Six novel susceptibility loci for coronary artery disease and cerebral infarction identified by longitudinal exome-wide association studies in a Japanese population

Coronary artery disease (CAD) and cerebral infarction (CI) remain major causes of morbidity and mortality in humans. Recent genome-wide association studies have identified various genetic variants associated with these diseases. However, these studies were commonly conducted in a cross-sectional manner. Therefore, the present research performed longitudinal exome-wide association studies for CAD and CI using data on ~244,000 genotyped variants and the clinical data of 6,026 Japanese individuals who had attended annual health checkups for several years (mean followed-up period, 5±3 years). Following quality controls, the significance [false discovery rate (FDR) of <0.05] of association of the diseases with 24,651 single nucleotide polymorphisms (SNPs) in 5,989 individuals for three inheritance models was tested using the generalized estimating equation model. SNPs that reached statistical significance were further screened against a threshold of approxdf (a scale of small effective sample size) of >30. The longitudinal exome-wide association studies revealed that three SNPs [rs4606855 of ADGRE3 (P=2.5×10(−6); FDR=0.031; approxdf=71), rs3746414 of ZFP64 (P=5.9×10(−6); FDR=0.048; approxdf=93) and rs7132908 of FAIM2 (P<2.0×10(−16); FDR<4.9×10(−12); approxdf=65)] were significantly associated with the prevalence of CAD. A different set of three SNPs [rs6580741 of FAM186A (P<2.0×10(−16); FDR<4.9×10(−12); approxdf=48), rs1324015 of LINC00400 (P<2.0×10(−16); FDR<4.9×10(−12); approxdf=49) and rs884205 of TNFRSF11A (P<2.0×10(−16); FDR<4.9×10(−12); approxdf=32)] was significantly associated with CI. The comparison of disease incidence with these SNPs demonstrated that all the minor alleles were associated with decreased susceptibility to CAD or CI. In conclusion, six novel SNPs were identified as susceptibility loci for CAD (rs4606855 of ADGRE3, rs3746414 of ZFP64, and rs7132908 of FAIM2) or CI (rs6580741 of FAM186A, rs1324015 of LINC00400, and rs884205 of TNFRSF11A).