title: Neuroimaging genetic analyses of novel candidate genes associated with reading and language.
abstract: Neuroimaging measures provide useful endophenotypes for tracing genetic effects on reading and language. A recent Genome-Wide Association Scan Meta-Analysis (GWASMA) of reading and language skills (N=1862) identified strongest associations with the genes CCDC136/FLNC and RBFOX2. Here, we follow up the top findings from this GWASMA, through neuroimaging genetics in an independent sample of 1275 healthy adults. To minimize multiple-testing, we used a multivariate approach, focusing on cortical regions consistently implicated in prior literature on developmental dyslexia and language impairment. Specifically, we investigated grey matter surface area and thickness of five regions selected a priori: middle temporal gyrus (MTG); pars opercularis and pars triangularis in the inferior frontal gyrus (IFG-PO and IFG-PT); postcentral parietal gyrus (PPG) and superior temporal gyrus (STG). First, we analysed the top associated polymorphisms from the reading/language GWASMA: rs59197085 (CCDC136/FLNC) and rs5995177 (RBFOX2). There was significant multivariate association of rs5995177 with cortical thickness, driven by effects on left PPG, right MTG, right IFG (both PO and PT), and STG bilaterally. The minor allele, previously associated with reduced reading-language performance, showed negative effects on grey matter thickness. Next, we performed exploratory gene-wide analysis of CCDC136/FLNC and RBFOX2; no other associations surpassed significance thresholds. RBFOX2 encodes an important neuronal regulator of alternative splicing. Thus, the prior reported association of rs5995177 with reading/language performance could potentially be mediated by reduced thickness in associated cortical regions. In future, this hypothesis could be tested using sufficiently large samples containing both neuroimaging data and quantitative reading/language scores from the same individuals.
authors.affiliation: Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, Netherlands; Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gialluisi
authors.affiliation: Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, Netherlands.
authors.forename: Tulio
authors.initials: T
authors.lastname: Guadalupe
authors.affiliation: Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Netherlands.
authors.forename: Clyde
authors.initials: C
authors.lastname: Francks
authors.affiliation: Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Netherlands. Electronic address: simon.fisher@mpi.nl.
authors.forename: Simon E
authors.initials: SE
authors.lastname: Fisher
mesh_terms: D017398:Alternative Splicing; D001931:Brain Mapping; D002877:Chromosomes, Human / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D066128:Gray Matter / Q000502:physiology; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000072260:RNA Splicing Factors / Q000235:genetics; D011932:Reading; D012097:Repressor Proteins / Q000235:genetics
chemical_list: C491796:CCDC136 protein, human; D009363:Neoplasm Proteins; C454924:RBFOX2 protein, human; D000072260:RNA Splicing Factors; D012097:Repressor Proteins
keywords: Brain; Cortical thickness; Imaging genetics; Language; RBFOX2; Reading