Co-senior author Ying-Hui-Fu, PhD, a professor of neurology in the School of Medicine at the University of California-San Francisco (UCSF), and colleagues publish the details of their discovery in the Proceedings of the National Academy of Sciences.
Seasonal affective disorder (SAD), also known as seasonal depression, is estimated to affect around 3% of Americans, with onset most common between the ages of 18-30.
Symptoms of SAD – which include depression, anxiety, mood changes and sleep problems – almost always occur during winter months, when the days are shorter and darker. This has led researchers to believe that the condition is induced by seasonal changes in light.
It is thought that changes in sunlight patterns disrupt the circadian rhythms of people with SAD, putting their biological clocks out of sync.
Furthermore, researchers have suggested that SAD may be triggered by an increase in the hormone melatonin, which controls our sleep-wake cycles. The brain produces melatonin at higher levels in the dark, so it is possible that production of the hormone is increased during the shorter, darker days of winter among people with SAD.
However, it has been unclear why some people are more vulnerable to seasonal daylight changes than others. Fu and colleagues wondered whether there might be a genetic explanation.
PER3 led to depression-like symptoms in response to light changes
In previous research, the team uncovered numerous genetic mutations among people with a condition called familial advanced sleep phase (FASP) syndrome – a condition in which a person’s body clock is too fast, causing them to go to bed early (around 8-9 pm) and wake up early (around 4-5 am).
For the new study, the researchers analyzed the genes of people with a family history of FASP and/or SAD, and among three people who had a family history of both conditions, they identified a mutation in a gene called PER3. This suggested to the team that the gene is associated with both sleep and mood.
To further investigate how PER3 might impact circadian rhythm and depression in winter months, the researchers inserted a mutated version of the gene to genetically engineered mice and assessed how they reacted to altered lengths of “day” and “night” in a laboratory.
The team found that when lengths of day and night were equal, the mice appeared normal. When the rodents were exposed to 4-hour days and 20-hour nights, however, they showed mild depression-like symptoms. When PER3 was eliminated completely, the depression-like symptoms worsened.
While the researchers note that it is impossible to know whether a mouse is experiencing depression like a human with SAD would, they say that certain changes in mouse behavior – such as quickly surrendering in adverse circumstances – are good indicators of how the PER3 gene may affect human mood.
PER3 mutation impairs key protein for body clock regulation
Next, the researchers set out to investigate how the PER3 gene affects circadian rhythms and mood at a cellular level.
They applied the PER3 mutation to isolated cells in a petri dish, comparing its effects with a normal PER3 gene.
The team found that the mutated version of the gene produced much less PER3 protein than the normal version, which impaired the function of a protein called PER2 – known to regulate circadian rhythm.
The researchers speculate that the loss of the PER2 protein is likely what speeds up the circadian rhythms of people with FASP.
While the researchers are unable to pinpoint exactly how the PER3 gene mutation affects mood, they say this is something they plan to investigate in further mouse studies.
Still, the team says the current findings strongly suggest that there may be a genetic explanation for SAD.
Co-senior author Dr. Louis Ptáček, also a professor of neurology in the UCSF School of Medicine, says:
“This is the first human mutation directly linked to seasonal affective disorder, and the first clear sign of a mechanism that could link sleep to mood disorders.”
“It’s an exciting time,” adds Fu. “People have known for decades that light and mood were linked, but this is our first real finger-hold on the problem.”
Earlier this year, Medical News Today reported on a study that questions whether SAD really exists, after researchers found that the prevalence of depression was stable across different latitudes, seasons and sunlight exposures.