Results
The discovery GWAS for pulse rate included 352,225 SNPs profiled with Affymetrix Genome-Wide human SNP array 5.0 in 8,842 individuals from the Ansung and Ansan cohorts as described previously [5]. Characteristics of the study, including age, sex, and trait summaries, are presented in Table 1. The association analysis identified several genomic locations as potentially associated with pulse rate. Unlike the previous GWAS [5], we did not apply a threshold with a p < 0.01 in both Ansung and Ansan cohort in addition to a combined p < 1 × 10-5 for the SNP selection for the replication study so that we could include more promising SNPs for their association with pulse rate. We observed 61 significant SNPs by applying only a threshold with a combined p < 1 × 10-5. After excluding SNPs by cluster plot inspection and removing singletons, 3 independent SNPs (that is, with pairwise linkage disequilibrium statistics r2 < 0.2 and MAF ≥ 0.05 within a 500-kb window of the genomic region) were finally chosen to validate in the independent population - i.e., the HEXA cohort, comprising 3,703 individuals. In the replication study, all 3 SNPs were confirmed for their association with pulse rate at a p < 0.05 (Table 2).
The first pulse rate signal located to 1q32.2a (rs12731740, MAF = 0.103, poverall = 2.20 × 10-8). Three genes, such as CD46, Clorf132, and CD34, appear near this locus [5]. The physiological relevance of the 3 genes in relation to pulse rate is not clear [8, 9]. Thus, fine mapping surrounding this locus by targeted resequencing is highly recommended to discover the causal variants for pulse rate. The second pulse rate SNP is rs12110693 (MAF = 0.494, poverall = 1.10 × 10-8) on 6q22.31c. The only gene located near this SNP is LOC644502, which has no known function. The third locus associated with pulse rate is at 6q22.31c (rs2892767, MAF = 0.261, poverall = 2.50 × 10-7). This locus is near GJA1 (Gap junction protein, alpha 1, 43 kDa), which is a member of the connexin gene family. The protein encoded by GJA1 is a component of gap junctions, which are intercellular channels that provide a route for the diffusion of low-molecular-weight materials from cell to cell.