rs9491696 — RSPO3

The Body-Shape Blueprint: How RSPO3 Determines Where Fat Goes

The shape of your body — whether fat accumulates at the waist or at the hips — is not purely a matter of diet and exercise. A robust body of genetic research has identified RSPO3 (R-spondin 3) as the single strongest genetic determinant of waist-to-hip ratio adjusted for BMI¹¹ waist-to-hip ratio adjusted for BMI
WHRadjBMI — a measure of fat distribution that is independent of total body fatness; it captures whether fat concentrates in the abdomen (android) or hips and thighs (gynoid), a trait that independently predicts cardiometabolic disease beyond obesity itself. The rs9491696 variant within RSPO3 is one of two independent GWAS signals at this locus and is in high linkage disequilibrium (r² = 0.89) with the sentinel proxy variant rs1936807. Together, these signals explain a meaningful portion of the variance in human body shape, with effects that are substantially stronger in women than in men.

The Mechanism

RSPO3 encodes a secreted R-spondin protein²² R-spondin protein
R-spondins (RSPO1-4) are a family of secreted glycoproteins that potentiate WNT signaling by binding LGR4/5/6 receptors, blocking the ubiquitin ligases RNF43 and ZNRF3, and thereby keeping Frizzled WNT receptors at the cell surface. WNT/beta-catenin signaling is a potent suppressor of adipogenesis: when WNT signaling is active, preadipocytes are directed away from fat-cell fate. RSPO3 amplifies this WNT brake in a depot-specific fashion.

The rs9491696 G allele lies within intron 1 of RSPO3 and falls in an adipocyte enhancer region. Mechanistic studies using allele-specific expression analyses and formal co-localisation with adipose cis-eQTLs confirmed that the G allele increases RSPO3 expression specifically in mature adipocytes and in abdominal subcutaneous adipose tissue. The downstream effects are strikingly depot-specific. In gluteal (hip/thigh) progenitors³³ gluteal (hip/thigh) progenitors
Gluteofemoral fat — the fat depot at hips, buttocks, and thighs — is considered metabolically protective, releasing anti-inflammatory adipokines and sequestering atherogenic lipids away from visceral organs, higher RSPO3 suppresses adipogenesis and increases susceptibility to apoptosis — meaning fewer, larger gluteal fat cells are formed and they die more readily. In abdominal progenitors, the same RSPO3 signal stimulates proliferation. The net effect: fat shifts from the lower body to the abdomen, increasing the waist-to-hip ratio. This explains why G allele carriers tend toward an apple shape rather than a pear shape, independent of how much total fat they carry.

Estrogen appears to suppress RSPO3 expression in females, which may partly explain why women generally carry more lower-body fat than men. When estrogen levels fall after menopause, RSPO3 expression rises, contributing to the central fat redistribution that accompanies the menopausal transition — a shift that carries increased cardiovascular risk.

The Evidence

The RSPO3 locus was first identified by Heid et al. 2010⁴⁴ Heid et al. 2010
Meta-analysis of 32 GWAS with up to 77,167 participants plus follow-up in up to 113,636 individuals; the RSPO3 locus was the strongest signal genome-wide for WHRadjBMI as the strongest genetic determinant of WHRadjBMI. Seven of the 13 loci identified showed marked sexual dimorphism, all with stronger effects in women. This was replicated in the larger Shungin et al. 2015⁵⁵ Shungin et al. 2015
Meta-analysis in 224,459 individuals of European and other ancestries; identified 49 novel WHRadjBMI loci on top of the 2010 findings meta-analysis (224,459 individuals), and in the most powerful analysis to date, Pulit et al. 2019⁶⁶ Pulit et al. 2019
694,649 individuals; identified 463 independent signals in 346 loci, the largest genetic atlas of body fat distribution published (694,649 participants), which confirmed RSPO3 among the most significant hits.

The mechanistic connection was established by Loh et al. 2020⁷⁷ Loh et al. 2020
Mechanistic study combining GWAS, adipose eQTL co-localisation, allele-specific expression, in vitro knockout in human adipose progenitors from multiple depots, and zebrafish rspo3 mutant models; published in Nature Communications: rs9491696 and the primary signal rs72959041 both increase RSPO3 expression in subcutaneous adipocytes. The WHRadjBMI-increasing G allele was associated with reduced leg fat mass and an increase in android fat. In vitro, RSPO3 knockdown in gluteal progenitors enhanced adipogenesis, while RSPO3 knockdown in abdominal progenitors suppressed proliferation — confirming opposite depot roles. The android/gynoid fat ratio showed a significant association (beta = 0.03, p = 0.0008) in Oxford Biobank analyses. Zebrafish rspo3 mutants displayed altered fat distribution patterns consistent with the human data.

Relevance to lipedema: a GWAS of an inferred lipedema phenotype⁸⁸ GWAS of an inferred lipedema phenotype
24,450 cases and 165,227 controls from the UK Biobank, defined by high leg fat percentage with small waist; 18 genome-wide significant loci identified in the UK Biobank identified the RSPO3 locus (rs72959041, OR = 1.24, p = 2.7×10⁻¹⁹) among 18 loci associated with the lipedema phenotype. This directly links RSPO3's role in promoting lower-body fat loss to the pathological absence of that fat redistribution seen in lipedema, where gynoid fat is locked in place and resistant to mobilization. The RSPO3 locus was among several WHRadjBMI loci known to exert stronger effects in women.

Additionally, the RSPO3 locus demonstrates pleiotropy⁹⁹ pleiotropy
Pleiotropy occurs when a single genetic variant affects multiple biological traits; RSPO3 variants affect both adipose and skeletal tissues through the shared WNT pathway across adipose and skeletal tissues: RSPO3 variants also associate with trabecular bone mineral density and fracture risk, with the fracture-reducing allele associated with increased RSPO3 expression and greater trabecular bone density. This has implications for G allele carriers: the same variant that shifts fat toward the abdomen may confer modest skeletal benefits.

Practical Actions

For G allele carriers — particularly women — the actionable implications focus on three areas: monitoring cardiometabolic risk markers that android fat distribution worsens, counteracting abdominal fat accumulation through dietary approaches that target visceral/subcutaneous abdominal fat specifically, and understanding that body-shape changes with menopause (or other estrogen-depleted states) are partly genetically driven and predictable.

DEXA body composition scans, which measure the android/gynoid fat ratio directly, provide genotype-relevant feedback: G allele carriers with a high android/gynoid ratio are expressing their genotype and face higher cardiometabolic risk than overall BMI alone suggests. Fasting insulin and triglyceride/HDL ratio are the most genotype-relevant biomarkers to monitor, as the RSPO3 variants are specifically associated with insulin-resistant phenotypes in GWAS studies.

For CC homozygotes (no G allele), fat distribution tends toward the gynoid (pear) pattern. In the context of lipedema research, the CC genotype represents the direction in which RSPO3 activity is lower — allowing more lower-body fat accumulation. This is consistent with the lipedema phenotype, though lipedema involves multiple genetic and biological factors beyond this single locus.

Interactions

rs9491696 is one of two independent GWAS signals at the RSPO3 locus; the other is rs72959041 (the primary/sentinel signal). These two SNPs are not in complete LD with each other (they represent independent signals adjustable for each other), so carriers of both risk alleles may have additive effects on WHRadjBMI. The mechanistic study confirmed both signals act through increased RSPO3 expression in adipocytes.

The RSPO3 locus also shares the WNT pathway with other fat distribution and lipedema-related loci identified in GWAS. GRB14-COBLL1¹⁰¹⁰ GRB14-COBLL1
A locus associated with WHRadjBMI and replicated in the clinical lipedema GWAS; GRB14 modulates insulin receptor signaling in adipose tissue and VEGFA¹¹¹¹ VEGFA
Vascular endothelial growth factor A; associated with fat distribution and replicated in clinical lipedema GWAS; may influence adipose vascularization and lymphatic function loci identified in the lipedema phenotype GWAS may compound RSPO3 effects, as these pathways collectively regulate adipose progenitor differentiation, vascular support, and insulin sensitivity.

Supervisor note — candidate compound action: individuals carrying the risk (G) allele at rs9491696 and the risk allele at rs72959041 (the sentinel RSPO3 signal) represent the highest-RSPO3-expression genotype at this locus. These two signals are conditionally independent and additive; combined carriers may have the greatest shift toward android fat distribution and the highest associated insulin resistance risk at this locus. A compound recommendation targeting insulin sensitivity monitoring (fasting insulin, HOMA-IR, triglyceride/HDL ratio) along with abdominal fat tracking via DEXA would be appropriate for this combination.