Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> Gene <s> Recent genetic studies have implicated a number of candidate genes in the pathogenesis of Autism Spectrum Disorder (ASD). Polymorphisms of CNTNAP2 (contactin-associated like protein-2), a member of the neurexin family, have already been implicated as a susceptibility gene for autism by at least 3 separate studies. We investigated variation in white and grey matter morphology using structural MRI and diffusion tensor imaging. We compared volumetric differences in white and grey matter and fractional anisotropy values in control subjects characterised by genotype at rs7794745, a single nucleotide polymorphism in CNTNAP2. Homozygotes for the risk allele showed significant reductions in grey and white matter volume and fractional anisotropy in several regions that have already been implicated in ASD, including the cerebellum, fusiform gyrus, occipital and frontal cortices. Male homozygotes for the risk alleles showed greater reductions in grey matter in the right frontal pole and in FA in the right rostral fronto-occipital fasciculus compared to their female counterparts who showed greater reductions in FA of the anterior thalamic radiation. Thus a risk allele for autism results in significant cerebral morphological variation, despite the absence of overt symptoms or behavioural abnormalities. The results are consistent with accumulating evidence of CNTNAP2's function in neuronal development. The finding suggests the possibility that the heterogeneous manifestations of ASD can be aetiologically characterised into distinct subtypes through genetic-morphological analysis. <s> BIB001 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> Gene <s> Background ::: Heterozygous disruption of FOXP2 causes a rare form of speech and language impairment. Screens of the FOXP2 sequence in individuals with speech/language-related disorders have identified several rare protein-altering variants, but their phenotypic relevance is often unclear. FOXP2 encodes a transcription factor with a forkhead box DNA-binding domain, but little is known about the functions of protein regions outside this domain. <s> BIB002 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> Gene <s> The main objective of the multi-site Pediatric Imaging, Neurocognition, and Genetics (PING) study was to create a large repository of standardized measurements of behavioral and imaging phenotypes accompanied by whole genome genotyping acquired from typically-developing children varying widely in age (3 to 20 years). This cross-sectional study produced sharable data from 1493 children, and these data have been described in several publications focusing on brain and cognitive development. Researchers may gain access to these data by applying for an account on the PING portal and filing a data use agreement. Here we describe the recruiting and screening of the children and give a brief overview of the assessments performed, the imaging methods applied, the genetic data produced, and the numbers of cases for whom different data types are available. We also cite sources of more detailed information about the methods and data. Finally we describe the procedures for accessing the data and for using the PING data exploration portal. <s> BIB003
Chr Location Function Imaging Phenotype (language/reading) References BIB001 Udden et al. Whalley et al. Note. Publications focused on patient populations and/or individuals with disorders other than SRD and DLD were excluded from our review. including some of the FOXP2 variants associated with speech and language impairment (e.g., see BIB002 . Under both the CDRV and CDCV approaches, two primary methods are used for the identification of genes associated with complex neurodevelopmental disorders. Hypothesis-driven candidate gene association studies investigating specific SNPs allow researchers to identify how alleles at one or more pre-identified locations on the gene are related to specific phenotypes . Alternatively, an exploratory approach may be taken using a genome-wide association study (GWAS) to identify SNPs associated with a trait of interest; this approach is especially useful for detection of new variants (Hirschhorn & Daly, 2005) . GWAS is a powerful tool, but it is costly and effortful to genotype thousands of SNPs per individual, and GWAS requires large sample sizes for sufficient power to detect small effects associated with complex traits (Hirschhorn & Daly, 2005) . Recent efforts to build and share large genetic databases (e.g. the Pediatric Imaging, Neurocognition, and Genetics [PING] Data Repository; BIB003 aim to reduce the burden and increase power of GWAS studies. The field of neuroimaging genetics applies these genetic methods in combination with neuroimaging techniques to improve characterization of complex traits through the identification of intermediate phenotypes that link genes to behaviors through neural mechanisms. Using these methods, geneticists, neuroscientists, and psychologists may work together to deepen the understanding of complex developmental disorders such as specific reading disability (SRD) and developmental language disorder (DLD) in a step to improve identification and treatment of these conditions.