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

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  • Cohorts for Heart and Aging Research in Genomic Epidemiology consortium

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
Issue number10
Number of pages17
Publication statusPublished - Oct 2016
Externally publishedYes

    Research areas

  • 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

ID: 242837320