Shared predicted effector genes of insomnia, anxiety and depression implicate synaptic processes as transdiagnostic drug targets

Abstract

BackgroundInsomnia (INS) is a major factor determining the risk, severity, treatment resistance and relapse of depression (DEP) and anxiety disorders (ANX), suggesting shared neurobiological vulnerability. Identifying common biological mechanisms that are therapeutically actionable is a foundational step towards improving current clinical care. Since INS, DEP, and ANX share substantial genetic risk, pinpointing the specific genetic factors that influence these three conditions simultaneously offers a route to discover pharmacological targets with transdiagnostic potential. MethodsWe propose a framework of multi-level trivariate genetic analysis to identify the shared genetic component of INS, DEP and ANX using genome-wide association studies (GWAS). We trace shared components through trivariate genetic overlap, local genetic correlations, overlapping genome-wide significant loci, shared predicted effector genes, and shared putative causal variants. ResultsWe show that INS, DEP and ANX share 55% of their GWAS signal. We identify 195 cross-disorder loci, many of which are likely arising from the same causal variant (at least 50%) or predicted effector gene (60-80%). We find convergence of shared predicted effector genes on biological processes such as inhibitory synaptic transmission, neuronal organization, and axonal development. The majority of shared predicted effector genes that are also druggable are involved in synaptic transmission and located in synaptic membranes, nominating CACNA2D3, DRD2, GRIA1 and GRM5 as key targets for drug development to treat comorbid INS, DEP and ANX. ConclusionThese results reveal an interconnected but mechanistically diverse basis for shared genetic liability across co-occurring INS, DEP and ANX, and offer potential candidates for future pathway-tailored transdiagnostic therapeutic targets.