The stiffness index (SI) from quantitative ultrasound measurements is a good indicator of bone‐mineral density and may be used to predict risk of osteoporotic fracture. We conducted a genome‐wide association study (GWAS) for SI using 7,742 individuals from the Taiwan Biobank, followed by a replication study in a Korean population (n = 2,955). Approximately 6.1 million SNPs were subjected to association analysis, and SI‐associated variants were identified. We further conducted meta‐analysis of Taiwan Biobank significant SNPs with a Korean population‐based cohort. Candidate genes were prioritized according to epigenetic annotations, gene ontology, protein‐protein interaction, GWAS catalog, and expression quantitative trait loci analyses. Our results revealed seven significant single‐nucleotide polymorphisms (SNPs) within three loci, 7q31.31, 17p13.3 and 11q14.2. Conditional analysis showed that three SNPs, rs2536195 (CPED1/WNT16), rs1231207 (SMG6), and rs4944661 (LOC10050636/TMEM135), were the most important signals within these regions. The associations for the three SNPs were confirmed in a UK Biobank eBMD GWAS, and these three cytobands were replicated successfully after meta‐analysis with Korean population cohort as well. However, two SNPs were not replicated. Further studies in larger East Asian populations are needed. After prioritization, we identified two novel genes, RAB15 and FNTB, as strong candidates for association with SI. Our study identified three SI‐associated SNPs as well as two novel SI‐related genes. Overall, these results provided further insight into the genetic architecture of osteoporosis.
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