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

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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; Salazar, Jose L.; DeStefano, Anita L.; Brody, Jennifer A.; Smith, Albert V.; Amin, Najaf; Sims, Rebecca; Ibrahim-Verbaas, Carla A.; Choi, Seung Hoan; Satizabal, Claudia L.; Lopez, Oscar L.; Beiser, Alexa; Ikram, M. Arfan; Garcia, Melissa E.; Hayward, Caroline; Varga, Tibor V.; Ripatti, Samuli; Franks, Paul W.; Hallmans, Göran; Rolandsson, Olov; Jansson, Jan Håkon; Porteous, David J.; Salomaa, Veikko; Eiriksdottir, Gudny; Rice, Kenneth M.; Bellen, Hugo J.; Levy, Daniel; Uitterlinden, Andre G.; Emilsson, Valur; Rotter, Jerome I.; Aspelund, Thor; O’Donnell, Christopher J.; Fitzpatrick, Annette L.; Launer, Lenore J.; Hofman, Albert; Wang, Li San; Williams, Julie; Schellenberg, Gerard D.; Boerwinkle, Eric; Psaty, Bruce M.; Seshadri, Sudha; Shulman, Joshua M.; Gudnason, Vilmundur; van Duijn, Cornelia M.

In: PLoS Genetics, Vol. 12, No. 10, e1006327, 01.10.2016.

Research output: Contribution to journalArticle

Harvard

Jakobsdottir, J, van der Lee, SJ, Bis, JC, Chouraki, V, Li-Kroeger, D, Yamamoto, S, Grove, ML, Naj, A, Vronskaya, M, Salazar, JL, DeStefano, AL, Brody, JA, Smith, AV, Amin, N, Sims, R, Ibrahim-Verbaas, CA, Choi, SH, Satizabal, CL, Lopez, OL, Beiser, A, Ikram, MA, Garcia, ME, Hayward, C, Varga, TV, Ripatti, S, Franks, PW, Hallmans, G, Rolandsson, O, Jansson, JH, Porteous, DJ, Salomaa, V, Eiriksdottir, G, Rice, KM, Bellen, HJ, Levy, D, Uitterlinden, AG, Emilsson, V, Rotter, JI, Aspelund, T, O’Donnell, CJ, Fitzpatrick, AL, Launer, LJ, Hofman, A, Wang, LS, Williams, J, Schellenberg, GD, Boerwinkle, E, Psaty, BM, Seshadri, S, Shulman, JM, Gudnason, V & van Duijn, CM 2016, 'Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease', PLoS Genetics, vol. 12, no. 10, e1006327. https://doi.org/10.1371/journal.pgen.1006327

APA

Jakobsdottir, J., van der Lee, S. J., Bis, J. C., Chouraki, V., Li-Kroeger, D., Yamamoto, S., ... van Duijn, C. M. (2016). Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease. PLoS Genetics, 12(10), [e1006327]. https://doi.org/10.1371/journal.pgen.1006327

CBE

Jakobsdottir J, van der Lee SJ, Bis JC, Chouraki V, Li-Kroeger D, Yamamoto S, Grove ML, Naj A, Vronskaya M, Salazar JL, DeStefano AL, Brody JA, Smith AV, Amin N, Sims R, Ibrahim-Verbaas CA, Choi SH, Satizabal CL, Lopez OL, Beiser A, Ikram MA, Garcia ME, Hayward C, Varga TV, Ripatti S, Franks PW, Hallmans G, Rolandsson O, Jansson JH, Porteous DJ, Salomaa V, Eiriksdottir G, Rice KM, Bellen HJ, Levy D, Uitterlinden AG, Emilsson V, Rotter JI, Aspelund T, O’Donnell CJ, Fitzpatrick AL, Launer LJ, Hofman A, Wang LS, Williams J, Schellenberg GD, Boerwinkle E, Psaty BM, Seshadri S, Shulman JM, Gudnason V, van Duijn CM. 2016. Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease. PLoS Genetics. 12(10). https://doi.org/10.1371/journal.pgen.1006327

MLA

Vancouver

Jakobsdottir J, van der Lee SJ, Bis JC, Chouraki V, Li-Kroeger D, Yamamoto S et al. Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease. PLoS Genetics. 2016 Oct 1;12(10). e1006327. https://doi.org/10.1371/journal.pgen.1006327

Author

Jakobsdottir, Johanna ; van der Lee, Sven J. ; Bis, Joshua C. ; Chouraki, Vincent ; Li-Kroeger, David ; Yamamoto, Shinya ; Grove, Megan L. ; Naj, Adam ; Vronskaya, Maria ; Salazar, Jose L. ; DeStefano, Anita L. ; Brody, Jennifer A. ; Smith, Albert V. ; Amin, Najaf ; Sims, Rebecca ; Ibrahim-Verbaas, Carla A. ; Choi, Seung Hoan ; Satizabal, Claudia L. ; Lopez, Oscar L. ; Beiser, Alexa ; Ikram, M. Arfan ; Garcia, Melissa E. ; Hayward, Caroline ; Varga, Tibor V. ; Ripatti, Samuli ; Franks, Paul W. ; Hallmans, Göran ; Rolandsson, Olov ; Jansson, Jan Håkon ; Porteous, David J. ; Salomaa, Veikko ; Eiriksdottir, Gudny ; Rice, Kenneth M. ; Bellen, Hugo J. ; Levy, Daniel ; Uitterlinden, Andre G. ; Emilsson, Valur ; Rotter, Jerome I. ; Aspelund, Thor ; O’Donnell, Christopher J. ; Fitzpatrick, Annette L. ; Launer, Lenore J. ; Hofman, Albert ; Wang, Li San ; Williams, Julie ; Schellenberg, Gerard D. ; Boerwinkle, Eric ; Psaty, Bruce M. ; Seshadri, Sudha ; Shulman, Joshua M. ; Gudnason, Vilmundur ; van Duijn, Cornelia M. / Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease. In: PLoS Genetics. 2016 ; Vol. 12, No. 10.

RIS

TY - JOUR

T1 - Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease

AU - Jakobsdottir, Johanna

AU - van der Lee, Sven J.

AU - Bis, Joshua C.

AU - Chouraki, Vincent

AU - Li-Kroeger, David

AU - Yamamoto, Shinya

AU - Grove, Megan L.

AU - Naj, Adam

AU - Vronskaya, Maria

AU - Salazar, Jose L.

AU - DeStefano, Anita L.

AU - Brody, Jennifer A.

AU - Smith, Albert V.

AU - Amin, Najaf

AU - Sims, Rebecca

AU - Ibrahim-Verbaas, Carla A.

AU - Choi, Seung Hoan

AU - Satizabal, Claudia L.

AU - Lopez, Oscar L.

AU - Beiser, Alexa

AU - Ikram, M. Arfan

AU - Garcia, Melissa E.

AU - Hayward, Caroline

AU - Varga, Tibor V.

AU - Ripatti, Samuli

AU - Franks, Paul W.

AU - Hallmans, Göran

AU - Rolandsson, Olov

AU - Jansson, Jan Håkon

AU - Porteous, David J.

AU - Salomaa, Veikko

AU - Eiriksdottir, Gudny

AU - Rice, Kenneth M.

AU - Bellen, Hugo J.

AU - Levy, Daniel

AU - Uitterlinden, Andre G.

AU - Emilsson, Valur

AU - Rotter, Jerome I.

AU - Aspelund, Thor

AU - O’Donnell, Christopher J.

AU - Fitzpatrick, Annette L.

AU - Launer, Lenore J.

AU - Hofman, Albert

AU - Wang, Li San

AU - Williams, Julie

AU - Schellenberg, Gerard D.

AU - Boerwinkle, Eric

AU - Psaty, Bruce M.

AU - Seshadri, Sudha

AU - Shulman, Joshua M.

AU - Gudnason, Vilmundur

AU - van Duijn, Cornelia M.

PY - 2016/10/1

Y1 - 2016/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84994310331&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1006327

DO - 10.1371/journal.pgen.1006327

M3 - Article

VL - 12

JO - PLoS Genetics

T2 - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7404

IS - 10

M1 - e1006327

ER -