Genetic factors involved in depression have been difficult to identify. In 2003 Science published an influential[1] study of Avshalom Caspi et al. who found that a gene-environment interaction (GxE) may explain why life stress is a predictor for depressive episodes in some individuals, but not in others, depending on an allelic variation of the serotonin-transporter-linked promoter region (5-HTTLPR).[2] Soon after, the results were replicated by Kenneth Kendler‘s group, raising hopes in the psychiatric genetics community.[3] By 2007 there were 11 replications, 3 partial replication and 3 non-replications of this proposed GxE. However, two of the largest studies[4][5]were negative.[6] Two 2009 meta-analyses were also negative; one included 14 studies,[7] and the other five, owing to different study selection criteria.[8]

A 2010 review found 17 replications, 8 partial replications (interaction only in females or only with one of several types of adversity), and 9 non-replications (no interaction or an interaction in the opposite direction). It also found that all studies using objective indicators or structured interviews to assess stress replicated the gene–environment interaction fully or partially, whereas all non-replications relied on self-reported measures of adversity. This review also argued that both 2009 meta-analyses were significantly biased toward negative studies.[9]

BDNF polymorphisms have also been hypothesized to have a genetic influence, but replication results have been mixed and, as of 2005, were insufficient for a meta-analysis.[10] Studies also indicate an association of decreased BDNF production with suicidal behavior.[11] However, findings from gene-environment interactions studies suggest that the current BDNF models of depression are too simplistic.[12]

A 2008 study found interactions (biological epistasis) in the signaling pathways of the BDNF and the serotonin transporter; the BDNF Val66Met allele, which was predicted to have reduced responsitivity to serotonin, was found to exercise protective effects in individuals with the short 5-HTTLPR allele that is otherwise believed to predispose individuals to depressive episodes after stressful events.[13] Thus, the BDNF-mediated signalling involved in neuroplastic responses to stress and antidepressants is influenced by other genetic and environmental modifiers.[12]

The largest genome-wide study to date failed to identify variants with genome-wide significance in over 9000 cases.[14]

Recently, a genetics study positively identified two variants with genome-wide association with major depressive disorder (MDD).[15] This study, conducted in Chinese Han women, identified two variants in intronic regions near SIRT1 and LHPP.[16]

Attempts to find a correlation between norepinephrine transporter polymorphisms and depression have yielded negative results.[17]

One review identified multiple frequently studied candidate genes. The 5-HTT SLC6A4 and 5-HTR2A gene’s yielded inconsistent results, however they may predict treatment results. Mixed results were found for BDNF Val66Met polymorphisms. Polymorphisms in tryptophan hydroxylase genes were found to be associated with suicidal behavior.[18]

A meta analysis of 182 case controlled genetic studies published in 2008 found Apolipoprotein verepsilon 2 to be protective, and found GNB3 825T, MTHFR 677T, SLC6A4 44bp insertion or deletions, and SLC6A3 40 bpVNTR 9/10 genotype conferred risk.[


Methylene tetrahydrofolate reductase (MTHFR) is the rate-limiting enzyme in the methyl cycle, and it is encoded by the MTHFR gene.[3] Methylenetetrahydrofolate reductase catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine. Natural variation in this gene is common in healthy people. Although some variants have been reported to influence susceptibility to occlusive vascular disease, neural tube defects, Alzheimer’s disease and other forms of dementia, colon cancer, and acute leukemia, findings from small early studies have not been reproduced. Some mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency.





LHPP (Phospholysine Phosphohistidine Inorganic Pyrophosphate Phosphatase) is a Protein Coding gene. Among its related pathways are Purine metabolism (REACTOME) and Respiratory electron transport, ATP synthesis by chemiosmotic coupling, and heat production by uncoupling proteins.. GO annotations related to this gene include protein homodimerization activity and inorganic diphosphatase activity. An important paralog of this gene is HDHD2.