A statistical method for region-based meta-analysis of genome-wide association studies in genetically diverse populations

被引：11

作者：

Wang, Xu ^{[2
]}

Liu, Xuanyao ^{[3
]}

Sim, Xueling ^{[4
]}

Xu, Haiyan ^{[4
]}

Khor, Chiea-Chuen ^{[5
]}

Ong, Rick Twee-Hee ^{[3
,4
]}

Tay, Wan-Ting ^{[6
]}

Suo, Chen ^{[4
]}

Poh, Wan-Ting ^{[2
]}

Ng, Daniel Peng-Keat ^{[2
]}

Liu, Jianjun ^{[5
]}

Aung, Tin ^{[6
,7
]}

Chia, Kee-Seng ^{[2
,3
,4
]}

Wong, Tien-Yin ^{[6
,7
,8
,9
]}

Tai, E-Shyong ^{[2
,9
]}

Teo, Yik-Ying ^{[1
,2
,3
,4
,5
]}

机构：

[1] Natl Univ Singapore, Dept Stat & Appl Probabil, Fac Sci, Singapore 117546, Singapore

[2] Natl Univ Singapore, Dept Epidemiol & Publ Hlth, Singapore 117546, Singapore

[3] Natl Univ Singapore, NUS Grad Sch Integrat Sci & Engn, Singapore 117546, Singapore

[4] Natl Univ Singapore, Ctr Mol Epidemiol, Singapore 117546, Singapore

[5] Agcy Sci Technol & Res, Genome Inst Singapore, Singapore, Singapore

[6] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore

[7] Natl Univ Singapore, Dept Ophthalmol, Singapore 117546, Singapore

[8] Univ Melbourne, Ctr Eye Res Australia, Melbourne, Vic, Australia

[9] Natl Univ Singapore, Dept Med, Singapore 117546, Singapore

来源：

EUROPEAN JOURNAL OF HUMAN GENETICS | 2012年 / 20卷 / 04期

基金：

英国医学研究理事会; 新加坡国家研究基金会; 英国惠康基金;

关键词：

genome-wide association studies; linkage disequilibrium; meta-analysis; pathway analysis; RISK LOCI; SUSCEPTIBILITY LOCI; VARIANTS; REPLICATION; CHALLENGES; DISEASES; TESTS; KEGG;

D O I：

10.1038/ejhg.2011.219

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Genome-wide association studies (GWAS) have become the preferred experimental design in exploring the genetic etiology of complex human traits and diseases. Standard SNP-based meta-analytic approaches have been utilized to integrate the results from multiple experiments. This fundamentally assumes that the patterns of linkage disequilibrium (LD) between the underlying causal variants and the directly genotyped SNPs are similar across the populations for the same SNPs to emerge with surrogate evidence of disease association. We introduce a novel strategy for assessing regional evidence of phenotypic association that explicitly incorporates the extent of LD in the region. This provides a natural framework for combining evidence from multiethnic studies of both dichotomous and quantitative traits that (i) accommodates different patterns of LD, (ii) integrates different genotyping platforms and (iii) allows for the presence of allelic heterogeneity between the populations. Our method can also be generalized to perform gene-based or pathway-based analyses. Applying this method on real GWAS data in type 2 diabetes (T2D) boosted the association evidence in regions well-established for T2D etiology in three diverse South-East Asian populations, as well as identified two novel gene regions and a biologically convincing pathway that are subsequently validated with data from the Wellcome Trust Case Control Consortium. European Journal of Human Genetics (2012) 20, 469-475; doi: 10.1038/ejhg.2011.219; published online 30 November 2011

引用

页码：469 / 475

页数：7

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