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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

Authors :
Lars A. Ross
Brett S. Abrahams
Sophie Molholm
Simon E. Fisher
Marcel P. Zwiers
Tulio Guadalupe
Young Jae Woo
John J. Foxe
Rebecca A. Nebel
Arianna Vino
Victor A. Del Bene
Tao Wang
Source :
PLoS One, 11, 6, PLoS One, 11, PLoS ONE, Vol 11, Iss 6, p e0158036 (2016), PLoS ONE, PLoS One
Publication Year :
2016

Abstract

s Metrics Comments Related Content Abstract Introduction Materials and Methods Results Discussion Supporting Information Acknowledgments Author Contributions References Reader Comments (0) Media Coverage Figures Abstract 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.

Details

ISSN :
19326203
Database :
OpenAIRE
Journal :
PLoS One, 11, 6, PLoS One, 11, PLoS ONE, Vol 11, Iss 6, p e0158036 (2016), PLoS ONE, PLoS One
Accession number :
edsair.doi.dedup.....9de509e6ce2856c23a5b1bd4e0433f32