Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci

被引：208

作者：

Asselbergs, Folkert W. ^{[2
,3
,4
]}

Guo, Yiran ^{[1
,5
]}

van Iperen, Erik P. A. ^{[6
,7
]}

Sivapalaratnam, Suthesh ^{[8
]}

Tragante, Vinicius ^{[2
,4
]}

Lanktree, Matthew B. ^{[9
,10
]}

Lange, Leslie A. ^{[11
]}

Almoguera, Berta ^{[1
]}

Appelman, Yolande E. ^{[12
]}

Barnard, John ^{[13
]}

Baumert, Jens ^{[14
]}

Beitelshees, Amber L. ^{[15
]}

Bhangale, Tushar R. ^{[16
]}

Chen, Yii-Der Ida ^{[17
]}

Gaunt, Tom R. ^{[18
]}

Gong, Yan ^{[19
,20
]}

Hopewell, Jemma C. ^{[21
]}

Johnson, Toby ^{[22
]}

Kleber, Marcus E. ^{[23
,24
]}

Langaee, Taimour Y. ^{[19
,20
]}

Li, Mingyao ^{[25
]}

Li, Yun R. ^{[1
]}

Liu, Kiang ^{[26
]}

McDonough, Caitrin W. ^{[19
,20
]}

Meijs, Matthijs El. ^{[2
]}

Middelberg, Rita P. S. ^{[27
,28
]}

Musunuru, Kiran ^{[29
,30
,31
]}

Nelson, Christopher P. ^{[32
]}

O'Connell, Jeffery R. ^{[33
]}

Padmanabhan, Sandosh ^{[34
]}

Pankow, James S. ^{[35
]}

Pankratz, Nathan ^{[36
]}

Rafelt, Suzanne ^{[32
]}

Rajagopalan, Ramakrishnan ^{[37
,38
]}

Romaine, Simon P. R. ^{[39
]}

Schork, Nicholas J. ^{[40
,41
]}

Shaffer, Jonathan ^{[42
]}

Shen, Haiqing ^{[33
]}

Smith, Erin N. ^{[43
,44
]}

Tischfield, Sam E. ^{[45
]}

van der Most, Peter J. ^{[46
]}

van Vliet-Ostaptchouk, Jana V. ^{[47
,48
]}

Verweij, Niek ^{[49
,50
]}

Volcik, Kelly A. ^{[51
]}

Zhang, Li ^{[13
]}

Bailey, Kent R. ^{[52
]}

Bailey, Kristian M. ^{[39
]}

Bauer, Florianne ^{[3
,53
]}

Boer, Jolanda M. A. ^{[54
]}

Braund, Peter S. ^{[32
]}

机构：

[1] Childrens Hosp Philadelphia, Abramson Res Ctr, Ctr Appl Genom, Philadelphia, PA 19104 USA

[2] Univ Med Ctr Utrecht, Dept Cardiol, Div Heart & Lungs, NL-3508 GA Utrecht, Netherlands

[3] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, NL-3508 GA Utrecht, Netherlands

[4] Univ Med Ctr Utrecht, Dept Med Genet, NL-3584 CX Utrecht, Netherlands

[5] BGI Shenzhen, Shenzhen 518083, Peoples R China

[6] Durrer Ctr Cardiogenet Res, NL-1105 AZ Amsterdam, Netherlands

[7] Univ Amsterdam, Acad Med Ctr, Dept Clin Epidemiol Biostat & Bioinformat, NL-1105 AZ Amsterdam, Netherlands

[8] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands

[9] Univ Western Ontario, Schulich Sch Med & Dent, Dept Med, London, ON N6A 3K6, Canada

[10] Univ Western Ontario, Schulich Sch Med & Dent, Dept Biochem, London, ON N6A 3K6, Canada

[11] Univ N Carolina, Sch Med, Dept Genet, Chapel Hill, NC 27514 USA

[12] Vrije Univ Amsterdam Med Ctr, Dept Cardiol, NL-1081 HV Amsterdam, Netherlands

[13] Cleveland Clin, Lerner Res Inst, Dept Quantitat Hlth Sci, Cleveland, OH 44195 USA

[14] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, D-85764 Neuherberg, Germany

[15] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA

[16] Genentech Inc, Dept Bioinformat & Computat Biol, San Francisco, CA 94080 USA

[17] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA

[18] Univ Bristol, Sch Social & Community Med, Ctr Causal Anal Translat Epidemiol, MRC, Bristol BS8 2BN, Avon, England

[19] Univ Florida, Dept Pharmacotherapy & Translat Res, Gainesville, FL 32603 USA

[20] Univ Florida, Ctr Pharmacogen, Gainesville, FL 32603 USA

[21] Univ Oxford, Clin Trial Serv Unit, Oxford OX3 7BN, England

[22] Queen Mary Univ London, Barts & London Sch Med, William Harvey Res Inst, Barts & London Genome Ctr, London EC1M 6BQ, England

[23] LURIC Study, D-79098 Freiburg, Germany

[24] Heidelberg Univ, Med Fac Mannheim, Mannheim Inst Publ Hlth Social & Prevent Med, D-68167 Mannheim, Germany

[25] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA

[26] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA

[27] Royal Brisbane Hosp, Queensland Inst Med Res, Brisbane, Qld 4029, Australia

[28] Prince Charles Hosp, Dept Med, Chermside, Qld 4032, Australia

[29] Broad Inst MIT & Harvard, Cambridge, MA 02141 USA

[30] Massachusetts Gen Hosp, Boston, MA 02114 USA

[31] Harvard Univ, Sch Med, Boston, MA 02115 USA

[32] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England

[33] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA

[34] Univ Glasgow, Coll Med Vet & Life Sci, Inst Cardiovasc & Med Sci, BHF Glasgow Cardiovasc Res Ctr, Glasgow G12 8TA, Lanark, Scotland

[35] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA

[36] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA

[37] Univ Washington, Div Med Genet, Dept Med, Seattle, WA 98195 USA

[38] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[39] Univ Leeds, Leeds Inst Genet Hlth & Therapeut, Leeds LS2 9JT, W Yorkshire, England

[40] Scripps Res Inst, La Jolla, CA 92037 USA

[41] Scripps Translat Sci Inst, La Jolla, CA 92037 USA

[42] Columbia Univ, Dept Med, Ctr Behav Cardiovasc Hlth, New York, NY 10032 USA

[43] Univ Calif San Diego, Sch Med, Dept Pediat, La Jolla, CA USA

[44] Univ Calif San Diego, Sch Med, Radys Childrens Hosp, La Jolla, CA USA

[45] Weill Cornell Med Coll, Triinst Training Program Computat Biol & Med, New York, NY 10065 USA

[46] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-9700 RB Groningen, Netherlands

[47] Univ Groningen, Univ Med Ctr Groningen, Dept Pathol & Med Biol, Med Biol Div,Mol Genet Lab, NL-9700 RB Groningen, Netherlands

[48] Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, NL-9700 RB Groningen, Netherlands

[49] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9700 RB Groningen, Netherlands

[50] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2012年 / 91卷 / 05期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; DENSITY-LIPOPROTEIN CHOLESTEROL; CORONARY-HEART-DISEASE; FAMILIAL HYPERCHOLESTEROLEMIA; APOLIPOPROTEIN B-100; MISSING HERITABILITY; PLASMA TRIGLYCERIDES; QUANTITATIVE TRAITS; STATISTICAL-MODEL; COMPLEX TRAITS;

D O I：

10.1016/j.ajhg.2012.08.032

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering similar to 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.

引用

页码：823 / 838

页数：16

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