title: Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol.
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.
authors: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Leslie A
authors: LA
authors: Lange
authors: Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Youna
authors: Y
authors: Hu
authors: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors: He
authors: H
authors: Zhang
authors: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Chenyi
authors: C
authors: Xue
authors: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Ellen M
authors: EM
authors: Schmidt
authors: Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Zheng-Zheng
authors: ZZ
authors: Tang
authors: Renaissance Computing Institute, Chapel Hill, NC 27517, USA.
authors: Chris
authors: C
authors: Bizon
authors: 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.
authors: Ethan M
authors: EM
authors: Lange
authors: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors: Joshua D
authors: JD
authors: Smith
authors: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors: Emily H
authors: EH
authors: Turner
authors: Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Goo
authors: G
authors: Jun
authors: Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Hyun Min
authors: HM
authors: Kang
authors: 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.
authors: Gina
authors: G
authors: Peloso
authors: 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.
authors: Paul
authors: P
authors: Auer
authors: Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Kuo-Ping
authors: KP
authors: Li
authors: Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Jason
authors: J
authors: Flannick
authors: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Ji
authors: J
authors: Zhang
authors: Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Christian
authors: C
authors: Fuchsberger
authors: Wellcome Trust Centre for Human Genetics, University of Oxford, OX1 2JD Oxford, UK.
authors: Kyle
authors: K
authors: Gaulton
authors: Wellcome Trust Centre for Human Genetics, University of Oxford, OX1 2JD Oxford, UK.
authors: Cecilia
authors: C
authors: Lindgren
authors: Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Adam
authors: A
authors: Locke
authors: 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.
authors: Alisa
authors: A
authors: Manning
authors: Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Xueling
authors: X
authors: Sim
authors: Wellcome Trust Centre for Human Genetics, University of Oxford, OX1 2JD Oxford, UK.
authors: Manuel A
authors: MA
authors: Rivas
authors: HUNT Research Center, Department of Public Health, Norwegian University of Science and Technology, 7600 Levanger, Norway.
authors: Oddgeir L
authors: OL
authors: Holmen
authors: The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Omri
authors: O
authors: Gottesman
authors: 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.
authors: Yingchang
authors: Y
authors: Lu
authors: Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Douglas
authors: D
authors: Ruderfer
authors: Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Eli A
authors: EA
authors: Stahl
authors: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Qing
authors: Q
authors: Duan
authors: 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.
authors: Yun
authors: Y
authors: Li
authors: Department of Pathology, University of Vermont, Colchester, VT 05446, USA.
authors: Peter
authors: P
authors: Durda
authors: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors: Shuo
authors: S
authors: Jiao
authors: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, 3015 DR Rotterdam, the Netherlands.
authors: Aaron
authors: A
authors: Isaacs
authors: Department of Epidemiology, Erasmus University Medical Center, 3000 DR Rotterdam, the Netherlands.
authors: Albert
authors: A
authors: Hofman
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
authors: Joshua C
authors: JC
authors: Bis
authors: Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors: Adolfo
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authors: Correa
authors: Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors: Michael E
authors: ME
authors: Griswold
authors: Icelandic Heart Association, IS-201 Kopavogur, Iceland.
authors: Johanna
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authors: Jakobsdottir
authors: Icelandic Heart Association, IS-201 Kopavogur, Iceland; University of Iceland, 101 Reykjavik, Iceland.
authors: Albert V
authors: AV
authors: Smith
authors: Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55454, USA.
authors: Pamela J
authors: PJ
authors: Schreiner
authors: Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Mary F
authors: MF
authors: Feitosa
authors: Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Qunyuan
authors: Q
authors: Zhang
authors: Medical Research Center for Human Genetics, Medical Research Center Institute of Genetics and Molecular Medicine, University of Edinburgh, EH4 2XU Edinburgh, UK.
authors: Jennifer E
authors: JE
authors: Huffman
authors: Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors: Jacy
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authors: Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors: Christina L
authors: CL
authors: Wassel
authors: 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.
authors: Ron
authors: R
authors: Do
authors: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Nora
authors: N
authors: Franceschini
authors: Division of Cardiology, George Washington School of Medicine and Health Sciences, Washington, DC 20037, USA.
authors: Lisa W
authors: LW
authors: Martin
authors: Departments of Epidemiology and Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors: Jennifer G
authors: JG
authors: Robinson
authors: Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Themistocles L
authors: TL
authors: Assimes
authors: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA; Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
authors: David R
authors: DR
authors: Crosslin
authors: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
authors: Elisabeth A
authors: EA
authors: Rosenthal
authors: Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55454, USA.
authors: Michael
authors: M
authors: Tsai
authors: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors: Mark J
authors: MJ
authors: Rieder
authors: Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA.
authors: Deborah N
authors: DN
authors: Farlow
authors: Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55454, USA.
authors: Aaron R
authors: AR
authors: Folsom
authors: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA; Department of Statistics, University of Auckland, Auckland 1142, New Zealand.
authors: Thomas
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authors: Lumley
authors: Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors: Ervin R
authors: ER
authors: Fox
authors: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors: Christopher S
authors: CS
authors: Carlson
authors: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors: Ulrike
authors: U
authors: Peters
authors: Division of Endocrinology, Ohio State University, Columbus, OH 43210, USA.
authors: Rebecca D
authors: RD
authors: Jackson
authors: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, 3015 DR Rotterdam, the Netherlands.
authors: Cornelia M
authors: CM
authors: van Duijn
authors: Department of Internal Medicine, Erasmus University Medical Center, 3000 DR Rotterdam, the Netherlands.
authors: André G
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authors: Uitterlinden
authors: 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.
authors: Daniel
authors: D
authors: Levy
authors: Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute, and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
authors: Jerome I
authors: JI
authors: Rotter
authors: 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.
authors: Herman A
authors: HA
authors: Taylor
authors: Icelandic Heart Association, IS-201 Kopavogur, Iceland; University of Iceland, 101 Reykjavik, Iceland.
authors: Vilmundur
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authors: Gudnason
authors: 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.
authors: David S
authors: DS
authors: Siscovick
authors: 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.
authors: Myriam
authors: M
authors: Fornage
authors: Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Ingrid B
authors: IB
authors: Borecki
authors: Medical Research Center for Human Genetics, Medical Research Center Institute of Genetics and Molecular Medicine, University of Edinburgh, EH4 2XU Edinburgh, UK.
authors: Caroline
authors: C
authors: Hayward
authors: Centre for Population Health Sciences, Medical School, University of Edinburgh, EH8 9YL Edinburgh, UK.
authors: Igor
authors: I
authors: Rudan
authors: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Y Eugene
authors: YE
authors: Chen
authors: The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Erwin P
authors: EP
authors: Bottinger
authors: 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.
authors: Ruth J F
authors: RJ
authors: Loos
authors: 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.
authors: Pål
authors: P
authors: Sætrom
authors: HUNT Research Center, Department of Public Health, Norwegian University of Science and Technology, 7600 Levanger, Norway.
authors: Kristian
authors: K
authors: Hveem
authors: Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Michael
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authors: Boehnke
authors: 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.
authors: Leif
authors: L
authors: Groop
authors: 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.
authors: Mark
authors: M
authors: McCarthy
authors: 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.
authors: Thomas
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authors: Meitinger
authors: Baylor College of Medicine, Houston, TX 77030, USA; Houston Methodist DeBakey Heart and Vascular Center, Houston, TX 77030, USA.
authors: Christie M
authors: CM
authors: Ballantyne
authors: Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA.
authors: Stacey B
authors: SB
authors: Gabriel
authors: Center for Population Studies, National Heart, Lung, and Blood Institute, Framingham, MA 01702, USA; Cardiology Division, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Christopher J
authors: CJ
authors: O'Donnell
authors: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors: Wendy S
authors: WS
authors: Post
authors: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Kari E
authors: KE
authors: North
authors: Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
authors: Alexander P
authors: AP
authors: Reiner
authors: Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors: Eric
authors: E
authors: Boerwinkle
authors: 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.
authors: Bruce M
authors: BM
authors: Psaty
authors: 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.
authors: David
authors: D
authors: Altshuler
authors: 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.
authors: Sekar
authors: S
authors: Kathiresan
authors: Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Dan-Yu
authors: DY
authors: Lin
authors: 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.
authors: Gail P
authors: GP
authors: Jarvik
authors: 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.
authors: L Adrienne
authors: LA
authors: Cupples
authors: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors: Charles
authors: C
authors: Kooperberg
authors: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors: James G
authors: JG
authors: Wilson
authors: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors: Deborah A
authors: DA
authors: Nickerson
authors: Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Goncalo R
authors: GR
authors: Abecasis
authors: Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
authors: Stephen S
authors: SS
authors: Rich
authors: Department of Pathology, University of Vermont, Colchester, VT 05446, USA; Department of Biochemistry, University of Vermont, Burlington, VT 05405, USA.
authors: Russell P
authors: RP
authors: Tracy
authors: 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.
authors: Cristen J
authors: CJ
authors: Willer
mesh_terms: D000328:Adult; D000368:Aged; D001057:Apolipoproteins E / Q000097:blood / Q000235:genetics; D008078:Cholesterol, LDL / Q000235:genetics*; D015331:Cohort Studies; D050171:Dyslipidemias / Q000097:blood / Q000235:genetics; D059472:Exome; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D005815:Genetic Code; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008049:Lipase / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics; D017422:Sequence Analysis, DNA; D012697:Serine Endopeptidases / Q000235:genetics; D000217:Acyltransferases
chemical_list: D001057:Apolipoproteins E; D008078:Cholesterol, LDL; D008049:Lipase; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011973:Receptors, LDL; D012697:Serine Endopeptidases; C573412:LDLR protein, human; C549685:PNPLA5 protein, human; D000217:Acyltransferases; C472125:PCSK9 protein, human