Expressive

rs10914746 (CSMD2): Venlafaxine Response in Anxiety

Key takeaways

  • rs10914746 in the CSMD2 gene showed a marginal association with how well venlafaxine XR relieved anxiety symptoms in a small study
  • No variant in the study met the genome-wide significance threshold, so this finding is preliminary
  • The study enrolled only 98 European Americans and lacked a replication cohort
  • GTEx data independently links this variant to reduced CSMD2 expression in thyroid tissue
  • Researchers flagged CSMD2 as potentially relevant across multiple neuropsychiatric conditions

Key takeaways

  • rs10914746 sits within the CSMD2 gene and showed a marginal association with how well patients responded to the antidepressant drug venlafaxine XR in a small genome-wide association study of generalized anxiety disorder
  • No variant in the study met the standard genome-wide significance threshold; this association is preliminary and unconfirmed
  • The study enrolled only 98 European American patients and had no replication cohort, making independent validation essential before any conclusions can be drawn
  • GTEx population data independently links this variant to reduced CSMD2 expression specifically in thyroid tissue
  • Researchers flagged CSMD2 as potentially relevant across multiple neuropsychiatric diagnostic categories

What the research says A genome-wide association study (GWAS - a method that scans hundreds of thousands of genetic markers across participants to find disease-related variants) enrolled 98 European American patients with generalized anxiety disorder (GAD) who received venlafaxine XR (an antidepressant in the serotonin-norepinephrine reuptake inhibitor, or SNRI, class) at flexible doses for 24 weeks, testing 266,820 common single nucleotide polymorphisms (SNPs - single-letter DNA variants) for association with treatment outcomes on the Hamilton Anxiety Scale (HAM-A - a clinician-administered scale measuring anxiety symptom severity). rs10914746 was one of 8 SNPs that reached marginal significance (p < 0.00001) for treatment response and remission at weeks 12 and 24, though none reached the conventional genome-wide significance threshold of p < 5×10^-8. Separately, GTEx v11 data from 953 donors shows the variant is associated with reduced CSMD2 expression in thyroid tissue GTEx Portal.

Reported associations

  • Venlafaxine XR treatment response in GAD: rs10914746 was one of 8 SNPs marginally associated (p < 0.00001) with HAM-A score reduction and response/remission outcomes at 12 and 24 weeks in a 98-person European American cohort; the association did not reach genome-wide significance
  • Thyroid tissue CSMD2 expression: The variant is associated with reduced expression of the gene in thyroid tissue (p=1.0×10^-7, 953 donors) GTEx Portal

Evidence quality The pharmacogenetic association rests on a single small study (n=98 European Americans), and no variant tested - including rs10914746 - crossed the genome-wide significance threshold (p < 5×10^-8). The analysis covered only a European ancestry population, limiting generalizability, and the study lacked an independent replication cohort; the authors themselves describe findings as identifying "potential predictors" rather than confirmed associations. The GTEx eQTL signal (eQTL - expression quantitative trait locus, a variant that influences how much a nearby gene is transcribed) in thyroid is better powered (953 donors, FDR < 0.05) and statistically robust, but eQTL data reflects gene-expression mechanics rather than clinical outcomes. Overall, the evidence for rs10914746 is weak and preliminary.

Tissue-specific expression effects

  • CSMD2: Carriers of the effect allele show reduced expression of the gene in thyroid tissue at the population level; no expression effect in other tissues was present in the available GTEx data GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.

Frequently asked questions

What is rs10914746?

rs10914746 is a single nucleotide polymorphism - a single-letter variation in DNA - located within the CSMD2 gene. It was studied in relation to how patients with generalized anxiety disorder respond to the antidepressant drug venlafaxine XR.

Is rs10914746 linked to anxiety disorder treatment?

A small genome-wide association study found a marginal statistical association (p < 0.00001) between rs10914746 and response to venlafaxine XR in generalized anxiety disorder, but the finding did not reach genome-wide significance and has not been independently replicated.

What does the CSMD2 gene do?

The available studies do not describe CSMD2's biological function in detail, but researchers noted it may be a marker relevant across multiple neuropsychiatric diagnostic categories.

Why is a variant associated with anxiety also linked to thyroid gene expression?

GTEx population data shows rs10914746 is associated with reduced CSMD2 expression in thyroid tissue, but the biological reason for this tissue-specific effect is not explained in the available studies. The clinical significance of the thyroid expression signal is unknown.

How reliable is the evidence for rs10914746?

The evidence is preliminary. The only pharmacogenetic study was small (98 participants), did not achieve genome-wide significance, and has not been replicated in an independent cohort. Validation in larger, diverse populations is needed before any conclusions can be drawn.