Multi-level genomic analysis identifies pleiotropic genetic liability for insomnia, anxiety and depression

Insomnia (INS), major depression (DEP) and anxiety disorders (ANX) frequently co-occur and share a substantial proportion of their genetic risk. Most genetic studies have focused on shared risk between DEP and ANX, often omitting INS. Other studies that include INS have been limited to genome-wide correlations or overlap. Identifying the specific genetic factors that influence these three conditions could offer a route to identify therapeutic targets with potential transdiagnostic benefits. Realizing this potential requires pinpointing the likely causal variants and genes that are shared, estimating how pleiotropic effects are mediated, as well as identifying the biological processes they affect. Here we conduct a multi-level trivariate genetic analysis of INS, DEP and ANX using genome-wide association studies (GWAS) of more than one million individuals from multiple ancestries. We show that 55% of the genetic signal is shared across all three conditions. Supporting its importance, INS shares a significant fraction of the genetic overlap (75%) and correlation (7%) between DEP and ANX. We identify 195 genomic loci with shared signal for at least two conditions, many of which are likely arising from the same causal variant (at least 50%) or effector gene (60-80%). Pairwise mediation analyses suggest that these shared likely causal variants are more consistent with models of vertical pleiotropy where DEP and INS are risk factors towards ANX, rather than with models of horizontal pleiotropy. We find convergence of shared effector genes on biological processes in inhibitory synaptic transmission, neuronal organization, and axonal development. These results reveal an interconnected but mechanistically diverse basis for shared genetic risk across INS, DEP and ANX, and offer potential candidates for future pathway-tailored therapeutic targets with transdiagnostic benefits.