Large-scale genome-wide association study of coronary artery disease in genetically diverse populations

Abstract

Coronary artery disease (CAD) is a leading cause of death, yet its genetic determinants are not fully elucidated. We report a multi-ethnic genome-wide association study of CAD involving nearly a quarter of a million cases, incorporating the largest cohorts to date of Whites, Blacks, and Hispanics from the Million Veteran Program with existing studies including CARDIoGRAMplusC4D, UK Biobank, and Biobank Japan. We verify substantial and nearly equivalent heritability of CAD across multiple ancestral groups, discover 107 novel loci including the first nine on the X-chromosome, identify the first eight genome-wide significant loci among Blacks and Hispanics, and demonstrate that two common haplotypes are largely responsible for the risk stratification at the well-known 9p21 locus in most populations except those of African origin where both haplotypes are virtually absent. We identify 15 loci for angiographically derived burden of coronary atherosclerosis, which robustly overlap with the strongest and earliest loci reported to date for clinical CAD. Phenome-wide association analyses of novel loci and externally validated polygenic risk scores (PRS) augment signals from the insulin resistance cluster of risk factors and consequences, extend previously established pleiotropic associations of loci with traditional risk factors to include smoking and family history, and confirm a substantially reduced transferability of existing PRS to Blacks. Downstream integrative genomic analyses reinforce the critical role of endothelial, fibroblast, and smooth muscle cells within the coronary vessel wall in CAD susceptibility. Our study highlights the value of a multi-ethnic design in efficiently characterizing the genetic architecture of CAD across all human populations.

Genome-Wide Transcriptional Profiling Reveals PHACTR1 as a Novel Molecular Target of Resveratrol in Endothelial Homeostasis

“…By using bio-informatics research methods such as the validation of data correlation, the screening of DEGs, and functional enrichment analysis, DEGs and signaling pathways between the two groups were studied. At the same time, DEGs were overlaid using the GWAS-CAD database and the UK Biobank database and the screened genes were validated with the GSE41571 dataset [ 30 , 31 , 32 ]. Finally, the expression of screened genes was verified by real-time PCR and Western blotting, and the role of the target gene was determined using cell adhesion assay.…”

Single and Combined Associations of Plasma and Urine Essential Trace Elements (Zn, Cu, Se, and Mn) with Cardiovascular Risk Factors in a Mediterranean Population

“…Finally, we did not analyze the genetic factors that may influence cardiovascular risk, which is still another limitation of our study. Several genetic polymorphisms are currently known to be associated with higher concentrations of plasma lipids (i.e., polymorphisms in the APOE gene determining LDL-c levels), blood glucose (i.e., polymorphisms in the TCF7L2 gene), body mass index (i.e., polymorphisms in the FTO gene), and other cardiovascular risk factors [ 179 , 180 , 181 , 182 , 183 ]. More recently, associations of cardiovascular risk factors with microbiota-related polymorphisms have been reported [ 184 ].…”

Polygenic Risk Score and Statin Relative Risk Reduction for Primary Prevention of Myocardial Infarction in a Real‐World Population

“…16,17 CHD polygenic risk score We selected the 164 variants independently associated with CHD (and corresponding odds ratios) in prior genome-wide association studies from the UK Biobank and Coronary Artery Disease Genome-Wide Replication and Meta-Analysis plus The Coronary Artery Disease (CARDIoGRAMplusC4D) (Table S1). [18][19][20] To calculate a polygenic risk score for each participant, the count of each variant allele (or allelic dosage for imputed variants) was weighted (log of the odds ratios for the prior strength of association between each variant and CHD) and summed. See Supplementary Methods for more details.…”