Project Summary Our goal is to determine the connection among genes, brain structure and neuropsychiatric disorders. These disorders are common and increasing in incidence worldwide. Lower costs of both genotyping and magnetic resonance imaging (MRI) acquisition have provided an unprecedented opportunity to understand how genetic factors shape brain morphology. Given that structural brain measures may reflect intermediate phenotypes of neuropsychiatric disorders on the pathway between genotypes and clinical phenotypes. These findings in turn may help us better understand the pathogenesis of neuropsychiatric disorders. Data released by UK Biobank and ABCD Study (Adolescent Brain Cognitive Development Study) containing individual-level genotypes and rich phenotype variables allow genome-wide association studies (GWAS) in brain imaging phenotypes to identify genetic variants associated with brain morphology. Our study and work from other groups in brain imaging GWAS have confirmed that many identified genes are related to neurodevelopmental processes. The first objective in the current study is to uncover genetic variants associated with brain imaging phenotypes (Aim 1). Our second objective is to test genetic heterogeneity between the sexes in association with brain morphology and to include the X chromosome in the analysis (Aim 2). Our third objective is to determine the impact of neuropsychiatric genetic risks on the brain (Aim 3). Previously we produced the genetic atlases of the human cortex based on MRI data of twins using fuzzy clustering. Our most recent work demonstrated the value of using the atlases to determine genetic variants influencing brain structure. In this proposal, we will leverage an increased sample size with both MRI and single nucleotide polymorphism (SNP) data. The larger sample increases power for discovering and replicating SNPs associated with individual brain structures and will enable us to examine genetic heterogeneity between the sexes. Many GWAS loci are located in non- coding genomic regions thus it is hard to have functional interpretation of GWAS findings. We will use new methods for SNP-to-gene mapping to tackle this daunting challenge. We will also characterize pleiotropy among multiple brain regions. This will provide insight into shared and distinct genetic influences among brain regions, given that different brain regions have previously been implicated in neuropsychiatric disorders (Aim 1). Second, we will include the X chromosome in the association analysis with brain structure and determine X- linked dosage compensation (Aim 2). Third, building on improved genetic knowledge of the brain, we will determine its genetic relationship with neuropsychiatric disorders. We will estimate effects of neuropsychiatric genetic risks on brain structure and how the disorders are mediated by brain structure. (Aim 3). This current project has potential to significantly increase our understanding of the genetic basis of th...