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

Cohorts for Heart and Aging Research in Genomic Epidemiology consortium

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Abstract

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.

Original languageEnglish
Article numbere1006327
JournalPLOS Genetics
Volume12
Issue number10
Number of pages17
ISSN1553-7390
DOIs
Publication statusPublished - Oct 2016
Externally publishedYes

Keywords

  • Age of Onset
  • Aged
  • Alleles
  • Alzheimer Disease/genetics
  • Amyloid beta-Protein Precursor/genetics
  • Animals
  • Apolipoproteins E/genetics
  • Drosophila Proteins/genetics
  • Drosophila melanogaster/genetics
  • European Continental Ancestry Group
  • Exome/genetics
  • Female
  • Genome-Wide Association Study
  • Genomics
  • Humans
  • Iceland
  • Intracellular Signaling Peptides and Proteins/genetics
  • Male
  • Membrane Proteins/genetics
  • Mutation
  • Phenotype
  • Receptors, Notch/genetics
  • Tropomyosin/genetics

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