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 an...
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Public Library of Science (PLoS)
2016-10-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1006327&type=printable |
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| author | Johanna Jakobsdottir Sven J van der Lee Joshua C Bis Vincent Chouraki David Li-Kroeger Shinya Yamamoto Megan L Grove Adam Naj Maria Vronskaya Jose L Salazar Anita L DeStefano Jennifer A Brody Albert V Smith Najaf Amin Rebecca Sims Carla A Ibrahim-Verbaas Seung-Hoan Choi Claudia L Satizabal Oscar L Lopez Alexa Beiser M Arfan Ikram Melissa E Garcia Caroline Hayward Tibor V Varga Samuli Ripatti Paul W Franks Göran Hallmans Olov Rolandsson Jan-Håkon Jansson David J Porteous Veikko Salomaa Gudny Eiriksdottir Kenneth M Rice Hugo J Bellen Daniel Levy Andre G Uitterlinden Valur Emilsson Jerome I Rotter Thor Aspelund Cohorts for Heart and Aging Research in Genomic Epidemiology consortium Alzheimer’s Disease Genetic Consortium Genetic and Environmental Risk in Alzheimer’s Disease consortium Christopher J O'Donnell Annette L Fitzpatrick Lenore J Launer Albert Hofman Li-San Wang Julie Williams Gerard D Schellenberg Eric Boerwinkle Bruce M Psaty Sudha Seshadri Joshua M Shulman Vilmundur Gudnason Cornelia M van Duijn |
| author_facet | Johanna Jakobsdottir Sven J van der Lee Joshua C Bis Vincent Chouraki David Li-Kroeger Shinya Yamamoto Megan L Grove Adam Naj Maria Vronskaya Jose L Salazar Anita L DeStefano Jennifer A Brody Albert V Smith Najaf Amin Rebecca Sims Carla A Ibrahim-Verbaas Seung-Hoan Choi Claudia L Satizabal Oscar L Lopez Alexa Beiser M Arfan Ikram Melissa E Garcia Caroline Hayward Tibor V Varga Samuli Ripatti Paul W Franks Göran Hallmans Olov Rolandsson Jan-Håkon Jansson David J Porteous Veikko Salomaa Gudny Eiriksdottir Kenneth M Rice Hugo J Bellen Daniel Levy Andre G Uitterlinden Valur Emilsson Jerome I Rotter Thor Aspelund Cohorts for Heart and Aging Research in Genomic Epidemiology consortium Alzheimer’s Disease Genetic Consortium Genetic and Environmental Risk in Alzheimer’s Disease consortium Christopher J O'Donnell Annette L Fitzpatrick Lenore J Launer Albert Hofman Li-San Wang Julie Williams Gerard D Schellenberg Eric Boerwinkle Bruce M Psaty Sudha Seshadri Joshua M Shulman Vilmundur Gudnason Cornelia M van Duijn |
| author_sort | Johanna Jakobsdottir |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-03cd00851ca345d0aedc6937fe264fab |
| institution | OA Journals |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2016-10-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-03cd00851ca345d0aedc6937fe264fab2025-08-20T02:03:17ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042016-10-011210e100632710.1371/journal.pgen.1006327Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease.Johanna JakobsdottirSven J van der LeeJoshua C BisVincent ChourakiDavid Li-KroegerShinya YamamotoMegan L GroveAdam NajMaria VronskayaJose L SalazarAnita L DeStefanoJennifer A BrodyAlbert V SmithNajaf AminRebecca SimsCarla A Ibrahim-VerbaasSeung-Hoan ChoiClaudia L SatizabalOscar L LopezAlexa BeiserM Arfan IkramMelissa E GarciaCaroline HaywardTibor V VargaSamuli RipattiPaul W FranksGöran HallmansOlov RolandssonJan-Håkon JanssonDavid J PorteousVeikko SalomaaGudny EiriksdottirKenneth M RiceHugo J BellenDaniel LevyAndre G UitterlindenValur EmilssonJerome I RotterThor AspelundCohorts for Heart and Aging Research in Genomic Epidemiology consortiumAlzheimer’s Disease Genetic ConsortiumGenetic and Environmental Risk in Alzheimer’s Disease consortiumChristopher J O'DonnellAnnette L FitzpatrickLenore J LaunerAlbert HofmanLi-San WangJulie WilliamsGerard D SchellenbergEric BoerwinkleBruce M PsatySudha SeshadriJoshua M ShulmanVilmundur GudnasonCornelia M van DuijnWe 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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1006327&type=printable |
| spellingShingle | Johanna Jakobsdottir Sven J van der Lee Joshua C Bis Vincent Chouraki David Li-Kroeger Shinya Yamamoto Megan L Grove Adam Naj Maria Vronskaya Jose L Salazar Anita L DeStefano Jennifer A Brody Albert V Smith Najaf Amin Rebecca Sims Carla A Ibrahim-Verbaas Seung-Hoan Choi Claudia L Satizabal Oscar L Lopez Alexa Beiser M Arfan Ikram Melissa E Garcia Caroline Hayward Tibor V Varga Samuli Ripatti Paul W Franks Göran Hallmans Olov Rolandsson Jan-Håkon Jansson David J Porteous Veikko Salomaa Gudny Eiriksdottir Kenneth M Rice Hugo J Bellen Daniel Levy Andre G Uitterlinden Valur Emilsson Jerome I Rotter Thor Aspelund Cohorts for Heart and Aging Research in Genomic Epidemiology consortium Alzheimer’s Disease Genetic Consortium Genetic and Environmental Risk in Alzheimer’s Disease consortium Christopher J O'Donnell Annette L Fitzpatrick Lenore J Launer Albert Hofman Li-San Wang Julie Williams Gerard D Schellenberg Eric Boerwinkle Bruce M Psaty Sudha Seshadri Joshua M Shulman Vilmundur Gudnason Cornelia M van Duijn Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease. PLoS Genetics |
| title | Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease. |
| title_full | Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease. |
| title_fullStr | Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease. |
| title_full_unstemmed | Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease. |
| title_short | Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease. |
| title_sort | rare functional variant in tm2d3 is associated with late onset alzheimer s disease |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1006327&type=printable |
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