Disruptions at different stages of brain development (embryonic, early postnatal, adolescent, etc.) lead to numerous neuropsychiatric disorders, such as ASD, ADHD, and schizophrenia. It has been well-accepted that both genetic and environmental factors contribute to these disorders. However, we do not know the exact relationships between individual factors and developmental phenotypes on anatomy and function of the nervous system. Notably, human genomic studies revealed that over 90% of disease associated SNPs are in the non-coding region, suggesting that changes on spatiotemporal expression pattern of genes are more etiologically relevant than changes on protein structure and function. In parallel, our previous studies demonstrated that normal visual environment during early postnatal development is required for the maturation of mouse visual cortex by regulating spatially graded expression pattern of genes defining cell-type identity. Many of these genes, such as Cdh13 and Igsf11, are critical for brain wiring. Interestingly, SNPs in the intron of these two genes are highly associated with various neuropsychiatric disorders (i.e. ADHD, ASD, ODD, etc.). Due to its complexity, there must be a repertoire of genes that are regulated by environment and control brain development.
We aim to use the rich multi-dimensional data hosted by the UK Biobank, including imaging, behavior, genomics and environment dataset, to search for candidate genomic loci that are associated with anatomical and functional phenotypes of the brain, and further identify substrates for genetic-environmental interactions among these candidates. We also aim to assign these loci to potential target genes that can regulate different stages of brain development. The project will be running for about 36 months. Our proposed research fits well with purposes of the UK Biobank because it will identify various genomic loci that are potentially regulated by environment and contribute to the spectrum of anatomical and functional phenotypes of the brain. Thus, it will help to understand how genetic-environmental interactions regulate brain development and guide us to better prevent or treat neuropsychiatric disorders by optimizing our environment and behavior based on our genomic characteristics.
