Jakobsdottir, Johannavan der Lee, Sven J.Bis, Joshua C.Chouraki, VincentLi-Kroeger, DavidYamamoto, ShinyaGrove, Megan L.Naj, AdamVronskaya, MariaSalazar, Jose L.DeStefano, Anita L.Brody, Jennifer A.Smith, Albert V.Amin, NajafSims, RebeccaIbrahim-Verbaas, Carla A.Choi, Seung-HoanSatizabal, Claudia L.Lopez, Oscar L.Beiser, AlexaIkram, M. ArfanGarcia, Melissa E.Hayward, CarolineVarga, Tibor V.Ripatti, SamuliFranks, PaulHallmans, GöranRolandsson, OlovJansson, Jan-HåkonPorteous, David J.Salomaa, VeikkoEiriksdottir, GudnyRice, Kenneth M.Bellen, Hugo J.Levy, DanielUitterlinden, Andre G.Emilsson, ValurRotter, Jerome I.Aspelund, ThorO’Donnell, Christopher J.Fitzpatrick, Annette L.Launer, Lenore J.Hofman, AlbertWang, Li-SanWilliams, JulieSchellenberg, Gerard D.Boerwinkle, EricPsaty, Bruce M.Seshadri, SudhaShulman, Joshua M.Gudnason, Vilmundurvan Duijn, Cornelia M.2016-11-182016Jakobsdottir, J., S. J. van der Lee, J. C. Bis, V. Chouraki, D. Li-Kroeger, S. Yamamoto, M. L. Grove, et al. 2016. “Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease.” PLoS Genetics 12 (10): e1006327. doi:10.1371/journal.pgen.1006327. http://dx.doi.org/10.1371/journal.pgen.1006327.1553-7390http://nrs.harvard.edu/urn-3:HUL.InstRepos:29408358We 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.en-USMedicine and Health SciencesMental Health and PsychiatryDementiaAlzheimer DiseaseNeurologyNeurodegenerative DiseasesModel OrganismsAnimal ModelsDrosophila MelanogasterBiology and Life SciencesOrganismsAnimalsInvertebratesArthropodaInsectsDrosophilaDevelopmental BiologyEmbryologyEmbryosGeneticsGenetic LociAllelesPhenotypesGenomicsAnimal GenomicsInvertebrate GenomicsCell BiologySignal TransductionCell SignalingNotch SignalingSocial SciencesSociologyConsortiaJournal Article2016-11-1810.1371/journal.pgen.1006327