Two Genome-Wide Linkage Scans For Coronary Artery Disease:Identification Of Multiple New Linkage Loci, Systematic Review And Cross-Comparison To GWAS

Objective:Identify new susceptibility genetic loci for coronary artery disease by genome-wide linkage scan. And compare our results to previously reported data.Methods:It contains two independent cohorts in this study. The GeneQuest cohort consists of 1,613 subjects from 428 multiplex families.974 affected individuals were recruited, and the average age at onset was 44.4±9.7 years. The majority (423 pedigrees) of the recruited pedigrees with early-onset CAD consist of mainly two-generation nuclear families with an average family size of 4.7 members. It was characterized by predominantly males (n=1,152) and white (91.7% for all the participants). A total of 24 white families with 458 family members were enrolled in the GeneQuest Ⅱ cohort, the average family size of which was 15.7±9.18, and 100% whites. The distinguished features for the second QenenQuest Ⅱ cohort are large families with three or more generations,100% whites and a well-balanced male versus female ratio (226/232). Whole blood samples were drawn from all the participants and genomic DNA were genotyped after been isolated. Linkage analysis of these two unique, well-characterized U.S. populations was performed. Then the results from our GWLS were compared to previously reported GWLS data as well as GWAS data reported to date.ResultsIn GeneQuest, affected only nonparametric linkage (NPL) analysis identified two CAD loci with highly significant evidence of linkage on chromosome 3p25.1 (peak NPL=5.49) and 3q29 (peak NPL=6.84). In GeneQuest Ⅱ, we identified two CAD loci with evidence of highly significant linkage on 3q29 and 7p22.3 with peak NPL scores of 5.93 and 5.26, respectively, and four loci with significant linkage on 3q23,5q11.2, 7p22.2, and 17q11.2 (NPL=4.08-4.98). We also identified 11 loci with suggestive linkage (3p26.3,5q13.2,5q15,7q35,9p24.2,9q22.33,9q34.11,10q24.32,17p12, 20q13.32, and 21q22.3; NPL=3.18-4.07). The 3q29 and 9q22.33 CAD linkages were cross-replicated in both GeneQuest and GeneQuest Ⅱ. The 3q23,9p24.2, 9q34.11 linkage peaks are 1.07-2.1 Mb from respective CAD variants, rs2306374, rs7025417, and rs579459 identified by GWAS. The data were compared systematically to summary results from all reported GWLS and GWAS, highlighting similarities, differences, advantages and disadvantages of each strategy.ConclusionWe identified novel, highly significant CAD linkage loci on chromosome 3p25.1 and 3q29 and suggested loci on 9q22.33,9q34.11,17p12, and 21q22.3 in the GeneQuest population. We also identified novel, highly significant CAD linkage loci on chromosome 3q29 and 7p22.3, significant loci on 3q23,5q11.2,7p22.2, and 17q11.2 and suggested loci on 3p26.3,5q13.2,5q15,7q35,9p24.2,9q22.33, 10q24.32, and 20q13.32 in the GeneQuest Ⅱ population.