Abstract
Postmenopausal osteoporosis (PMO) is the most common bone disorder in elderly Chinese women. Although genetic factors have been shown to have a pivotal role in PMO, studies on genetic loci associated with PMO in Chinese individuals are still lacking. We aimed to identify SNPs that contribute to PMO in Chinese individuals by conducting a genome-wide association study (GWAS). Bone mineral density (BMD) of postmenopausal Chinese women was assessed. Participants with T-score < −2.5 standard deviations (n = 341) were recruited and divided into a discovery group (n = 150) and a replication group (n = 191). GWAS was performed, with T-score as the quantitative trait, using linear regression. Our results revealed that an SNP cluster upstream of RREB1 showed a trend of association with BMD in Chinese PMO patients. The leading SNP of the cluster was rs475011 (p combined = 1.15 × 10−6, beta = 0.51), which is a splicing quantitative trait locus (sQTL) of RREB1. This association was further supported by data from the UK Biobank (UKBB; p = 9.56 × 10−12). The high BMD-associated allele G of rs475011 is related to a high intron excision ratio. This SNP may increase BMD by upregulating mature RREB1 mRNA, based on data from the Genotype-Tissue Expression (GTEx) database. We identified BMD-associated SNPs that regulate RREB1 in Chinese PMO patients. Future functional experiments are needed to further link rs475011, RREB1, and PMO in Chinese individuals.
Highlights
Postmenopausal osteoporosis (PMO) is the most common bone disorder in elderly women worldwide (Black and Rosen, 2016; Eastell et al, 2016)
By analyzing the relationships among these variables in our samples (Figure 1 and Supplementary Table S1), we found that age (p 1.25 × 10−11, Pearson’s r −0.44) and years since menopause (YSM, p 3.83 × 10−10, Pearson’s r −0.41) were significantly negatively correlated with bone mineral density (BMD), and body mass index (BMI) was significantly positively correlated with BMD (p 4.85 × 10−5, Pearson’s r 0.27), which is consistent with previous reports (Ravn et al, 1999; Warming et al, 2002)
As only ∼70% of the participants had YSM data available (Table 1) and there was a high correlation between age and YSM (p < 10−16, Pearson’s r 0.87), we used age and BMI as covariates in the genome-wide association study (GWAS)
Summary
Postmenopausal osteoporosis (PMO) is the most common bone disorder in elderly women worldwide (Black and Rosen, 2016; Eastell et al, 2016). In China, its estimated prevalence is 34.65% (Chen et al, 2016). It is characterized by altered bone microstructure and decreased bone mineral density (BMD), and it is the leading cause of nonstress fractures in the elderly (Zhuang et al, 2020; Porter and Varacallo, 2021). RREB1 Associated With Chinese PMO et al, 2002) and the heritability of osteoporotic fracture is 0.5–0.7 (Deng et al, 2002). These findings indicate that genetics play a pivotal role in PMO
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