Genetic profiles of familial late-onset Alzheimer's disease in China: The Shanghai FLOAD study.
Genetic profiles of familial late-onset Alzheimer's disease in China: The Shanghai FLOAD study.
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中国家族性迟发性阿尔茨海默病的基因谱：上海 FLOAD 研究。
DOI：
10.1016/j.gendis.2021.05.001
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发表时间：
2022-11
期刊：
影响因子：
6.8
通讯作者：
Alzheimer's Dis Neuroimaging Initiat
中科院分区：
文献类型：
--
作者：
Xie, Xin-Yi;Zhao, Qian-Hua;Huang, Qiang;Dammer, Eric;Chen, Sheng-di;Ren, Ru-Jing;Wang, Gang;Alzheimer's Dis Neuroimaging Initiat
与早发性家族性AD（FAD）相比，大多数家族性晚发性AD（FLOAD）病例的遗传度仍不清楚。然而，迄今为止，很少有报道的FLOAD的基因谱。本研究对中国汉族人群中90例FLOAD先证者和101例无血缘关系的正常对照进行了候选基因的靶向测序。结果显示APP和PSENs的突变率显著较低，而FLOAD的APOE ε4遗传风险较高。在中国FLOAD人群中，最常见的变异是CR1 rs116806486 [5.6%，95%CI（1.8%，12.5%）]，其次是TREM2编码变异（4.4%，95%CI（1.2%，10.9%））和ACE新突变[3.3%，95%CI（0.7%，9.4%）]。接下来，我们发现ACE中新的致病性突变包括移码突变和无义突变与FLOAD相关，而与APOE ε4状态无关。来自阿尔茨海默病神经影像学倡议（ADNI）数据库的证据也支持不同种族的这一发现。体外分析结果表明，ACE的移码和无义突变可能通过降低ACE蛋白水平而不影响APP的直接加工而参与LOAD。
Compared with early-onset familial AD (FAD), the heritability of most familial late-onset Alzheimer's disease (FLOAD) cases still remains unclear. However, there are few reported genetic profiles of FLOAD to date. In the present study, targeted sequencing of selected candidate genes was conducted for each of 90 probands with FLOAD and 101 unrelated matched normal controls among Chinese Han population. Results show a significantly lower rate of mutation in APP and PSENs, and APOE ε4 genetic risk is higher for FLOAD. Among the Chinese FLOAD population, the most frequent variant was CR1 rs116806486 [5.6%, 95% CI (1.8%, 12.5%)], followed by coding variants of TREM2 (4.4%, 95%CI (1.2%, 10.9%)) and novel mutations of ACE [3.3%, 95%CI (0.7%, 9.4%)]. Next, we found that novel pathogenic mutations in ACE including frame-shift and nonsense mutations were in association with FLOAD regardless of APOE ε4 status. Evidence from the Alzheimer's disease Neuroimaging Initiative (ADNI) database also supported this finding in different ethnicities. Results of in vitro analysis suggest that frame-shift and nonsense mutations in ACE may be involved in LOAD through decreased ACE protein levels without affecting direct processing of APP.
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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：
10.6
作者：
Karch CM;Goate AM
通讯作者：
Goate AM
影响因子：
4
作者：
Davies, Neil M.;Kehoe, Patrick G.;Martin, Richard M.
通讯作者：
Martin, Richard M.
影响因子：
4.2
作者：
Guerreiro, Rita Joao;Baquero, Miguel;Blesa, Rafael;Boada, Merce;Bras, Jose Miguel;Bullido, Maria J.;Calado, Ana;Crook, Richard;Ferreira, Carla;Frank, Ana;Gomez-Isla, Teresa;Hernandez, Isabel;Lleo, Alberto;Machado, Alvaro;Martinez-Lage, Pablo;Masdeu, Jose;Molina-Porcel, Laura;Molinuevo, Jose L.;Pastor, Pau;Perez-Tur, Jordi;Relvas, Rute;Oliveira, Catarina Resende;Ribeiro, Maria Helena;Rogaeva, Ekaterina;Sa, Alfredo;Samaranch, Lluis;Sanchez-Valle, Raquel;Santana, Isabel;Tarraga, Lluis;Valdivieso, Fernando;Singleton, Andrew;Hardy, John;Clarimon, Jordi
通讯作者：
Clarimon, Jordi
影响因子：
9.9
作者：
Haag, M. D. M.;Hofman, A.;Stricker, B. H. C.
通讯作者：
Stricker, B. H. C.