Searching for osteoporosis genes : the use of WGS in an extended Maltese family with osteoporosis

Abstract

INTRODUCTION: Osteoporosis is a complex metabolic and skeletal disease having a strong genetic background. Indeed, heritability of bone mineral density (BMD) in twin and family studies ranges from 50 to 85%. The aim of the study was to identify known and/or novel genes and gene variants that play a role in the susceptibility of primary osteoporosis in an extended Maltese family.

MATERIALS AND METHODS: A 2-generation family having multiple relatives with osteoporosis (T-score: <-2.5 or Z-score: <-2.0) at the spine or hip were recruited. Biochemical analysis was performed to exclude other bone diseases. Whole genome sequencing was performed on 12 members and comprehensive filtering strategies were carried out on the single nucleotide variant and indel files. In silico modelling and prediction tools were used to determine potential causality of the variants.

RESULTS: Eleven shortlisted variants segregating in a dominant inheritance pattern were identified in the affected relatives having a minor allele frequency of ≤2%. Variants included missense variants within ADAMTS20 (rs138035327), ARSD (rs78034736), BMP1 (rs368615556), CLDN18 (rs114998965), SELP (rs754086574), TGFβ2 (rs773943154), TRIM45 (rs146244405), PCDHGA11 (rs138408376), PLEC (rs138924815) and SPARC (rs41290587), and one stop gain variant within WDR89 (rs944955056).

CONCLUSIONS: Future studies will evaluate the shortlisted variants by replicating in the Malta Osteoporotic Fracture Study - a case-control collection of more than 1000 Maltese postmenopausal women and other extended Maltese pedigrees so as to determine association with osteoporosis and low-trauma fracture risk at different anatomical sites. Top candidates will in turn be assessed using functional studies.