What genetic mutations are linked to major depressive disorder (MDD)?

From the Guidelines

Genetic mutations linked to major depressive disorder (MDD) include variations in the catechol-O-methyltransferase (COMT) and monoamine oxidase-A (MAO-A) genes, which are involved in dopamine and serotonin metabolism. These genetic variations have been associated with increased depressive symptoms, particularly in individuals with a history of stressful life events 1. The COMT Val158Met polymorphism, specifically the low-activity Met/Met genotype, has been linked to a higher risk of postpartum depression 1. Additionally, the MAO-A gene has been implicated in the development of depressive symptoms, with the low-activity variant of the MAO-A uVNTR polymorphism associated with increased depression risk 1.

Some of the key findings from the studies include:

• The low-activity variants of the MAO-A and COMT polymorphisms were associated with increased depressive symptoms at 6 weeks postpartum 1
• The COMT Val158Met polymorphism was associated with 30% of the variance in postpartum depression 1
• The MAO-A and COMT genes were associated with postpartum depression symptoms in an additive model 1

It's worth noting that while the study 1 discusses the importance of genetic variation in pharmacokinetic pharmacogenetic prescribing guidelines for antidepressants, it does not directly address the question of which genetic mutations are linked to MDD. Therefore, the recommendation is based on the most relevant and highest quality study 1, which highlights the importance of COMT and MAO-A genetic variations in the development of depressive symptoms.

From the Research

Genetic Mutations Linked to Major Depressive Disorder (MDD)

• The SLC6A4 gene has been associated with MDD, with allele C carriers at rs6354 and allele G carriers at rs12150214 being significantly prone to poorer treatment response to fluoxetine 2.
• The combination of three loci (rs929377-rs6191-rs32897) located in the HPA pathway was significantly associated with the treatment outcome of fluoxetine 2.
• In female MDD patients, the minor allele of rs6323 and rs1137070 on the MAOA gene likely lead to a worse response to venlafaxine 2.
• Genetic variants linked to drug efficacy tended to concentrate on the neurotrophin pathway in depressed patients comorbid with anxiety 2.
• Other genes associated with MDD include COMT, TPH2, FKBP5, MDD1, HTR2A, and MDD2 3.
• The serotonin transporter promoter region (5-HTTLPR) has been linked to depression-related personality traits, but not yet to MDD itself 4.
• Brain-derived neurotrophic factor (BDNF) has been studied in relation to MDD, with mixed evidence regarding association with polymorphisms in this gene 4.

Key Findings

• Genetic factors play a significant role in the development of MDD, with heritability estimates suggesting a substantial genetic contribution 5, 4.
• Epigenetic changes, such as DNA methylation and histone modification, may also contribute to the development of MDD 3, 5.
• Gene-environment interactions and gene-expression array studies may provide further insights into the genetic basis of MDD 5, 4.
• The use of animal models of depression may help to supplement association studies between DD pathogenesis and epigenetic factors 5.