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DNA Methylation at Three Sites Linked to Depression in Middle-Aged, Elderly

NEW YORK (GenomeWeb) – A new study has linked DNA methylation at three sites in the human genome to symptoms of depression among middle-aged and elderly individuals.

More than 300 million people across the world suffer from depression, according to the World Health Organization. While genetics contributes to depression risk, so do environmental factors such as adverse life events and stress, particularly among individuals who develop depression later in life. This, the study authors said, makes DNA methylation a promising candidate for the molecular basis of late-life depression.

The researchers, led by Erasmus MC-University Medical Center Rotterdam's Najaf Amin, conduced an epigenome-wide association study of depressive symptoms in about 11,000 individuals. As they reported today in JAMA Psychiatry, they uncovered three genomic sites where methylation was associated with depressive symptoms and suggested that the axon guidance pathway could be disrupted in disease.

"Our findings provide new insights into the molecular mechanisms underlying the complex pathophysiology of depression," the researchers wrote in their paper.

Amin and his colleagues analyzed DNA extracted from blood samples from 7,948 individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium using the Illumina Infinium Human Methylation 450K BeadChip. At the same time their blood samples were collected, the participants answered questionnaires or were interviewed by a trained researcher, psychologist, or psychiatrist to assess their depressive symptoms. The participants had a mean age of 65.4 years.

Through an EWAS of this cohort, the researchers identified one CpG site on chromosome 14q32.32 that reached genome-wide significance and noted suggestive associations at a further 19 sites.

They tested all 20 sites in a replication cohort of 3,308 people of either African American or European backgrounds with a mean age of 60.3 years. In this set, the chromosome 14q32.32 CpG site reached nominal association and another CpG site reached significance.

In a meta-analysis of the combined discovery and validation cohorts, both sites reached significance with depressive symptoms, as did a third intergenic CpG site.

Using the BIOS database, the researchers uncovered a link between one of the sites and increased expression of CDC42BPB as well as between another site and decreased expression of SEMA4B. Additionally, they found that the predicted expression of CDC42BPB in the basal ganglia of the brain and of ARHGEF3 in fibroblasts were linked to major depression.

CDC42BPB, the researchers noted, encodes a member of the serine/threonine protein kinase family that is a downstream effector of CDC42 and has a role in the regulation of cytoskeleton reorganization, cell migration, and neurite outgrowth. It is also highly expressed in the brain. ARHGEF3, meanwhile, encodes the rho guanine nucleotide exchange factor 3 protein that is highly expressed in the adrenal glands, uterus, and brain.

Additionally, both CDC42BPB and ARHGEF3 are co-expressed with members of the rho subfamily of rho guanosine triphosphatases, which are involved in the p75 neurotrophin receptor-mediated signaling and semaphorin-signaling pathways. Both those pathways, the researchers said, are involved in axon guidance. Likewise, the intergenic methylation site is linked to changes in the expression of SEMA4B.

All three CpG sites, Amin and his colleagues said, suggest that axon guidance is a common pathway that is disrupted in depression.

"The findings provide new insights into the molecular mechanisms underlying the complex pathophysiology of depression," the authors wrote. "Further research is warranted to determine the utility of these findings as biomarkers of depression and evaluate any potential role in the pathophysiology of depression and their downstream clinical effects."

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