Deep-coverage whole genome sequences and blood lipids among 16,324 individuals
Pradeep Natarajan(Broad Institute), Gina M. Peloso(Boston University), Seyedeh M. Zekavat(Broad Institute), May E. Montasser(University of Maryland, Baltimore), Andrea Ganna(Broad Institute), Mark Chaffin(Broad Institute), Amit V. Khera(Broad Institute), Wei Zhou(University of Michigan), Jonathan M. Bloom(Broad Institute), J Engreitz(Broad Institute), Jason Ernst(University of California, Los Angeles), Jeffrey R. O’Connell(University of Maryland, Baltimore), Sanni Ruotsalainen(Institute for Molecular Medicine Finland), Maris Alver(University of Tartu), Ani Manichaikul(University of Virginia), W. Craig Johnson(University of Washington), James A. Perry(University of Maryland, Baltimore), Timothy Poterba(Broad Institute), Cotton Seed(Broad Institute), Ida Surakka(Institute for Molecular Medicine Finland), Tõnu Esko(University of Tartu), Samuli Ripatti(Institute for Molecular Medicine Finland), Veikko Salomaa(Institute for Molecular Medicine Finland), Adolfo Correa(Jackson Memorial Hospital), Ramachandran S. Vasan(Boston University), Manolis Kellis(Broad Institute), Benjamin M. Neale(Broad Institute), Eric S. Lander(Broad Institute), Gonçalo R. Abecasis(University of Michigan), Braxton D. Mitchell(University of Maryland, Baltimore), Stephen S. Rich(University of Virginia), James G. Wilson(Jackson Memorial Hospital), L. Adrienne Cupples(Boston University), Jerome I. Rotter(The Lundquist Institute), Cristen J. Willer(University of Michigan), Sekar Kathiresan(Broad Institute), NHLBI TOPMed Lipids Working Group(New York Genome Center), Namiko Abe(Massachusetts General Hospital), Christine M. Albert(University of Michigan), Nicholette Palmer Allred(Children's Hospital of Philadelphia), Laura Almasy(Emory University), Álvaro Alonso(University of Maryland, Baltimore), Seth A. Ament(University of Washington), Peter Anderson(University of Mississippi), Pramod Anugu(National Institutes of Health), Deborah Applebaum‐Bowden(Johns Hopkins University), Dan E. Arking(University of Kentucky), Donna K. Arnett(Duke University), Allison E. Ashley‐Koch(University of Alabama at Birmingham), Stella Aslibekyan(Stanford University), Tim Assimes(University of Wisconsin–Milwaukee), Paul L. Auer(Johns Hopkins University), Dimitrios Avramopoulos(Cleveland Clinic), J. A. Barnard(University of Colorado Denver), Kathleen C. Barnes(Columbia University), R. Graham Barr(Johns Hopkins University), Emily Barron‐Casella(Johns Hopkins University), Terri H. Beaty(Johns Hopkins University), Diane M. Becker(Johns Hopkins University), Lewis C. Becker(National Institutes of Health), Rebecca Beer(Johns Hopkins University), Ferdouse Begum(University of Maryland, Baltimore), Amber L. Beitelshees(Massachusetts General Hospital), Emelia J. Benjamin(Fundação Hemopa), Marcos Bezerra(University of Michigan), Larry Bielak(University of Washington), Joshua C. Bis(University of Michigan), Thomas W. Blackwell(The University of Texas Rio Grande Valley), John Blangero(The University of Texas Health Science Center at Houston), Eric Boerwinkle(University of Washington), Ingrid B. Borecki(National Jewish Health), Russell P. Bowler(University of Washington), Jennifer A. Brody(Medical College of Wisconsin), Ulrich Broeckel(University of Washington), Jai Broome(New York Genome Center), Karen Bunting(University of California, San Francisco), Esteban Burchard(University of Colorado Denver), Jonathan Cardwell(Women's Health Initiative), Cara L. Carty(University of California, Los Angeles), Richard Casaburi(Johns Hopkins University), James F. Casella(University of Maryland, Baltimore), Christy Chang(Brigham and Women's Hospital), Daniel I. Chasman(University of Colorado Denver), Sameer Chavan(New York Genome Center), Bo-Juen Chen(University of Virginia), Wei‐Min Chen(The Lundquist Institute), Yii-Der Ida Chen(Brigham and Women's Hospital), Michael H. Cho(Broad Institute), Seung Hoan Choi(National Taiwan University), Lee‐Ming Chuang(Cleveland Clinic), Mina K. Chung(University of Vermont), Elaine Cornell(University of California, Los Angeles), Carolyn Crandall(National Jewish Health), James D. Crapo(The University of Texas Rio Grande Valley), Joanne E. Curran(University of Michigan), Jeffrey L. Curtis(Blood Systems Research Institute), Brian Custer(University of Maryland, Baltimore), Coleen Damcott(University of Illinois Chicago), Dawood Darbar(University of Michigan), Sayantan Das(Stanford University), Sean P. David(University of Washington), Colleen Davis(University of Colorado Denver), Michelle Daya(Mayo Clinic in Arizona), Mariza de Andrade(Vanderbilt University), Michael R. DeBaun(University of Cincinnati), Ranjan Deka(Brigham and Women's Hospital), Dawn L. DeMeo(University of Maryland, Baltimore), Scott E. Devine(Icahn School of Medicine at Mount Sinai), Ron Do(University of North Carolina at Chapel Hill), Qing Duan(The University of Texas Rio Grande Valley), Ravi Duggirala(University of Vermont), Peter Durda(Washington University in St. Louis), Susan K. Dutcher(Brown University), Charles B. Eaton(University of Mississippi), Lynette Ekunwe(Massachusetts General Hospital), Patrick T. Ellinor(University of Washington), Leslie S. Emery(University of Virginia), Charles R. Farber(Brigham and Women's Hospital), Leanna Farnam(National Jewish Health), Tasha E. Fingerlin(University of Michigan), Matthew Flickinger(The University of Texas Health Science Center at Houston), Myriam Fornage(University of North Carolina at Chapel Hill), Nora Franceschini(University of Maryland, Baltimore), Mao Fu(University of Washington), Malia Fullerton(Washington University in St. Louis), Lucinda A. Fulton(Broad Institute), Stacey Gabriel(National Institutes of Health), Weiniu Gan(University of Mississippi), Yan Gao(Fred Hutch Cancer Center), Margery Gass(Icahn School of Medicine at Mount Sinai), Bruce D. Gelb, Xiaoqi Geng(New York Genome Center), Søren Germer(Stanford University), Chris Gignoux(University of Pittsburgh), Mark T. Gladwin(Yale University), David C. Glahn(University of Washington), Stephanie M. Gogarten(University of Maryland, Baltimore), Da‐Wei Gong(The University of Texas Rio Grande Valley), Harald H.H. Göring(Washington University in St. Louis), C. Charles Gu(University of Maryland, Baltimore), Yue Guan(The Lundquist Institute), Xiuqing Guo(Women's Health Initiative), Jeff Haessler(University of Mississippi), Michael E. Hall(University of Maryland, Baltimore), Daniel Harris(Yale University), Nicola L. Hawley(Tulane University), Jiang He(University of Washington), Ben Heavner(University of Washington), Susan R. Heckbert(University of California, San Francisco), Ryan D. Hernandez(Atrium Health Wake Forest Baptist), David M. Herrington(Brigham and Women's Hospital), Craig P. Hersh(University of Alabama at Birmingham), Bertha Hidalgo(The University of Texas Health Science Center at Houston), James E. Hixson(University of Colorado Denver), John S. Hokanson(University of Maryland, Baltimore), Elliott Hong(University of Iowa), Karin F. Hoth, Chao A. Hsiung(Bloodworks Northwest), Haley Huston(Taichung Veterans General Hospital), Chii Min Hwu(University of Alabama at Birmingham), Marguerite R. Irvin(The Ohio State University Wexner Medical Center), Rebecca Jackson(University of Washington), Deepti Jain(National Institutes of Health), Cashell E. Jaquish(University of Michigan), Min A. Jhun(University of Washington), Jill M. Johnsen(National Heart Lung and Blood Institute), Andrew D. Johnson(Emory University), Rich Johnston(Johns Hopkins University), Kimberly Marie Jones(University of Michigan), Hyun Min Kang(Albert Einstein College of Medicine), Robert C. Kaplan(University of Michigan), Sharon L. R. Kardia(Brigham and Women's Hospital), Laura J. Kaufman(Blood Systems Research Institute), Shannon Kelly(Icahn School of Medicine at Mount Sinai), Eimear E. Kenny(University of Maryland, Baltimore), Michael Kessler(University of Washington), Alyna Khan(University of Colorado Denver), Gregory L. Kinney(Bloodworks Northwest), Barbara A. Konkle(Fred Hutch Cancer Center), Charles Kooperberg(Loyola University Chicago), Holly Kramer(University of Washington), Stephanie Krauter(Harvard University), Christoph Lange(University of Colorado Denver), Ethan M. Lange(University of Colorado Denver), Leslie A. Lange(University of Washington), Cathy C. Laurie(University of Washington), Cecelia Laurie(Brigham and Women's Hospital), Meryl S. LeBoff(University of Michigan), Seunggeun Shawn Lee(Taichung Veterans General Hospital), Wen‐Jane Lee(University of Michigan), Jonathon LeFaive(University of Washington), David Levine(National Heart Lung and Blood Institute), Daniel Levy(University of Maryland, Baltimore), Joshua R. Lewis(University of North Carolina at Chapel Hill), Yun Li(Boston University), Honghuang Lin(University of Michigan), Keng Han Lin(Women's Health Initiative), Simin Liu(Atrium Health Wake Forest Baptist), Yongmei Liu(Icahn School of Medicine at Mount Sinai), Ruth J. F. Loos(Massachusetts General Hospital), Steven A. Lubitz(Boston University), Kathryn L. Lunetta(National Heart Lung and Blood Institute), James Luo(The University of Texas Rio Grande Valley), Michael C. Mahaney(Johns Hopkins University), Barry J. Make(Brigham and Women's Hospital), JoAnn E. Manson(Broad Institute), Lauren Margolin(George Washington University), Lisa W. Martin(University of Colorado Denver), Susan Mathai(Johns Hopkins University), Rasika A. Mathias(University of Maryland, Baltimore), Patrick F. McArdle(University of Alabama at Birmingham), Merry‐Lynn McDonald(Harvard University Press), Sean McFarland(Brown University), Stephen T. McGarvey(University of Mississippi), Hao Mei(University of Arizona), Deborah A. Meyers(National Institutes of Health), Julie Mikulla(University of Mississippi), Yuan‐I Min(National Institutes of Health), Mollie Minear(University of Pittsburgh), Ryan L. Minster(University of Mississippi), Solomon K. Musani(University of Mississippi), Stanford Mwasongwe(University of Virginia), Josyf C. Mychaleckyj(Icahn School of Medicine at Mount Sinai), Girish N. Nadkarni(Johns Hopkins University), Rakhi P. Naik(Howard University), Sergeï Nekhai(University of Washington), Deborah A. Nickerson(University of North Carolina at Chapel Hill), Kari North(University of Maryland, Baltimore), Tim O’Connor(University at Buffalo, State University of New York), Heather M. Ochs‐Balcom(University of Minnesota), James S. Pankow(National Institutes of Health), George Papanicolaou(Brigham and Women's Hospital), Margaret M. Parker(University of Maryland, Baltimore), Afshin Parsa(National Jewish Health), Sara Penchev(The University of Texas Rio Grande Valley), Juan M. Peralta(Stanford University), Marco Perez(Fred Hutch Cancer Center), Ulrike Peters(University of Michigan), Patricia A. Peyser(Emory University), Larry Phillips(University of Washington), Sam Phillips(University of Maryland, Baltimore), Toni I. Pollin(Johns Hopkins University), Wendy S. Post(University of Colorado Denver), Julia Powers Becker(University of Colorado Denver), Meher Preethi Boorgula(Icahn School of Medicine at Mount Sinai), Michael Preuß(Harvard University Press), Dmitry Prokopenko(University of Washington), Bruce M. Psaty(National Institutes of Health), Pankaj Qasba(Brigham and Women's Hospital), Dandi Qiao(Emory University), Zhaohui Qin(University of Colorado Denver), Nicholas Rafaels(University of North Carolina at Chapel Hill), Laura M. Raffield(Washington University in St. Louis), D. C. Rao(Northwestern University), Laura J. Rasmussen‐Torvik(University of Virginia), Aakrosh Ratan(Brigham and Women's Hospital), Susan Redline(University of Maryland, Baltimore), Robert D. Reed(National Jewish Health), Elizabeth Regan(Fred Hutch Cancer Center), Alex P. Reiner(University of Washington), Kenneth Rice(Vanderbilt University), Dan M. Roden(Broad Institute), Carolina Roselli(Johns Hopkins University), Ingo Ruczinski(University of Colorado Denver), Pamela Russell(Bloodworks Northwest), Sarah Ruuska(University of Maryland, Baltimore), Kathleen A. Ryan(Brigham and Women's Hospital), Phuwanat Sakornsakolpat(University of Maryland, Baltimore), Shabnam Salimi(Johns Hopkins University), Steven L. Salzberg(The Lundquist Institute), Kevin Sandow(Harvard University Press), Vijay G. Sankaran(University of Michigan), Ellen M. Schmidt(Washington University in St. Louis), Karen Schwander(University of Colorado Denver), David Schwartz(University of Pittsburgh), Frank C. Sciurba(Harvard University), Christine E. Seidman(Baylor College of Medicine), Vivien Sheehan(University of Maryland, Baltimore), Amol C. Shetty(University of Colorado Denver), Aniket Shetty(Taichung Veterans General Hospital), Wayne Hui-Heng Sheu(Vanderbilt University), M. Benjamin Shoemaker(UMass Memorial Health Care), Brian Silver(Brigham and Women's Hospital), Edwin K. Silverman(University of Michigan), Jennifer A. Smith(University of Washington), Josh Smith(University of Washington), Nicholas L. Smith(New York Genome Center), Tanja Smith(Albert Einstein College of Medicine), Sylvia Smoller(Atrium Health Wake Forest Baptist), Beverly M. Snively(Brigham and Women's Hospital), Tamar Sofer(University of Washington), Nona Sotoodehnia(University of Washington), Adrienne M. Stilp(University of Maryland, Baltimore), Elizabeth A. Streeten(Washington University in St. Louis), Yun Ju Sung(Brigham and Women's Hospital), Jody Sylvia(University of Washington), Adam A. Szpiro(University of Maryland, Baltimore), Carole Sztalryd(University of Michigan), Daniel Taliun(Stanford University), Hua Tang(Johns Hopkins University), Margaret A. Taub(The Lundquist Institute), Kent D. Taylor(University of Maryland, Baltimore), Simeon I. Taylor(Duke University), Marilyn J. Telen(University of Washington), Timothy Thornton(Women's Health Initiative), Lesley F. Tinker(University of Washington), David Tirschwell(University of Alabama at Birmingham), Hemant K. Tiwari(University of Vermont), Russell P. Tracy(University of Minnesota), Michael Tsai(Johns Hopkins University), Dhananjay Vaidya(University of Michigan), Peter VandeHaar(University of Minnesota), Scott Vrieze(University of Colorado Denver), Tarik Walker(University of Iowa), Robert K. Wallace(University of Colorado Denver), Avram Walts(Brigham and Women's Hospital), Emily S. Wan(University of Washington), Fei Fei Wang(University of California, Los Angeles), Karol Watson(University of Pittsburgh), Daniel E. Weeks(University of Washington), B. S. Weir(Brigham and Women's Hospital), Scott T. Weiss(Massachusetts General Hospital), Lu‐Chen Weng(University of Michigan), Cristen J. Willer(University of Washington), Kayleen Williams(Henry Ford Health System), L. Keoki Williams(Brigham and Women's Hospital), Carla Wilson(University of Washington), Quenna Wong(University of Maryland, Baltimore), Huichun Xu(Johns Hopkins University), Lisa R. Yanek(University of Colorado Denver), Ivana V. Yang(University of Maryland, Baltimore), Rongze Yang(University of Maryland, Baltimore), Norann A. Zaghloul(University of Pittsburgh), Yingze Zhang(National Jewish Health), Snow Xueyan Zhao(University of Washington), Xiuwen Zheng(The University of Texas Health Science Center at Houston), Degui Zhi(University of Michigan), Xiang Zhou(New York Genome Center), Michael C. Zody(University of Michigan), Sebastian Zoellner
Cited by 200Open Access
Abstract
Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth >29X and analyze genotypes with four quantitative traits-plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among those with severe hypercholesterolemia, 23% have a high polygenic score and only 2% carry a monogenic mutation. At these sample sizes and for these phenotypes, the incremental value of WGS for discovery is limited but WGS permits simultaneous assessment of monogenic and polygenic models to severe hypercholesterolemia.
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