Across-cohort QC analyses of GWAS summary statistics from complex traits.

Eur J Hum Genet
Authors
Abstract

Genome-wide association studies (GWASs) have been successful in discovering SNP trait associations for many quantitative traits and common diseases. Typically, the effect sizes of SNP alleles are very small and this requires large genome-wide association meta-analyses (GWAMAs) to maximize statistical power. A trend towards ever-larger GWAMA is likely to continue, yet dealing with summary statistics from hundreds of cohorts increases logistical and quality control problems, including unknown sample overlap, and these can lead to both false positive and false negative findings. In this study, we propose four metrics and visualization tools for GWAMA, using summary statistics from cohort-level GWASs. We propose methods to examine the concordance between demographic information, and summary statistics and methods to investigate sample overlap. (I) We use the population genetics Fst statistic to verify the genetic origin of each cohort and their geographic location, and demonstrate using GWAMA data from the GIANT Consortium that geographic locations of cohorts can be recovered and outlier cohorts can be detected. (II) We conduct principal component analysis based on reported allele frequencies, and are able to recover the ancestral information for each cohort. (III) We propose a new statistic that uses the reported allelic effect sizes and their standard errors to identify significant sample overlap or heterogeneity between pairs of cohorts. (IV) To quantify unknown sample overlap across all pairs of cohorts, we propose a method that uses randomly generated genetic predictors that does not require the sharing of individual-level genotype data and does not breach individual privacy.

Year of Publication
2016
Journal
Eur J Hum Genet
Volume
25
Issue
1
Pages
137-146
Date Published
2016 Jan
ISSN
1476-5438
DOI
10.1038/ejhg.2016.106
PubMed ID
27552965
PubMed Central ID
PMC5159754
Links
Grant list
P01 GM099568 / GM / NIGMS NIH HHS / United States
P30 DK020541 / DK / NIDDK NIH HHS / United States