NEW YORK – New research suggests that hundreds of genetic loci — including those falling in genes or pathways previously implicated in metabolic and psychiatric conditions — can influence individuals' propensity for insomnia.
Reporting in Nature Genetics on Thursday, senior and corresponding author Danielle Posthuma, a researcher at Vrije Universiteit Amsterdam and VU Medical Center, and her colleagues noted that the study "suggests that insomnia is a genetically heterogeneous phenotype consisting of different genetic subtypes — for example, insomnia symptoms that are related more to either metabolic disturbances or other factors in the brain that may require different treatment approaches."
With a genome-wide association study meta-analysis that included nearly 594,000 genotyped individuals with insomnia and almost 1.8 million unaffected controls enrolled through the UK Biobank and 23andMe, researchers from VU Amsterdam and elsewhere tracked down significant insomnia associations at almost 51,900 SNPs falling at more than 550 loci, including 364 loci not linked to the sleep disorder in the past.
That set included 419 loci that appeared to have genome-wide significant associations in the 23andMe cohort, the authors reported, and 11 significant loci specific to the UK Biobank participants. Another nine loci showed associations with insomnia in both groups.
Because almost 3,900 genes were potentially impacted by the insomnia-related loci based on functional annotation and gene-based analyses, the team brought in additional in silico fine-mapping, "cross-locus" gene links found with protein-protein interaction data, gene regulation, and gene expression clues to focus in on gene clusters and pathways most likely to contribute to the condition.
"We propose an … in silico approach in which we combine statistical fine-mapping with cross-locus linking of genes for which external data are available, aimed at more specific hypotheses and targets for wet-lab experiments. This approach is especially suited for GWAS that identify hundreds of loci," the authors explained, noting that "this novel gene prioritization strategy yields specific hypotheses on underlying mechanisms of insomnia that would have been missed by traditional approaches."
Along with gene clusters implicated in everything from metabolic or cardiovascular traits to psychiatric conditions, the researchers flagged more than 200 loci and 289 "high-confidence prioritized" genes as being most relevant to the condition, uncovering a subset of insomnia-associated genes with ties to chemical signaling at neuronal synapses and involved in neuronal development-related processes.
"Our current results … hint at heterogeneous forms of insomnia, one that is due to a metabolic-genetic pathway and a second due to a psychiatric-genetic pathway," the authors wrote. "Future studies aimed at increasing prediction may benefit from the collection of deep phenotyping data on insomnia patients and identify subtypes of insomnia."
More broadly, the study's authors explained, the current work suggests that "for extremely polygenic traits such as insomnia, increasing sample size does lead to an increase in detected SNPs, loci, genes, and pathways, providing more confidence in existing and novel mechanisms."