Identification of 26 novel loci that confer susceptibility to early-onset coronary artery disease in a Japanese population

Early-onset coronary artery disease (CAD) has a strong genetic component. Although genome-wide association studies have identified various genes and loci significantly associated with CAD mainly in European populations, genetic variants that contribute toward susceptibility to this condition in Japanese patients remain to be definitively identified. In the present study, exome-wide association studies (EWASs) were performed to identify genetic variants that confer susceptibility to early-onset CAD in Japanese. A total of 7,256 individuals aged ≤65 years were enrolled in the present study. EWAS were conducted on 1,482 patients with CAD and 5,774 healthy controls. Genotyping of single nucleotide polymorphisms (SNPs) was performed using Illumina Human Exome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. The association between allele frequencies for 31,465 SNPs that passed quality control and CAD was examined using Fisher's exact test. To compensate for multiple comparisons of allele frequencies with CAD, a false discovery rate (FDR) of <0.05 was applied for statistically significant associations. The association between allele frequencies for 31,465 SNPs and CAD, as determined by Fisher's exact test, demonstrated that 170 SNPs were significantly (FDR <0.05) associated with CAD. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of hypertension, diabetes mellitus and dyslipidemia revealed that 162 SNPs were significantly (P<0.05) associated with CAD. A stepwise forward selection procedure was performed to examine the effects of genotypes for the 162 SNPs on CAD. The 54 SNPs were significant (P<0.05) and independent [coefficient of determination (R(2)), 0.0008 to 0.0297] determinants of CAD. These SNPs together accounted for 15.5% of the cause of CAD. Following examination of results from previous genome-wide association studies and linkage disequilibrium of the identified SNPs, 21 genes (RNF2, YEATS2, USP45, ITGB8, TNS3, FAM170B-AS1, PRKG1, BTRC, MKI67, STIM1, OR52E4, KIAA1551, MON2, PLUT, LINC00354, TRPM1, ADAT1, KRT27, LIPE, GFY and EIF3L) and five chromosomal regions (2p13, 4q31.2, 5q12, 13q34 and 20q13.2) that were significantly associated with CAD were newly identified in the present study. Gene ontology analysis demonstrated that various biological functions were predicted in the 18 genes identified in the present study. The network analysis revealed that the 18 genes had potential direct or indirect interactions with the 30 genes previously revealed to be associated with CAD or with the 228 genes identified in previous genome-wide association studies. The present study newly identified 26 loci that confer susceptibility to CAD. Determination of genotypes for the SNPs at these loci may prove informative for assessment of the genetic risk for CAD in Japanese patients.