Genetic associations with carotid intima-media thickness in the Chinese population and shared genetic architecture with cardiometabolic diseases and trait
Wang W., Huang N., Yu C., Sun D., Pei P., Yang L., Millwood IY., Walters RG., Chen Y., Du H., Barnard M., Liu X., Chen J., Chen Z., Lv J., Huang T., Li L.
Background: Carotid artery intima-media thickness (cIMT) is a highly heritable measure of subclinical atherosclerosis and a predictor of cardiovascular diseases. However, knowledge about their shared genetic basis remains limited. The majority of genome-wide association studies (GWASs) have been conducted in individuals of European ancestry, leaving the genetic determinants of cIMT in non-European ancestry populations largely understudied. Methods:A single-trait GWAS was performed in 22,370 participants from the China Kadoorie Biobank (CKB) to identify new genetic variants associated with cIMT. We then leveraged cIMT and cardiometabolic diseases and traits data from populations of European and East Asian ancestries, to conduct linkage disequilibrium score regression and genomewide cross-trait analysis, followed by gene-based analysis and Mendelian randomization (MR). Results: We identified two genome-wide significant loci for cIMT in the overall CKB analysis, including the known APOE locus and a novel locus at GGT5. In addition, a femalespecific analysis identified a further novel locus at LINC02732. cIMT showed significant positive genetic correlation with coronary artery disease (CAD), type 2 diabetes (T2D), body mass index (BMI), and systolic blood pressure (SBP) in both European and East Asian populations. Pleiotropic analysis found 110 and 699 significant pleiotropic variants in four trait pairs for East Asian and European populations, respectively, with 27 and 186 colocalized loci detected. Gene-based analysis highlighted important biological pathways involving lipid metabolism and carbohydrate metabolism. MR estimates indicated that higher SBP and BMI levels, and CAD and T2D were causal for cIMT, and a reverse effect was observed between cIMT and SBP. Conclusion: Our large-scale GWAS of cIMT identified novel loci in Chinese population and shared genetic underpinnings and causal relationships with cardiometabolic diseases and traits. These findings potentially provide targets of intervention that may allow the development of new strategies targeting this aspect of atherosclerosis.