Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease.

TitleRare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease.
Publication TypeJournal Article
Year of Publication2016
AuthorsJakobsdottir, 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, San Wang, L-, Williams, J, Schellenberg, GD, Boerwinkle, E, Psaty, BM, Seshadri, S, Shulman, JM, Gudnason, V, van Duijn, CM
Corporate Authors, ,
JournalPLoS Genet
Volume12
Issue10
Paginatione1006327
Date Published2016 Oct
ISSN1553-7404
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.

DOI10.1371/journal.pgen.1006327
Alternate JournalPLoS Genet.
PubMed ID27764101
PubMed Central IDPMC5072721
Grant ListCZD/16/6/4 / / Chief Scientist Office / United Kingdom
U01 AG032984 / AG / NIA NIH HHS / United States