Concept, design and implementation of a cardiovascular gene-centric 50 k SNP array for large-scale genomic association studies.
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 approximately 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.
Keating
Brendan J
BJ
The Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvannia, USA.
Tischfield
Sam
S
Murray
Sarah S
SS
Bhangale
Tushar
T
Price
Thomas S
TS
Glessner
Joseph T
JT
Galver
Luana
L
Barrett
Jeffrey C
JC
Grant
Struan F A
SF
Farlow
Deborah N
DN
Chandrupatla
Hareesh R
HR
Hansen
Mark
M
Ajmal
Saad
S
Papanicolaou
George J
GJ
Guo
Yiran
Y
Li
Mingyao
M
Derohannessian
Stephanie
S
de Bakker
Paul I W
PI
Bailey
Swneke D
SD
Montpetit
Alexandre
A
Edmondson
Andrew C
AC
Taylor
Kent
K
Gai
Xiaowu
X
Wang
Susanna S
SS
Fornage
Myriam
M
Shaikh
Tamim
T
Groop
Leif
L
Boehnke
Michael
M
Hall
Alistair S
AS
Hattersley
Andrew T
AT
Frackelton
Edward
E
Patterson
Nick
N
Chiang
Charleston W K
CW
Kim
Cecelia E
CE
Fabsitz
Richard R
RR
Ouwehand
Willem
W
Price
Alkes L
AL
Munroe
Patricia
P
Caulfield
Mark
M
Drake
Thomas
T
Boerwinkle
Eric
E
Reich
David
D
Whitehead
A Stephen
AS
Cappola
Thomas P
TP
Samani
Nilesh J
NJ
Lusis
A Jake
AJ
Schadt
Eric
E
Wilson
James G
JG
Koenig
Wolfgang
W
McCarthy
Mark I
MI
Kathiresan
Sekar
S
Gabriel
Stacey B
SB
Hakonarson
Hakon
H
Anand
Sonia S
SS
Reilly
Muredach
M
Engert
James C
JC
Nickerson
Deborah A
DA
Rader
Daniel J
DJ
Hirschhorn
Joel N
JN
Fitzgerald
Garret A
GA
D002318:Cardiovascular Diseases / Q000208:ethnology / Q000235:genetics*; D003210:Concept Formation; D005787:Gene Frequency; D055106:Genome-Wide Association Study / Q000295:instrumentation / Q000379:methods*; D005838:Genotype; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D044382:Population Groups / Q000235:genetics; D011786:Quality Control; D012107:Research Design