The Framingham Heart Study 100K SNP genome-wide association study resource: overview of 17 phenotype working group reports.
BACKGROUND
The Framingham Heart Study (FHS), founded in 1948 to examine the epidemiology of cardiovascular disease, is among the most comprehensively characterized multi-generational studies in the world. Many collected phenotypes have substantial genetic contributors; yet most genetic determinants remain to be identified. Using single nucleotide polymorphisms (SNPs) from a 100K genome-wide scan, we examine the associations of common polymorphisms with phenotypic variation in this community-based cohort and provide a full-disclosure, web-based resource of results for future replication studies.


METHODS
Adult participants (n = 1345) of the largest 310 pedigrees in the FHS, many biologically related, were genotyped with the 100K Affymetrix GeneChip. These genotypes were used to assess their contribution to 987 phenotypes collected in FHS over 56 years of follow up, including: cardiovascular risk factors and biomarkers; subclinical and clinical cardiovascular disease; cancer and longevity traits; and traits in pulmonary, sleep, neurology, renal, and bone domains. We conducted genome-wide variance components linkage and population-based and family-based association tests.


RESULTS
The participants were white of European descent and from the FHS Original and Offspring Cohorts (examination 1 Offspring mean age 32 +/- 9 years, 54% women). This overview summarizes the methods, selected findings and limitations of the results presented in the accompanying series of 17 manuscripts. The presented association results are based on 70,897 autosomal SNPs meeting the following criteria: minor allele frequency > or + 10%, genotype call rate > or = 80%, Hardy-Weinberg equilibrium p-value > or = 0.001, and satisfying Mendelian consistency. Linkage analyses are based on 11,200 SNPs and short-tandem repeats. Results of phenotype-genotype linkages and associations for all autosomal SNPs are posted on the NCBI dbGaP website at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 webcite.


CONCLUSIONS
We have created a full-disclosure resource of results, posted on the dbGaP website, from a genome-wide association study in the FHS. Because we used three analytical approaches to examine the association and linkage of 987 phenotypes with thousands of SNPs, our results must be considered hypothesis-generating and need to be replicated. Results from the FHS 100K project with NCBI web posting provides a resource for investigators to identify high priority findings for replication.
Cupples
L Adrienne
LA
National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
Arruda
Heather T
HT
Benjamin
Emelia J
EJ
D'Agostino
Ralph B
RB
Demissie
Serkalem
S
DeStefano
Anita L
AL
Dupuis
Josée
J
Falls
Kathleen M
KM
Fox
Caroline S
CS
Gottlieb
Daniel J
DJ
Govindaraju
Diddahally R
DR
Guo
Chao-Yu
CY
Heard-Costa
Nancy L
NL
Hwang
Shih-Jen
SJ
Kathiresan
Sekar
S
Kiel
Douglas P
DP
Laramie
Jason M
JM
Larson
Martin G
MG
Levy
Daniel
D
Liu
Chun-Yu
CY
Lunetta
Kathryn L
KL
Mailman
Matthew D
MD
Manning
Alisa K
AK
Meigs
James B
JB
Murabito
Joanne M
JM
Newton-Cheh
Christopher
C
O'Connor
George T
GT
O'Donnell
Christopher J
CJ
Pandey
Mona
M
Seshadri
Sudha
S
Vasan
Ramachandran S
RS
Wang
Zhen Y
ZY
Wilk
Jemma B
JB
Wolf
Philip A
PA
Yang
Qiong
Q
Atwood
Larry D
LD
D000328:Adult; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000503:physiopathology; D015331:Cohort Studies; D004198:Disease Susceptibility; D005260:Female; D005819:Genetic Markers; D015894:Genome, Human; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
D005819:Genetic Markers