Abstract
Coronary artery disease (CAD) is the leading cause of death, and genetic factors contribute significantly to risk of CAD. This study aims to identify new CAD genetic loci through a large-scale linkage analysis of 24 large and multigenerational families with 433 family members (GeneQuest II). All family members were genotyped with markers spaced by every 10 cM and a model-free nonparametric linkage (NPL-all) analysis was carried out. Two highly significant CAD loci were identified on chromosome 17q21.2 (NPL score of 6.20) and 7p22.2 (NPL score of 5.19). We also identified four loci with significant NPL scores between 4.09 and 4.99 on 2q33.3, 3q29, 5q13.2 and 9q22.33. Similar analyses in individual families confirmed the six significant CAD loci and identified seven new highly significant linkages on 9p24.2, 9q34.2, 12q13.13, 15q26.1, 17q22, 20p12.3, and 22q12.1, and two significant loci on 2q11.2 and 11q14.1. Two loci on 3q29 and 9q22.33 were also successfully replicated in our previous linkage analysis of 428 nuclear families. Moreover, two published risk variants, SNP rs46522 in UBE2Z and SNP rs6725887 in WDR12 by GWAS, were found within the 17q21.2 and 2q33.3 loci. These studies lay a foundation for future identification of causative variants and genes for CAD.
Highlights
In contrast to aforementioned GWASs, the number of genetic loci identified by Genome-wide linkage analysis (GWLA) was much smaller and independent, suggesting that many linkage loci remain to be identified in new Coronary artery disease (CAD) or myocardial infarction (MI) families[40]
The pedigrees of the 24 GeneQuest II families are shown in Fig. 1. 433 family members from the 24 families were included in the linkage analysis
There were 162 patients affected with CAD and 247 family members without a diagnosis of CAD
Summary
We have completed a genome-wide linkage scan in a well characterized U.S GeneQuest cohort with 428 nuclear families and identified six novel CAD loci on chromosomes 3p25.1, 3p29, 9q22.3, 9p34.11, 17p12, and 21q22.340. We performed a large scale GWLA in a well-characterized U.S cohort of 24 large, multigenerational CAD families (mean pedigree size = 18) This cohort, referred to as GeneQuest II, was independent from our previously reported GeneQuest cohort with 428 nuclear families[40]. The most attractive feature of the GeneQuest II cohort is the inclusion of extended family members of affected siblings or trios To our knowledge, this is the largest linkage analysis of multiple large pedigrees to identify genetic loci for CAD, and significant susceptibility loci were identified
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