rs9921222

badMag 4.5

This is a intron variant variant in the AXIN1 gene.

Key Literature Trait Associations

Bone Mineral Density

rs9921222 is an intronic variant of AXIN1, a scaffold protein in the beta-catenin destruction complex that acts as a negative regulator of WNT signaling. The T allele creates a higher-affinity binding site for GATA4 and estrogen receptor alpha in osteoblasts, resulting in increased AXIN1 expression, suppressed WNT/beta-catenin activity, and reduced osteoblast differentiation. TT homozygotes show markedly lower lumbar spine and femoral neck BMD.

Morris JA et al. “An atlas of genetic influences on osteoporosis in humans and mice.” Nature Genetics 51(2):258-266 (2019)

Allele T

OR —

β 0.040

p 1.0e-16

N 426,824

Large GWAS

European

Suthon S et al. “GATA4 and estrogen receptor alpha bind at SNPs rs9921222 and rs10794639 to regulate AXIN1 expression in osteoblasts.” Human Genetics 141(12):1849-1861 (2022)

Allele T

OR —

p 1.0e-3

Candidate gene study

Greenbaum J et al. “A multiethnic whole genome sequencing study to identify novel loci for bone mineral density.” Human Molecular Genetics (2022)

Allele T

OR —

p 9.0e-24

N 44,506

Large GWAS

multi-ancestry

Styrkarsdottir U et al. “Sequence variants in the PTCH1 gene associate with spine bone mineral density and osteoporotic fractures.” Nature Communications 7:10129 (2016)

Allele T

OR —

β 0.040

p 3.0e-6

N 20,132

Small GWAS

European

Osteoporosis

Multiple candidate gene studies have directly examined rs9921222 and osteoporosis risk. An Egyptian case-control study (50 OP patients vs. 51 controls) found the T allele strongly associated with osteoporosis risk (OR=10.5, p=0.001), with TT homozygotes showing the lowest lumbar spine and femoral neck BMD values. A Chinese Han study (599 cases, 599 controls) similarly found rs9921222 significantly increased osteoporosis risk particularly in individuals with BMI ≤24, as part of a multi-locus WNT pathway model. These findings are consistent with the large GWAS BMD data and the mechanistic role of AXIN1 in osteoblast function.

Nassar ES et al. “Association between AXIN1 gene polymorphism (rs9921222) of WNT signaling pathway and susceptibility to osteoporosis in Egyptian patients: a case-control study.” Bmc Musculoskeletal Disorders (2023)

Allele T

OR 10.50

p 1.0e-3

N 101

Candidate gene study

Egyptian

Cui Y et al. “The genetic polymorphisms of key genes in WNT pathway (LRP5 and AXIN1) was associated with osteoporosis susceptibility in Chinese Han population.” Endocrine (2022)

Allele T

OR —

p 5.0e-2

N 1,198

Preliminary work

East Asian

Ferritin measurement

A large genome-wide meta-analysis of iron homeostasis biomarkers (n=246,139) identified rs9921222-C as significantly associated with higher serum ferritin levels (β=0.025 SD, p=1×10⁻¹²). This association at the AXIN1 locus is notable given that WNT/β-catenin signaling influences hepcidin expression and iron metabolism. The effect size is modest but the study is well-powered and the locus was among 46 novel findings for iron homeostasis biomarkers. The clinical significance of this association for iron-related disease is not yet established.

Bell S et al. “A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis.” Communications Biology 4(1):156 (2021)

Allele C

OR —

β 0.025

p 1.0e-12

N 246,139

Meta-analysisLarge GWAS

European

Parkinson's disease

A cross-sectional study in Northern Han Chinese participants and a White replication cohort (PPMI) found that the T allele of rs9921222 was associated with increased Parkinson's disease susceptibility (OR=1.351, 95% CI 1.045–1.747, p=0.042 after correction), with stronger effects observed in males. The association is biologically plausible via WNT signaling dysregulation in dopaminergic neurons, but this is a single candidate gene study and replication in large independent cohorts is needed.

Kong Z et al. “AXIN1 Polymorphisms Potentially Modulate Parkinson's Disease Susceptibility: A Cross-Sectional Study in Northern Han Chinese and White Populations.” Neurology and Therapy (2026)

Allele T

OR 1.35

p 4.2e-2

Candidate gene study

East Asian

Colorectal cancer

A candidate gene study of WNT pathway variants in 180 colorectal cancer patients and 150 healthy controls found that rs9921222-T (AXIN1) was associated with increased susceptibility to colorectal cancer. This is biologically plausible given AXIN1's role as a negative regulator of WNT/β-catenin, a key pathway in colorectal carcinogenesis. However, the study was small and has not been replicated in large GWAS; this association should be considered preliminary.

Rosales-Reynoso MA et al. “Genetic Polymorphisms in APC, DVL2, and AXIN1 Are Associated with Susceptibility, Advanced TNM Stage or Tumor Location in Colorectal Cancer.” The Tohoku Journal of Experimental Medicine (2019)

Allele T

OR —

p —

N 330

Candidate gene study

Mexican

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GWAS Catalog Trait Associations (6)

Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.

rs9921222

Key Literature Trait Associations

Bone Mineral Density

Osteoporosis

Ferritin measurement

Parkinson's disease

Colorectal cancer

GWAS Catalog Trait Associations (6)

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