Copy-number variants as modulators of common disease susceptibility

ABSTRACT Background Copy-number variations (CNVs) have been associated with rare and debilitating genomic syndromes but their impact on health later in life in the general population remains poorly described. Methods Assessing four modes of CNV action, we performed genome-wide association scans (GWASs) between the copy-number of CNV-proxy probes and 60 curated ICD-10 based clinical diagnoses in 331,522 unrelated white UK Biobank participants with replication in the Estonian Biobank. Results We identified 73 signals involving 40 diseases, all of which indicating that CNVs increased disease risk and caused earlier onset. Even after correcting for these signals, a higher CNV burden increased risk for 18 disorders, mainly through the number of deleted genes, suggesting a polygenic CNV architecture. Number and identity of genes disturbed by CNVs affected their pathogenicity, with many associations being supported by colocalization with both common and rare single nucleotide variant association signals. Dissection of association signals provided insights into the epidemiology of known gene-disease pairs (e.g., deletions in BRCA1 and LDLR increased risk for ovarian cancer and ischemic heart disease, respectively), clarified dosage mechanisms of action (e.g., both increased and decreased dosage of 17q12 impacts renal health), and identified putative causal genes (e.g., ABCC6 for kidney stones). Characterization of the pleiotropic pathological consequences of recurrent CNVs at 15q13, 16p13.11, 16p12.2, and 22q11.2 in adulthood indicated variable expressivity of these regions and the involvement of multiple genes. Conclusions Our results shed light on the prominent role of CNVs in determining common disease susceptibility within the general population and provide actionable insights allowing to anticipate later-onset comorbidities in carriers of recurrent CNVs.