Advanced

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

Jakobsdottir, Johanna; van der Lee, Sven J.; Bis, Joshua C.; Chouraki, Vincent; Li-Kroeger, David; Yamamoto, Shinya; Grove, Megan L.; Naj, Adam; Vronskaya, Maria and Salazar, Jose L., et al. (2016) In PLoS Genetics 12(10).
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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS Genetics
volume
12
issue
10
publisher
Public Library of Science
external identifiers
  • scopus:84994310331
  • wos:000386683300009
ISSN
1553-7390
DOI
10.1371/journal.pgen.1006327
language
English
LU publication?
yes
id
2bceeac0-cc27-42d2-8748-be9a02d9841d
date added to LUP
2016-12-01 10:10:53
date last changed
2017-11-05 05:10:15
@article{2bceeac0-cc27-42d2-8748-be9a02d9841d,
  abstract     = {<p>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 &lt;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<sup>-9</sup>]. 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.</p>},
  articleno    = {e1006327},
  author       = {Jakobsdottir, Johanna and van der Lee, Sven J. and Bis, Joshua C. and Chouraki, Vincent and Li-Kroeger, David and Yamamoto, Shinya and Grove, Megan L. and Naj, Adam and Vronskaya, Maria and Salazar, Jose L. and DeStefano, Anita L. and Brody, Jennifer A. and Smith, Albert V. and Amin, Najaf and Sims, Rebecca and Ibrahim-Verbaas, Carla A. and Choi, Seung Hoan and Satizabal, Claudia L. and Lopez, Oscar L. and Beiser, Alexa and Ikram, M. Arfan and Garcia, Melissa E. and Hayward, Caroline and Varga, Tibor V. and Ripatti, Samuli and Franks, Paul W. and Hallmans, Göran and Rolandsson, Olov and Jansson, Jan Håkon and Porteous, David J. and Salomaa, Veikko and Eiriksdottir, Gudny and Rice, Kenneth M. and Bellen, Hugo J. and Levy, Daniel and Uitterlinden, Andre G. and Emilsson, Valur and Rotter, Jerome I. and Aspelund, Thor and O’Donnell, Christopher J. and Fitzpatrick, Annette L. and Launer, Lenore J. and Hofman, Albert and Wang, Li San and Williams, Julie and Schellenberg, Gerard D. and Boerwinkle, Eric and Psaty, Bruce M. and Seshadri, Sudha and Shulman, Joshua M. and Gudnason, Vilmundur and van Duijn, Cornelia M.},
  issn         = {1553-7390},
  language     = {eng},
  month        = {10},
  number       = {10},
  publisher    = {Public Library of Science},
  series       = {PLoS Genetics},
  title        = {Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease},
  url          = {http://dx.doi.org/10.1371/journal.pgen.1006327},
  volume       = {12},
  year         = {2016},
}