rs71575922 — SYNE1 SYNE1 Endometriosis Pain Subphenotype Variant

SYNE1 at 6q25.1 — When Endometriosis Pain Has a Neurological Signature

Endometriosis affects roughly 1 in 10 women of reproductive age, yet the severity of pain symptoms varies enormously among those who carry the disease. A woman with minimal lesion burden may be disabled by pain, while another with extensive disease reports few symptoms. The emerging explanation for this paradox lies partly in genetics: specific variants do not merely increase the risk of developing endometriosis — they shape which kind of endometriosis a woman develops, and specifically whether pain mechanisms are amplified beyond the lesions themselves. SYNE1¹¹ SYNE1
Spectrin Repeat Containing Nuclear Envelope Protein 1; also known as Nesprin-1; encodes a large scaffolding protein that tethers the nucleus to the cytoskeleton in muscle and nerve cells at chromosome 6q25.1 is one such variant locus — its lead SNP rs71575922 is most strongly enriched in women whose endometriosis presents with severe dysmenorrhea and dyspareunia.

The Mechanism

SYNE1 encodes Nesprin-1, a giant spectrin-repeat protein that spans the outer nuclear envelope and connects it to the actin cytoskeleton and microtubule network via the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex. In neurons, Nesprin-1 is essential for nuclear positioning during axonal development and for maintaining synaptic architecture. Pathogenic coding mutations in SYNE1 cause autosomal recessive cerebellar ataxia type 8 (SCAR8), confirming the gene's fundamental role in neuronal function.

The rs71575922 G allele is an intronic regulatory variant — it does not alter the Nesprin-1 protein sequence but likely modulates SYNE1 expression or isoform splicing in relevant cell types. The 6q25.1 locus shows expression quantitative trait locus (eQTL) effects in endometrial and neural tissue. The biological plausibility for pain-subphenotype enrichment is strong: endometriosis lesions recruit sensory nerve fibres from surrounding tissue, and the degree of nerve fibre ingrowth, pelvic floor neuromuscular dysfunction, and central sensitization that follows is shaped by the molecular architecture of neuronal and smooth muscle cells — precisely the cell types where SYNE1/Nesprin-1 expression matters most.

The Evidence

The SYNE1 6q25.1 locus was first identified as genome-wide significant for endometriosis in the Sapkota et al. 2017 meta-analysis²² Sapkota et al. 2017 meta-analysis
17,045 cases, 191,596 controls across 11 GWAS datasets; five novel loci discovered including SYNE1, FN1, CCDC170, ESR1, and FSHB; together these explained up to 5.19% of disease variance.

The Rahmioglu et al. 2023 mega-GWAS³³ Rahmioglu et al. 2023 mega-GWAS
60,674 cases, 701,926 controls of European and East Asian descent; 42 genome-wide significant loci comprising 49 distinct signals; genes regulated at pain-associated loci include NGF, BSN, GDAP1, and MLLT10; significant genetic correlation with 11 pain conditions including migraine and multisite chronic pain confirmed the SYNE1 locus and demonstrated a striking pattern: the 6q25.1 signal was disproportionately enriched in the pain subphenotype analyses. Women with endometriosis carrying the G allele showed substantially higher odds of reporting dysmenorrhea (OR ~1.49) and dyspareunia (OR ~2.07) compared to an overall endometriosis OR of approximately 1.11, indicating that this variant is more a determinant of pain severity and type than of lesion development per se.

The 2023 study also found significant genetic correlations between endometriosis and 11 other pain conditions — migraine, back pain, multisite chronic pain — and substantial sharing of variants underlying these comorbidities. The SYNE1 locus participates in this shared pain architecture, consistent with a central sensitization or neuromuscular mechanism amplifying pelvic nociception beyond what the lesions alone would predict.

Practical Actions

The clinical implication of carrying the G allele is a shift in treatment framing: pain management for G-allele carriers should not rely exclusively on hormonal suppression or surgical lesion removal, because the pain pathway extends into the pelvic floor musculature and central nervous system. Pelvic floor physiotherapy specifically targets the neuromuscular dysfunction that accompanies endometriosis-associated dyspareunia — a randomised controlled trial by Del Forno et al. 2021⁴⁴ randomised controlled trial by Del Forno et al. 2021
n=34 women with deep infiltrating endometriosis; PFP vs waitlist control; median NRS score for dyspareunia decreased by 3 points in the treatment group vs 0 in controls (p<0.01); pelvic floor muscle relaxation measurably improved on 3D/4D ultrasound demonstrated significant dyspareunia reduction with this approach.

Neuromodulatory pain management — including TENS (transcutaneous electrical nerve stimulation), pain psychology, and evaluation for central sensitization — should be discussed with a specialist if pain persists after standard treatment, because the neurological contribution to pain is a primary mechanism at this genetic locus, not a secondary complication.

Tracking pain subphenotypes (separately documenting dysmenorrhea intensity vs. dyspareunia vs. non-cyclical pelvic pain vs. dyschezia) is particularly valuable for G-allele carriers because the phenotype profile guides treatment selection: predominantly myofascial and penetrative pain points toward pelvic floor PT; predominantly cyclical dysmenorrhea with central spread may respond better to combined hormonal and neuromodulatory approaches.

Interactions

The SYNE1 rs71575922 locus interacts genetically with other endometriosis risk loci in the context of the overall pain phenotype. The 2023 Rahmioglu meta-analysis identified substantial genetic overlap between endometriosis pain variants and variants for migraine and multisite chronic pain — suggesting that women carrying both SYNE1 G and migraine-susceptibility variants (e.g. rs1835740 near MTDH) may experience more pronounced central sensitization. No compound action is proposed here without specific published interaction data at the genotype level, but this locus should be evaluated together with other pelvic pain and neurological pain variants when interpreting a full genetic profile.