What genes are associated with an increased risk of developing depression?

Genetic Associations with Depression

Direct Answer

Yes, multiple genes have been identified with associations to depression, though the genetic architecture is complex and polygenic, with the strongest evidence pointing to genes involved in serotonin transmission (SLC6A4/5-HTT), catecholamine metabolism (COMT, MAO-A), neurotrophic factors (BDNF), and estrogen signaling (ESR2). 1

Key Genes with Replicated Evidence

Serotonin System Genes

The serotonin transporter gene (SLC6A4/5-HTT) shows the most extensively studied associations with depression:

• The 5-HTTLPR polymorphism affects transcriptional activity of the serotonin promoter, with the short allele associated with reduced serotonin expression and increased depression risk in multiple studies 1
• However, findings are inconsistent—some studies link the short allele to depression while others implicate the long allele, suggesting gene-environment interactions modify the effect 1
• A critical finding shows that socioeconomic status interacts with 5-HTTLPR genotype: homozygous short allele carriers have higher depression rates only when combined with low SES 1
• The STin2 VNTR variant (particularly the 9-repeat allele) has also been associated with major depression 1

Tryptophan hydroxylase genes (TPH1, TPH2) involved in serotonin synthesis show mixed evidence, with some studies finding associations with specific haplotype blocks while others report null findings 1, 2

Catecholamine Metabolism Genes

COMT (catechol-O-methyltransferase) gene variants show robust associations:

• The Val158Met polymorphism affects dopamine and noradrenaline metabolism, with the low-activity Met/Met genotype consistently associated with increased depression risk 1, 3, 4
• One study found that 30% of depression variance could be explained by COMT Val158Met genotype combined with psychiatric history and stressors 1
• COMT variants affect treatment response to SSRIs and other antidepressants, with Met carriers potentially experiencing altered drug metabolism 3, 2

MAO-A (monoamine oxidase-A) gene:

• Low-activity variants of the MAO-A uVNTR polymorphism are associated with increased depressive symptoms 1
• The effect is particularly pronounced in individuals carrying both low-activity MAO-A and COMT variants 1

Neurotrophic and Plasticity Genes

BDNF (brain-derived neurotrophic factor):

• The Val66Met polymorphism has been associated with depression and interacts with the serotonin system 1, 5
• BDNF plays a crucial role in synaptic plasticity and neurogenesis, pathways implicated in treatment-resistant depression 5

Additional genes identified in genome-wide studies:

• NEGR1, TMEM106B, LRFN5, and PROX2 represent high-confidence associations with potentially causal relationships to depression 6
• GRIK4 (glutamate receptor gene) shows replicated associations with treatment-resistant depression 5

Hormonal System Genes

ESR1 and ESR2 (estrogen receptor genes):

• Multiple polymorphisms in ESR1 show associations with depression, particularly in postpartum contexts 1
• ESR2 represents a strong, colocalized association with major depression in transcriptome-wide studies 6
• Estrogen receptors influence depression partly through effects on serotonin transmission 1

Stress Response Genes

Glucocorticoid and CRH system genes:

• Glucocorticoid receptor BclI (C/G) variant and CRH receptor 1 (CRHR1) A/G variant are associated with higher depression risk 1
• The C-G-T haplotype of CRHR1 is overrepresented in individuals with depression 1
• FKBP5 gene variants affecting HPA axis function have been identified in depression studies 2

Other candidate genes:

• HTR2A (serotonin receptor 2A) shows associations in multiple studies 2
• Protein kinase C and kininogen 1 SNPs emerged in large-scale association studies 1

Heritability Context

Twin studies establish that youth-onset depression shows heritability ranging from 30-80%, with the remaining variance explained by environmental factors 1, 7. This moderate-to-high heritability confirms substantial genetic contribution while emphasizing that genes alone do not determine outcome 1, 7.

Critical Limitations and Caveats

Despite identified associations, no single gene shows genome-wide significant effects in isolation:

• Candidate gene studies have not identified robust associations that replicate consistently across populations 1
• Genome-wide association studies have not yet identified genome-wide significant associations at the variant level for treatment-resistant depression 5
• The genetic architecture of depression is highly polygenic, involving many variants of small effect 8

Gene-environment interactions are critical:

• Environmental factors (poverty, family relationships, child maltreatment) account for 20-70% of variance in youth depression 1
• Genetic effects are often only apparent in the presence of specific environmental stressors 1
• Socioeconomic status, life events, and early adversity modify genetic risk 1

Methodological heterogeneity limits interpretation:

• Studies vary widely in depression assessment methods (clinical diagnosis vs. self-report), age ranges, and genetic analysis approaches 1
• Many studies have small sample sizes and use non-specific depression screeners 1
• Phenotype definition significantly impacts heritability estimates and gene identification 7

Clinical Implications

Pharmacogenetic testing for COMT and other variants may help identify:

• Patients who might experience altered metabolism of catecholamine-affecting drugs 3, 4
• Individuals at higher risk for medication side effects 3
• Patients requiring dose adjustments for optimal therapeutic effect 3

However, current evidence does not support universal preemptive genetic testing for depression risk prediction, as the identified variants explain only a small proportion of overall risk 5, 8.