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

PLoS Genet. 2016 Oct 20;12(10):e1006327. doi: 10.1371/journal.pgen.1006327. eCollection 2016 Oct.

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.

MeSH terms

  • Age of Onset
  • Aged
  • Alleles
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / pathology
  • 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*

Substances

  • Amx protein, Drosophila
  • Amyloid beta-Protein Precursor
  • ApoE protein, human
  • Apolipoproteins E
  • Drosophila Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Receptors, Notch
  • TM2D1 protein, human
  • Tropomyosin
  • src kinase associated phosphoprotein 2