Partitioning Tagged Non-Additive Genetic Effects in Summary Statistics Provides Evidence of Pervasive Epistasis in Complex Traits

Author:

Darnell GregoryORCID,Smith Samuel PattilloORCID,Udwin DanaORCID,Ramachandran SohiniORCID,Crawford LorinORCID

Abstract

AbstractThe inflation of test statistics in genome-wide association (GWA) studies due to confounding factors such as cryptic relatedness, population stratification, and spurious non-zero genetic effects driven by linkage disequilibrium (LD) has been well characterized in the literature. The key theoretical contribution of this work is that epistasis (i.e., the interaction between multiple loci and/or genes) can also lead to misestimated GWA summary statistics. To address this challenge, we develop marginal epistatic LD score regression and the accompanying software package MELD: an extended framework which takes in GWA test statistics and accurately partitions true additive genetic variation from non-additive genetic variation, as well as other biases. By re-analyzing 25 well-studied quantitative phenotypes from 349,468 individuals of European ancestry in the UK Biobank and up to 159,095 individuals in BioBank Japan, we illustrate that nonlinear effects are a significant source of signal in reported GWA summary statistics and provide evidence that epistasis is more widespread in human phenotypes than previously reported. Of the 25 complex traits we analyzed in the UK Biobank, 23 phenotypes have a significant amount of tagged epistasis captured within additive summary statistics, including height, urate level, and cholesterol levels. The MELD software and its application to these biobanks represent a significant step towards resolving the true contribution of epistasis to human complex traits.

Publisher

Cold Spring Harbor Laboratory

Cited by 3 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3