title: Across-cohort QC analyses of GWAS summary statistics from complex traits.
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 Fststatistic 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.
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia. chenguobo@gmail.com.
authors.forename: Guo-Bo
authors.identifier: http://orcid.org/0000-0001-5475-8237
authors.initials: GB
authors.lastname: Chen
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.|School of Environmental and Rural Science, The University of New England, Armidale, New South Walsh, Australia.
authors.forename: Sang Hong
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Robinson
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Maciej
authors.initials: M
authors.lastname: Trzaskowski
authors.affiliation: SPLUS Game, Guangzhou, Guangdong, China.
authors.forename: Zhi-Xiang
authors.initials: ZX
authors.lastname: Zhu
authors.affiliation: Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Winkler
authors.affiliation: Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Felix R
authors.identifier: http://orcid.org/0000-0003-3789-7651
authors.initials: FR
authors.lastname: Day
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Damien C
authors.initials: DC
authors.lastname: Croteau-Chonka
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Wood
authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Adam E
authors.initials: AE
authors.lastname: Locke
authors.affiliation: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.|Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.|Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Kutalik
authors.affiliation: The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Ruth J F
authors.initials: RJF
authors.lastname: Loos
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts, USA.|Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.|The University of Queensland Diamantina Institute, Translation Research Institute, Brisbane, Queensland, Australia.
authors.forename: Jian
authors.identifier: http://orcid.org/0000-0003-2001-2474
authors.initials: J
authors.lastname: Yang
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Naomi R
authors.identifier: http://orcid.org/0000-0001-7421-3357
authors.initials: NR
authors.lastname: Wray
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia. peter.visscher@uq.edu.au.|The University of Queensland Diamantina Institute, Translation Research Institute, Brisbane, Queensland, Australia. peter.visscher@uq.edu.au.
authors.forename: Peter M
authors.identifier: http://orcid.org/0000-0002-2143-8760
authors.initials: PM
authors.lastname: Visscher
mesh_terms: D000483:Alleles; D015331:Cohort Studies; D018740:Genetic Heterogeneity; D055106:Genome-Wide Association Study / Q000706:statistics & numerical data*; D005838:Genotype; D006801:Humans; D015201:Meta-Analysis as Topic; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics*; D012984:Software