Genome-wide analysis of INSOMNIA in more than 1 million individuals !!!

These GEITP pages have often discussed genome-wide association studies (GWAS). GWAS are studies in which some phenotype (trait) is selected to be studied, and then thousands of individuals’ genomes are screened for statistically significant genetic loci associated with that selected trait. Benefits of GWAS findings are not as useful for “risk assessment” or “prediction of risk” — as much as they are for “identifying genetic pathways” that may lead to drug development to treat the phenotype being studied. Two articles [attached] just came out today and will appear in the March 2019 issue of Nature Genetics. The trait selected is INSOMNIA; this depends on self-reported problems recorded in questionnaires. GEITP would regard this phenotype as “soft” (i.e. not every individual is as reliable as other individuals).

Insomnia is the second most prevalent mental disorder (after depression). One-third of the general population reports insomnia complaints. Diagnostic criteria for insomnia disorder (i.e. difficulties with initiating or maintaining sleep, with accompanying daytime complaints, at least three times a week for at least three months, which cannot be attributed to inadequate circumstances for sleep) are met by 10% of individuals, and as much as one-third of older age individuals. Insomnia contributes significantly to risk and severity of cardiovascular, metabolic, mood, and neurodegenerative disorders. Insomnia also increases risk of developing anxiety disorders, alcohol abuse, and major depression. Common drug treatments target synaptic neurotransmission (via GABA-ergic pathways), hypothalamic neuropeptides (via hypocretin/orexin), cortical arousal (via histamine receptors), or the melatonin system, but these drugs have had variable effectiveness, can be habit-forming, and have side-effects.

Despite evidence of a considerable genetic component (heritability 38–59%), only a small number of genetic loci moderating the risk of insomnia have been identified until now. Authors [see Jansen et al., the 4-MB pdf attachment] decided to increase substantially the sample size, to allow detection of additional genetic risk variants for insomnia complaints, which may aid in understanding its neurobiological mechanisms. By combining data collected in the UK Biobank (UKB) version 29 (n = 386,533) and in 23andMe [a privately held personal genomics and biotechnology company (n = 944,477)] — authors obtained an unprecedented sample size of 1,331,010 individuals (this is the largest cohort yet for any GWAS). Insomnia complaints were measured using questionnaire data; an independent sample (the Netherlands Sleep Register), which gives access to similar question data, as well as clinical interviews assessing insomnia disorder, was used to validate the specific questions so that they were good proxies of insomnia disorder. Meta-analysis explained 2.6% of the variance.

Authors [see Lane et al., the 2-MB pdf attachment] studied UK Biobank participants of European ancestry (n = 453,379). In this sample, 29% of individuals self-reported frequent insomnia symptoms (“usually”), and the prevalence was relatively higher in women (32% versus 24% in men) and in older participants, shift workers, and individuals with shorter self-reported sleep duration. Authors adjusted for age, sex, ten principal components of ancestry, and genotyping array using 14,661,600 genotyped — and imputed genetic variants across the autosomes (i.e. all chromosomes except the sex chromosomes) and genotyped variants on the X chromosome. They identified 57 association signals explaining 1% of the variance; of these, 20 loci were identified in both analyses, 28 loci were identified in analysis of frequent insomnia symptoms only, and 9 were identified in analysis of any insomnia symptoms only.

Both studies identified considerable genetic correlations with psychiatric traits and sleep duration, and modest correlations with other sleep-related traits. Mendelian randomization recognized causal effects of insomnia on depression, diabetes, and cardiovascular disease, and “protective effects” of educational attainment and intracranial volume [???] Evidence of shared genetic factors was found between insomnia — and restless legs syndrome, aging, and cardiometabolic, behavioral, psychiatric, and reproductive traits. Evidence was also found for a possible causal link between insomnia and coronary artery disease, depressive symptoms, and subjective well-being. These mind-boggling studies represent harbingers of “things to come” with GWAS: bigger cohorts, more small-effect genes and genetic loci discovered, and more possibilities for uncovering novel genetic pathways for which drug therapy might be developed in the future. 🙂


Nat Genet March 2019; vol 51: pages to be determined soon !!

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