Research involving families, and particularly twins, suggests that insomnia can be inherited. Now scientists at Massachusetts General Hospital (MGH) and the University of Exeter Medical School have pinpointed 57 gene regions, or loci, that are associated with sleeplessness. They believe their findings could spark new ideas for insomnia therapies.
In addition to identifying the gene sites, the researchers discovered that insomnia doubles the risk of coronary artery disease and also raises the risk of depression. They reported their findings in Nature Genetics.
To identify the gene sites associated with insomnia, the researchers analyzed records from more than 450,000 participants in the UK Biobank, nearly one-third of whom reported frequent insomnia. They matched up gene regions with self-reported sleep troubles, discovering associations that were not affected by known lifestyle risks, like caffeine consumption and recent stress. They they confirmed their findings by analyzing 15,000 participants in a Norwegian study and another 2,200 people whose data is stored in MGH’s Partners Biobank.
The 57 loci included genes that are active in the brain, skeletal regions and adrenal gland, the researchers reported. There were also several genes involved in “ubiquitin-mediated proteolysis,” a process that leads to the destruction of certain proteins. The team pegged 16 of the newly discovered gene regions as known drug targets.
“There are problems with current treatments for insomnia—including issues with accessibility, addiction and side effects,” said co-senior author Michael Weedon, Ph.D., of the University of Exeter, in a statement. “We hope that understanding more about the underlying processes involved in insomnia will pave the way for better and more personalized treatments, which in turn could reduce the number of people suffering from insomnia and improve the long-term health of those that do."
The researchers wanted to understand more about the association of the genes they discovered with insomnia, so they analyzed a subset of 85,000 UK Biobank participants who wore motion-detecting devices for up to a week. They discovered that the 57 gene regions were associated with impairments in sleep efficiency, as well as the duration of sleep. Some genes were also connected to restless leg syndrome, a disorder that’s known to disrupt sleep.
Insomnia remains a popular target for drug development, with many biopharma companies aiming to invent a new generation of products that overcome the safety issues connected to medicines like Ambien, including early wakeups and next-day grogginess. Eisai and Purdue Pharma, for example, are working on lemborexant, dual orexin receptor antagonist. Data from a phase 3 trial released last year showed that the drug kept patients asleep through the night, with fewer side effects than currently marketed drugs.
Several research groups are also making progress in their efforts to tie genetics to insomnia. The current MGH-Exeter study builds on 2017 research out of MGH that identified three gene loci associated with self-reported sleeplessness. Separately, researchers at Washington State University have been probing a variant of the gene FABP7 that affects sleep quality, while Brown University scientists have tied molecular changes in the gene ZFYVE28 to sleep duration.
The next step for the MGH-Exeter team is to figure out how changes in the 57 gene loci actually cause insomnia. To achieve that, they plan to launch studies in several models, including human cells, mice, fruit flies and zebrafish, they said.