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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;
- consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology;
- Consortium, Alzheimer’s Disease Genetic;
- consortium, Genetic and Environmental Risk in Alzheimer’s Disease;
- 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;
- van Duijn, Cornelia M
- Editor(s): Haines, Jonathan L
- et al.
Published Web Location
https://doi.org/10.1371/journal.pgen.1006327Abstract
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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