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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL121358-01A1
Application #
8762112
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Papanicolaou, George
Project Start
2014-07-15
Project End
2018-04-30
Budget Start
2014-07-15
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Li, Xia; Poschmann, Sibylle; Chen, Qiuyun et al. (2018) De novo BK channel variant causes epilepsy by affecting voltage gating but not Ca2+ sensitivity. Eur J Hum Genet 26:220-229
Yu, Gang; Liu, Yinan; Qin, Jun et al. (2018) Mechanistic insights into the interaction of the MOG1 protein with the cardiac sodium channel Nav1.5 clarify the molecular basis of Brugada syndrome. J Biol Chem 293:18207-18217
Wang, Pengxia; Qin, Weixi; Wang, Pengyun et al. (2018) Genomic Variants in NEURL, GJA1 and CUX2 Significantly Increase Genetic Susceptibility to Atrial Fibrillation. Sci Rep 8:3297
Naji, Duraid Hamid; Tan, Chengcheng; Han, Fabin et al. (2018) Significant genetic association of a functional TFPI variant with circulating fibrinogen levels and coronary artery disease. Mol Genet Genomics 293:119-128
Wang, Fan; Wang, Isabel Z; Ellis, Stephen et al. (2018) Analysis of causal effect of APOA5 variants on premature coronary artery disease. Ann Hum Genet 82:437-447
Wang, Zhijie; Yu, Gang; Liu, Yinan et al. (2018) Small GTPases SAR1A and SAR1B regulate the trafficking of the cardiac sodium channel Nav1.5. Biochim Biophys Acta Mol Basis Dis 1864:3672-3684
Si, Wenxia; Xie, Wen; Deng, Wenbing et al. (2018) Angiotensin II increases angiogenesis by NF-?B-mediated transcriptional activation of angiogenic factor AGGF1. FASEB J 32:5051-5062
Li, Sisi; Xi, Quansheng; Zhang, Xiaoyu et al. (2018) Identification of a mutation in CNNM4 by whole exome sequencing in an Amish family and functional link between CNNM4 and IQCB1. Mol Genet Genomics 293:699-710
Wang, Xiaojing; Li, Jia; Yang, Zhongcheng et al. (2018) phlda3 overexpression impairs specification of hemangioblasts and vascular development. FEBS J 285:4071-4081
Wang, Li; Wang, Xiaojing; Wang, Longfei et al. (2018) Identification of a new adtrp1-tfpi regulatory axis for the specification of primitive myelopoiesis and definitive hematopoiesis. FASEB J 32:183-194

Showing the most recent 10 out of 31 publications