Genes associated with sleep, BMI, puberty revealed

Researchers have modeled the hypothalamus and to implicate genes associated with sleep, BMI, puberty, and more. The reason this study is important is that hypothalamus is particularly hard to study region of the brain. The findings will help further a lot of research specifically the causes of dysfunction for many important traits regulated by the hypothalamus, such as sleep, stress, and reproduction. The findings were published today in the journal Nature Communications.

The hypothalamus helps maintain health and stable metabolism by influencing a variety of vital functions, including appetite and thirst, puberty and reproductive timing, sleep cycles, and body temperature. However, the hypothalamus is located in the center of the brain, making it extremely difficult to study the gene regulation associated with these traits.

To overcome that hurdle, the researchers used an embryonic stem cell (ESC) model to study gene expression during development of the hypothalamus. This model allowed them to study the genetic architecture first in hypothalamic progenitor cells – cells prior to their full development into a hypothalamus – and then in arcuate nucleus-like hypothalamic neurons. The hypothalamus contains several different subtypes of neurons, and the researchers integrated results from various genome-wide association studies (GWAS) to implicate genes driving particular traits regulated by the hypothalamus.

Researchers assessed variants associated with puberty, body mass index, height, bipolar disorder, sleep, and major depressive disorder, among others. They identified both known and novel genes associated with these traits. For example, their data confirmed the role of the BDNF of gene in influencing body mass index and obesity risk. Another gene of interest identified in the study was PER2, which was implicated in sleep regulation.

All the data ascertained from this study will be made publicly available. Many of the disorders studied can be caused by other factors, so the findings will help researchers distinguish which genes play a more central role in this tissue and in turn inform clinical practice. For example, body mass index can be affected by variants in genes conferring their effects in hypothalamus or fat tissue cells, so being able to distinguish the context in which genes and subsequent tissues or hormones operate can lead to more personalized treatment options.

Pahl et al, “Cis-regulatory architecture of human ESC-derived hypothalamic neuron differentiation aids in variant-to-gene mapping of relevant complex traits. Nat Comm. Online November 19, 2021. DOI: 10.1038/s41467-021-27001-4.

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