rs78534766 — ADCY7 ADCY7 D439E

Low-frequency missense variant in adenylyl cyclase 7 that reduces cAMP synthesis by 40%, skews immune cells toward a pro-inflammatory Th2 phenotype, and is the strongest non-HLA coding risk factor for ulcerative colitis and autoimmune thyroid disease

See your personal result for ADCY7

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

The Immune Brake That Shapes Thyroid Risk

Every cell in your immune system uses cyclic AMP (cAMP) as a molecular brake pedal — a second messenger that dials down inflammatory activation and keeps immune responses proportionate. Adenylyl cyclase 7 (ADCY7) is the enzyme that produces cAMP in lymphocytes11 lymphocytes
white blood cells that orchestrate adaptive immunity, myeloid cells, and thyroid epithelium. The rs78534766 variant swaps one amino acid in ADCY7 (aspartate 439 → glutamate) and cuts the enzyme's cAMP output by roughly 40% — loosening the brake on immune activation.

This is a rare variant. Only about 1 in 100 people of European descent carries even one copy. But when it does occur, the effect is large enough that it stands out in studies involving tens of thousands of people, ranking among the most significant non-HLA coding effects identified in autoimmune disease genetics.

The Mechanism

When ADCY7 carries the D439E substitution, the protein still reaches the cell membrane but produces substantially less cAMP in response to G protein-coupled receptor signals — including the TSH receptor22 TSH receptor
thyroid-stimulating hormone receptor, the primary driver of thyroid cell growth and function on thyroid epithelial cells and immune receptors on T cells and macrophages.

Without adequate cAMP signaling, immune cells shift toward a Th2 phenotype33 Th2 phenotype
T-helper 2 pattern: characterised by interleukin-4, IL-5, and IL-13 production, which promotes allergic and certain autoimmune responses and simultaneously upregulate surface expression of MHC class II molecules and CD86 (a co-stimulatory signal). The combined effect — more antigen presentation, more co-stimulatory signal, Th2-polarised cytokine environment — creates conditions that favour inappropriate immune activation against self-antigens, including thyroid peroxidase and thyroglobulin.

The Evidence

The initial discovery came from a 2017 whole-genome sequencing study of 16,432 inflammatory bowel disease cases and 18,843 controls by Luo et al.: the ADCY7 missense variant (0.6% MAF) doubled ulcerative colitis risk44 the ADCY7 missense variant (0.6% MAF) doubled ulcerative colitis risk and was the most significant non-HLA coding association in the dataset (OR ≈ 2.0–2.16; p = 1×10⁻¹⁴). The same variant has since been replicated in the GWAS Catalog with an OR of 2.16 [1.77–2.62] for ulcerative colitis across independent cohorts.

In parallel, thyroid disease GWAS studies identified the same variant. A 2024 autoimmune hypothyroidism GWAS by Reeve et al. lists ADCY7 among established coding variants with OR 1.46 for autoimmune thyroid disease55 OR 1.46 for autoimmune thyroid disease (p = 1×10⁻¹⁴). The 2025 Nature Genetics GWAS by Rand et al. (113,393 hypothyroidism cases, 1,065,268 controls)66 (113,393 hypothyroidism cases, 1,065,268 controls) — the largest hypothyroidism genetic study to date — independently confirms the ADCY7 locus at p = 1×10⁻¹⁶.

Mechanistic confirmation came from Cardinale et al. in 2025: cell-based experiments showed the D439E protein retains membrane localisation but produces 40% less cAMP77 cell-based experiments showed the D439E protein retains membrane localisation but produces 40% less cAMP. ADCY7 knockdown in immune cells replicated the molecular phenotype — Th2 cytokine skewing and elevated MHC class II + CD86 — explaining the autoimmune predisposition. The authors proposed that enhancing cAMP production (by direct ADCY7 activation or phosphodiesterase inhibition) could be a therapeutic strategy.

Population data shows the A allele is absent in East Asian populations and very rare in African populations, with the highest frequency (~0.6%) in Europeans. Eosinophil counts are also elevated in carriers (GWAS effect 0.097 SD/allele), consistent with a Th2-shifted immune baseline.

Practical Actions

Carrying the A allele means your ADCY7 enzyme is operating at roughly 60% of its normal cAMP-generating capacity. This has two practical implications: (1) earlier and more regular thyroid screening is warranted, since the same immune dysregulation that raises ulcerative colitis risk also raises autoimmune thyroid disease risk; and (2) thyroid peroxidase antibody testing identifies autoimmune thyroid disease years before TSH levels shift.

Selenium has a specific, well-documented role in reducing thyroid peroxidase antibody titres in autoimmune thyroiditis. This is a genuinely genotype-relevant recommendation: the A allele creates an immune environment that promotes antibody-mediated thyroid attack, and selenium supplementation targets exactly that mechanism by supporting selenoprotein-based antioxidant defence in thyroid tissue.

If diagnosed with Hashimoto's thyroiditis or early hypothyroidism, monitoring the free T4/T3 ratio alongside TSH is useful — the GWAS data shows A allele carriers who receive levothyroxine treatment require larger dose adjustments (beta 0.45 dose units; GWAS Catalog GCST90042535), suggesting altered thyroid hormone sensitivity or clearance.

Interactions

The strongest interaction of interest is with other autoimmune loci. Carriers of the ADCY7 A allele who also carry risk variants at immune checkpoint genes (PTPN22 rs2476601, TYK2, IFIH1) face a compounded autoimmune predisposition. These interactions are not yet quantified in published compound heterozygosity studies, but the biological logic is clear — multiple immune regulatory defects are additive.

The ADCY7 variant also shares its cAMP-regulatory pathway with adenylyl cyclase isoforms expressed in the thyroid, suggesting potential interactions with TSH receptor signalling variants (e.g., rs4704397 in PDE8B, which regulates TSH-driven cAMP clearance). Whether carrying both variants additively impairs thyroid cAMP signalling awaits direct study.

Genotype Interpretations

What each possible genotype means for this variant.

CC Normal ADCY7 Activity Normal

Full adenylyl cyclase 7 activity — standard autoimmune and thyroid risk

You carry two copies of the common C allele at rs78534766. Your ADCY7 enzyme produces cAMP at normal capacity in immune cells and thyroid tissue, maintaining standard immune regulation. About 99% of people share this genotype.

AC Reduced ADCY7 Activity Reduced

One copy of the ADCY7 D439E variant — elevated autoimmune and thyroid risk

The D439E substitution reduces ADCY7's cAMP output while leaving its membrane localisation intact. In immune cells, lower cAMP biases cytokine production toward the Th2 pattern (IL-4, IL-5, IL-13) and increases surface expression of MHC class II and CD86 — both signals that lower the threshold for autoreactive T cell activation. In thyroid tissue, reduced TSH-driven cAMP signalling may alter follicular cell regulation.

The downstream consequences include increased susceptibility to autoimmune thyroid conditions (Hashimoto's thyroiditis, Graves' disease) and inflammatory bowel disease. The GWAS Catalog records levothyroxine dose requirement as an additional association (GCST90042535, beta 0.45 dose units), suggesting that A allele carriers who develop hypothyroidism may need higher or more carefully titrated replacement doses. Annual thyroid antibody testing (anti-TPO) catches autoimmune thyroid disease years before TSH values leave the reference range.

AA Homozygous D439E High Risk

Two copies of the ADCY7 D439E variant — substantially elevated autoimmune risk

With two D439E copies, both ADCY7 alleles produce reduced cAMP. The molecular consequences described for heterozygotes — Th2 skewing, elevated MHC class II, increased CD86 co-stimulatory signalling — apply with greater magnitude. Published mechanistic data specifically for AA homozygotes is limited because the genotype is so rare, but additive genetic models for this variant are supported by the GWAS data.

Proactive thyroid antibody monitoring, early levothyroxine titration if hypothyroidism develops, and gastroenterology awareness are all warranted. Genetic counselling is appropriate if you are considering IVF or reproductive planning, as rare autoimmune variants can have relevance for family health.