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From SNPedia

Geno Mag Summary
(A;A) 2.5 short form of 5-HTTLPR. lower levels of serotonin, slightly less happy, benefits from more support
(G;G) 2.1 long form of 5-HTTLPR. less sensitive to pain
Make rs25531(A;G)
ReferenceGRCh38 38.1/141
GeneLOC105371720, SLC6A4
is asnp
is mentioned by
dbSNP (classic)rs25531
1000 genomesrs25531
GWAS Ctlgrs25531
Max Magnitude2.5

According to David Hinds of 23andMe on community forums, "nearly everyone (99.97%) is getting called as CC, and there is no clear heterozygote cluster" ... "the genotype calls for rs25531 on our platform are not meaningful." Looking at OpenSNP frequency data, this seems to be universal for direct to consumer genotyping services at this stage.

The minor allele (G) of rs25531 is almost always in phase with the long (L) allele of the 5-HTTLPR, which is the most commonly studied variation in this region. The (L) long allele may be associated with lower levels of serotonin.[PMID 8929413]

The article and video from "The Atlantic" suggests that children with the short allele (A), may need and benefit greatly from more maternal support

In contrast to earlier reports linking rs25531, a SNP in the serotonin transporter SLC6A4 gene, to obsessive compulsive disorder (OCD), a March 2007 publication finds no significant association studying "the largest sample size of OCD patients (N=347) and controls (N=749) ever investigated". [PMID 17375136]

A separate study of 75 patients suffering mood disorders after traumatic brain injury (TBI) concluded that there was no evidence of association between rs25531 and depression post-TBI.[PMID 18465388]

A small study (62 patients and 62 matched controls) investigated this SNP in relation to blushing. (Blushing is considered to be one of the prime pathophysiological markers of social anxiety disorder.) The less active 5-HTTLPR genotypes were nominally significantly associated with increased blushing propensity in patients with social anxiety disorder, and association remained significant even when statistically controlled for he influence of depression.[PMID 18629430]

A study of 94 depressed patients who attempted suicide compared to 94 without psychiatric disorders found no evidence of an association with rs25531.[PMID 19103261]

A study of 97 "normal" individuals concluded that rs25531(G;G) individuals selectively process positive affective material alongside selective avoidance of negative affective material, in a manner absent among individuals carrying a rs25531(A) allele. To put it another way, if this conclusion drawn from a very small sample of people can be replicated, rs25531(G;G) individuals may have a tendency to be optimists and to be more resilient to stress.10.1098/rspb.2008.1788

A study published in 2011 of 2,500+ individuals followed from 1995 - 2008 as part of the US National Longitudinal Study of Adolescent Health found that twice as many respondents with two 5-HTTLPR long variants said they were very satisfied with life compared with carriers of two short versions. Conversely, 26% of those carrying two short alleles said they were dissatisfied with life, compared with 20% of people carrying two long variants.10.1038/jhg.2011.39 This blog post investigates the statistics.

A study of 135 patients with major depressive disorder (mean age 31.1+/-11.6 years, 68% females) treated with escitalopram 10-20 mg/day for 12 weeks concluded that patients carrying the rs25531(A) allele may be at increased risk for side effects (e.g. headaches), but they say no associations with efficacy.[PMID 19272758]

[PMID 19487392] Serotonin Transporter Gene (SLC6A4) Promoter Polymorphisms and the Susceptibility to Posttraumatic Stress Disorder in the General Population

[PMID 19521089] Serotonin Transporter Gene Polymorphic Element 5-HTTLPR Increases the Risk of Sporadic Parkinson's Disease in Italy

Protocol for genotyping rs25531

[PMID 19570226OA-icon.png] Genetic variation in the serotonin transporter gene (5-HTTLPR, rs25531) influences the analgesic response to the short acting opioid Remifentanil in humans

[PMID 19685963OA-icon.png] Association of the serotonin transporter gene promoter region (5-HTTLPR) polymorphism with biased attention for emotional stimuli

[PMID 19806148OA-icon.png] Association of SLC6A4 variants with obsessive-compulsive disorder in a large multicenter US family study

[PMID 19911410OA-icon.png] Do 5HTTLPR and stress interact in risk for depression and suicidality? Item response analyses of a large sample

[PMID 20031235] Serotonin transporter polymorphisms and early response to antipsychotic treatment in first episode of psychosis

[PMID 20090673OA-icon.png] Serotonin Transporter Genotype and Action Monitoring Dysfunction: A Possible Substrate Underlying Increased Vulnerability to Depression

[PMID 20146650] Association analysis between gene variants of the tyrosine hydroxylase and the serotonin transporter in borderline personality disorder

[PMID 20175892OA-icon.png] Study of the serotonin transporter (SLC6A4) and BDNF genes in French patients with non syndromic mental deficiency

[PMID 20462563] Analysis of the serotonin transporter promoter rs25531 polymorphism in premenstrual dysphoric disorder

[PMID 20468059OA-icon.png] No association of the serotonin transporter polymorphisms 5-HTTLPR and RS25531 with schizophrenia or neurocognition

[PMID 20588071] Norepinephrine and Serotonin Transporter Genes: Impact on Treatment Response in Depression

[PMID 20694965OA-icon.png] Association of the serotonin transporter promoter region polymorphism with biased attention for negative word stimuli

[PMID 20920548] Lack of association between the 5-HTTLPR and the error-related negativity (ERN)

[PMID 21245616OA-icon.png] Association of serotonin transporter gene polymorphisms with obsessive-compulsive disorder (OCD) in a South Indian population

[PMID 21319930] Associations between serotonin transporter gene promoter region (5-HTTLPR) polymorphism and gaze bias for emotional information

[PMID 21105279OA-icon.png] Relation of serotonin transporter genetic variation to efficacy of escitalopram for generalized anxiety disorder in older adults


[PMID 21660253OA-icon.png] A novel study and meta-analysis of the genetic variation of the serotonin transporter promoter in the italian population do not support a large effect on Alzheimer's disease risk

[PMID 21658141] Genetic variants in the serotonin transporter influence the efficacy of bupropion and nortriptyline in smoking cessation

[PMID 21423614OA-icon.png] Perception of thermal pain and the thermal grill illusion is associated with polymorphisms in the serotonin transporter gene

[PMID 22086748] The Serotonin Transporter Promoter Polymorphism (5-HTTLPR) Affects the Relation between Antidepressant Serum Concentrations and Effectiveness in Major Depression

[PMID 22271509OA-icon.png] Association between the serotonin transporter triallelic genotype and eating problems is moderated by the experience of childhood trauma in women

[PMID 21364197OA-icon.png] Effects of 5HTTLPR on cardiovascular response to an emotional stressor

[PMID 21681867] Serotonin transporter gene and childhood trauma--a G × E effect on anxiety sensitivity

[PMID 22590463OA-icon.png] Influence of threat and serotonin transporter genotype on interference effects

[PMID 16402131] Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531.

[PMID 17284168] Serotonergic genes modulate amygdala activity in major depression.

[PMID 18050262] Serotonin transporter polymorphism (5-HTTLPR) association with melancholic depression: a female specific effect?

[PMID 18441666] Extended evaluation of serotonin transporter gene functional polymorphisms in subjects with post-stroke depression.

[PMID 18444253OA-icon.png] Additional functional variation at the SLC6A4 gene.

[PMID 18661222OA-icon.png] 5-HTTLPR and gender moderate changes in negative affect responses to tryptophan infusion.

[PMID 18824000OA-icon.png] How the serotonin story is being rewritten by new gene-based discoveries principally related to SLC6A4, the serotonin transporter gene, which functions to influence all cellular serotonin systems.

[PMID 18951433] Lack of association of the serotonin transporter gene promoter region polymorphism, 5-HTTLPR, including rs25531 with cigarette smoking and alcohol consumption.

[PMID 18981341OA-icon.png] Association of serotonin transporter gene polymorphisms with poststroke depression.

[PMID 19015103OA-icon.png] Oxytocin receptor (OXTR) and serotonin transporter (5-HTT) genes associated with observed parenting.

[PMID 19020798] Association study to evaluate the serotonin transporter and apolipoprotein E genes in frontotemporal lobar degeneration in Italy.

[PMID 19032574OA-icon.png] Characterization of a functional polymorphism in the 3' UTR of SLC6A4 and its association with drinking intensity.

[PMID 19122845OA-icon.png] An examination of the association between the 5-HTT promoter region polymorphism and depressogenic attributional styles in childhood.

[PMID 19125330OA-icon.png] The serotonin transporter polymorphism rs25531 is associated with irritable bowel syndrome.

[PMID 19249159] Sex-specific association between the 5-HTT gene-linked polymorphic region and basal cortisol secretion.

[PMID 19429111] No association between polymorphism of serotonin transporter gene and depression in Parkinson's disease in Chinese.

[PMID 19541292OA-icon.png] Accurate, Large-Scale Genotyping of 5HTTLPR and Flanking Single Nucleotide Polymorphisms in an Association Study of Depression, Anxiety, and Personality Measures.

[PMID 19625753] The serotonin transporter promoter polymorphic region is not a risk factor for Alzheimer's disease related behavioral disturbances.

[PMID 19742166OA-icon.png] Epistasis between IL1A, IL1B, TNF, HTR2A, 5-HTTLPR and TPH2 variations does not impact alcohol dependence disorder features.

[PMID 19860858OA-icon.png] Combinatorial interaction between two human serotonin transporter gene variable number tandem repeats and their regulation by CTCF.

[PMID 19884608OA-icon.png] Interactive effect of stressful life events and the serotonin transporter 5-HTTLPR genotype on posttraumatic stress disorder diagnosis in 2 independent populations.

[PMID 19962442] Emotion specific modulation of automatic amygdala responses by 5-HTTLPR genotype.

[PMID 19996755OA-icon.png] Serotonin transporter triallelic genotype and response to citalopram and risperidone in dementia with behavioral symptoms.

[PMID 20406689] Serotonin transporter polymorphisms (SLC6A4 insertion/deletion and rs25531) do not affect the availability of 5-HTT to [11C] DASB binding in the living human brain.

[PMID 20450949] Serotonin transporter gene polymorphisms and treatment-resistant depression.

[PMID 20452607] Influence of serotonin transporter gene polymorphisms on clozapine response in Brazilian schizophrenics.

[PMID 20452754] Mixture regression analysis on age at onset in bipolar disorder patients: investigation of the role of serotonergic genes.

[PMID 20455953OA-icon.png] Serotonin transporter gene, childhood emotional abuse and cognitive vulnerability to depression.

[PMID 20505557] Haplotypes of dopamine and serotonin transporter genes are associated with antisocial personality disorder in alcoholics.

[PMID 20515362OA-icon.png] Genetic predictors of response to treatment with citalopram in depression secondary to traumatic brain injury.

[PMID 20584552] The role of clinical variables, neuropsychological performance and SLC6A4 and COMT gene polymorphisms on the prediction of early response to fluoxetine in major depressive disorder.

[PMID 20862697] Rare genotype combination of the serotonin transporter gene associated with treatment response in severe personality disorder.

[PMID 20971165] Relationships among 5-HTT genotype, life events and gender in the recognition of facial emotions.

[PMID 21166770OA-icon.png] Dopamine D4 receptor and serotonin transporter gene effects on the longitudinal development of infant temperament.

[PMID 21172166OA-icon.png] Pharmacogenetics of antidepressant response.

[PMID 21232011] Serotonin transporter allelic variation in mothers predicts maternal sensitivity, behavior and attitudes toward 6-month-old infants.

[PMID 21290142] Parent of origin effect and allelic expression imbalance of the serotonin transporter in bipolar disorder and suicidal behaviour.

[PMID 21356267] 5-HTTLPR and COMTval158met genotype gate amygdala reactivity and habituation.

[PMID 21429092] Serotonin transporter gene variants and prediction of stress-induced risk for psychological distress.

[PMID 21441157] Serotonin transporter gene polymorphism in Chinese patients with poststroke depression: a case-control study.

[PMID 21453464OA-icon.png] The influence of psychiatric screening in healthy populations selection: a new study and meta-analysis of functional 5-HTTLPR and rs25531 polymorphisms and anxiety-related personality traits.

[PMID 21497794OA-icon.png] A functional variant of the serotonin transporter gene (SLC6A4) moderates impulsive choice in attention-deficit/hyperactivity disorder boys and siblings.

[PMID 21818827OA-icon.png] The relationship between combat-related posttraumatic stress disorder and the 5-HTTLPR/rs25531 polymorphism.

[PMID 21893641OA-icon.png] Acute and posttraumatic stress symptoms in a prospective gene x environment study of a university campus shooting.

[PMID 22094432OA-icon.png] Perception of a naturalistic stressor interacts with 5-HTTLPR/rs25531 genotype and gender to impact reward responsiveness.

[PMID 22348680] Somatic markers mediate the effect of serotonin transporter gene polymorphisms on Iowa Gambling Task.

[PMID 22489680] No difference in 5-HTTLPR and Stin2 polymorphisms frequency between premature ejaculation patients and controls.

[PMID 22520017] Suicide ideators and attempters with schizophrenia--the role of 5-HTTLPR, rs25531, and 5-HTT VNTR Intron 2 variants.

[PMID 23236014] Polymorphisms of the serotonin transporter gene and post-stroke depression: a meta-analysis

[PMID 23288236] 5-HTTLPR rs25531A > G differentially influence paroxetine and fluvoxamine antidepressant efficacy: a randomized, controlled trial

[PMID 23787408] Prediction of the time-course pattern of remission in depression by using clinical, neuropsychological, and genetic variables

[PMID 23021380] Strong effects of environmental factors on prevalence and course of major depressive disorder are not moderated by 5-HTTLPR polymorphisms in a large Dutch sample

[PMID 23499791] Resting-state cerebral blood flow in amygdala is modulated by sex and serotonin transporter genotype

[PMID 22390669OA-icon.png] Interaction between serotonin transporter polymorphism (5-HTTLPR) and stressful life events in adolescents' trajectories of anxious/depressed symptoms.

[PMID 22623017] Serotonin transporter-linked polymorphic region (5-HTTLPR) genotype is associated with cortisol responsivity to naloxone challenge.

[PMID 22836288] 5-HTTLPR X stress in adolescent depression: moderation by MAOA and gender.

[PMID 22884012] Influence of serotonin transporter promoter variation on the effects of separation from parent/partner on depression.

[PMID 22907732] Interaction between polymorphisms in serotonin transporter (SLC6A4) and serotonin receptor 2A (HTR2A) genes predict treatment response to venlafaxine XR in generalized anxiety disorder.

[PMID 22913298] Respiratory sinus arrhythmia and serotonin transporter promoter gene polymorphisms: taking a triallelic approach makes a difference.

[PMID 22921508] Association between serotonin transporter promoter polymorphisms and psychological distress in a diabetic population.

[PMID 23033208] Characterization of serotonin transporter gene (SLC6A4) polymorphisms and its association with drug dependence in a Jordanian Arab population.

[PMID 23101739] The Generation R Study: A review of design, findings to date, and a study of the 5-HTTLPR by environmental interaction from fetal life onward.

[PMID 23123360OA-icon.png] Allele-specific associations of 5-HTTLPR/rs25531 with ADHD and autism spectrum disorder.

[PMID 23149035] Association study of serotonin transporter availability and SLC6A4 gene polymorphisms in patients with major depression.

[PMID 23261136] State dependent gene-environment interaction: serotonin transporter gene-child abuse interaction associated with suicide attempt history among depressed psychiatric inpatients.

[PMID 23277270] 5-HTTLPR rs25531A > G Differentially Influence Paroxetine and Fluvoxamine Antidepressant Efficacy: A Randomized Controlled Trial.

[PMID 23313272] An association study of suicide and candidate genes in the serotonergic system.

[PMID 23510579] Worldwide population variation and haplotype analysis at the serotonin transporter gene SLC6A4 and implications for association studies.

[PMID 23630162OA-icon.png] Common and rare alleles of the serotonin transporter gene, SLC6A4, associated with Tourette's disorder.

[PMID 24776739] Multimodal imaging of a tescalcin (TESC)-regulating polymorphism (rs7294919)-specific effects on hippocampal gray matter structure

[PMID 25214390] Interaction among childhood trauma and functional polymorphisms in the serotonin pathway moderate the risk of depressive disorders

[PMID 25564228OA-icon.png] Population Frequencies of the Triallelic 5HTTLPR in Six Ethnicially Diverse Samples from North America, Southeast Asia, and Africa

[PMID 25671637] Relationship of Genetic Variation in the Serotonin Transporter Gene (SLC6A4) and Congenital and Acquired Cardiovascular Diseases

[PMID 25793742OA-icon.png] An Examination of the Association between 5-HTTLPR, Combat Exposure, and PTSD Diagnosis among U.S. Veterans

[PMID 25903736] Serotonin transporter gene polymorphisms: Relation with platelet serotonin level in patients with primary Sjogren's syndrome

[PMID 25990886] Impact of monoamine-related gene polymorphisms on hippocampal volume in treatment-resistant depression

[PMID 24021217OA-icon.png] Common selective serotonin reuptake inhibitor side effects in older adults associated with genetic polymorphisms in the serotonin transporter and receptors: data from a randomized controlled trial

[PMID 26175754OA-icon.png] DNA methylation and single nucleotide variants in the brain-derived neurotrophic factor (BDNF) and oxytocin receptor (OXTR) genes are associated with anxiety/depression in older women

[PMID 26232751] Interaction of the 5-HTTLPR and childhood trauma influences memory bias in healthy individuals

[PMID 26542422OA-icon.png] Interaction between SLC6A4 promoter variants and childhood trauma on the age at onset of bipolar disorders

[PMID 29551185] Susceptibility and severity of cancer-related fatigue in colorectal cancer patients is associated with SLC6A4 gene single nucleotide polymorphism rs25531 A>G genotype.

[PMID 30707907] Stress response genes associated with attention deficit hyperactivity disorder: a case-control study in Chinese children.

[PMID 31809838] Association of the DRD4 Exon III and 5-HTTLPR VNTR Polymorphisms with Substance Abuse in Jordanian Arab population.