Meta-Analysis of Genome-Wide Association Studies Identifies Three Loci Associated With Stiffness Index of the Calcaneus

Abstract

The stiffness index (SI) from quantitative ultrasound measurements is a good indicator of BMD and may be used to predict the risk of osteoporotic fracture. We conducted a genomewide association study (GWAS) for SI using 7742 individuals from the Taiwan Biobank, followed by a replication study in a Korean population (n = 2955). Approximately 6.1 million SNPs were subjected to association analysis, and SI‐associated variants were identified. We further conducted a 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 estimated BMD GWAS; these three cytobands were replicated successfully after a meta‐analysis with a Korean population cohort as well. However, two SNPs were not replicated. After prioritization, we identified two novel genes, RAB15 and FNTB, as strong candidates for association with SI. Our study identified three SI‐associated SNPs and two novel SI‐related genes. Overall, these results provide further insight into the genetic architecture of osteoporosis. Further studies in larger East Asian populations are needed. © 2019 American Society for Bone and Mineral Research.

The Polygenic and Monogenic Basis of Paediatric Fractures

“…Multiple association signals mapping to the 7q31.31 locus have been consistently reported in GWAS of BMD of paediatric populations [17,[25][26][27][28]31] and adult populations [21,22,36,37]. There is considerable evidence that either WNT16 [38][39][40][41][42], CPED1 [39], ING3 [43] or FAM3C [44] are underlying the association signal.…”

Genetic Variants in WNT16 and PKD2L1 Locus Affect Heel Ultrasound Bone Stiffness: Analyses from the General Population and Patients Evaluated for Osteoporosis

“…In the present work, we focused on two non-coding SNPs, rs2707518 ( CPED1 / WNT16 ) and rs3779381 ( WNT16 ), which were highly associated with eBMD in the UK Biobank [ 13 ] and with stiffness index in the SHIP cohorts. Rs2707518 is highly genetically linked (r 2 = 0.99) to rs2536195 ( CPED1 / WNT16 ) which previously showed an association with stiffness index in a GWAS meta-analysis [ 33 ]. Rs3779381, in turn, was observed to be related to an increased osteoporosis risk in postmenopausal, overweight Chinese women [ 29 ].…”

Roles of transmembrane protein 135 in mitochondrial and peroxisomal functions - implications for age-related retinal disease

“…There have been published associations with TMEM135 and other human medical conditions such as osteoporosis (122)(123)(124)(125)(126)(127), breast cancer (128,129), prostate cancer (130,131), melanoma (132,133), non-small lung cancer (134), glioblastoma multiforme (134), non-alcoholic fatty liver disease (135), cognitive disorders (136), and metabolic disease (25). Significance of TMEM135 functions have been also indicated by phenotypes in other tissues due to Tmem135 mutation and overexpression.…”