Journal
PLOS GENETICS
Volume 12, Issue 10, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1006327
Keywords
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Categories
Funding
- National Heart, Lung, and Blood Institute (NHLBI) [HL105756]
- NHLBI [HL120393]
- NIH [U01-AG049506, U01-AG049505, U54-HG003273, GMR2556929]
- National Institute on Aging (NIA) [N01-AG-12100, HHSN271201200022C]
- NIH/NIA [R01-AG033193, R01-AG050631, C06-RR029965]
- Alzheimer's Association
- American Federation for Aging Research
- Huffington Foundation
- Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital
- Burroughs Wellcome Fund
- Eunice Kennedy Shriver National Institute of Child Health & Human Development [U54HD083092]
- Alzheimer's Association [NIRH-15-364099]
- Robert and Renee Belfer Family Foundation
- Target ALS
- MRC [G0902227, MR/L023784/2, MR/L023784/1, G0300429, MR/K013041/1, MC_PC_U127561128] Funding Source: UKRI
- Alzheimers Research UK [ARUK-PG2014-1] Funding Source: researchfish
- Chief Scientist Office [CZD/16/6/4] Funding Source: researchfish
- Medical Research Council [MR/L023784/1, G0902227, MR/L501517/1, MR/L023784/2, MR/K013041/1, G0300429, MR/L010305/1, MC_PC_U127561128] Funding Source: researchfish
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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 (similar to 0.5% versus < 0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES substudy, 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 beta-amyloid cascade.
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