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

J Jakobsdottir; Sven van der Lee; JC Bis; V Chouraki; D Li-Kroeger; S Yamamoto; ML Grove; A Naj; M Vronskaya; JL Salazar; AL DeStefano; JA Brody; AV Smith; Najaf Amin; R Sims; Carla Verbaas; SH Choi; CL Satizabal; OL Lopez; A Beiser; Arfan Ikram; ME Garcia; C Hayward; TV Varga; S Ripatti; PW Franks; G Hallmans; O Rolandsson; JH Jansson; DJ Porteous; V Salomaa; G Eiriksdottir; KM Rice; HJ Bellen; D Levy; André Uitterlinden; V Emilsson; JI Rotter; T Aspelund; CJ O'Donnell; AL Fitzpatrick; LJ Launer; Bert Hofman; LS (Li-San) Wang; J Williams; GD Schellenberg; E Boerwinkle; BM Psaty; S Seshadri; JM Shulman; V Gudnason; Cornelia Duijn

doi:10.1371/journal.pgen.1006327

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

J Jakobsdottir, Sven van der Lee, JC Bis, V Chouraki, D Li-Kroeger, S Yamamoto, ML Grove, A Naj, M Vronskaya, JL Salazar, AL DeStefano, JA Brody, AV Smith, Najaf Amin, R Sims, Carla Verbaas, SH Choi, CL Satizabal, OL Lopez, A BeiserArfan Ikram, ME Garcia, C Hayward, TV Varga, S Ripatti, PW Franks, G Hallmans, O Rolandsson, JH Jansson, DJ Porteous, V Salomaa, G Eiriksdottir, KM Rice, HJ Bellen, D Levy, André Uitterlinden, V Emilsson, JI Rotter, T Aspelund, CJ O'Donnell, AL Fitzpatrick, LJ Launer, Bert Hofman, LS (Li-San) Wang, J Williams, GD Schellenberg, E Boerwinkle, BM Psaty, S Seshadri, JM Shulman, V Gudnason, Cornelia Duijn

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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 (similar to 0.5% versus < 0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES substudy, 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 beta-amyloid cascade.

Original language	Undefined/Unknown
Journal	PLoS Genetics (online)
Volume	12
Issue number	10
DOIs	https://doi.org/10.1371/journal.pgen.1006327
Publication status	Published - 2016

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Jakobsdottir, J., van der Lee, S., 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., Verbaas, C., Choi, SH., Satizabal, CL., Lopez, OL., ... Duijn, C. (2016). Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease. PLoS Genetics (online), 12(10). https://doi.org/10.1371/journal.pgen.1006327

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title = "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 (similar to 0.5% versus < 0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES substudy, 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 beta-amyloid cascade.",

author = "J Jakobsdottir and {van der Lee}, Sven and JC Bis and V Chouraki and D Li-Kroeger and S Yamamoto and ML Grove and A Naj and M Vronskaya and JL Salazar and AL DeStefano and JA Brody and AV Smith and Najaf Amin and R Sims and Carla Verbaas and SH Choi and CL Satizabal and OL Lopez and A Beiser and Arfan Ikram and ME Garcia and C Hayward and TV Varga and S Ripatti and PW Franks and G Hallmans and O Rolandsson and JH Jansson and DJ Porteous and V Salomaa and G Eiriksdottir and KM Rice and HJ Bellen and D Levy and Andr{\'e} Uitterlinden and V Emilsson and JI Rotter and T Aspelund and CJ O'Donnell and AL Fitzpatrick and LJ Launer and Bert Hofman and Wang, {LS (Li-San)} and J Williams and GD Schellenberg and E Boerwinkle and BM Psaty and S Seshadri and JM Shulman and V Gudnason and Cornelia Duijn",

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journal = "PLoS Genetics",

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Jakobsdottir, J, van der Lee, S, 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, Verbaas, C, Choi, SH, Satizabal, CL, Lopez, OL, Beiser, A, Ikram, A, 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, A, Emilsson, V, Rotter, JI, Aspelund, T, O'Donnell, CJ, Fitzpatrick, AL, Launer, LJ, Hofman, B, Wang, LS, Williams, J, Schellenberg, GD, Boerwinkle, E, Psaty, BM, Seshadri, S, Shulman, JM, Gudnason, V & Duijn, C 2016, 'Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease', PLoS Genetics (online), vol. 12, no. 10. https://doi.org/10.1371/journal.pgen.1006327

TY - JOUR

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

AU - Jakobsdottir, J

AU - van der Lee, Sven

AU - Bis, JC

AU - Chouraki, V

AU - Li-Kroeger, D

AU - Yamamoto, S

AU - Grove, ML

AU - Naj, A

AU - Vronskaya, M

AU - Salazar, JL

AU - DeStefano, AL

AU - Brody, JA

AU - Smith, AV

AU - Amin, Najaf

AU - Sims, R

AU - Verbaas, Carla

AU - Choi, SH

AU - Satizabal, CL

AU - Lopez, OL

AU - Beiser, A

AU - Ikram, Arfan

AU - Garcia, ME

AU - Hayward, C

AU - Varga, TV

AU - Ripatti, S

AU - Franks, PW

AU - Hallmans, G

AU - Rolandsson, O

AU - Jansson, JH

AU - Porteous, DJ

AU - Salomaa, V

AU - Eiriksdottir, G

AU - Rice, KM

AU - Bellen, HJ

AU - Levy, D

AU - Uitterlinden, André

AU - Emilsson, V

AU - Rotter, JI

AU - Aspelund, T

AU - O'Donnell, CJ

AU - Fitzpatrick, AL

AU - Launer, LJ

AU - Hofman, Bert

AU - Wang, LS (Li-San)

AU - Williams, J

AU - Schellenberg, GD

AU - Boerwinkle, E

AU - Psaty, BM

AU - Seshadri, S

AU - Shulman, JM

AU - Gudnason, V

AU - Duijn, Cornelia

PY - 2016

Y1 - 2016

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 (similar to 0.5% versus < 0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES substudy, 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 beta-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 (similar to 0.5% versus < 0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES substudy, 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 beta-amyloid cascade.

U2 - 10.1371/journal.pgen.1006327

DO - 10.1371/journal.pgen.1006327

M3 - Article

SN - 1553-7390

VL - 12

JO - PLoS Genetics

JF - PLoS Genetics

IS - 10

ER -