Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease.
Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease.
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DOI：
10.1371/journal.pgen.1006327
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发表时间：
2016-10
期刊：
影响因子：
4.5
通讯作者：
van Duijn CM
中科院分区：
文献类型：
--
作者：
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;Cohorts for Heart and Aging Research in Genomic Epidemiology consortium;Alzheimer’s Disease Genetic Consortium;Genetic and Environmental Risk in Alzheimer’s Disease consortium;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
我们对来自CHARGE联盟的1393例迟发性阿尔茨海默病（LOAD）病例和8141例对照进行了外显子组全关联分析。我们发现TM 2D 3中的一种罕见变体（P155 L）在冰岛人中富集（约0.5%，而其他欧洲人群中<0.05%）。在来自冰岛AGES子研究的433例LOAD病例和3903例对照中，P155 L与LOAD风险增加和早发相关[比值比（95% CI）= 7.5（3.5-15.9），p = 6.6x10-9]。果蝇TM 2D 3同源物almondex的突变导致与Notch/Presenilin信号转导丧失相似的表型。人TM 2D 3能够挽救这些表型，但这种活性被P155 L消除，将其确立为功能性损伤等位基因。我们的研究结果建立了一种罕见的TM 2D 3变异与LOAD易感性相关，并与先前的工作一起表明可能与β-淀粉样蛋白级联反应有关。阿尔茨海默病（AD）是老年人群体中痴呆症的最常见原因。有大量证据表明，基因对AD风险有重要贡献。虽然先前的工作已经全面评估了常见遗传变异在大型人群队列中的贡献，但罕见变异的作用仍有待确定。在这里，我们使用了一种新的基因分型阵列来表征不太常见的变异，包括那些可能影响编码蛋白质功能的变异，在1393例AD病例和8141例无AD对照受试者的联合队列中。我们的研究结果暗示了TM 2D 3基因中一种新的氨基酸变化变体P155 L。发现这种变异在冰岛人群中更常见，在那里它与AD的风险增加和早期发病年龄显着相关。最后，为了检查所涉及的变体的潜在功能影响，我们在果蝇中进行了额外的研究。我们的研究结果表明，P155 L导致TM 2D 3的功能丧失，在Notch-Presenilin信号转导的背景下。总之，我们确定了一种新的，罕见的TM 2D 3变异与AD风险相关，并强调了与AD相关生物学的功能联系。
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. Alzheimer’s disease (AD) is the most common cause of dementia in the older adult population. There is substantial evidence for an important genetic contribution to AD risk. While prior work has comprehensively evaluated the contribution of common genetic variants in large population-based cohorts, the role of rare variants remains to be defined. Here, we have used a newer genotyping array to characterize less common variants, including those likely to impact the function of encoded proteins, in a combined cohort of 1393 AD cases and 8141 control subjects without AD. Our results implicate a novel, amino acid-changing variant, P155L, in the TM2D3 gene. This variant was discovered to be more common in the Icelandic population, where it was significantly associated with both increased risk and earlier age of onset of AD. Lastly, in order to examine the potential functional impact of the implicated variant, we performed additional studies in the fruit fly. Our results suggest that P155L causes a loss-of-function in TM2D3, in the context of Notch-Presenilin signal transduction. In sum, we identify a novel, rare TM2D3 variant in association with AD risk and highlight functional connections with AD-relevant biology.
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DOI：
10.1056/nejmoa1211851
发表时间：
2013-01-10
期刊：
The New England journal of medicine
影响因子：
--
作者：
Guerreiro R;Wojtas A;Bras J;Carrasquillo M;Rogaeva E;Majounie E;Cruchaga C;Sassi C;Kauwe JS;Younkin S;Hazrati L;Collinge J;Pocock J;Lashley T;Williams J;Lambert JC;Amouyel P;Goate A;Rademakers R;Morgan K;Powell J;St George-Hyslop P;Singleton A;Hardy J;Alzheimer Genetic Analysis Group
通讯作者：
Alzheimer Genetic Analysis Group
影响因子：
14.8
作者：
Kumar, Prateek;Henikoff, Steven;Ng, Pauline C.
通讯作者：
Ng, Pauline C.
影响因子：
30.8
作者：
Harold, Denise;Abraham, Richard;Hollingworth, Paul;Sims, Rebecca;Gerrish, Amy;Hamshere, Marian L.;Pahwa, Jaspreet Singh;Moskvina, Valentina;Dowzell, Kimberley;Williams, Amy;Jones, Nicola;Thomas, Charlene;Stretton, Alexandra;Morgan, Angharad R.;Lovestone, Simon;Powell, John;Proitsi, Petroula;Lupton, Michelle K.;Brayne, Carol;Rubinsztein, David C.;Gill, Michael;Lawlor, Brian;Lynch, Aoibhinn;Morgan, Kevin;Brown, Kristelle S.;Passmore, Peter A.;Craig, David;McGuinness, Bernadette;Todd, Stephen;Holmes, Clive;Mann, David;Smith, A. David;Love, Seth;Kehoe, Patrick G.;Hardy, John;Mead, Simon;Fox, Nick;Rossor, Martin;Collinge, John;Maier, Wolfgang;Jessen, Frank;Schuermann, Britta;van den Bussche, Hendrik;Heuser, Isabella;Kornhuber, Johannes;Wiltfang, Jens;Dichgans, Martin;Froelich, Lutz;Hampel, Harald;Huell, Michael;Rujescu, Dan;Goate, Alison M.;Kauwe, John S. K.;Cruchaga, Carlos;Nowotny, Petra;Morris, John C.;Mayo, Kevin;Sleegers, Kristel;Bettens, Karolien;Engelborghs, Sebastiaan;De Deyn, Peter P.;Van Broeckhoven, Christine;Livingston, Gill;Bass, Nicholas J.;Gurling, Hugh;McQuillin, Andrew;Gwilliam, Rhian;Deloukas, Panagiotis;Al-Chalabi, Ammar;Shaw, Christopher E.;Tsolaki, Magda;Singleton, Andrew B.;Guerreiro, Rita;Muehleisen, Thomas W.;Noethen, Markus M.;Moebus, Susanne;Joeckel, Karl-Heinz;Klopp, Norman;Wichmann, H-Erich;Carrasquillo, Minerva M.;Pankratz, V. Shane;Younkin, Steven G.;Holmans, Peter A.;O'Donovan, Michael;Owen, Michael J.;Williams, Julie
通讯作者：
Williams, Julie
影响因子：
9.9
作者：
James, Bryan D.;Leurgans, Sue E.;Bennett, David A.
通讯作者：
Bennett, David A.
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay