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

Abstract

While extensively studied in clinical cohorts, the phenotypic consequences of 22q11.2 copy number variants (CNVs) in the general population remain understudied. To address this gap, we performed a phenome-wide association scan in 405324 unrelated UK Biobank (UKBB) participants using CNV calls from genotyping array. We mapped 236 Human Phenotype Ontology terms linked to any of the 90 genes encompassed by the region to 170 UKBB traits and assessed the association between these traits and the copy-number state of 504 SNP-array probes in the region. We found significant associations for eight continuous and nine binary traits associated under different models (duplication-only, deletion-only, U-shape and mirror model). The causal effect of the expression level of 22q11.2 genes on associated traits was assessed through transcriptome-wide mendelian randomization (TWMR), revealing that increased expression of ARVCF increased BMI. Similarly, increased DGCR6 expression causally reduced mean platelet volume, in line with the corresponding CNV effect. Furthermore, cross-trait multivariable mendelian randomization (MVMR) suggested a predominant role of genuine (horizontal) pleiotropy in the CNV region. Our findings show that within the general population, 22q11.2 CNVs are associated with traits previously linked to genes in the region, with duplications and deletions acting upon traits in different fashion. We also showed that gain or loss of distinct segments within 22q11.2 may impact a trait under different association models. Our results have provided new insights to help further the understanding of the complex 22q11.2 region.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This study was supported by funding from the Department of Computational Biology (Z.K.), the Swiss National Science Foundation (310030-189147) as well as financial support from Fundação de Amparo à Pesquisa do Estado de São Paulo [2020/11241-2, M.Z.; 2019/21644-0, M.I.M] and from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior ‐ Brasil (CAPES).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

UK Biobank: Participants signed a broad informed consent form and data was accessed through the application number 16389.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

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I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

Data Availability

All data produced in the present study are available upon reasonable request to the authors.

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