Genome-wide association study identifies a new locus for coronary artery disease on chromosome 10p11.23

Aims Recent genome-wide association (GWA) studies identified 10 chromosomal loci for coronary artery disease (CAD) or myocardial infarction (MI). However, these loci explain only a small proportion of the genetic variability of these pertinent diseases. We sought to identify additional CAD/MI loci by applying a three-stage approach. Methods and results We genotyped n = 1157 MI cases and n = 1748 controls from a population-based study population [German MI Family Study (GerMIFS) III (KORA)] with genome-wide SNP arrays. At this first stage, n = 462 SNPsshowed association with MI at P <1 × 10−3 in two-sided logistic regression. In a second stage, 415 of these SNPswere evaluated in silicoin two independent GWA samples, the GerMIFS I (875 cases/1644 controls) and GerMIFS II (1222 cases/1298 controls). Nine SNPs, representing three regions, displayed consistent replication in this in silicoanalysis ( P <0.05 for each GWA sample): five SNPsat 9p21.3, a well-known CAD/MI locus, two SNPsat 10p11.21, and two SNPsat 2p24.3. Wet-lab replication, i.e. the third stage, of SNPrs3739998 (representing the novel locus at 10p11.21, p.S1002T in the KIAA1462 gene) in additional 5790 cases and 5302 controls confirmed the association ( P =9.54 × 10−4), but not for the 2p24.3 locus. The combined P -value across all stages for SNPrs3739998 is P =1.27 × 10−11 [odds ratio (OR) = 1.15 (1.11–1.20)]. Conclusion Analysis of a GWA study followed by in silicoand wet-lab replication steps identified the KIAA1462 gene, encoding a yet uncharacterized protein, on chromosome 10p11.23 with genome-wide significant association for CAD/MI. Further studies are needed to characterize the functional role of this locus in the aetiology of these diseases.