Using genetic variability in whole transcriptome expression in cells and tissues to understand the pathogenesis of Parkinson's and Alzheimer's disease

利用细胞和组织中全转录组表达的遗传变异来了解帕金森病和阿尔茨海默病的发病机制

• 批准号: MR/K01417X/1
• 负责人: John Hardy
• 金额: $ 136.12万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK01417X%2F1
• 关键词: Using; genetic; variability; whole; transcriptome

Parkinson's and Alzheimer's disease (PD & AD) are common diseases that affect the brain, causing certain cells to die. When these cells are lost people experience, amongst other problems, difficulty remembering recent events in the case of AD and difficulties moving in the case of PD. At the moment these diseases affect over 1 million people in the United Kingdom with a devastating impact on patients and their families. Since both these diseases become more common with age, the number of sufferers is likely to increase as the number of elderly people rises in the UK. Unfortunately, at the moment we know relatively little about why certain people suffer from these diseases and until we do it is hard for researchers and doctors to develop effective treatments. In the past 3 years scientists have been able to show that some individuals have common changes in their DNA (the instruction manual for all the building blocks needed to make the human body) that put them at higher risk of developing these conditions. Although this has been an amazing step forward, it has not been easy for scientists to understand how these changes in the DNA, termed genetic risk factors, act to help cause disease. Many people believe that one way in which these genetic risk factors might cause disease is by changing how much or the way in which particular genes (the basic building blocks) are expressed in brain cells. In order to check this, researchers need to make measurements about the genetic variation an individual carries and link this information to the genes they express in their cells.Although this type of investigation is particularly challenging for diseases that affect the brain, it is possible and meeting those challenges is the aim of this project. One of the difficulties is accurately measuring the amount of the gene expressed in the right cells in the brain. The brain is extremely complex and even within a single region there are many different types of cells. We will address this problem by making use of a technique called laser capture microdissection to obtain pure collections of cells from brain regions relevant to PD and AD. In this technique, using very thin slices of the human brain tissue, we shoot out just the cells we are interested in collecting with a high power laser and then extract the RNA (the gene copies) from the pellets we shoot out. Another advance is the advent of new technology for measuring all the genes expressed in a single cell type or tissue sample. This technology is called "RNA-seq" or "whole transcriptome sequencing" and it allows us to measure all kinds of gene product from any gene. It also allows us to measure the relative quantities of alternative versions of the same gene, and to measure these quantities in such a way that the influence of genetic risk factors can be more sensitively detected by directly comparing the relative product quantities in individuals who happen to have both a "good" and a "bad" copy of a given genetic variant. We believe that we are in an ideal position to complete this project and so add important insights to the understanding of PD and AD. We already have many of the RNA samples needed to perform this study and while some new RNA samples will be created during the project, through our close collaboration with the MRC Sudden Death Brain and Tissue Bank in Edinburgh we have the brain samples needed to do this (all of which have been donated for research). We have also already carried out extensive analysis of DNA from these samples, which means that the new information we generate during this grant can be quickly and cost-effectively added to existing sources of data in order to progress this research. As a final benefit, all the data we will generate on the human brain will be made publically available so that other scientists interested in understanding how the human brain works in health and disease can use this information.

帕金森病和阿尔茨海默病（PD & AD）是影响大脑的常见疾病，导致某些细胞死亡。当这些细胞丢失时，人们会遇到其他问题，例如在AD的情况下难以记住最近的事件，在PD的情况下难以移动。目前，这些疾病影响着联合王国100多万人，对病人及其家庭造成了毁灭性的影响。由于这两种疾病随着年龄的增长而变得更加常见，随着英国老年人数量的增加，患者人数可能会增加。不幸的是，目前我们对为什么某些人患有这些疾病知之甚少，在我们这样做之前，研究人员和医生很难开发出有效的治疗方法。在过去的3年里，科学家们已经能够证明，一些人的DNA（构成人体所需的所有构件的指导手册）发生了共同的变化，这使他们处于更高的风险中。虽然这是一个惊人的进步，但科学家们并不容易理解这些DNA变化，称为遗传风险因素，如何帮助导致疾病。许多人认为，这些遗传风险因素可能导致疾病的一种方式是改变特定基因（基本构建模块）在脑细胞中表达的数量或方式。为了验证这一点，研究人员需要测量个体携带的遗传变异，并将这些信息与他们在细胞中表达的基因联系起来。尽管这种类型的调查对于影响大脑的疾病来说特别具有挑战性，但这是可能的，而应对这些挑战正是该项目的目标。困难之一是准确测量大脑中正确细胞中表达的基因数量。大脑是非常复杂的，即使在一个区域内也有许多不同类型的细胞。我们将通过使用一种称为激光捕获显微切割的技术来解决这个问题，以获得与PD和AD相关的脑区域的纯细胞集合。在这项技术中，使用非常薄的人脑组织切片，我们用高功率激光发射出我们感兴趣的细胞，然后从我们发射出的颗粒中提取RNA（基因拷贝）。另一个进步是测量单个细胞类型或组织样本中表达的所有基因的新技术的出现。这项技术被称为“RNA-seq”或“全转录组测序”，它允许我们测量任何基因的所有类型的基因产物。它还允许我们测量同一基因的替代版本的相对数量，并以这样一种方式测量这些数量，即通过直接比较碰巧具有给定遗传变异的“好”和“坏”拷贝的个体的相对产物数量，可以更灵敏地检测遗传风险因素的影响。我们相信，我们处于完成该项目的理想位置，因此为PD和AD的理解增加了重要的见解。我们已经有了许多进行这项研究所需的RNA样本，虽然在项目期间将创建一些新的RNA样本，但通过我们与爱丁堡MRC猝死脑和组织库的密切合作，我们有了进行这项研究所需的大脑样本（所有这些样本都已捐赠用于研究）。我们还对这些样本中的DNA进行了广泛的分析，这意味着我们在这笔赠款中产生的新信息可以快速，经济高效地添加到现有的数据来源中，以推进这项研究。最后一个好处是，我们将生成的所有关于人脑的数据都将以电子方式提供，以便其他有兴趣了解人脑在健康和疾病中如何工作的科学家可以使用这些信息。

项目成果

Heritability Enrichment Implicates Microglia in Parkinson's Disease Pathogenesis.

• DOI: 10.1002/ana.26032
• 发表时间: 2021-05
• 期刊: ANNALS OF NEUROLOGY
• 影响因子: 11.2
• 作者: Andersen, Maren Stolp;Bandres-Ciga, Sara;Reynolds, Regina H.;Hardy, John;Ryten, Mina;Krohn, Lynne;Gan-Or, Ziv;Holtman, Inge R.;Pihlstrom, Lasse
• 通讯作者: Pihlstrom, Lasse

Amyloid precursor protein processing in human neurons with an allelic series of the PSEN1 intron 4 deletion mutation and total presenilin-1 knockout

• DOI: 10.1093/braincomms/fcz024
• 发表时间: 2019-01-01
• 期刊: BRAIN COMMUNICATIONS
• 影响因子: 4.8
• 作者: Arber, Charles;Villegas-Llerena, Claudio;Wray, Selina
• 通讯作者: Wray, Selina

Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer's disease

• DOI: 10.1371/journal.pone.0218111
• 发表时间: 2019-07-08
• 期刊: PLOS ONE
• 影响因子: 3.7
• 作者: Baker, Emily;Sims, Rebecca;Escott-Price, Valentina
• 通讯作者: Escott-Price, Valentina

Novel genetic loci underlying human intracranial volume identified through genome-wide association.

• DOI: 10.1038/nn.4398
• 发表时间: 2016-12
• 期刊: Nature neuroscience
• 影响因子: 25
• 作者: Adams HH;Hibar DP;Chouraki V;Stein JL;Nyquist PA;Rentería ME;Trompet S;Arias-Vasquez A;Seshadri S;Desrivières S;Beecham AH;Jahanshad N;Wittfeld K;Van der Lee SJ;Abramovic L;Alhusaini S;Amin N;Andersson M;Arfanakis K;Aribisala BS;Armstrong NJ;Athanasiu L;Axelsson T;Beiser A;Bernard M;Bis JC;Blanken LM;Blanton SH;Bohlken MM;Boks MP;Bralten J;Brickman AM;Carmichael O;Chakravarty MM;Chauhan G;Chen Q;Ching CR;Cuellar-Partida G;Braber AD;Doan NT;Ehrlich S;Filippi I;Ge T;Giddaluru S;Goldman AL;Gottesman RF;Greven CU;Grimm O;Griswold ME;Guadalupe T;Hass J;Haukvik UK;Hilal S;Hofer E;Hoehn D;Holmes AJ;Hoogman M;Janowitz D;Jia T;Kasperaviciute D;Kim S;Klein M;Kraemer B;Lee PH;Liao J;Liewald DC;Lopez LM;Luciano M;Macare C;Marquand A;Matarin M;Mather KA;Mattheisen M;Mazoyer B;McKay DR;McWhirter R;Milaneschi Y;Mirza-Schreiber N;Muetzel RL;Maniega SM;Nho K;Nugent AC;Loohuis LM;Oosterlaan J;Papmeyer M;Pappa I;Pirpamer L;Pudas S;Pütz B;Rajan KB;Ramasamy A;Richards JS;Risacher SL;Roiz-Santiañez R;Rommelse N;Rose EJ;Royle NA;Rundek T;Sämann PG;Satizabal CL;Schmaal L;Schork AJ;Shen L;Shin J;Shumskaya E;Smith AV;Sprooten E;Strike LT;Teumer A;Thomson R;Tordesillas-Gutierrez D;Toro R;Trabzuni D;Vaidya D;Van der Grond J;Van der Meer D;Van Donkelaar MM;Van Eijk KR;Van Erp TG;Van Rooij D;Walton E;Westlye LT;Whelan CD;Windham BG;Winkler AM;Woldehawariat G;Wolf C;Wolfers T;Xu B;Yanek LR;Yang J;Zijdenbos A;Zwiers MP;Agartz I;Aggarwal NT;Almasy L;Ames D;Amouyel P;Andreassen OA;Arepalli S;Assareh AA;Barral S;Bastin ME;Becker DM;Becker JT;Bennett DA;Blangero J;van Bokhoven H;Boomsma DI;Brodaty H;Brouwer RM;Brunner HG;Buckner RL;Buitelaar JK;Bulayeva KB;Cahn W;Calhoun VD;Cannon DM;Cavalleri GL;Chen C;Cheng CY;Cichon S;Cookson MR;Corvin A;Crespo-Facorro B;Curran JE;Czisch M;Dale AM;Davies GE;De Geus EJ;De Jager PL;de Zubicaray GI;Delanty N;Depondt C;DeStefano AL;Dillman A;Djurovic S;Donohoe G;Drevets WC;Duggirala R;Dyer TD;Erk S;Espeseth T;Evans DA;Fedko IO;Fernández G;Ferrucci L;Fisher SE;Fleischman DA;Ford I;Foroud TM;Fox PT;Francks C;Fukunaga M;Gibbs JR;Glahn DC;Gollub RL;Göring HH;Grabe HJ;Green RC;Gruber O;Gudnason V;Guelfi S;Hansell NK;Hardy J;Hartman CA;Hashimoto R;Hegenscheid K;Heinz A;Le Hellard S;Hernandez DG;Heslenfeld DJ;Ho BC;Hoekstra PJ;Hoffmann W;Hofman A;Holsboer F;Homuth G;Hosten N;Hottenga JJ;Hulshoff Pol HE;Ikeda M;Ikram MK;Jack CR Jr;Jenkinson M;Johnson R;Jönsson EG;Jukema JW;Kahn RS;Kanai R;Kloszewska I;Knopman DS;Kochunov P;Kwok JB;Lawrie SM;Lemaître H;Liu X;Longo DL;Longstreth WT Jr;Lopez OL;Lovestone S;Martinez O;Martinot JL;Mattay VS;McDonald C;McIntosh AM;McMahon KL;McMahon FJ;Mecocci P;Melle I;Meyer-Lindenberg A;Mohnke S;Montgomery GW;Morris DW;Mosley TH;Mühleisen TW;Müller-Myhsok B;Nalls MA;Nauck M;Nichols TE;Niessen WJ;Nöthen MM;Nyberg L;Ohi K;Olvera RL;Ophoff RA;Pandolfo M;Paus T;Pausova Z;Penninx BW;Pike GB;Potkin SG;Psaty BM;Reppermund S;Rietschel M;Roffman JL;Romanczuk-Seiferth N;Rotter JI;Ryten M;Sacco RL;Sachdev PS;Saykin AJ;Schmidt R;Schofield PR;Sigurdsson S;Simmons A;Singleton A;Sisodiya SM;Smith C;Smoller JW;Soininen H;Srikanth V;Steen VM;Stott DJ;Sussmann JE;Thalamuthu A;Tiemeier H;Toga AW;Traynor BJ;Troncoso J;Turner JA;Tzourio C;Uitterlinden AG;Hernández MC;Van der Brug M;Van der Lugt A;Van der Wee NJ;Van Duijn CM;Van Haren NE;Van T Ent D;Van Tol MJ;Vardarajan BN;Veltman DJ;Vernooij MW;Völzke H;Walter H;Wardlaw JM;Wassink TH;Weale ME;Weinberger DR;Weiner MW;Wen W;Westman E;White T;Wong TY;Wright CB;Zielke HR;Zonderman AB;Deary IJ;DeCarli C;Schmidt H;Martin NG;De Craen AJ;Wright MJ;Launer LJ;Schumann G;Fornage M;Franke B;Debette S;Medland SE;Ikram MA;Thompson PM
• 通讯作者: Thompson PM