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

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Autor(es):
Zamariolli, Malu ; Auwerx, Chiara ; Sadler, Marie C. ; van der Graaf, Adriaan ; Lepik, Kaido ; Schoeler, Tabea ; Moyses-Oliveira, Mariana ; Dantas, Anelisa G. ; Melaragno, Maria Isabel ; Kutalik, Zoltan
Número total de Autores: 10
Tipo de documento: Artigo Científico
Fonte: American Journal of Human Genetics; v. 110, n. 2, p. 14-pg., 2023-02-02.
Resumo

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 405,324 unrelated UK Biobank (UKBB) participants by 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 genotyping array probes in the region. We found significant associations for eight continuous and nine binary traits associated un-der different models (duplication-only, deletion-only, U-shape, and mirror models). 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 expres-sion of ARVCF increased BMI. Similarly, increased DGCR6 expression causally reduced mean platelet volume, in line with the corre-sponding 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, and duplications and deletions act upon traits in different fashions. 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. (AU)

Processo FAPESP: 20/11241-2 - Busca por modificadores genéticos para defeitos cardíacos na síndrome de deleção 22q11.2 usando traços complexas na população em geral
Beneficiário:Malú Zamariolli de Souza
Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado
Processo FAPESP: 19/21644-0 - Impacto de variantes genéticas na estabilidade do genoma e seus efeitos no fenótipo
Beneficiário:Maria Isabel de Souza Aranha Melaragno
Modalidade de apoio: Auxílio à Pesquisa - Temático