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

  • Johanna Jakobsdottir
  • Sven J. van der Lee
  • Joshua C. Bis
  • Vincent Chouraki
  • David Li-Kroeger
  • Shinya Yamamoto
  • Megan L. Grove
  • Adam Naj
  • Maria Vronskaya
  • Jose L. Salazar
  • Anita L. DeStefano
  • Jennifer A. Brody
  • Albert V. Smith
  • Najaf Amin
  • Rebecca Sims
  • Carla A. Ibrahim-Verbaas
  • Seung Hoan Choi
  • Claudia L. Satizabal
  • Oscar L. Lopez
  • Alexa Beiser
  • M. Arfan Ikram
  • Melissa E. Garcia
  • Caroline Hayward
  • Tibor V. Varga
  • Samuli Ripatti
  • Paul W. Franks
  • Göran Hallmans
  • Olov Rolandsson
  • Jan Håkon Jansson
  • David J. Porteous
  • Veikko Salomaa
  • Gudny Eiriksdottir
  • Kenneth M. Rice
  • Hugo J. Bellen
  • Daniel Levy
  • Andre G. Uitterlinden
  • Valur Emilsson
  • Jerome I. Rotter
  • Thor Aspelund
  • Christopher J. O’Donnell
  • Annette L. Fitzpatrick
  • Lenore J. Launer
  • Albert Hofman
  • Li San Wang
  • Julie Williams
  • Gerard D. Schellenberg
  • Eric Boerwinkle
  • Bruce M. Psaty
  • Sudha Seshadri
  • Joshua M. Shulman
  • Vilmundur Gudnason
  • Cornelia M. van Duijn
Publishing year: 2016-10-01
Language: English
Publication/Series: PLoS Genetics
Volume: 12
Issue: 10
Document type: Journal article
Publisher: Public Library of Science

Abstract english

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.


  • Medical Genetics


  • Genetic and Molecular Epidemiology
  • ISSN: 1553-7390
Paul Franks
E-mail: paul [dot] franks [at] med [dot] lu [dot] se

Principal investigator

Genetic and Molecular Epidemiology

+46 40 39 11 49



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