A common CYFIP1 variant at the 15q11.2 disease locus is associated with structural variation at the language-related left supramarginal gyrus

Young Jae Woo, Tao Wang, Tulio Guadalupe, Rebecca A. Nebel, Arianna Vino, Victor A. Del Bene, Sophie Molholm, Lars A. Ross, Marcel P. Zwiers, Simon E. Fisher, John J. Foxe, Brett S. Abrahams

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere0158036
JournalPLoS One
Volume11
Issue number6
DOIs
StatePublished - Jun 1 2016

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Parietal Lobe
Brain
Language
Polymorphism
loci
Messenger RNA
brain
Magnetic resonance
surface area
Transcription Factors
Nucleotides
Genes
Binding Sites
Gene Dosage
Imaging techniques
magnetic resonance imaging
Computer Simulation
single nucleotide polymorphism
Single Nucleotide Polymorphism
binding sites

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

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.

In: PLoS One, Vol. 11, No. 6, e0158036, 01.06.2016.

Research output: Contribution to journalArticle

Woo, YJ, Wang, T, Guadalupe, T, Nebel, RA, Vino, A, Del Bene, VA, Molholm, S, Ross, LA, Zwiers, MP, Fisher, SE, Foxe, JJ & Abrahams, BS 2016, 'A common CYFIP1 variant at the 15q11.2 disease locus is associated with structural variation at the language-related left supramarginal gyrus', PLoS One, vol. 11, no. 6, e0158036. https://doi.org/10.1371/journal.pone.0158036
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. In: PLoS One. 2016 ; Vol. 11, No. 6.
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