Attention-deficit hyperactivity disorder (ADHD) and post-traumatic stress disorder (PTSD) are common, burdensome, and heritable psychiatric disorders. These disorders highly comorbid; individuals with ADHD are up to four times more likely to develop PTSD compared to the general population. Their co-occurrence is associated with more severe symptoms, greater functional impairment, and poorer treatment outcomes. The comorbidity between ADHD and PTSD is reflected by substantial genetic overlap (rg = 0.66). However, the specific genetic and biological mechanisms underlying their comorbidity are not known, limiting the development of more effective therapeutics. In this presentation, we discuss how shared genetic risk factors (i.e., pleotropic effects) can be leveraged to identify putative causal genes and drug targets for ADHD and PTSD.
We dissect the shared genetic architecture of ADHD and PTSD and identify the specific underlying mechanisms that are shared by or specific to these disorders. First, we implement novel genomic structural equation models to partition the genetic effects of ADHD and PTSD into shared (N loci=163) and disorder-specific components (ADHD N loci = 7; PTSD N loci = 10) using the largest available GWAS of both ADHD (effective N = 117,827) and PTSD (effective N = 641,533). Second, we integrate gene expression data to functionally annotate the genetic associations and identify the cell types, genes, and biological pathways that are implicated in the comorbidity of ADHD and PTSD. Third, we will integrate highly annotated drug-gene interaction data and drug target information to identify novel drug candidates for the shared and disorder-specific components of ADHD and PTSD. Our study demonstrates how leveraging pleiotropic effects provides opportunities for the discovery of novel drug targets and drug repurposing candidates for psychiatric disorders.