- Though depression is thought to have a genetic link, the specific genes contributing to it remained elusive.
- New findings reveal that rare variants in the gene, NKPD1, increases the risk of depression.
- Exome sequencing of DNA portions that codes proteins revealed that this single gene may account for as much as 4% of the heritable risk for depression.
Rare variants in the gene NKPD1, increases the risk of depression.
The study, conducted on people from an isolated village in Netherlands was led by co-first authors Najaf Amin, PhD, of Erasmus University Medical Center in the Netherlands and Nadezhda Belonogova of the Russian Academy of Sciences in Novosibirsk, Russia.
‘The knowledge of the involvement of NKPD1 in the synthesis of sphingolipids, the blood level fluctuations of which, trigger depression, implies that targeted therapy might benefit patients carrying risk variants in the NKPD1 gene.’
The findings help to understand the molecular pathology of the disease, which could eventually improve how depression is diagnosed and treated.
Genetics play a strong role in risk for depression, but the identification of specific genes contributing to the disorder has not been successful. Also depression lacks genetic or biochemical markers that could help in diagnosis and treatment of the disorder.
"By sequencing all of the DNA that codes for mRNA and ultimately, proteins, Dr. Amin and colleagues found a single gene that may account for as much as 4% of the heritable risk for depression," said Doctor John Krystal, Editor of Biological Psychiatry.
For the analysis, nearly 2000 people who were assessed for depressive symptoms were included. The data was collected from the Erasmus Rucphen Family study, that composed of many families and their descendants living in social isolation until the past few decades.
In such a population genetic isolation leads to an amplification of rarely occurring variants within a gene, thus providing a more powerful cohort for the discovery of rare variants.
When the research team analyzed portions of DNA containing genetic code that produce mRNA and proteins, using whole-exome sequencing, they found that several variants of NKPD1 were associated with higher depressive symptom scores.
This genetic association was also replicated in an independent sample of people from the general population, although the variants within the gene, NKPD1, were different.
The synthesis of sphingolipids and its altered levels in the blood have been implicated in the pathogenesis of depression and the gene NKPD1 is predicted to be involved in the process its synthesis. The blood sphingolipids levels has also been proposed as a therapeutic target for major depressive disorder
"The involvement of NKPD1 in the synthesis of sphingolipids and eventually of ceramides is interesting," said Dr. Amin, referring to the predicted role of NKPD1 in the body.
"We are the first to show a possible genetic connection in this respect," said Dr. Amin, adding that this implies that such a therapy might be beneficial for patients carrying risk variants in the NKPD1 gene.
The findings are published in the current issue of Biological Psychiatry
- Najaf Amin et al. Nonsynonymous Variation in NKPD1 Increases Depressive Symptoms in European Populations. Biological Psychiatry; (2017) DOI: http://dx.doi.org/10.1016/j.biopsych.2016.08.008