Open AccessWhole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol
Author(s) -
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 M. Peloso,
Paul L. Auer,
Kuo-ping Li,
Jason Flannick,
Ji Zhang,
Christian Fuchsberger,
Kyle J. Gaulton,
Cecilia M. Lindgren,
Adam E. Locke,
Alisa K. Manning,
Xueling Sim,
Manuel A. Rivas,
Oddgeir L. Holmen,
Omri Gottesman,
Yingchang Lu,
Douglas M. Ruderfer,
Eli A. Stahl,
Qing Duan,
Yun Li,
Peter Durda,
Shuo Jiao,
Aaron Isaacs,
Albert Hofman,
Joshua C. Bis,
Adolfo Correa,
Michael Griswold,
Jóhanna Jakobsdóttir,
Albert V. Smith,
Pamela J. Schreiner,
Mary F. Feitosa,
Qunyuan Zhang,
Jennifer E. Huffman,
Jacy R. Crosby,
Christina L. Wassel,
Ron Do,
Nora Franceschini,
Lisa W. Martin,
Jennifer G. Robinson,
Themistocles L. Assimes,
David R. Crosslin,
Elisabeth A. Rosenthal,
Michael Y. Tsai,
Mark J. Rieder,
Deborah 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 Guðnason,
David S. Siscovick,
Myriam Fornage,
Ingrid B. Borecki,
Caroline Hayward,
Igor Rudan,
Y. Eugene Chen,
Erwin P. Böttinger,
Ruth J. F. Loos,
Pål Sætrom,
Kristian Hveem,
Michael Boehnke,
Leif Groop,
Mark I. McCarthy,
Thomas Meitinger,
Christie M. Ballantyne,
Stacey 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,
Gonçalo R. Abecasis,
Stephen S. Rich,
Russell P. Tracy,
Cristen J. Willer,
Hooman Allayee,
Sharon Cresci,
Mark J. Daly,
Paul I. W. de Bakker,
Mark A. DePristo,
Peter Donnelly,
Tim Fennell,
Kiran Garimella,
Stanley L. Hazen,
Daniel M. Jordan,
Adam Kieżun,
Guillaume Lettre,
Bingshan Li,
Mingyao Li,
Christopher NewtonCheh,
Sandosh Padmanabhan,
Sara L. Pulit,
Daniel J. Rader,
David Reich,
Muredach P. Reilly,
Steven M. Schwartz,
Laura J. Scott,
John A. Spertus,
Nathaniel O. Stitziel,
Nina Stoletzki,
Shamil Sunyaev,
Benjamin F. Voight,
Ermeg L. Akylbekova,
Larry D. Atwood,
Maja Barbalić,
R. Graham Barr,
Emelia J. Benjamin,
Donald W. Bowden,
Jennifer A. Brody,
Matthew J. Budoff,
Greg Burke,
Sarah G. Buxbaum,
J. Jeffrey Carr,
Donna T. Chen,
Ida Y. Chen,
WeiMin Chen,
Patrick Concan,
Ralph B. D’Agostino,
Anita L. DeStefano,
Albert W. Dreisbach,
Josée Dupuis,
Jon Peter Durda,
Jaclyn C. Ellis,
Caroline S. Fox,
Vincent Funari,
Santhi K. Ganesh,
Julius M. Gardin,
David C. Goff,
Ora Gordon,
Wayne W. Grody,
Myron Gross,
Xiuqing Guo,
Ira M. Hall,
Nancy L. HeardCosta,
Susan R. Heckbert,
Nicholas H. Heintz,
David M. Herrington,
DeMarc A. Hickson,
Jie Huang,
ShihJen Hwang,
David R. Jacobs,
Nancy S. Jenny,
Andrew D. Johnson,
Craig Johnson,
Steven M. Kawut,
Richard A. Kronmal,
Raluca Kurz,
Martin G. Larson,
Mark Lawson,
Cora E. Lewis,
Dalin Li,
Honghuang Lin,
Chunyu Liu,
Jiankang Liu,
Kiang Liu,
Xiaoming Liu,
Yongmei Liu,
W.T. Longstreth,
Cay Loria,
Kathryn L. Lunetta,
Aaron J. Mackey,
Rachel H. Mackey,
Ani Manichaikul,
Taylor J. Maxwell,
Barbara McKnight,
James B. Meigs,
Alanna C. Morrison,
Solomon K. Musani,
Josyf C. Mychaleckyj,
Jennifer A. Nettleton,
Daniel S. OʼLeary,
Frank S Ong,
Walter Palmas,
James S. Pankow,
Nathan Pankratz,
Shom Paul,
Marco Pérez,
Sharina D. Person,
Joseph F. Polak,
Aaron R. Quinlan,
Leslie J. Raffel,
Ramachandran S. Vasan,
Kenneth Rice,
Jill P. Sanders,
Sudha Seshadri,
Steve Shea,
Stephen Sidney,
Kevin A.T. Silverstein,
Nicholas L. Smith,
a Sotoodehnia,
Asoke Srinivasan,
Kent D. Taylor,
Fridtjof Thomas,
Kelly A. Volcik,
Chrstina L. Wassel,
Karol Watson,
Gina S. Wei,
Wendy White,
Kerri L. Wiggins,
Jemma B. Wilk,
O. Dale Williams,
G. Wilson,
Phillip Wolf,
Neil A. Zakai,
John Hardy,
James F. Meschia,
Michael A. Nalls,
Andrew B. Singleton,
Brad Worrall,
Michael J. Bamshad,
Kathleen C. Barnes,
Ibrahim Abdulhamid,
Frank J. Accurso,
Ran D. Anbar,
Terri Beaty,
Abigail W. Bigham,
Phillip Black,
Eugene R. Bleecker,
Kati J. Buckingham,
Anne Marie Cairns,
Daniel B. Caplan,
Barbara A. Chatfield,
Aaron Chidekel,
Michael Cho,
David C. Christiani,
James D. Crapo,
Julia M. Crouch,
Denise Daley,
Anthony T. Dang,
Hong Dang,
Alicia De Paula,
Joan DeCelieGermana,
Allen DozorMitch Drumm,
Maynard Dyson,
Julia Emerson,
Mary J. Emond,
Thomas W. Ferkol,
Robert Fink,
Cassandra Foster,
Deborah Froh,
Li Gao,
William M. Gershan,
Ronald L. Gibson,
Elizabeth Godwin,
Magdalen Gondor,
Héctor Gutiérrez,
Nadia N. Hansel,
Paul M. Hassoun,
Peter Hiatt,
John E. Hokanson,
Michelle S. Howenstine,
Laura K. Hummer,
Jamshed F. Kanga,
Yoonhee Kim,
Michael R. Knowles,
Michael W. Konstan,
Thomas Lahiri,
Nan M. Laird,
Christoph Lange,
Lin Lin,
Xihong Lin,
Tin L. Louie,
David R. Lynch,
Barry J. Make,
Thomas R. Martin,
Steve C. Mathai,
Rasika A. Mathias,
John McNamara,
Sharon McNamara,
Deborah A. Meyers,
Susan L. Millard,
Peter J. Mogayzel,
Richard B. Moss,
Tanda Murray,
Dennis W. Nielson,
Blakeslee E. Noyes,
Wanda K. O’Neal,
David Orenstein,
Brian O’Sullivan,
Rhonda G. Pace,
Peter D. Paré,
H. Worth Parker,
Mary Ann Passero,
Elizabeth A. Perkett,
Adrienne Prestridge,
Nicholas Rafaels,
Bonnie Ramsey,
Elizabeth A. Regan,
Clement L. Ren,
George RetschBogart,
Michael J. Rock,
Antony Rosen,
Margaret Rosenfeld,
Ingo Ruczinski,
Andrew Sanford,
David J. Schaeffer,
Cindy Sell,
Daniel P. Sheehan,
Edwin K. Silverman,
Don D. Sin,
Terry Spencer,
J. Stonebraker,
Holly K. Tabor,
Laurie Varlotta,
Candelaria Vergara,
Robert Weiss,
Fred Wigley,
Robert A. Wise,
Fred A. Wright,
Mark M. Wurfel,
Robert Zanni,
Fei Zou,
Phil Green,
Jay Shendure,
Joshua M. Akey,
Carlos D. Bustamante,
Evan E. Eichler,
Phillips Fox,
Wenqing Fu,
Allan Gordon,
Simon Gravel,
Jill M. Johnsen,
Mengyuan Kan,
Eimear E. Kenny,
Jeffrey M. Kidd,
Fremiet Lara-Garduno,
Suzanne M. Leal,
Dajiang J. Liu,
Sean McGee,
Timothy D. O’Connor,
Bryan Paeper,
Peggy D. Robertson,
Jeffrey Staples,
Jacob A. Tennessen,
Gao Wang,
Yi Qian,
Annette Peters,
Garnet L. Anderson,
Hoda AntonCulver,
Shirley A.A. Beresford,
Henry R. Black,
Robert L. Brunner,
Robert G. Brzyski,
Dale R. Burwen,
Bette J. Caan,
Cara L. Carty,
Rowan T. Chlebowski,
Steven R. Cummings,
J. David Curb,
Charles B. Eaton,
Leslie Ford,
Stephanie M. Fullerton,
Margery Gass,
Nancy L. Geller,
G. Heiss,
Barbara V. Howard,
Li Hsu,
Carolyn M. Hutter,
John P. A. Ioannidis,
Karen Johnson,
Lewis Kuller,
Andrea Z. LaCroix,
Kamakshi Lakshminarayan,
Dorothy S. Lane,
Norman L. Lasser,
Erin S. LeBlanc,
Marian C. Limacher,
Benjamin A. Logsdon,
Shari Ludlam,
JoAnn E. Manson,
Karen L. Margolis,
Joan McGowan,
Keri L. Monda,
Jane Morley Kotchen,
Lauren Nathan,
Judith K. Ockene,
Mary Jo O’Sullivan,
Lawrence S. Phillips,
Ross L. Prentice,
John Robbins,
Jacques E. Rossouw,
Haleh SangiHaghpeykar,
Gloria E. Sarto,
Sally A. Shumaker,
Michael S. Simon,
Marcia L. Stefanick,
Evan A. Stein,
Hua Tang,
Kira C. Taylor,
Cynthia A. Thomson,
Timothy A. Thornton,
Linda Van Horn,
Mara Z. Vitolins,
Jean WactawskiWende,
Robert W. Wallace,
Sylvia WassertheilSmoller,
Donglin Zeng,
Deborah ApplebaumBowden,
Michael Feolo,
Weiniu Gan,
Di. Paltoo,
Phyliss Sholinsky,
Anne Sturcke
Publication year - 2014
Publication title -
the american journal of human genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.661
H-Index - 302
eISSN - 1537-6605
pISSN - 0002-9297
DOI - 10.1016/j.ajhg.2014.01.010
Subject(s) - exome sequencing , exome , genetics , pcsk9 , biology , allele frequency , single nucleotide polymorphism , gene , genotype , ldl receptor , computational biology , cholesterol , lipoprotein , mutation , endocrinology
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.
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