NGS in Large CAD Families: In-Depth Identification of Rare Risk Genomic Variants Abstract Coronary artery disease (CAD) is the leading cause of death worldwide. Genetic factors contribute significantly to the development of CAD. The long-term objective of this project is thus to identify novel genetic and molecular determinants/markers for CAD. To achieve this goal, we have spent more than 10 years of extensive efforts to identify and acquire data for 24 very large, multigenerational families (GeneQuest II, mean pedigree size=16). This has become a unique and highly valuable resource for discovering susceptibility genes and genomic variants that confer risk of CAD. We have completed a genome-wide linkage scan with 408 polymorphic markers that cover the entire human genome by every 10 cM in GeneQuest II families, and identified two highly significant CAD loci on chromosome 3q28 and 7p22.3 and four other significant loci. Back in the 90s, we also had established another well-characterized US cohort of 428 CAD families with familial, early onset CAD (GeneQuest, mean pedigree size=5). The same 3q28 CAD locus showed a highly significant linkage in GeneQuest, too. Whole genome next generation sequencing (NGS) has become an enabling technology to identify susceptibility genes for complex diseases. Thus, we propose to employ an innovative, integrated strategy that combines whole genome NGS and genome-wide linkage analysis in the 24 GeneQuest II families to identify genomic variants associated with CAD. All affected family members in the 24 GeneQuest II families will be subjected to whole genome NGS, and novel rare genomic variants will be identified. Private variants will be characterized by simple co- segregation with disease i families to determine whether they are disease-causing mutations. Other rare variants will be analyzed for association with CAD in the 24 large GeneQuest II families using family-based rare variant association studies that incorporate multiple variants in a gene or a functional region as well as haplotypes from multiple variants. Positive associations will be validated in the replication population (428 GeneQuest families). We prioritize rare variants in the following succeeding order: (1) Rare variants under linkage peaks;(2) Rare variants at or near CAD loci identified by GWAS;(3) Rare variants outside of linkage peaks or GWAS loci. Bioinformatics analysis and relevant functional/expression studies will be used to determine whether variants associated with CAD affect the function or expression of nearby genes. These studies should lead to identification of new genomic variants that confer risk of CAD and uncover novel genetic/molecular pathways for the pathogenesis of CAD.

Public Health Relevance

NGS in Large CAD Families: In-Depth Identification of Rare Risk Genomic Variants Public Health Relevance This study may lead to the identification of novel susceptibility genes and rare genomic variants associated with coronary artery disease, which could lead to more effective screening and early treatment of high-risk individuals. The study may identify unrecognized genetic and molecular pathways for the development of coronary atherosclerosis, and could also suggest novel molecular targets for treatment, prevention, and drug development.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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Papanicolaou, George
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
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Ye, Jian; Yao, Yufeng; Song, Qixue et al. (2016) Up-regulation of miR-95-3p in hepatocellular carcinoma promotes tumorigenesis by targeting p21 expression. Sci Rep 6:34034
Huang, Yuan; Wang, Zhijie; Liu, Yinan et al. (2016) αB-Crystallin Interacts with Nav1.5 and Regulates Ubiquitination and Internalization of Cell Surface Nav1.5. J Biol Chem 291:11030-41
Chen, Shanshan; Wang, Xiaojing; Wang, Junhan et al. (2016) Genomic variant in CAV1 increases susceptibility to coronary artery disease and myocardial infarction. Atherosclerosis 246:148-56
Wang, Chuchu; Wu, Manman; Qian, Jin et al. (2016) Identification of rare variants in TNNI3 with atrial fibrillation in a Chinese GeneID population. Mol Genet Genomics 291:79-92
Zhou, Juan; Wang, Longfei; Zuo, Mengxia et al. (2016) Cardiac sodium channel regulator MOG1 regulates cardiac morphogenesis and rhythm. Sci Rep 6:21538
Zhang, Ke K; Xiang, Menglan; Zhou, Lun et al. (2016) Gene network and familial analyses uncover a gene network involving Tbx5/Osr1/Pcsk6 interaction in the second heart field for atrial septation. Hum Mol Genet 25:1140-51
Huang, Yufeng; Wang, Chuchu; Yao, Yufeng et al. (2015) Molecular Basis of Gene-Gene Interaction: Cyclic Cross-Regulation of Gene Expression and Post-GWAS Gene-Gene Interaction Involved in Atrial Fibrillation. PLoS Genet 11:e1005393
Wang, Pengyun; Xu, Chengqi; Wang, Chuchu et al. (2015) Association of SNP Rs9943582 in APLNR with Left Ventricle Systolic Dysfunction in Patients with Coronary Artery Disease in a Chinese Han GeneID Population. PLoS One 10:e0125926
Zhao, Yuanyuan; Huang, Yuan; Li, Weihua et al. (2015) Post-transcriptional regulation of cardiac sodium channel gene SCN5A expression and function by miR-192-5p. Biochim Biophys Acta 1852:2024-34
Chen, Shanshan; Wang, Chuchu; Wang, Xiaojing et al. (2015) Significant Association Between CAV1 Variant rs3807989 on 7p31 and Atrial Fibrillation in a Chinese Han Population. J Am Heart Assoc 4:

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