=1,024) and PAD (N= 2,738) cases with about 30,000 population controls each showed that the variant confers risk of LC (OR=1.31, P=1.5×10−8) and PAD (OR=1.19, P=1.4×10−7). The findings highlight the role of nicotine addiction in the pathogenesis of other serious diseases and provide a case study of the role of active gene-environment correlation20 in the pathogenesis of disease.
PMCID: PMC4539558  PMID: 18385739
4.  Sequence variant on 8q24 confers susceptibility to urinary bladder cancer 
Nature genetics  2008;40(11):1307-1312.
We conducted a genome wide SNP association study on 1,803 Urinary Bladder Cancer (UBC) cases and 34,336 controls from Iceland and the Netherlands and follow up studies in seven additional case control groups (2,165 cases and 3,800 controls). The strongest association was observed with allele T of rs9642880 on chromosome 8q24, 30kb upstream of the c-Myc gene (allele specific OR=1.22; P=9.34×10−12). Approximately 20% of individuals of European ancestry are homozygous for rs9642880 (T) and their estimated risk of developing UBC is 1.49 times that of non-carriers with population attributable risk (PAR) of 17%. No association was observed between UBC and the four 8q24 variants previously associated with prostate, colorectal and breast cancers, nor did rs9642880 associate with any of these three cancers. A weaker signal, but nonetheless of genome wide significance, was captured by rs710521 (A) located near the TP63 gene on chromosome 3q28 (allele specific OR=1.19; P=1. 15× 10−7).
PMCID: PMC4539560  PMID: 18794855
5.  Detection of sharing by descent, long-range phasing and haplotype imputation 
Nature genetics  2008;40(9):1068-1075.
Uncertainty about the phase of strings of single nucleotide polymorphisms (SNPs) creates complications in genetic analysis although methods have been developed for phasing population-based samples. However, these methods can only phase a small number of SNPs effectively, and become unreliable when applied to SNPs spanning many linkage disequilibrium (LD) blocks. Here we show how to phase more than one thousand SNPs simultaneously for a large fraction of the 35,528 Icelanders genotyped by Illumina chips. Moreover, haplotypes that are identical by descent (IBD) between close and distant relatives, e.g. those separated by 10 meioses or more, can often be reliably detected. This method is particularly powerful in studies of the inheritance of recurrent mutations and fine-scale recombinations in large sample sets. A further extension of the method allows us to impute long haplotypes for individuals who are not genotyped.
PMCID: PMC4540081  PMID: 19165921
6.  Sequence variants at the TERT- CLPTM1L locus associate with many cancer types 
Rafnar, Thorunn | Sulem, Patrick | Stacey, Simon N. | Geller, Frank | Gudmundsson, Julius | Sigurdsson, Asgeir | Jakobsdottir, Margret | Helgadottir, Hafdis | Thorlacius, Steinunn | Aben, Katja K.H. | Blöndal, Thorarinn | Thorgeirsson, Thorgeir E. | Thorleifsson, Gudmar | Kristjansson, Kristleifur | Thorisdottir, Kristin | Ragnarsson, Rafn | Sigurgeirsson, Bardur | Skuladottir, Halla | Gudbjartsson, Tomas | Isaksson, Helgi J. | Einarsson, Gudmundur V. | Benediktsdottir, Kristrun R. | Agnarsson, Bjarni A. | Olafsson, Karl | Salvarsdottir, Anna | Bjarnason, Hjordis | Asgeirsdottir, Margret | Kristinsson, Kari T. | Matthiasdottir, Sigurborg | Sveinsdottir, Steinunn G. | Polidoro, Silvia | Höiom, Veronica | Botella-Estrada, Rafael | Hemminki, Kari | Rudnai, Peter | Bishop, D. Timothy | Campagna, Marcello | Kellen, Eliane | Zeegers, Maurice P. | de Verdier, Petra | Ferrer, Ana | Isla, Dolores | Vidal, Maria Jesus | Andres, Raquel | Saez, Berta | Juberias, Pablo | Banzo, Javier | Navarrete, Sebastian | Tres, Alejandro | Kan, Donghui | Lindblom, Annika | Gurzau, Eugene | Koppova, Kvetoslava | de Vegt, Femmie | Schalken, Jack A. | van der Heijden, Henricus F.M. | Smit, Hans J. | Termeer, René A. | Oosterwijk, Egbert | van Hooij, Onno | Nagore, Eduardo | Porru, Stefano | Steineck, Gunnar | Hansson, Johan | Buntinx, Frank | Catalona, William J. | Matullo, Giuseppe | Vineis, Paolo | Kiltie, Anne E. | Mayordomo, José I. | Kumar, Rajiv | Kiemeney, Lambertus A. | Frigge, Michael L. | Jonsson, Thorvaldur | Saemundsson, Hafsteinn | Barkardottir, Rosa B. | Jonsson, Eirikur | Jonsson, Steinn | Olafsson, Jon H. | Gulcher, Jeffrey R. | Masson, Gisli | Gudbjartsson, Daniel F. | Kong, Augustine | Thorsteinsdottir, Unnur | Stefansson, Kari
Nature genetics  2009;41(2):221-227.
The common sequence variants that have recently been associated with cancer risk are particular to a single, or at most two, cancer types. Following up on our genome-wide scan of basal cell carcinoma1, we identified rs401681(C) on chromosome 5p15.33 satisfying our threshold for genome-wide significance (OR=1.25, P=3.7×10−12). We tested rs401681 for association with sixteen additional cancer types in over 30,000 cancer cases and 45,000 controls and found association with lung cancer (OR=1.15, P=7.2×10−8) and urinary bladder, prostate and cervix cancer (ORs 1.07–1.31, all P<4×10−4). However, rs401681(C) appears to confer protection against cutaneous melanoma (OR=0.88, P=8.0×10−4). Interestingly, most of these cancer types have a strong environmental component to their risk. Investigation of the region led us to rs2736098(A), that 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 while rs401681 is in an intron of the CLPTM1L gene.
PMCID: PMC4525478  PMID: 19151717
7.  Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation 
Horikoshi, Momoko | Mӓgi, Reedik | van de Bunt, Martijn | Surakka, Ida | Sarin, Antti-Pekka | Mahajan, Anubha | Marullo, Letizia | Thorleifsson, Gudmar | Hӓgg, Sara | Hottenga, Jouke-Jan | Ladenvall, Claes | Ried, Janina S. | Winkler, Thomas W. | Willems, Sara M. | Pervjakova, Natalia | Esko, Tõnu | Beekman, Marian | Nelson, Christopher P. | Willenborg, Christina | Wiltshire, Steven | Ferreira, Teresa | Fernandez, Juan | Gaulton, Kyle J. | Steinthorsdottir, Valgerdur | Hamsten, Anders | Magnusson, Patrik K. E. | Willemsen, Gonneke | Milaneschi, Yuri | Robertson, Neil R. | Groves, Christopher J. | Bennett, Amanda J. | Lehtimӓki, Terho | Viikari, Jorma S. | Rung, Johan | Lyssenko, Valeriya | Perola, Markus | Heid, Iris M. | Herder, Christian | Grallert, Harald | Müller-Nurasyid, Martina | Roden, Michael | Hypponen, Elina | Isaacs, Aaron | van Leeuwen, Elisabeth M. | Karssen, Lennart C. | Mihailov, Evelin | Houwing-Duistermaat, Jeanine J. | de Craen, Anton J. M. | Deelen, Joris | Havulinna, Aki S. | Blades, Matthew | Hengstenberg, Christian | Erdmann, Jeanette | Schunkert, Heribert | Kaprio, Jaakko | Tobin, Martin D. | Samani, Nilesh J. | Lind, Lars | Salomaa, Veikko | Lindgren, Cecilia M. | Slagboom, P. Eline | Metspalu, Andres | van Duijn, Cornelia M. | Eriksson, Johan G. | Peters, Annette | Gieger, Christian | Jula, Antti | Groop, Leif | Raitakari, Olli T. | Power, Chris | Penninx, Brenda W. J. H. | de Geus, Eco | Smit, Johannes H. | Boomsma, Dorret I. | Pedersen, Nancy L. | Ingelsson, Erik | Thorsteinsdottir, Unnur | Stefansson, Kari | Ripatti, Samuli | Prokopenko, Inga | McCarthy, Mark I. | Morris, Andrew P.
PLoS Genetics  2015;11(7):e1005230.
Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.
Author Summary
Human genetic studies have demonstrated that quantitative human anthropometric and metabolic traits, including body mass index, waist-hip ratio, and plasma concentrations of glucose and insulin, are highly heritable, and are established risk factors for type 2 diabetes and cardiovascular diseases. Although many regions of the genome have been associated with these traits, the specific genes responsible have not yet been identified. By making use of advanced statistical “imputation” techniques applied to more than 87,000 individuals of European ancestry, and publicly available “reference panels” of more than 37 million genetic variants, we have been able to identify novel regions of the genome associated with these glycaemic and obesity-related traits and localise genes within these regions that are most likely to be causal. This improved understanding of the biological mechanisms underlying glycaemic and obesity-related traits is extremely important because it may advance drug development for downstream disease endpoints, ultimately leading to public health benefits.
PMCID: PMC4488845  PMID: 26132169
8.  Large-Scale Analysis of Association Between GDF5 and FRZB Variants and Osteoarthritis of the Hip, Knee, and Hand 
Arthritis and rheumatism  2009;60(6):1710-1721.
GDF5 and FRZB have been proposed as genetic loci conferring susceptibility to osteoarthritis (OA); however, the results of several studies investigating the association of OA with the rs143383 polymorphism of the GDF5 gene or the rs7775 and rs288326 polymorphisms of the FRZB gene have been conflicting or inconclusive. To examine these associations, we performed a large-scale meta-analysis of individual-level data.
Fourteen teams contributed data on polymorphisms and knee, hip, and hand OA. For rs143383, the total number of cases and controls, respectively, was 5,789 and 7,850 for hip OA, 5,085 and 8,135 for knee OA, and 4,040 and 4,792 for hand OA. For rs7775, the respective sample sizes were 4,352 and 10,843 for hip OA, 3,545 and 6,085 for knee OA, and 4,010 and 5,151 for hand OA, and for rs288326, they were 4,346 and 8,034 for hip OA, 3,595 and 6,106 for knee OA, and 3,982 and 5,152 for hand OA. For each individual study, sex-specific odds ratios (ORs) were calculated for each OA phenotype that had been investigated. The ORs for each phenotype were synthesized using both fixed-effects and random-effects models for allele-based effects, and also for haplotype effects for FRZB.
A significant random-effects summary OR for knee OA was demonstrated for rs143383 (1.15 [95% confidence interval 1.09–1.22]) (P = 9.4 × 10−7), with no significant between-study heterogeneity. Estimates of effect sizes for hip and hand OA were similar, but a large between-study heterogeneity was observed, and statistical significance was borderline (for OA of the hip [P = 0.016]) or absent (for OA of the hand [P = 0.19]). Analyses for FRZB polymorphisms and haplotypes did not reveal any statistically significant signals, except for a borderline association of rs288326 with hip OA (P = 0.019).
Evidence of an association between the GDF5 rs143383 polymorphism and OA is substantially strong, but the genetic effects are consistent across different populations only for knee OA. Findings of this collaborative analysis do not support the notion that FRZB rs7775 or rs288326 has any sizable genetic effect on OA phenotypes.
PMCID: PMC4412885  PMID: 19479880
9.  New basal cell carcinoma susceptibility loci 
Nature Communications  2015;6:6825.
In an ongoing screen for DNA sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conduct a genome-wide association study (GWAS) of 24,988,228 SNPs and small indels detected through whole-genome sequencing of 2,636 Icelanders and imputed into 4,572 BCC patients and 266,358 controls. Here we show the discovery of four new BCC susceptibility loci: 2p24 MYCN (rs57244888[C], OR=0.76, P=4.7 × 10−12), 2q33 CASP8-ALS2CR12 (rs13014235[C], OR=1.15, P=1.5 × 10−9), 8q21 ZFHX4 (rs28727938[G], OR=0.70, P=3.5 × 10−12) and 10p14 GATA3 (rs73635312[A], OR=0.74, P=2.4 × 10−16). Fine mapping reveals that two variants correlated with rs73635312[A] occur in conserved binding sites for the GATA3 transcription factor. In addition, expression microarrays and RNA-seq show that rs13014235[C] and a related SNP rs700635[C] are associated with expression of CASP8 splice variants in which sequences from intron 8 are retained.
Basal cell carcinoma is a common cancer among people of European ancestry, with associated high economic costs to monitor and treat. Here Stacey et al. conduct a genome-wide association study on Icelandic and other European populations, identifying four novel loci associated with cancer susceptibility.
PMCID: PMC4403348  PMID: 25855136
10.  Parent-of-origin specific allelic associations among 106 genomic loci for age at menarche 
Perry, John RB | Day, Felix | Elks, Cathy E | Sulem, Patrick | Thompson, Deborah J | Ferreira, Teresa | He, Chunyan | Chasman, Daniel I | Esko, Tõnu | Thorleifsson, Gudmar | Albrecht, Eva | Ang, Wei Q | Corre, Tanguy | Cousminer, Diana L | Feenstra, Bjarke | Franceschini, Nora | Ganna, Andrea | Johnson, Andrew D | Kjellqvist, Sanela | Lunetta, Kathryn L | McMahon, George | Nolte, Ilja M | Paternoster, Lavinia | Porcu, Eleonora | Smith, Albert V | Stolk, Lisette | Teumer, Alexander | Tšernikova, Natalia | Tikkanen, Emmi | Ulivi, Sheila | Wagner, Erin K | Amin, Najaf | Bierut, Laura J | Byrne, Enda M | Hottenga, Jouke-Jan | Koller, Daniel L | Mangino, Massimo | Pers, Tune H | Yerges-Armstrong, Laura M | Zhao, Jing Hua | Andrulis, Irene L | Anton-Culver, Hoda | Atsma, Femke | Bandinelli, Stefania | Beckmann, Matthias W | Benitez, Javier | Blomqvist, Carl | Bojesen, Stig E | Bolla, Manjeet K | Bonanni, Bernardo | Brauch, Hiltrud | Brenner, Hermann | Buring, Julie E | Chang-Claude, Jenny | Chanock, Stephen | Chen, Jinhui | Chenevix-Trench, Georgia | Collée, J. Margriet | Couch, Fergus J | Couper, David | Coveillo, Andrea D | Cox, Angela | Czene, Kamila | D’adamo, Adamo Pio | Smith, George Davey | De Vivo, Immaculata | Demerath, Ellen W | Dennis, Joe | Devilee, Peter | Dieffenbach, Aida K | Dunning, Alison M | Eiriksdottir, Gudny | Eriksson, Johan G | Fasching, Peter A | Ferrucci, Luigi | Flesch-Janys, Dieter | Flyger, Henrik | Foroud, Tatiana | Franke, Lude | Garcia, Melissa E | García-Closas, Montserrat | Geller, Frank | de Geus, Eco EJ | Giles, Graham G | Gudbjartsson, Daniel F | Gudnason, Vilmundur | Guénel, Pascal | Guo, Suiqun | Hall, Per | Hamann, Ute | Haring, Robin | Hartman, Catharina A | Heath, Andrew C | Hofman, Albert | Hooning, Maartje J | Hopper, John L | Hu, Frank B | Hunter, David J | Karasik, David | Kiel, Douglas P | Knight, Julia A | Kosma, Veli-Matti | Kutalik, Zoltan | Lai, Sandra | Lambrechts, Diether | Lindblom, Annika | Mägi, Reedik | Magnusson, Patrik K | Mannermaa, Arto | Martin, Nicholas G | Masson, Gisli | McArdle, Patrick F | McArdle, Wendy L | Melbye, Mads | Michailidou, Kyriaki | Mihailov, Evelin | Milani, Lili | Milne, Roger L | Nevanlinna, Heli | Neven, Patrick | Nohr, Ellen A | Oldehinkel, Albertine J | Oostra, Ben A | Palotie, Aarno | Peacock, Munro | Pedersen, Nancy L | Peterlongo, Paolo | Peto, Julian | Pharoah, Paul DP | Postma, Dirkje S | Pouta, Anneli | Pylkäs, Katri | Radice, Paolo | Ring, Susan | Rivadeneira, Fernando | Robino, Antonietta | Rose, Lynda M | Rudolph, Anja | Salomaa, Veikko | Sanna, Serena | Schlessinger, David | Schmidt, Marjanka K | Southey, Mellissa C | Sovio, Ulla | Stampfer, Meir J | Stöckl, Doris | Storniolo, Anna M | Timpson, Nicholas J | Tyrer, Jonathan | Visser, Jenny A | Vollenweider, Peter | Völzke, Henry | Waeber, Gerard | Waldenberger, Melanie | Wallaschofski, Henri | Wang, Qin | Willemsen, Gonneke | Winqvist, Robert | Wolffenbuttel, Bruce HR | Wright, Margaret J | Boomsma, Dorret I | Econs, Michael J | Khaw, Kay-Tee | Loos, Ruth JF | McCarthy, Mark I | Montgomery, Grant W | Rice, John P | Streeten, Elizabeth A | Thorsteinsdottir, Unnur | van Duijn, Cornelia M | Alizadeh, Behrooz Z | Bergmann, Sven | Boerwinkle, Eric | Boyd, Heather A | Crisponi, Laura | Gasparini, Paolo | Gieger, Christian | Harris, Tamara B | Ingelsson, Erik | Järvelin, Marjo-Riitta | Kraft, Peter | Lawlor, Debbie | Metspalu, Andres | Pennell, Craig E | Ridker, Paul M | Snieder, Harold | Sørensen, Thorkild IA | Spector, Tim D | Strachan, David P | Uitterlinden, André G | Wareham, Nicholas J | Widen, Elisabeth | Zygmunt, Marek | Murray, Anna | Easton, Douglas F | Stefansson, Kari | Murabito, Joanne M | Ong, Ken K
Nature  2014;514(7520):92-97.
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 mortality1. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation2,3, 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<5×10−8) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1/WDR25, MKRN3/MAGEL2 and KCNK9) demonstrating parent-of-origin specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signaling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
PMCID: PMC4185210  PMID: 25231870
11.  Genome-wide analysis of multiethnic cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma 
Hysi, Pirro G | Cheng, Ching-Yu | Springelkamp, Henriët | Macgregor, Stuart | Bailey, Jessica N Cooke | Wojciechowski, Robert | Vitart, Veronique | Nag, Abhishek | Hewitt, Alex W | Höhn, René | Venturini, Cristina | Mirshahi, Alireza | Ramdas, Wishal D. | Thorleifsson, Gudmar | Vithana, Eranga | Khor, Chiea-Chuen | Stefansson, Arni B | Liao, Jiemin | Haines, Jonathan L | Amin, Najaf | Wang, Ya Xing | Wild, Philipp S | Ozel, Ayse B | Li, Jun Z | Fleck, Brian W | Zeller, Tanja | Staffieri, Sandra E | Teo, Yik-Ying | Cuellar-Partida, Gabriel | Luo, Xiaoyan | Allingham, R Rand | Richards, Julia E | Senft, Andrea | Karssen, Lennart C | Zheng, Yingfeng | Bellenguez, Céline | Xu, Liang | Iglesias, Adriana I | Wilson, James F | Kang, Jae H | van Leeuwen, Elisabeth M | Jonsson, Vesteinn | Thorsteinsdottir, Unnur | Despriet, Dominiek D.G. | Ennis, Sarah | Moroi, Sayoko E | Martin, Nicholas G | Jansonius, Nomdo M | Yazar, Seyhan | Tai, E-Shyong | Amouyel, Philippe | Kirwan, James | van Koolwijk, Leonieke M.E. | Hauser, Michael A | Jonasson, Fridbert | Leo, Paul | Loomis, Stephanie J | Fogarty, Rhys | Rivadeneira, Fernando | Kearns, Lisa | Lackner, Karl J | de Jong, Paulus T.V.M. | Simpson, Claire L | Pennell, Craig E | Oostra, Ben A | Uitterlinden, André G | Saw, Seang-Mei | Lotery, Andrew J | Bailey-Wilson, Joan E | Hofman, Albert | Vingerling, Johannes R | Maubaret, Cécilia | Pfeiffer, Norbert | Wolfs, Roger C.W. | Lemij, Hans G | Young, Terri L | Pasquale, Louis R | Delcourt, Cécile | Spector, Timothy D | Klaver, Caroline C.W. | Small, Kerrin S | Burdon, Kathryn P | Stefansson, Kari | Wong, Tien-Yin | Viswanathan, Ananth | Mackey, David A | Craig, Jamie E | Wiggs, Janey L | van Duijn, Cornelia M | Hammond, Christopher J | Aung, Tin
Nature genetics  2014;46(10):1126-1130.
Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma and IOP variability may herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multiethnic participants for IOP. We confirm genetic association of known loci for IOP and primary open angle glaucoma (POAG) and identify four new IOP loci located on chromosome 3q25.31 within the FNDC3B gene (p=4.19×10−08 for rs6445055), two on chromosome 9 (p=2.80×10−11 for rs2472493 near ABCA1 and p=6.39×10−11 for rs8176693 within ABO) and one on chromosome 11p11.2 (best p=1.04×10−11 for rs747782). Separate meta-analyses of four independent POAG cohorts, totaling 4,284 cases and 95,560 controls, show that three of these IOP loci are also associated with POAG.
PMCID: PMC4177225  PMID: 25173106
12.  Sequence variants from whole genome sequencing a large group of Icelanders 
Scientific Data  2015;2:150011.
We have accumulated considerable data on the genetic makeup of the Icelandic population by sequencing the whole genomes of 2,636 Icelanders to depth of at least 10X and by chip genotyping 101,584 more. The sequencing was done with Illumina technology. The median sequencing depth was 20X and 909 individuals were sequenced to a depth of at least 30X. We found 20 million single nucleotide polymorphisms (SNPs) and 1.5 million insertions/deletions (indels) that passed stringent quality control. Almost all the common SNPs (derived allele frequency (DAF) over 2%) that we identified in Iceland have been observed by either dbSNP (build 137) or the Exome Sequencing Project (ESP) while only 60 and 20% of rare (DAF<0.5%) SNPs and indels in coding regions, the most heavily studied parts of the genome, have been observed in the public databases. Features of our variant data, such as the transition/transversion ratio and the length distribution of indels, are similar to published reports.
PMCID: PMC4413226  PMID: 25977816
13.  Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease 
Nature genetics  2014;46(9):989-993.
We conducted a meta analysis of Parkinson’s disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as genome-wide significant; these and six additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 novel loci. Conditional analyses within loci show four loci including GBA, GAK/DGKQ, SNCA, and HLA contain a secondary independent risk variant. In total we identified and replicated 28 independent risk variants for Parkinson disease across 24 loci. While the effect of each individual locus is small, a risk profile analysis revealed a substantial cummulative risk in a comparison highest versus lowest quintiles of genetic risk (OR=3.31, 95% CI: 2.55, 4.30; p-value = 2×10−16). We also show 6 risk loci associated with proximal gene expression or DNA methylation.
PMCID: PMC4146673  PMID: 25064009
14.  Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization 
Arking, Dan E. | Pulit, Sara L. | Crotti, Lia | van der Harst, Pim | Munroe, Patricia B. | Koopmann, Tamara T. | Sotoodehnia, Nona | Rossin, Elizabeth J. | Morley, Michael | Wang, Xinchen | Johnson, Andrew D. | Lundby, Alicia | Gudbjartsson, Daníel F. | Noseworthy, Peter A. | Eijgelsheim, Mark | Bradford, Yuki | Tarasov, Kirill V. | Dörr, Marcus | Müller-Nurasyid, Martina | Lahtinen, Annukka M. | Nolte, Ilja M. | Smith, Albert Vernon | Bis, Joshua C. | Isaacs, Aaron | Newhouse, Stephen J. | Evans, Daniel S. | Post, Wendy S. | Waggott, Daryl | Lyytikäinen, Leo-Pekka | Hicks, Andrew A. | Eisele, Lewin | Ellinghaus, David | Hayward, Caroline | Navarro, Pau | Ulivi, Sheila | Tanaka, Toshiko | Tester, David J. | Chatel, Stéphanie | Gustafsson, Stefan | Kumari, Meena | Morris, Richard W. | Naluai, Åsa T. | Padmanabhan, Sandosh | Kluttig, Alexander | Strohmer, Bernhard | Panayiotou, Andrie G. | Torres, Maria | Knoflach, Michael | Hubacek, Jaroslav A. | Slowikowski, Kamil | Raychaudhuri, Soumya | Kumar, Runjun D. | Harris, Tamara B. | Launer, Lenore J. | Shuldiner, Alan R. | Alonso, Alvaro | Bader, Joel S. | Ehret, Georg | Huang, Hailiang | Kao, W.H. Linda | Strait, James B. | Macfarlane, Peter W. | Brown, Morris | Caulfield, Mark J. | Samani, Nilesh J. | Kronenberg, Florian | Willeit, Johann | Smith, J. Gustav | Greiser, Karin H. | zu Schwabedissen, Henriette Meyer | Werdan, Karl | Carella, Massimo | Zelante, Leopoldo | Heckbert, Susan R. | Psaty, Bruce M. | Rotter, Jerome I. | Kolcic, Ivana | Polašek, Ozren | Wright, Alan F. | Griffin, Maura | Daly, Mark J. | Arnar, David O. | Hólm, Hilma | Thorsteinsdottir, Unnur | Denny, Joshua C. | Roden, Dan M. | Zuvich, Rebecca L. | Emilsson, Valur | Plump, Andrew S. | Larson, Martin G. | O'Donnell, Christopher J. | Yin, Xiaoyan | Bobbo, Marco | D'Adamo, Adamo P. | Iorio, Annamaria | Sinagra, Gianfranco | Carracedo, Angel | Cummings, Steven R. | Nalls, Michael A. | Jula, Antti | Kontula, Kimmo K. | Marjamaa, Annukka | Oikarinen, Lasse | Perola, Markus | Porthan, Kimmo | Erbel, Raimund | Hoffmann, Per | Jöckel, Karl-Heinz | Kälsch, Hagen | Nöthen, Markus M. | consortium, HRGEN | den Hoed, Marcel | Loos, Ruth J.F. | Thelle, Dag S. | Gieger, Christian | Meitinger, Thomas | Perz, Siegfried | Peters, Annette | Prucha, Hanna | Sinner, Moritz F. | Waldenberger, Melanie | de Boer, Rudolf A. | Franke, Lude | van der Vleuten, Pieter A. | Beckmann, Britt Maria | Martens, Eimo | Bardai, Abdennasser | Hofman, Nynke | Wilde, Arthur A.M. | Behr, Elijah R. | Dalageorgou, Chrysoula | Giudicessi, John R. | Medeiros-Domingo, Argelia | Barc, Julien | Kyndt, Florence | Probst, Vincent | Ghidoni, Alice | Insolia, Roberto | Hamilton, Robert M. | Scherer, Stephen W. | Brandimarto, Jeffrey | Margulies, Kenneth | Moravec, Christine E. | Fabiola Del, Greco M. | Fuchsberger, Christian | O'Connell, Jeffrey R. | Lee, Wai K. | Watt, Graham C.M. | Campbell, Harry | Wild, Sarah H. | El Mokhtari, Nour E. | Frey, Norbert | Asselbergs, Folkert W. | Leach, Irene Mateo | Navis, Gerjan | van den Berg, Maarten P. | van Veldhuisen, Dirk J. | Kellis, Manolis | Krijthe, Bouwe P. | Franco, Oscar H. | Hofman, Albert | Kors, Jan A. | Uitterlinden, André G. | Witteman, Jacqueline C.M. | Kedenko, Lyudmyla | Lamina, Claudia | Oostra, Ben A. | Abecasis, Gonçalo R. | Lakatta, Edward G. | Mulas, Antonella | Orrú, Marco | Schlessinger, David | Uda, Manuela | Markus, Marcello R.P. | Völker, Uwe | Snieder, Harold | Spector, Timothy D. | Ärnlöv, Johan | Lind, Lars | Sundström, Johan | Syvänen, Ann-Christine | Kivimaki, Mika | Kähönen, Mika | Mononen, Nina | Raitakari, Olli T. | Viikari, Jorma S. | Adamkova, Vera | Kiechl, Stefan | Brion, Maria | Nicolaides, Andrew N. | Paulweber, Bernhard | Haerting, Johannes | Dominiczak, Anna F. | Nyberg, Fredrik | Whincup, Peter H. | Hingorani, Aroon | Schott, Jean-Jacques | Bezzina, Connie R. | Ingelsson, Erik | Ferrucci, Luigi | Gasparini, Paolo | Wilson, James F. | Rudan, Igor | Franke, Andre | Mühleisen, Thomas W. | Pramstaller, Peter P. | Lehtimäki, Terho J. | Paterson, Andrew D. | Parsa, Afshin | Liu, Yongmei | van Duijn, Cornelia | Siscovick, David S. | Gudnason, Vilmundur | Jamshidi, Yalda | Salomaa, Veikko | Felix, Stephan B. | Sanna, Serena | Ritchie, Marylyn D. | Stricker, Bruno H. | Stefansson, Kari | Boyer, Laurie A. | Cappola, Thomas P. | Olsen, Jesper V. | Lage, Kasper | Schwartz, Peter J. | Kääb, Stefan | Chakravarti, Aravinda | Ackerman, Michael J. | Pfeufer, Arne | de Bakker, Paul I.W. | Newton-Cheh, Christopher
Nature genetics  2014;46(8):826-836.
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 QT interval loci, that collectively explain ∼8-10% of QT variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT loci in 298 unrelated LQTS probands identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode for 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 novel candidate genes for ventricular arrhythmias, LQTS,and SCD.
PMCID: PMC4124521  PMID: 24952745
genome-wide association study; QT interval; Long QT Syndrome; sudden cardiac death; myocardial repolarization; arrhythmias
15.  Biological Insights From 108 Schizophrenia-Associated Genetic Loci 
Ripke, Stephan | Neale, Benjamin M | Corvin, Aiden | Walters, James TR | Farh, Kai-How | Holmans, Peter A | Lee, Phil | Bulik-Sullivan, Brendan | Collier, David A | Huang, Hailiang | Pers, Tune H | Agartz, Ingrid | Agerbo, Esben | Albus, Margot | Alexander, Madeline | Amin, Farooq | Bacanu, Silviu A | Begemann, Martin | Belliveau, Richard A | Bene, Judit | Bergen, Sarah E | Bevilacqua, Elizabeth | Bigdeli, Tim B | Black, Donald W | Bruggeman, Richard | Buccola, Nancy G | Buckner, Randy L | Byerley, William | Cahn, Wiepke | Cai, Guiqing | Campion, Dominique | Cantor, Rita M | Carr, Vaughan J | Carrera, Noa | Catts, Stanley V | Chambert, Kimberley D | Chan, Raymond CK | Chan, Ronald YL | Chen, Eric YH | Cheng, Wei | Cheung, Eric FC | Chong, Siow Ann | Cloninger, C Robert | Cohen, David | Cohen, Nadine | Cormican, Paul | Craddock, Nick | Crowley, James J | Curtis, David | Davidson, Michael | Davis, Kenneth L | Degenhardt, Franziska | Del Favero, Jurgen | Demontis, Ditte | Dikeos, Dimitris | Dinan, Timothy | Djurovic, Srdjan | Donohoe, Gary | Drapeau, Elodie | Duan, Jubao | Dudbridge, Frank | Durmishi, Naser | Eichhammer, Peter | Eriksson, Johan | Escott-Price, Valentina | Essioux, Laurent | Fanous, Ayman H | Farrell, Martilias S | Frank, Josef | Franke, Lude | Freedman, Robert | Freimer, Nelson B | Friedl, Marion | Friedman, Joseph I | Fromer, Menachem | Genovese, Giulio | Georgieva, Lyudmila | Giegling, Ina | Giusti-Rodríguez, Paola | Godard, Stephanie | Goldstein, Jacqueline I | Golimbet, Vera | Gopal, Srihari | Gratten, Jacob | de Haan, Lieuwe | Hammer, Christian | Hamshere, Marian L | Hansen, Mark | Hansen, Thomas | Haroutunian, Vahram | Hartmann, Annette M | Henskens, Frans A | Herms, Stefan | Hirschhorn, Joel N | Hoffmann, Per | Hofman, Andrea | Hollegaard, Mads V | Hougaard, David M | Ikeda, Masashi | Joa, Inge | Julià, Antonio | Kahn, René S | Kalaydjieva, Luba | Karachanak-Yankova, Sena | Karjalainen, Juha | Kavanagh, David | Keller, Matthew C | Kennedy, James L | Khrunin, Andrey | Kim, Yunjung | Klovins, Janis | Knowles, James A | Konte, Bettina | Kucinskas, Vaidutis | Kucinskiene, Zita Ausrele | Kuzelova-Ptackova, Hana | Kähler, Anna K | Laurent, Claudine | Lee, Jimmy | Lee, S Hong | Legge, Sophie E | Lerer, Bernard | Li, Miaoxin | Li, Tao | Liang, Kung-Yee | Lieberman, Jeffrey | Limborska, Svetlana | Loughland, Carmel M | Lubinski, Jan | Lönnqvist, Jouko | Macek, Milan | Magnusson, Patrik KE | Maher, Brion S | Maier, Wolfgang | Mallet, Jacques | Marsal, Sara | Mattheisen, Manuel | Mattingsdal, Morten | McCarley, Robert W | McDonald, Colm | McIntosh, Andrew M | Meier, Sandra | Meijer, Carin J | Melegh, Bela | Melle, Ingrid | Mesholam-Gately, Raquelle I | Metspalu, Andres | Michie, Patricia T | Milani, Lili | Milanova, Vihra | Mokrab, Younes | Morris, Derek W | Mors, Ole | Murphy, Kieran C | Murray, Robin M | Myin-Germeys, Inez | Müller-Myhsok, Bertram | Nelis, Mari | Nenadic, Igor | Nertney, Deborah A | Nestadt, Gerald | Nicodemus, Kristin K | Nikitina-Zake, Liene | Nisenbaum, Laura | Nordin, Annelie | O’Callaghan, Eadbhard | O’Dushlaine, Colm | O’Neill, F Anthony | Oh, Sang-Yun | Olincy, Ann | Olsen, Line | Van Os, Jim | Pantelis, Christos | Papadimitriou, George N | Papiol, Sergi | Parkhomenko, Elena | Pato, Michele T | Paunio, Tiina | Pejovic-Milovancevic, Milica | Perkins, Diana O | Pietiläinen, Olli | Pimm, Jonathan | Pocklington, Andrew J | Powell, John | Price, Alkes | Pulver, Ann E | Purcell, Shaun M | Quested, Digby | Rasmussen, Henrik B | Reichenberg, Abraham | Reimers, Mark A | Richards, Alexander L | Roffman, Joshua L | Roussos, Panos | Ruderfer, Douglas M | Salomaa, Veikko | Sanders, Alan R | Schall, Ulrich | Schubert, Christian R | Schulze, Thomas G | Schwab, Sibylle G | Scolnick, Edward M | Scott, Rodney J | Seidman, Larry J | Shi, Jianxin | Sigurdsson, Engilbert | Silagadze, Teimuraz | Silverman, Jeremy M | Sim, Kang | Slominsky, Petr | Smoller, Jordan W | So, Hon-Cheong | Spencer, Chris C A | Stahl, Eli A | Stefansson, Hreinn | Steinberg, Stacy | Stogmann, Elisabeth | Straub, Richard E | Strengman, Eric | Strohmaier, Jana | Stroup, T Scott | Subramaniam, Mythily | Suvisaari, Jaana | Svrakic, Dragan M | Szatkiewicz, Jin P | Söderman, Erik | Thirumalai, Srinivas | Toncheva, Draga | Tosato, Sarah | Veijola, Juha | Waddington, John | Walsh, Dermot | Wang, Dai | Wang, Qiang | Webb, Bradley T | Weiser, Mark | Wildenauer, Dieter B | Williams, Nigel M | Williams, Stephanie | Witt, Stephanie H | Wolen, Aaron R | Wong, Emily HM | Wormley, Brandon K | Xi, Hualin Simon | Zai, Clement C | Zheng, Xuebin | Zimprich, Fritz | Wray, Naomi R | Stefansson, Kari | Visscher, Peter M | Adolfsson, Rolf | Andreassen, Ole A | Blackwood, Douglas HR | Bramon, Elvira | Buxbaum, Joseph D | Børglum, Anders D | Cichon, Sven | Darvasi, Ariel | Domenici, Enrico | Ehrenreich, Hannelore | Esko, Tõnu | Gejman, Pablo V | Gill, Michael | Gurling, Hugh | Hultman, Christina M | Iwata, Nakao | Jablensky, Assen V | Jönsson, Erik G | Kendler, Kenneth S | Kirov, George | Knight, Jo | Lencz, Todd | Levinson, Douglas F | Li, Qingqin S | Liu, Jianjun | Malhotra, Anil K | McCarroll, Steven A | McQuillin, Andrew | Moran, Jennifer L | Mortensen, Preben B | Mowry, Bryan J | Nöthen, Markus M | Ophoff, Roel A | Owen, Michael J | Palotie, Aarno | Pato, Carlos N | Petryshen, Tracey L | Posthuma, Danielle | Rietschel, Marcella | Riley, Brien P | Rujescu, Dan | Sham, Pak C | Sklar, Pamela | St Clair, David | Weinberger, Daniel R | Wendland, Jens R | Werge, Thomas | Daly, Mark J | Sullivan, Patrick F | O’Donovan, Michael C
Nature  2014;511(7510):421-427.
Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here, we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain providing biological plausibility for the findings. Many findings have the potential to provide entirely novel insights into aetiology, but associations at DRD2 and multiple genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that play important roles in immunity, providing support for the hypothesized link between the immune system and schizophrenia.
PMCID: PMC4112379  PMID: 25056061
16.  Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer 
Wang, Yufei | McKay, James D. | Rafnar, Thorunn | Wang, Zhaoming | Timofeeva, Maria | Broderick, Peter | Zong, Xuchen | Laplana, Marina | Wei, Yongyue | Han, Younghun | Lloyd, Amy | Delahaye-Sourdeix, Manon | Chubb, Daniel | Gaborieau, Valerie | Wheeler, William | Chatterjee, Nilanjan | Thorleifsson, Gudmar | Sulem, Patrick | Liu, Geoffrey | Kaaks, Rudolf | Henrion, Marc | Kinnersley, Ben | Vallée, Maxime | LeCalvez-Kelm, Florence | Stevens, Victoria L. | Gapstur, Susan M. | Chen, Wei V. | Zaridze, David | Szeszenia-Dabrowska, Neonilia | Lissowska, Jolanta | Rudnai, Peter | Fabianova, Eleonora | Mates, Dana | Bencko, Vladimir | Foretova, Lenka | Janout, Vladimir | Krokan, Hans E. | Gabrielsen, Maiken Elvestad | Skorpen, Frank | Vatten, Lars | Njølstad, Inger | Chen, Chu | Goodman, Gary | Benhamou, Simone | Vooder, Tonu | Valk, Kristjan | Nelis, Mari | Metspalu, Andres | Lener, Marcin | Lubiński, Jan | Johansson, Mattias | Vineis, Paolo | Agudo, Antonio | Clavel-Chapelon, Francoise | Bueno-de-Mesquita, H.Bas | Trichopoulos, Dimitrios | Khaw, Kay-Tee | Johansson, Mikael | Weiderpass, Elisabete | Tjønneland, Anne | Riboli, Elio | Lathrop, Mark | Scelo, Ghislaine | Albanes, Demetrius | Caporaso, Neil E. | Ye, Yuanqing | Gu, Jian | Wu, Xifeng | Spitz, Margaret R. | Dienemann, Hendrik | Rosenberger, Albert | Su, Li | Matakidou, Athena | Eisen, Timothy | Stefansson, Kari | Risch, Angela | Chanock, Stephen J. | Christiani, David C. | Hung, Rayjean J. | Brennan, Paul | Landi, Maria Teresa | Houlston, Richard S. | Amos, Christopher I.
Nature genetics  2014;46(7):736-741.
We conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. We identified large-effect genome-wide associations for squamous lung cancer with the rare variants of BRCA2-K3326X (rs11571833; odds ratio [OR]=2.47, P=4.74×10−20) and of CHEK2-I157T (rs17879961; OR=0.38 P=1.27×10−13). We also showed an association between common variation at 3q28 (TP63; rs13314271; OR=1.13, P=7.22×10−10) and lung adenocarcinoma previously only reported in Asians. These findings provide further evidence for inherited genetic susceptibility to lung cancer and its biological basis. Additionally, our analysis demonstrates that imputation can identify rare disease-causing variants having substantive effects on cancer risk from pre-existing GWAS data.
PMCID: PMC4074058  PMID: 24880342
17.  Shared genetic susceptibility to ischemic stroke and coronary artery disease – a genome-wide analysis of common variants 
Background and Purpose
Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each have a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases.
Genome-wide association data were obtained from the METASTROKE, CARDIoGRAM, and C4D consortia. We first analyzed common variants reaching a nominal threshold of significance (p<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2,167 individuals with the ischemic large artery stroke (LAS) subtype.
Common variants associated with CAD at p<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, three and five loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (p<5×10-8) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Since these loci had prior evidence for genome-wide significance for CAD we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (pIS=1.62×10-07) and ABO (pIS =2.6×10-4) as well as at HDAC9 (pLAS=2.32×10-12), 9p21 (pLAS =3.70×10-6), RAI1-PEMT-RASD1 (pLAS =2.69×10-5), EDNRA (pLAS =7.29×10-4), and CYP17A1-CNNM2-NT5C2 (pLAS =4.9×10-4).
Our results demonstrate substantial overlap in the genetic risk of ischemic stroke and particularly the large artery stroke subtype with coronary artery disease.
PMCID: PMC4112102  PMID: 24262325
18.  A polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF/TFAP2A pathway 
Cell  2013;155(5):10.1016/j.cell.2013.10.022.
Sequence polymorphisms linked to human diseases and phenotypes in genome-wide association studies often affect non-coding regions. A single nucleotide polymorphism (SNP) within an intron of the gene encoding Interferon Regulatory Factor 4 (IRF4), a transcription factor with no known role in melanocyte biology, is strongly associated with sensitivity of skin to sun exposure, freckles, blue eyes and brown hair color. Here we demonstrate that this SNP lies within an enhancer of IRF4 transcription in melanocytes. The allele associated with this pigmentation phenotype impairs binding of the TFAP2A transcription factor which together with the melanocyte master regulator MITF, regulates activity of the enhancer. Assays in zebrafish and mice reveal that IRF4 cooperates with MITF to activate expression of Tyrosinase (TYR), an essential enzyme in melanin synthesis. Our findings provide a clear example of a non-coding polymorphism that affects a phenotype by modulating a developmental gene regulatory network.
PMCID: PMC3873608  PMID: 24267888
19.  Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process 
Springelkamp, Henriët. | Höhn, René | Mishra, Aniket | Hysi, Pirro G. | Khor, Chiea-Chuen | Loomis, Stephanie J. | Bailey, Jessica N. Cooke | Gibson, Jane | Thorleifsson, Gudmar | Janssen, Sarah F. | Luo, Xiaoyan | Ramdas, Wishal D. | Vithana, Eranga | Nongpiur, Monisha E. | Montgomery, Grant W. | Xu, Liang | Mountain, Jenny E. | Gharahkhani, Puya | Lu, Yi | Amin, Najaf | Karssen, Lennart C. | Sim, Kar-Seng | van Leeuwen, Elisabeth M. | Iglesias, Adriana I. | Verhoeven, Virginie J. M. | Hauser, Michael A. | Loon, Seng-Chee | Despriet, Dominiek D. G. | Nag, Abhishek | Venturini, Cristina | Sanfilippo, Paul G. | Schillert, Arne | Kang, Jae H. | Landers, John | Jonasson, Fridbert | Cree, Angela J. | van Koolwijk, Leonieke M. E. | Rivadeneira, Fernando | Souzeau, Emmanuelle | Jonsson, Vesteinn | Menon, Geeta | Weinreb, Robert N. | de Jong, Paulus T. V. M. | Oostra, Ben A. | Uitterlinden, André G. | Hofman, Albert | Ennis, Sarah | Thorsteinsdottir, Unnur | Burdon, Kathryn P. | Spector, Timothy D. | Mirshahi, Alireza | Saw, Seang-Mei | Vingerling, Johannes R. | Teo, Yik-Ying | Haines, Jonathan L. | Wolfs, Roger C. W. | Lemij, Hans G. | Tai, E-Shyong | Jansonius, Nomdo M. | Jonas, Jost B. | Cheng, Ching-Yu | Aung, Tin | Viswanathan, Ananth C. | Klaver, Caroline C. W. | Craig, Jamie E. | Macgregor, Stuart | Mackey, David A. | Lotery, Andrew J. | Stefansson, Kari | Bergen, Arthur A. B. | Young, Terri L. | Wiggs, Janey L. | Pfeiffer, Norbert | Wong, Tien-Yin | Pasquale, Louis R. | Hewitt, Alex W. | van Duijn, Cornelia M. | Hammond, Christopher J.
Nature Communications  2014;5:4883.
Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 individuals of European ancestry and 6,784 individuals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition.
Glaucoma is the most common cause of irreversible blindness worldwide. Here, the authors carry out a large meta-analysis of genetic data from individuals of European and Asian ancestry and identify 10 new loci associated with vertical cup-disc ratio, a key factor in the clinical assessment of patients with glaucoma.
PMCID: PMC4199103  PMID: 25241763
20.  Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm 
Gretarsdottir, Solveig | Baas, Annette F | Thorleifsson, Gudmar | Holm, Hilma | den Heijer, Martin | de Vries, Jean-Paul P M | Kranendonk, Steef E | Zeebregts, Clark J A M | van Sterkenburg, Steven M | Geelkerken, Robert H | van Rij, Andre M | Williams, Michael J A | Boll, Albert P M | Kostic, Jelena P | Jonasdottir, Adalbjorg | Jonasdottir, Aslaug | Walters, G Bragi | Masson, Gisli | Sulem, Patrick | Saemundsdottir, Jona | Mouy, Magali | Magnusson, Kristinn P | Tromp, Gerard | Elmore, James R | Sakalihasan, Natzi | Limet, Raymond | Defraigne, Jean-Olivier | Ferrell, Robert E | Ronkainen, Antti | Ruigrok, Ynte M | Wijmenga, Cisca | Grobbee, Diederick E | Shah, Svati H | Granger, Christopher B | Quyyumi, Arshed A | Vaccarino, Viola | Patel, Riyaz S | Zafari, A Maziar | Levey, Allan I | Austin, Harland | Girelli, Domenico | Pignatti, Pier Franco | Olivieri, Oliviero | Martinelli, Nicola | Malerba, Giovanni | Trabetti, Elisabetta | Becker, Lewis C | Becker, Diane M | Reilly, Muredach P | Rader, Daniel J | Mueller, Thomas | Dieplinger, Benjamin | Haltmayer, Meinhard | Urbonavicius, Sigitas | Lindblad, Bengt | Gottsäter, Anders | Gaetani, Eleonora | Pola, Roberto | Wells, Philip | Rodger, Marc | Forgie, Melissa | Langlois, Nicole | Corral, Javier | Vicente, Vicente | Fontcuberta, Jordi | España, Francisco | Grarup, Niels | Jørgensen, Torben | Witte, Daniel R | Hansen, Torben | Pedersen, Oluf | Aben, Katja K | de Graaf, Jacqueline | Holewijn, Suzanne | Folkersen, Lasse | Franco-Cereceda, Anders | Eriksson, Per | Collier, David A | Stefansson, Hreinn | Steinthorsdottir, Valgerdur | Rafnar, Thorunn | Valdimarsson, Einar M | Magnadottir, Hulda B | Sveinbjornsdottir, Sigurlaug | Olafsson, Isleifur | Magnusson, Magnus Karl | Palmason, Robert | Haraldsdottir, Vilhelmina | Andersen, Karl | Onundarson, Pall T | Thorgeirsson, Gudmundur | Kiemeney, Lambertus A | Powell, Janet T | Carey, David J | Kuivaniemi, Helena | Lindholt, Jes S | Jones, Gregory T | Kong, Augustine | Blankensteijn, Jan D | Matthiasson, Stefan E | Thorsteinsdottir, Unnur | Stefansson, Kari
Nature genetics  2010;42(8):692-697.
We performed a genome-wide association study on 1,292 individuals with abdominal aortic aneurysms (AAAs) and 30,503 controls from Iceland and The Netherlands, with a follow-up of top markers in up to 3,267 individuals with AAAs and 7,451 controls. The A allele of rs7025486 on 9q33 was found to associate with AAA, with an odds ratio (OR) of 1.21 and P = 4.6 × 10−10. In tests for association with other vascular diseases, we found that rs7025486[A] is associated with early onset myocardial infarction (OR = 1.18, P = 3.1 × 10−5), peripheral arterial disease (OR = 1.14, P = 3.9 × 10−5) and pulmonary embolism (OR = 1.20, P = 0.00030), but not with intracranial aneurysm or ischemic stroke. No association was observed between rs7025486[A] and common risk factors for arterial and venous diseases—that is, smoking, lipid levels, obesity, type 2 diabetes and hypertension. Rs7025486 is located within DAB2IP, which encodes an inhibitor of cell growth and survival.
PMCID: PMC4157066  PMID: 20622881
21.  A sequence variant associated with sortilin-1 (SORT1) on 1p13.3 is independently associated with abdominal aortic aneurysm 
Human Molecular Genetics  2013;22(14):2941-2947.
Abdominal aortic aneurysm (AAA) is a common human disease with a high estimated heritability (0.7); however, only a small number of associated genetic loci have been reported to date. In contrast, over 100 loci have now been reproducibly associated with either blood lipid profile and/or coronary artery disease (CAD) (both risk factors for AAA) in large-scale meta-analyses. This study employed a staged design to investigate whether the loci for these two phenotypes are also associated with AAA. Validated CAD and dyslipidaemia loci underwent screening using the Otago AAA genome-wide association data set. Putative associations underwent staged secondary validation in 10 additional cohorts. A novel association between the SORT1 (1p13.3) locus and AAA was identified. The rs599839 G allele, which has been previously associated with both dyslipidaemia and CAD, reached genome-wide significance in 11 combined independent cohorts (meta-analysis with 7048 AAA cases and 75 976 controls: G allele OR 0.81, 95% CI 0.76–0.85, P = 7.2 × 10−14). Modelling for confounding interactions of concurrent dyslipidaemia, heart disease and other risk factors suggested that this marker is an independent predictor of AAA susceptibility. In conclusion, a genetic marker associated with cardiovascular risk factors, and in particular concurrent vascular disease, appeared to independently contribute to susceptibility for AAA. Given the potential genetic overlap between risk factor and disease phenotypes, the use of well-characterized case–control cohorts allowing for modelling of cardiovascular disease risk confounders will be an important component in the future discovery of genetic markers for conditions such as AAA.
PMCID: PMC3690970  PMID: 23535823
22.  A Method for Detecting Long Non-Coding RNAs with Tiled RNA Expression Microarrays 
PLoS ONE  2014;9(6):e99899.
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.
PMCID: PMC4061049  PMID: 24937006
23.  Loss-of-function mutations in SLC30A8 protect against type 2 diabetes 
Flannick, Jason | Thorleifsson, Gudmar | Beer, Nicola L. | Jacobs, Suzanne B. R. | Grarup, Niels | Burtt, Noël P. | Mahajan, Anubha | Fuchsberger, Christian | Atzmon, Gil | Benediktsson, Rafn | Blangero, John | Bowden, Don W. | Brandslund, Ivan | Brosnan, Julia | Burslem, Frank | Chambers, John | Cho, Yoon Shin | Christensen, Cramer | Douglas, Desirée A. | Duggirala, Ravindranath | Dymek, Zachary | Farjoun, Yossi | Fennell, Timothy | Fontanillas, Pierre | Forsén, Tom | Gabriel, Stacey | Glaser, Benjamin | Gudbjartsson, Daniel F. | Hanis, Craig | Hansen, Torben | Hreidarsson, Astradur B. | Hveem, Kristian | Ingelsson, Erik | Isomaa, Bo | Johansson, Stefan | Jørgensen, Torben | Jørgensen, Marit Eika | Kathiresan, Sekar | Kong, Augustine | Kooner, Jaspal | Kravic, Jasmina | Laakso, Markku | Lee, Jong-Young | Lind, Lars | Lindgren, Cecilia M | Linneberg, Allan | Masson, Gisli | Meitinger, Thomas | Mohlke, Karen L | Molven, Anders | Morris, Andrew P. | Potluri, Shobha | Rauramaa, Rainer | Ribel-Madsen, Rasmus | Richard, Ann-Marie | Rolph, Tim | Salomaa, Veikko | Segrè, Ayellet V. | Skärstrand, Hanna | Steinthorsdottir, Valgerdur | Stringham, Heather M. | Sulem, Patrick | Tai, E Shyong | Teo, Yik Ying | Teslovich, Tanya | Thorsteinsdottir, Unnur | Trimmer, Jeff K. | Tuomi, Tiinamaija | Tuomilehto, Jaakko | Vaziri-Sani, Fariba | Voight, Benjamin F. | Wilson, James G. | Boehnke, Michael | McCarthy, Mark I. | Njølstad, Pål R. | Pedersen, Oluf | Groop, Leif | Cox, David R. | Stefansson, Kari | Altshuler, David
Nature genetics  2014;46(4):357-363.
Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets1,2,3, yet none are described for type 2 diabetes (T2D). Through sequencing or genotyping ~150,000 individuals across five ethnicities, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8)4 and harbors a common variant (p.Trp325Arg) associated with T2D risk, glucose, and proinsulin levels5–7. Collectively, protein-truncating variant carriers had 65% reduced T2D risk (p=1.7×10−6), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34SerfsX50) demonstrated reduced glucose levels (−0.17 s.d., p=4.6×10−4). The two most common protein-truncating variants (p.Arg138X and p.Lys34SerfsX50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested reduced zinc transport increases T2D risk8,9, yet phenotypic heterogeneity was observed in rodent Slc30a8 knockouts10–15. Contrastingly, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, proposing ZnT8 inhibition as a therapeutic strategy in T2D prevention.
PMCID: PMC4051628  PMID: 24584071
24.  Genome-wide meta-analysis identifies new susceptibility loci for migraine 
Anttila, Verneri | Winsvold, Bendik S. | Gormley, Padhraig | Kurth, Tobias | Bettella, Francesco | McMahon, George | Kallela, Mikko | Malik, Rainer | de Vries, Boukje | Terwindt, Gisela | Medland, Sarah E. | Todt, Unda | McArdle, Wendy L. | Quaye, Lydia | Koiranen, Markku | Ikram, M. Arfan | Lehtimäki, Terho | Stam, Anine H. | Ligthart, Lannie | Wedenoja, Juho | Dunham, Ian | Neale, Benjamin M. | Palta, Priit | Hamalainen, Eija | Schürks, Markus | Rose, Lynda M | Buring, Julie E. | Ridker, Paul M. | Steinberg, Stacy | Stefansson, Hreinn | Jakobsson, Finnbogi | Lawlor, Debbie A. | Evans, David M. | Ring, Susan M. | Färkkilä, Markus | Artto, Ville | Kaunisto, Mari A | Freilinger, Tobias | Schoenen, Jean | Frants, Rune R. | Pelzer, Nadine | Weller, Claudia M. | Zielman, Ronald | Heath, Andrew C. | Madden, Pamela A.F. | Montgomery, Grant W. | Martin, Nicholas G. | Borck, Guntram | Göbel, Hartmut | Heinze, Axel | Heinze-Kuhn, Katja | Williams, Frances M.K. | Hartikainen, Anna-Liisa | Pouta, Anneli | van den Ende, Joyce | Uitterlinden, Andre G. | Hofman, Albert | Amin, Najaf | Hottenga, Jouke-Jan | Vink, Jacqueline M. | Heikkilä, Kauko | Alexander, Michael | Muller-Myhsok, Bertram | Schreiber, Stefan | Meitinger, Thomas | Wichmann, Heinz Erich | Aromaa, Arpo | Eriksson, Johan G. | Traynor, Bryan | Trabzuni, Daniah | Rossin, Elizabeth | Lage, Kasper | Jacobs, Suzanne B.R. | Gibbs, J. Raphael | Birney, Ewan | Kaprio, Jaakko | Penninx, Brenda W. | Boomsma, Dorret I. | van Duijn, Cornelia | Raitakari, Olli | Jarvelin, Marjo-Riitta | Zwart, John-Anker | Cherkas, Lynn | Strachan, David P. | Kubisch, Christian | Ferrari, Michel D. | van den Maagdenberg, Arn M.J.M. | Dichgans, Martin | Wessman, Maija | Smith, George Davey | Stefansson, Kari | Daly, Mark J. | Nyholt, Dale R. | Chasman, Daniel | Palotie, Aarno
Nature genetics  2013;45(8):912-917.
PMCID: PMC4041123  PMID: 23793025
25.  Identification of heart rate–associated loci and their effects on cardiac conduction and rhythm disorders 
den Hoed, Marcel | Eijgelsheim, Mark | Esko, Tõnu | Brundel, Bianca J J M | Peal, David S | Evans, David M | Nolte, Ilja M | Segrè, Ayellet V | Holm, Hilma | Handsaker, Robert E | Westra, Harm-Jan | Johnson, Toby | Isaacs, Aaron | Yang, Jian | Lundby, Alicia | Zhao, Jing Hua | Kim, Young Jin | Go, Min Jin | Almgren, Peter | Bochud, Murielle | Boucher, Gabrielle | Cornelis, Marilyn C | Gudbjartsson, Daniel | Hadley, David | Van Der Harst, Pim | Hayward, Caroline | Heijer, Martin Den | Igl, Wilmar | Jackson, Anne U | Kutalik, Zoltán | Luan, Jian’an | Kemp, John P | Kristiansson, Kati | Ladenvall, Claes | Lorentzon, Mattias | Montasser, May E | Njajou, Omer T | O’Reilly, Paul F | Padmanabhan, Sandosh | Pourcain, Beate St. | Rankinen, Tuomo | Salo, Perttu | Tanaka, Toshiko | Timpson, Nicholas J | Vitart, Veronique | Waite, Lindsay | Wheeler, William | Zhang, Weihua | Draisma, Harmen H M | Feitosa, Mary F | Kerr, Kathleen F | Lind, Penelope A | Mihailov, Evelin | Onland-Moret, N Charlotte | Song, Ci | Weedon, Michael N | Xie, Weijia | Yengo, Loic | Absher, Devin | Albert, Christine M | Alonso, Alvaro | Arking, Dan E | de Bakker, Paul I W | Balkau, Beverley | Barlassina, Cristina | Benaglio, Paola | Bis, Joshua C | Bouatia-Naji, Nabila | Brage, Søren | Chanock, Stephen J | Chines, Peter S | Chung, Mina | Darbar, Dawood | Dina, Christian | Dörr, Marcus | Elliott, Paul | Felix, Stephan B | Fischer, Krista | Fuchsberger, Christian | de Geus, Eco J C | Goyette, Philippe | Gudnason, Vilmundur | Harris, Tamara B | Hartikainen, Anna-liisa | Havulinna, Aki S | Heckbert, Susan R | Hicks, Andrew A | Hofman, Albert | Holewijn, Suzanne | Hoogstra-Berends, Femke | Hottenga, Jouke-Jan | Jensen, Majken K | Johansson, Åsa | Junttila, Juhani | Kääb, Stefan | Kanon, Bart | Ketkar, Shamika | Khaw, Kay-Tee | Knowles, Joshua W | Kooner, Angrad S | Kors, Jan A | Kumari, Meena | Milani, Lili | Laiho, Päivi | Lakatta, Edward G | Langenberg, Claudia | Leusink, Maarten | Liu, Yongmei | Luben, Robert N | Lunetta, Kathryn L | Lynch, Stacey N | Markus, Marcello R P | Marques-Vidal, Pedro | Leach, Irene Mateo | McArdle, Wendy L | McCarroll, Steven A | Medland, Sarah E | Miller, Kathryn A | Montgomery, Grant W | Morrison, Alanna C | Müller-Nurasyid, Martina | Navarro, Pau | Nelis, Mari | O’Connell, Jeffrey R | O’Donnell, Christopher J | Ong, Ken K | Newman, Anne B | Peters, Annette | Polasek, Ozren | Pouta, Anneli | Pramstaller, Peter P | Psaty, Bruce M | Rao, Dabeeru C | Ring, Susan M | Rossin, Elizabeth J | Rudan, Diana | Sanna, Serena | Scott, Robert A | Sehmi, Jaban S | Sharp, Stephen | Shin, Jordan T | Singleton, Andrew B | Smith, Albert V | Soranzo, Nicole | Spector, Tim D | Stewart, Chip | Stringham, Heather M | Tarasov, Kirill V | Uitterlinden, André G | Vandenput, Liesbeth | Hwang, Shih-Jen | Whitfield, John B | Wijmenga, Cisca | Wild, Sarah H | Willemsen, Gonneke | Wilson, James F | Witteman, Jacqueline C M | Wong, Andrew | Wong, Quenna | Jamshidi, Yalda | Zitting, Paavo | Boer, Jolanda M A | Boomsma, Dorret I | Borecki, Ingrid B | Van Duijn, Cornelia M | Ekelund, Ulf | Forouhi, Nita G | Froguel, Philippe | Hingorani, Aroon | Ingelsson, Erik | Kivimaki, Mika | Kronmal, Richard A | Kuh, Diana | Lind, Lars | Martin, Nicholas G | Oostra, Ben A | Pedersen, Nancy L | Quertermous, Thomas | Rotter, Jerome I | van der Schouw, Yvonne T | Verschuren, W M Monique | Walker, Mark | Albanes, Demetrius | Arnar, David O | Assimes, Themistocles L | Bandinelli, Stefania | Boehnke, Michael | de Boer, Rudolf A | Bouchard, Claude | Caulfield, W L Mark | Chambers, John C | Curhan, Gary | Cusi, Daniele | Eriksson, Johan | Ferrucci, Luigi | van Gilst, Wiek H | Glorioso, Nicola | de Graaf, Jacqueline | Groop, Leif | Gyllensten, Ulf | Hsueh, Wen-Chi | Hu, Frank B | Huikuri, Heikki V | Hunter, David J | Iribarren, Carlos | Isomaa, Bo | Jarvelin, Marjo-Riitta | Jula, Antti | Kähönen, Mika | Kiemeney, Lambertus A | van der Klauw, Melanie M | Kooner, Jaspal S | Kraft, Peter | Iacoviello, Licia | Lehtimäki, Terho | Lokki, Marja-Liisa L | Mitchell, Braxton D | Navis, Gerjan | Nieminen, Markku S | Ohlsson, Claes | Poulter, Neil R | Qi, Lu | Raitakari, Olli T | Rimm, Eric B | Rioux, John D | Rizzi, Federica | Rudan, Igor | Salomaa, Veikko | Sever, Peter S | Shields, Denis C | Shuldiner, Alan R | Sinisalo, Juha | Stanton, Alice V | Stolk, Ronald P | Strachan, David P | Tardif, Jean-Claude | Thorsteinsdottir, Unnur | Tuomilehto, Jaako | van Veldhuisen, Dirk J | Virtamo, Jarmo | Viikari, Jorma | Vollenweider, Peter | Waeber, Gérard | Widen, Elisabeth | Cho, Yoon Shin | Olsen, Jesper V | Visscher, Peter M | Willer, Cristen | Franke, Lude | Erdmann, Jeanette | Thompson, John R | Pfeufer, Arne | Sotoodehnia, Nona | Newton-Cheh, Christopher | Ellinor, Patrick T | Stricker, Bruno H Ch | Metspalu, Andres | Perola, Markus | Beckmann, Jacques S | Smith, George Davey | Stefansson, Kari | Wareham, Nicholas J | Munroe, Patricia B | Sibon, Ody C M | Milan, David J | Snieder, Harold | Samani, Nilesh J | Loos, Ruth J F
Nature genetics  2013;45(6):621-631.
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.
PMCID: PMC3696959  PMID: 23583979

Results 1-25 (146)