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

• Published in: PloS one Vol. 11; no. 6; p. e0158036
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 28.06.2016; Public Library of Science (PLoS)
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Autism; Binding sites; Biology and Life Sciences; Brain; Brain research; Case-Control Studies; Children & youth; Chromosome 15; Chromosomes, Human, Pair 15 - genetics; Copy number; Cortex; Developmental disabilities; Diagnostic imaging; DNA Copy Number Variations; Drug dosages; Dyslexia; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Foxp2 protein; Gene expression; Genetic Loci; Genetics; Humans; Laboratories; Language; Language Development; Loci; Luteinizing hormone; Magnetic resonance; Magnetic resonance imaging; Medicine; Medicine and Health Sciences; Migraine; Mutation; Neural networks; Neurodevelopmental disorders; Neuroimaging; Neurosciences; NMR; Nuclear magnetic resonance; Parietal Lobe - diagnostic imaging; Parietal Lobe - metabolism; Parietal Lobe - physiology; Pattern formation; Pediatrics; Proteins; Reading; Rehabilitation; Research and Analysis Methods; RNA; Schizophrenia; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Social Sciences; Speech; Studies; Surface area; United States; United States > US; Netherlands
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0158036

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.