Guidelines for Evaluating the Comparability of Down-Sampled GWAS Summary Statistics

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Proprietary genetic datasets are valuable for boosting the statistical power of genome-wide association studies (GWASs), but their use can restrict investigators from publicly sharing the resulting summary statistics. Although researchers can resort to sharing down-sampled versions that exclude restricted data, down-sampling reduces power and might change the genetic etiology of the phenotype being studied. These problems are further complicated when using multivariate GWAS methods, such as genomic structural equation modeling (Genomic SEM), that model genetic correlations across multiple traits. Here, we propose a systematic approach to assess the comparability of GWAS summary statistics that include versus exclude restricted data. Illustrating this approach with a multivariate GWAS of an externalizing factor, we assessed the impact of down-sampling on (1) the strength of the genetic signal in univariate GWASs, (2) the factor loadings and model fit in multivariate Genomic SEM, (3) the strength of the genetic signal at the factor level, (4) insights from gene-property analyses, (5) the pattern of genetic correlations with other traits, and (6) polygenic score analyses in independent samples. For the externalizing GWAS, down-sampling resulted in a loss of genetic signal and fewer genome-wide significant loci, while the factor loadings and model fit, gene-property analyses, genetic correlations, and polygenic score analyses are robust. Given the importance of data sharing for the advancement of open science, we recommend that investigators who share down-sampled summary statistics report these analyses as accompanying documentation to support other researchers' use of the summary statistics.

Authors 15

1. Camille Michèle Williams corresponding

   The University of Texas at Austin

   Affiliation as printed

   Department of Psychology and Population Research Center, University of Texas at Austin

2. Holly E. Poore

   Rutgers, The State University of New Jersey

   Affiliation as printed

   Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University

3. Peter T. Tanksley

   The University of Texas at Austin

   Affiliation as printed

   Population Research Center, the University of Texas at Austin

4. Hyeokmoon Kweon

   Vrije Universiteit Amsterdam

   Affiliation as printed

   Department of Economics, School of Business and Economics, Vrije Universiteit Amsterdam

5. Natasia S. Courchesne‐Krak

   University of California San Diego

   Affiliation as printed

   Department of Psychiatry, University of California San Diego

6. Diego Londoño-Correa

   The University of Texas at Austin

   Affiliation as printed

   Population Research Center, the University of Texas at Austin

7. Travis T. Mallard

   Broad Institute · Harvard University · Massachusetts General Hospital · Stanley Center for Psychiatric Research · Massachusetts Institute of Technology

   Affiliation as printed

   Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Department of Psychiatry, Harvard Medical School, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Boston, MA, USA

   Department of Psychiatry, Harvard Medical School, Boston, MA, USA

   Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA

   Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Boston, MA, USA

8. Peter B. Barr

   SUNY Downstate Health Sciences University

   Affiliation as printed

   Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University

9. Philipp Koellinger

   Vrije Universiteit Amsterdam

   Affiliation as printed

   Department of Economics, Vrije Universiteit Amsterdam

10. Irwin D. Waldman

    Emory University

    Affiliation as printed

    Department of Psychology, Emory University

11. Sandra Sanchez‐Roige

    Vanderbilt University · University of California San Diego

    Affiliation as printed

    Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.; Department of Medicine, Division of Genetic Medicine, Vanderbilt University, Nashville, TN, USA

    Department of Medicine, Division of Genetic Medicine, Vanderbilt University, Nashville, TN, USA

    Department of Psychiatry, University of California San Diego, La Jolla, CA, USA

12. K. Paige Harden

    The University of Texas at Austin

    Affiliation as printed

    Department of Psychology and Population Research Center, University of Texas at Austin

13. Abraham A. Palmer

    University of California San Diego

    Affiliation as printed

    Department of Psychiatry, University of California San Diego; Institute for Genomic Medicine, University of California San Diego

    Department of Psychiatry, University of California San Diego

    Institute for Genomic Medicine, University of California San Diego

14. Danielle M. Dick corresponding

    Rutgers, The State University of New Jersey

    Affiliation as printed

    Rutgers Addiction Research Center in the Brain Health Institute, Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University

15. Richard Karlsson Linnér corresponding Aachen Department of Economics, Universiteit Leiden

    Leiden University

    Affiliation as printed

    Department of Economics, Universiteit Leiden