Jakobsdottir, J., van der Lee, S.J., Bis, J.C., Chouraki, V., Li-Kroeger, D., Yamamoto, S., Grove, M.L., Naj, A., Vronskaya, M., Salazar, J.L., DeStefano, A.L., Brody, J.A., Smith, A.V., Amin, N., Sims, R., Ibrahim-Verbaas, C.A., Choi, S.H., Satizabal, C.L., Lopez, O.L., Beiser, A., Ikram, M.A., Garcia, M.E., Hayward, C., Varga, T.V., Ripatti, S., Franks, P.W., Hallmans, G., Rolandsson, O., Jansson, J.H., Porteous, D.J., Salomaa, V., Eiriksdottir, G., Rice, K.M., Bellen, H.J., Levy, D., Uitterlinden, A.G., Emilsson, V., Rotter, J.I., Aspelund, T., Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, , Alzheimer’s Disease Genetic Consortium, , Genetic and Environmental Risk in Alzheimer’s Disease consortium, , O'Donnell, C.J., Fitzpatrick, A.L., Launer, L.J., Hofman, A., Wang, L.S., Williams, J., Schellenberg, G.D., Boerwinkle, E., Psaty, B.M., Seshadri, S., Shulman, J.M., Gudnason, V., van Duijn, C.M. (2016). Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease.  PLoS Genet. 12(10): e1006327.

FBrf0233803

Research paper

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.

PMC5072721 (PMC) (EuropePMC)