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https://doi.org/10.1371/journal.pgen.1006327
| Title: | Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease | Authors: | Jakobsdottir J. van der Lee S.J. Bis J.C. Chouraki V. Li-Kroeger D. Yamamoto S. Grove M.L. Naj A. Vronskaya M. Salazar J.L. DeStefano A.L. Brody J.A. Smith A.V. Amin N. Sims R. Ibrahim-Verbaas C.A. Choi S.-H. Satizabal C.L. Lopez O.L. Beiser A. Ikram M.A. Garcia M.E. Hayward C. Varga T.V. Ripatti S. Franks P.W. Hallmans G. Rolandsson O. Jansson J.-H. Porteous D.J. Salomaa V. Eiriksdottir G. Rice K.M. Bellen H.J. Levy D. Uitterlinden A.G. Emilsson V. Rotter J.I. Aspelund T. O?Donnell C.J. Fitzpatrick A.L. Launer L.J. Hofman A. Wang L.-S. Williams J. Schellenberg G.D. Boerwinkle E. Psaty B.M. Seshadri S. |
Keywords: | amyloid beta protein apolipoprotein E membrane protein Notch receptor presenilin protein SKAP2 protein TM2D3 unclassified drug Amx protein, Drosophila amyloid precursor protein ApoE protein, human apolipoprotein E Drosophila protein membrane protein Notch receptor signal peptide src kinase associated phosphoprotein 2 TM2D1 protein, human tropomyosin aged Alzheimer disease Article chromosome 15q controlled study ethnic difference exome female gene gene mutation genetic analysis genetic association genetic susceptibility genetic variability human Icelander major clinical study male molecular pathology nonhuman population based case control study protein structure signal transduction single nucleotide polymorphism TM2D3 gene allele Alzheimer disease animal Caucasian Drosophila melanogaster genetics genome-wide association study genomics Iceland mutation onset age pathology phenotype Age of Onset Aged Alleles Alzheimer Disease Amyloid beta-Protein Precursor Animals Apolipoproteins E Drosophila melanogaster Drosophila Proteins European Continental Ancestry Group Exome Female Genome-Wide Association Study Genomics Humans Iceland Intracellular Signaling Peptides and Proteins Male Membrane Proteins Mutation Phenotype Receptors, Notch Tropomyosin |
Issue Date: | 2016 | Citation: | Jakobsdottir J., van der Lee S.J., Bis J.C., Chouraki V., Li-Kroeger D., Yamamoto S., Grove M.L., Naj A., Vronskaya M., Salazar J.L., DeStefano A.L., Brody J.A., Smith A.V., Amin N., Sims R., Ibrahim-Verbaas C.A., Choi S.-H., Satizabal C.L., Lopez O.L., Beiser A., Ikram M.A., Garcia M.E., Hayward C., Varga T.V., Ripatti S., Franks P.W., Hallmans G., Rolandsson O., Jansson J.-H., Porteous D.J., Salomaa V., Eiriksdottir G., Rice K.M., Bellen H.J., Levy D., Uitterlinden A.G., Emilsson V., Rotter J.I., Aspelund T., O?Donnell C.J., Fitzpatrick A.L., Launer L.J., Hofman A., Wang L.-S., Williams J., Schellenberg G.D., Boerwinkle E., Psaty B.M., Seshadri S. (2016). Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease. PLoS Genetics 12 (10) : e1006327. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pgen.1006327 | Rights: | CC0 1.0 Universal | Abstract: | We performed an exome-wide association analysis in 1393 late-onset Alzheimer?s disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5?15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the ?-amyloid cascade. ? 2016 Public Library of Science. All rights reserved. | Source Title: | PLoS Genetics | URI: | https://scholarbank.nus.edu.sg/handle/10635/161904 | ISSN: | 15537390 | DOI: | 10.1371/journal.pgen.1006327 | Rights: | CC0 1.0 Universal |
| Appears in Collections: | Elements Staff Publications |
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