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Am J Hum Genet. 2019 Aug 1;105(2):373-383. doi: 10.1016/j.ajhg.2019.07.001. Epub 2019 Jul 25.

Phenome-wide Burden of Copy-Number Variation in the UK Biobank.

Author information

1
Department of Biomedical Data Science, School of Medicine, Stanford University, Stanford, CA 94305, USA; Department of Pediatrics, School of Medicine, Stanford University, Stanford, CA 94305, USA.
2
Department of Biomedical Data Science, School of Medicine, Stanford University, Stanford, CA 94305, USA.
3
Department of Pediatrics, School of Medicine, Stanford University, Stanford, CA 94305, USA; Stanford Cardiovascular Institute, Stanford University, Stanford, CA 94035, USA. Electronic address: jpriest@stanford.edu.

Abstract

Copy-number variations (CNVs) represent a significant proportion of the genetic differences between individuals and many CNVs associate causally with syndromic disease and clinical outcomes. Here, we characterize the landscape of copy-number variation and their phenome-wide effects in a sample of 472,228 array-genotyped individuals from the UK Biobank. In addition to population-level selection effects against genic loci conferring high mortality, we describe genetic burden from potentially pathogenic and previously uncharacterized CNV loci across more than 3,000 quantitative and dichotomous traits, with separate analyses for common and rare classes of variation. Specifically, we highlight the effects of CNVs at two well-known syndromic loci 16p11.2 and 22q11.2, previously uncharacterized variation at 9p23, and several genic associations in the context of acute coronary artery disease and high body mass index. Our data constitute a deeply contextualized portrait of population-wide burden of copy-number variation, as well as a series of dosage-mediated genic associations across the medical phenome.

KEYWORDS:

UK Biobank; association testing; copy number variation; genetics; genomics; microdeletion/microduplication syndrome; population database; selection bias; structural variation

PMID:
31353025
PMCID:
PMC6699064
[Available on 2020-02-01]
DOI:
10.1016/j.ajhg.2019.07.001

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