A genome-wide association study of non-pathological cognitive ageing

非病理性认知衰老的全基因组关联研究

• 批准号: BB/F019394/1
• 负责人: Ian Deary
• 金额: $ 88.95万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FF019394%2F1
• 关键词: genome; wide; association; study; non

There are growing proportions of older people in Western societies, and people are living longer. Therefore, the changes to the body that occur as people grow older have become a research priority. The changes that worry older people most are the changes to the brain. Cognitive decline--changes to thinking skills like memory, reasoning, and speed of thinking--is the most feared aspect of ageing. Cognitive decline is a major contribution to lower quality of life and lost independence in old age. In the United Kingdom, cognitive failure as the critical reason is the cause for 40% of admissions to institutional care. Cognitive impairment is a major personal and social burden both currently and in the future. Retaining cognitive functions must be a priority for older people and good research is needed to inform how this can be done. Cognitive ageing is far more than the medical conditions of dementia and mild cognitive impairment. The greater part of cognitive ageing occurs among otherwise healthy old people. This is known as 'normal, 'usual' and 'non-pathological' cognitive ageing. One of the more remarkable features of normal cognitive ageing is the range of effects. Some people decline quite markedly in thinking skills. whereas others retain these powers very well as they grow older. The aim of this project will be to try to find some of the clues to successful cognitive ageing, to why some people appear to have more cognitive reserve than others. There are a number of hints as to why some people's cognitive abilities show differences in ageing. There are physiological, lifestyle, and social contributions to the ageing of cognitive functions. The emphasis of the present project is on possible genetic contributions to the ageing of cognitive functions. It is important to appreciate that, to conduct such an investigation, it is important to have cognitive functions assessed on at least two occasions, many years apart. It is this aspect of the design that properly allows actual cognitive change to be studied. Few human studies have such data. For this project there will be two of the largest cohorts in the world with the correct cognitive information for such a study. There are about 2000 DNA samples from the University of Edinburgh. Among the subjects who provided these are those that have valid mental test data from the Scottish Mental Surveys of 1932 and 1947, at age 11, and have been tested on cognitive functions in old age. There are about 2000 DNA samples from the University of Manchester's Dyne Steele DNA bank. Again, these subjects are rare in having cognitive function data decades apart. In addition to these rare cognitive data, the cohorts have additional information on health, lifestyle, personality and brain imaging. There are 6000 replication samples available. Since 1998 over twenty genetic variants have been associated with cognitive ability. Unfortunately, a combination of small genetic effects and study populations have resulted in inconsistencies within the literature and confusion as to the whether or not a particular gentic variation is genuinely associated with cognitive ability. Far fewer studies, still, have information on genetic contributions to cognitive change within old age. The project will combine two of the largest and most informative elderly cognitive ageing cohorts in the world. A whole genome screen of their DNA will be conducted using the most up to date genetic testing platform to allow the most detailed screening of an elderly cohort for genes that influence cognitive ability and decline ever attempted. This data may provide invaluable information that could be used in the screening and treatment of cognitive impairment in the elderly. Genetic contributions to cognitive ageing do not imply something untreateable: genetic discoveries lead to understanding of mechanisms, which can lead to intervention. The study will provide definitive and therefore cost effective research.

在西方社会，老年人的比例越来越大，人们的寿命也越来越长。因此，随着人们年龄的增长，身体发生的变化已成为研究的重点。老年人最担心的变化是大脑的变化。认知能力下降--记忆力、推理能力和思维速度等思维能力的变化--是衰老最令人担忧的方面。认知能力下降是导致老年人生活质量下降和丧失独立性的主要原因。在英国，认知障碍是导致40%的住院患者接受机构护理的关键原因。认知障碍是当前和未来的主要个人和社会负担。保持认知功能必须是老年人的优先事项，需要进行良好的研究来告知如何做到这一点。认知老化远不止痴呆症和轻度认知障碍的医疗条件。认知老化的大部分发生在其他方面健康的老年人中。这被称为“正常”、“平常”和“非病理性”认知老化。正常认知老化的一个更显著的特征是影响的范围。有些人的思维能力明显下降。而另一些人随着年龄的增长，这些能力仍然保持得很好。这个项目的目的是试图找到一些成功的认知老化的线索，为什么有些人似乎比其他人有更多的认知储备。关于为什么有些人的认知能力在衰老过程中表现出差异，有很多线索。认知功能的老化有生理、生活方式和社会因素的影响。本项目的重点是对认知功能老化的可能遗传贡献。重要的是要认识到，要进行这样的调查，重要的是要在至少两个场合，相隔多年的认知功能进行评估。正是设计的这一方面，才使得我们能够研究实际的认知变化。很少有人类研究有这样的数据。对于这个项目，将有两个世界上最大的队列，具有正确的认知信息。爱丁堡大学大约有2000个DNA样本。在提供这些数据的受试者中，有1932年和1947年苏格兰心理调查的有效心理测试数据，年龄为11岁，并接受了老年认知功能测试。曼彻斯特大学的Dyne Steele DNA库中有大约2000个DNA样本。同样，这些受试者很少有几十年的认知功能数据。除了这些罕见的认知数据外，这些队列还提供了有关健康，生活方式，个性和大脑成像的其他信息。有6000个复制样本可用。自1998年以来，超过20种遗传变异与认知能力有关。不幸的是，小的遗传效应和研究人群的结合导致了文献中的不一致和混淆，即特定的遗传变异是否真的与认知能力相关。然而，关于基因对老年认知变化的影响的研究却少得多。该项目将联合收割机结合世界上两个最大和信息量最大的老年认知老化群体。将使用最新的基因检测平台对他们的DNA进行全基因组筛选，以便对老年人群体进行最详细的筛选，以寻找影响认知能力和衰退的基因。这些数据可以提供宝贵的信息，可用于筛选和治疗老年人的认知障碍。基因对认知老化的贡献并不意味着不可治疗的东西：基因的发现导致对机制的理解，这可能导致干预。这项研究将提供明确的，因此具有成本效益的研究。

项目成果

Associations between APOE and low-density lipoprotein cholesterol genotypes and cognitive and physical capability: the HALCyon programme.

• DOI: 10.1007/s11357-014-9673-9
• 发表时间: 2014
• 期刊: AGE
• 作者: Alfred, Tamuno;Ben-Shlomo, Yoav;Cooper, Rachel;Hardy, Rebecca;Cooper, Cyrus;Deary, Ian J.;Elliott, Jane;Gunnell, David;Harris, Sarah E.;Kivimaki, Mika;Kumari, Meena;Martin, Richard M.;Power, Chris;Sayer, Avan Aihie;Starr, John M.;Kuh, Diana;Day, Ian Nm
• 通讯作者: Day, Ian Nm

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

Associations between a polymorphism in the pleiotropic GCKR and Age-related phenotypes: the HALCyon programme.

• DOI: 10.1371/journal.pone.0070045
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Alfred T;Ben-Shlomo Y;Cooper R;Hardy R;Deary IJ;Elliott J;Harris SE;Kivimaki M;Kumari M;Power C;Starr JM;Kuh D;Day IN;HALCyon study team
• 通讯作者: HALCyon study team

Genetic variants influencing biomarkers of nutrition are not associated with cognitive capability in middle-aged and older adults.

• DOI: 10.3945/jn.112.171520
• 发表时间: 2013-05
• 期刊: The Journal of nutrition
• 作者: Alfred T;Ben-Shlomo Y;Cooper R;Hardy R;Deary IJ;Elliott J;Harris SE;Hyppönen E;Kivimaki M;Kumari M;Maddock J;Power C;Starr JM;Kuh D;Day IN;HALCyon Study Team
• 通讯作者: HALCyon Study Team