Genetic Analysis in UK Biobank Links Insulin Resistance and Transendothelial Migration Pathways to Coronary Artery Disease

UK Biobank is among the world's largest repositories for phenotypic and genotypic information in individuals of European ancestry. We performed a genome-wide association study in UK Biobank testing ∼9 million DNA sequence variants for association with coronary artery disease (4,831 cases and 115,455 controls) and carried out meta-analysis with previously published results. We identified 15 new loci, bringing the total number of loci associated with coronary artery disease to 95 at the time of analysis. Phenome-wide association scanning showed that CCDC92 likely affects coronary artery disease through insulin resistance pathways, whereas experimental analysis suggests that ARHGEF26 influences the transendothelial migration of leukocytes.

[1]  Tanya M. Teslovich,et al.  Discovery and refinement of loci associated with lipid levels , 2013, Nature Genetics.

[2]  J. Shendure,et al.  LOX Mutations Predispose to Thoracic Aortic Aneurysms and Dissections. , 2016, Circulation research.

[3]  Tamara S. Roman,et al.  New genetic loci link adipose and insulin biology to body fat distribution , 2014, Nature.

[4]  Karen L. Mohlke,et al.  Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals , 2012, PLoS genetics.

[5]  Olle Melander,et al.  From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus , 2010, Nature.

[6]  Klaus Ley,et al.  Monocyte trafficking across the vessel wall. , 2015, Cardiovascular research.

[7]  Benjamin J. Wright,et al.  Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease , 2009, Nature Genetics.

[8]  Ashutosh Kumar Singh,et al.  Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015 , 2016, The Lancet.

[9]  He Zhang,et al.  Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease , 2017, Journal of the American College of Cardiology.

[10]  K. Hahn,et al.  The Guanine-Nucleotide Exchange Factor SGEF Plays a Crucial Role in the Formation of Atherosclerosis , 2013, PloS one.

[11]  K. Wennerberg,et al.  SGEF, a RhoG guanine nucleotide exchange factor that stimulates macropinocytosis. , 2004, Molecular biology of the cell.

[12]  Dermot F. Reilly,et al.  Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease , 2018 .

[13]  N. Mehta.  Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. , 2011, Circulation. Cardiovascular genetics.

[14]  Claude Bouchard,et al.  A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance , 2012, Nature Genetics.

[15]  Eric Banks,et al.  Tools and best practices for data processing in allelic expression analysis , 2015, Genome Biology.

[16]  R. Collins.  What makes UK Biobank special? , 2012, The Lancet.

[17]  Yun Li,et al.  METAL: fast and efficient meta-analysis of genomewide association scans , 2010, Bioinform..

[18]  A. Schober,et al.  Dicer generates a regulatory microRNA network in smooth muscle cells that limits neointima formation during vascular repair , 2016, Cellular and Molecular Life Sciences.

[19]  Alberto Piazza,et al.  Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants , 2009, Nature Genetics.

[20]  Eleazar Eskin,et al.  Local genetic effects on gene expression across 44 human tissues , 2016, bioRxiv.

[21]  Ross M. Fraser,et al.  Defining the role of common variation in the genomic and biological architecture of adult human height , 2014, Nature Genetics.

[22]  Melinda Larsen,et al.  Fibronectin requirement in branching morphogenesis , 2003, Nature.

[23]  D. Gudbjartsson,et al.  Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease. , 2016, The New England journal of medicine.

[24]  A. Khera,et al.  Genetics of coronary artery disease: discovery, biology and clinical translation , 2017, Nature Reviews Genetics.

[25]  Wen-Harn Pan,et al.  A Genome-Wide Association Study Reveals a Quantitative Trait Locus of Adiponectin on CDH13 That Predicts Cardiometabolic Outcomes , 2011, Diabetes.

[26]  C. Gieger,et al.  Genomewide association analysis of coronary artery disease. , 2007, The New England journal of medicine.

[27]  Jing He,et al.  Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation , 2015, Nature Genetics.

[28]  Mark I. McCarthy,et al.  A Central Role for GRB10 in Regulation of Islet Function in Man , 2014, PLoS genetics.

[29]  Michael J. Allingham,et al.  RhoG regulates endothelial apical cup assembly downstream from ICAM1 engagement and is involved in leukocyte trans-endothelial migration , 2007, The Journal of cell biology.

[30]  Tom R. Gaunt,et al.  Edinburgh Research Explorer Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function , 2022 .

[31]  Bonnie Berger,et al.  Efficient Bayesian mixed model analysis increases association power in large cohorts , 2014 .

[32]  J. Danesh,et al.  Large-scale association analysis identifies new risk loci for coronary artery disease , 2013 .

[33]  Alan D. Lopez,et al.  The Global Burden of Disease Study , 2003 .

[34]  Andreas Busjahn,et al.  PDE3A mutations cause autosomal dominant hypertension with brachydactyly , 2015, Nature Genetics.

[35]  L. Wain,et al.  Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank , 2015, The Lancet. Respiratory medicine.

[36]  C. Lian,et al.  Loss of function mutation in LOX causes thoracic aortic aneurysm and dissection in humans , 2016, Proceedings of the National Academy of Sciences.

[37]  J. Danesh,et al.  A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease , 2016 .

[38]  Quynh-Thu Le,et al.  Lysyl oxidase is essential for hypoxia-induced metastasis , 2006, Nature.

[39]  Andrew D. Johnson,et al.  Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms , 2017, Nature Genetics.

[40]  D. Geerts,et al.  The Rho-guanine nucleotide exchange factor Trio controls leukocyte transendothelial migration by promoting docking structure formation , 2012, Molecular biology of the cell.

[41]  Judy H. Cho,et al.  Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations , 2015, Nature Genetics.

[42]  Bernadette A. Thomas,et al.  Global, regional, and national age–sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013 , 2015, The Lancet.

[43]  Christian Gieger,et al.  Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture , 2013, Nature Genetics.

[44]  Melissa A. Basford,et al.  Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data , 2013, Nature Biotechnology.

[45]  Inês Barroso,et al.  Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance , 2016, Nature Genetics.

[46]  Tanya M. Teslovich,et al.  Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes , 2012, Nature Genetics.

[47]  David A. Cheresh,et al.  Role of integrins in cell invasion and migration , 2002, Nature Reviews Cancer.