Challenge accepted: uncovering the role of rare genetic variants in Alzheimer's disease.
Challenge accepted: uncovering the role of rare genetic variants in Alzheimer's disease.
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DOI：
10.1186/s13024-021-00505-9
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发表时间：
2022-01-09
影响因子：
15.1
通讯作者：
Guerreiro R
中科院分区：
文献类型：
--
作者：
Khani M;Gibbons E;Bras J;Guerreiro R
寻找阿尔茨海默病（AD）的罕见变异通常被认为是一种高风险高回报的情况。与这一奋进相关的挑战是真实的。尽管如此，将全基因组技术应用于大量病例和对照或小的、特征明确的家庭已经开始取得成果。与AD相关的罕见变异已被证明会增加风险或导致疾病，但也可以防止AD的发展。所有这些都有可能成为新药开发的目标。多项独立研究现已表明，NOTCH 3、TREM 2、SORL 1、ABCA 7、BIN 1、CLU、NCK 2、AKAP 9、UNC 5C、PLCG 2和ABI 3中的罕见变异与AD相关，并表明它们可能通过多种机制影响疾病。这些基因在免疫系统、脂质代谢、突触可塑性和细胞凋亡中具有功能。然而，从携带与AD相关的罕见变体的基因集合中出现的主要途径是Aβ途径。也有人提出了其他几十个基因中的罕见变异的关联，但尚未在独立研究中复制。复制这种类型的发现是与研究复杂疾病（如AD）中的罕见变异相关的挑战之一。在本文中，我们将讨论其中一些主要挑战以及可能的解决方案。综合方法、大型数据集和数据库的可用性以及新分析方法的开发将继续产生新的基因，这些基因具有影响AD的罕见变异性。未来，更广泛、更多样化的遗传学研究，以及对具有深刻特征的家族的研究，将增强我们对疾病发病机制的理解，并使我们走上开发成功药物的正确道路。在线版本包含补充材料，可通过10.1186/s13024-021-00505-9获得。
The search for rare variants in Alzheimer’s disease (AD) is usually deemed a high-risk - high-reward situation. The challenges associated with this endeavor are real. Still, the application of genome-wide technologies to large numbers of cases and controls or to small, well-characterized families has started to be fruitful. Rare variants associated with AD have been shown to increase risk or cause disease, but also to protect against the development of AD. All of these can potentially be targeted for the development of new drugs. Multiple independent studies have now shown associations of rare variants in NOTCH3, TREM2, SORL1, ABCA7, BIN1, CLU, NCK2, AKAP9, UNC5C, PLCG2, and ABI3 with AD and suggested that they may influence disease via multiple mechanisms. These genes have reported functions in the immune system, lipid metabolism, synaptic plasticity, and apoptosis. However, the main pathway emerging from the collective of genes harboring rare variants associated with AD is the Aβ pathway. Associations of rare variants in dozens of other genes have also been proposed, but have not yet been replicated in independent studies. Replication of this type of findings is one of the challenges associated with studying rare variants in complex diseases, such as AD. In this review, we discuss some of these primary challenges as well as possible solutions. Integrative approaches, the availability of large datasets and databases, and the development of new analytical methodologies will continue to produce new genes harboring rare variability impacting AD. In the future, more extensive and more diverse genetic studies, as well as studies of deeply characterized families, will enhance our understanding of disease pathogenesis and put us on the correct path for the development of successful drugs. The online version contains supplementary material available at 10.1186/s13024-021-00505-9.
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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
影响因子：
4.2
作者：
Bras J;Djaldetti R;Alves AM;Mead S;Darwent L;Lleo A;Molinuevo JL;Blesa R;Singleton A;Hardy J;Clarimon J;Guerreiro R
通讯作者：
Guerreiro R
增强剂中的罕见变体负担分析将CAV1识别为ALS风险基因。
影响因子：
8.8
作者：
Cooper-Knock J;Zhang S;Kenna KP;Moll T;Franklin JP;Allen S;Nezhad HG;Iacoangeli A;Yacovzada NY;Eitan C;Hornstein E;Elhaik E;Celadova P;Bose D;Farhan S;Fishilevich S;Lancet D;Morrison KE;Shaw CE;Al-Chalabi A;Project MinE ALS Sequencing Consortium;Veldink JH;Kirby J;Snyder MP;Shaw PJ
通讯作者：
Shaw PJ
影响因子：
4.4
作者：
Chilamakuri CS;Lorenz S;Madoui MA;Vodák D;Sun J;Hovig E;Myklebost O;Meza-Zepeda LA
通讯作者：
Meza-Zepeda LA
影响因子：
6.8
作者：
Carolina Dalmasso, Maria;Ignacio Brusco, Luis;Ramirez, Alfredo
通讯作者：
Ramirez, Alfredo