Association of Genetic Risk Variants With Expression of Proximal Genes Identifies Novel Susceptibility Genes for Cardiovascular Disease (original) (raw)
Transcriptome-wide association studies (TWAS) explore genetic variants affecting gene expression for association with a trait. Here we studied coronary artery disease (CAD) using this approach by first determining genotype-regulated expression levels in nine CAD relevant tissues by EpiXcan in two genetics-of-gene-expression panels, the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) and the Genotype-Tissue Expression (GTEx). Based on these data we next imputed gene expression in respective nine tissues from individual level genotype data on 37,997 CAD cases and 42,854 controls for a subsequent gene-trait association analysis. Transcriptome-wide significant association (P < 3.85e-6) was observed for 114 genes, which by genetic means were differentially expressed predominately in arterial, liver, and fat tissues. Of these, 96 resided within previously identified GWAS risk loci and 18 were novel (CAND1, EGFLAM, EZR, FAM114A1, FOCAD, GAS8, HOMER3, KPTN, MGP...
Implications of discoveries from genome-wide association studies in current cardiovascular practice
Genome-wide association studies (GWAS) have identified several genetic variants associated with coronary heart disease (CHD), and variations in plasma lipoproteins and blood pressure (BP). Loci corresponding to CDKN2A/CDKN2B/ANRIL , MTHFD1L , CELSR2 , PSRC1 and SORT1 genes have been associated with CHD, and TMEM57 , DOCK7 , CELSR2 , APOB , ABCG5 , HMGCR , TRIB1 , FADS2/S3 , LDLR , NCAN and TOMM40-APOE with total cholesterol. Similarly, CELSR2-PSRC1-SORT1 , PCSK9 , APOB , HMGCR , NCAN-CILP2-PBX4 , LDLR , TOMM40-APOE , and APOC1-APOE are associated with variations in low-density lipoprotein cholesterol levels. Altogether, forty, forty three and twenty loci have been associated with high-density lipoprotein cholesterol, triglycerides and BP phenotypes, respectively. Some of these identified loci are common for all the traits, some do not map to functional genes, and some are located in genes that encode for proteins not previously known to be involved in the biological pathway of the trait. GWAS have been successful at identifying new and unexpected genetic loci common to diseases and traits, thus rapidly providing key novel insights into disease biology. Since genotype information is fixed, with minimum biological variability, it is useful in early life risk prediction. However, these variants explain only a small proportion of the observed variance of these traits. Therefore, the utility of genetic determinants in assessing risk at later stages of life has limited immediate clinical impact. The future application of genetic screening will be in identifying risk groups early in life to direct targeted preventive measures.