Phenotypic variance heterogeneity across genotypes at a single nucleotide polymorphism (SNP) may reflect underlying gene-environment (G×E) or gene-gene interactions. We modeled variance heterogeneity for blood lipids and BMI in up to 44,211 participants and investigated relationships between variance effects (P$_v$), G×E interaction effects (with smoking and physical activity), and marginal genetic effects (P$_m$). Correlations between P$_v$ and P$_m$ were stronger for SNPs with established marginal effects (Spearman's ρ = 0.401 for triglycerides, and ρ = 0.236 for BMI) compared to all SNPs. When P$_v$ and P$_m$ were compared for all pruned SNPs, only BMI was statistically significant (Spearman's ρ = 0.010). Overall, SNPs with established marginal effects were overrepresented in the nominally significant part of the P$_v$ distribution (P$_{binomial}$ <0.05). SNPs from the top 1% of the P$_m$ distribution for BMI had more significant Pv values (P$_{Mann-Whitney}$ = 1.46×10$^{-5}$), and the odds ratio of SNPs with nominally significant (<0.05) P$_m$ and P$_v$ was 1.33 (95% CI: 1.12, 1.57) for BMI. Moreover, BMI SNPs with nominally significant G×E interaction P-values (P$_{int}$<0.05) were enriched with nominally significant P$_v$ values (P$_{binomial}$ = 8.63×10$^{-9}$ and 8.52×10$^{-7}$ for SNP × smoking and SNP × physical activity, respectively). We conclude that some loci with strong marginal effects may be good candidates for G×E, and variance-based prioritization can be used to identify them. ; This research was undertaken as part of a research program supported by the European Commission (CoG-2015_681742_NASCENT), Swedish Research Council (Distinguished Young Researchers Award in Medicine), Swedish HeartLung Foundation, and the Novo Nordisk Foundation, all grants to PWF. DS is supported by the Swedish Research Council International Postdoc Fellowship (4.1-2016-00416). TVV is supported by the Novo Nordisk Foundation Postdoctoral Fellowship within Endocrinology/ Metabolism at International Elite Research Environments via NNF16OC0020698. TWW was supported by the grants "Bundesministerium fur Bildung und Forschung": BMBF-01ER1206, BMBF- 01ER1507. APM is a Wellcome Trust Senior Fellow in Basic Biomedical Science (grant WT098017). LAC acknowledges funding for the Framingham Heart Study: This research was conducted in part using data and resources from the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195 and Contract No. HHSN268201500001I) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. This research was partially supported by grant R01-DK089256 from the National Institute of Diabetes and Digestive and Kidney Diseases (MPIs: I.B. Borecki, LAC, K. North). TOK was supported by the Danish Council for Independent Research (DFF—1333-00124) and Sapere Aude program grant (DFF—1331-00730B). RM would like to acknowledge the High Performance Computing Center of University of Tartu. EGCUT was supported by EU H2020 grants 692145, 676550, 654248, 692065, Estonian Research Council Grant IUT20-60, and PerMed I NIASC, EIT—Health and European Union through the European Regional Development Fund (Project No, 2014-2020.4.01.15-0012 GENTRANSMED).
This work was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (grant 01ZX1313A-2014). The ADVANCE study was supported by a grant from the Reynold's Foundation and NHLBI grant HL087647. Sample collection in the Cardiogenics Consortium (http://www.cardiogenics.eu/web/) was funded by the 6th Framework Program of the European Union (LSHM-CT-2006-037593). We thank all the participants and clinicians involved in the recruitment process at Cambridge and Leicester (UK), Luebeck and Regensburg (Germany), and Paris (France). CATHGEN was supported by NIH grants HL095987 and HL101621. The Cleveland Clinic Gene Bank study was funded by P01HL076491 (to S.L.H). EGCUT was supported by Estonian Research Council grant no. IUT20-60 and Research Roadmap grant no. 3.2.0304.11-0312 and by University Tartu grant no. ARENG SP1GV. The FGENTCARD-Functional Genomic diagnostic tools for coronary artery disease project was funded by an EU FP6 award. We thank the patients for agreeing to participate in the study. We thank Sonia Youhanna, Nour Moukalled and Bariaa Khalil for their help with subject recruitment and data collection. The work of FINCAVAS was supported by the Competitive Research Funding of the Tampere University Hospital (Grant 9M048 and 9N035), the Finnish Cultural Foundation, the Finnish Foundation for Cardiovascular Research, the Emil Aaltonen Foundation, Finland, and the Tampere Tuberculosis Foundation. The authors thank the staff of the Department of Clinical Physiology for collecting the exercise test data. The GerMIFS studies were supported by grants from the German Federal Ministry of Education and Research (BMBF) within the framework of NGFN and NGFN-plus (Atherogenomics) and e:Med research and funding concept (e:AtheroSysMed, grant 01ZX1313A-2014), the Fondation Leducq (CADgenomics: Understanding CAD Genes, 12CVD02), and the European Union Sixth Framework Programme FP6 (under grant agreement FP6-LIFESCIHEALTH (Cardiogenics)) and the Seventh Framework Programme FP7/2007-2013 under grant agreement n° HEALTH-F2-2013-601456 (CVgenes-at-target). The Heart Protection Study (HPS) (ISRCTN48489393) was supported by the UK Medical Research Council (MRC), British Heart Foundation, Merck and Co (manufacturers of simvastatin), and Roche Vitamins Ltd (manufacturers of vitamins). Genotyping was supported by a grant to Oxford University and CNG from Merck and Co. Jemma C. Hopewell acknowledges support from the British Heart Foundation (FS/14/55/30806). HPS acknowledges the National Blood Service (NBS) donors and UK Twin study for using as population controls. A full list of the investigators who contributed to the generation of the NBS data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 07611. The UK Twin study was funded by the Wellcome Trust; European Community"s Seventh Framework Programme (FP7/2007–2013). The Helsinki Sudden Death Study (HSDS) was financially supported by EU's 7th Framework Programme (grant no. 201668 for AtheroRemo), the Tampere University Foundation, the Tampere University Hospital Medical Funds (grants X51001, 9M048 and 9N035 for Terho Lehtimäki, the Emil Aaltonen Foundation (Terho Lehtimäki, the Finnish Foundation of Cardiovascular Research (Terho Lehtimäki, Pekka J. Karhunen), the Pirkanmaa Regional Fund of the Finnish Cultural Foundation, the Yrjö Jahnsson Foundation, and the Tampere Tuberculosis Foundation (Terho Lehtimäki). LIFE-Heart is a part of the LIFE – Leipzig Research Center for Civilization Diseases, Universität Leipzig. LIFE is funded by means of the European Union, by the European Regional Development Fund (ERDF) and by means of the Free State of Saxony within the framework of the excellence initiative. The LOLIPOP study is supported by the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust, the British Heart Foundation (SP/04/002), the Medical Research Council (G0601966, G0700931), the Wellcome Trust (084723/Z/08/Z), the NIHR (RP-PG-0407-10371), European Union FP7 (EpiMigrant, 279143) and Action on Hearing (G51). We thank the participants and research staff who made the study possible. LURIC was supported by the 7th Framework Program (integrated project AtheroRemo, grant agreement number 201668 and RiskyCAD, grant agreement number 305739) of the European Union and by the INTERREG IV Oberrhein Program (Project A28, Genetic mechanisms of cardiovascular diseases) with support from the European Regional Development Fund (ERDF) and the Wissenschaftsoffensive TMO. We extend our appreciation to the participants of the LURIC study and thank the LURIC study team who were either temporarily or permanently involved in patient recruitment as well as sample and data handling, in addition to the laboratory staff at the Ludwigshafen General Hospital and the Universities of Freiburg and Ulm, Germany. The MIGen study was funded by R01HL087676 from the US National Heart, Lung, and Blood Institute. The Mount Sinai IPM Biobank Program is supported by The Andrea and Charles Bronfman Philanthropies. It was in part supported by NHGRI U01HG007417. OHGS_A2, OHGS_B2, and OHGS_C2 were funded by Canadian Institutes of Health Research (# MOP-2380941 to R.M.), (#MOP82810, MOP77682 to R.R., A.F.S. & R.M.); Canada Foundation for Innovation (#11966 to R.R., R.M. & A.F.S.; Heart & Stroke Foundation of Canada (#NA6001, #NA6650 to R.M). PIVUS was supported by Knut and Alice Wallenberg Foundation (Wallenberg Academy Fellow), European Research Council (ERC Starting Grant), Swedish Diabetes Foundation (grant no. 2013-024), Swedish Research Council (grant no. 2012-1397), and Swedish Heart-Lung Foundation (20120197). We thank the SNP&SEQ Technology Platform in Uppsala (www.genotyping.se) for excellent genotyping. The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under Project b2011036. PROCARDIS was supported by the European Community Sixth Framework Program (LSHM-CT- 2007-037273), AstraZeneca, the British Heart Foundation, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Swedish Heart-Lung Foundation, the Torsten and Ragnar Söderberg Foundation, the Strategic Cardiovascular Program of Karolinska Institutet and Stockholm County Council, the Foundation for Strategic Research and the Stockholm County Council (560283). Research in SDS was partly supported by NIH grants -R01DK082766 funded by the National Institute of Diabetes and Digestive and Kidney Diseases and NOT-HG-11-009 funded by National Genome Research Institute, and VPR Bridge grant from University of Oklahoma Health Sciences Center, Oklahoma City, USA. Recruitment for THISEAS was partially funded by a research grant (PENED 2003) from the Greek General Secretary of Research and Technology; we thank all the dieticians and clinicians for their contribution to the project. TwinGene was supported by grants from the Ministry for Higher Education, the Swedish Research Council (M-2005-1112 and 2009-2298), GenomEUtwin (EU/QLRT-2001-01254; QLG2-CT-2002-01254), NIH grant DK U01-066134, Knut and Alice Wallenberg Foundation (Wallenberg Academy Fellow), European Research Council (ERC Starting Grant), Swedish Diabetes Foundation (grant no. 2013-024), Swedish Research Council (grant no. 2012-1397), and Swedish Heart-Lung Foundation (20120197). We thank the SNP&SEQ Technology Platform in Uppsala (www. genotyping.se) for excellent genotyping. The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under Project b2011036. ULSAM was supported by Knut and Alice Wallenberg Foundation (Wallenberg Academy Fellow), European Research Council (ERC Starting Grant), Swedish Diabetes Foundation (grant no. 2013-024), Swedish Research Council (grant no. 2012-1397), and Swedish Heart-Lung Foundation (20120197). We thank the SNP&SEQ Technology Platform in Uppsala (www.genotyping.se) for excellent genotyping. The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under Project b2011036. Recruitment for the WTCCC study was funded by the British Heart Foundation and genotyping by the Wellcome Trust. Themistocles L. Assimes was supported by an NIDDK career development award DK088942. Panos Deloukas's work forms part of the research themes contributing to the translational research portfolio of Barts Cardiovascular Biomedical Research Unit which is supported and funded by the National Institute for Health Research. Analysis was partly supported by BHF grant (to Panos Deloukas) RG/14/5/30893. Martin Farrall and Hugh Watkins acknowledge the support of the Wellcome Trust core award (090532/Z/09/Z) and Martin Farrall, Hugh Watkins and Theodosios Kyriakou, the BHF Centre of Research Excellence. Anuj Goel, Hugh Watkins and Theodosios Kyriakou acknowledge European Union Seventh Framework Programme FP7/2007-2013 under grant agreement no. HEALTH-F2-2013-601456 (CVGenes@Target) & and Anuj Goel, the Wellcome Trust Institutional strategic support fund. The UK Twin study was funded by the Wellcome Trust; European Community's Seventh Framework Programme (FP7/2007- 2013). PoBI samples from the Wellcome Trust funded People of the British Isles project. Sekar Kathiresan is supported by the Donovan Family Foundation, Fondation Leducq, MGH Research Scholar Award, and R01 HL107816. Andrew P. Morris is a Wellcome Trust Senior Fellow in Basic Biomedical Science, funded under grant WT098017. Christopher P. Nelson and Nilesh J. Samani are funded by the British Heart Foundation and Nilesh J. Samani is a UK NIUHR Senior Investigator. Christopher P. Nelson and Nilesh J. Samani are funded by the British Heart Foundation and Nilesh J. Samani is a UK NIUHR Senior Investigator. Samuli Ripatti was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (Grant No. 213506 and 129680), Academy of Finland (Grant No. 251217 and 285380), the Finnish foundation for Cardiovascular Research, the Sigrid Juselius Foundation and the European Community's Seventh Framework Programme (FP7/2007-2013) through the BioSHaRE-EU (Biobank Standardisation and Harmonisation for Research Excellence in the European Union) project, grant agreement 261433. Alexandre F. R. Stewart is supported by operating grants from the Canadian Institute of Health Research and Natural Sciences and Engineering Research Council of Canada. Hong-Hee Won is supported by a postdoctoral award from the American Heart Association (15POST23280019).
Supplementary information accompanies this paper at http://www.nature.com/srep ; In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD. ; This work was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (grant 01ZX1313A-2014). The ADVANCE study was supported by a grant from the Reynold's Foundation and NHLBI grant HL087647. Sample collection in the Cardiogenics Consortium (http://www.cardiogenics.eu/web/) was funded by the 6th Framework Program of the European Union (LSHM-CT-2006-037593). We thank all the participants and clinicians involved in the recruitment process at Cambridge and Leicester (UK), Luebeck and Regensburg (Germany), and Paris (France). CATHGEN was supported by NIH grants HL095987 and HL101621. The Cleveland Clinic Gene Bank study was funded by P01HL076491 (to S.L.H). EGCUT was supported by Estonian Research Council grant no. IUT20-60 and Research Roadmap grant no. 3.2.0304.11-0312 and by University Tartu grant no. ARENG SP1GV. The FGENTCARD-Functional Genomic diagnostic tools for coronary artery disease project was funded by an EU FP6 award. We thank the patients for agreeing to participate in the study. We thank Sonia Youhanna, Nour Moukalled and Bariaa Khalil for their help with subject recruitment and data collection. The work of FINCAVAS was supported by the Competitive Research Funding of the Tampere University Hospital (Grant 9M048 and 9N035), the Finnish Cultural Foundation, the Finnish Foundation for Cardiovascular Research, the Emil Aaltonen Foundation, Finland, and the Tampere Tuberculosis Foundation. The authors thank the staff of the Department of Clinical Physiology for collecting the exercise test data. The GerMIFS studies were supported by grants from the German Federal Ministry of Education and Research (BMBF) within the framework of NGFN and NGFN-plus (Atherogenomics) and e:Med research and funding concept (e:AtheroSysMed, grant 01ZX1313A-2014), the Fondation Leducq (CADgenomics: Understanding CAD Genes, 12CVD02), and the European Union Sixth Framework Programme FP6 (under grant agreement FP6-LIFESCIHEALTH (Cardiogenics)) and the Seventh Framework Programme FP7/2007-2013 under grant agreement n° HEALTH-F2-2013-601456 (CVgenes-at-target). The Heart Protection Study (HPS) (ISRCTN48489393) was supported by the UK Medical Research Council (MRC), British Heart Foundation, Merck and Co (manufacturers of simvastatin), and Roche Vitamins Ltd (manufacturers of vitamins). Genotyping was supported by a grant to Oxford University and CNG from Merck and Co. Jemma C. Hopewell acknowledges support from the British Heart Foundation (FS/14/55/30806). HPS acknowledges the National Blood Service (NBS) donors and UK Twin study for using as population controls. A full list of the investigators who contributed to the generation of the NBS data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 07611. The UK Twin study was funded by the Wellcome Trust; European Community"s Seventh Framework Programme (FP7/2007–2013). The Helsinki Sudden Death Study (HSDS) was financially supported by EU's 7th Framework Programme (grant no. 201668 for AtheroRemo), the Tampere University Foundation, the Tampere University Hospital Medical Funds (grants X51001, 9M048 and 9N035 for Terho Lehtimäki, the Emil Aaltonen Foundation (Terho Lehtimäki, the Finnish Foundation of Cardiovascular Research (Terho Lehtimäki, Pekka J. Karhunen), the Pirkanmaa Regional Fund of the Finnish Cultural Foundation, the Yrjö Jahnsson Foundation, and the Tampere Tuberculosis Foundation (Terho Lehtimäki). LIFE-Heart is a part of the LIFE – Leipzig Research Center for Civilization Diseases, Universität Leipzig. LIFE is funded by means of the European Union, by the European Regional Development Fund (ERDF) and by means of the Free State of Saxony within the framework of the excellence initiative. The LOLIPOP study is supported by the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust, the British Heart Foundation (SP/04/002), the Medical Research Council (G0601966, G0700931), the Wellcome Trust (084723/Z/08/Z), the NIHR (RP-PG-0407-10371), European Union FP7 (EpiMigrant, 279143) and Action on Hearing (G51). We thank the participants and research staff who made the study possible. LURIC was supported by the 7th Framework Program (integrated project AtheroRemo, grant agreement number 201668 and RiskyCAD, grant agreement number 305739) of the European Union and by the INTERREG IV Oberrhein Program (Project A28, Genetic mechanisms of cardiovascular diseases) with support from the European Regional Development Fund (ERDF) and the Wissenschaftsoffensive TMO. We extend our appreciation to the participants of the LURIC study and thank the LURIC study team who were either temporarily or permanently involved in patient recruitment as well as sample and data handling, in addition to the laboratory staff at the Ludwigshafen General Hospital and the Universities of Freiburg and Ulm, Germany. The MIGen study was funded by R01HL087676 from the US National Heart, Lung, and Blood Institute. The Mount Sinai IPM Biobank Program is supported by The Andrea and Charles Bronfman Philanthropies. It was in part supported by NHGRI U01HG007417. OHGS_A2, OHGS_B2, and OHGS_C2 were funded by Canadian Institutes of Health Research (# MOP-2380941 to R.M.), (#MOP82810, MOP77682 to R.R., A.F.S. & R.M.); Canada Foundation for Innovation (#11966 to R.R., R.M. & A.F.S.; Heart & Stroke Foundation of Canada (#NA6001, #NA6650 to R.M). PIVUS was supported by Knut and Alice Wallenberg Foundation (Wallenberg Academy Fellow), European Research Council (ERC Starting Grant), Swedish Diabetes Foundation (grant no. 2013-024), Swedish Research Council (grant no. 2012-1397), and Swedish Heart-Lung Foundation (20120197). We thank the SNP&SEQ Technology Platform in Uppsala (www.genotyping.se) for excellent genotyping. The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under Project b2011036. PROCARDIS was supported by the European Community Sixth Framework Program (LSHM-CT- 2007-037273), AstraZeneca, the British Heart Foundation, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Swedish Heart-Lung Foundation, the Torsten and Ragnar Söderberg Foundation, the Strategic Cardiovascular Program of Karolinska Institutet and Stockholm County Council, the Foundation for Strategic Research and the Stockholm County Council (560283). Research in SDS was partly supported by NIH grants -R01DK082766 funded by the National Institute of Diabetes and Digestive and Kidney Diseases and NOT-HG-11-009 funded by National Genome Research Institute, and VPR Bridge grant from University of Oklahoma Health Sciences Center, Oklahoma City, USA. Recruitment for THISEAS was partially funded by a research grant (PENED 2003) from the Greek General Secretary of Research and Technology; we thank all the dieticians and clinicians for their contribution to the project. TwinGene was supported by grants from the Ministry for Higher Education, the Swedish Research Council (M-2005-1112 and 2009-2298), GenomEUtwin (EU/QLRT-2001-01254; QLG2-CT-2002-01254), NIH grant DK U01-066134, Knut and Alice Wallenberg Foundation (Wallenberg Academy Fellow), European Research Council (ERC Starting Grant), Swedish Diabetes Foundation (grant no. 2013-024), Swedish Research Council (grant no. 2012-1397), and Swedish Heart-Lung Foundation (20120197). We thank the SNP&SEQ Technology Platform in Uppsala (www.genotyping.se) for excellent genotyping. The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under Project b2011036. ULSAM was supported by Knut and Alice Wallenberg Foundation (Wallenberg Academy Fellow), European Research Council (ERC Starting Grant), Swedish Diabetes Foundation (grant no. 2013-024), Swedish Research Council (grant no. 2012-1397), and Swedish Heart-Lung Foundation (20120197). We thank the SNP&SEQ Technology Platform in Uppsala (www.genotyping.se) for excellent genotyping. The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under Project b2011036. Recruitment for the WTCCC study was funded by the British Heart Foundation and genotyping by the Wellcome Trust. Themistocles L. Assimes was supported by an NIDDK career development award DK088942. Panos Deloukas's work forms part of the research themes contributing to the translational research portfolio of Barts Cardiovascular Biomedical Research Unit which is supported and funded by the National Institute for Health Research. Analysis was partly supported by BHF grant (to Panos Deloukas) RG/14/5/30893. Martin Farrall and Hugh Watkins acknowledge the support of the Wellcome Trust core award (090532/Z/09/Z) and Martin Farrall, Hugh Watkins and Theodosios Kyriakou, the BHF Centre of Research Excellence. Anuj Goel, Hugh Watkins and Theodosios Kyriakou acknowledge European Union Seventh Framework Programme FP7/2007-2013 under grant agreement no. HEALTH-F2-2013-601456 (CVGenes@Target) & and Anuj Goel, the Wellcome Trust Institutional strategic support fund. The UK Twin study was funded by the Wellcome Trust; European Community's Seventh Framework Programme (FP7/2007-2013). PoBI samples from the Wellcome Trust funded People of the British Isles project. Sekar Kathiresan is supported by the Donovan Family Foundation, Fondation Leducq, MGH Research Scholar Award, and R01 HL107816. Andrew P. Morris is a Wellcome Trust Senior Fellow in Basic Biomedical Science, funded under grant WT098017. Christopher P. Nelson and Nilesh J. Samani are funded by the British Heart Foundation and Nilesh J. Samani is a UK NIUHR Senior Investigator. Christopher P. Nelson and Nilesh J. Samani are funded by the British Heart Foundation and Nilesh J. Samani is a UK NIUHR Senior Investigator. Samuli Ripatti was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (Grant No. 213506 and 129680), Academy of Finland (Grant No. 251217 and 285380), the Finnish foundation for Cardiovascular Research, the Sigrid Juselius Foundation and the European Community's Seventh Framework Programme (FP7/2007-2013) through the BioSHaRE-EU (Biobank Standardisation and Harmonisation for Research Excellence in the European Union) project, grant agreement 261433. Alexandre F. R. Stewart is supported by operating grants from the Canadian Institute of Health Research and Natural Sciences and Engineering Research Council of Canada. Hong-Hee Won is supported by a postdoctoral award from the American Heart Association (15POST23280019). ; Peer-reviewed ; Publisher Version
BACKGROUND: Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. OBJECTIVES: This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. METHODS: In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. RESULTS: We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10(-4) with a range of other diseases/traits. CONCLUSIONS: We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk. ; Drs. Akinsanya, Wu, Yin, and Reilly are employees of Merck Sharp & Dohme; and Dr. Vogt was an employee of Merck when aspects of this research was conducted, but is now retired from Merck. A cholesteryl ester transfer protein inhibitor, Anacetrapib (MK-0859), is currently undergoing clinical investigation in the REVEAL outcome trial sponsored by Merck Sharp & Dohme. Dr. Schick is an employee of Recombine. Dr. Dube has equity in DalCor Pharmaceuticals. Dr. McCarthy is a member of advisory boards for Pfizer and Novo Nordisk; has received honoraria from Pfizer, Novo Nordisk, and Eli Lilly; and has received research funding provided by Pfizer, Novo Nordisk, Eli Lilly, Servier, Sanofi-Aventis, Janssen, Roche, Boehringer-Ingelheim, Takeda, Merck, and AstraZeneca. Dr. Ferrieres has received grants from Merck Sharp & Dohme, Amgen, and Sanofi. Dr. Sattar has served as a consultant for Amgen and Sanofi. Dr. Butterworth has received grants from Pfizer and Merck. Dr. Danesh has served as a consultant for Takeda; has served on the Novartis Cardiovascular & Metabolic Advisory Board and International Cardiovascular and Metabolism Research and Development Portfolio Committee of Novartis; has served on the UK Atherosclerosis Advisory Board of Merck Sharp & Dohme; has served on the advisory board of Sanofi; has served on the Pfizer Population Research Advisory Panel; and has financial relationships with the British Heart Foundation, BUPA Foundation, diaDexus, European Research Council, European Union, Evelyn Trust, Fogarty International Centre, GlaxoSmithKline, Merck, National Heart, Lung, and Blood Institute, National Health Service Blood and Transplant, National Institute for Health Research, National Institute of Neurological Disorders and Stroke, Novartis, Pfizer, Roche, Sanofi, Takeda, The Wellcome Trust, UK Biobank, University of British Columbia, and UK Medical Research Council. Dr. Tardif has received research grants from Amarin, AstraZeneca, Merck, Pfizer, Eli Lilly, Sanofi, Servier, and DalCor; has received honoraria from Pfizer (to his institution), Servier, DalCor, and Sanofi (to his institution); and has received modest equity interest from DalCor. Dr. Kathiresan has financial/other relationships with Regeneron, Bayer, Catabasis, Merck, Celera, Genomics PLC, San Therapeutics, Novartis, Sanofi, AstraZeneca, Alnylam, Eli Lilly, Leerink Partners, and Noble Insights. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. A full list of acknowledgments and funding sources is included in the Online Appendix.
This is the final version. Available on open access from Nature Research via the DOI in this record. ; Data availability: GWAS summary statistics for FG/FI analyses presented in this manuscript are deposited on https://www.magicinvestigators.org/downloads/ and will be also be available through the NHGRI-EBI GWAS Catalog https://www.ebi.ac.uk/gwas/downloads/summary-statistics. Raw files for RNA-seq mRNA expression in islet donors have been deposited in NCBI GEO database with the accession code GSE50398. Summary-level GWAS results for genetic correlation analysis with glycemic traits were downloaded from the LDHub database (http://ldsc.broadinstitute.org/ldhub/). Islets from 89 cadaver donors were provided by the Nordic Islet Transplantation Programme (http://www.medscinet.com/nordicislets/). The dexseq_count python script for RNA sequencing analysis in human pancreatic islets was downloaded from http://www-huber.embl.de/pub/DEXSeq/analysis/scripts/. Raw files for RNA-seq mRNA expression in islet donors have been deposited in NCBI GEO database with the accession code GSE50398. ; Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes. ; Academy of Finland ; ADA ; Biotechnology and Biological Sciences Research Council (BBSRC) ; BHF ; Clinical Translational Science Institute ; Croatian Ministry of Science ; Directorate C - Public Health and Risk Assessment, Health & Consumer Protection ; Dutch Kidney Foundation ; Estonian Research Council ; European Research Council (ERC) ; European Regional Development Fund (ERDF) ; European Union Horizon 2020 ; Federal Ministry of Education and Research (BMBF), Germany ; Finnish Funding Agency for Technology and Innovation ; German Research Foundation ; Greek General Secretary of Research and Technology ; Icelandic National Bioethics Committee ; IFB Adiposity Diseases ; IngaBritt och Arne Lundberg's Research Foundation ; Italian Ministry of Health ; Knut & Alice Wallenberg foundation ; Kuopio University Hospital from Ministry of Health and Social Affairs ; Affymetrix, Inc ; Lundberg Foundation ; Medical Research Council (MRC) ; Mid-Atlantic Nutrition Obesity Research Center ; Ministry of Education and Culture of Finland ; MRC-GSK pilot programme ; NHLBI ; NIA ; NIH ; Nordic Centre of Excellence on Systems biology in controlled dietary interventions and cohort studies, SYSDIET ; Novo Nordisk Foundation ; NWO/ZonMW ; Spinozapremie ; Rutgers University Cell and DNA Repository ; Stockholm County Council ; Swedish Foundation for Strategic Research ; Swedish Heart-Lung Foundation ; Swedish Research Council ; Swiss National Science Foundation ; TEKES ; Torsten och Ragnar Söderbergs Stiftelser ; Wellcome Trust ; Yrjö Jahnsson Foundation ; Note that the full list of funders and grant numbers is available in the online article and in the PDF in this record