New risk loci and functional pathways involved in insomnia identified

An international team of researchers has identified, for the first time, the cell types, areas and biological processes in the brain that mediate the genetic risk of insomnia. This was made possible by assessing DNA and sleep features in no less than 1.3 million people. The findings published in Nature Genetics are a major step towards getting grip on the biological mechanisms that cause insomnia.

Insomnia is one of the most common disorders. Many people occasionally have a bad night of sleep. One out of ten people chronically experience poor sleep and suffer severely from the daytime consequences. Worldwide, 770 million people have chronic insomnia.

While treatment alleviates symptoms, most sufferers feel that they remain vulnerable to experiencing poor nights of sleep. The vulnerability to insomnia runs in families and seems hard-wired in the brain. So far, only few genes involved in the vulnerability had been identified. It had also remained enigmatic where in the brain insomnia risk genes exerted their disturbing role. This knowledge is crucial to develop better treatments.

The researchers identified 956 genes in which variants contributed to the risk of insomnia. They then extensively investigated which biological processes, cell types and brain areas utilize these genes. They found that part of these genes had an important role in the functionality of axons, which are the long protrusions of brain cells that allow them to communicate with each other. Another significant part of the insomnia risk genes was active in specific cell types of parts of the frontal cortex and the subcortical nuclei of the brain. These brain areas had also recently been marked as suspect in brain imaging studies of people suffering from insomnia. The findings thus seem consistent.

"Our study shows that insomnia, like so many other neuropsychiatric disorders, is influenced by 100's of genes, each of small effect. These genes by themselves are not that interesting to look at. What counts is their combined effect on the risk of insomnia. We investigated that with a new method, which enabled us to identify specific types of brain cells, like the so-called medium spiny neurons." says the author. "These findings are a breakthrough, since we can now for the first time start searching for underlying mechanisms in individual brain cells in the laboratory" says another author. The first author of the paper, continues: "It is fascinating that we can nowadays start to understand what happens at the micro-level of molecules and cells in the brain, just because we can assemble so many data at the macro-level, worldwide".

The researchers compared risk genes of insomnia with those of other traits and disorders. Surprisingly, they found little overlap with genes involved in individual differences in other sleep traits, like being a morning- or evening-type. Instead there was a strong genetic similarity with depression and anxiety. "A very important finding, because we have always searched for causes of insomnia in the brain circuits that regulate sleep. We have to shift our attention to the circuits that regulate emotion, stress and tension. Our first results in that direction are already spectacular", says the author. "This study is an immense step forward in understanding the genetic background of insomnia. The findings underline that insomnia is a serious condition, because of the shared genetic risk of psychiatric disorders metabolic disturbances involved in obesity and diabetes", states another author.

https://www.vu.nl/en/news-agenda/news/2019/jan-mrt/brain-cells-involved-in-insomnia-identified.aspx

https://www.nature.com/articles/s41588-018-0333-3