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

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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.


  • 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
  • Samuli Ripatti
  • 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
External organisations
  • Icelandic Heart Association
  • Erasmus University Medical Center
  • University of Washington
  • Framingham Heart Study
  • Texas Children’s Hospital
  • Baylor College of Medicine
  • University of Texas
  • University of Pennsylvania
  • Cardiff University
  • Boston University
  • University of Iceland
  • University of Pittsburgh Medical Center
  • National Institute on Aging, United States
  • University of Edinburgh
  • University of Helsinki
  • Umeå University
  • Skellefteå Hospital
  • Finnish National Institute for Health and Welfare
  • Howard Hughes Medical Institute
  • National Heart Lung and Blood Institute
  • University of California, Los Angeles
  • Kaiser Permanente Research Institute
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
Original languageEnglish
Article numbere1006327
JournalPLoS Genetics
Issue number10
Publication statusPublished - 2016 Oct 1
Publication categoryResearch