Genome-wide meta-analysis of insomnia in over 2.3 million individuals implicates involvement of specific biological pathways through gene-prioritization

Insomnia is a heritable, highly prevalent sleep disorder, for which no sufficient treatment currently exists. Previous genome-wide association studies (GWASs) with up to 1.3 million subjects identified over 200 associated loci. This extreme polygenicity suggested many more loci to be discovered. The current study almost doubled the sample size to over 2.3 million individuals thereby increasing statistical power. We identified 554 risk loci (confirming 190 previously associated loci and detecting 364 novel), and capitalizing on this large number of loci, we propose a novel strategy to prioritize genes using external biological resources and information on functional interactions between genes across risk loci. Of all 3,898 genes naively implicated from the risk loci, we prioritize 289. For these, we find brain-tissue expression specificity and enrichment in specific gene-sets of synaptic signaling functions and neuronal differentiation. We show that the novel gene prioritization strategy yields specific hypotheses on causal mechanisms underlying insomnia, which would not fully have been detected using traditional approaches.