rs1053051 (TMEM263): Bone Mineral Density Variant

Key takeaways

• This variant, near TMEM263 and MTERF2, was identified among 56 genetic loci linked to bone mineral density in a large-scale meta-analysis covering more than 83,000 people.
• At the time of publication, neither gene was previously known to play a role in bone biology.
• Gene expression data show this variant is linked to lower activity of a TMEM263-related transcript in thyroid, pancreas, fat tissue, breast, and testis.
• Fourteen of the 56 bone density loci in the source study were also associated with fracture risk; whether this locus is among them is not specified in the available data.
• The finding was supported by both a discovery phase (about 33,000 participants) and a separate replication phase (about 51,000 additional participants).

What the research says rs1053051, located near TMEM263 (Transmembrane Protein 263) and MTERF2 (Mitochondrial Transcription Termination Factor 2), was identified as one of 56 loci associated with bone mineral density (BMD) at genome-wide significance (P<5x10-8) in a meta-analysis of 17 genome-wide association studies covering 32,961 discovery participants and 50,933 replication participants of European and East Asian ancestry. The study also tested these loci for association with low-trauma fracture risk in 31,016 cases and 102,444 controls, finding that 14 loci reached at least nominal fracture significance (P<5x10-4, Bonferroni corrected), with 6 of those reaching genome-wide fracture significance. Gene expression data from 953 GTEx donors show that the alternate allele at this variant is linked to lower expression of TMEM263-DT (a transcript at the TMEM263 locus) across six tissue types, with the strongest statistical effect in thyroid (p=1.6x10-29), and increased expression of an uncharacterized gene (ENSG00000287957) in testis GTEx Portal.

Reported associations

• Bone mineral density: This locus was identified among 56 genome-wide significant BMD associations in a meta-analysis of 17 GWAS studies; specific effect sizes for this variant are not provided in the available study excerpt.
• Fracture risk (potential): The source study found that 14 of the 56 BMD loci were also nominally associated with fracture risk (P<5x10-4, Bonferroni corrected), with 6 reaching genome-wide fracture significance; whether this locus is among the 14 is not confirmed in the available data.
• TMEM263-DT expression - multiple tissues: The alternate allele is associated with reduced expression of TMEM263-DT in testis, pancreas, thyroid, breast mammary tissue, subcutaneous adipose tissue, and sun-exposed lower leg skin GTEx Portal.
• TMEM263 expression - tibial artery: The alternate allele is associated with reduced expression of TMEM263 in tibial artery GTEx Portal.
• ENSG00000287957 expression - testis: The alternate allele is associated with increased expression of this uncharacterized gene in testis GTEx Portal.

Evidence quality The BMD association was established in a multi-stage, multi-ancestry meta-analysis (discovery n=32,961; replication n=50,933) using a strict genome-wide significance threshold (P<5x10-8) and double genomic control correction for population stratification. The provided study excerpt does not include effect-size statistics (odds ratios, beta coefficients, or percentage of variance explained) specific to rs1053051. Fracture association was evaluated in 31,016 cases and 102,444 controls; 14 of the 56 BMD loci reached at least nominal fracture significance (P<5x10-4), but the available data do not confirm whether this locus is among them. The GTEx eQTL signals are based on 953 donors with FDR<0.05 correction applied; the strongest tissue effect for TMEM263-DT is in thyroid (p=1.6x10-29), which is considered a strong eQTL signal, though eQTL data reflect gene-regulatory effects and do not by themselves establish disease causality GTEx Portal.

Tissue-specific expression effects

• TMEM263-DT: The alternate allele is associated with reduced expression of this transcript in testis, pancreas, thyroid, breast mammary tissue, subcutaneous adipose tissue, and sun-exposed lower leg skin; effects are statistically significant across all six tissue types GTEx Portal.
• TMEM263: The alternate allele is associated with reduced expression of TMEM263 in tibial artery GTEx Portal.
• ENSG00000287957: The alternate allele is associated with increased expression of this uncharacterized gene in testis GTEx Portal.

Lifestyle considerations No lifestyle considerations on file for this variant.