rs11127199 (TOGARAM2): Ketamine Antidepressant Response

Key takeaways

• rs11127199 is a TOGARAM2 gene variant identified as a candidate marker for ketamine antidepressant response in a small pilot study of people with major depressive disorder or bipolar disorder.
• The study included only 157 subjects in the ketamine arm and 37 in the scopolamine arm; the authors explicitly noted findings require replication in larger samples.
• The ALT allele increases TOGARAM2 expression in the brain, including the anterior cingulate cortex and cortex, as well as in nerve, pituitary, and vascular tissues.
• No independent replication of this association exists in the provided evidence; treat all findings as exploratory.

What the research says A pilot genome-wide association study (GWAS, a method that scans the entire genome for variants linked to a trait) examined genetic predictors of acute antidepressant response to ketamine in 157 unrelated European subjects diagnosed with major depressive disorder (MDD) or bipolar disorder (BD) who were in a current major depressive episode, measuring change in standardized depression rating scales (the Montgomery-Asberg Depression Rating Scale or the 17-item Hamilton Depression Rating Scale) at 24 hours post-infusion. A polygenic risk score (PRS, a single number summarizing the combined effect of many genetic variants weighted by their estimated effect sizes) built from the ketamine GWAS findings was then tested in a separate group of 37 subjects treated with scopolamine, an anticholinergic agent (one that blocks acetylcholine receptors) also studied for rapid antidepressant effects. The authors described these analyses as pilot work and explicitly stated that findings require replication due to low statistical power from small sample sizes.

Reported associations

• Ketamine antidepressant response (MDD/BD): rs11127199, in the TOGARAM2 region, emerged as a candidate signal in a pilot GWAS of acute ketamine antidepressant response in 157 European subjects with major depressive disorder or bipolar depression. No variant-level effect size or p-value for this specific SNP (single-nucleotide polymorphism) is reported in the available study text.
• Scopolamine antidepressant response (exploratory): A polygenic risk score derived from the ketamine GWAS was tested as a predictor of response to scopolamine in 37 subjects, as an exploratory extension. No variant-level statistics for rs11127199 are available from this arm of the study.

Evidence quality All available evidence for rs11127199 comes from a single pilot GWAS published in 2019 in Translational Psychiatry (Guo et al.) examining ketamine and scopolamine antidepressant response in European subjects with mood disorders. The ketamine arm comprised 157 subjects and the scopolamine arm 37 subjects, both sample sizes acknowledged by the authors as underpowered. The authors stated directly that "findings require replication in larger samples in light of low power of analyses of these small samples." No independent replication cohort, confirmed p-value for rs11127199 specifically, or effect size estimate is available from the provided study text. This is very preliminary, exploratory evidence.

Tissue-specific expression effects

• TOGARAM2: The ALT allele of rs11127199 is associated with increased TOGARAM2 expression across eight tissue types in GTEx v11 data (953 donors). Effects are largest in brain regions: the anterior cingulate cortex (a brain area involved in emotion regulation and cognitive control) and the general cortex show the greatest increases in expression. Increased expression is also observed in tibial nerve, pituitary gland, aorta, cultured fibroblasts, and two esophageal tissue regions (gastroesophageal junction and muscularis). GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.