Genome-wide association studies (GWAS) — trait chosen to be studied is “Insomnia”

As these GEITP pages continue to report, genome-wide association studies (GWAS) represent a screen of large portions of the entire genome (genotype), plus an attempt to find highly significant statistical significance (P < 5.0 x 10–8; also designated as P < 5.0e–08) of specific single-nucleotide variants (SNVs) correlated with a selected phenotype (trait). Furthermore, as databases (of DNA, combined with personal and medical history registered in questionnaires) become larger (i.e. into the tens or hundreds of thousands of individuals) — cohort sizes (cases vs controls) have become staggering in number. Intriguingly, the phenotype chosen for the two [attached] articles is "insomnia". [One could also choose "drug efficacy" or "drug toxicity" or "frequency of an environmental toxicant-caused symptom" — as the multifactorial phenotype.] "Insomnia" is a common disorder linked with adverse long-term medical and psychiatric outcomes; insomnia is regarded as the second most prevalent mental disorder — with no clear-cut treatment available. The underlying pathophysiological processes and causal relationships of insomnia with various diseases are poorly understood. Authors [in first attached paper; 2 MB) identified 57 genetic loci for "self-reported insomnia symptoms" in the UK Biobank (n = 453,379 persons); then authors confirmed their effects on [a] "self-reported insomnia symptoms" in the HUNT Study (n = 14,923 cases and 47,610 controls), [b] "physician-diagnosed insomnia" in the Partners Biobank (n = 2,217 cases and 14,240 controls), and [c] "accelerometer-derived measures of sleep efficiency and sleep duration" in the UK Biobank (n = 83,726 persons). Their data suggest an enrichment "of genes involved in ubiquitin-mediated proteolysis" (Adding multiple copies of ubiquitin to a protein targets that protein for destruction by an intracellular protease (enzyme); the resulting free amino acids are then available to be used again elsewhere), and "of genes expressed in multiple brain regions, skeletal muscle, and adrenal gland. Evidence of shared genetic factors (pleiotropism) was found between frequent insomnia and: restless legs syndrome (RLS), aging, and cardiometabolic, behavioral, psychiatric, and reproductive traits. Evidence was also found for a possible causal link between frequent insomnia and: coronary artery disease, depressive symptoms, and "subjective well-being". Authors [in second attached paper; 4 MB) carried out a large GWAS (n = 1,331,010 individuals), again with insomnia as the selected trait. They identified 202 loci — implicating 956 genes — by means of positional mapping, expression quantitative trait loci (eQTL) mapping, and chromatin mapping. Their meta-analysis explained only 2.6% of the variance, however..!! Their findings showed gene-set enrichments for the axonal part of neurons, brain cortex and subcortex tissues, and specific cell types — including striatal, hypothalamic, and claustrum neurons (parts of the brain). Authors found substantial genetic correlations with psychiatric traits and sleep duration, and modest correlations with other sleep-related traits. Mendelian randomization (epidemiological method of using measured variation in genes (of known function) to examine the causal effect of a modifiable exposure on disease) identified causal effects of insomnia on depression, diabetes, and cardiovascular disease, and protective effects of educational attainment and intracranial volume. Both publications suggest that their findings highlight key brain areas and cell-types implicated in insomnia, and (should) provide novel druggable (i.e. able to be treated) targets. 🙂 DwN Nat Genet Mar 2o19; 51: 387-393 & ibid 394-403

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