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P4‐338: Phylogenetic mapping of phased haplotype data for post‐GWAS mapping
Author(s) -
Roses Allen,
Lutz Michael,
Crenshaw Donna,
Saunders Ann,
Caselli Richard,
Grossman Iris,
ChibaFalek Ornit,
Burns Daniel
Publication year - 2011
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2011.09.083
Subject(s) - biology , genetics , haplotype , allele , single nucleotide polymorphism , apolipoprotein e , snp , association mapping , genome wide association study , genetic association , gene , genotype , disease , medicine , pathology
rectly on one phenotype and through their potential causal relationship to have indirect effects on the other or to impact susceptibility to both diseases via independent mechanisms i.e. have pleiotropic effects. The aim of this study was to investigatewhether a genotype score based on the top T2D candidates could predict LOAD risk.Methods: 17 Single-nucleotide polymorphisms (SNPs) associated with T2D were genotyped in 3500 Caucasian LOAD patients and controls, 2500 of which had diabetes information available. A genotype risk score (GRS) from the number of risk alleles was created and logistic regression was used to investigate its association with LOAD. Interactions between the GRS and APOE e4 status we used to investigate whether any observed associations were e4 stratum specific. Analyses were repeated for 2500 subjects with T2D info. Adjustment for T2D investigated whether any associations were through T2D status and an interaction with T2D was used to examine T2D stratum specific effects. Results: Six SNPs were associated with LOAD status, but only two of these increased LOAD risk. The GRS score was linearly associated with a decreased risk for AD (OR 1⁄4 0.97; 95% CI: 0.94-0.99; p 1⁄4 0.032 per allele). Also, the OR for LOAD in individuals at the top 5% of allele count distribution against those at the bottom 5% was OR 1⁄4 0.25 (95% CI: 0.0960.65, p 1⁄4 0.005). The association of the GRS with AD risk was independent of T2D status. However, the GRS was associated with decreased LOAD risk in APOE e4 carriers (OR 1⁄4 0.91; 95% CI from 0.87 to 0.96; p <0.001 per risk allele) but not in non-e4 carriers (OR 1⁄4 1.00; 95% CI 0.96 to 1.04; p 1⁄4 0.946) (p 1⁄4 0.005 for the interaction term). Conclusions: A GRS based on the top T2D candidates was associated with a decreased risk for LOAD in APOE e4 carriers. Such an observation could partly explain why only some e4 carriers have LOAD.