rs11590235 — SKI

TGF-beta signaling regulator variant identified as the top shared locus between migraine and type 2 diabetes

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The TGF-Beta Gatekeeper Linking Inflammation, Migraine, and Metabolic Disease

The SKI proto-oncogene encodes a transcriptional co-repressor that acts as one of the most potent negative regulators of the TGF-beta signaling pathway11 TGF-beta signaling pathway
TGF-beta (Transforming Growth Factor-beta) controls cell proliferation, differentiation, apoptosis, and immune regulation throughout the body. The rs11590235 variant, located within an intron of SKI on chromosome 1p36.33, achieved the highest statistical significance of any shared locus between migraine and type 2 diabetes in a large cross-trait GWAS meta-analysis (P = 3.11 x 10-12).

The Mechanism

SKI protein binds directly to SMAD proteins, which are the intracellular signal transducers of TGF-beta. By disrupting SMAD2/SMAD4 complexes and recruiting histone deacetylases (HDACs), SKI keeps TGF-beta target genes silenced under basal conditions. When TGF-beta signaling is activated (by injury, inflammation, or metabolic stress), SKI is degraded, allowing target gene expression. 22 SKI and the related protein SnoN constitute a small family of nuclear oncoproteins that modulate the cellular response to TGF-beta superfamily ligands

The Evidence

The cross-trait GWAS meta-analysis33 cross-trait GWAS meta-analysis
Siewert-Rocks et al. Genetic Overlap Analysis Identifies a Shared Etiology between Migraine and Headache with Type 2 Diabetes. Genes, 2022 identified rs11590235 at the SKI locus as the most significant of 23 novel shared loci between migraine and T2D, with concordant risk effects (migraine OR 1.05, T2D OR 1.05 for the T allele). The signal was robust with P = 3.11 x 10-12, far exceeding genome-wide significance.

A complementary study44 complementary study
Islam et al. Cross-trait analyses identify shared genetics between migraine, headache, and glycemic traits. Hum Genet, 2023 identified pleiotropic regions between migraine and fasting insulin, fasting glucose, and glycated haemoglobin. Mendelian randomisation analyses suggested increased fasting proinsulin levels may causally decrease the risk of headache.

The T allele is notably rare in East Asian (0.1%) and African (1.3%) populations but more common in South Asians (8.1%) and Europeans (6.0%).

Practical Actions

Carriers may benefit from monitoring glycemic biomarkers to detect early metabolic changes.

Interactions

TGF-beta signaling intersects with insulin signaling at multiple nodes, including SMAD-mediated regulation of glucose transporter expression and pancreatic beta-cell function. Carriers who also have TCF7L2 risk alleles (rs7903146) may experience compounding effects on diabetes risk through independent but converging pathways.

Genotype Interpretations

What each possible genotype means for this variant.

CC Normal TGF-Beta Regulation Normal

Standard SKI-mediated TGF-beta pathway control

You carry two copies of the common C allele at this SKI locus. Your TGF-beta signaling pathway has normal regulation through the SKI co-repressor. About 91% of the global population shares this genotype. Your baseline vascular and inflammatory signaling through TGF-beta operates at standard levels.

CT Altered TGF-Beta Balance Intermediate

One copy shifts TGF-beta regulation with shared migraine-metabolic risk

SKI is a key negative regulator of TGF-beta signaling. The T allele at rs11590235 was identified with the strongest cross-trait signal (P = 3.11 x 10-12) between migraine and type 2 diabetes, with concordant odds ratios of 1.05 for both conditions. TGF-beta signaling plays central roles in vascular smooth muscle function, endothelial integrity, and pancreatic beta-cell regulation.

TT Strongly Altered TGF-Beta Balance High Risk

Two copies significantly shift TGF-beta signaling with elevated migraine-metabolic risk

Homozygous TT carriers at rs11590235 have the maximum genetic loading at the most significant shared migraine-T2D locus identified to date. SKI normally acts as a brake on TGF-beta signaling. The rarity of this genotype means direct clinical data is limited.