title: A Common CYFIP1 Variant at the 15q11.2 Disease Locus Is Associated with Structural Variation at the Language-Related Left Supramarginal Gyrus.
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.
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, United States of America.
authors.forename: Young Jae
authors.initials: YJ
authors.lastname: Woo
authors.affiliation: Department of Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, United States of America.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands.
authors.forename: Tulio
authors.initials: T
authors.lastname: Guadalupe
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, United States of America.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Nebel
authors.affiliation: Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands.
authors.forename: Arianna
authors.initials: A
authors.lastname: Vino
authors.affiliation: The Sheryl and Daniel R. Tishman Cognitive Neurophysiology Laboratory, Children's Evaluation and Rehabilitation Center (CERC), Albert Einstein College of Medicine, Bronx, United States of America.|Department of Pediatrics, Albert Einstein College of Medicine, Bronx, United States of America.|Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, United States of America.
authors.forename: Victor A
authors.initials: VA
authors.lastname: Del Bene
authors.affiliation: The Sheryl and Daniel R. Tishman Cognitive Neurophysiology Laboratory, Children's Evaluation and Rehabilitation Center (CERC), Albert Einstein College of Medicine, Bronx, United States of America.|Department of Pediatrics, Albert Einstein College of Medicine, Bronx, United States of America.|Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, United States of America.
authors.forename: Sophie
authors.initials: S
authors.lastname: Molholm
authors.affiliation: The Sheryl and Daniel R. Tishman Cognitive Neurophysiology Laboratory, Children's Evaluation and Rehabilitation Center (CERC), Albert Einstein College of Medicine, Bronx, United States of America.|Department of Pediatrics, Albert Einstein College of Medicine, Bronx, United States of America.|Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, United States of America.
authors.forename: Lars A
authors.initials: LA
authors.lastname: Ross
authors.affiliation: Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands.
authors.forename: Marcel P
authors.initials: MP
authors.lastname: Zwiers
authors.affiliation: Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
authors.forename: Simon E
authors.initials: SE
authors.lastname: Fisher
authors.affiliation: The Sheryl and Daniel R. Tishman Cognitive Neurophysiology Laboratory, Children's Evaluation and Rehabilitation Center (CERC), Albert Einstein College of Medicine, Bronx, United States of America.|Department of Pediatrics, Albert Einstein College of Medicine, Bronx, United States of America.|The Cognitive Neurophysiology Laboratory, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, United States of America.|Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, United States of America.
authors.forename: John J
authors.initials: JJ
authors.lastname: Foxe
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, United States of America.|Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, United States of America.
authors.forename: Brett S
authors.initials: BS
authors.lastname: Abrahams
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D056915:DNA Copy Number Variations; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D056426:Genetic Loci; D006801:Humans; D007804:Language Development; D010296:Parietal Lobe / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000502:physiology; D013060:Speech
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C109916:CYFIP1 protein, human; C465448:FOXP2 protein, human; D051858:Forkhead Transcription Factors