Review and further developments in statistical corrections for Winner’s Curse in genetic association studies

Amanda Forde*, Gibran Hemani, John Ferguson

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

11 Citations (Scopus)

Abstract

Genome-wide association studies (GWAS) are commonly used to identify genomic variants that are associated with complex traits, and estimate the magnitude of this association for each variant. However, it has been widely observed that the association estimates of variants tend to be lower in a replication study than in the study that discovered those associations. A phenomenon known as Winner’s Curse is responsible for this upward bias present in association estimates of significant variants in the discovery study. We review existing Winner’s Curse correction methods which require only GWAS summary statistics in order to make adjustments. In addition, we propose modifications to improve existing methods and propose a novel approach which uses the parametric bootstrap. We evaluate and compare methods, first using a wide variety of simulated data sets and then, using real data sets for three different traits. The metric, estimated mean squared error (MSE) over significant SNPs, was primarily used for method assessment. Our results indicate that widely used conditional likelihood based methods tend to perform poorly. The other considered methods behave much more similarly, with our proposed bootstrap method demonstrating very competitive performance. To complement this review, we have developed an R package, ‘winnerscurse’ which can be used to implement these various Winner’s Curse adjustment methods to GWAS summary statistics.
Original languageEnglish
Article numbere1010546
JournalPLoS Genetics
Volume19
Issue number9
DOIs
Publication statusPublished - 18 Sept 2023

Bibliographical note

Funding Information:
Funding: AF is funded by Science Foundation Ireland under award 18/CRT/6214. GH is supported by the Wellcome Trust and Royal Society [208806/Z/17/Z]. JF is supported by HRB grant number EIA2017–017. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
Copyright: © 2023 Forde et al.

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