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Joint effects of known type 2 diabetes susceptibility loci in genome-wide association study of Singapore Chinese: The Singapore Chinese health study

Chen, Z and Pereira, MA and Seielstad, M and Koh, WP and Tai, ES and Teo, YY and Liu, J and Hsu, C and Wang, R and Odegaard, AO and Thyagarajan, B and Koratkar, R and Yuan, JM and Gross, MD and Stram, DO (2014) Joint effects of known type 2 diabetes susceptibility loci in genome-wide association study of Singapore Chinese: The Singapore Chinese health study. PLoS ONE, 9 (2).

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Abstract

Background: Genome-wide association studies (GWAS) have identified genetic factors in type 2 diabetes (T2D), mostly among individuals of European ancestry. We tested whether previously identified T2D-associated single nucleotide polymorphisms (SNPs) replicate and whether SNPs in regions near known T2D SNPs were associated with T2D within the Singapore Chinese Health Study. Methods: 2338 cases and 2339 T2D controls from the Singapore Chinese Health Study were genotyped for 507,509 SNPs. Imputation extended the genotyped SNPs to 7,514,461 with high estimated certainty (r2>0.8). Replication of known index SNP associations in T2D was attempted. Risk scores were computed as the sum of index risk alleles. SNPs in regions ±100 kb around each index were tested for associations with T2D in conditional fine-mapping analysis. Results: Of 69 index SNPs, 20 were genotyped directly and genotypes at 35 others were well imputed. Among the 55 SNPs with data, disease associations were replicated (at p<0.05) for 15 SNPs, while 32 more were directionally consistent with previous reports. Risk score was a significant predictor with a 2.03 fold higher risk CI (1.69-2.44) of T2D comparing the highest to lowest quintile of risk allele burden (p = 5.72×10-14). Two improved SNPs around index rs10923931 and 5 new candidate SNPs around indices rs10965250 and rs1111875 passed simple Bonferroni corrections for significance in conditional analysis. Nonetheless, only a small fraction (2.3% on the disease liability scale) of T2D burden in Singapore is explained by these SNPs. Conclusions: While diabetes risk in Singapore Chinese involves genetic variants, most disease risk remains unexplained. Further genetic work is ongoing in the Singapore Chinese population to identify unique common variants not already seen in earlier studies. However rapid increases in T2D risk have occurred in recent decades in this population, indicating that dynamic environmental influences and possibly gene by environment interactions complicate the genetic architecture of this disease. © 2014 Chen et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Chen, Z
Pereira, MA
Seielstad, M
Koh, WP
Tai, ES
Teo, YY
Liu, J
Hsu, C
Wang, Rrew59@pitt.eduREW59
Odegaard, AO
Thyagarajan, B
Koratkar, R
Yuan, JMyuanj@pitt.eduYUANJ
Gross, MD
Stram, DO
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorHuang, QingyangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 10 February 2014
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 9
Number: 2
DOI or Unique Handle: 10.1371/journal.pone.0087762
Schools and Programs: Graduate School of Public Health > Epidemiology
Refereed: Yes
Date Deposited: 18 Jun 2014 20:06
Last Modified: 22 Jun 2021 15:55
URI: http://d-scholarship.pitt.edu/id/eprint/21906

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