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

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. © 2016 public library of science. all rights reserved.