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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.
Highlights
Rare multi-gene copy number variants (CNVs) are well established to increase risk for neurodevelopmental disorders, but translational efforts have been hindered by a limited understanding of underlying mechanisms
Hypothesizing that common regulatory variants within the interval would give rise to effects like those seen in rare CNV carriers, we restricted analyses to regions of interest (ROIs) shown previously to be sensitive to breakpoints 1 and 2 (BP1-2) dosage [4]
Towards insight into how genetic variation at the 15q11.2 BP1-2 region may influence disease risk, we examined the relationship between tag-single nucleotide polymorphism (SNP) spanning the interval and aspects of regional brain structure
Summary
Rare multi-gene copy number variants (CNVs) are well established to increase risk for neurodevelopmental disorders, but translational efforts have been hindered by a limited understanding of underlying mechanisms. The four gene region between breakpoints 1 and 2 (BP1-2) at 15q11.2 is interesting in this regard in that deletions are associated with increased risk for epilepsy and schizophrenia [1,2,3,4,5,6], and the reciprocal duplications may be relevant to autism [7,8,9]. Recent work found a relationship between gene dosage at BP1-2 and structural variation at multiple disease associated brain regions [4]. The volumes of the lh.insula, rh.ACC, lh.SMG, and lh.tempWM were reduced in deletion carriers and increased in duplication carriers, whereas the opposite directionality was observed for the CC. Structural and functional alterations of the lh.SMG have been implicated in speech and language [14,15] Taken together, these data support a model whereby altered gene dosage at BP1-2 influences regional brain development and increases risk for disease. We hypothesized that common regulatory variants at the locus might be associated with similar effects in healthy individuals, and that their identification might clarify mechanisms of disease
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