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

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 ?-amyloid cascade.

SUBMITTER: Jakobsdottir J 

PROVIDER: S-EPMC5072721 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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

Jakobsdottir Johanna J   van der Lee Sven J SJ   Bis Joshua C JC   Chouraki Vincent V   Li-Kroeger David D   Yamamoto Shinya S   Grove Megan L ML   Naj Adam A   Vronskaya Maria M   Salazar Jose L JL   DeStefano Anita L AL   Brody Jennifer A JA   Smith Albert V AV   Amin Najaf N   Sims Rebecca R   Ibrahim-Verbaas Carla A CA   Choi Seung-Hoan SH   Satizabal Claudia L CL   Lopez Oscar L OL   Beiser Alexa A   Ikram M Arfan MA   Garcia Melissa E ME   Hayward Caroline C   Varga Tibor V TV   Ripatti Samuli S   Franks Paul W PW   Hallmans Göran G   Rolandsson Olov O   Jansson Jan-Håkon JH   Porteous David J DJ   Salomaa Veikko V   Eiriksdottir Gudny G   Rice Kenneth M KM   Bellen Hugo J HJ   Levy Daniel D   Uitterlinden Andre G AG   Emilsson Valur V   Rotter Jerome I JI   Aspelund Thor T   O'Donnell Christopher J CJ   Fitzpatrick Annette L AL   Launer Lenore J LJ   Hofman Albert A   Wang Li-San LS   Williams Julie J   Schellenberg Gerard D GD   Boerwinkle Eric E   Psaty Bruce M BM   Seshadri Sudha S   Shulman Joshua M JM   Gudnason Vilmundur V   van Duijn Cornelia M CM  

PLoS genetics 20161020 10

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 hom  ...[more]

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