SLC6A4

MEDIUM

Solute carrier family 6 member 4

Chromosome: 17q11.2

Gene Overview

SLC6A4 encodes the serotonin transporter (5-HTT), which reuptakes serotonin from the synaptic cleft and terminates serotonergic signaling. The promoter polymorphism 5-HTTLPR (short vs long) modulates transporter expression and has been extensively studied in depression, stress response, and suicidal behavior. Short allele carriers show exaggerated amygdala reactivity and may be more vulnerable to depression following adversity. SLC6A4 is the target of SSRIs. Expression is highest in raphe nuclei, platelets, and placenta. Genetic variation influences SSRI response. The gene-denvironment interaction (5-HTTLPR × stress → depression) has been debated but remains influential in psychiatric genetics.

Molecular Function

  • serotonin transport
  • neurotransmitter reuptake
  • sodium symport

Protein class: solute carrier

Regulatory Annotation

Promoter activity: 5-HTTLPR length polymorphism affects transcriptional efficiency; short allele reduces expression.

Enhancer associations: Depression-associated variants in regulatory region.

Methylation sensitivity: SLC6A4 promoter methylation correlates with stress exposure and depression.

eQTL tissues: brain, whole blood

Tissue Expression Context

brainTPM range: 3-12GTEx vv8
whole bloodTPM range: 1-5GTEx vv8

Pathways

Linked Diseases & Exposures

Diseases

Exposures

Mechanistic Hypotheses

Short 5-HTTLPR allele reduces SLC6A4 expression and serotonin reuptake; under psychosocial stress, reduced extracellular serotonin clearance may amplify stress reactivity and predispose to depression.

Meta-analyses support G×E; short allele associated with amygdala reactivity and stress-related depression in some studies.

MEDIUM

Confidence Rating

Overall evidence confidence for this gene entry: MEDIUM

References

  1. 1.Caspi A, et al. (2003). Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. doi:10.1126/science.1083968
  2. 2.GTEx Consortium (2020). GTEx Consortium. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science. doi:10.1126/science.aaz1776
  3. 3.Hariri AR, et al. (2002). Serotonin transporter genetic variation and the response of the human amygdala. Science. doi:10.1126/science.1071829