Variance-quantitative trait loci enable systematic discovery of gene-environment interactions for cardiometabolic serum biomarkers.
Variance-quantitative trait loci enable systematic discovery of gene-environment interactions for cardiometabolic serum biomarkers.
复制标题
DOI：
10.1038/s41467-022-31625-5
复制
发表时间：
2022-07-09
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
基因-环境相互作用代表了环境暴露对遗传效应的改变，对于理解疾病和提供个性化医疗信息至关重要。这些通常会导致基因型之间的差异表型变异；这些变异-数量性状位点可以在两阶段相互作用检测策略中进行优先排序，从而大大减少计算和统计负担，并能够测试更大范围的暴露。我们通过对英国生物银行350,016名无血缘关系的参与者进行多祖先荟萃分析，对20种血清心脏代谢生物标志物进行了全基因组方差-数量性状位点分析，鉴定出182对独立的基因座-生物标志物对（p < 4.5×10−9）。在女性基因组健康研究（N = 23,294）中，大多数集中在具有全基因组显著主效应的一小部分位点（4%）中，44%重复（p < 0.05）。接下来，我们测试了每个基因座-生物标记对在2380个暴露中的相互作用，确定了847个显著相互作用（p < 2.4×10−7），其中132个在考虑暴露之间的相关性后是独立的（p < 0.05）。具体的例子证明了甘油三酯相关变异与不同的体重和体脂相关暴露之间的相互作用，以及酒精消耗与ADH1B基因的肝脏应激之间的基因型特异性关联。我们的变异-数量性状位点和基因-环境相互作用目录在在线门户网站上公开提供。了解我们的基因如何与环境相互作用对改善健康至关重要。利用大规模的发现管道，本文作者研究了遗传变异与影响心脏代谢健康的广泛环境因素之间的协同作用。
Gene-environment interactions represent the modification of genetic effects by environmental exposures and are critical for understanding disease and informing personalized medicine. These often induce differential phenotypic variance across genotypes; these variance-quantitative trait loci can be prioritized in a two-stage interaction detection strategy to greatly reduce the computational and statistical burden and enable testing of a broader range of exposures. We perform genome-wide variance-quantitative trait locus analysis for 20 serum cardiometabolic biomarkers by multi-ancestry meta-analysis of 350,016 unrelated participants in the UK Biobank, identifying 182 independent locus-biomarker pairs (p < 4.5×10−9). Most are concentrated in a small subset (4%) of loci with genome-wide significant main effects, and 44% replicate (p < 0.05) in the Women’s Genome Health Study (N = 23,294). Next, we test each locus-biomarker pair for interaction across 2380 exposures, identifying 847 significant interactions (p < 2.4×10−7), of which 132 are independent (p < 0.05) after accounting for correlation between exposures. Specific examples demonstrate interaction of triglyceride-associated variants with distinct body mass- versus body fat-related exposures as well as genotype-specific associations between alcohol consumption and liver stress at the ADH1B gene. Our catalog of variance-quantitative trait loci and gene-environment interactions is publicly available in an online portal. Understanding how our genes interact with the environment is critical to improving health. Using a large-scale discovery pipeline, here the authors investigate synergies between genetic variants and a broad range of environmental factors impacting cardiometabolic health.
登录
查看更多内容
影响因子：
7.7
作者：
Millard LAC;Davies NM;Gaunt TR;Davey Smith G;Tilling K
通讯作者：
Tilling K
影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
3.7
作者：
RAND, WM
通讯作者：
RAND, WM