No large-effect low-frequency coding variation found for myocardial infarction.

Area of Science:

• Genetics
• Cardiovascular Disease Research

Background:

• Genome-wide association studies (GWAS) have identified common variants linked to coronary artery disease and myocardial infarction (MI).
• The role of low-frequency and rare coding variants in MI risk remains largely unexplored.

Purpose of the Study:

• To test the hypothesis that low-frequency (1-5% MAF) and rare (<1% MAF) coding variants are associated with MI.
• To identify novel genetic factors contributing to MI susceptibility.

Main Methods:

• Genotyped 2906 MI cases and 6738 controls using the Illumina HumanExome Beadchip.
• Follow-up genotyping of 34 coding variants in an additional 4668 individuals.
• Assessed exome array coverage using whole exome sequencing (N=151).

Main Results:

• The exome array achieved successful genotyping for a substantial proportion of Norwegian coding variants.
• Despite 80% power to detect associations with high-effect low-frequency variants, no novel significant genes or variants for MI were identified.
• The study suggests that low-frequency coding variants with large effect sizes (OR >2) may not be a significant factor in MI etiology.

Conclusions:

• The current study did not find evidence for low-frequency coding variants with large effect sizes contributing to MI risk.
• Larger sample sizes may be required to detect associations with coding variants that have more moderate effect sizes.