Investigation of MAPT Subhaplotypes as Risk Factors for Late-Onset Alzheimer's Disease (S34.003)

OBJECTIVE: To evaluate MAPT subhaplotypes for association with risk for LOAD and MAPT brain expression levels. BACKGROUND: Neurofibrillary tangles composed of tau protein (MAPT) are a classic neuropathological feature of AD. MAPT variants associate with primary tauopathies, however evidence for genetic involvement of MAPT in LOAD has been inconsistent. We sought to examine well-established MAPT subhaplotype-tagging variants in our LOAD case-control series to determine their effect on risk for LOAD. We also hypothesize that some of the MAPT variants may confer disease risk by influencing brain expression levels of MAPT, based on our expression GWAS (eGWAS). DESIGN/METHODS: We genotyped four SNPs which tag the most common MAPT subhaplotypes (frequencies >5%), in three Caucasian LOAD case-control series (N-cases=1,886; N-controls=3,236). SNPs were tested for association with LOAD risk using logistic regression, adjusted for covariates. We measured gene expression levels in the cerebellum (N=197) and temporal cortex (N=202) of autopsied AD subjects as part of our eGWAS. We tested associations of the four MAPT SNPs with expression of MAPT, using linear regression with appropriate covariate adjustments. RESULTS: The H2-tagging SNP (rs8070723), known to associate with decreased risk of other tauopathies, was significantly associated with decreased risk of LOAD (OR = 0.783, p=3.05E-04). This SNP was also associated with decreased MAPT expression in both brain regions (beta=-0.16 to -0.47, p=6.2E-03 to 8.92E-31). The H1b tagging SNP (rs1467967) had nominally significant association with increased risk of LOAD (OR=1.25, p=0.04) and increased expression of MAPT in both brain regions. Though the H1c-tagging SNP (rs242557) associated with higher brain MAPT levels, it did not associate with AD risk. CONCLUSIONS: In our large LOAD series we find significant evidence for association of MAPT variants with risk of LOAD and brain gene expression. It will be important to investigate the effects of the rarer MAPT subhaplotypes, which is underway. Disclosure: Dr. Allen has nothing to disclose. Dr. Kachadoorian has nothing to disclose. Dr. Quicksall has nothing to disclose. Dr. Zou has nothing to disclose. Dr. Chai has nothing to disclose. Dr. Younkin has nothing to disclose. Dr. Crook has nothing to disclose. Dr. Pankratz received financial support for research activities from Abbott Laboratories. Dr. Carrasquillo has nothing to disclose. Dr. Krishnan has nothing to disclose. Dr. Nguyen has nothing to disclose. Dr. Ma has nothing to disclose. Dr. Malphrus has nothing to disclose. Dr. Lincoln has nothing to disclose. Dr. Bisceglio has nothing to disclose. Dr. Kolbert has nothing to disclose. Dr. Jen has nothing to disclose. Dr. Petersen has received personal compensation for activities with Pfizer, Inc., Janssen Alzheimer9s Immunotherapy, Elan Pharmaceuticals, GE Healthcare, and Novartis. Dr. Graff-Radford has received personal compensation for activities with Codman. Dr. Graff-Radford has received personal compensation in an editorial capacity for the Neurologist. Dr. Graff-Radford has received research support from Janssen, Pfizer Pharmaceuticals, Medivation, Forrest, and Allon. Dr. Dickson has received personal compensation for activities with Neotope, Inc. as a consultant. Dr. Younkin has nothing to disclose. Dr. Taner has nothing to disclose.