Genome-wide association study and multi-ancestry meta-analysis identify common variants associated with carotid artery intima-media thickness

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) have identified only a fraction of the genetic variants associated with cIMT. We performed the largest GWAS for cIMT involving up to 131,000 individuals. For the first time, we meta-analysed a diverse range of ancestries including populations with African, Asian (Chinese), Brazilian, European, and Hispanic ancestries. Our study identified 59 independent loci (53 loci from the multi-ancestry single variant analysis of which 19 are novel, P<5x10 -8 ; 6 novel in gene-based analysis from single variant analysis, P=2.6x10 -6 , 2 novel in meta-regression) 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 that circulatory levels of seven proteins, including ACAN, BCAM, DUT, ERI1, APOE, FN1, and GLRX were potentially causally associated with cIMT levels. We found a strong genome-wide correlation between cIMT and various cardiometabolic, smoking phenotypes, 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 study extends our genetic knowledge of atherosclerosis and highlights potential causal relations between risk factors, atherosclerosis and clinical diagnoses.