CHARGE Targeted Sequencing

The
CHARGE Targeted Sequencing Study aims to follow-up GWAS signals to comprehensively localize the functional variants and to evaluate the contribution of rare variants to a wide array of cardiovascular-related traits. A total of 77 genomic loci previously implicated by GWAS were selected and sequenced in 4,231 participants from three CHARGE cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, and the Framingham Heart Study.  

The CHARGE Targeted Sequencing Study used a case–cohort study design with a large sex-stratified random sample and approximately 200 participants from each of 14 key phenotypes selected on the basis of either case status for discrete phenotypes or extreme values of quantitative traits. The phenotypes studied were atrial fibrillation, blood pressure, body mass index, bone mineral density, C-reactive protein, carotid intima-media thickness, echocardiography, electrocardiographic PR and QRS interval, fasting insulin, hematocrit, pulmonary function, retinal venule diameter, and stroke.  

In total 77 regions, selected on the basis of previous GWAS findings or evidence of pleiotropy, encompassing approximately 2 megabases of the genome and were captured by a specific SOLiD platform–based multiplexed capture sequencing protocol developed at the Baylor College of Medicine Human Genome Sequencing Center

Publications describing the findings from this effort are collected below; when possible, we include a link to the "toll-free" full-text article for personal use or to the PubMed ID.

 

 Methods

  • Strategies to Design and Analyze Targeted Sequencing Data: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. 
    Honghuang Lin, Min Wang, Jennifer A. Brody, Joshua C. Bis, Josée Dupuis, Thomas Lumley, Barbara McKnight, Kenneth M. Rice, Colleen M. Sitlani, Jeffrey G. Reid, Jan Bressler, Xiaoming Liu, Brian C. Davis, Andrew D. Johnson, Christopher J. O’Donnell, Christie L. Kovar, Huyen Dinh, Yuanqing Wu, Irene Newsham, Han Chen, Andi Broka, Anita L. DeStefano, Mayetri Gupta, Kathryn L. Lunetta, Ching-Ti Liu, Charles C. White, Chuanhua Xing, Yanhua Zhou, Emelia J. Benjamin, Renate B. Schnabel, Susan R. Heckbert, Bruce M. Psaty, Donna M. Muzny, L. Adrienne Cupples, Alanna C. Morrison, and Eric Boerwinkle
    Circ Cardiovasc Genet. 2014;7:335-343

Results

  • Association of Levels of Fasting Glucose and Insulin With Rare Variants at the Chromosome 11p11.2-MADD Locus: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.
    Belinda K. Cornes, Jennifer A. Brody, Naghmeh Nikpoor, Alanna C. Morrison, Huan Chu Pham Dang, Byung Soo Ahn, Shuai Wang, Marco Dauriz, Joshua I. Barzilay, Josée Dupuis, Jose C. Florez, Josef Coresh, Richard A. Gibbs, W.H. Linda Kao, Ching-Ti Liu, Barbara McKnight, Donna Muzny, James S. Pankow, Jeffrey G. Reid, Charles C. White, Andrew D. Johnson, Tien Y. Wong, Bruce M. Psaty, Eric Boerwinkle, Jerome I Rotter, David S. Siscovick, Robert Sladek, and James B. Meigs.
    Circ Cardiovasc Genet. 2014;7:374-382 
  • ADAM19 and HTR4 Variants and Pulmonary Function: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. 
    Stephanie J. London, Wei Gao, Sina A. Gharib, Dana B. Hancock, Jemma B. Wilk, John S. House, Richard A. Gibbs, Donna M. Muzny, Thomas Lumley, Nora Franceschini, Kari E. North, Bruce M. Psaty, Christie L. Kovar, Josef Coresh, Yanhua Zhou, Susan R. Heckbert, Jennifer A. Brody, Alanna C. Morrison, and Josée Dupuis. 
    Circ Cardiovasc Genet. 2014;7:350-358 

  • Sequencing of 2 Subclinical Atherosclerosis Candidate Regions in 3669 Individuals: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. 
    Joshua C. Bis, Charles C. White, Nora Franceschini, Jennifer Brody, Xiaoling Zhang, Donna Muzny, Jireh Santibanez, Richard Gibbs, Xiaoming Liu, Honghuang Lin, Eric Boerwinkle, Bruce M. Psaty, Kari E. North, L. Adrienne Cupples, and Christopher J. O’Donnell , on behalf of the CHARGE Subclinical Atherosclerosis Working Group. 
    Circ Cardiovasc Genet. 2014;7:359-364 

  • Sequencing of SCN5A Identifies Rare and Common Variants Associated With Cardiac Conduction: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.
    Jared W. Magnani, Jennifer A. Brody, Bram P. Prins, Dan E. Arking, Honghuang Lin, Xiaoyan Yin, Ching-Ti Liu, Alanna C. Morrison, Feng Zhang, Tim D. Spector, Alvaro Alonso, Joshua C. Bis, Susan R. Heckbert, Thomas Lumley, Colleen M. Sitlani, L. Adrienne Cupples, Steven A. Lubitz, Elsayed Z. Soliman, Sara L. Pulit, Christopher Newton-Cheh, Christopher J. O’Donnell, Patrick T. Ellinor, Emelia J. Benjamin, Donna M. Muzny, Richard A. Gibbs, Jireh Santibanez, Herman A. Taylor, Jerome I. Rotter, Leslie A. Lange, Bruce M. Psaty, Rebecca Jackson, Stephen S. Rich, Eric Boerwinkle, Yalda Jamshidi, and Nona Sotoodehnia , for CHARGE Consortium, the NHLBI’s Exome Sequencing Project (ESP), and the UK10K
    Circ Cardiovasc Genet. 2014;7:365-373

  • Sequence Variation in TMEM18 in Association With Body Mass Index: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.
    Ching-Ti Liu, Kristin L. Young, Jennifer A. Brody, Matthias Olden, Mary K. Wojczynski, Nancy Heard-Costa, Guo Li, Alanna C. Morrison, Donna Muzny, Richard A. Gibbs, Jeffrey G. Reid, Yaming Shao, Yanhua Zhou, Eric Boerwinkle, Gerardo Heiss, Lynne Wagenknecht, Barbara McKnight, Ingrid B. Borecki, Caroline S. Fox, Kari E. North, and L. Adrienne Cupples.
    Circ Cardiovasc Genet. 2014;7:344-349

  • Targeted Sequencing in Candidate Genes for Atrial Fibrillation: The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study
    Honghuang Lin, Moritz F. Sinner, Jennifer A. Brody, Dan E. Arking, Kathryn L. Lunetta, Michiel Rienstra, Steven A. Lubitz, Jared W. Magnani, Nona Sotoodehnia, Barbara McKnight, David D. McManus, Eric Boerwinkle, Bruce M. Psaty, Jerome I. Rotter, Joshua C. Bis, Richard A. Gibbs, Donna Muzny, Christie L. Kovar, Alanna C. Morrison, Mayetri Gupta, Aaron R. Folsom, Stefan Kääb, Susan R. Heckbert, Alvaro Alonso, Patrick T. Ellinor, Emelia J. Benjamin, on behalf of the CHARGE Atrial Fibrillation Working Group.
    Heart Rhythm. 2014 Mar;11(3):452-7. (subscription requiredPMID:24239840)

  • Associations of NINJ2 Sequence Variants with Incident Ischemic Stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) Consortium.
    Joshua C. Bis, Anita DeStefano, Xiaoming Liu, Jennifer A. Brody, Seung Hoan Choi, Benjamin F. J. Verhaaren, Stéphanie Debette, M. Arfan Ikram, Eyal Shahar, Kenneth R. Butler Jr, Rebecca F. Gottesman, Donna Muzny, Christie L. Kovar, Bruce M. Psaty, Albert Hofman, Thomas Lumley,Mayetri Gupta, Philip A. Wolf, Cornelia van Duijn, Richard A. Gibbs, Thomas H. Mosley, W. T. Longstreth Jr, Eric Boerwinkle, Sudha Seshadri, Myriam Fornage.
    PLoS One. 2014 Jun 24;9(6):e99798. doi: 10.1371/journal.pone.0099798. eCollection 2014.

  • Sequence Analysis of Six Blood Pressure Candidate Regions in 4,178 Individuals: The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study. Alanna C. Morrison, Joshua C. Bis, Shih-Jen Hwang, Georg B. Ehret, Thomas Lumley, Kenneth Rice, Donna Muzny, Richard A. Gibbs, Eric Boerwinkle, Bruce M. Psaty, Aravinda Chakravarti, Daniel Levy.
    PLoS One. 2014 Oct 2;9(10):e109155. doi: 10.1371/journal.pone.0109155. eCollection 2014.

Perspective

  • Following-Up Genome-Wide Association Study Signals: Lessons Learned From Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.
    Eric Boerwinkle and Susan R. Heckbert.
    Circ Cardiovasc Genet. 2014;7:332-334





Funding support for "Building on GWAS for NHLBI-diseases: the U.S. CHARGE Consortium" was provided by the NIH through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). Data for "Building on GWAS for NHLBI-diseases: the U.S. CHARGE Consortium" was provided by Eric Boerwinkle on behalf of the Atherosclerosis Risk in Communities (ARIC) Study, L. Adrienne Cupples, principal investigator for the Framingham Heart Study, and Bruce Psaty, principal investigator for the Cardiovascular Health Study. Sequencing was carried out at the Baylor Genome Center (U54 HG003273).

The ARIC Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). The Framingham Heart Study is conducted and supported by the NHLBI in collaboration with Boston University (Contract No. N01-HC-25195), and its contract with Affymetrix, Inc., for genome-wide genotyping services (Contract No. N02-HL-6-4278), for quality control by Framingham Heart Study investigators using genotypes in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.