Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification

Area of Science:

• Genetics and genomics
• Cardiovascular disease research
• Atherosclerosis and calcification

Background:

• Coronary artery calcification (CAC) is a key indicator of subclinical atherosclerosis and predicts future symptomatic coronary artery disease (CAD).
• Limited genetic risk factors for CAC have been identified, highlighting the need for larger, diverse genetic studies.
• Understanding the genetic basis of CAC can reveal novel therapeutic targets for cardiovascular disease prevention.

Approach:

• Conducted the largest multi-ancestry genome-wide association study (GWAS) meta-analysis for CAC to date.
• Included 26,909 individuals of European ancestry and 8,867 individuals of African ancestry.
• Identified and analyzed independent genetic risk loci associated with CAC.

Key Points:

• Identified 11 independent risk loci for CAC, with eight novel loci for CAC and five previously unreported for CAD.
• New CAC loci are associated with bone mineralization, phosphate catabolism, and hormone metabolic pathways.
• Several identified loci contain candidate causal genes that regulate smooth muscle cell-mediated calcification, supported by functional evidence.

Conclusions:

• The findings refine the genetic architecture of coronary artery calcification.
• The study expands the understanding of biological pathways involved in CAC.
• Identified genetic factors and pathways may represent potential therapeutic targets for CAC and CAD prevention.