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However, the aggregation of controls from multiple sources is challenging due to batch effects, difficulty in identifying genotyping errors and the use of different genotyping platforms. These obstacles have impeded the use of external controls in GWAS and can lead to spurious results if not carefully addressed. We propose a unified data harmonization pipeline that includes an iterative approach to quality control and imputation, implemented before and after merging cohorts and arrays. We apply this harmonization pipeline to aggregate 27\u2009517 European control samples from 16 collections within dbGaP. We leverage these harmonized controls to conduct a GWAS of Crohn\u2019s disease. We demonstrate a boost in power over using the cohort samples alone, and that our procedure results in summary statistics free of any significant batch effects. This harmonization pipeline for aggregating genotype data from multiple sources can also serve other applications where individual level genotypes, rather than summary statistics, are required.<\/jats:p>","DOI":"10.1093\/hmg\/ddab261","type":"journal-article","created":{"date-parts":[[2021,9,8]],"date-time":"2021-09-08T07:28:18Z","timestamp":1631086098000},"page":"481-489","source":"Crossref","is-referenced-by-count":13,"title":["A data harmonization pipeline to leverage external controls and boost power in GWAS"],"prefix":"10.1093","volume":"31","author":[{"given":"Danfeng","family":"Chen","sequence":"first","affiliation":[{"name":"Lewis-Sigler Institute for Integrative Genomics , , Princeton, 08544 NJ, USA"},{"name":"Princeton University , , Princeton, 08544 NJ, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine","family":"Tashman","sequence":"additional","affiliation":[{"name":"Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital , Boston, 02114 MA, USA"},{"name":"Stanley Center for Psychiatric Research , , Cambridge, 02142 MA, USA"},{"name":"Broad Institute of MIT and Harvard , , Cambridge, 02142 MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Duncan S","family":"Palmer","sequence":"additional","affiliation":[{"name":"Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital , Boston, 02114 MA, USA"},{"name":"Stanley Center for Psychiatric Research , , Cambridge, 02142 MA, USA"},{"name":"Broad Institute of MIT and Harvard , , Cambridge, 02142 MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin","family":"Neale","sequence":"additional","affiliation":[{"name":"Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital , Boston, 02114 MA, USA"},{"name":"Stanley Center for Psychiatric Research , , Cambridge, 02142 MA, USA"},{"name":"Broad Institute of MIT and Harvard , , Cambridge, 02142 MA, USA"},{"name":"Program in Medical and Population Genetics , , Cambridge, 02142 MA, USA"},{"name":"Broad Institute of Harvard and MIT , , Cambridge, 02142 MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathryn","family":"Roeder","sequence":"additional","affiliation":[{"name":"Department of Statistics , , Pittsburgh, 15213 PA, USA"},{"name":"Carnegie Mellon University , , Pittsburgh, 15213 PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alex","family":"Bloemendal","sequence":"additional","affiliation":[{"name":"Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital , Boston, 02114 MA, USA"},{"name":"Stanley Center for Psychiatric Research , , Cambridge, 02142 MA, USA"},{"name":"Broad Institute of MIT and Harvard , , Cambridge, 02142 MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claire","family":"Churchhouse","sequence":"additional","affiliation":[{"name":"Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital , Boston, 02114 MA, USA"},{"name":"Stanley Center for Psychiatric Research , , Cambridge, 02142 MA, USA"},{"name":"Broad Institute of MIT and Harvard , , Cambridge, 02142 MA, USA"},{"name":"Program in Medical and Population Genetics , , Cambridge, 02142 MA, USA"},{"name":"Broad Institute of Harvard and MIT , , Cambridge, 02142 MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4550-235X","authenticated-orcid":false,"given":"Zheng Tracy","family":"Ke","sequence":"additional","affiliation":[{"name":"Department of Statistics , , Cambridge, 02138 MA, USA"},{"name":"Harvard University , , Cambridge, 02138 MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,9,11]]},"reference":[{"key":"2022091100033083300_ref1","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/nature13595","article-title":"Biological insights from 108 schizophrenia-associated genetic loci","volume":"511","author":"Ripke","year":"2014","journal-title":"Nature"},{"key":"2022091100033083300_ref2","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1038\/s41588-019-0397-8","article-title":"Genome-wide association study identifies 30 loci associated with bipolar disorder","volume":"51","author":"Stahl","year":"2019","journal-title":"Nat. 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