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

J Jakobsdottir, Sven van der Lee, JC Bis, V Chouraki, D Li-Kroeger, S Yamamoto, ML Grove, A Naj, M Vronskaya, JL Salazar, AL DeStefano, JA Brody, AV Smith, Najaf Amin, R Sims, Carla Verbaas, SH Choi, CL Satizabal, OL Lopez, A BeiserArfan Ikram, ME Garcia, C Hayward, TV Varga, S Ripatti, PW Franks, G Hallmans, O Rolandsson, JH Jansson, DJ Porteous, V Salomaa, G Eiriksdottir, KM Rice, HJ Bellen, D Levy, André Uitterlinden, V Emilsson, JI Rotter, T Aspelund, CJ O'Donnell, AL Fitzpatrick, LJ Launer, Bert Hofman, LS (Li-San) Wang, J Williams, GD Schellenberg, E Boerwinkle, BM Psaty, S Seshadri, JM Shulman, V Gudnason, Cornelia Duijn

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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 (similar to 0.5% versus < 0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES substudy, 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 beta-amyloid cascade.
Original languageUndefined/Unknown
JournalPLoS Genetics (online)
Issue number10
Publication statusPublished - 2016

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