Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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20686565
TITLE
Biological, clinical and population relevance of 95 loci for blood lipids.
ABSTRACT
Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
DATE PUBLISHED
2010 Aug 5
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2010/02/25
accepted 2010/06/11
entrez 2010/08/06 06:00
pubmed 2010/08/06 06:00
medline 2010/09/25 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Teslovich TM Teslovich Tanya M TM Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.
Musunuru K Musunuru Kiran K
Smith AV Smith Albert V AV
Edmondson AC Edmondson Andrew C AC
Stylianou IM Stylianou Ioannis M IM
Koseki M Koseki Masahiro M
Pirruccello JP Pirruccello James P JP
Ripatti S Ripatti Samuli S
Chasman DI Chasman Daniel I DI
Willer CJ Willer Cristen J CJ
Johansen CT Johansen Christopher T CT
Fouchier SW Fouchier Sigrid W SW
Isaacs A Isaacs Aaron A
Peloso GM Peloso Gina M GM
Barbalic M Barbalic Maja M
Ricketts SL Ricketts Sally L SL
Bis JC Bis Joshua C JC
Aulchenko YS Aulchenko Yurii S YS
Thorleifsson G Thorleifsson Gudmar G
Feitosa MF Feitosa Mary F MF
Chambers J Chambers John J
Orho-Melander M Orho-Melander Marju M
Melander O Melander Olle O
Johnson T Johnson Toby T
Li X Li Xiaohui X
Guo X Guo Xiuqing X
Li M Li Mingyao M
Shin Cho Y Shin Cho Yoon Y
Jin Go M Jin Go Min M
Jin Kim Y Jin Kim Young Y
Lee JY Lee Jong-Young JY
Park T Park Taesung T
Kim K Kim Kyunga K
Sim X Sim Xueling X
Twee-Hee Ong R Twee-Hee Ong Rick R
Croteau-Chonka DC Croteau-Chonka Damien C DC
Lange LA Lange Leslie A LA
Smith JD Smith Joshua D JD
Song K Song Kijoung K
Hua Zhao J Hua Zhao Jing J
Yuan X Yuan Xin X
Luan J Luan Jian'an J
Lamina C Lamina Claudia C
Ziegler A Ziegler Andreas A
Zhang W Zhang Weihua W
Zee RY Zee Robert Y L RY
Wright AF Wright Alan F AF
Witteman JC Witteman Jacqueline C M JC
Wilson JF Wilson James F JF
Willemsen G Willemsen Gonneke G
Wichmann HE Wichmann H-Erich HE
Whitfield JB Whitfield John B JB
Waterworth DM Waterworth Dawn M DM
Wareham NJ Wareham Nicholas J NJ
Waeber G Waeber Gérard G
Vollenweider P Vollenweider Peter P
Voight BF Voight Benjamin F BF
Vitart V Vitart Veronique V
Uitterlinden AG Uitterlinden Andre G AG
Uda M Uda Manuela M
Tuomilehto J Tuomilehto Jaakko J
Thompson JR Thompson John R JR
Tanaka T Tanaka Toshiko T
Surakka I Surakka Ida I
Stringham HM Stringham Heather M HM
Spector TD Spector Tim D TD
Soranzo N Soranzo Nicole N
Smit JH Smit Johannes H JH
Sinisalo J Sinisalo Juha J
Silander K Silander Kaisa K
Sijbrands EJ Sijbrands Eric J G EJ
Scuteri A Scuteri Angelo A
Scott J Scott James J
Schlessinger D Schlessinger David D
Sanna S Sanna Serena S
Salomaa V Salomaa Veikko V
Saharinen J Saharinen Juha J
Sabatti C Sabatti Chiara C
Ruokonen A Ruokonen Aimo A
Rudan I Rudan Igor I
Rose LM Rose Lynda M LM
Roberts R Roberts Robert R
Rieder M Rieder Mark M
Psaty BM Psaty Bruce M BM
Pramstaller PP Pramstaller Peter P PP
Pichler I Pichler Irene I
Perola M Perola Markus M
Penninx BW Penninx Brenda W J H BW
Pedersen NL Pedersen Nancy L NL
Pattaro C Pattaro Cristian C
Parker AN Parker Alex N AN
Pare G Pare Guillaume G
Oostra BA Oostra Ben A BA
O'Donnell CJ O'Donnell Christopher J CJ
Nieminen MS Nieminen Markku S MS
Nickerson DA Nickerson Deborah A DA
Montgomery GW Montgomery Grant W GW
Meitinger T Meitinger Thomas T
McPherson R McPherson Ruth R
McCarthy MI McCarthy Mark I MI
McArdle W McArdle Wendy W
Masson D Masson David D
Martin NG Martin Nicholas G NG
Marroni F Marroni Fabio F
Mangino M Mangino Massimo M
Magnusson PK Magnusson Patrik K E PK
Lucas G Lucas Gavin G
Luben R Luben Robert R
Loos RJ Loos Ruth J F RJ
Lokki ML Lokki Marja-Liisa ML
Lettre G Lettre Guillaume G
Langenberg C Langenberg Claudia C
Launer LJ Launer Lenore J LJ
Lakatta EG Lakatta Edward G EG
Laaksonen R Laaksonen Reijo R
Kyvik KO Kyvik Kirsten O KO
Kronenberg F Kronenberg Florian F
König IR König Inke R IR
Khaw KT Khaw Kay-Tee KT
Kaprio J Kaprio Jaakko J
Kaplan LM Kaplan Lee M LM
Johansson A Johansson Asa A
Jarvelin MR Jarvelin Marjo-Riitta MR
Janssens AC Janssens A Cecile J W AC
Ingelsson E Ingelsson Erik E
Igl W Igl Wilmar W
Kees Hovingh G Kees Hovingh G G
Hottenga JJ Hottenga Jouke-Jan JJ
Hofman A Hofman Albert A
Hicks AA Hicks Andrew A AA
Hengstenberg C Hengstenberg Christian C
Heid IM Heid Iris M IM
Hayward C Hayward Caroline C
Havulinna AS Havulinna Aki S AS
Hastie ND Hastie Nicholas D ND
Harris TB Harris Tamara B TB
Haritunians T Haritunians Talin T
Hall AS Hall Alistair S AS
Gyllensten U Gyllensten Ulf U
Guiducci C Guiducci Candace C
Groop LC Groop Leif C LC
Gonzalez E Gonzalez Elena E
Gieger C Gieger Christian C
Freimer NB Freimer Nelson B NB
Ferrucci L Ferrucci Luigi L
Erdmann J Erdmann Jeanette J
Elliott P Elliott Paul P
Ejebe KG Ejebe Kenechi G KG
Döring A Döring Angela A
Dominiczak AF Dominiczak Anna F AF
Demissie S Demissie Serkalem S
Deloukas P Deloukas Panagiotis P
de Geus EJ de Geus Eco J C EJ
de Faire U de Faire Ulf U
Crawford G Crawford Gabriel G
Collins FS Collins Francis S FS
Chen YD Chen Yii-der I YD
Caulfield MJ Caulfield Mark J MJ
Campbell H Campbell Harry H
Burtt NP Burtt Noel P NP
Bonnycastle LL Bonnycastle Lori L LL
Boomsma DI Boomsma Dorret I DI
Boekholdt SM Boekholdt S Matthijs SM
Bergman RN Bergman Richard N RN
Barroso I Barroso Inês I
Bandinelli S Bandinelli Stefania S
Ballantyne CM Ballantyne Christie M CM
Assimes TL Assimes Themistocles L TL
Quertermous T Quertermous Thomas T
Altshuler D Altshuler David D
Seielstad M Seielstad Mark M
Wong TY Wong Tien Y TY
Tai ES Tai E-Shyong ES
Feranil AB Feranil Alan B AB
Kuzawa CW Kuzawa Christopher W CW
Adair LS Adair Linda S LS
Taylor HA Jr Taylor Herman A HA
Borecki IB Borecki Ingrid B IB
Gabriel SB Gabriel Stacey B SB
Wilson JG Wilson James G JG
Holm H Holm Hilma H
Thorsteinsdottir U Thorsteinsdottir Unnur U
Gudnason V Gudnason Vilmundur V
Krauss RM Krauss Ronald M RM
Mohlke KL Mohlke Karen L KL
Ordovas JM Ordovas Jose M JM
Munroe PB Munroe Patricia B PB
Kooner JS Kooner Jaspal S JS
Tall AR Tall Alan R AR
Hegele RA Hegele Robert A RA
Kastelein JJ Kastelein John J P JJ
Schadt EE Schadt Eric E EE
Rotter JI Rotter Jerome I JI
Boerwinkle E Boerwinkle Eric E
Strachan DP Strachan David P DP
Mooser V Mooser Vincent V
Stefansson K Stefansson Kari K
Reilly MP Reilly Muredach P MP
Samani NJ Samani Nilesh J NJ
Schunkert H Schunkert Heribert H
Cupples LA Cupples L Adrienne LA
Sandhu MS Sandhu Manjinder S MS
Ridker PM Ridker Paul M PM
Rader DJ Rader Daniel J DJ
van Duijn CM van Duijn Cornelia M CM
Peltonen L Peltonen Leena L
Abecasis GR Abecasis Gonçalo R GR
Boehnke M Boehnke Michael M
Kathiresan S Kathiresan Sekar S
INVESTIGATORS
JOURNAL
VOLUME: 466
ISSUE: 7307
TITLE: Nature
ISOABBREVIATION: Nature
YEAR: 2010
MONTH: Aug
DAY: 5
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1476-4687
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Nature
COUNTRY: England
ISSNLINKING: 0028-0836
NLMUNIQUEID: 0410462
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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Cites Science. 2009 Jul 3;325(5936):100-4 19520913
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Cites Nat Genet. 2006 Feb;38(2):218-22 16429159
Cites Science. 2007 Jun 1;316(5829):1331-6 17463246
Cites BMC Med Genet. 2007;8 Suppl 1:S17 17903299
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Cites Am J Hum Genet. 2008 Jan;82(1):139-49 18179892
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CommentIn Nat Rev Endocrinol. 2010 Nov;6(11):598 21038508
CommentIn Nature. 2010 Aug 5;466(7307):703-4 20686562
CommentIn Am J Transplant. 2011 Sep;11(9):1763 21884406
GRANTS
GRANTID AGENCY COUNTRY
068545/Z/02 Wellcome Trust United Kingdom
076113/B/04/Z Wellcome Trust United Kingdom
077016/Z/05/Z Wellcome Trust United Kingdom
079895 Wellcome Trust United Kingdom
1Z01 HG000024 NHGRI NIH HHS United States
5R01DK06833603 NIDDK NIH HHS United States
5R01DK07568102 NIDDK NIH HHS United States
5R01HL087679-02 NHLBI NIH HHS United States
5R01HL08770003 NHLBI NIH HHS United States
5R01HL08821502 NHLBI NIH HHS United States
CA 047988 NCI NIH HHS United States
CZB/4/710 Chief Scientist Office United Kingdom
DK062370 NIDDK NIH HHS United States
DK063491 NIDDK NIH HHS United States
DK072193 NIDDK NIH HHS United States
DK078150 NIDDK NIH HHS United States
DK56350 NIDDK NIH HHS United States
ES10126 NIEHS NIH HHS United States
G0000934 Medical Research Council United Kingdom
G0401527 Medical Research Council United Kingdom
G0601966 Medical Research Council United Kingdom
G0700931 Medical Research Council United Kingdom
G0701863 Medical Research Council United Kingdom
G0801056 Medical Research Council United Kingdom
G0801566 Medical Research Council United Kingdom
G9521010 Medical Research Council United Kingdom
G9521010D Medical Research Council United Kingdom
HHSN268200625226C PHS HHS United States
HL 04381 NHLBI NIH HHS United States
HL 080467 NHLBI NIH HHS United States
HL-54776 NHLBI NIH HHS United States
HL085144 NHLBI NIH HHS United States
K99 HL098364 NHLBI NIH HHS United States
K99 HL098364 NHLBI NIH HHS United States
K99 HL098364-01 NHLBI NIH HHS United States
K99HL094535 NHLBI NIH HHS United States
M01-RR00425 NCRR NIH HHS United States
MC_QA137934 Medical Research Council United Kingdom
MC_U106179471 Medical Research Council United Kingdom
MC_U106188470 Medical Research Council United Kingdom
MC_U127561128 Medical Research Council United Kingdom
N01 HC-15103 NHLBI NIH HHS United States
N01 HC-55222 NHLBI NIH HHS United States
N01-AG-12100 NIA NIH HHS United States
N01-HC-25195 NHLBI NIH HHS United States
N01-HC-35129 NHLBI NIH HHS United States
N01-HC-45133 NHLBI NIH HHS United States
N01-HC-55015 NHLBI NIH HHS United States
N01-HC-55016 NHLBI NIH HHS United States
N01-HC-55018 NHLBI NIH HHS United States
N01-HC-55019 NHLBI NIH HHS United States
N01-HC-55020 NHLBI NIH HHS United States
N01-HC-55021 NHLBI NIH HHS United States
N01-HC-55022 NHLBI NIH HHS United States
N01-HC-75150 NHLBI NIH HHS United States
N01-HC-85079 NHLBI NIH HHS United States
N01-HC-85080 NHLBI NIH HHS United States
N01-HC-85081 NHLBI NIH HHS United States
N01-HC-85082 NHLBI NIH HHS United States
N01-HC-85083 NHLBI NIH HHS United States
N01-HC-85084 NHLBI NIH HHS United States
N01-HC-85085 NHLBI NIH HHS United States
N01-HC-85086 NHLBI NIH HHS United States
N01-HG-65403 NHGRI NIH HHS United States
N02-HL-6-4278 NHLBI NIH HHS United States
PG/02/128 British Heart Foundation United Kingdom
PG/08/094 British Heart Foundation United Kingdom
PG/08/094/26019 British Heart Foundation United Kingdom
R01 DK072193 NIDDK NIH HHS United States
R01 DK078150 NIDDK NIH HHS United States
R01 HL087647 NHLBI NIH HHS United States
R01 HL087676 NHLBI NIH HHS United States
R01 HL089650 NHLBI NIH HHS United States
R01HL086694 NHLBI NIH HHS United States
R01HL087641 NHLBI NIH HHS United States
R01HL087652 NHLBI NIH HHS United States
R01HL59367 NHLBI NIH HHS United States
R24 HD050924 NICHD NIH HHS United States
RC1 HL099634 NHLBI NIH HHS United States
RC1 HL099634 NHLBI NIH HHS United States
RC1 HL099634-02 NHLBI NIH HHS United States
RC1 HL099793 NHLBI NIH HHS United States
RC2 HL101864, NHLBI NIH HHS United States
RC2 HL102419 NHLBI NIH HHS United States
RG/07/005/23633 British Heart Foundation United Kingdom
RR20649 NCRR NIH HHS United States
SP/08/005/25115 British Heart Foundation United Kingdom
T32 GM007092 NIGMS NIH HHS United States
T32 HG00040 NHGRI NIH HHS United States
T32HL007208 NHLBI NIH HHS United States
TW05596 FIC NIH HHS United States
U01 DK062370 NIDDK NIH HHS United States
U01 DK062418 NIDDK NIH HHS United States
U01 HL069757 NHLBI NIH HHS United States
U01 HL080295 NHLBI NIH HHS United States
U01HG004402 NHGRI NIH HHS United States
U54 RR020278 NCRR NIH HHS United States
UL1RR025005 NCRR NIH HHS United States
Intramural NIH HHS United States
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
African Americans genetics
Animals genetics
Asian Continental Ancestry Group genetics
Cholesterol, HDL blood
Cholesterol, LDL blood
Coronary Artery Disease therapy
Europe ethnology
European Continental Ancestry Group genetics
Female genetics
Genetic Loci genetics
Genome-Wide Association Study genetics
Genotype genetics
Humans genetics
Lipid Metabolism genetics
Lipids blood
Liver metabolism
Male metabolism
Mice metabolism
N-Acetylgalactosaminyltransferases metabolism
Phenotype metabolism
Polymorphism, Single Nucleotide genetics
Protein Phosphatase 1 metabolism
Reproducibility of Results metabolism
Triglycerides blood
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 Cholesterol, HDL
0 Cholesterol, LDL
0 Lipids
0 Triglycerides
EC 2.4.1.- N-Acetylgalactosaminyltransferases
EC 2.4.1.41 polypeptide N-acetylgalactosaminyltransferase
EC 3.1.3.16 Ppp1r3b protein, mouse
EC 3.1.3.16 Protein Phosphatase 1
OTHER ID's
OTHERID SOURCE
NIHMS213289 NLM
PMC3039276 NLM