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Clinical and Research NewsFull Access

Researchers Uncover New Clues About Genetics of Major Depression

Published Online:https://doi.org/10.1176/appi.pn.2015.8b2

Abstract

The search for genes conferring risk for major depressive disorder may have taken a step forward with a study of severely depressed Chinese women.

Researchers have made important strides in recent years in finding genetic loci associated with risk for schizophrenia, bipolar disorder, and autism, but similar progress in depression has remained more elusive.

Now, however, researchers from the China, Oxford, and Virginia Commonwealth University Experimental Research on Genetic Epidemiology (CONVERGE) consortium say they have reason to suspect two loci found on chromosome 10 may contribute to the risk of major depressive disorder (MDD).

The study, published online July 15 in the journal Nature, was led by Kenneth Kendler, M.D., a professor of psychiatry at Virginia Commonwealth University School of Medicine; Jonathan Flint, Ph.D., a professor at the Wellcome Trust Centre for Human Genetics at the University of Oxford; and Jun Wang, Ph.D., a director of BGI (formerly the Beijing Genomics Institute).

The consortium used low-coverage, whole-genome sequencing to compare 5,303 Han Chinese women diagnosed with recurrent MDD (average, 5.6 reported episodes) to 5,337 controls.

The team found one locus contributing to risk of MDD lies near the SIRT1 gene and the other in an intron of the LHPP gene. Previous studies suggest that LHPP may interact with the gene HTR1A in the pathogenesis of major depression.

SIRT1 is involved in mitochondrial biogenesis, “which, together with our [other recent] finding that MDD is associated with increased amounts of mitochondrial DNA, suggests an unexpected origin for at least some of the phenotypic manifestations of MDD,” they said.

“If replicated by other groups, the results will be a real advance in the study of the genetics of depression,” commented William Lawson, M.D., Ph.D., a professor of psychiatry at Howard University School of Medicine in Washington, D.C. Lawson also researches the genetics of the illness but was not involved in Kendler’s study.

“This is a tremendous advance because it shows what can be done,” Lawson told Psychiatric News. “Why they succeeded and why others have not is well worth looking at.”

Kendler and colleagues noted that the single nucleotide polymorphisms (SNPs) associated with these genes were not as strongly represented in the Psychiatric Genomics Consortium’s analysis of European populations. This may be due to differences in sample ascertainment, ethnicity, or other factors, they said.

“We attribute the discovery and replication of two SNPs associated with MDD in the CONVERGE cohort to the recruitment of cases who were probably more homogeneous and more severely impaired than those collected in previous studies from Western cultures,” the researchers wrote.

The ability to identify illness severity may have also helped focus the outcome. The researchers replicated their findings in a separate cohort of more than 6,000 Han Chinese men and women (including 3,231 cases of recurrent MDD). When the analysis was limited to those with melancholia, a severe subtype of MDD, it also yielded an increased genetic signal at the SIRT1 locus.

Depression probably occurs in several variants, some more environmentally influenced than others, said Lawson. Risk is likely due to many genes, with rare mutations.

“Identification of those genes will ultimately tell us more about the illness and lead to more specific treatments,” Lawson said.

The work described in the Nature paper was funded by the Wellcome Trust, the National Institutes of Health, and the Brain & Behavior Research Foundation. ■

An abstract of “Sparse Whole-Genome Sequencing Identifies Two Loci for Major Depressive Disorder” can be accessed here.