Candidate gene association resource (CARe): design, methods, and proof of concept.
BACKGROUND
The National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe), a planned cross-cohort analysis of genetic variation in cardiovascular, pulmonary, hematologic, and sleep-related traits, comprises >40,000 participants representing 4 ethnic groups in 9 community-based cohorts. The goals of CARe include the discovery of new variants associated with traits using a candidate gene approach and the discovery of new variants using the genome-wide association mapping approach specifically in African Americans.


RESULTS
CARe has assembled DNA samples for >40,000 individuals self-identified as European American, African American, Hispanic, or Chinese American, with accompanying data on hundreds of phenotypes that have been standardized and deposited in the CARe Phenotype Database. All participants were genotyped for 7 single-nucleotide polymorphisms (SNPs) selected based on prior association evidence. We performed association analyses relating each of these SNPs to lipid traits, stratified by sex and ethnicity, and adjusted for age and age squared. In at least 2 of the ethnic groups, SNPs near CETP, LIPC, and LPL strongly replicated for association with high-density lipoprotein cholesterol concentrations, PCSK9 with low-density lipoprotein cholesterol levels, and LPL and APOA5 with serum triglycerides. Notably, some SNPs showed varying effect sizes and significance of association in different ethnic groups.


CONCLUSIONS
The CARe Pilot Study validates the operational framework for phenotype collection, SNP genotyping, and analytic pipeline of the CARe project and validates the planned candidate gene study of approximately 2000 biological candidate loci in all participants and genome-wide association study in approximately 8000 African American participants. CARe will serve as a valuable resource for the scientific community.
Musunuru
Kiran
K
Broad Institute, Cambridge, MA 02142, USA.
Lettre
Guillaume
G
Young
Taylor
T
Farlow
Deborah N
DN
Pirruccello
James P
JP
Ejebe
Kenechi G
KG
Keating
Brendan J
BJ
Yang
Qiong
Q
Chen
Ming-Huei
MH
Lapchyk
Nina
N
Crenshaw
Andrew
A
Ziaugra
Liuda
L
Rachupka
Anthony
A
Benjamin
Emelia J
EJ
Cupples
L Adrienne
LA
Fornage
Myriam
M
Fox
Ervin R
ER
Heckbert
Susan R
SR
Hirschhorn
Joel N
JN
Newton-Cheh
Christopher
C
Nizzari
Marcia M
MM
Paltoo
Dina N
DN
Papanicolaou
George J
GJ
Patel
Sanjay R
SR
Psaty
Bruce M
BM
Rader
Daniel J
DJ
Redline
Susan
S
Rich
Stephen S
SS
Rotter
Jerome I
JI
Taylor
Herman A
HA
Tracy
Russell P
RP
Vasan
Ramachandran S
RS
Wilson
James G
JG
Kathiresan
Sekar
S
Fabsitz
Richard R
RR
Boerwinkle
Eric
E
Gabriel
Stacey B
SB
D001741:Black or African American / Q000235:genetics; D008076:Cholesterol, HDL / Q000097:blood / Q000235:genetics; D008078:Cholesterol, LDL / Q000097:blood / Q000235:genetics; D015331:Cohort Studies; D030541:Databases, Genetic; D056726:Genetic Association Studies / Q000379:methods*; D005838:Genotype; D006801:Humans; D010641:Phenotype; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide; D012107:Research Design; D014280:Triglycerides / Q000097:blood / Q000235:genetics; D044465:White People / Q000235:genetics
D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D014280:Triglycerides
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