Brendan J. Keating 1 , Sam Tischfield 2 , 3 , Sarah S. Murray 4 , Tushar Bhangale 5 , Thomas S. Price 6 , Joseph T. Glessner 7 , Luana Galver 10 , Jeffrey C. Barrett 8 , Struan F. A. Grant 7 , Deborah N. Farlow 2 , Hareesh R. Chandrupatla 9 , Mark Hansen 10 , Saad Ajmal 9 , George J. Papanicolaou 11 , Yiran Guo 12 , Mingyao Li 9 , Stephanie DerOhannessian 9 , Paul I. W. de Bakker 13 , 2 , Swneke D. Bailey 32 , Alexandre Montpetit 36 , Andrew C. Edmondson 9 , Kent Taylor 14 , Xiaowu Gai 7 , Susanna S. Wang 15 , Myriam Fornage 16 , Tamim Shaikh 7 , Leif Groop 17 , Michael Boehnke 18 , Alistair S. Hall 19 , Andrew T. Hattersley 20 , Edward Frackelton 7 , Nick Patterson 2 , Charleston W. K. Chiang 2 , 21 , Cecelia E. Kim 7 , Richard R. Fabsitz 11 , Willem Ouwehand 23 , Alkes L. Price 33 , Patricia Munroe 22 , 24 , Mark Caulfield 24 , Thomas Drake 15 , Eric Boerwinkle 25 , David Reich 21 , 2 , A. Stephen Whitehead 1 , Thomas P. Cappola 9 , Nilesh J. Samani 26 , A. Jake Lusis 35 , 15 , Eric Schadt 27 , James G. Wilson 28 , Wolfgang Koenig 29 , Mark I. McCarthy 8 , 34 , Sekar Kathiresan 2 , 30 , Stacey B. Gabriel 2 , Hakon Hakonarson 7 , Sonia S. Anand 31 , Muredach Reilly 1 , 9 , James C. Engert 32 , Deborah A. Nickerson 5 , Daniel J. Rader 1 , 9 , Joel N. Hirschhorn 2 , 3 , 21 , Garret A. FitzGerald 1 , *
31 October 2008
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 ∼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.