rs10416265 (GPATCH1): Heel Bone Density Variant
Key takeaways
- rs10416265 near GPATCH1 (chromosome 19q13.11) reached genome-wide significance for heel bone density measures in a large multi-cohort meta-analysis
- The association was independently replicated across 22 additional cohorts with over 36,000 participants
- This locus sits alongside established osteoporosis genes such as WNT16 and ESR1 in its association profile
- GTEx data shows the alternative allele increases GPATCH1 expression in skeletal muscle and testis, and reduces expression of neighboring RHPN2 in multiple tissues
- rs10416265 was not among the three loci with the strongest fracture signal in the available fracture meta-analysis
Key takeaways
- rs10416265 near GPATCH1 (chromosome 19q13.11) reached genome-wide significance for heel bone density measures in a large multi-cohort meta-analysis
- The association was independently replicated across 22 additional cohorts, with combined replication samples exceeding 36,000 participants
- This locus sits alongside established osteoporosis genes such as WNT16 and ESR1 in its association profile
- GTEx data shows the alternative allele increases GPATCH1 expression in skeletal muscle and testis, and reduces expression of the neighboring gene RHPN2 in multiple tissues
- rs10416265 was not among the three loci with the strongest fracture signal in the available fracture meta-analysis
What the research says rs10416265, at chromosomal region 19q13.11 near GPATCH1 (G-patch domain containing 1, a gene involved in RNA processing), is among nine SNPs that reached genome-wide significance (P < 5 x 10^-8) for heel bone properties in a meta-analysis of 13 discovery cohorts covering broadband ultrasound attenuation (BUA, n = 14,260) and velocity of sound (VOS, n = 15,514) PMID 25416282. Independent replication was conducted across 22 further cohorts (7 in silico, n = 11,452; 15 de novo, n = 24,902), and a fracture meta-analysis spanned 25 cohorts with up to 14,985 fracture cases PMID 25416282. A separate large GWAS in UK Biobank (n = 394,929 European-ancestry participants) identified 899 loci for estimated heel BMD and demonstrated that genetic risk scores for this trait stratify osteoporosis and fracture risk PMID 30945275.
Reported associations
- Heel broadband ultrasound attenuation (BUA): genome-wide significant association (P < 5 x 10^-8) in combined discovery (n = 14,260) and replication meta-analysis PMID 25416282
- Velocity of sound (VOS): genome-wide significant association in the same meta-analysis (discovery n = 15,514) PMID 25416282
- Fracture (directional): among 10 heel-bone-associated SNPs tested for fracture, six showed the expected direction of association with any fracture (P < 0.05) across 25 cohorts with up to 14,985 fracture cases; rs10416265 was not among the three with the strongest fracture signal (P < 0.005, which were 6q22.33, 7q31.31, and 10q21.1), and whether it was among the six with a directional association is not specified in the available text PMID 25416282
Evidence quality The primary evidence comes from the GEFOS/GENOMOS consortium meta-analysis, which combined 13 discovery cohorts (BUA: n = 14,260; VOS: n = 15,514) with independent replication in 22 further cohorts (in silico n = 11,452; de novo n = 24,902) PMID 25416282. The variant cleared the conventional genome-wide significance threshold of P < 5 x 10^-8; no specific beta coefficient or odds ratio for rs10416265 was reported in the available study text, limiting interpretation of effect magnitude. The inclusion of both in silico and de novo replication strengthens confidence in the association. A large UK Biobank heel BMD GWAS (n = 394,929) PMID 30945275 does not specifically comment on this variant in the available text. No conflicting findings were identified across the provided studies.
Tissue-specific expression effects
- GPATCH1: the alternative allele is associated with increased expression in testis and skeletal muscle GTEx Portal
- RHPN2: the same allele is associated with reduced expression in pituitary gland, aorta, gastroesophageal junction, tibial nerve, tibial artery, and subcutaneous adipose tissue GTEx Portal
Lifestyle considerations No lifestyle considerations on file for this variant.
Frequently asked questions
What is GPATCH1?
GPATCH1, or G-patch domain containing 1, is a gene on chromosome 19 at position 19q13.11 that encodes a protein involved in RNA processing. GTEx data indicates the variant rs10416265 is associated with increased GPATCH1 expression in skeletal muscle and testis.
Is rs10416265 linked to osteoporosis or fracture risk?
rs10416265 is genome-wide significantly associated with heel bone properties including broadband ultrasound attenuation and velocity of sound, both of which relate to bone health and osteoporosis risk. In a fracture meta-analysis of 25 cohorts, this SNP was not among the three with the strongest fracture signal, and whether it carries any directional fracture association is not confirmed in the available text.
How large were the studies that identified this association?
The primary study combined 13 discovery cohorts (up to about 15,500 participants per measure) with 22 replication cohorts adding over 36,000 participants. A fracture meta-analysis within the same study covered 25 cohorts with up to 14,985 fracture cases.
What does RHPN2 have to do with rs10416265?
RHPN2 is a gene neighboring GPATCH1 whose expression is reduced in multiple tissues, including pituitary, aorta, and nerve tissue, by the same allele at rs10416265 according to GTEx data. Whether this reduction relates to the bone density association is not established by the available studies.
What heel bone measures is rs10416265 associated with?
The variant is associated with broadband ultrasound attenuation and velocity of sound, both measured by quantitative ultrasound of the heel. These measures are non-invasive proxies for bone health and independently predict fracture risk.