Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

Rare functional variant in TM2D3 is associated with late-onset Alzheimer's disease

Jakobsdottir, Johanna, van der Lee, Sven J., Bis, Joshua C., Chouraki, Vincent, Li-Kroeger, David, Yamamoto, Shinya, Grove, Megan L., Naj, Adam, Vronskaya, Maria, Salazar, Jose L., DeStefano, Anita L., Brody, Jennifer A., Smith, Albert V., Amin, Najaf, Sims, Rebecca, Ibrahim-Verbaas, Carla A., Choi, Seung-Hoan, Satizabal, Claudia L., Lopez, Oscar L., Beiser, Alexa, Ikram, M. Arfan, Garcia, Melissa E., Hayward, Caroline, Varga, Tibor V., Ripatti, Samuli, Franks, Paul W., Hallmans, Göran, Rolandsson, Olov, Jansson, Jan-Håkon, Porteous, David J., Salomaa, Veikko, Eiriksdottir, Gudny, Rice, Kenneth M., Bellen, Hugo J., Levy, Daniel, Uitterlinden, Andre G., Emilsson, Valur, Rotter, Jerome I., Aspelund, Thor, O'Donnell, Christopher J., Fitzpatrick, Annette L., Launer, Lenore J., Hofman, Albert, Wang, Li-San, Williams, Julie, Schellenberg, Gerard D., Boerwinkle, Eric, Psaty, Bruce M., Seshadri, Sudha, Shulman, Joshua M., Gudnason, Vilmundur and van Duijn, Cornelia M. 2016. Rare functional variant in TM2D3 is associated with late-onset Alzheimer's disease. PLoS Genetics 12 (10) , e1006327. 10.1371/journal.pgen.1006327

PDF - Published Version
Available under License Creative Commons Public Domain Dedication.

Download (3MB) | Preview


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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Neuroscience and Mental Health Research Institute (NMHRI)
Subjects: R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Publisher: Public Library of Science
ISSN: 1553-7404
Date of First Compliant Deposit: 10 November 2016
Date of Acceptance: 26 August 2016
Last Modified: 18 Jun 2019 13:51

Citation Data

Cited 17 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item