rs6311 — HTR2A -1438G>A

HTR2A -1438G>A: The SSRI Side Effect Variant

The serotonin 2A receptor gene (HTR2A) encodes one of the brain's most important receptors for serotonin signaling¹¹ serotonin signaling
Serotonin (5-HT) is a neurotransmitter involved in mood regulation, sleep, appetite, and cognition. The 5-HT2A receptor is a primary target for many antidepressants and antipsychotics.. The rs6311 polymorphism sits in the promoter region of this gene, 1438 bases upstream of the transcription start site, where it influences how much receptor protein your cells produce. This variant has been extensively studied for its role in psychiatric medication response²² psychiatric medication response
Over 149 publications have investigated this SNP in relation to mental health conditions and treatment response, though results have been notably inconsistent for efficacy and more consistent for side effects.

The Mechanism

Rs6311 is a regulatory variant³³ regulatory variant
Located in the promoter/5' UTR region, this SNP affects transcriptional regulation rather than changing the protein sequence directly that modulates HTR2A gene expression. The variant is transcribed in minor isoforms of HTR2A mRNA, particularly those with an extended 5' untranslated region (UTR). Research shows the A allele associates with reduced expression⁴⁴ A allele associates with reduced expression
The variant "A" allele of rs6311 is associated with reduced expression of isoforms containing the extended 5' UTR of these extended UTR isoforms. The G allele, conversely, allows higher expression of the extended 5' UTR, which may increase translational efficiency and ultimately receptor density in the brain.

Rs6311 exists in near-perfect linkage disequilibrium⁵⁵ near-perfect linkage disequilibrium
Rs6311 and rs6313 are in near-perfect LD, located 1538 bases apart on chromosome 13, with 99.6-99.7% concordance between alleles with rs6313 (T102C), a synonymous coding variant. In most cases, the rs6311 G allele pairs with rs6313 C, and rs6311 A pairs with rs6313 T. This tight linkage makes it difficult to determine which variant drives observed effects, though functional studies suggest rs6311's regulatory location may be more mechanistically relevant.

The Evidence

The most robust and replicated finding for rs6311 concerns SSRI side effects rather than efficacy. A weighted average of three paroxetine studies⁶⁶ weighted average of three paroxetine studies
All three studies (total n = 237) found significantly increased incidence of adverse events in patients with the -1438GG genotype, with side effect rates increasing from 15% among A carriers to 42% among GG homozygotes (n=237 total) showed side effect rates of 15% among A allele carriers versus 42% among GG homozygotes when treated with paroxetine. Similar patterns have been observed with other SSRIs including citalopram and fluvoxamine, though these findings await replication in larger cohorts.

In a Malay population study⁷⁷ Malay population study
The GG genotype of HTR2A polymorphism has decreased odds for dizziness but increased odds for poor concentration, while GA genotype increases odds for excessive sweating, diarrhea, constipation and blurred vision, the GG genotype showed decreased odds for dizziness but increased odds for poor concentration, while the GA genotype increased odds for excessive sweating, diarrhea, constipation, and blurred vision on SSRI treatment. A 2019 study on sexual dysfunction⁸⁸ 2019 study on sexual dysfunction
The -1438A/G and 102T/C polymorphisms appear associated with sexual dysfunction induced by citalopram, with risk increasing with number of "risky" alleles found that sexual dysfunction risk from citalopram/sertraline increased with the number of "risky" alleles (G for rs6311, C for rs6313, L for 5-HTTLPR).

Evidence for treatment efficacy is considerably less consistent. A large Chinese study⁹⁹ large Chinese study
Study of 290 patients treated with SSRIs found no association between rs6311 and treatment response or remission (n=290) found no association with SSRI response or remission. The STAR*D study, one of the largest antidepressant trials, also found no significant association¹⁰¹⁰ also found no significant association
Neither rs6311 nor rs6313 showed significant association with treatment response or remission in the STAR*D study for rs6311 with citalopram efficacy. A 2020 meta-analysis¹¹¹¹ 2020 meta-analysis
Pooled analyses of 16 studies (1931 subjects) indicated significant association with higher response in dominant model for 1438A/G polymorphism (OR: 1.40, 95% CI: 1.12-1.76) of 42 studies found some evidence for improved response with the GG genotype, but noted results were highly dependent on individual studies and publication bias may be present.

Beyond antidepressant effects, rs6311 has been studied extensively in schizophrenia. A meta-analysis of 15 case-control studies¹²¹² meta-analysis of 15 case-control studies
The -1438A/G polymorphism was a risk factor for schizophrenia, especially in Caucasians, with odds ratios ranging from 1.12-1.20 depending on genetic model found the G allele associated with increased schizophrenia risk in Caucasian populations (OR 1.12-1.20 depending on genetic model), though not in East Asian populations, highlighting important ancestry-specific effects.

Practical Implications

If you carry the GG genotype and are prescribed an SSRI, the evidence suggests heightened vigilance for side effects is warranted. The increased side effect risk with GG is one of the more consistent pharmacogenetic findings in psychiatry, though it's important to note this reflects population averages — individual responses vary considerably. Work closely with your prescriber to monitor for common SSRI side effects including gastrointestinal disturbances, sexual dysfunction, sleep changes, and activation symptoms, especially during the first 4-6 weeks of treatment.

The inconsistent efficacy data means rs6311 shouldn't guide initial drug selection, but it may inform how aggressively to pursue alternative medications if side effects emerge. If you experience intolerable side effects on one SSRI, alternatives include trying a different SSRI class (as pharmacokinetic differences may matter more than pharmacodynamic 5-HT2A effects), considering SNRIs or other antidepressant classes, or exploring non-serotonergic options depending on your clinical presentation.

For AA genotype carriers, the lower side effect risk doesn't guarantee a problem-free experience — individual factors including dose, drug-drug interactions, and comorbidities matter enormously. The same caution applies to those with AG genotypes, who show intermediate risk in the available data.

Interactions

Rs6311 interacts closely with rs6313 due to their near-complete linkage disequilibrium. Any effects attributed to one variant likely reflect the haplotype they share. Rs7997012, another HTR2A intronic SNP, has been studied primarily for antidepressant efficacy (with more consistent results than rs6311) and may compound effects on treatment response when combined with rs6311/rs6313 variants. Rs6314 (His452Tyr), a missense variant in HTR2A, also shows linkage with rs6311 and has been associated with aggressive traits and treatment response.

Compound effects involving rs6311 AG or GG genotypes plus rs6313 and 5-HTTLPR variants appear to increase sexual dysfunction risk on SSRIs in a dose-dependent manner. A 2011 study¹³¹³ 2011 study
Interaction between rs7997012, rs6311 and gender explained 14% of variance in treatment response, suggesting rs6311 may not independently influence outcome but plays a role through interactions found the interaction between rs7997012, rs6311, and gender explained 14% of variance in treatment response, suggesting rs6311's effects may emerge primarily through interactions rather than independently.