PLoS Genetics (Oct 2016)

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,
  • Cohorts for Heart and Aging Research in Genomic Epidemiology consortium,
  • Alzheimer’s Disease Genetic Consortium,
  • Genetic and Environmental Risk in Alzheimer’s Disease consortium,
  • 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

DOI
https://doi.org/10.1371/journal.pgen.1006327
Journal volume & issue
Vol. 12, no. 10
p. e1006327

Abstract

Read online

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.