The impact of 22q11.2 copy-number variants on human traits in the general population

Zamariolli, Malú; Auwerx, Chiara; Sadler, Marie C; Graaf, Adriaan van der; Lepik, Kaido; Schoeler, Tabea; Moysés-Oliveira, Mariana; Dantas, Anelisa Gollo; Melaragno, Maria Isabel; Kutalik, Zoltán

doi:10.1016/j.ajhg.2023.01.005

Cited by 3 publications

(2 citation statements)

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“…Awareness of this disease feature can mitigate kidney stone risk through adapted diet and sufficient water intake. Together, our results advocate for a complex model of variable CNV expressivity and penetrance that can result in a broad range of phenotypes along the rare-to-common disease spectrum and represent fertile ground for in-depth, phenome-wide studies aiming at better characterizing specific CNV regions [ 45 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

“…Beyond the inherent loss of power associated with the usage of binary variables [38], cases might be missed because an individual did not consult a physician, was misdiagnosed due to atypical clinical presentation, or is in a prodromal disease phase. Studies investigating CNV-disease associations in the general population have either focused on only a few diseases [29,[39][40][41][42][43][44] or well-established recurrent CNVs [24,[45][46][47][48]. Alternatively, high-throughput studies have assessed a broad range of continuous and binary traits simultaneously [18,20,21] without any precautions to accommodate the aforementioned challenges.…”

Section: Introductionmentioning

confidence: 99%

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Rare copy-number variants as modulators of common disease susceptibility

Auwerx,

Jõeloo,

Sadler

et al. 2024

Genome Med

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Background Copy-number variations (CNVs) have been associated with rare and debilitating genomic disorders (GDs) 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 British UK Biobank (UKBB) 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. We estimated that 16% of these associations are indirect, acting by increasing body mass index (BMI). Signals mapped to 45 unique, non-overlapping regions, nine of which being linked to known GDs. Number and identity of genes affected by CNVs modulated 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 impacted 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. Finally, we show that while the total burden of rare CNVs—and especially deletions—strongly associated with disease risk, it only accounted for ~ 0.02% of the UKBB disease burden. These associations are mainly driven by CNVs at known GD CNV regions, whose pleiotropic effect on common diseases was broader than anticipated by our CNV-GWAS. Conclusions Our results shed light on the prominent role of rare CNVs in determining common disease susceptibility within the general population and provide actionable insights for anticipating later-onset comorbidities in carriers of recurrent CNVs.

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Section: Discussionmentioning

confidence: 99%