TY - JOUR
T1 - Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease
AU - Cohorts for Heart and Aging Research in Genomic Epidemiology consortium
AU - Alzheimer's Disease Genetic Consortium
AU - Genetic and Environmental Risk in Alzheimer's Disease consortium
AU - Jakobsdottir, Johanna
AU - van der Lee, Sven J.
AU - Bis, Joshua C.
AU - Chouraki, Vincent
AU - Li-Kroeger, David
AU - Yamamoto, Shinya
AU - Grove, Megan L.
AU - Naj, Adam
AU - Vronskaya, Maria
AU - Salazar, Jose L.
AU - DeStefano, Anita L.
AU - Brody, Jennifer A.
AU - Smith, Albert V.
AU - Amin, Najaf
AU - Sims, Rebecca
AU - Ibrahim-Verbaas, Carla A.
AU - Choi, Seung Hoan
AU - Satizabal, Claudia L.
AU - Lopez, Oscar L.
AU - Beiser, Alexa
AU - Ikram, M. Arfan
AU - Garcia, Melissa E.
AU - Hayward, Caroline
AU - Varga, Tibor V.
AU - Ripatti, Samuli
AU - Franks, Paul W.
AU - Hallmans, Göran
AU - Rolandsson, Olov
AU - Jansson, Jan Håkon
AU - Porteous, David J.
AU - Salomaa, Veikko
AU - Eiriksdottir, Gudny
AU - Rice, Kenneth M.
AU - Bellen, Hugo J.
AU - Levy, Daniel
AU - Uitterlinden, Andre G.
AU - Emilsson, Valur
AU - Rotter, Jerome I.
AU - Aspelund, Thor
AU - O’Donnell, Christopher J.
AU - Fitzpatrick, Annette L.
AU - Launer, Lenore J.
AU - Hofman, Albert
AU - Wang, Li San
AU - Williams, Julie
AU - Schellenberg, Gerard D.
AU - Boerwinkle, Eric
AU - Psaty, Bruce M.
AU - Seshadri, Sudha
AU - Shulman, Joshua M.
N1 - Publisher Copyright:
© 2016 Public Library of Science. All rights reserved.
PY - 2016/10
Y1 - 2016/10
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pgen.1006327
DO - 10.1371/journal.pgen.1006327
M3 - Article
C2 - 27764101
AN - SCOPUS:84994310331
SN - 1553-7390
VL - 12
JO - PLoS Genetics
JF - PLoS Genetics
IS - 10
M1 - e1006327
ER -