title: Controlling for population structure and genotyping platform bias in the eMERGE multi-institutional biobank linked to electronic health records.
abstract: Combining samples across multiple cohorts in large-scale scientific research programs is often required to achieve the necessary power for genome-wide association studies. Controlling for genomic ancestry through principal component analysis (PCA) to address the effect of population stratification is a common practice. In addition to local genomic variation, such as copy number variation and inversions, other factors directly related to combining multiple studies, such as platform and site recruitment bias, can drive the correlation patterns in PCA. In this report, we describe the combination and analysis of multi-ethnic cohort with biobanks linked to electronic health records for large-scale genomic association discovery analyses. First, we outline the observed site and platform bias, in addition to ancestry differences. Second, we outline a general protocol for selecting variants for input into the subject variance-covariance matrix, the conventional PCA approach. Finally, we introduce an alternative approach to PCA by deriving components from subject loadings calculated from a reference sample. This alternative approach of generating principal components controlled for site and platform bias, in addition to ancestry differences, has the advantage of fewer covariates and degrees of freedom.
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington Seattle, WA, USA ; Department of Genome Sciences, University of Washington Seattle, WA, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Crosslin
authors.affiliation: The Sigfried and Janet Weis Center for Research, Geisinger Health System Danville, PA, USA.
authors.forename: Gerard
authors.initials: G
authors.lastname: Tromp
authors.affiliation: Department of Genome Sciences, University of Washington Seattle, WA, USA.
authors.forename: Amber
authors.initials: A
authors.lastname: Burt
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington Seattle, WA, USA ; Department of Genome Sciences, University of Washington Seattle, WA, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Systems Genomics, Pennsylvania State University University Park, PA, USA.
authors.forename: Shefali S
authors.initials: SS
authors.lastname: Verma
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Systems Genomics, Pennsylvania State University University Park, PA, USA.
authors.forename: Anastasia M
authors.initials: AM
authors.lastname: Lucas
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Systems Genomics, Pennsylvania State University University Park, PA, USA.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Bradford
authors.affiliation: Center for Human Genetics Research, School of Medicine, Vanderbilt University Nashville, TN, USA ; Department of Molecular Physiology and Biophysics, Vanderbilt University Nashville, TN, USA.
authors.forename: Dana C
authors.initials: DC
authors.lastname: Crawford
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic Rochester, MN, USA.
authors.forename: Sebastian M
authors.initials: SM
authors.lastname: Armasu
authors.affiliation: Division of Cardiovascular Diseases, Mayo Clinic Rochester, MN, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Heit
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University Chicago, IL, USA.
authors.forename: M Geoffrey
authors.initials: MG
authors.lastname: Hayes
authors.affiliation: The Sigfried and Janet Weis Center for Research, Geisinger Health System Danville, PA, USA.
authors.forename: Helena
authors.initials: H
authors.lastname: Kuivaniemi
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Systems Genomics, Pennsylvania State University University Park, PA, USA.
authors.forename: Marylyn D
authors.initials: MD
authors.lastname: Ritchie
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington Seattle, WA, USA ; Department of Genome Sciences, University of Washington Seattle, WA, USA.
authors.forename: Gail P
authors.initials: GP
authors.lastname: Jarvik
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic Rochester, MN, USA.
authors.forename: Mariza
authors.initials: M
authors.lastname: de Andrade
keywords: ancestry; biobank; genetic association study; loadings; principal component analysis