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Title | Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Jakobsdottir J, van der Lee SJ, Bis JC, Chouraki V, Li-Kroeger D, Yamamoto S, Grove ML, Naj A, Vronskaya M, Salazar JL, DeStefano AL, Brody JA, Smith AV, Amin N, Sims R, Ibrahim-Verbaas CA, Choi S-H, Satizabal CL, Lopez OL, Beiser A, M Ikram A, Garcia ME, Hayward C, Varga TV, Ripatti S, Franks PW, Hallmans G, Rolandsson O, Jansson J-H, Porteous DJ, Salomaa V, Eiriksdottir G, Rice KM, Bellen HJ, Levy D, Uitterlinden AG, Emilsson V, Rotter JI, Aspelund T, O'Donnell CJ, Fitzpatrick AL, Launer LJ, Hofman A, Wang L-S, Williams J, Schellenberg GD, Boerwinkle E, Psaty BM, Seshadri S, Shulman JM, Gudnason V, van Duijn CM |
Corporate Authors | Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, Alzheimer’s Disease Genetic Consortium, Genetic and Environmental Risk in Alzheimer’s Disease consortium |
Journal | PLoS Genet |
Volume | 12 |
Issue | 10 |
Pagination | e1006327 |
Date Published | 2016 Oct |
ISSN | 1553-7404 |
Keywords | 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 |
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 β-amyloid cascade. |
DOI | 10.1371/journal.pgen.1006327 |
Alternate Journal | PLoS Genet. |
PubMed ID | 27764101 |
PubMed Central ID | PMC5072721 |
Grant List | MR/K013041/1 / / Medical Research Council / United Kingdom P30 AG010124 / AG / NIA NIH HHS / United States R01 HL120393 / HL / NHLBI NIH HHS / United States U24 AG021886 / AG / NIA NIH HHS / United States U01 AG032984 / AG / NIA NIH HHS / United States R01 AG050631 / AG / NIA NIH HHS / United States U01 HL130114 / HL / NHLBI NIH HHS / United States U01 AG016976 / AG / NIA NIH HHS / United States U24 AG056270 / AG / NIA NIH HHS / United States UL1 TR000124 / TR / NCATS NIH HHS / United States G0902227 / / Medical Research Council / United Kingdom MR/L501517/1 / / Medical Research Council / United Kingdom R01 HL105756 / HL / NHLBI NIH HHS / United States P30 DK063491 / DK / NIDDK NIH HHS / United States R25 GM056929 / GM / NIGMS NIH HHS / United States CZD/16/6/4 / / Chief Scientist Office / United Kingdom MC_PC_U127561128 / / Medical Research Council / United Kingdom T32 GM008307 / GM / NIGMS NIH HHS / United States MR/L010305/1 / / Medical Research Council / United Kingdom |