%0 Journal Article %J PLoS Genet %D 2016 %T Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease. %A Jakobsdottir, Johanna %A van der Lee, Sven J %A Bis, Joshua C %A Chouraki, Vincent %A Li-Kroeger, David %A Yamamoto, Shinya %A Grove, Megan L %A Naj, Adam %A Vronskaya, Maria %A Salazar, Jose L %A DeStefano, Anita L %A Brody, Jennifer A %A Smith, Albert V %A Amin, Najaf %A Sims, Rebecca %A Ibrahim-Verbaas, Carla A %A Choi, Seung-Hoan %A Satizabal, Claudia L %A Lopez, Oscar L %A Beiser, Alexa %A Ikram, M Arfan %A Garcia, Melissa E %A Hayward, Caroline %A Varga, Tibor V %A Ripatti, Samuli %A Franks, Paul W %A Hallmans, Goran %A Rolandsson, Olov %A Jansson, Jan-Håkon %A Porteous, David J %A Salomaa, Veikko %A Eiriksdottir, Gudny %A Rice, Kenneth M %A Bellen, Hugo J %A Levy, Daniel %A Uitterlinden, André G %A Emilsson, Valur %A Rotter, Jerome I %A Aspelund, Thor %A O'Donnell, Christopher J %A Fitzpatrick, Annette L %A Launer, Lenore J %A Hofman, Albert %A Wang, Li-San %A Williams, Julie %A Schellenberg, Gerard D %A Boerwinkle, Eric %A Psaty, Bruce M %A Seshadri, Sudha %A Shulman, Joshua M %A Gudnason, Vilmundur %A van Duijn, Cornelia M %K Age of Onset %K Aged %K Alleles %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Animals %K Apolipoproteins E %K Drosophila melanogaster %K Drosophila Proteins %K Exome %K Female %K Genome-Wide Association Study %K Genomics %K Humans %K Iceland %K Intracellular Signaling Peptides and Proteins %K Male %K Membrane Proteins %K Mutation %K Phenotype %K Receptors, Notch %K Tropomyosin %K White People %X

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.

%B PLoS Genet %V 12 %P e1006327 %8 2016 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/27764101?dopt=Abstract %R 10.1371/journal.pgen.1006327