A common gene variant separates early birds from night owls, and can even predict someone’s hour of death.
The findings—published in the November issue of the journal Annals of Neurology—could help people schedule anything from work to medical treatments, while offering clues to the conditions of vulnerable patients.
Andrew Lim, M.D., now an assistant professor in the division of neurology at the University of Toronto, noted in a statement that previous work in twins and families had suggested that people may inherit the lateness or earliness of their body clocks, while animal experiments suggested that specific genes affected the lateness or earliness of the biological clock.
Dr. Lim—then a postdoctoral fellow working in the lab of Beth Israel Deaconess Medical Center Chief of Neurology Clifford Saper, M.D., Ph.D.—and lab colleagues were studying why older people have trouble sleeping. He joined a research project based at Rush University in Chicago involving 1,200 people who signed on as healthy 65-year-olds and would receive annual neurological and psychiatric examinations.
The study’s original goal was to identify any precursors to the development of Parkinson’s disease or Alzheimer’s disease. Subjects were undergoing sleep-wake analyses, and had agreed to donate their brains after they died to provide scientists with information on sleep-wake patterns within a year of death.
But when Dr. Lim learned that the same subjects had also had their DNA genotyped, he joined his colleagues and investigators from Brigham and Women's Hospital (BWH) in comparing the sleep-wake behavior of the patients with their genotypes.
The study findings—later verified in a volunteer group—uncovered a single nucleotide near a gene called “Period 1” that varied between two groups that differed in their wake-sleep behavior. At this site in the genome, 60% of individuals have the nucleotide base termed adenine (A) while the other 40% have the nucleotide base termed guanine (G). Since people have two sets of chromosomes, in any given individual there’s about a 36% chance of having two As, a 16% chance of having two Gs, and a 48% chance of having a mixture of A and G.
“People who have the A-A genotype wake up about an hour earlier than the people who have the G-G genotype, and the A-Gs wake up almost exactly in the middle,” Dr. Saper, who is also the James Jackson Putnam Professor of Neurology and Neuroscience at Harvard Medical School, said in the statement. He added that expression of the Period 1 gene was lower in the brains and white blood cells of people with the G-G genotype than in people with the A-A, but only in the daytime when the gene is normally expressed.
When investigators re-examined patients who died, they found that this same genotype predicted six hours of the variation in the time of death: those with the A-A or A-G genotype died just before 11 a.m., the average time, while those with the G-G on average died at just before 6 p.m.
Dr. Lim said future studies will look to determine the mechanisms by which this and other gene variants influence the body’s biological clock. The research, he said, could help people optimize their schedules, and yield new therapies against disturbances of this clock such as jet lag or shift work.
The study was supported by grants from NIH as well the Canadian Institutes of Health Research Bisby Fellowship, an American Academy of Neurology Clinical Research Training Fellowship, and a Dana Foundation Clinical Neuroscience Grant.