Genetic compendium of 1511 human brains available through the UK Medical Research Council Brain Banks Network Resource.
Genetic compendium of 1511 human brains available through the UK Medical Research Council Brain Banks Network Resource.
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DOI：
10.1101/gr.210609.116
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发表时间：
2017-01
期刊：
影响因子：
7
通讯作者：
Chinnery PF
中科院分区：
文献类型：
--
作者：
Keogh MJ;Wei W;Wilson I;Coxhead J;Ryan S;Rollinson S;Griffin H;Kurzawa-Akanbi M;Santibanez-Koref M;Talbot K;Turner MR;McKenzie CA;Troakes C;Attems J;Smith C;Al Sarraj S;Morris CM;Ansorge O;Pickering-Brown S;Ironside JW;Chinnery PF
鉴于遗传因素在常见神经退行性疾病发病机制中的核心作用，在遗传学启蒙的背景下解释人体组织中的机制研究至关重要。为了解决这个问题，我们对1511例诊断为阿尔茨海默病的冷冻人脑进行了外显子组测序和拷贝数变异分析（AD，n = 289），额颞叶痴呆/肌萎缩侧索硬化（FTD/ALS，n = 252），克雅氏病（CJD，n = 239），帕金森病（PD，n = 39），路易体痴呆（DLB，n = 58）、其他神经退行性、血管或神经遗传性疾病（n = 266）和无显著神经病理学的对照（n = 368）。在所有情况下从脑组织中提取基因组DNA，然后进行外显子组测序（Illumina Nextera 62 Mb捕获），其中变体由FreeBayes命名;拷贝数变体（CNV）分析（Illumina HumanOmniExpress-12 BeadChip）; C9 orf 72重复扩增检测;和APOE基因分型。在61例脑中发现了已建立或可能致病的杂合、复合杂合或纯合变异体，以及C9 orf 72六核苷酸重复扩增和APP拷贝数增加。除了349个大脑中已知的风险等位基因（1461个进行外显子组测序的23.9%）之外，我们还发现了GRN和DLB中罕见变异之间的关联。在<1.5%的大脑中发现了罕见的CNV，包括在AD中过度表达的PRPH拷贝数增加。临床、病理学和遗传学数据都是可用的，使得能够通过英国医学研究理事会大脑银行网络检索特定的冷冻大脑。这允许基于个体的遗传结构直接访问病理和对照人脑组织，从而能够在未来研究中鉴定已知遗传风险因素和潜在致病等位基因的功能验证。
Given the central role of genetic factors in the pathogenesis of common neurodegenerative disorders, it is critical that mechanistic studies in human tissue are interpreted in a genetically enlightened context. To address this, we performed exome sequencing and copy number variant analysis on 1511 frozen human brains with a diagnosis of Alzheimer's disease (AD, n = 289), frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS, n = 252), Creutzfeldt-Jakob disease (CJD, n = 239), Parkinson's disease (PD, n = 39), dementia with Lewy bodies (DLB, n = 58), other neurodegenerative, vascular, or neurogenetic disorders (n = 266), and controls with no significant neuropathology (n = 368). Genomic DNA was extracted from brain tissue in all cases before exome sequencing (Illumina Nextera 62 Mb capture) with variants called by FreeBayes; copy number variant (CNV) analysis (Illumina HumanOmniExpress-12 BeadChip); C9orf72 repeat expansion detection; and APOE genotyping. Established or likely pathogenic heterozygous, compound heterozygous, or homozygous variants, together with the C9orf72 hexanucleotide repeat expansions and a copy number gain of APP, were found in 61 brains. In addition to known risk alleles in 349 brains (23.9% of 1461 undergoing exome sequencing), we saw an association between rare variants in GRN and DLB. Rare CNVs were found in <1.5% of brains, including copy number gains of PRPH that were overrepresented in AD. Clinical, pathological, and genetic data are available, enabling the retrieval of specific frozen brains through the UK Medical Research Council Brain Banks Network. This allows direct access to pathological and control human brain tissue based on an individual's genetic architecture, thus enabling the functional validation of known genetic risk factors and potentially pathogenic alleles identified in future studies.
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来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
3.5
作者：
Jin, Sheng Chih;Benitez, Bruno A.;Cruchaga, Carlos
通讯作者：
Cruchaga, Carlos
影响因子：
4.2
作者：
Sassi C;Guerreiro R;Gibbs R;Ding J;Lupton MK;Troakes C;Al-Sarraj S;Niblock M;Gallo JM;Adnan J;Killick R;Brown KS;Medway C;Lord J;Turton J;Bras J;Alzheimer's Research UK Consortium;Morgan K;Powell JF;Singleton A;Hardy J
通讯作者：
Hardy J
影响因子：
9.8
作者：
Beck, Jon;Poulter, Mark;Mead, Simon
通讯作者：
Mead, Simon
影响因子：
12.3
作者：
Langmead B;Trapnell C;Pop M;Salzberg SL
通讯作者：
Salzberg SL