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Title: Across-cohort QC analyses of GWAS summary statistics from complex traits
Contributor(s): Chen, Guo-Bo (author); Lee, Sang Hong  (author); Kutalik, Zoltan (author); Loos, Ruth J F (author); Frayling, Timothy M (author); Hirschhorn, Joel N (author); Yang, Jian (author); Wray, Naomi R (author); Visscher, Peter M (author); Robinson, Matthew R (author); Trzaskowski, Maciej (author); Zhu, Zhi-Xiang (author); Winkler, Thomas W (author); Day, Felix R (author); Croteau-Chonka, Damien C (author); Wood, Andrew R (author); Locke, Adam E (author)
Publication Date: 2016
Open Access: Yes
DOI: 10.1038/ejhg.2016.106Open Access Link
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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.
Publication Type: Journal Article
Source of Publication: European Journal of Human Genetics, 25(1), p. 137-146
Publisher: Nature Publishing Group
Place of Publication: United Kingdom
ISSN: 1476-5438
Fields of Research (FoR) 2008: 060412 Quantitative Genetics (incl. Disease and Trait Mapping Genetics)
Fields of Research (FoR) 2020: 310506 Gene mapping
Socio-Economic Objective (SEO) 2008: 920110 Inherited Diseases (incl. Gene Therapy)
Socio-Economic Objective (SEO) 2020: 200101 Diagnosis of human diseases and conditions
Peer Reviewed: Yes
HERDC Category Description: C1 Refereed Article in a Scholarly Journal
Appears in Collections:Journal Article

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