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Am J Hum Genet. 2014 Feb 6;94(2):233-45. doi: 10.1016/j.ajhg.2014.01.010.

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

Collaborators (383)

Gabriel SB, Altshuler DM, Abecasis GR, Allayee H, Cresci S, Daly MJ, de Bakker PI, Depristo MA, Do R, Donnelly P, Farlow DN, Fennell T, Garimella K, Hazen SL, Hu Y, Jordan DM, Jun G, Kathiresan S, Kang HM, Kiezun A, Lettre G, Li B, Li M, Newton-Cheh CH, Padmanabhan S, Peloso G, Pulit S, Rader DJ, Reich D, Reilly MP, Rivas MA, Schwartz S, Scott L, Siscovick DS, Spertus JA, Stitziel NO, Stoletzki N, Sunyaev SR, Voight BF, Willer CJ, Rich SS, Akylbekova E, Atwood LD, Ballantyne CM, Barbalic M, Barr RG, Benjamin EJ, Bis J, Boerwinkle E, Bowden DW, Brody J, Budoff M, Burke G, Buxbaum S, Carr J, Chen DT, Chen IY, Chen WM, Concannon P, Crosby J, Cupples LA, D'Agostino R, Destefano AL, Dreisbach A, Dupuis J, Durda JP, Ellis J, Folsom AR, Fornage M, Fox CS, Fox E, Funari V, Ganesh SK, Gardin J, Goff D, Gordon O, Grody W, Gross M, Guo X, Hall IM, Heard-Costa NL, Heckbert SR, Heintz N, Herrington DM, Hickson D, Huang J, Hwang SJ, Jacobs DR, Jenny NS, Johnson AD, Johnson CW, Kawut S, Kronmal R, Kurz R, Lange EM, Lange LA, Larson MG, Lawson M, Lewis CE, Levy D, Li D, Lin H, Liu C, Liu J, Liu K, Liu X, Liu Y, Longstreth WT, Loria C, Lumley T, Lunetta K, Mackey AJ, Mackey R, Manichaikul A, Maxwell T, McKnight B, Meigs JB, Morrison AC, Musani SK, Mychaleckyj JC, Nettleton JA, North K, O'Donnell CJ, O'Leary D, Ong F, Palmas W, Pankow JS, Pankratz ND, Paul S, Perez M, Person SD, Polak J, Post WS, Psaty BM, Quinlan AR, Raffel LJ, Ramachandran VS, Reiner AP, Rice K, Rotter JI, Sanders JP, Schreiner P, Seshadri S, Shea S, Sidney S, Silverstein K, Smith NL, Sotoodehnia N, Srinivasan A, Taylor HA, Taylor K, Thomas F, Tracy RP, Tsai MY, Volcik KA, Wassel CL, Watson K, Wei G, White W, Wiggins KL, Wilk JB, Williams OD, Wilson G, Wilson JG, Wolf P, Zakai NA, Hardy J, Meschia JF, Nalls M, Singleton A, Worrall B, Bamshad MJ, Barnes KC, Abdulhamid I, Accurso F, Anbar R, Beaty T, Bigham A, Black P, Bleecker E, Buckingham K, Cairns AM, Caplan D, Chatfield B, Chidekel A, Cho M, Christiani DC, Crapo JD, Crouch J, Daley D, Dang A, Dang H, De Paula A, Decelie-Germana J, Drumm AD, Dyson M, Emerson J, Emond MJ, Ferkol T, Fink R, Foster C, Froh D, Gao L, Gershan W, Gibson RL, Godwin E, Gondor M, Gutierrez H, Hansel NN, Hassoun PM, Hiatt P, Hokanson JE, Howenstine M, Hummer LK, Kanga J, Kim Y, Knowles MR, Konstan M, Lahiri T, Laird N, Lange C, Lin L, Lin X, Louie TL, Lynch D, Make B, Martin TR, Mathai SC, Mathias RA, McNamara J, McNamara S, Meyers D, Millard S, Mogayzel P, Moss R, Murray T, Nielson D, Noyes B, O'Neal W, Orenstein D, O'Sullivan B, Pace R, Pare P, Parker HW, Passero MA, Perkett E, Prestridge A, Rafaels NM, Ramsey B, Regan E, Ren C, Retsch-Bogart G, Rock M, Rosen A, Rosenfeld M, Ruczinski I, Sanford A, Schaeffer D, Sell C, Sheehan D, Silverman EK, Sin D, Spencer T, Stonebraker J, Tabor HK, Varlotta L, Vergara CI, Weiss R, Wigley F, Wise RA, Wright FA, Wurfel MM, Zanni R, Zou F, Nickerson DA, Rieder MJ, Green P, Shendure J, Akey JM, Bustamante CD, Crosslin DR, Eichler EE, Fox PK, Fu W, Gordon A, Gravel S, Jarvik GP, Johnsen JM, Kan M, Kenny EE, Kidd JM, Lara-Garduno F, Leal SM, Liu DJ, McGee S, O'Connor TD, Paeper B, Robertson PD, Smith JD, Staples JC, Tennessen JA, Turner EH, Wang G, Yi Q, Jackson R, Peters U, Carlson CS, Anderson G, Anton-Culver H, Assimes TL, Auer PL, Beresford S, Bizon C, Black H, Brunner R, Brzyski R, Burwen D, Caan B, Carty CL, Chlebowski R, Cummings S, Curb JD, Eaton CB, Ford L, Franceschini N, Fullerton SM, Gass M, Geller N, Heiss G, Howard BV, Hsu L, Hutter CM, Ioannidis J, Jiao S, Johnson KC, Kooperberg C, Kuller L, Lacroix A, Lakshminarayan K, Lane D, Lasser N, Leblanc E, Li KP, Limacher M, Lin DY, Logsdon BA, Ludlam S, Manson JE, Margolis K, Martin L, McGowan J, Monda KL, Kotchen JM, Nathan L, Ockene J, O'Sullivan MJ, Phillips LS, Prentice RL, Robbins J, Robinson JG, Rossouw JE, Sangi-Haghpeykar H, Sarto GE, Shumaker S, Simon MS, Stefanick ML, Stein E, Tang H, Taylor KC, Thomson CA, Thornton TA, Van Horn L, Vitolins M, Wactawski-Wende J, Wallace R, Wassertheil-Smoller S, Zeng D, Applebaum-Bowden D, Feolo M, Gan W, Paltoo DN, Sholinsky P, Sturcke A.

Author information

1
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
2
Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
3
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
4
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
5
Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
6
Renaissance Computing Institute, Chapel Hill, NC 27517, USA.
7
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.
8
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
9
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.
10
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.
11
Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
12
Wellcome Trust Centre for Human Genetics, University of Oxford, OX1 2JD Oxford, UK.
13
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.
14
HUNT Research Center, Department of Public Health, Norwegian University of Science and Technology, 7600 Levanger, Norway.
15
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
16
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.
17
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
18
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.
19
Department of Pathology, University of Vermont, Colchester, VT 05446, USA.
20
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
21
Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, 3015 DR Rotterdam, the Netherlands.
22
Department of Epidemiology, Erasmus University Medical Center, 3000 DR Rotterdam, the Netherlands.
23
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
24
Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
25
Icelandic Heart Association, IS-201 Kopavogur, Iceland.
26
Icelandic Heart Association, IS-201 Kopavogur, Iceland; University of Iceland, 101 Reykjavik, Iceland.
27
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55454, USA.
28
Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
29
Medical Research Center for Human Genetics, Medical Research Center Institute of Genetics and Molecular Medicine, University of Edinburgh, EH4 2XU Edinburgh, UK.
30
Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
31
Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
32
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
33
Division of Cardiology, George Washington School of Medicine and Health Sciences, Washington, DC 20037, USA.
34
Departments of Epidemiology and Medicine, University of Iowa, Iowa City, IA 52242, USA.
35
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
36
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA; Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
37
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
38
Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA.
39
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA; Department of Statistics, University of Auckland, Auckland 1142, New Zealand.
40
Division of Endocrinology, Ohio State University, Columbus, OH 43210, USA.
41
Department of Internal Medicine, Erasmus University Medical Center, 3000 DR Rotterdam, the Netherlands.
42
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.
43
Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute, and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
44
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.
45
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.
46
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.
47
Centre for Population Health Sciences, Medical School, University of Edinburgh, EH8 9YL Edinburgh, UK.
48
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.
49
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.
50
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.
51
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.
52
Baylor College of Medicine, Houston, TX 77030, USA; Houston Methodist DeBakey Heart and Vascular Center, Houston, TX 77030, USA.
53
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA.
54
Center for Population Studies, National Heart, Lung, and Blood Institute, Framingham, MA 01702, USA; Cardiology Division, Massachusetts General Hospital, Boston, MA 02114, USA.
55
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
56
Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
57
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.
58
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.
59
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.
60
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.
61
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.
62
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
63
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
64
Department of Pathology, University of Vermont, Colchester, VT 05446, USA; Department of Biochemistry, University of Vermont, Burlington, VT 05405, USA.
65
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.

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.

PMID:
24507775
PMCID:
PMC3928660
DOI:
10.1016/j.ajhg.2014.01.010
[Indexed for MEDLINE]
Free PMC Article

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