Genetic sharing with coronary artery disease identifies potential novel loci for bone mineral density

Area of Science:

• Genetics
• Metabolic Diseases
• Osteoporosis Research

Background:

• Bone mineral density (BMD) is a complex heritable trait with significant missing heritability.
• Growing evidence suggests a link between BMD variation and coronary artery disease (CAD), potentially due to pleiotropy (shared genetic basis).
• Leveraging pleiotropy may enhance the power to detect genetic variants associated with BMD.

Purpose of the Study:

• To jointly analyze genome-wide association study (GWAS) data for lumbar spine (LS) BMD and CAD using a conditional false discovery rate (cFDR) method.
• To identify pleiotropic genetic variants shared between LS BMD and CAD.
• To discover novel genetic variants associated with LS BMD and explore their functional significance.

Main Methods:

• Utilized a conditional false discovery rate (cFDR) method to jointly analyze summary statistics from large-scale GWAS of LS BMD and CAD.
• Identified pleiotropic single nucleotide polymorphisms (SNPs) and SNPs associated with LS BMD.
• Performed gene expression assays, functional enrichment analysis (GO terms, KEGG pathways), and protein-protein interaction analysis.

Main Results:

• Detected strong pleiotropic enrichment and identified 7 pleiotropic SNPs between LS BMD and CAD.
• Discovered 41 SNPs associated with LS BMD (cFDR<0.05), including 21 potentially novel variants.
• Partially validated 4 genes linked to 9 cFDR-significant SNPs via gene expression assays; these genes were enriched in bone metabolism pathways and showed strong protein interactions.

Conclusions:

• The cFDR method proved reliable and efficient for detecting trait-associated genetic variants.
• The study provides novel insights into the genetic variability of BMD and the shared genetic basis of osteoporosis and CAD.
• Findings highlight the potential for leveraging pleiotropy to understand complex traits and related diseases.