期刊
PLOS ONE
卷 7, 期 12, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0050354
关键词
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资金
- National Institutes of Health (NIH)
- National Institute on Aging [R37-AG15473, P01-AG07232]
- Blanchett Hooker Rockefeller Foundation
- Paul B. Beeson Career Development Award [K23AG034550]
- National Institute on Aging - Late Onset Alzheimer's Disease Family Study [U24AG026390]
- National Cell Repository for Alzheimer's Disease (NCRAD) [U24 AG21886]
- Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]
- National Institute of Biomedical Imaging and Bioengineering
- Canadian Institutes of Health Research
- Northern California Institute for Research and Education
- NIH [P30 AG010129, K01 AG030514]
- Dana Foundation
- National Institute on Aging (NIA)
- Abbott
- Amorfix Life Sciences Ltd.
- AstraZeneca
- Bayer HealthCare
- BioClinica, Inc.
- Biogen Idec Inc.
- Bristol-Myers Squibb Company
- Eisai Inc.
- Elan Pharmaceuticals Inc.
- Eli Lilly and Company
- F. Hoffmann-La Roche Ltd
- GE Healthcare
- Innogenetics, N.V.
- Janssen Alzheimer Immunotherapy Research & Development, LLC.
- Johnson & Johnson Pharmaceutical Research & Development LLC.
- Medpace, Inc.
- Merck Co., Inc.
- Meso Scale Diagnostics, LLC.
- Novartis Pharmaceuticals Corporation
- Pfizer Inc.
- Servier
- Synarc Inc.
- Takeda Pharmaceutical Company
Background: Recent studies showed that polymorphisms in the Fat and Obesity-Associated (FTO) gene have robust effects on obesity, obesity-related traits and endophenotypes associated with Alzheimer's disease (AD). Methods: We used 1,877 Caucasian cases and controls from the NIA-LOAD study and 1,093 Caribbean Hispanics to further explore the association of FTO with AD. Using logistic regression, we assessed 42 SNPs in introns 1 and 2, the region previously reported to be associated with AD endophenotypes, which had been derived by genome-wide screenings. In addition, we performed gene expression analyses of neuropathologically confirmed AD cases and controls of two independent datasets (19 AD cases, 10 controls; 176 AD cases, 188 controls) using within-and between-group factors ANOVA of log(10) transformed rank invariant normalized expression data. Results: In the NIALOAD study, one SNP was significantly associated with AD and three additional markers were close to significance (rs6499640, rs10852521, rs16945088, rs8044769, FDR p-value: 0.05 <0.09). Two of the SNPs are in strong LD (D'>0.9) with the previously reported SNPs. In the Caribbean Hispanic dataset, we identified three SNPs (rs17219084, rs11075996, rs11075997, FDR p-value: 0.009 <0.01) that were associated with AD. These results were confirmed by haplotype analyses and in a metaanalysis in which we included the ADNI dataset. FTO had a significantly lower expresssion in AD cases compared to controls in two independent datasets derived from human cortex and amygdala tissue, respectively (p = 2.18x10-5 and p<0.0001). Conclusions: Our data support the notion that genetic variation in Introns 1 and 2 of the FTO gene may contribute to AD risk.
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