The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease.
Τίτλος | The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | Gerrish, A., Russo G., Richards A., Moskvina V., Ivanov D., Harold D., Sims R., Abraham R., Hollingworth P., Chapman J., Hamshere M., Pahwa J. Singh, Dowzell K., Williams A., Jones N., Thomas C., Stretton A., Morgan A. R., Lovestone S., Powell J., Proitsi P., Lupton M. K., Brayne C., Rubinsztein D. C., Gill M., Lawlor B., Lynch A., Morgan K., Brown K. S., Passmore P. A., Craig D., McGuinness B., Todd S., Johnston J. A., Holmes C., Mann D., A Smith D., Love S., Kehoe P. G., Hardy J., Mead S., Fox N., Rossor M., Collinge J., Maier W., Jessen F., Kölsch H., Heun R., Schürmann B., van den Bussche H., Heuser I., Kornhuber J., Wiltfang J., Dichgans M., Frölich L., Hampel H., Hüll M., Rujescu D., Goate A. M., Kauwe J. S. K., Cruchaga C., Nowotny P., Morris J. C., Mayo K., Livingston G., Bass N. J., Gurling H., McQuillin A., Gwilliam R., Deloukas P., Davies G., Harris S. E., Starr J. M., Deary I. J., Al-Chalabi A., Shaw C. E., Tsolaki M., Singleton A. B., Guerreiro R., Mühleisen T. W., Nöthen M. M., Moebus S., Jöckel K-H., Klopp N., Wichmann H-E., Carrasquillo M. M., V Pankratz S., Younkin S. G., Jones L., Holmans P. A., O'Donovan M. C., Owen M. J., & Williams J. |
Journal | J Alzheimers Dis |
Volume | 28 |
Issue | 2 |
Pagination | 377-87 |
Date Published | 2012 |
ISSN | 1875-8908 |
Λέξεις κλειδιά | Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Protein Precursor, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Meta-Analysis as Topic, Odds Ratio, Polymorphism, Single Nucleotide, Presenilin-1, Presenilin-2, tau Proteins |
Abstract | Rare mutations in AβPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AβPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study. |
DOI | 10.3233/JAD-2011-110824 |
Alternate Journal | J. Alzheimers Dis. |
PubMed ID | 22027014 |
PubMed Central ID | PMC4118466 |
Grant List | 095317 / / Wellcome Trust / United Kingdom BB/F019394/1 / / Biotechnology and Biological Sciences Research Council / United Kingdom G-0907 / / Parkinson's UK / United Kingdom G0601846 / / Medical Research Council / United Kingdom G0700704/84698 / / Biotechnology and Biological Sciences Research Council / United Kingdom G0701075 / / Medical Research Council / United Kingdom G0900688 / / Medical Research Council / United Kingdom G0902227 / / Medical Research Council / United Kingdom MC_U123160651 / / Medical Research Council / United Kingdom MC_U123160657 / / Medical Research Council / United Kingdom NF-SI-0611-10084 / / Department of Health / United Kingdom P01 AG003991 / AG / NIA NIH HHS / United States P50 AG005681 / AG / NIA NIH HHS / United States / / Chief Scientist Office / United Kingdom / / Medical Research Council / United Kingdom / / Wellcome Trust / United Kingdom |