Evaluation of type 2 diabetes genetic risk variants in Chinese adults: findings from 93,000 individuals from the China Kadoorie Biobank.
Evaluation of type 2 diabetes genetic risk variants in Chinese adults: findings from 93,000 individuals from the China Kadoorie Biobank.
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DOI：
10.1007/s00125-016-3920-9
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发表时间：
2016-07
期刊：
影响因子：
8.2
通讯作者：
China Kadoorie Biobank Collaborative Group
中科院分区：
文献类型：
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作者：
Gan W;Walters RG;Holmes MV;Bragg F;Millwood IY;Banasik K;Chen Y;Du H;Iona A;Mahajan A;Yang L;Bian Z;Guo Y;Clarke RJ;Li L;McCarthy MI;Chen Z;China Kadoorie Biobank Collaborative Group
全基因组关联研究（GWAS）发现了许多2型糖尿病的风险变异。然而，风险变异对2型糖尿病易感性的贡献的估计通常基于高度选择的病例对照样本，并且缺乏对人群水平效应量的可靠估计，特别是在非欧洲人群中。在一项基于人群的中国嘉道理生物样本库（CKB）研究中，测量了59个已建立的2型糖尿病风险位点的个体和累积效应，该研究纳入了93，000名中国成年人，其中包括> 7，100例糖尿病病例。CKB和最初发现的GWAS之间的关联信号方向一致：在通过质量控制的56个变体中，48个显示出相同的效应方向（二项式检验，p = 2.3 × 10−8）。我们观察到CKB的风险变量效应量低于GWAS荟萃分析的病例对照样本的总体趋势一致（对数比值平均降低19-22%，p ≤ 0.0048），可能反映了“赢家诅咒”和频谱偏倚效应的校正。遗传风险评分与糖尿病风险的相关性，基于25个位点的先导变异，被认为通过β细胞功能起作用，证明了与几种肥胖指标（BMI，腰围[WC]，WHR和体脂百分比[PBF];所有p相互作用< 1 × 10−4）的显著相互作用，在较瘦的成年人中观察到更大的影响。我们的研究提供了欧洲人和东亚人之间2型糖尿病共有遗传结构的进一步证据。它还表明，即使是非常大的GWAS荟萃分析可能容易受到影响大小估计值的大幅膨胀，与大规模人群为基础的队列研究中观察到的。有关如何获取中国嘉道理生物样本库数据的详情及数据发布时间表的详情，请浏览www.ckbiobank.org/site/Data+Access。本文的在线版本（doi：10.1007/s 00125 -016-3920-9）包含同行评审但未经编辑的补充材料，可供授权用户使用。
Genome-wide association studies (GWAS) have discovered many risk variants for type 2 diabetes. However, estimates of the contributions of risk variants to type 2 diabetes predisposition are often based on highly selected case–control samples, and reliable estimates of population-level effect sizes are missing, especially in non-European populations. The individual and cumulative effects of 59 established type 2 diabetes risk loci were measured in a population-based China Kadoorie Biobank (CKB) study of 93,000 Chinese adults, including >7,100 diabetes cases. Association signals were directionally consistent between CKB and the original discovery GWAS: of 56 variants passing quality control, 48 showed the same direction of effect (binomial test, p = 2.3 × 10−8). We observed a consistent overall trend towards lower risk variant effect sizes in CKB than in case–control samples of GWAS meta-analyses (mean 19–22% decrease in log odds, p ≤ 0.0048), likely to reflect correction of both ‘winner’s curse’ and spectrum bias effects. The association with risk of diabetes of a genetic risk score, based on lead variants at 25 loci considered to act through beta cell function, demonstrated significant interactions with several measures of adiposity (BMI, waist circumference [WC], WHR and percentage body fat [PBF]; all pinteraction < 1 × 10−4), with a greater effect being observed in leaner adults. Our study provides further evidence of shared genetic architecture for type 2 diabetes between Europeans and East Asians. It also indicates that even very large GWAS meta-analyses may be vulnerable to substantial inflation of effect size estimates, compared with those observed in large-scale population-based cohort studies. Details of how to access China Kadoorie Biobank data and details of the data release schedule are available from www.ckbiobank.org/site/Data+Access. The online version of this article (doi:10.1007/s00125-016-3920-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users.