rs2180439 — WNT10A

The 20p11 Hair Loss Hotspot — Beyond Androgens

Male pattern baldness has long been blamed on testosterone and genes inherited from your mother's side. But the discovery of rs2180439 represents a paradigm shift¹¹ rs2180439 represents a paradigm shift
Hillmer et al. Susceptibility variants for male-pattern baldness on chromosome 20p11. Nature Genetics 2008: this variant on chromosome 20 is inherited from either parent and appears to drive hair loss through a pathway completely independent of androgens. The 20p11 locus, where this SNP resides, is the strongest autosomal (non-sex chromosome) genetic risk factor for androgenetic alopecia, with the T allele increasing risk approximately 1.8-fold per copy.

Located in the intergenic region between PAX1 and FOXA2 genes, rs2180439 sits at the epicenter of a genomic region that has been replicated in GWAS studies across European²² GWAS studies across European
Hillmer et al. 2008, Chinese³³ Chinese
Liang et al. 2013, Korean⁴⁴ Korean
Kim et al. 2017, and Australian populations⁵⁵ Australian populations
Richards et al. 2008. The TT genotype confers approximately 6-fold increased risk compared to CC carriers, and critically, this locus shows no statistical interaction with the androgen receptor gene⁶⁶ this locus shows no statistical interaction with the androgen receptor gene
meaning its effects are additive and operate through a distinct biological mechanism.

The Mechanism

While the exact causal variant and gene remain under investigation, the 20p11 region likely influences hair follicle biology through Wnt signaling pathways. FOXA2, located near rs2180439, binds to the WNT7b promoter⁷⁷ FOXA2, located near rs2180439, binds to the WNT7b promoter
and regulates hair-inductive activity in follicular keratinocytes. Wnt/β-catenin signaling is the master regulator of hair follicle cycling, controlling the transition between growth (anagen), regression (catagen), and rest (telogen) phases. Disruption of Wnt signaling leads to premature entry into catagen and follicular miniaturization — the hallmark of androgenetic alopecia.

The WNT10A gene, though not immediately adjacent to rs2180439, is a plausible candidate given its well-established role in hair biology. WNT10A is expressed in the inner root sheath and matrix during anagen⁸⁸ WNT10A is expressed in the inner root sheath and matrix during anagen
and mutations in WNT10A cause ectodermal dysplasia with sparse hair. Hair follicle stem cells upregulate WNT10A expression to activate stem cells⁹⁹ Hair follicle stem cells upregulate WNT10A expression to activate stem cells
making it essential for initiating hair growth cycles. The rs2180439 variant may affect regulatory elements that modulate WNT10A or other Wnt pathway genes, tipping the balance toward follicle quiescence and miniaturization.

The Evidence

The original 2008 genome-wide association study by Hillmer and colleagues¹⁰¹⁰ 2008 genome-wide association study by Hillmer and colleagues
scanned 296 early-onset male pattern baldness cases and 347 controls, identifying five SNPs on chromosome 20p11 reaching genome-wide significance, with rs2180439 as the lead variant (combined P = 2.7 × 10⁻¹⁵). The effect was most pronounced in men with early-onset baldness before age 40. A simultaneous study by Richards et al.¹¹¹¹ A simultaneous study by Richards et al.
replicated the 20p11 association in 1,125 men across four European cohorts, finding that the 14% of men carrying risk alleles at both 20p11 and the androgen receptor locus have a 7-fold increased risk of baldness (OR = 7.12, P = 3.7 × 10⁻¹⁵).

Critically, the 20p11 association has been validated beyond European populations. In 445 Chinese Han cases and 546 controls¹²¹² In 445 Chinese Han cases and 546 controls
rs2180439 showed highly significant association (P = 1.29 × 10⁻¹⁰), with conditional analysis demonstrating that rs2180439 drives the association of other SNPs in the region. A 2012 meta-analysis of 12,806 individuals¹³¹³ A 2012 meta-analysis of 12,806 individuals
confirmed 20p11 as one of the six most strongly associated loci for early-onset AGA, explaining approximately 13.7% of the variance when combined with other known loci.

Interestingly, the 20p11 locus shows sex-specific effects. When tested in female pattern hair loss¹⁴¹⁴ When tested in female pattern hair loss
the association did not replicate in 82 Chinese women, suggesting that the genetic architecture of hair loss differs between sexes, or that female pattern hair loss represents a distinct entity from male androgenetic alopecia.

Practical Implications

Unlike the androgen receptor variants that affect response to DHT, the 20p11 variants appear to operate through Wnt signaling, suggesting that Wnt pathway modulators might be therapeutic targets¹⁵¹⁵ Wnt pathway modulators might be therapeutic targets
particularly for individuals carrying TT genotypes at rs2180439. Current FDA-approved treatments (finasteride and minoxidil) target androgen metabolism and blood flow respectively, but neither directly addresses Wnt pathway dysfunction.

The TT genotype indicates genetic predisposition to early hair loss that operates independently of androgen sensitivity. This means that even with normal androgen levels and androgen receptor function, individuals with TT genotypes face elevated risk of follicular miniaturization. Hair density monitoring starting in early adulthood allows for early intervention, and miniaturization can be detected via densitometry years before visible thinning¹⁶¹⁶ miniaturization can be detected via densitometry years before visible thinning
when preventive treatments are most effective.

The additive nature of genetic risk means that rs2180439 should be considered alongside other known hair loss variants, particularly those affecting the androgen receptor. While genetic testing cannot predict with certainty who will experience severe baldness, the TT genotype at rs2180439 is one of the strongest single autosomal predictors and may warrant earlier monitoring and intervention discussions with a dermatologist.

Interactions

The 20p11 locus (rs2180439) combines additively with the X-chromosomal androgen receptor variants (particularly rs1160312 and nearby SNPs) to produce markedly increased risk. Men carrying both 20p11 TT genotypes and AR risk alleles face up to 7-fold increased odds of early-onset baldness. These loci operate through independent mechanisms — AR through androgen sensitivity, 20p11 through Wnt signaling dysfunction — meaning their effects compound rather than interact statistically. Other 20p11 SNPs in tight linkage disequilibrium with rs2180439 (rs1160312, rs6113491, rs201571, rs1998076) represent the same genetic signal rather than independent risk factors.