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Meta-analysis of genome-wide association studies in East Asian-ancestry populations identifies four new loci for body mass index.

ABSTRACT: Recent genetic association studies have identified 55 genetic loci associated with obesity or body mass index (BMI). The vast majority, 51 loci, however, were identified in European-ancestry populations. We conducted a meta-analysis of associations between BMI and ?2.5 million genotyped or imputed single nucleotide polymorphisms among 86 757 individuals of Asian ancestry, followed by in silico and de novo replication among 7488-47 352 additional Asian-ancestry individuals. We identified four novel BMI-associated loci near the KCNQ1 (rs2237892, P = 9.29 × 10(-13)), ALDH2/MYL2 (rs671, P = 3.40 × 10(-11); rs12229654, P = 4.56 × 10(-9)), ITIH4 (rs2535633, P = 1.77 × 10(-10)) and NT5C2 (rs11191580, P = 3.83 × 10(-8)) genes. The association of BMI with rs2237892, rs671 and rs12229654 was significantly stronger among men than among women. Of the 51 BMI-associated loci initially identified in European-ancestry populations, we confirmed eight loci at the genome-wide significance level (P < 5.0 × 10(-8)) and an additional 14 at P < 1.0 × 10(-3) with the same direction of effect as reported previously. Findings from this analysis expand our knowledge of the genetic basis of obesity.

SUBMITTER: Wen W

PROVIDER: S-EPMC4168820 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Meta-analysis of genome-wide association studies in East Asian-ancestry populations identifies four new loci for body mass index.

Wen Wanqing W Zheng Wei W Okada Yukinori Y Takeuchi Fumihiko F Tabara Yasuharu Y Hwang Joo-Yeon JY Dorajoo Rajkumar R Li Huaixing H Tsai Fuu-Jen FJ Yang Xiaobo X He Jiang J Wu Ying Y He Meian M Zhang Yi Y Liang Jun J Guo Xiuqing X Sheu Wayne Huey-Herng WH Delahanty Ryan R Guo Xingyi X Kubo Michiaki M Yamamoto Ken K Ohkubo Takayoshi T Go Min Jin MJ Liu Jian Jun JJ Gan Wei W Chen Ching-Chu CC Gao Yong Y Li Shengxu S Lee Nanette R NR Wu Chen C Zhou Xueya X Song Huaidong H Yao Jie J Lee I-Te IT Long Jirong J Tsunoda Tatsuhiko T Akiyama Koichi K Takashima Naoyuki N Cho Yoon Shin YS Ong Rick Th RT Lu Ling L Chen Chien-Hsiun CH Tan Aihua A Rice Treva K TK Adair Linda S LS Gui Lixuan L Allison Matthew M Lee Wen-Jane WJ Cai Qiuyin Q Isomura Minoru M Umemura Satoshi S Kim Young Jin YJ Seielstad Mark M Hixson James J Xiang Yong-Bing YB Isono Masato M Kim Bong-Jo BJ Sim Xueling X Lu Wei W Nabika Toru T Lee Juyoung J Lim Wei-Yen WY Gao Yu-Tang YT Takayanagi Ryoichi R Kang Dae-Hee DH Wong Tien Yin TY Hsiung Chao Agnes CA Wu I-Chien IC Juang Jyh-Ming Jimmy JM Shi Jiajun J Choi Bo Youl BY Aung Tin T Hu Frank F Kim Mi Kyung MK Lim Wei Yen WY Wang Tzung-Dao TD Shin Min-Ho MH Lee Jeannette J Ji Bu-Tian BT Lee Young-Hoon YH Young Terri L TL Shin Dong Hoon DH Chun Byung-Yeol BY Cho Myeong-Chan MC Han Bok-Ghee BG Hwu Chii-Min CM Assimes Themistocles L TL Absher Devin D Yan Xiaofei X Kim Eric E Kuo Jane Z JZ Kwon Soonil S Taylor Kent D KD Chen Yii-Der I YD Rotter Jerome I JI Qi Lu L Zhu Dingliang D Wu Tangchun T Mohlke Karen L KL Gu Dongfeng D Mo Zengnan Z Wu Jer-Yuarn JY Lin Xu X Miki Tetsuro T Tai E Shyong ES Lee Jong-Young JY Kato Norihiro N Shu Xiao-Ou XO Tanaka Toshihiro T

Human molecular genetics 20140526 20

Recent genetic association studies have identified 55 genetic loci associated with obesity or body mass index (BMI). The vast majority, 51 loci, however, were identified in European-ancestry populations. We conducted a meta-analysis of associations between BMI and ∼2.5 million genotyped or imputed single nucleotide polymorphisms among 86 757 individuals of Asian ancestry, followed by in silico and de novo replication among 7488-47 352 additional Asian-ancestry individuals. We identified four nov ...[more]

PMID: 24861553

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Project description:BackgroundCurrently, there is very limited knowledge about the genes involved in normal pigmentation variation in East Asian populations. We carried out a genome-wide scan of signatures of positive selection using the 1000 Genomes Phase I dataset, in order to identify pigmentation genes showing putative signatures of selective sweeps in East Asia. We applied a broad range of methods to detect signatures of selection including: 1) Tests designed to identify deviations of the Site Frequency Spectrum (SFS) from neutral expectations (Tajima's D, Fay and Wu's H and Fu and Li's D* and F*), 2) Tests focused on the identification of high-frequency haplotypes with extended linkage disequilibrium (iHS and Rsb) and 3) Tests based on genetic differentiation between populations (LSBL). Based on the results obtained from a genome wide analysis of 25 kb windows, we constructed an empirical distribution for each statistic across all windows, and identified pigmentation genes that are outliers in the distribution.ResultsOur tests identified twenty genes that are relevant for pigmentation biology. Of these, eight genes (ATRN, EDAR, KLHL7, MITF, OCA2, TH, TMEM33 and TRPM1,) were extreme outliers (top 0.1% of the empirical distribution) for at least one statistic, and twelve genes (ADAM17, BNC2, CTSD, DCT, EGFR, LYST, MC1R, MLPH, OPRM1, PDIA6, PMEL (SILV) and TYRP1) were in the top 1% of the empirical distribution for at least one statistic. Additionally, eight of these genes (BNC2, EGFR, LYST, MC1R, OCA2, OPRM1, PMEL (SILV) and TYRP1) have been associated with pigmentary traits in association studies.ConclusionsWe identified a number of putative pigmentation genes showing extremely unusual patterns of genetic variation in East Asia. Most of these genes are outliers for different tests and/or different populations, and have already been described in previous scans for positive selection, providing strong support to the hypothesis that recent selective sweeps left a signature in these regions. However, it will be necessary to carry out association and functional studies to demonstrate the implication of these genes in normal pigmentation variation.

Dataset Information

Meta-analysis of genome-wide association studies in East Asian-ancestry populations identifies four new loci for body mass index.

Publications

Meta-analysis of genome-wide association studies in East Asian-ancestry populations identifies four new loci for body mass index.

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