Experimental Research Uncovers Genetic Insights Into Sleep, Other Traits

A new model of the hypothalamus can lead to potential new genetic targets for a number of disorders.

Researchers may be on the cusp of better understanding one of the most elusive parts of the human brain, and their findings could have major implications for our understanding of sleep problems and related disorders.

Investigators from the Children’s Hospital of Philadelphia (CHOP) last month released the findings of a study of the genomic architecture of the hypothalamus. The results highlight potential target genes that appear to be associated with a number of functions, such as sleep cycles, body temperature, appetite, and thirst.

Struan F.A. Grant, Ph.D., the study’s senior author, told Managed Healthcare Executive® that the hypothalamus can be particularly difficult to study given that it is located in the center of the brain. As director of the Center for Spatial and Functional Genomics at CHOP, he and colleagues had been looking into body mass index and puberty, and in both cases their research pointed to the hypothalamus. The problem, though, was that very little was known about that region of the brain.

They found out that Rudolph L. Leibel, M.D., and his colleagues at Columbia University had been studying the hypothalamus using a model derived from embryonic stem cells (ESC).

“They were already working with a hypothalamic model derived from ESC cells,” Grant said. “And that's where we generated our 3D genomic maps, using the cells that they generated up at Colombia.”

Leibel is a co-author on the new study, which was published in Nature Communications.

The model made it possible for Grant and colleagues to better understand the genetic architecture of hypothalamic progenitor cells and the arcuate nucleus-like hypothalamic neurons. By looking at the various subtypes of neurons on the hypothalamus and using existing data from genome-wide association studies, Grant and colleagues were able to identify genes associated with particular traits that were regulated by the hypothalamus.

For example, the work confirmed that the BDNF gene in body mass index and obesity risk. They also identified PER2as playing a role in sleep regulation.

The science is early and investigational, Grant said. Its importance is in pointing investigators in meaningful directions that could eventually lead to better understandings of the pathogenesis of diseases and possibly future therapeutic targets.

In terms of sleep, Grant noted that there have been a number of studies highlighting the genetic roots of sleep problems. The model helped elucidate the genetic links to insomnia, as well as depression and bipolar disorder.

Adding to the intrigue, Grant noted that there’s significant literature linking sleep with body mass index. Yet, it is not clear whether sleep dysfunction is the first mover, leading to obesity, or whether a patient’s weight might affect his sleep. He said one active area of research is in Mendelian randomization, a method in which investigators use genetic variants to determine causes and effects.

“There's a lot of literature actually on Mendelian randomization on the relationships between sleep and various traits,” he said. “Some studies agree with each other; some disagree. So I think the jury's still out.”

Grant and colleagues said they are making their data from these studies publicly available in hopes that the wider scientific community can build upon their findings. He noted that over the past 15 years, there has been a tremendous amount of scientific work on genome-wide association studies. One of the outgrowths of that research, he said, has been the realization that identifying causal genes is more complicated than initially thought. This new research can help investigators identify the right genes to target.

“If you’ve got the right gene, and it’s therapeutically tractable, that could be exciting,” he said.