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 AuthorsCohorts for Heart and Aging Research in Genomic Epidemiology consortium, Alzheimer’s Disease Genetic Consortium, Genetic and Environmental Risk in Alzheimer’s Disease consortium
JournalPLoS Genet
Date Published2016 Oct

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.

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