Twelve New Genomic Loci Associated With Bone Mineral Density

Area of Science:

• Genetics
• Bone Biology
• Genomics

Background:

• Bone mineral density (BMD) is a key determinant of skeletal health and fracture risk.
• Genome-wide association studies (GWAS) have identified numerous genetic loci associated with BMD, but a significant portion of heritability remains unexplained.
• Understanding the genetic architecture of BMD is crucial for developing targeted interventions for bone diseases.

Purpose of the Study:

• To identify novel genomic loci associated with bone mineral density (BMD) by conducting a joint association analysis of two large genome-wide association studies (GWAS).
• To leverage the integrative association method Multi-Trait Analysis of GWAS (MTAG) to combine data from estimated heel BMD (eBMD) and total body BMD (TB-BMD) GWAS.
• To prioritize candidate genes and credible risk variants (CRVs) within the identified loci for future functional investigations.

Main Methods:

• A joint association analysis was performed using the Multi-Trait Analysis of GWAS (MTAG) method, integrating a single GWAS of eBMD in the UK Biobank cohort (N = 426,824) and a GWAS meta-analysis of TB-BMD (N = 66,628).
• Approximate conditional association analysis was used to identify secondary association signals in novel loci.
• Statistical fine-mapping, cis-expression quantitative trait locus (cis-eQTL), and cis-protein quantitative trait locus (cis-pQTL) analyses were conducted to prioritize credible risk variants and candidate genes.

Main Results:

• The study identified 12 novel genomic loci associated with BMD at genome-wide significance (p = 5.0 × 10⁻⁸), including nine for eBMD and four for TB-BMD.
• These newly identified loci explained an additional 0.11% heritability for eBMD and 0.23% for TB-BMD.
• A secondary signal was identified in locus 5q13.2, and 269 CRVs and 65 candidate genes, including FGF1, COL11A2, and DEPTOR, were prioritized.

Conclusions:

• This largest joint analysis of BMD GWAS to date has significantly expanded the number of known genetic loci influencing BMD.
• The identified loci and prioritized candidate genes provide novel insights into the genetic mechanisms underlying bone development.
• These findings offer a valuable resource for future functional studies aimed at understanding bone biology and developing therapeutic strategies for bone-related disorders.