Candidate Pathway-Based GWAS Identifies Novel Associations of Genomic Variants in the Complement System Associated with Coronary Artery Disease

Coronary artery disease (CAD) and its major complication myocardial infarction (MI) are the major cause of morbidity and mortality in the Western world as well as in China.1; 2 The pathogenesis of CAD is a complex process mediated by many genetic and environmental factors and their interactions.3 CAD is known to be influenced by abnormal lipid metabolism, smoking, diabetes, hypertension, obesity, physical inactivity, alcohol intake, and psychosocial situation.4 Heritability of CAD was estimated to be 40%–60%, indicating that genetic factors contribute significantly to the development of this disease.5 Identification of novel genetic variants may reveal new biological pathways and mechanisms of CAD and facilitate improved diagnosis, prevention and treatment. Genome-wide association studies (GWAS) and their meta-analyses (Meta-GWAS) have identified about 50 risk variants associated with CAD and MI (Catalog of Published GWAS: http://www.genome.gov/26525384).6; 7 However, GWAS identify mostly common variants and all variants for CAD and MI identified by GWAS account for 10.60% of heritability in aggregate.8 Therefore, a large portion of heritability remains missing for CAD and MI (referred to as missing heritability), and much effort is needed to identify new risk variants for CAD and MI to account for missing heritability. Most GWAS for CAD and MI were completed in European ancestry populations, but recently two GWAS were reported in the Chinese population. We reported the first GWAS for CAD in the Chinese Han population using a large GeneID database in 2011 and identified the C6orf105 gene (now known as ADTRP) as a susceptibility gene for CAD specifically in the Chinese population.9 The finding was replicated in two independent reports.10; 11 In 2012, another GWAS identified four new loci for CAD in or near TTC32-WDR35, GUCY1A3, C6orf10-BTNL2, and ATP2B1.12 However, these identified variants may explain little heredity of CAD in the Chinese population. In order to identify new genomic variants associated with CAD and MI in the Chinese population, we focused on mining of GWAS genotyping data for variants in individual pathways for positive association with CAD without adjusting for multiple testing (P<0.01), followed by identification of functional variants by eQTL analysis and association analysis between functional variants and CAD. We refer this strategy as candidate pathway-based GWAS. Using this approach, we found that functional SNPs in two genes in the complement system, C3AR1 encoding complement component 3a receptor and the C6 encoding complement component 6, were significantly associated with risk of CAD.