Phenome-wide screening for traits causally associated with the risk of coronary artery disease

Area of Science:

• Genetics and Cardiovascular Epidemiology
• Complex Trait Genetics
• Human Phenomics

Background:

• Coronary artery disease (CAD) is a multifactorial condition with numerous identified risk factors.
• Understanding the complex interplay between genetic predispositions and diverse phenotypic traits is crucial for effective CAD risk assessment.
• Previous research has explored various risk factors, but a comprehensive phenome-wide search for causal associations with CAD is needed.

Purpose of the Study:

• To conduct a comprehensive phenome-wide search (PheWAS) for traits causally associated with the risk of coronary artery disease (CAD).
• To investigate genetic correlations and causal associations between diverse risk factors across different categories.
• To identify novel, independent causal risk factors for CAD and elucidate their mediating roles.

Main Methods:

• Employed Mendelian randomization and Polygenic risk score analyses in a large cohort of European ancestry (6194 CAD cases, 4287 controls).
• Performed a phenome-wide search (PheWAS) to identify traits causally linked to CAD risk.
• Utilized conditional analysis to dissect the influence of specific traits, such as age of first sexual intercourse (AFS).

Main Results:

• Identified 46 risk factors for CAD across cardiovascular, central nervous system (CNS), diabetes, lipid, immune, anthropometric, and lifestyle categories.
• Observed significant genetic correlations and causal links between risk factors from different categories, with thrombotic conditions showing the highest genetic relatedness to CAD.
• Lifestyle features, particularly those with CNS overlap, were prominent; higher cognition was linked to lower CAD risk via lifestyle and cardiometabolic factors, partly mediated by a higher age of first sexual intercourse (AFS).
• Lower AFS was identified as an independent causal risk factor for CAD, associated with adverse cardiometabolic profiles (e.g., higher fasting insulin, glucose, LDL, HbA1c; lower HDL) and increased risk of type 2 diabetes (T2D) and pulmonary embolism.

Conclusions:

• Coronary artery disease (CAD) arises from multiple, distinct yet genetically interrelated sources.
• Lower age of first sexual intercourse (AFS) is a newly identified independent causal risk factor for CAD.
• The findings highlight the complex genetic architecture of CAD and suggest AFS plays a role in mediating other risk factors, offering potential new avenues for prevention and intervention.