Body clock genes linked to depression

Genes believed to regulate sleep rhythm are expressed abnormally in people with major depressive disorders, scientists say. The study is one of the first in humans to provide direct evidence of a disturbed circadian rhythm in people with depression.

Symptoms of depression can include sleep disturbance, with difficulties in falling asleep at night or feeling fatigued during the day, but the precise mechanism for this remains unknown. Although the circadian rhythm — the 24-hour cycle in living beings — has been observed in gene expression in animal studies, its presence in the human brain has been difficult to confirm.

The study by researchers at the University of Michigan and other US institutions examined tissue taken from 55 'healthy' donated brains post-mortem and compared them with samples from 35 patients who had had a major depressive disorder. The researchers measured the genes thought to be associated with the body's circadian rhythm using DNA microarray analysis and found that in the 'normal' samples the cyclic gene expression in more than 100 genes across six different regions in the brain was consistent with observations in animal studies. Many of the genes showing a 24-hour cycle in these samples were genes known to be associated with the circadian rhythm, confirming the range of genes involved in regulating the body's internal clock.

'Hundreds of new genes that are very sensitive to circadian rhythms emerged from this research - not just the primary clock genes that have been studied in animals or cell cultures, but other genes whose activity rises and falls throughout the day', said Dr Huda Akil, one of the senior authors of the study, co-director of the University of Michigan's Molecular and Behavioural Neuroscience Institute and co-director of the UM site of the Pritzker Neuropsychiatric Disorders Research Consortium, which supported the research.

However, the specimens taken from patients with depression showed a weaker and disrupted gene expression. The gene expression for the active hours would resemble a nocturnal pattern, while at night would often look like a day pattern. 'It's as if they were living in a different time zone than the one they died in', said lead author Dr Jun Li at the Department of Human Genetics, University of Michigan.

The researchers also explained the pattern of gene activity in the daytime was so distinctive that they were able to estimate the time of day each donor had died. 'We were truly able to watch the daily rhythm play out in a symphony of biological activity, by studying where the clock had stopped at the time of death. And then, in depressed people, we could see how this was disrupted', said Dr Akil.

The researchers said that the findings add to the growing understanding of the biological causes of depression, but the sample size was small, with only 55 patients used to identify the 'normal' pattern of gene expression. The authors also point out that drug treatment and the depression itself may have caused the findings. 'The disruption [of circadian rhythm] seen in depression may have more than one cause', Dr Akil said.