A general framework for two-stage analysis of genome-wide association studies and its application to case-control studies.

American Journal of Human Genetics
James M S Wason, Frank Dudbridge

Abstract

Two-stage analyses of genome-wide association studies have been proposed as a means to improving power for designs including family-based association and gene-environment interaction testing. In these analyses, all markers are first screened via a statistic that may not be robust to an underlying assumption, and the markers thus selected are then analyzed in a second stage with a test that is independent from the first stage and is robust to the assumption in question. We give a general formulation of two-stage designs and show how one can use this formulation both to derive existing methods and to improve upon them, opening up a range of possible further applications. We show how using simple regression models in conjunction with external data such as average trait values can improve the power of genome-wide association studies. We focus on case-control studies and show how it is possible to use allele frequencies derived from an external reference to derive a powerful two-stage analysis. An illustration involving the Wellcome Trust Case-Control Consortium data shows several genome-wide-significant associations, subsequently validated, that were not significant in the standard analysis. We give some analytic properties of the ...Continue Reading

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Citations

Dec 19, 2014·BMC Proceedings·Zhao Yang, Duncan C Thomas
Jan 13, 2016·American Journal of Epidemiology·Philip S BoonstraNilanjan Chatterjee
Aug 26, 2014·American Journal of Human Genetics·Frank Dudbridge, Olivia Fletcher
Aug 13, 2014·Genetic Epidemiology·Dalin LiDavid W Fardo
Jan 22, 2013·American Journal of Human Genetics·Liang TangYu Hu
Sep 6, 2013·European Journal of Epidemiology·Markus J Ege, David P Strachan
May 30, 2020·Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology·Eleanor C SemmesKyle M Walsh
Jan 20, 2021·Nature Genetics·Alexander KurilshikovAlexandra Zhernakova
Mar 9, 2021·PLoS Genetics·Arjun BhattacharyaMichael I Love

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