15q11.2 disease locus: From cognition to molecular
Woo, Young Jae
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A large number of copy number variants (CNVs) associated with clinically defined psychiatric disorders show incomplete penetrance and variable expressivity. To better understand mechanisms and work towards personalized interventions, my research focused on investigating the intermediate brain and behavior phenotypes associated with BP1-2 deletion at 15g11.2, a multi-genic region that increases risk for schizophrenia and epilepsy. We have recruited genetically defined research subjects through social media and used online tools to perform cognitive assessments. We find that BP1-2 deletion carriers, but not their non-carrier family members, show domain specific cognitive impairments. Profound deficits in grammatical reasoning, arithmetic tasks, and visuo-spatial working memory are observed despite normal performance on non-verbal tasks.;Towards mechanisms, we looked for relationships between quantitative measures of brain structure obtained by MRI and common variants within BP1-2 region. After correcting for multiple comparisons, we observed an association between a variant 2 kb upstream of cytoplasmic FMR1 interacting protein 1 gene (CYFIP1) and the left supramarginal gyrus (lh.SMG), a brain region implicated in schizophrenia and language processing. Separate analyses in an independent cohort of 2622 typically developing adults showed an association between Ih.SMG and this same variant identified in our discovery cohort. Genotype at this Single Nucleotide Polimorphism (SNP), as well as seven linked SNPs, showed a significant correlation with CYFIP1 mRNA levels in human brain. In an attempt to understand how genetic variation in this region might come to impact CYFIP1 expression, we looked for transcription factor binding sites predicted to show allele specific binding. Strikingly, these investigations revealed that one of the seven CYFIP1 regulatory variants we identified is predicted to show allele specific binding for FOXP2, a transcription factor well known for its role in language. Separate analyses showing a strong correlation between FOXP2 and CYFIP1 levels in human brain (r 2=0.36), is consistent with FOXP2 being a key regulator of CYFIP1.;Genomic imbalance at BP1-2 region increases disease risk for a number of neurodevelopmental disorders and may be responsible for variety of clinically relevant traits. We performed online-based cognitive assessment and found a specific role of BP1-2 deletion in language processing and arithmetic tasks. Our work also shows the feasibility of using online tools to recruit populations of interest located worldwide and study disease-related quantitative traits that could be used in clinical trials. Our neuroimaging work points toward an importance of CYFIP1 in lh.SMG development, an effect that may be mediated by altered binding of the language-implicated transcription factor FOXP2. This work demonstrates the usage of neuroimaging in disease gene detection.
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