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

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. types in a cohort of 332,584 participants from the UK Biobank. 18 We replicate well-established syndromic effects of common CNVs-namely 22q11.2 deletion (DiGeorge) syndrome and two variants of 16p11.2 deletion syndrome-and highlight associations for body mass index (BMI), acute coronary artery disease (CAD), and related adipose and cardiovascular phenotypes. Summary statistics from traditional genome-wide associations for common CNVs as well as from gene-level aggregate burden tests of rare variants across all phenotypes are available for download on the Global Biobank Engine. 19 Material and Methods CNVs were called using PennCNV v.1.0.4 on raw signal intensity data from each genotyping array. Phenotype data were derived from data-fields collected for UK Biobank corresponding to various body measurements, biomarkers, disease diagnoses, and medical procedures from medical records, as well as a questionnaire about lifestyle and medical history. Summary-level data from all statistical tests described here, as well as more thorough documentation on phenotyping, are available on the Global Biobank Engine 19 and can be found in related publications. 20 CNV Calling in UK Biobank Methods for genetic data acquisition and quality control as performed by the UK Biobank have been previously described. 18 In brief, two similar arrays were used for targeted genotyping within the study population: the UK BiLEVE Axiom Array (n ¼ 49,950) by Affymetrix and the UK Biobank Axiom Array (n ¼ 438,427), which was custom designed by Applied Biosystems. Samples and array markers were subject to threshold-based filtration and quality control prior to public release. Specifically, markers were tested for discordance across control replicates, departures from Hardy-Weinberg equilibrium, as well as effects due to batch, plate, array, and sex; affected markers were set as missing in affected batches or

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