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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

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 T...

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Autores principales: Chen, Zhanghua, Pereira, Mark A., Seielstad, Mark, Koh, Woon-Puay, Tai, E. Shyong, Teo, Yik-Ying, Liu, Jianjun, Hsu, Chris, Wang, Renwei, Odegaard, Andrew O., Thyagarajan, Bharat, Koratkar, Revati, Yuan, Jian-Min, Gross, Myron D., Stram, Daniel O.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3919750/
https://www.ncbi.nlm.nih.gov/pubmed/24520337
http://dx.doi.org/10.1371/journal.pone.0087762
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author Chen, Zhanghua
Pereira, Mark A.
Seielstad, Mark
Koh, Woon-Puay
Tai, E. Shyong
Teo, Yik-Ying
Liu, Jianjun
Hsu, Chris
Wang, Renwei
Odegaard, Andrew O.
Thyagarajan, Bharat
Koratkar, Revati
Yuan, Jian-Min
Gross, Myron D.
Stram, Daniel O.
author_facet Chen, Zhanghua
Pereira, Mark A.
Seielstad, Mark
Koh, Woon-Puay
Tai, E. Shyong
Teo, Yik-Ying
Liu, Jianjun
Hsu, Chris
Wang, Renwei
Odegaard, Andrew O.
Thyagarajan, Bharat
Koratkar, Revati
Yuan, Jian-Min
Gross, Myron D.
Stram, Daniel O.
author_sort Chen, Zhanghua
collection PubMed
description 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 (r(2)>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.
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spelling pubmed-39197502014-02-11 Joint Effects of Known Type 2 Diabetes Susceptibility Loci in Genome-Wide Association Study of Singapore Chinese: The Singapore Chinese Health Study Chen, Zhanghua Pereira, Mark A. Seielstad, Mark Koh, Woon-Puay Tai, E. Shyong Teo, Yik-Ying Liu, Jianjun Hsu, Chris Wang, Renwei Odegaard, Andrew O. Thyagarajan, Bharat Koratkar, Revati Yuan, Jian-Min Gross, Myron D. Stram, Daniel O. PLoS One Research Article 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 (r(2)>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. Public Library of Science 2014-02-10 /pmc/articles/PMC3919750/ /pubmed/24520337 http://dx.doi.org/10.1371/journal.pone.0087762 Text en © 2014 Chen et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Chen, Zhanghua
Pereira, Mark A.
Seielstad, Mark
Koh, Woon-Puay
Tai, E. Shyong
Teo, Yik-Ying
Liu, Jianjun
Hsu, Chris
Wang, Renwei
Odegaard, Andrew O.
Thyagarajan, Bharat
Koratkar, Revati
Yuan, Jian-Min
Gross, Myron D.
Stram, Daniel O.
Joint Effects of Known Type 2 Diabetes Susceptibility Loci in Genome-Wide Association Study of Singapore Chinese: The Singapore Chinese Health Study
title Joint Effects of Known Type 2 Diabetes Susceptibility Loci in Genome-Wide Association Study of Singapore Chinese: The Singapore Chinese Health Study
title_full Joint Effects of Known Type 2 Diabetes Susceptibility Loci in Genome-Wide Association Study of Singapore Chinese: The Singapore Chinese Health Study
title_fullStr Joint Effects of Known Type 2 Diabetes Susceptibility Loci in Genome-Wide Association Study of Singapore Chinese: The Singapore Chinese Health Study
title_full_unstemmed Joint Effects of Known Type 2 Diabetes Susceptibility Loci in Genome-Wide Association Study of Singapore Chinese: The Singapore Chinese Health Study
title_short Joint Effects of Known Type 2 Diabetes Susceptibility Loci in Genome-Wide Association Study of Singapore Chinese: The Singapore Chinese Health Study
title_sort joint effects of known type 2 diabetes susceptibility loci in genome-wide association study of singapore chinese: the singapore chinese health study
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3919750/
https://www.ncbi.nlm.nih.gov/pubmed/24520337
http://dx.doi.org/10.1371/journal.pone.0087762
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