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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.