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- Title
Genome-Wide Association with Diabetes-Related Traits in the Framingham Heart Study.
- Authors
Florez, Jose C.; Manning, Alisa K.; Dupuis, Josée;; Gianniny, Lauren; Irenze, Kathryn; McAteer, Jarred; Mirel, Daniel B.; Fox, Caroline S.; Cupples, L. A.; Meigs, James B.
- Abstract
Susceptibility to type 2 diabetes may be conferred by genetic variants having modest effects on risk. Genome-wide fixed marker arrays offer a novel approach to detect these variants. We used the Affymetrix 100K SNP array in 1,087 Framingham Offspring Study family members to examine genetic associations with 3 diabetes-related quantitative glucose traits (fasting plasma glucose [FPG], hemoglobin A1c, 28-yr time-averaged FPG [tFPG]), 3 insulin traits (fasting insulin, homeostasis model-insulin resistance, and 0-120 min insulin sensitivity index); and with risk for diabetes. We used additive GEE and FBAT models to test associations of common SNPs (minor allele frequency > 10%) with sex-age-age²-adjusted residual trait values, and Cox survival models to test incident diabetes (N=92 cases). We devised a 'multiple related trait' strategy to prioritize SNPs associated (at nominal P<0.01) with all 3 glucose traits, or all 3 insulin traits, or 2 glucose and 2 insulin traits. This multiple related trait strategy yielded 203 SNPs, 53 of which also showed P<0.01 for incident diabetes, and 116 of which had P<0.001 for at least one trait. We used linkage disequilibrium (LD) between SNPs (pairwise r² >0.8) to select a non-redundant subset of 143 SNPs, and genotyped them in a non-overlapping replication sample of 1,465 Framingham unrelated subjects. Ten SNPs were associated with one of the same traits (at nominal P<0.05) in the replication dataset (9 expected under the null); 4 of them were associated with more than one trait, and one of these was also associated with incident diabetes. Four other SNPs (one of which was also associated with diabetes incidence initially) showed association with diabetes incidence in replication (6 expected under the null). As a positive control, SNP rs7100927 was in moderate LD (r²=0.50) with TCF7L2 SNP rs7903146, and was associated with risk of diabetes (Cox P=0.007, additive hazard ratio for diabetes 1.56) and with tFPG (GEE P=0.03) in the initial dataset. We conclude that traits measured in a community-based sample and 100K genome-wide data show promise as a resource for association tests of known and novel type 2 diabetes susceptibility genes. ADA-Funded Research
- Subjects
GENOMES; TYPE 2 diabetes; BLOOD sugar; INSULIN; GENETIC polymorphisms; GENES
- Publication
Diabetes, 2007, Vol 56, pA94
- ISSN
0012-1797
- Publication type
Article