Statistical correction of the Winner's Curse explains replication variability in quantitative trait genome-wide association studies

Genome-wide association studies (GWAS) have identified hundreds of SNPs responsible for variation in human quantitative traits. However, genome-wide-significant associations often fail to replicate across independent cohorts, in apparent inconsistency with their apparent strong effects in discovery...

Full description

Saved in:
Bibliographic Details
Published in:PLoS genetics 2017-07, Vol.13 (7), p.e1006916-e1006916
Main Authors: Palmer, Cameron, Pe'er, Itsik
Format: Article
Language:English
Subjects:
Bias
Binomial distribution
Biology and Life Sciences
Computer science
Confidence intervals
Databases, Factual
DNA Replication
Estimates
Genome, Human
Genome-wide association studies
Genome-Wide Association Study
Genomes
Genotype & phenotype
Humans
Linear Models
Linkage Disequilibrium
Models, Genetic
Phenotype
Physical Sciences
Polymorphism, Single Nucleotide
Population
Quantitative Trait Loci
Replication
Research and Analysis Methods
Single-nucleotide polymorphism
Statistical models
Studies
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Genome-wide association studies (GWAS) have identified hundreds of SNPs responsible for variation in human quantitative traits. However, genome-wide-significant associations often fail to replicate across independent cohorts, in apparent inconsistency with their apparent strong effects in discovery cohorts. This limited success of replication raises pervasive questions about the utility of the GWAS field. We identify all 332 studies of quantitative traits from the NHGRI-EBI GWAS Database with attempted replication. We find that the majority of studies provide insufficient data to evaluate replication rates. The remaining papers replicate significantly worse than expected (p < 10-14), even when adjusting for regression-to-the-mean of effect size between discovery- and replication-cohorts termed the Winner's Curse (p < 10-16). We show this is due in part to misreporting replication cohort-size as a maximum number, rather than per-locus one. In 39 studies accurately reporting per-locus cohort-size for attempted replication of 707 loci in samples with similar ancestry, replication rate matched expectation (predicted 458, observed 457, p = 0.94). In contrast, ancestry differences between replication and discovery (13 studies, 385 loci) cause the most highly-powered decile of loci to replicate worse than expected, due to difference in linkage disequilibrium.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1006916