Multivariate genetic analysis reveals three distinct pathological dimensions in musculoskeletal disorders

Area of Science:

• Genetics
• Musculoskeletal Disorders
• Immunology

Background:

• Musculoskeletal disorders share overlapping symptoms and pathology, necessitating research into their common genetic mechanisms.
• Identifying distinct genetic factors can improve understanding and treatment of these complex conditions.

Purpose of the Study:

• To investigate the shared genetic architecture of musculoskeletal disorders using multivariate genetic modeling.
• To identify distinct pathological factors and their associated genetic loci and candidate genes.

Main Methods:

• Multivariate genetic modeling was employed to analyze genetic variance in musculoskeletal disorders.
• Genome-wide association analyses were conducted to identify risk loci and candidate genes.
• Polygenic enrichment analyses were used to explore biological pathways associated with identified factors.

Main Results:

• Three distinct pathological factors were identified: degenerative musculoskeletal disorder, bone mass, and autoimmune disorder, explaining 48.27% of genetic variance.
• 795 genomic risk loci, including 136 novel ones, and 273 candidate genes were identified.
• The degenerative factor is linked to the brain-joint neural axis, while the autoimmune factor involves the gut-joint immune axis.

Conclusions:

• Distinct genetic dimensions underlie musculoskeletal disorders, emphasizing the need for genetic-guided patient stratification.
• Optimizing co-prevention and co-management strategies for musculoskeletal disorders can be achieved through understanding these genetic factors.