A 100K Genome-Wide Association Scan for Diabetes and Related Traits in the Framingham Heart Study
Open Access
- 1 December 2007
- journal article
- research article
- Published by American Diabetes Association in Diabetes
- Vol. 56 (12), 3063-3074
- https://doi.org/10.2337/db07-0451
Abstract
OBJECTIVE— To use genome-wide fixed marker arrays and improved analytical tools to detect genetic associations with type 2 diabetes in a carefully phenotyped human sample. RESEARCH DESIGN AND METHODS— A total of 1,087 Framingham Heart Study (FHS) family members were genotyped on the Affymetrix 100K single nucleotide polymorphism (SNP) array and examined for association with incident diabetes and six diabetes-related quantitative traits. Quality control filters yielded 66,543 SNPs for association testing. We used two complementary SNP selection strategies (a “lowest P value” strategy and a “multiple related trait” strategy) to prioritize 763 SNPs for replication. We genotyped a subset of 150 SNPs in a nonoverlapping sample of 1,465 FHS unrelated subjects and examined all 763 SNPs for in silico replication in three other 100K and one 500K genome-wide association (GWA) datasets. RESULTS— We replicated associations of 13 SNPs with one or more traits in the FHS unrelated sample (16 expected under the null); none of them showed convincing in silico replication in 100K scans. Seventy-eight SNPs were nominally associated with diabetes in one other 100K GWA scan, and two (rs2863389 and rs7935082) in more than one. Twenty-five SNPs showed promising associations with diabetes-related traits in 500K GWA data; one of them (rs952635) replicated in FHS. Five previously reported associations were confirmed in our initial dataset. CONCLUSIONS— The FHS 100K GWA resource is useful for follow-up of genetic associations with diabetes-related quantitative traits. Discovery of new diabetes genes will require larger samples and a denser array combined with well-powered replication strategies.Keywords
This publication has 46 references indexed in Scilit:
- The Framingham Heart Study 100K SNP genome-wide association study resource: overview of 17 phenotype working group reportsBMC Medical Genetics, 2007
- A Genome-Wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility VariantsScience, 2007
- A genome-wide association study identifies novel risk loci for type 2 diabetesNature, 2007
- Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolutionNature Genetics, 2007
- TCF7L2Polymorphisms and Progression to Diabetes in the Diabetes Prevention ProgramNew England Journal of Medicine, 2006
- Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studiesNature Genetics, 2006
- A haplotype map of the human genomeNature, 2005
- Efficiency and power in genetic association studiesNature Genetics, 2005
- Haploview: analysis and visualization of LD and haplotype mapsBioinformatics, 2004
- The International HapMap ProjectNature, 2003