rs4570625

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This is a 2kb upstream variant variant in the TPH2 gene.

Key Literature Trait Associations

Major Depressive Disorder

rs4570625 (G-703T) is a promoter polymorphism in TPH2, the gene encoding the rate-limiting enzyme for serotonin synthesis in the brain. A meta-analysis of 27 studies found that the T allele was protective against major depressive disorder (OR = 0.83), meaning the G allele confers elevated risk. The G allele is also associated with enhanced amygdala reactivity to negative stimuli and higher harm-avoidance scores in healthy volunteers.

Gao J et al. “TPH2 gene polymorphisms and major depression--a meta-analysis.” Plos One 7(5):e36721 (2012)

Allele G

OR 1.20

p 1.1e-3

Meta-analysis

Ottenhof KW et al. “TPH2 polymorphisms across the spectrum of psychiatric morbidity: A systematic review and meta-analysis.” Neuroscience and Biobehavioral Reviews (2018)

Allele G

OR —

p —

N 30,000

Meta-analysis

multi-ancestry

Liu ZL et al. “Meta-analysis of association between TPH2 single nucleotide poiymorphism and depression.” Neuroscience and Biobehavioral Reviews (2022)

Allele G

OR —

p —

N 11,754

Meta-analysis

multi-ancestry (predominantly East Asian)

Anxiety disorders

The G allele of rs4570625 has been associated with elevated anxiety susceptibility across multiple study designs. A longitudinal Estonian birth cohort study (Laas et al. 2017) found that G-allele carriers had dramatically higher anxiety disorder prevalence by age 25 (OR = 9.38 versus TT homozygotes), though this was a small cohort with few TT individuals. A 2023 within-subject pharmacological fMRI trial (n = 51) showed GG carriers experienced greater subjective anxiety and reduced ventromedial prefrontal cortex reactivity under acute tryptophan depletion compared to TT carriers, providing a plausible serotonergic mechanism. Evidence remains limited to small studies.

Laas K et al. “Nice guys: Homozygocity for the TPH2 -703G/T (rs4570625) minor allele promotes low aggressiveness and low anxiety.” Journal of Affective Disorders (2017)

Allele G

OR 9.38

p —

Candidate gene study

European (Estonian)

Liu C et al. “A central serotonin regulating gene polymorphism (TPH2) determines vulnerability to acute tryptophan depletion-induced anxiety and ventromedial prefrontal threat reactivity in healthy young men.” European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology (2023)

Allele G

OR —

p —

N 51

Candidate gene study

East Asian (Chinese)

Aggression and impulsivity

The T allele of rs4570625 appears protective against aggressive behavior and maladaptive impulsivity. The Laas et al. 2017 Estonian longitudinal cohort found TT homozygous males showed significantly lower scores on the Life History of Aggression interview, lower bully-scale peer reports, fewer ADHD symptoms at ages 9 and 15, and lower maladaptive impulsivity at ages 18 and 25. These findings converge with the serotonin-regulating role of TPH2: higher brain serotonin synthesis capacity in T carriers may dampen impulsive and aggressive responses. Evidence is currently limited to a single cohort with a small number of TT individuals.

Laas K et al. “Nice guys: Homozygocity for the TPH2 -703G/T (rs4570625) minor allele promotes low aggressiveness and low anxiety.” Journal of Affective Disorders (2017)

Allele G

OR —

p —

Candidate gene study

European (Estonian)

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Research that mentions this SNP (3)

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Interaction among childhood trauma and functional polymorphisms in the serotonin pathway moderate the risk of depressive disorders

AssociationN=4,504Sandra Van der Auwera et al.(2014)· European Archives of Psychiatry and Clinical Neuroscience

This gene-environment interaction study examined 4,504 Caucasian subjects from two independent cohorts (SHIP-LEGEND and SHIP-TREND-0) to assess how variants in serotonergic pathway genes TPH2 (rs7305115) and 5-HTTLPR moderate depression risk after childhood abuse. The three-way interaction between abuse, TPH2 GG genotype, and 5-HTTLPR SS genotype showed significant association with depression severity (p=0.023), with GG/SS carriers exposed to abuse displaying mean BDI-II scores of 15.0 compared to 6.8 in AA carriers, supporting the serotonin deficiency hypothesis in depression.

Traits studied:Depression severityDepressive disordersDepressive symptoms

PubMed DOI Metascience Observatory

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A gene–environment investigation on personality traits in two independent clinical sets of adult patients with personality disorder and attention deficit/hyperactive disorder

AssociationN=306Christian P. Jacob et al.(2010)· European Archives of Psychiatry and Clinical Neuroscience

A gene-environment interaction study in 183 personality disorder patients and 123 adult ADHD patients examining serotonergic candidate genes (5-HTT, HTR1A, TPH2) with stressful life events. HTR1A rs6295 G allele increased risk of cluster B personality disorders (OR=1.99, p=0.019) and decreased cluster C risk in ADHD (OR=0.44, p=0.016). 5-HTTLPR and TPH2 rs4570625 showed significant G×E interactions with life events for personality disorder traits.

Traits studied:Adult attention deficit/hyperactivity disorderHarm avoidanceNeuroticismPersonality disorder - cluster B (emotional-dramatic)Personality disorder - cluster C (anxious-fearful)

PubMed DOI Metascience Observatory

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NOS‐I and ‐III gene variants are differentially associated with facets of suicidal behavior and aggression‐related traits

ReviewDan Rujescu et al.(2008)· American Journal of Medical Genetics Part B: Neuropsychiatric Genetics

A comprehensive review of the genetic basis of aggressive behavior, covering candidate genes in neurotransmitter systems (TPH1, TPH2, SLC6A4, DRD4, COMT, MAOA), hypothalamic-pituitary genes (OXT, OXTR, AVPR1A, AVPR1B), and GWAS findings (LRRTM4 rs11126630 p=5.30×10⁻⁸, CDH13 rs11649622 p=4.19×10⁻⁶, FYN rs2148710 p=2.9×10⁻⁸, DYRK1A). The review concludes that genetic predisposition to aggressive behavior involves multiple genes with small individual effects (1-2% each).

Traits studied:Aggressive behaviorAngerAntisocial behaviorCriminal behaviorHostilitySelf-harmSuicidal behaviorViolence

rs4570625

Key Literature Trait Associations

Major Depressive Disorder

Anxiety disorders

Aggression and impulsivity

Research that mentions this SNP (3)

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