1. Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease
- Author
-
Jakobsdottir, J, van der Lee, Sven, Bis, JC, Chouraki, V, Li-Kroeger, D, Yamamoto, S, Grove, ML, Naj, A, Vronskaya, M, Salazar, JL, DeStefano, AL, Brody, JA, Smith, AV, Amin, Najaf, Sims, R, Verbaas, Carla, Choi, SH, Satizabal, CL, Lopez, OL, Beiser, A, Ikram, Arfan, Garcia, ME, Hayward, C, Varga, TV, Ripatti, S, Franks, PW, Hallmans, G, Rolandsson, O, Jansson, JH, Porteous, DJ, Salomaa, V, Eiriksdottir, G, Rice, KM, Bellen, HJ, Levy, D, Uitterlinden, André, Emilsson, V, Rotter, JI, Aspelund, T, O'Donnell, CJ, Fitzpatrick, AL, Launer, LJ, Hofman, Bert, Wang, LS (Li-San), Williams, J, Schellenberg, GD, Boerwinkle, E, Psaty, BM, Seshadri, S, Shulman, JM, Gudnason, V, Duijn, Cornelia, Jakobsdottir, J, van der Lee, Sven, Bis, JC, Chouraki, V, Li-Kroeger, D, Yamamoto, S, Grove, ML, Naj, A, Vronskaya, M, Salazar, JL, DeStefano, AL, Brody, JA, Smith, AV, Amin, Najaf, Sims, R, Verbaas, Carla, Choi, SH, Satizabal, CL, Lopez, OL, Beiser, A, Ikram, Arfan, Garcia, ME, Hayward, C, Varga, TV, Ripatti, S, Franks, PW, Hallmans, G, Rolandsson, O, Jansson, JH, Porteous, DJ, Salomaa, V, Eiriksdottir, G, Rice, KM, Bellen, HJ, Levy, D, Uitterlinden, André, Emilsson, V, Rotter, JI, Aspelund, T, O'Donnell, CJ, Fitzpatrick, AL, Launer, LJ, Hofman, Bert, Wang, LS (Li-San), Williams, J, Schellenberg, GD, Boerwinkle, E, Psaty, BM, Seshadri, S, Shulman, JM, Gudnason, V, and Duijn, Cornelia
- 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 (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.
- Published
- 2016