Concept, Design and Implementation of a Cardiovascular Gene-Centric 50 K SNP Array for Large-Scale Genomic Association Studies

被引：319

作者：

Keating, Brendan J. ^{[1
]}

Tischfield, Sam ^{[2
,3
]}

Murray, Sarah S. ^{[4
]}

Bhangale, Tushar ^{[5
]}

Price, Thomas S. ^{[6
]}

Glessner, Joseph T. ^{[7
]}

Galver, Luana ^{[10
]}

Barrett, Jeffrey C. ^{[8
]}

Grant, Struan F. A. ^{[7
]}

Farlow, Deborah N. ^{[2
]}

Chandrupatla, Hareesh R. ^{[9
]}

Hansen, Mark ^{[10
]}

Ajmal, Saad ^{[9
]}

Papanicolaou, George J. ^{[11
]}

Guo, Yiran ^{[12
]}

Li, Mingyao ^{[9
]}

DerOhannessian, Stephanie ^{[9
]}

de Bakker, Paul I. W. ^{[2
,13
]}

Bailey, Swneke D. ^{[32
]}

Montpetit, Alexandre ^{[36
]}

Edmondson, Andrew C. ^{[9
]}

Taylor, Kent ^{[14
]}

Gai, Xiaowu ^{[7
]}

Wang, Susanna S. ^{[15
]}

Fornage, Myriam ^{[16
]}

Shaikh, Tamim ^{[7
]}

Groop, Leif ^{[17
]}

Boehnke, Michael ^{[18
]}

Hall, Alistair S. ^{[19
]}

Hattersley, Andrew T. ^{[20
]}

Frackelton, Edward ^{[7
]}

Patterson, Nick ^{[2
]}

Chiang, Charleston W. K. ^{[2
,21
]}

Kim, Cecelia E. ^{[7
]}

Fabsitz, Richard R. ^{[11
]}

Ouwehand, Willem ^{[23
]}

Price, Alkes L. ^{[33
]}

Munroe, Patricia ^{[22
,24
]}

Caulfield, Mark ^{[24
]}

Drake, Thomas ^{[15
]}

Boerwinkle, Eric ^{[25
]}

Reich, David ^{[2
,21
]}

Whitehead, A. Stephen ^{[1
]}

Cappola, Thomas P. ^{[9
]}

Samani, Nilesh J. ^{[26
]}

Lusis, A. Jake ^{[15
,35
]}

Schadt, Eric ^{[27
]}

Wilson, James G. ^{[28
]}

Koenig, Wolfgang ^{[29
]}

McCarthy, Mark I. ^{[8
,34
]}

机构：

[1] Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA

[2] MIT, Broad Inst Harvard, Cambridge, MA 02139 USA

[3] Childrens Hosp, Div Genet, Endocrinol, Program Genom, Boston, MA USA

[4] Scripps Genom Med, La Jolla, CA USA

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

[6] MRC SGDP Ctr, Inst Psychiat, London, England

[7] CHOP, Dept Pediat, Div Human Genet, Ctr Applied Genom, Philadelphia, PA USA

[8] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX1 2JD, England

[9] Univ Penn, Cardiovasc Inst, Philadelphia, PA 19104 USA

[10] Illumina Inc, San Diego, CA USA

[11] NHLBI, Div Prevent & Populat Sci, Bethesda, MD USA

[12] Beijing Genom Inst Shenzhen, Shenzhen, Peoples R China

[13] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA USA

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

[15] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA

[16] Univ Texas, Hlth Sci Ctr, Inst Mol Med, Houston, TX USA

[17] Lund Univ, Dept Clin Sci Malmoe, Diabetes & Endocrinol, S-22100 Lund, Sweden

[18] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA

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

[20] Peninsula Med Sch, Inst Biomed & Clin Sci, Diabetes Genet Grp, Exeter, Devon, England

[21] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA

[22] Barts & The London, Dept Clin Pharmacol, London, England

[23] Univ Cambridge, NHS Blood & Transplant, Dept Haematol, Cambridge CB2 1TN, England

[24] Barts & The London, William Harvey Res Inst, London, England

[25] Univ Texas, Hlth Sci Ctr, Human Genet Ctr, Houston, TX USA

[26] Univ Leicester, Dept Cardiovasc Sci, Leicester LE1 7RH, Leics, England

[27] Merck & Co Inc, Rosetta Inpharmat LLC, Seattle, WA USA

[28] Univ Mississippi, Med Ctr, VA Med Ctr, University, MS 38677 USA

[29] Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, D-89069 Ulm, Germany

[30] Massachusetts Gen Hosp, Cardiol Div, Boston, MA USA

[31] McMaster Univ, Hamilton Gen Hosp, Hamilton Hlth Sci, Clin Epidemiol & Biostat, Populat Genom Program, Hamilton, ON L8S 4L8, Canada

[32] McGill Univ, Dept Med & Human Genet, Montreal, PQ H3A 2T5, Canada

[33] Harvard Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Cambridge, MA 02138 USA

[34] Univ Oxford, Churchill Hosp, Oxford NIHR Biomed Res Ctr, Oxford Ctr Diabetes, Endocrinol & Metabolism, Oxford OX1 2JD, England

[35] Univ Calif Los Angeles, Sch Med, Dept Microbiol, Immunol & Mol Genet, Los Angeles, CA 90024 USA

[36] Genome Quebec Innovat Ctr, Montreal, PQ, Canada

来源：

PLOS ONE | 2008年 / 3卷 / 10期

基金：

英国医学研究理事会;

关键词：

D O I：

10.1371/journal.pone.0003583

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

A wealth of genetic associations for cardiovascular and metabolic phenotypes in humans has been accumulating over the last decade, in particular a large number of loci derived from recent genome wide association studies (GWAS). True complex disease-associated loci often exert modest effects, so their delineation currently requires integration of diverse phenotypic data from large studies to ensure robust meta-analyses. We have designed a gene-centric 50 K single nucleotide polymorphism (SNP) array to assess potentially relevant loci across a range of cardiovascular, metabolic and inflammatory syndromes. The array utilizes a "cosmopolitan'' tagging approach to capture the genetic diversity across similar to 2,000 loci in populations represented in the HapMap and SeattleSNPs projects. The array content is informed by GWAS of vascular and inflammatory disease, expression quantitative trait loci implicated in atherosclerosis, pathway based approaches and comprehensive literature searching. The custom flexibility of the array platform facilitated interrogation of loci at differing stringencies, according to a gene prioritization strategy that allows saturation of high priority loci with a greater density of markers than the existing GWAS tools, particularly in African HapMap samples. We also demonstrate that the IBC array can be used to complement GWAS, increasing coverage in high priority CVD-related loci across all major HapMap populations. DNA from over 200,000 extensively phenotyped individuals will be genotyped with this array with a significant portion of the generated data being released into the academic domain facilitating in silico replication attempts, analyses of rare variants and cross-cohort meta-analyses in diverse populations. These datasets will also facilitate more robust secondary analyses, such as explorations with alternative genetic models, epistasis and gene-environment interactions.

引用

页数：9

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