Abstract 23: Genome Wide Association Study and Multi-Ancestry Meta-Analysis Identify Common Variants Associated With Carotid Artery Intima Media Thickness

Abstract

Carotid artery intima-media thickness (cIMT) is a measurement of subclinical atherosclerosis that predicts future cardiovascular events, including stroke and myocardial infarction. Genome-wide association studies (GWAS) in the past have identified only a fraction of the genetic variants associated with cIMT. We performed the largest GWAS to date for cIMT in a multi-ancestry meta-analysis in up to 131,000 individuals of African, Asian (Chinese), Brazilian, European, and Hispanic ancestries. Our study identified 57 independent loci (51 loci from the multi-ancestry single variant analysis of which 17 are novel, P<5x10 -8 ; 6 novel in gene-based analysis from single variant analysis, P = 2.6x10 -6 ) associated with cIMT. Gene-based, tissue-expression and gene-set enrichment analyses revealed novel genes of potential interest and highlighted significant relationships between vascular tissues (aorta, coronary and tibial arteries) and genetic associations. We found strong genome-wide correlation between cIMT and various cardiometabolic, smoking and lipid traits. Using Mendelian randomisation, our analyses provide robust evidence for causal associations between cIMT and several clinically relevant traits, including lipids, blood pressure, and waist circumference. Our results provide the first evidence of substantial pleiotropy in colocalisation signals between APOE SNPs and metabolite biomarkers for coronary artery disease and cIMT but not for Alzheimer's disease.In summary, we identify 57 loci robustly associated with cIMT that are expressed in a range of vascular tissue types including aorta, coronary and tibial arteries. Our findings suggest a bidirectional relationship between cIMT and hypertension but do not support a link between atherosclerosis and Alzheimer’s disease based on the APOE locus.