Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families.
Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families.
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DOI：
10.1371/journal.pone.0031039
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
NIA-LOAD/NCRAD Family Study Consortium
中科院分区：
文献类型：
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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
APP，PSEN 1，PSEN 2，MAPT和GRN中的致病性突变先前已与家族性早发性痴呆有关。这些基因的突变筛查已经在非常小的系列或迟发性AD（LOAD）的单个家族中进行。类似地，在单个家族中的研究已经报道了与临床AD相关的MAPT和GRN突变，但是没有对大数据集进行系统筛选以确定这种情况发生的频率。我们报告了439个先证者的序列数据，这些先证者来自有4个或更多受影响个体病史的晚发性AD家族。60个测序个体（13.7%）携带新的或致病性突变。在14个样本中发现了8个致病性变异体，其中3个是新的（APP和MAPT各1个，PSEN 1 2个，GRN 4个）。存在于23个家族中的另外13个变体没有与疾病分离，但这些变体在AD病例中的频率高于对照组，表明这些变体也可能改变疾病的风险。在这个系列中，这些基因中罕见变异的频率显著高于1，000基因组计划（p = 5.09×10−5; OR = 2.21; 95%CI = 1.49-3.28）或12，481个样本的随机群体（p = 6.82×10−5; OR = 2.19; 95%CI = 1.347-3.26）。 APP、PSEN 1和PSEN 2中的罕见编码变异增加了迟发性AD的风险或导致迟发性AD。在LOAD和早发性AD中这些基因中存在变异表明，突变以外的因素可以影响至少一些与AD相关的变异的发病年龄和发病率。MAPT和GRN突变可在AD的临床系列中发现，最可能是由于误诊。这项研究清楚地表明，这些基因中的罕见变异可以解释AD遗传性的重要比例，而GWAS没有检测到。
Pathogenic mutations in APP, PSEN1, PSEN2, MAPT and GRN have previously been linked to familial early onset forms of dementia. Mutation screening in these genes has been performed in either very small series or in single families with late onset AD (LOAD). Similarly, studies in single families have reported mutations in MAPT and GRN associated with clinical AD but no systematic screen of a large dataset has been performed to determine how frequently this occurs. We report sequence data for 439 probands from late-onset AD families with a history of four or more affected individuals. Sixty sequenced individuals (13.7%) carried a novel or pathogenic mutation. Eight pathogenic variants, (one each in APP and MAPT, two in PSEN1 and four in GRN) three of which are novel, were found in 14 samples. Thirteen additional variants, present in 23 families, did not segregate with disease, but the frequency of these variants is higher in AD cases than controls, indicating that these variants may also modify risk for disease. The frequency of rare variants in these genes in this series is significantly higher than in the 1,000 genome project (p = 5.09×10−5; OR = 2.21; 95%CI = 1.49–3.28) or an unselected population of 12,481 samples (p = 6.82×10−5; OR = 2.19; 95%CI = 1.347–3.26). Rare coding variants in APP, PSEN1 and PSEN2, increase risk for or cause late onset AD. The presence of variants in these genes in LOAD and early-onset AD demonstrates that factors other than the mutation can impact the age at onset and penetrance of at least some variants associated with AD. MAPT and GRN mutations can be found in clinical series of AD most likely due to misdiagnosis. This study clearly demonstrates that rare variants in these genes could explain an important proportion of genetic heritability of AD, which is not detected by GWAS.
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DOI：
10.1186/alzrt26
发表时间：
2010-03-05
期刊：
Alzheimer's research & therapy
影响因子：
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作者：
Ertekin-Taner N
通讯作者：
Ertekin-Taner N
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：
4.2
作者：
Bernardi, Livia;Tomaino, Carmine;Bruni, Amalia C.
通讯作者：
Bruni, Amalia C.
影响因子：
5.1
作者：
Cortini, F.;Fenoglio, C.;Galimberti, D.
通讯作者：
Galimberti, D.
影响因子：
30.8
作者：
通讯作者：
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