The Genetic Effect of Copy Number Variations on the Risk of Type 2 Diabetes in a Korean Population

Abstract

BackgroundUnlike Caucasian populations, genetic factors contributing to the risk of type 2 diabetes mellitus (T2DM) are not well studied in Asian populations. In light of this, and the fact that copy number variation (CNV) is emerging as a new way to understand human genomic variation, the objective of this study was to identify type 2 diabetes–associated CNV in a Korean cohort.Methodology/Principal FindingsUsing the Illumina HumanHap300 BeadChip (317,503 markers), genome-wide genotyping was performed to obtain signal and allelic intensities from 275 patients with type 2 diabetes mellitus (T2DM) and 496 nondiabetic subjects (Total n = 771). To increase the sensitivity of CNV identification, we incorporated multiple factors using PennCNV, a program that is based on the hidden Markov model (HMM). To assess the genetic effect of CNV on T2DM, a multivariate logistic regression model controlling for age and gender was used. We identified a total of 7,478 CNVs (average of 9.7 CNVs per individual) and 2,554 CNV regions (CNVRs; 164 common CNVRs for frequency>1%) in this study. Although we failed to demonstrate robust associations between CNVs and the risk of T2DM, our results revealed a putative association between several CNVRs including chr15:45994758–45999227 (P = 8.6E-04, Pcorr = 0.01) and the risk of T2DM. The identified CNVs in this study were validated using overlapping analysis with the Database of Genomic Variants (DGV; 71.7% overlap), and quantitative PCR (qPCR). The identified variations, which encompassed functional genes, were significantly enriched in the cellular part, in the membrane-bound organelle, in the development process, in cell communication, in signal transduction, and in biological regulation.Conclusion/SignificanceWe expect that the methods and findings in this study will contribute in particular to genome studies of Asian populations.

Copy Number Variations in Candidate Genes and Intergenic Regions Affect Body Mass Index and Abdominal Obesity in Mexican Children

“…Bae et al found three new regions with CNVs (chr15: 45994758–45999227, chr22: 20722473–21702142, and chr18: 3559620–3561217) that were significantly associated with the risk of T2D, particularly, the 15q21.1 region of chr15: 45994758–45999227 [9]. We found a significant association between the gain in the copy number in intergenic regions with abdominal obesity and increasing BMI.…”

“…At least two distinct pathways are known to be involved in the formation of CNVs-associated diseases: unequal meiotic recombination and replication errors. In particular, CNVs associated with diseases of polygenic origin such as autism [7], metabolic syndrome, obesity [8], and type 2 diabetes (T2D) [9] have been identified.…”

Unique characteristics of the Ainu population in Northern Japan

“…We further merged these data with genome-wide SNP data for 50 randomly sampled Korean individuals from Seoul who were originally used as a control group in a genome-wide association study. 13 With the inclusion of the Korean data, the number of overlapping SNPs was reduced to 65 256. The list of populations used in this study is shown in Table 1.…”

Genetic Determinants of Type 2 Diabetes in Asians

“…Each locus had previously been identified in SNP-based studies. Another GWAS of CNVs, however, failed to observe robust associations between CNVs and the risk of T2D in a Korean population [99]. These analyses suggest that common CNVs on existing platforms are not likely to have major contributions to T2D genetic susceptibility.…”

“…However, to date there are few reported associations between common CNVs and obesity and T2D [97–99]. In 2010, the Well come Trust Case Control Consortium performed a GWAS between CNVs and eight common human diseases in European populations, confirming three loci where CNVs were associated with Crohn’s disease ( IRGM locus ), rheumatoid arthritis and type 1 diabetes (HLA loci), and T2D ( TSPAN8 locus ) [98].…”