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

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 fr...

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Autores principales: Zamariolli, Malú, Auwerx, Chiara, Sadler, Marie C., van der Graaf, Adriaan, Lepik, Kaido, Schoeler, Tabea, Moysés-Oliveira, Mariana, Dantas, Anelisa G., Melaragno, Maria Isabel, Kutalik, Zoltán
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9943723/
https://www.ncbi.nlm.nih.gov/pubmed/36706759
http://dx.doi.org/10.1016/j.ajhg.2023.01.005
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author Zamariolli, Malú
Auwerx, Chiara
Sadler, Marie C.
van der Graaf, Adriaan
Lepik, Kaido
Schoeler, Tabea
Moysés-Oliveira, Mariana
Dantas, Anelisa G.
Melaragno, Maria Isabel
Kutalik, Zoltán
author_facet Zamariolli, Malú
Auwerx, Chiara
Sadler, Marie C.
van der Graaf, Adriaan
Lepik, Kaido
Schoeler, Tabea
Moysés-Oliveira, Mariana
Dantas, Anelisa G.
Melaragno, Maria Isabel
Kutalik, Zoltán
author_sort Zamariolli, Malú
collection PubMed
description 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 under 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 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, 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.
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spelling pubmed-99437232023-02-23 The impact of 22q11.2 copy-number variants on human traits in the general population Zamariolli, Malú Auwerx, Chiara Sadler, Marie C. van der Graaf, Adriaan Lepik, Kaido Schoeler, Tabea Moysés-Oliveira, Mariana Dantas, Anelisa G. Melaragno, Maria Isabel Kutalik, Zoltán Am J Hum Genet Article 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 under 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 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, 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. Elsevier 2023-02-02 2023-01-26 /pmc/articles/PMC9943723/ /pubmed/36706759 http://dx.doi.org/10.1016/j.ajhg.2023.01.005 Text en © 2023 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zamariolli, Malú
Auwerx, Chiara
Sadler, Marie C.
van der Graaf, Adriaan
Lepik, Kaido
Schoeler, Tabea
Moysés-Oliveira, Mariana
Dantas, Anelisa G.
Melaragno, Maria Isabel
Kutalik, Zoltán
The impact of 22q11.2 copy-number variants on human traits in the general population
title The impact of 22q11.2 copy-number variants on human traits in the general population
title_full The impact of 22q11.2 copy-number variants on human traits in the general population
title_fullStr The impact of 22q11.2 copy-number variants on human traits in the general population
title_full_unstemmed The impact of 22q11.2 copy-number variants on human traits in the general population
title_short The impact of 22q11.2 copy-number variants on human traits in the general population
title_sort impact of 22q11.2 copy-number variants on human traits in the general population
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9943723/
https://www.ncbi.nlm.nih.gov/pubmed/36706759
http://dx.doi.org/10.1016/j.ajhg.2023.01.005
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