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

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title = "Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease",
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 (~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.",
author = "Johanna Jakobsdottir and {van der Lee}, {Sven J.} and Bis, {Joshua C.} and Vincent Chouraki and David Li-Kroeger and Shinya Yamamoto and Grove, {Megan L.} and Adam Naj and Maria Vronskaya and Salazar, {Jose L.} and DeStefano, {Anita L.} and Brody, {Jennifer A.} and Smith, {Albert V.} and Najaf Amin and Rebecca Sims and Ibrahim-Verbaas, {Carla A.} and Choi, {Seung Hoan} and Satizabal, {Claudia L.} and Lopez, {Oscar L.} and Alexa Beiser and Ikram, {M. Arfan} and Garcia, {Melissa E.} and Caroline Hayward and Varga, {Tibor V.} and Samuli Ripatti and Franks, {Paul W.} and G{\"o}ran Hallmans and Olov Rolandsson and Jansson, {Jan H{\aa}kon} and Porteous, {David J.} and Veikko Salomaa and Gudny Eiriksdottir and Rice, {Kenneth M.} and Bellen, {Hugo J.} and Daniel Levy and Uitterlinden, {Andre G.} and Valur Emilsson and Rotter, {Jerome I.} and Thor Aspelund and O’Donnell, {Christopher J.} and Fitzpatrick, {Annette L.} and Launer, {Lenore J.} and Albert Hofman and Wang, {Li San} and Julie Williams and Schellenberg, {Gerard D.} and Eric Boerwinkle and Psaty, {Bruce M.} and Sudha Seshadri and Shulman, {Joshua M.} and Vilmundur Gudnason and {van Duijn}, {Cornelia M.}",
year = "2016",
month = "10",
day = "1",
doi = "10.1371/journal.pgen.1006327",
language = "English",
volume = "12",
journal = "PLoS Genetics",
issn = "1553-7404",
publisher = "Public Library of Science",
number = "10",