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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23063622
TITLE
Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci.
ABSTRACT
Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.
Copyright 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
DATE PUBLISHED
2012 Nov 2
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2012/05/12
revised 2012/08/02
accepted 2012/08/30
aheadofprint 2012/10/11
entrez 2012/10/16 06:00
pubmed 2012/10/16 06:00
medline 2013/01/15 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Asselbergs FW Asselbergs Folkert W FW Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
Guo Y Guo Yiran Y
van Iperen EP van Iperen Erik P A EP
Sivapalaratnam S Sivapalaratnam Suthesh S
Tragante V Tragante Vinicius V
Lanktree MB Lanktree Matthew B MB
Lange LA Lange Leslie A LA
Almoguera B Almoguera Berta B
Appelman YE Appelman Yolande E YE
Barnard J Barnard John J
Baumert J Baumert Jens J
Beitelshees AL Beitelshees Amber L AL
Bhangale TR Bhangale Tushar R TR
Chen YD Chen Yii-Der Ida YD
Gaunt TR Gaunt Tom R TR
Gong Y Gong Yan Y
Hopewell JC Hopewell Jemma C JC
Johnson T Johnson Toby T
Kleber ME Kleber Marcus E ME
Langaee TY Langaee Taimour Y TY
Li M Li Mingyao M
Li YR Li Yun R YR
Liu K Liu Kiang K
McDonough CW McDonough Caitrin W CW
Meijs MF Meijs Matthijs F L MF
Middelberg RP Middelberg Rita P S RP
Musunuru K Musunuru Kiran K
Nelson CP Nelson Christopher P CP
O'Connell JR O'Connell Jeffery R JR
Padmanabhan S Padmanabhan Sandosh S
Pankow JS Pankow James S JS
Pankratz N Pankratz Nathan N
Rafelt S Rafelt Suzanne S
Rajagopalan R Rajagopalan Ramakrishnan R
Romaine SP Romaine Simon P R SP
Schork NJ Schork Nicholas J NJ
Shaffer J Shaffer Jonathan J
Shen H Shen Haiqing H
Smith EN Smith Erin N EN
Tischfield SE Tischfield Sam E SE
van der Most PJ van der Most Peter J PJ
van Vliet-Ostaptchouk JV van Vliet-Ostaptchouk Jana V JV
Verweij N Verweij Niek N
Volcik KA Volcik Kelly A KA
Zhang L Zhang Li L
Bailey KR Bailey Kent R KR
Bailey KM Bailey Kristian M KM
Bauer F Bauer Florianne F
Boer JM Boer Jolanda M A JM
Braund PS Braund Peter S PS
Burt A Burt Amber A
Burton PR Burton Paul R PR
Buxbaum SG Buxbaum Sarah G SG
Chen W Chen Wei W
Cooper-Dehoff RM Cooper-Dehoff Rhonda M RM
Cupples LA Cupples L Adrienne LA
deJong JS deJong Jonas S JS
Delles C Delles Christian C
Duggan D Duggan David D
Fornage M Fornage Myriam M
Furlong CE Furlong Clement E CE
Glazer N Glazer Nicole N
Gums JG Gums John G JG
Hastie C Hastie Claire C
Holmes MV Holmes Michael V MV
Illig T Illig Thomas T
Kirkland SA Kirkland Susan A SA
Kivimaki M Kivimaki Mika M
Klein R Klein Ronald R
Klein BE Klein Barbara E BE
Kooperberg C Kooperberg Charles C
Kottke-Marchant K Kottke-Marchant Kandice K
Kumari M Kumari Meena M
LaCroix AZ LaCroix Andrea Z AZ
Mallela L Mallela Laya L
Murugesan G Murugesan Gurunathan G
Ordovas J Ordovas Jose J
Ouwehand WH Ouwehand Willem H WH
Post WS Post Wendy S WS
Saxena R Saxena Richa R
Scharnagl H Scharnagl Hubert H
Schreiner PJ Schreiner Pamela J PJ
Shah T Shah Tina T
Shields DC Shields Denis C DC
Shimbo D Shimbo Daichi D
Srinivasan SR Srinivasan Sathanur R SR
Stolk RP Stolk Ronald P RP
Swerdlow DI Swerdlow Daniel I DI
Taylor HA Jr Taylor Herman A HA
Topol EJ Topol Eric J EJ
Toskala E Toskala Elina E
van Pelt JL van Pelt Joost L JL
van Setten J van Setten Jessica J
Yusuf S Yusuf Salim S
Whittaker JC Whittaker John C JC
Zwinderman AH Zwinderman A H AH
LifeLines Cohort Study
Anand SS Anand Sonia S SS
Balmforth AJ Balmforth Anthony J AJ
Berenson GS Berenson Gerald S GS
Bezzina CR Bezzina Connie R CR
Boehm BO Boehm Bernhard O BO
Boerwinkle E Boerwinkle Eric E
Casas JP Casas Juan P JP
Caulfield MJ Caulfield Mark J MJ
Clarke R Clarke Robert R
Connell JM Connell John M JM
Cruickshanks KJ Cruickshanks Karen J KJ
Davidson KW Davidson Karina W KW
Day IN Day Ian N M IN
de Bakker PI de Bakker Paul I W PI
Doevendans PA Doevendans Pieter A PA
Dominiczak AF Dominiczak Anna F AF
Hall AS Hall Alistair S AS
Hartman CA Hartman Catharina A CA
Hengstenberg C Hengstenberg Christian C
Hillege HL Hillege Hans L HL
Hofker MH Hofker Marten H MH
Humphries SE Humphries Steve E SE
Jarvik GP Jarvik Gail P GP
Johnson JA Johnson Julie A JA
Kaess BM Kaess Bernhard M BM
Kathiresan S Kathiresan Sekar S
Koenig W Koenig Wolfgang W
Lawlor DA Lawlor Debbie A DA
März W März Winfried W
Melander O Melander Olle O
Mitchell BD Mitchell Braxton D BD
Montgomery GW Montgomery Grant W GW
Munroe PB Munroe Patricia B PB
Murray SS Murray Sarah S SS
Newhouse SJ Newhouse Stephen J SJ
Onland-Moret NC Onland-Moret N Charlotte NC
Poulter N Poulter Neil N
Psaty B Psaty Bruce B
Redline S Redline Susan S
Rich SS Rich Stephen S SS
Rotter JI Rotter Jerome I JI
Schunkert H Schunkert Heribert H
Sever P Sever Peter P
Shuldiner AR Shuldiner Alan R AR
Silverstein RL Silverstein Roy L RL
Stanton A Stanton Alice A
Thorand B Thorand Barbara B
Trip MD Trip Mieke D MD
Tsai MY Tsai Michael Y MY
van der Harst P van der Harst Pim P
van der Schoot E van der Schoot Ellen E
van der Schouw YT van der Schouw Yvonne T YT
Verschuren WM Verschuren W M Monique WM
Watkins H Watkins Hugh H
Wilde AA Wilde Arthur A M AA
Wolffenbuttel BH Wolffenbuttel Bruce H R BH
Whitfield JB Whitfield John B JB
Hovingh GK Hovingh G Kees GK
Ballantyne CM Ballantyne Christie M CM
Wijmenga C Wijmenga Cisca C
Reilly MP Reilly Muredach P MP
Martin NG Martin Nicholas G NG
Wilson JG Wilson James G JG
Rader DJ Rader Daniel J DJ
Samani NJ Samani Nilesh J NJ
Reiner AP Reiner Alex P AP
Hegele RA Hegele Robert A RA
Kastelein JJ Kastelein John J P JJ
Hingorani AD Hingorani Aroon D AD
Talmud PJ Talmud Philippa J PJ
Hakonarson H Hakonarson Hakon H
Elbers CC Elbers Clara C CC
Keating BJ Keating Brendan J BJ
Drenos F Drenos Fotios F
INVESTIGATORS
LASTNAME FORENAME INITIALS AFFILIATION
de Boer Rudolf R
Hillege Hans H
van der Klauw Melanie M
Navis Gerjan G
Ormel Hans H
Postma Dirkje D
Rosmalen Judith J
Slaets Joris J
Stolk Ronald R
Wolffenbuttel Bruce B
Alizadeh Behrooz B
Boezen Marike M
Bruinenberg Marcel M
Festen Noortje N
Franke Lude L
van der Harst Pim P
Navis Gerjan G
Postma Dirkje D
Snieder Harold H
Wijmenga Cisca C
Wolffenbuttel Bruce B
JOURNAL
VOLUME: 91
ISSUE: 5
TITLE: American journal of human genetics
ISOABBREVIATION: Am. J. Hum. Genet.
YEAR: 2012
MONTH: Nov
DAY: 2
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1537-6605
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Am J Hum Genet
COUNTRY: United States
ISSNLINKING: 0002-9297
NLMUNIQUEID: 0370475
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
Research Support, U.S. Gov't, P.H.S.
COMMENTS AND CORRECTIONS
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GRANTS
GRANTID AGENCY COUNTRY
090532 Wellcome Trust United Kingdom
AG-16592 NIA NIH HHS United States
AG13196 NIA NIH HHS United States
CH/03/001 British Heart Foundation United Kingdom
CH/98001 British Heart Foundation United Kingdom
G0802432 Medical Research Council United Kingdom
G9521010 Medical Research Council United Kingdom
G9521010D Medical Research Council United Kingdom
HD-061437 NICHD NIH HHS United States
HD-062783 NICHD NIH HHS United States
HL36310 NHLBI NIH HHS United States
HS06516 AHRQ HHS United States
K24 HL084034 NHLBI NIH HHS United States
MC_U137686857 Medical Research Council United Kingdom
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P30 DK063491 NIDDK NIH HHS United States
P30 DK072488 NIDDK NIH HHS United States
P50HL81011 NHLBI NIH HHS United States
PG/02/128 British Heart Foundation United Kingdom
PG/07/131/24254 British Heart Foundation United Kingdom
PG/07/132/24256 British Heart Foundation United Kingdom
PG/07/133/24260 British Heart Foundation United Kingdom
R01 AG011099 NIA NIH HHS United States
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GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Cholesterol, HDL genetics
Cholesterol, LDL genetics
European Continental Ancestry Group genetics
Female genetics
Genome-Wide Association Study genetics
Genotype genetics
Humans genetics
Lipids genetics
Male genetics
Phenotype genetics
Polymorphism, Single Nucleotide genetics
Quantitative Trait Loci genetics
Sex Factors genetics
Triglycerides genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 Cholesterol, HDL
0 Cholesterol, LDL
0 Lipids
0 Triglycerides
OTHER ID's
OTHERID SOURCE
PMC3487124 NLM