Genome-Wide Association Study of Metabolic Syndrome in Koreans

Abstract

Metabolic syndrome (METS) is a disorder of energy utilization and storage and increases the risk of developing cardiovascular disease and diabetes. To identify the genetic risk factors of METS, we carried out a genome-wide association study (GWAS) for 2,657 cases and 5,917 controls in Korean populations. As a result, we could identify 2 single nucleotide polymorphisms (SNPs) with genome-wide significance level p-values (<5 × 10-8), 8 SNPs with genome-wide suggestive p-values (5 × 10-8 ≤ p < 1 × 10-5), and 2 SNPs of more functional variants with borderline p-values (5 × 10-5 ≤ p < 1 × 10-4). On the other hand, the multiple correction criteria of conventional GWASs exclude false-positive loci, but simultaneously, they discard many true-positive loci. To reconsider the discarded true-positive loci, we attempted to include the functional variants (nonsynonymous SNPs [nsSNPs] and expression quantitative trait loci [eQTL]) among the top 5,000 SNPs based on the proportion of phenotypic variance explained by genotypic variance. In total, 159 eQTLs and 18 nsSNPs were presented in the top 5,000 SNPs. Although they should be replicated in other independent populations, 6 eQTLs and 2 nsSNP loci were located in the molecular pathways of LPL, APOA5, and CHRM2, which were the significant or suggestive loci in the METS GWAS. Conclusively, our approach using the conventional GWAS, reconsidering functional variants and pathway-based interpretation, suggests a useful method to understand the GWAS results of complex traits and can be expanded in other genomewide association studies.

Susceptibility loci for metabolic syndrome and metabolic components identified in Han Chinese: a multi‐stage genome‐wide association study

“…Efforts have been made to map the metabolicassociated single-nucleotide polymorphisms (SNPs) using a single component as the quantitative outcome [13][14][15][16][17][18][19]. Consider MetS as a binary outcome, several genome-wide association studies (GWAS) attempted to find susceptible genetic loci affecting multiple metabolic outcome [20][21][22][23][24]. From these studies, tagSNPs mainly including rs9939609 on FTO, rs629301 on SORT1, rs12678919 near LPL, rs1532085 on LIPC, rs651821 on APOA5, rs7412 on APOE, rs1532624 on CETP, rs671 on ALDH2, rs4607517 on GCK and other variants had been reported as metabolic-associated loci.…”

Genome-wide association study identifies African-ancestry specific variants for metabolic syndrome

“…Candidate gene and whole exome sequencing studies have also identified mutations in patients with rare forms of MetS [16, 17]. Meta-analyses of genome-wide association studies (GWAS) in Europeans and Asians have reported associations between MetS and variants in or near several loci including ZPR1 , BUD13 , APOA5 , LPL , and CETP genes [18–20]. …”

Quantitative candidate gene association studies of metabolic traits in Han Chinese type 2 diabetes patients

“…MetS is a disorder of energy utilization and storage, and it increases the risk of developing cardiovascular disease and diabetes. MetS includes multiple clinical traits including increased plasma glucose, abdominal obesity, dyslipidemia, and high blood pressure (Jeong et al, 2014). All current definitions of MetS include five clinical parameters in different combinations, namely: obesity, hypertriglyceridemia, low levels of high density lipoprotein, hypertension, and elevated levels of fasting glucose (Cohen et al, 2012).…”