Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol

Leslie A Lange; Youna Hu; He Zhang; Chenyi Xue; Ellen M Schmidt; Zheng-Zheng Tang; Chris Bizon; Ethan M Lange; Joshua D Smith; Emily H Turner; Goo Jun; Hyun Min Kang; Gina Peloso; Paul Auer; Kuo-Ping Li; Jason Flannick; Ji Zhang; Christian Fuchsberger; Kyle Gaulton; Cecilia Lindgren; Adam Locke; Alisa Manning; Xueling Sim; Manuel A Rivas; Oddgeir L Holmen; Omri Gottesman; Yingchang Lu; Douglas Ruderfer; Eli A Stahl; Qing Duan; Yun Li; Peter Durda; Shuo Jiao; Aaron Isaacs; Albert Hofman; Joshua C Bis; Adolfo Correa; Michael E Griswold; Johanna Jakobsdottir; Albert V Smith; Pamela J Schreiner; Mary F Feitosa; Jennifer E Huffman; Jacy Crosby; Christina L Wassel; Ron Do; Nora Franceschini; Lisa W Martin; Jennifer G Robinson; Themistocles L Assimes; David R Crosslin; Elisabeth A Rosenthal; Michael Tsai; Mark J Rieder; Deborah N Farlow; Aaron R Folsom; Thomas Lumley; Ervin R Fox; Christopher S Carlson; Ulrike Peters; Rebecca D Jackson; Cornelia M van Duijn; André G Uitterlinden; Daniel Levy; Jerome I Rotter; Herman A Taylor; Vilmundur Gudnason Jr; David S Siscovick; Myriam Fornage; Ingrid B Borecki; Caroline Hayward; Igor Rudan; Y Eugene Chen; Erwin P Bottinger; Ruth J F Loos; Pål Sætrom; Kristian Hveem; Michael Boehnke; Leif Groop; Mark McCarthy; Thomas Meitinger; Christie M Ballantyne; Stacey B Gabriel; Christopher J O'Donnell; Wendy S Post; Kari E North; Alexander P Reiner; Eric Boerwinkle; Bruce M Psaty; David Altshuler; Sekar Kathiresan; Dan-Yu Lin; Gail P Jarvik; L Adrienne Cupples; Charles Kooperberg; James G Wilson; Deborah A Nickerson; Goncalo R Abecasis; Stephen S Rich; Russell P Tracy; Cristen J Willer; NHLBI Grand Opportunity Exome Sequencing Project; Qunyuan Zhang

doi:10.1016/j.ajhg.2014.01.010

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Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol

Journal article

Open access

Peer reviewed

Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol

Leslie A Lange, Youna Hu, He Zhang, Chenyi Xue, Ellen M Schmidt, Zheng-Zheng Tang, Chris Bizon, Ethan M Lange, Joshua D Smith, Emily H Turner, …

American journal of human genetics, Vol.94(2), pp.233-245

02/06/2014

DOI: 10.1016/j.ajhg.2014.01.010

PMCID: PMC3928660

PMID: 24507775

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Abstract

Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.

Phenotype

Dyslipidemias - genetics

Genetic Code

Follow-Up Studies

Humans

Middle Aged

Male

Proprotein Convertases - genetics

Exome

Dyslipidemias - blood

Serine Endopeptidases - genetics

Adult

Female

Receptors, LDL - genetics

Genome-Wide Association Study

Gene Frequency

Genotype

Sequence Analysis, DNA

Cholesterol, LDL - genetics

Apolipoproteins E - blood

Apolipoproteins E - genetics

Aged

Polymorphism, Single Nucleotide

Cohort Studies

Lipase - genetics

Proprotein Convertase 9

Details

Title: Subtitle: Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol
Creators: Leslie A Lange - Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Youna Hu - Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA
He Zhang - Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
Chenyi Xue - Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA
Ellen M Schmidt - Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA
Zheng-Zheng Tang - Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Chris Bizon - Renaissance Computing Institute, Chapel Hill, NC 27517, USA
Ethan M Lange - Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Joshua D Smith - Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
Emily H Turner - Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
Goo Jun - Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA
Hyun Min Kang - Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA
Gina Peloso - Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA
Paul Auer - Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; School of Public Health, University of Wisconsin - Milwaukee, Milwaukee, WI 53201, USA
Kuo-Ping Li - Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA
Jason Flannick - Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA
Ji Zhang - University of Michigan–Ann Arbor
Christian Fuchsberger - Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA
Kyle Gaulton - Wellcome Trust Centre for Human Genetics, University of Oxford, OX1 2JD Oxford, UK
Cecilia Lindgren - Wellcome Trust Centre for Human Genetics, University of Oxford, OX1 2JD Oxford, UK
Adam Locke - Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA
Alisa Manning - Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA; School of Public Health, University of Wisconsin - Milwaukee, Milwaukee, WI 53201, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA; Department of Genetics, Harvard Medical School, Boston, MA 02138, USA
Xueling Sim - Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA
Manuel A Rivas - Wellcome Trust Centre for Human Genetics, University of Oxford, OX1 2JD Oxford, UK
Oddgeir L Holmen - HUNT Research Center, Department of Public Health, Norwegian University of Science and Technology, 7600 Levanger, Norway
Omri Gottesman - The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Yingchang Lu - The Genetics of Obesity and Related Metabolic Traits Program, The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Douglas Ruderfer - Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Eli A Stahl - Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Qing Duan - Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Yun Li - Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Peter Durda - Department of Pathology, University of Vermont, Colchester, VT 05446, USA
Shuo Jiao - Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
Aaron Isaacs - Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, 3015 DR Rotterdam, the Netherlands
Albert Hofman - Department of Epidemiology, Erasmus University Medical Center, 3000 DR Rotterdam, the Netherlands
Joshua C Bis - Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98195, USA
Adolfo Correa - Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA
Michael E Griswold - Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA
Johanna Jakobsdottir - Icelandic Heart Association, IS-201 Kopavogur, Iceland
Albert V Smith - Icelandic Heart Association, IS-201 Kopavogur, Iceland; University of Iceland, 101 Reykjavik, Iceland
Pamela J Schreiner - Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55454, USA
Mary F Feitosa - Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
Jennifer E Huffman - Medical Research Center for Human Genetics, Medical Research Center Institute of Genetics and Molecular Medicine, University of Edinburgh, EH4 2XU Edinburgh, UK
Jacy Crosby - Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Christina L Wassel - Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA 15261, USA
Ron Do - Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA
Nora Franceschini - Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Lisa W Martin - Division of Cardiology, George Washington School of Medicine and Health Sciences, Washington, DC 20037, USA
Jennifer G Robinson - Departments of Epidemiology and Medicine, University of Iowa, Iowa City, IA 52242, USA
Themistocles L Assimes - Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
David R Crosslin - Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA; Department of Biostatistics, University of Washington, Seattle, WA 98195, USA
Elisabeth A Rosenthal - Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA
Michael Tsai - Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55454, USA
Mark J Rieder - Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
Deborah N Farlow - Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA
Aaron R Folsom - Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55454, USA
Thomas Lumley - Department of Biostatistics, University of Washington, Seattle, WA 98195, USA; Department of Statistics, University of Auckland, Auckland 1142, New Zealand
Ervin R Fox - Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA
Christopher S Carlson - Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
Ulrike Peters - Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
Rebecca D Jackson - Division of Endocrinology, Ohio State University, Columbus, OH 43210, USA
Cornelia M van Duijn - Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, 3015 DR Rotterdam, the Netherlands
André G Uitterlinden - Department of Internal Medicine, Erasmus University Medical Center, 3000 DR Rotterdam, the Netherlands
Daniel Levy - Center for Population Studies, National Heart, Lung, and Blood Institute, Framingham, MA 01702, USA; Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA 01702, USA
Jerome I Rotter - Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute, and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA 90502, USA
Herman A Taylor - Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA; Tougaloo College, Jackson, MS 39174, USA; Jackson State University, Jackson, MS 39217, USA
Vilmundur Gudnason Jr - Icelandic Heart Association, IS-201 Kopavogur, Iceland; University of Iceland, 101 Reykjavik, Iceland
David S Siscovick - Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98195, USA; Department of Epidemiology, University of Washington, Seattle, WA 98195, USA; Department of Medicine, University of Washington Medical Center, Seattle, WA 98195, USA
Myriam Fornage - Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Ingrid B Borecki - Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
Caroline Hayward - Medical Research Center for Human Genetics, Medical Research Center Institute of Genetics and Molecular Medicine, University of Edinburgh, EH4 2XU Edinburgh, UK
Igor Rudan - Centre for Population Health Sciences, Medical School, University of Edinburgh, EH8 9YL Edinburgh, UK
Y Eugene Chen - Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
Erwin P Bottinger - The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Ruth J F Loos - The Genetics of Obesity and Related Metabolic Traits Program, The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Pål Sætrom - Department of Computer and Information Science, Norwegian University of Science and Technology, 7491 Trondheim, Norway; Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7489 Trondheim, Norway
Kristian Hveem - HUNT Research Center, Department of Public Health, Norwegian University of Science and Technology, 7600 Levanger, Norway
Michael Boehnke - Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA
Leif Groop - Department of Clinical Sciences, Diabetes, and Endocrinology, Lund University, Skåne University Hospital, 221 00 Malmö, Sweden; Glostrup Research Institute, Glostrup University Hospital, 2600 Glostrup, Denmark
Mark McCarthy - Oxford Centre for Diabetes, Endocrinology, and Metabolism and Oxford National Institute for Health Research Biomedical Research Centre, University of Oxford, Churchill Hospital, OX1 2JD Oxford, UK
Thomas Meitinger - Institute of Human Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Human Genetics, Technical University of Munich, 85764 Neuherberg, Germany
Christie M Ballantyne - Baylor College of Medicine, Houston, TX 77030, USA; Houston Methodist DeBakey Heart and Vascular Center, Houston, TX 77030, USA
Stacey B Gabriel - Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA
Christopher J O'Donnell - Center for Population Studies, National Heart, Lung, and Blood Institute, Framingham, MA 01702, USA; Cardiology Division, Massachusetts General Hospital, Boston, MA 02114, USA
Wendy S Post - Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Kari E North - Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Alexander P Reiner - Department of Epidemiology, University of Washington, Seattle, WA 98195, USA
Eric Boerwinkle - Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Bruce M Psaty - Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98195, USA; Department of Epidemiology, University of Washington, Seattle, WA 98195, USA; Department of Medicine, University of Washington Medical Center, Seattle, WA 98195, USA; Group Health Research Institute, Group Health Cooperative, Seattle, WA 98195, USA
David Altshuler - Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02138, USA
Sekar Kathiresan - Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA; Cardiology Division, Massachusetts General Hospital, Boston, MA 02114, USA
Dan-Yu Lin - Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Gail P Jarvik - Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA
L Adrienne Cupples - Center for Population Studies, National Heart, Lung, and Blood Institute, Framingham, MA 01702, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA 02215, USA
Charles Kooperberg - Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
James G Wilson - Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA
Deborah A Nickerson - Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
Goncalo R Abecasis - Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA
Stephen S Rich - Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA
Russell P Tracy - Department of Pathology, University of Vermont, Colchester, VT 05446, USA; Department of Biochemistry, University of Vermont, Burlington, VT 05405, USA
Cristen J Willer - Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: cristen@umich.edu
NHLBI Grand Opportunity Exome Sequencing Project
Qunyuan Zhang - Washington University in St. Louis
Resource Type: Journal article
Publication Details: American journal of human genetics, Vol.94(2), pp.233-245
Publisher: United States
DOI: 10.1016/j.ajhg.2014.01.010
PMID: 24507775
PMCID: PMC3928660
ISSN: 1537-6605
eISSN: 1537-6605
Grant note: R01 HL67406 / NHLBI NIH HHS U01 AG049505 / NIA NIH HHS R01 HL107816 / NHLBI NIH HHS RC2 HL-103010 / NHLBI NIH HHS R01 HL067406 / NHLBI NIH HHS RC2 HL102923 / NHLBI NIH HHS R01 HL109946 / NHLBI NIH HHS R01 AG033193 / NIA NIH HHS R01 CA082659 / NCI NIH HHS 090532 / Wellcome Trust RC2 HL-102926 / NHLBI NIH HHS T32 HL007208 / NHLBI NIH HHS P30 DK079637 / NIDDK NIH HHS RC2 HL102925 / NHLBI NIH HHS UL1 TR000124 / NCATS NIH HHS RC2 HL103010 / NHLBI NIH HHS P20 MD006899 / NIMHD NIH HHS RC2 HL-102923 / NHLBI NIH HHS R01HL107816 / NHLBI NIH HHS RC2 HL102924 / NHLBI NIH HHS R00 HL094535 / NHLBI NIH HHS R01 AG008122 / NIA NIH HHS RC2 HL102926 / NHLBI NIH HHS RC2 HL-102925 / NHLBI NIH HHS U01 DK062370 / NIDDK NIH HHS UC2 HL102925 / NHLBI NIH HHS UC2 HL102924 / NHLBI NIH HHS P30 DK020572 / NIDDK NIH HHS U01 HG007416 / NHGRI NIH HHS MC_PC_U127561128 / Medical Research Council R00HL94535 / NHLBI NIH HHS RC2 HL-102924 / NHLBI NIH HHS P30 DK063491 / NIDDK NIH HHS
Language: English
Date published: 02/06/2014
Academic Unit: Epidemiology; Internal Medicine
Record Identifier: 9983995028502771

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