title: Meta-GWAS Accuracy and Power (MetaGAP) Calculator Shows that Hiding Heritability Is Partially Due to Imperfect Genetic Correlations across Studies.
abstract: Large-scale genome-wide association results are typically obtained from a fixed-effects meta-analysis of GWAS summary statistics from multiple studies spanning different regions and/or time periods. This approach averages the estimated effects of genetic variants across studies. In case genetic effects are heterogeneous across studies, the statistical power of a GWAS and the predictive accuracy of polygenic scores are attenuated, contributing to the so-called 'missing heritability'. Here, we describe the online Meta-GWAS Accuracy and Power (MetaGAP) calculator (available at www.devlaming.eu) which quantifies this attenuation based on a novel multi-study framework. By means of simulation studies, we show that under a wide range of genetic architectures, the statistical power and predictive accuracy provided by this calculator are accurate. We compare the predictions from the MetaGAP calculator with actual results obtained in the GWAS literature. Specifically, we use genomic-relatedness-matrix restricted maximum likelihood to estimate the SNP heritability and cross-study genetic correlation of height, BMI, years of education, and self-rated health in three large samples. These estimates are used as input parameters for the MetaGAP calculator. Results from the calculator suggest that cross-study heterogeneity has led to attenuation of statistical power and predictive accuracy in recent large-scale GWAS efforts on these traits (e.g., for years of education, we estimate a relative loss of 51-62% in the number of genome-wide significant loci and a relative loss in polygenic score R2 of 36-38%). Hence, cross-study heterogeneity contributes to the missing heritability.
authors.affiliation: Erasmus University Rotterdam Institute for Behavior and Biology, Erasmus School of Economics, Rotterdam, the Netherlands.|Department of Applied Economics, Erasmus School of Economics, Rotterdam, the Netherlands.|Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam, the Netherlands.
authors.forename: Ronald
authors.identifier: http://orcid.org/0000-0001-6416-6067
authors.initials: R
authors.lastname: de Vlaming
authors.affiliation: Erasmus University Rotterdam Institute for Behavior and Biology, Erasmus School of Economics, Rotterdam, the Netherlands.|Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam, the Netherlands.
authors.forename: Aysu
authors.identifier: http://orcid.org/0000-0002-5170-7781
authors.initials: A
authors.lastname: Okbay
authors.affiliation: Erasmus University Rotterdam Institute for Behavior and Biology, Erasmus School of Economics, Rotterdam, the Netherlands.|Department of Applied Economics, Erasmus School of Economics, Rotterdam, the Netherlands.
authors.forename: Cornelius A
authors.initials: CA
authors.lastname: Rietveld
authors.affiliation: Department of Economics, Stockholm School of Economics, Stockholm, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Johannesson
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Patrik K E
authors.initials: PK
authors.lastname: Magnusson
authors.affiliation: Erasmus University Rotterdam Institute for Behavior and Biology, Erasmus School of Economics, Rotterdam, the Netherlands.|Department of Epidemiology, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Frank J A
authors.initials: FJ
authors.lastname: van Rooij
authors.affiliation: Erasmus University Rotterdam Institute for Behavior and Biology, Erasmus School of Economics, Rotterdam, the Netherlands.|Department of Epidemiology, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Erasmus University Rotterdam Institute for Behavior and Biology, Erasmus School of Economics, Rotterdam, the Netherlands.|Econometric Institute, Erasmus School of Economics, Rotterdam, the Netherlands.
authors.forename: Patrick J F
authors.identifier: http://orcid.org/0000-0001-6683-8971
authors.initials: PJ
authors.lastname: Groenen
authors.affiliation: Erasmus University Rotterdam Institute for Behavior and Biology, Erasmus School of Economics, Rotterdam, the Netherlands.|Department of Applied Economics, Erasmus School of Economics, Rotterdam, the Netherlands.|Montpellier Business School, Montpellier, France.
authors.forename: A Roy
authors.identifier: http://orcid.org/0000-0002-0242-6908
authors.initials: AR
authors.lastname: Thurik
authors.affiliation: Erasmus University Rotterdam Institute for Behavior and Biology, Erasmus School of Economics, Rotterdam, the Netherlands.|Department of Applied Economics, Erasmus School of Economics, Rotterdam, the Netherlands.|Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam, the Netherlands.
authors.forename: Philipp D
authors.identifier: http://orcid.org/0000-0001-7413-0412
authors.initials: PD
authors.lastname: Koellinger
mesh_terms: D000068598:Data Accuracy; D055106:Genome-Wide Association Study / Q000379:methods / Q000592:standards*; D006801:Humans; D015201:Meta-Analysis as Topic; D012984:Software