Please use this identifier to cite or link to this item: 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
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