Expressive

rs10204266 (ADCY3): Antidepressant Response Variant

Key takeaways

  • rs10204266 sits in the ADCY3-DNAJC27 locus, a region examined in a genome-wide study of antidepressant response in late-life depression
  • A GWAS of 307 older adults treated with venlafaxine found no variants at this locus reaching genome-wide significance
  • GTEx eQTL data show this variant increases ADCY3 expression in whole blood but decreases it in brain cortex and cerebellar hemisphere
  • DNAJC27 and CENPO expression in whole blood are also increased by this variant
  • All clinical association evidence for this variant is preliminary and has not been independently replicated

Key takeaways

  • rs10204266 sits in the ADCY3-DNAJC27 locus, a region examined in a genome-wide study of antidepressant response in late-life depression
  • A GWAS of 307 older adults treated with venlafaxine found no variants at this locus reaching genome-wide significance
  • GTEx eQTL data show this variant increases ADCY3 expression in whole blood but decreases it in brain cortex and cerebellar hemisphere
  • DNAJC27 and CENPO expression in whole blood are also increased by this variant
  • All clinical association evidence for this variant is preliminary and has not been independently replicated

What the research says A genome-wide association study (GWAS) enrolled 307 older adults (≥60 years) with major depressive disorder treated with venlafaxine extended-release for 12 weeks to investigate the genetic architecture of antidepressant remission; the ADCY3 (adenylate cyclase 3)-DNAJC27 locus was among the regions analyzed, though no variant here reached conventional genome-wide significance. Pathway analysis in the same study implicated the ubiquitin-proteasome system - a cellular machinery that degrades damaged proteins - (25 of 190 relevant genes, FDR-corrected p = 0.01) alongside vascular biology, and polygenic risk for cardioembolic stroke ranked among the strongest predictors of treatment non-remission (accuracy = 0.70, sensitivity = 0.72, specificity = 0.67; p = 2.45 × 10^-4). Independently, tissue eQTL data from GTEx v11 (953 donors, cis-window, FDR < 0.05) show the ALT allele of rs10204266 has opposing effects on ADCY3 expression depending on tissue - increased in whole blood but decreased in brain cortex and cerebellar hemisphere GTEx Portal.

Reported associations

  • Antidepressant remission, late-life depression: The locus was analyzed in a GWAS of 307 older adults on venlafaxine; no variant here reached genome-wide significance, and the study authors described their results as preliminary support for the roles of vascular and neuroinflammatory pathways in late-life antidepressant response
  • ADCY3 expression - whole blood (eQTL): The ALT allele is associated with increased ADCY3 expression in whole blood (slope +0.42, p = 1.1 × 10^-¹²) GTEx Portal
  • ADCY3 expression - brain cortex (eQTL): The ALT allele is associated with decreased ADCY3 expression in brain cortex (slope −0.34, p = 3.5 × 10^-8) GTEx Portal
  • ADCY3 expression - cerebellar hemisphere (eQTL): The ALT allele is associated with decreased ADCY3 expression in cerebellar hemisphere (slope −0.20, p = 1.2 × 10^-5) GTEx Portal
  • DNAJC27 expression - whole blood (eQTL): The ALT allele is associated with increased DNAJC27 expression in whole blood (slope +0.21, p = 3.3 × 10^-6) GTEx Portal
  • CENPO expression - whole blood (eQTL): The ALT allele is associated with increased CENPO expression in whole blood (slope +0.30, p = 1.1 × 10^-8) GTEx Portal
  • ENSG00000309587 expression - hippocampus (eQTL): The ALT allele is associated with decreased expression of an uncharacterized gene (ENSG00000309587) in hippocampus (slope −0.61, p = 1.9 × 10^-6) GTEx Portal
  • ENSG00000309570 expression - frontal cortex and tibial nerve (eQTL): The ALT allele is associated with decreased expression of an uncharacterized gene (ENSG00000309570) in frontal cortex BA9 (slope −0.43, p = 1.0 × 10^-4) and tibial nerve (slope −0.27, p = 2.2 × 10^-5) GTEx Portal

Evidence quality The single GWAS examining this locus in a clinical context used a discovery cohort of 307 older adults - a modest sample by contemporary GWAS standards - and the study authors explicitly stated that no findings reached genome-wide significance (p < 5 × 10^-8); no replication cohort data are available in the provided text. The eQTL evidence from GTEx v11 (953 donors, FDR < 0.05) provides statistically robust evidence for tissue-specific regulatory effects of rs10204266, but eQTL signals reflect gene-expression changes rather than direct links to clinical outcomes and should not be interpreted as proof of disease causation. No between-study conflicts were identified; the divergence in ADCY3 expression direction across tissues (increased in blood, decreased in brain) is a single-dataset tissue-specific phenomenon rather than a contradiction. Overall, clinical association evidence is weak and preliminary; molecular expression evidence is moderate in confidence.

Tissue-specific expression effects

  • ADCY3: Increased expression in whole blood; reduced expression in brain cortex and cerebellar hemisphere - the ALT allele produces opposing regulatory effects in peripheral blood versus brain tissue GTEx Portal
  • DNAJC27: Increased expression in whole blood GTEx Portal
  • CENPO: Increased expression in whole blood GTEx Portal
  • ENSG00000309587 (uncharacterized gene): Reduced expression in hippocampus GTEx Portal
  • ENSG00000309570 (uncharacterized gene): Reduced expression in frontal cortex (BA9) and tibial nerve GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.

Lifestyle context

Concrete actions anchored to the cited research. We do not prescribe, we describe.

Discuss with your doctor

  • Antidepressant pharmacogenetic response Moderate

    The T allele of rs10204266 associates with improved symptom improvement rates on antidepressants in GWAS data

Frequently asked questions

What is rs10204266 associated with?

rs10204266 is located in the ADCY3-DNAJC27 genomic region and was examined in a genome-wide study of antidepressant response in older adults with depression. GTEx data also show it influences the expression of ADCY3, DNAJC27, and other nearby genes in a tissue-specific way.

What does the ADCY3 gene do?

ADCY3 encodes adenylate cyclase 3, an enzyme that produces cyclic AMP (cAMP), a key intracellular signaling molecule. cAMP pathways are involved in neuronal signaling and have been studied in relation to mood regulation and antidepressant mechanisms.

Is rs10204266 linked to depression or antidepressant response?

The ADCY3-DNAJC27 locus was examined in a genome-wide study of antidepressant remission in 307 older adults treated with venlafaxine, but no variant in this region reached genome-wide significance. The clinical association evidence is preliminary and has not been replicated.

Why does rs10204266 affect ADCY3 differently in blood versus brain?

GTEx eQTL data show the ALT allele increases ADCY3 expression in whole blood but decreases it in brain cortex and cerebellar hemisphere. This tissue-specific divergence reflects differences in gene regulatory environments across cell types and is a well-recognized phenomenon in human genetics.

What is an eQTL and why does it matter for rs10204266?

An eQTL (expression quantitative trait locus) is a genetic variant statistically associated with changes in how much a nearby gene is expressed. For rs10204266, eQTL data from GTEx show it regulates ADCY3, DNAJC27, and other nearby genes differently across tissues, providing mechanistic clues about possible biology - though eQTL effects alone do not prove disease causation.