Two genetic variants linked to depression

Major depressive disorder (MDD) is a common form of mental illness ranked by the World Health Organization as the fourth biggest cause of disability worldwide. 

Although identified as a severe form of depression about a century ago, its genetic basis has proven difficult to study; no genetic risk factors have been highlighted as yet, but previous research suggests that the genetic influence is stronger in females than in males. 

Na Cai of the Wellcome Trust Centre for Human Genetics in Oxford and colleagues from around the world recruited 5,303 Han Chinese women with recurrent MDD and 5,337 healthy control subjects from 58 Chinese hospitals involved in the China, Oxford and Virginia Commonwealth University Experimental Research on Genetic Epidemiology (CONVERGE) consortium.   

The researchers genotyped the study participants using low-coverage DNA sequencing, isolating two single nucleotide polymorphisms (SNPs) –DNA sequence variations at a specific nucleotide within the genome – on chromosome 10, both associated with a small increase in risk of MDD.

They repeated this analysis in another sample of 4,509 Chinese women diagnosed with a severe sub-type of MDD called melancholia, and identified the same two SNPs, thus confirming the initial findings. 

One of these newly-identified variants lies near the SIRT1 gene, which encodes a protein known to be involved in forming energy-producing organelles called mitochondria, and may regulate its activity. The second lies within a non-coding region of the LHPP gene, which encodes a metabolic enzyme expressed in the brain and at lower levels in the liver and kidney.

MDD is a highly complex condition that probably involves multiple genetic variants yet to be discovered. The researchers attribute their success in identifying the variants to the homogeneity of their sample population. They say, however, that the effects of both variants on those people carrying them are slight, and are far less common in Europeans than in the Chinese population.     

Nevertheless, the identification of a variant near the SIRT1 gene, together with the recent finding that MDD is associated with increased amounts of mitochondrial DNA², suggests that at least some of the symptoms of this debilitating condition have unexpected origins.    

“Our earlier study showed that mitochondrial DNA levels increased in response to stress and came down when the stress was removed,” says Cai. “Environmental stress is a strong predictor of depression, and so we think mitochondria might somehow be involved in the response to stress.”

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