Polygenic risk score of sporadic late-onset Alzheimer's disease reveals a shared architecture with the familial and early-onset forms.
Polygenic risk score of sporadic late-onset Alzheimer's disease reveals a shared architecture with the familial and early-onset forms.
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DOI：
10.1016/j.jalz.2017.08.013
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Harari O
中科院分区：
文献类型：
--
作者：
Cruchaga C;Del-Aguila JL;Saef B;Black K;Fernandez MV;Budde J;Ibanez L;Deming Y;Kapoor M;Tosto G;Mayeux RP;Holtzman DM;Fagan AM;Morris JC;Bateman RJ;Goate AM;Dominantly Inherited Alzheimer Network (DIAN);Disease Neuroimaging Initiative (ADNI);NIA-LOAD family study;Harari O
确定散发性晚发性阿尔茨海默病（sLOAD）、家族性晚发性AD（fLOAD）、散发性早发性AD（sEOAD）和常染色体显性早发性AD（eADAD）之间的遗传结构重叠程度。多基因风险评分（PRS）构建使用先前确定的21个全基因组显着位点的LOAD风险。我们发现sEOAD、fLOAD和sLOAD之间的遗传结构存在重叠。在sEOAD中观察到PRS与风险的最高相关性（比值比[OR] = 2.27; P = 1.29 × 10−7），其次是fLOAD（OR = 1.75; P = 1.12 × 10−7）和sLOAD（OR = 1.40; P = 1.21 × 10−3）。PRS与eADAD上的脑脊液ptau 181-Aβ42相关（P = 4.36 × 10−2）。我们的分析证实，LOAD的遗传因素调节sLOAD和fLOAD以及sEOAD队列的风险。具体来说，我们的研究结果表明，这些风险变异的负担与家族聚集和AD的早期发病有关。虽然这些变异与eADAD的风险无关，但它们可能会调节发病年龄。
To determine whether the extent of overlap of the genetic architecture among the sporadic late-onset Alzheimer’s Disease (sLOAD), familial late-onset AD (fLOAD), sporadic earlyonset AD (sEOAD), and autosomal dominant early-onset AD (eADAD). Polygenic risk scores (PRSs) were constructed using previously identified 21 genome-wide significant loci for LOAD risk. We found that there is an overlap in the genetic architecture among sEOAD, fLOAD, and sLOAD. The highest association of the PRS and risk (odds ratio [OR] = 2.27; P = 1.29 × 10−7) was observed in sEOAD, followed by fLOAD (OR = 1.75; P = 1.12 × 10−7) and sLOAD (OR = 1.40; P = 1.21 × 10−3). The PRS was associated with cerebrospinal fluid ptau181-Aβ42 on eADAD (P = 4.36 × 10−2). Our analysis confirms that the genetic factors identified for LOAD modulate risk in sLOAD and fLOAD and also sEOAD cohorts. Specifically, our results suggest that the burden of these risk variants is associated with familial clustering and earlier onset of AD. Although these variants are not associated with risk in the eADAD, they may be modulating age at onset.
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磷酸化的tau-Aβ42比是在脑脊液的多重免疫测定面板中发现生物标志物的连续特征。
影响因子：
10.6
作者：
Harari, Oscar;Cruchaga, Carlos;Kauwe, John S. K.;Ainscough, Benjamin J.;Bales, Kelly;Pickering, Eve H.;Bertelsen, Sarah;Fagan, Anne M.;Holtzman, David M.;Morris, John C.;Goate, Alison M.
通讯作者：
Goate, Alison M.
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：
4.2
作者：
Harms, Matthew B.;Cady, Janet;Baloh, Robert H.
通讯作者：
Baloh, Robert H.
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：
3.7
作者：
Cruchaga C;Haller G;Chakraverty S;Mayo K;Vallania FL;Mitra RD;Faber K;Williamson J;Bird T;Diaz-Arrastia R;Foroud TM;Boeve BF;Graff-Radford NR;St Jean P;Lawson M;Ehm MG;Mayeux R;Goate AM;NIA-LOAD/NCRAD Family Study Consortium
通讯作者：
NIA-LOAD/NCRAD Family Study Consortium