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

• Main Authors: 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
• Other Authors: Haines, Jonathan L
• Format: Article in Journal/Newspaper
• Language: unknown
• Published: eScholarship, University of California 2016
• Subjects: Biological Sciences; Genetics; Clinical Research; Dementia; Aging; Human Genome; Brain Disorders; Neurodegenerative; Alzheimer's Disease; Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD); Acquired Cognitive Impairment; Neurosciences; Aetiology; 2.1 Biological and endogenous factors; Neurological; Age of Onset; Aged; Alleles; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Apolipoproteins E; Drosophila Proteins; Drosophila melanogaster; Exome; Female; Genome-Wide Association Study; Genomics; Humans; Iceland; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Mutation; Phenotype; Receptors; Notch; Tropomyosin; White People; Cohorts for Heart and Aging Research in Genomic Epidemiology consortium; Alzheimer’s Disease Genetic Consortium; Genetic and Environmental Risk in Alzheimer’s Disease consortium; Developmental Biology
• Online Access: https://escholarship.org/uc/item/2qs7n1fv

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.