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 language | English |
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Article number | e1006327 |
Journal | PLOS Genetics |
Volume | 12 |
Issue number | 10 |
Number of pages | 17 |
ISSN | 1553-7390 |
DOIs | |
Publication status | Published - Oct 2016 |
Externally published | Yes |
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