rs3801387 — WNT16

WNT16 and Cortical Bone Strength — A Key Determinant of Fracture Risk

The WNT16 gene encodes a signaling protein¹¹ signaling protein
WNT16 is a member of the Wingless-related integration site (WNT) family of secreted glycoproteins that regulate bone homeostasis crucial for bone development and maintenance. Among all the WNT family members, WNT16 stands out for its specific and powerful effect on cortical bone — the dense outer layer of bone that provides structural strength and accounts for about 80% of the skeleton's mass. The rs3801387 variant lies in the last intron of WNT16 and is part of a regulatory region²² regulatory region
The variant is in high linkage disequilibrium with other functional variants including eQTLs that affect WNT16 and neighboring gene expression that influences how much WNT16 protein your bone cells produce.

The Mechanism

WNT16 is primarily expressed by osteoblasts³³ primarily expressed by osteoblasts
bone-forming cells lining the cortical bone surface, where it plays a dual role in maintaining bone strength. First, it acts directly on osteoclast precursors to inhibit their differentiation into bone-resorbing osteoclasts through a non-canonical signaling pathway. Second, it increases expression of osteoprotegerin (OPG) in osteoblasts, which acts as a decoy receptor for RANKL, further suppressing osteoclastogenesis. The net result is reduced bone resorption on the inner (endocortical) surface, preserving cortical thickness.

The rs3801387 variant affects this system through regulatory mechanisms. The A allele is associated with lower bone mineral density⁴⁴ A allele is associated with lower bone mineral density, while the G allele appears protective, correlating with higher BMD and thicker cortical bone. In a region of high linkage disequilibrium spanning WNT16 and the adjacent FAM3C gene, rs3801387 tags multiple functional variants that influence gene expression. This makes rs3801387 a reliable proxy for overall WNT16 function, which is why it has emerged as the sentinel SNP in multiple GWAS⁵⁵ sentinel SNP in multiple GWAS for bone traits.

The Evidence

Multiple large-scale studies have established rs3801387's role in bone health. A GWAS meta-analysis of cortical bone thickness in 5,878 individuals⁶⁶ GWAS meta-analysis of cortical bone thickness in 5,878 individuals identified WNT16 variants associated with both cortical thickness and forearm BMD at genome-wide significance (P = 6.2×10⁻⁹ for cortical thickness). The study also demonstrated association with forearm fracture risk (OR = 1.33 for fractures, P = 7.3×10⁻⁹). A meta-analysis restricted to premenopausal women (n=4,061)⁷⁷ meta-analysis restricted to premenopausal women (n=4,061) found rs3801387 reached genome-wide significance for lumbar spine BMD (P = 1.7×10⁻⁹ in discovery, improving to P = 1.3×10⁻¹¹ in joint analysis). Each copy of the minor G allele was associated with approximately 0.16 SD higher BMD, explaining 0.6-1.8% of BMD variance.

Functional validation came from Wnt16 knockout mice⁸⁸ Wnt16 knockout mice, which developed spontaneous fractures due to 27% thinner cortical bone and high cortical porosity. Bone strength was reduced by 43-61% at both femur and tibia. Critically, trabecular (spongy) bone was unaffected, confirming WNT16's cortical-specific role. The effect persists through the lifespan — conditional inactivation in adult mice⁹⁹ conditional inactivation in adult mice showed that WNT16 continues to regulate cortical thickness even after peak bone mass is achieved, suggesting interventions targeting this pathway could benefit older adults.

Interestingly, the effect of rs3801387 may interact with mechanical loading. A study of male endurance runners¹⁰¹⁰ male endurance runners found AA genotype runners had 14% lower lumbar spine BMD than AA genotype non-athletes (P < 0.001), while AG+GG genotype runners actually had 5% higher leg BMD than non-athletes. This suggests that in individuals with lower baseline WNT16 function (AA genotype), the repetitive loading of endurance running may not adequately compensate for reduced WNT16-mediated osteoclast suppression.

Practical Implications

Your genotype at rs3801387 provides insight into your cortical bone health trajectory, particularly your risk of non-vertebral fractures — those occurring at the hip, wrist, and other sites rich in cortical bone. Non-vertebral fractures cause enormous disability and mortality in older adults, yet existing osteoporosis treatments have only marginally reduced their incidence compared to the dramatic reductions seen for vertebral fractures. Understanding your genetic predisposition allows for earlier and more targeted preventive measures.

If you carry the AA genotype (higher risk), optimizing peak bone mass in early adulthood and minimizing bone loss thereafter becomes especially important. This means ensuring adequate calcium (1,000-1,200 mg/day) and vitamin D (800-1,000 IU/day for adults over 50) throughout life. Weight-bearing exercise ¹¹¹¹ Weight-bearing exercise is the single best intervention for cortical bone, as mechanical loading stimulates periosteal (outer surface) bone formation. For AA individuals who participate in high-volume endurance exercise, monitoring bone density and potentially incorporating resistance training may be particularly important.

Because WNT16 specifically affects cortical bone, standard DEXA scans of the hip and forearm (cortical-rich sites) are more informative than lumbar spine scans for monitoring your bone health trajectory. Consider establishing a baseline BMD measurement in your 40s if you have the AA genotype and additional risk factors (family history, low body weight, smoking, glucocorticoid use).

Interactions

Rs3801387 is in high linkage disequilibrium with other WNT16 variants including two missense SNPs (rs2707466 Thr>Ile and rs2908004 Gly>Arg) and rs7776725 in the adjacent FAM3C gene. These variants form haplotype blocks where the minor alleles generally cluster together and have a protective effect on BMD. When assessing bone health risk, consider that these variants act as a functional unit rather than independent factors.

WNT16 is part of the broader WNT signaling pathway, which includes other bone-related genes identified in GWAS such as LRP5, SOST, DKK1, and RANKL. However, WNT16's effect is uniquely cortical-specific, distinguishing it from pathway members that affect trabecular bone. This suggests that individuals with risk variants in both WNT16 and trabecular-affecting genes (like SOST) may face compounded fracture risk across multiple skeletal sites.

The interaction between rs3801387 genotype and vitamin D status deserves attention. A study in adolescents found multi-locus interactions between WNT16 rs3801387, vitamin D receptor (VDR), and vitamin D binding protein (VDBP) variants affecting serum vitamin D levels and bone quality ¹²¹² multi-locus interactions between WNT16 rs3801387, vitamin D receptor (VDR), and vitamin D binding protein (VDBP) variants affecting serum vitamin D levels and bone quality . While this finding needs replication, it suggests that individuals with the AA genotype may derive particular benefit from maintaining optimal vitamin D status, as the two systems appear to interact in regulating bone homeostasis.