Cell-specific genetic regulatory mechanisms mediating risk for neuropsychiatric disorders in the developing human brain

Mental illnesses, such as schizophrenia, are complex disorders with poorly defined neurobiological causes. Large-scale studies have been successful in identifying hundreds of genetic variants that commonly increase risk for these conditions, but the precise molecular and cellular mechanisms by which they operate are currently unclear. There is strong evidence that many of these genetic variants confer risk for these disorders by altering the level at which genes are expressed during brain development. In this project, we will use cutting-edge technology to identify genetic variants affecting gene expression in individual cell populations of the prenatal human brain. We will then link these findings with genetic data for mental illnesses to identify cell-specific gene expression changes that mediate risk for these conditions. These studies will advance our understanding of the molecular and cellular mechanisms conferring susceptibility to major mental illnesses, through which improved treatments can be developed.

Large-scale genome-wide association studies (GWAS) have identified hundreds of genetic loci that are commonly involved in major neuropsychiatric disorders. Evidence suggests that a substantial proportion of these variants confer risk to these disorders through effects on gene expression in the developing human brain. Such variants can be identified through eQTL mapping studies that combine genome-wide genotyping with global measures of gene expression. However, all previous eQTL studies performed in the prenatal human brain have been conducted using 'bulk' tissue, where gene expression is averaged across all constituent cell types. As genetic effects on gene expression are often cell-specific, many of these effects will be masked using bulk tissue assays. To identify genetic variants associated with altered gene expression in individual cell populations of the human prenatal brain, we will perform an eQTL study based on single nuclei RNA sequencing and genome-wide genotyping of 140 foetal brains from the second trimester of gestation. We will integrate our findings with data from large-scale GWAS of neuropsychiatric disorders (e.g. schizophrenia, bipolar disorder, major depressive disorder and ADHD) to identify gene expression changes in specific cell populations that mediate genetic risk for these conditions. These studies will greatly advance our understanding of the molecular and cellular mechanisms conferring susceptibility to major neuropsychiatric disorders, through which improved treatments can be developed.