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A Common CYFIP1 Variant at the 15q11.2 Disease Locus Is Associated with Structural Variation at the Language-Related Left Supramarginal Gyrus

Copy number variants (CNVs) at the Breakpoint 1 to Breakpoint 2 region at 15q11.2 (BP1-2) are associated with language-related difficulties and increased risk for developmental disorders in which language is compromised. Towards underlying mechanisms, we investigated relationships between single nuc...

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Autores principales: Woo, Young Jae, Wang, Tao, Guadalupe, Tulio, Nebel, Rebecca A., Vino, Arianna, Del Bene, Victor A., Molholm, Sophie, Ross, Lars A., Zwiers, Marcel P., Fisher, Simon E., Foxe, John J., Abrahams, Brett S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4924813/
https://www.ncbi.nlm.nih.gov/pubmed/27351196
http://dx.doi.org/10.1371/journal.pone.0158036
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author Woo, Young Jae
Wang, Tao
Guadalupe, Tulio
Nebel, Rebecca A.
Vino, Arianna
Del Bene, Victor A.
Molholm, Sophie
Ross, Lars A.
Zwiers, Marcel P.
Fisher, Simon E.
Foxe, John J.
Abrahams, Brett S.
author_facet Woo, Young Jae
Wang, Tao
Guadalupe, Tulio
Nebel, Rebecca A.
Vino, Arianna
Del Bene, Victor A.
Molholm, Sophie
Ross, Lars A.
Zwiers, Marcel P.
Fisher, Simon E.
Foxe, John J.
Abrahams, Brett S.
author_sort Woo, Young Jae
collection PubMed
description Copy number variants (CNVs) at the Breakpoint 1 to Breakpoint 2 region at 15q11.2 (BP1-2) are associated with language-related difficulties and increased risk for developmental disorders in which language is compromised. Towards underlying mechanisms, we investigated relationships between single nucleotide polymorphisms (SNPs) across the region and quantitative measures of human brain structure obtained by magnetic resonance imaging of healthy subjects. We report an association between rs4778298, a common variant at CYFIP1, and inter-individual variation in surface area across the left supramarginal gyrus (lh.SMG), a cortical structure implicated in speech and language in independent discovery (n = 100) and validation cohorts (n = 2621). In silico analyses determined that this same variant, and others nearby, is also associated with differences in levels of CYFIP1 mRNA in human brain. One of these nearby polymorphisms is predicted to disrupt a consensus binding site for FOXP2, a transcription factor implicated in speech and language. Consistent with a model where FOXP2 regulates CYFIP1 levels and in turn influences lh.SMG surface area, analysis of publically available expression data identified a relationship between expression of FOXP2 and CYFIP1 mRNA in human brain. We propose that altered CYFIP1 dosage, through aberrant patterning of the lh.SMG, may contribute to language-related difficulties associated with BP1-2 CNVs. More generally, this approach may be useful in clarifying the contribution of individual genes at CNV risk loci.
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spelling pubmed-49248132016-07-18 A Common CYFIP1 Variant at the 15q11.2 Disease Locus Is Associated with Structural Variation at the Language-Related Left Supramarginal Gyrus Woo, Young Jae Wang, Tao Guadalupe, Tulio Nebel, Rebecca A. Vino, Arianna Del Bene, Victor A. Molholm, Sophie Ross, Lars A. Zwiers, Marcel P. Fisher, Simon E. Foxe, John J. Abrahams, Brett S. PLoS One Research Article Copy number variants (CNVs) at the Breakpoint 1 to Breakpoint 2 region at 15q11.2 (BP1-2) are associated with language-related difficulties and increased risk for developmental disorders in which language is compromised. Towards underlying mechanisms, we investigated relationships between single nucleotide polymorphisms (SNPs) across the region and quantitative measures of human brain structure obtained by magnetic resonance imaging of healthy subjects. We report an association between rs4778298, a common variant at CYFIP1, and inter-individual variation in surface area across the left supramarginal gyrus (lh.SMG), a cortical structure implicated in speech and language in independent discovery (n = 100) and validation cohorts (n = 2621). In silico analyses determined that this same variant, and others nearby, is also associated with differences in levels of CYFIP1 mRNA in human brain. One of these nearby polymorphisms is predicted to disrupt a consensus binding site for FOXP2, a transcription factor implicated in speech and language. Consistent with a model where FOXP2 regulates CYFIP1 levels and in turn influences lh.SMG surface area, analysis of publically available expression data identified a relationship between expression of FOXP2 and CYFIP1 mRNA in human brain. We propose that altered CYFIP1 dosage, through aberrant patterning of the lh.SMG, may contribute to language-related difficulties associated with BP1-2 CNVs. More generally, this approach may be useful in clarifying the contribution of individual genes at CNV risk loci. Public Library of Science 2016-06-28 /pmc/articles/PMC4924813/ /pubmed/27351196 http://dx.doi.org/10.1371/journal.pone.0158036 Text en © 2016 Woo et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Woo, Young Jae
Wang, Tao
Guadalupe, Tulio
Nebel, Rebecca A.
Vino, Arianna
Del Bene, Victor A.
Molholm, Sophie
Ross, Lars A.
Zwiers, Marcel P.
Fisher, Simon E.
Foxe, John J.
Abrahams, Brett S.
A Common CYFIP1 Variant at the 15q11.2 Disease Locus Is Associated with Structural Variation at the Language-Related Left Supramarginal Gyrus
title A Common CYFIP1 Variant at the 15q11.2 Disease Locus Is Associated with Structural Variation at the Language-Related Left Supramarginal Gyrus
title_full A Common CYFIP1 Variant at the 15q11.2 Disease Locus Is Associated with Structural Variation at the Language-Related Left Supramarginal Gyrus
title_fullStr A Common CYFIP1 Variant at the 15q11.2 Disease Locus Is Associated with Structural Variation at the Language-Related Left Supramarginal Gyrus
title_full_unstemmed A Common CYFIP1 Variant at the 15q11.2 Disease Locus Is Associated with Structural Variation at the Language-Related Left Supramarginal Gyrus
title_short A Common CYFIP1 Variant at the 15q11.2 Disease Locus Is Associated with Structural Variation at the Language-Related Left Supramarginal Gyrus
title_sort common cyfip1 variant at the 15q11.2 disease locus is associated with structural variation at the language-related left supramarginal gyrus
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4924813/
https://www.ncbi.nlm.nih.gov/pubmed/27351196
http://dx.doi.org/10.1371/journal.pone.0158036
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