Twelve years of GWAS discoveries for osteoporosis and related traits: advances, challenges and applications

Abstract

Osteoporosis is a common skeletal disease, affecting ~200 million people around the world. As a complex disease, osteoporosis is influenced by many factors, including diet (e.g. calcium and protein intake), physical activity, endocrine status, coexisting diseases and genetic factors. In this review, we first summarize the discovery from genome-wide association studies (GWASs) in the bone field in the last 12 years. To date, GWASs and meta-analyses have discovered hundreds of loci that are associated with bone mineral density (BMD), osteoporosis, and osteoporotic fractures. However, the GWAS approach has sometimes been criticized because of the small effect size of the discovered variants and the mystery of missing heritability, these two questions could be partially explained by the newly raised conceptual models, such as omnigenic model and natural selection. Finally, we introduce the clinical use of GWAS findings in the bone field, such as the identification of causal clinical risk factors, the development of drug targets and disease prediction. Despite the fruitful GWAS discoveries in the bone field, most of these GWAS participants were of European descent, and more genetic studies should be carried out in other ethnic populations to benefit disease prediction in the corresponding population.

Fig. 1

Timeline highlighting important milestones during the 12 years of GWAS discoveries for osteoporosis and related traits. Blue boxes indicate the studies from the GEFOS and GENOMOS consortia. The green box indicates the studies focused on the Chinese population. Red boxes indicate GWASs including rare variants. Yellow boxes indicate the UK Biobank-based GWAS. BMD bone mineral density, ESR1 estrogen receptor 1, GWAS genome-wide association study, LRP5 low-density lipoprotein receptor-related protein 5, LRP40 low-density lipoprotein receptor-related protein 4, OPG osteoprotegerin, RANK receptor activator of nuclear factor-kappa β, RANKL RANK ligand, SPTBN1 spectrin beta, nonerythrocytic 1, WES, whole-exome sequencing, WGS whole-genome sequencing, ZBTB40 zinc finger and BTB domain containing 40

Fig. 2

Genetic loci reported by the GWAS catalog for osteoporosis and related traits. ^# Fracture occurring at any site, except fingers, toes and skull, after age 18. BMC bone mineral content, BMD bone mineral density, BUA broadband ultrasound attenuation, FN femoral neck, LL lower limbs, OF osteoporotic fractures, SOS speed of sound

Fig. 3

Mendelian randomization in bone field. Panel A: Principal of Mendelian randomization. Panel B: The causality between the clinical risk factors and osteoporosis from the current literature. Red boxes indicate the causal relationship. Black boxes indicate the noncausal relationship. Blue boxes indicate controversial results. BMD bone mineral density, CAD coronary artery disease, IBD inflammatory bowel disease, DBP vitamin D binding protein, PsA psoriatic arthritis, T1D type 1 diabetes, T2D type 2 diabetes, TSH thyroid stimulating hormone