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Identifying the genes that contribute to the variability in brain regions involved in language processing may shed light on the evolution of brain structures essential to the emergence of language in Homosapiens. The superior temporal asymmetrical pit (STAP), which is not observed in chimpanzees, represents an ideal phenotype to investigate the genetic variations that support human communication. The left STAP depth was significantly associated with a predicted enhancer annotation located in the 14q23.1 locus, between DACT1 and KIAA0586, in the UK Biobank British discovery sample (N=16,515). The same locus also significantly associates with fractional anisotropy of the left auditory fibers of the corpus callosum and with functional networks involved in linguistic processing. Overall, this evidence demonstrates a specific relationship between this locus and the establishment of the superior temporal regions that support human communication.
Study of genes/SNPs association with the brain morphology, including in particular the sulci and the sulcal pits
We propose to investigate the existence of genes or gene networks involved in brain cortical structures normal variability. In preliminary works, we have estimated the heritability of these cortical structures by studying a variety of features such as the depth of sulci. To compute these estimate we used separately a pedigree study with SOLAR (Sequential Oligogenic Linkage Analysis Routines) and an independent population with the genetic information using GCTA (Genome-wide Complex Trait Analysis). Our results suggest that there are regions for which brain cortical structures are more heritable. Thus, they are pertinent phenotypes to perform variant and gene association studies. Our research meets the UK Biobank's stated purpose because characterizing the genes that shape the cortical structures would help to build a reference set of ?non-pathological variability?-causing genes. This will in turn help to better identify and understand the potential genetic patterns underlying diseases for which the particular shapes of cortical structures have been shown to be a biomarker, such as polymicrogyria, schizophrenia or autism. We will extract the features of interest on structural images (MRI images). For this task, we will use the same pipelines we used to estimate the heritability; they include functions available in Freesurfer and Brainvisa (brainvisa.info) software. Then, we will perform SNPs (Single Nucleotide Polymorphism) association studies with the previously extracted features to identify the SNPs , We will test various genetic model and follow GWAS (genome-wide association study) good practices analysis using genetic tools like PLINK (whole genome association analysis toolset). Ultimately the IMAGEN cohort with similar content accessible from our lab will be used as a replicate. The statistical power of our study will be increased if we can include all the subjects with structural images and genetic data available in UK Biobank (currently around ~10000 subjects). This would provide us with better statistical power to characterize the largest possible number of SNPs associated with these cortical structures considered as phenotypes.