Phenotypic expression of psychiatric disorders (age of onset, severity, and comorbidities) often vary between sexes. Genetic data from large-scale genome wide association studies (GWAS) establish that sex- differences also exist in the genetic contribution to psychiatric disorders. We have previously demonstrated that in sex-stratified cohorts, ADHD is genetically correlated with the behavioral phenotypes risk taking and age at first sexual intercourse. Furthermore, the forkhead box P2 (FOXP2) gene, involved in human complex speech, was significantly associated with ADHD in females, but is not detected in males. Genetic correlation results combined with GWAS signatures suggest that sex differences in psychiatric disorders may be caused by sex differences in biological mechanisms of the nervous system (e.g., FOXP2 expression is hormonally regulated by androgens, which themselves demonstrate clear sex-specific expression). We hypothesize that genetic liability to psychiatric disorders is affected by sex-specific mechanisms modulating nervous system traits. To address this hypothesis, we propose four specific aims addressing (Aim 1) the genetic correlation and overlap between sex-stratified psychiatric disorders and related traits, (Aim 2) the phenome-wide association of 1,202 genome-wide significant nervous system SNPs with the behavioral, anthropometric, and disease traits in the UK Biobank and other repositories, (Aim 3) causal relationships between psychiatric disorders and nervous system traits using a novel combination of latent causal variable and Mendelian randomization analyses, and (Aim 4) enrichment of biological pathways and gene expression signatures in sex-stratified psychiatric disorders. We expect to decipher the nuanced genetic correlations and causal relationships between sex-dichotomized psychiatric phenotypes and the human phenome. Elucidating the underlying mechanisms and gene expression signatures linking these traits also may contribute to developing pharmacological and nonpharmacological therapies for various disorders and provide biological evidence supporting the use of such therapies in combination with other interventions for mental health and/or psychiatric disorders. Through the described training plan, mastery will be developed in four key areas critical for a future career in academia. These training areas are (1) Build a strong computational biology and bioinformatics skill set, (2) Develop an operational knowledge of psychiatry and the genetics of complex traits, (3) Mentor trainees and develop my teaching portfolio, and (4) Improve written and oral communication and presentation skills. To accomplish these goals, a group of Co-Sponsors has been identified who will substantively contribute to the proposed research and training trajectories, a series of bioinformatics, bioethics, and pedagogy workshops and short-courses will be attended, and formal college-teaching certification will be obtained through a large multi- institutional collective. This rigorous training plan will produce a young researcher with the computational biology skills and teaching portfolio to obtain a highly competitive faculty position in the future.
Psychiatric disorders readily manifest in a heterogeneous nature depending on the sex of the affected individual. This proposal seeks to decipher the biological mechanisms that differ, or are similar, between males and females affected by psychiatric disorders using genome-wide data. The findings from this work will identify critical mechanistic signatures corresponding to sex-based phenotype heterogeneity which may contribute to the design and/or repurposing of applicable drugs and/or non-pharmacological psychiatric disorder treatment strategies.
