Age-related bone loss, which can lead to conditions like osteoporosis, is a complex trait influenced by a variety of genetic factors. Recent research in genetics has provided new insights into the specific genes and genetic variants that contribute to bone mineral density (BMD), especially when associated with osteoporosis, and fracture risk.
Genetic Determinants of Bone Mineral Density
Bone loss is primarily diagnosed using bone mineral density (BMD) measurements, and significant progress has been made in identifying the genetic determinants of BMD. A comprehensive study from 2018 assessed genetic determinants of BMD using heel quantitative ultrasound in over 426,000 individuals, identifying 518 genome-wide significant loci, with 301 being novel discoveries. These loci collectively explain 20% of the variance in BMD. Additionally, the study identified 13 loci associated with bone fractures, all linked to estimated BMD (BMD). This research underscores the genetic complexity of osteoporosis and highlights specific genes, such as SLC8A1, FGFRL1, RSPO3, and TMEM135Â that influence bone density and strength, providing valuable targets for drug development.
Genetic BMD Associations in Diverse Populations
Genetic studies have historically focused on populations of European ancestry, potentially limiting the generalizability of findings across different ethnic groups. To address this, a 2020 genome-wide association study (GWAS) involving 212,453 Japanese individuals across 42 diseases was conducted. This study identified 320 independent signals in 276 loci for 27 diseases, with 25 novel loci. Two previously found loci and 1 novel locus, at gene STK39 (SNP rs578031265), were found to be associated with BMD. The identification of East Asian–specific missense variants as candidate causal variants for several loci emphasizes the importance of including diverse populations in genetic research to uncover unique genetic contributions to disease susceptibility.
Genetic Loci for Osteoporotic Fractures and BMD
An early GWAS in the Chinese Han population examined the genetic basis of osteoporotic fractures (OF) and BMD. This study involved 700 elderly individuals and identified a significant SNP, rs13182402, within the ALDH7A1 gene on chromosome 5q31, which was strongly associated with OF. Follow-up replication studies confirmed this association in both Chinese and Caucasian populations, demonstrating the cross-ethnic relevance of this genetic variant. The ALDH7A1 gene’s role in degrading acetaldehyde, a compound that inhibits osteoblast proliferation, suggests a potential mechanism for its effect on bone formation and strength. This finding highlights the importance of specific genetic variants in understanding the pathogenesis of osteoporosis and provides a new avenue for potential therapeutic interventions.
Advancements in Genome-Wide Association Studies
Standard genome-wide association studies (GWAS) often have limitations, such as testing only additive models and excluding the X chromosome. An advanced GWAS strategy, GUIDANCE, addresses these limitations by incorporating multiple reference panels for genotype imputation and analyzing non-additive models and the X chromosome. Applying this methodology in a recent study of 62,281 subjects across 22 age-related diseases identified 94 genome-wide associated loci, including 26 previously unreported. This comprehensive approach uncovered novel low-frequency recessive variants with significant impact, underscoring the benefits of innovative strategies in elucidating the genetic architecture of complex diseases, including age-related bone loss. Specifically for osteoporosis, the study identified SNPs in genes CCDC170 (rs4869742), WNT16 (rs3779381), LRP5 (rs880610), and near HOXC4 (rs7308105)Â
Genetic research continues to unravel the complex genetic landscape of age-related bone loss. By incorporating diverse populations and employing advanced methodologies, scientists are identifying new genetic variants and mechanisms that contribute to bone health, offering promising targets for future therapeutic development.