JPND BRain Imaging, cognition, Dementia and next generation GEnomics

JPND 脑成像、认知、痴呆症和下一代基因组学

• 批准号: MR/N027558/1
• 负责人: Ian Deary
• 金额: $ 61.28万
• 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: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN027558%2F1
• 关键词: JPND; BRain; Imaging; cognition; Dementia

Establishing efficient prevention strategies for dementia and Alzheimer disease (AD) is a major health priority for the coming years. An important hurdle is that pathological processes leading to AD begin many years before clinical diagnosis, hence efficient prevention should be initiated very early. This requires identifying individuals in the general population who are at high risk of developing dementia and exploring the molecular pathways underlying the structural brain alterations that precede the occurrence of dementia, an essential step for identifying novel relevant drug targets. To tackle these important questions we propose to explore the genetic and epigenetic determinants of quantitative MRI-markers of brain aging that are powerful predictors of dementia/AD risk, and to examine the clinical significance of the markers in a population-based setting. Leveraging the extensive information collected within the largest European population-based cohort studies with neuroimaging data, we will first search for genetic variants associated with established and novel MRI-markers of brain aging, focusing particularly on rare variants, using both an agnostic and candidate locus approach (loci identified through genome-wide association studies [GWAS] as associated AD or with MRI-markers of brain aging). In contrast with GWAS signals, rare variants may lead to the discovery of causal variants, and have hardly been explored in association with structural MRI-markers. Second, we will take an original lifetime perspective, through examination of samples in various age categories spanning from young adulthood to older age, many of which with repeated MRI and blood sampling. Indeed, there is increasing evidence that early-life factors play an important role in the occurrence of late-onset neurodegenerative diseases. We propose an innovative exploration of lifetime changes in methylation associated with structural brain alterations using a novel bisulfite sequencing technology, to help identify functional and disease relevant variants. We will also study the modifying effect of vascular risk factors and socio-economic status on genetic/epigenetic determinants of brain aging. Third, we will explore the clinical significance of genetic and epigenetic markers we identify by examining their association with cognitive performance, cognitive decline and risk of dementia/AD, capitalizing on the elaborate cognitive testing and prospective dementia surveillance available in all studies.

建立有效的预防痴呆症和阿尔茨海默病（AD）的战略是未来几年的一个主要卫生优先事项。一个重要的障碍是导致AD的病理过程在临床诊断前开始许多年就开始了，因此应该非常早地开始有效的预防。这需要在一般人群中识别出患有痴呆症的高风险个体，并探索痴呆症发生前脑结构改变的分子途径，这是识别新的相关药物靶点的重要步骤。为了解决这些重要的问题，我们建议探索定量MRI标记物的大脑衰老的遗传和表观遗传决定因素，这些标记物是痴呆/AD风险的有力预测因子，并检查标记物在基于人群的环境中的临床意义。利用欧洲最大的基于人群的队列研究中收集的大量信息和神经影像学数据，我们将首先使用不可知和候选位点方法（通过全基因组关联研究[GWAS]确定的与AD相关的位点或与脑老化的MRI标记物相关的位点），搜索与脑老化的既定和新型MRI标记物相关的遗传变异，特别关注罕见变异。与GWAS信号相反，罕见的变异可能导致发现因果变异，并且几乎没有与结构MRI标记相关的探索。第二，我们将采取一个原始的终身视角，通过检查从年轻到老年的各种年龄组的样本，其中许多都有重复的MRI和血液采样。事实上，越来越多的证据表明，早期生活因素在迟发性神经退行性疾病的发生中起着重要作用。我们提出了一种创新的探索与结构性脑改变相关的甲基化的终身变化，使用一种新的亚硫酸氢盐测序技术，以帮助识别功能和疾病相关的变体。我们还将研究血管危险因素和社会经济地位对脑老化的遗传/表观遗传决定因素的修饰作用。第三，我们将探索我们通过检查其与认知表现，认知能力下降和痴呆/AD风险的相关性来确定的遗传和表观遗传标记的临床意义，利用所有研究中可用的精细认知测试和前瞻性痴呆监测。

项目成果

Do ADHD-impulsivity and BMI have shared polygenic and neural correlates?

ADHD 冲动性和 BMI 是否具有共同的多基因和神经相关性？

• DOI: 10.1038/s41380-019-0444-y
• 发表时间: 2021-03
• 期刊: Molecular psychiatry
• 影响因子: 11
• 作者: Barker ED;Ing A;Biondo F;Jia T;Pingault JB;Du Rietz E;Zhang Y;Ruggeri B;Banaschewski T;Hohmann S;Bokde ALW;Bromberg U;Büchel C;Quinlan EB;Sounga-Barke E;Bowling AB;Desrivières S;Flor H;Frouin V;Garavan H;Asherson P;Gowland P;Heinz A;Ittermann B;Martinot JL;Martinot MP;Nees F;Papadopoulos-Orfanos D;Poustka L;Smolka MN;Vetter NC;Walter H;Whelan R;Schumann G;IMAGEN Consortium
• 通讯作者: IMAGEN Consortium

Genetic variants associated with longitudinal changes in brain structure across the lifespan.

• DOI: 10.1038/s41593-022-01042-4
• 发表时间: 2022-04
• 期刊: NATURE NEUROSCIENCE
• 影响因子: 25
• 作者: Brouwer, Rachel M.;Klein, Marieke;Grasby, Katrina L.;Schnack, Hugo G.;Jahanshad, Neda;Teeuw, Jalmar;Thomopoulos, Sophia I.;Sprooten, Emma;Franz, Carol E.;Gogtay, Nitin;Kremen, William S.;Panizzon, Matthew S.;Olde Loohuis, Loes M.;Whelan, Christopher D.;Aghajani, Moji;Alloza, Clara;Alanaes, Dag;Artiges, Eric;Ayesa-Arriola, Rosa;Barker, Gareth J.;Bastin, Mark E.;Blok, Elisabet;Boen, Erlend;Breukelaar, Isabella A.;Bright, Joanna K.;Buimer, Elizabeth E. L.;Bulow, Robin;Cannon, Dara M.;Ciufolini, Simone;Crossley, Nicolas A.;Damatac, Christienne G.;Dazzan, Paola;de Mol, Casper L.;de Zwarte, Sonja M. C.;Desrivieres, Sylvane;Diaz-Caneja, Covadonga M.;Doan, Nhat Trung;Dohm, Katharina;Froehner, Juliane H.;Goltermann, Janik;Grigis, Antoine;Grotegerd, Dominik;Han, Laura K. M.;Harris, Mathew A.;Hartman, Catharina A.;Heany, Sarah J.;Heindel, Walter;Heslenfeld, Dirk J.;Hohmann, Sarah;Ittermann, Bernd;Jansen, Philip R.;Janssen, Joost;Jia, Tianye;Jiang, Jiyang;Jockwitz, Christiane;Karali, Temmuz;Keeser, Daniel;Koevoets, Martijn G. J. C.;Lenroot, Rhoshel K.;Malchow, Berend;Mandl, Rene C. W.;Medel, Vicente;Meinert, Susanne;Morgan, Catherine A.;Muehleisen, Thomas W.;Nabulsi, Leila;Opel, Nils;de la Foz, Victor Ortiz-Garcia;Overs, Bronwyn J.;Paillere Martinot, Marie-Laure;Redlich, Ronny;Marques, Tiago Reis;Repple, Jonathan;Roberts, Gloria;Roshchupkin, Gennady V.;Setiaman, Nikita;Shumskaya, Elena;Stein, Frederike;Sudre, Gustavo;Takahashi, Shun;Thalamuthu, Anbupalam;Tordesillas-Gutierrez, Diana;van der Lugt, Aad;van Haren, Neeltje E. M.;Wardlaw, Joanna M.;Wen, Wei;Westeneng, Henk-Jan;Wittfeld, Katharina;Zhu, Alyssa H.;Zugman, Andre;Armstrong, Nicola J.;Bonfiglio, Gaia;Bralten, Janita;Dalvie, Shareefa;Davies, Gail;Di Forti, Marta;Ding, Linda;Donohoe, Gary;Forstner, Andreas J.;Gonzalez-Penas, Javier;Guimaraes, Joao P. O. F. T.;Homuth, Georg;Hottenga, Jouke-Jan;Knol, Maria J.;Kwok, John B. J.;Le Hellard, Stephanie;Mather, Karen A.;Milaneschi, Yuri;Morris, Derek W.;Noethen, Markus M.;Papiol, Sergi;Rietschel, Marcella;Santoro, Marcos L.;Steen, Vidar M.;Stein, Jason L.;Streit, Fabian;Tankard, Rick M.;Teumer, Alexander;van 't Ent, Dennis;van der Meer, Dennis;van Eijk, Kristel R.;Vassos, Evangelos;Vazquez-Bourgon, Javier;Witt, Stephanie H.;Adams, Hieab H. H.;Agartz, Ingrid;Ames, David;Amunts, Katrin;Andreassen, Ole A.;Arango, Celso;Banaschewski, Tobias;Baune, Bernhard T.;Belangero, Sintia I.;Bokde, Arun L. W.;Boomsma, Dorret I.;Bressan, Rodrigo A.;Brodaty, Henry;Buitelaar, Jan K.;Cahn, Wiepke;Caspers, Svenja;Cichon, Sven;Crespo-Facorro, Benedicto;Cox, Simon R.;Dannlowski, Udo;Elvsashagen, Torbjorn;Espeseth, Thomas;Falkai, Peter G.;Fisher, Simon E.;Flor, Herta;Fullerton, Janice M.;Garavan, Hugh;Gowland, Penny A.;Grabe, Hans J.;Hahn, Tim;Heinz, Andreas;Hillegers, Manon;Hoare, Jacqueline;Hoekstra, Pieter J.;Ikram, Mohammad A.;Jackowski, Andrea P.;Jansen, Andreas;Jonsson, Erik G.;Kahn, Rene S.;Kircher, Tilo;Korgaonkar, Mayuresh S.;Krug, Axel;Lemaitre, Herve;Malt, Ulrik F.;Martinot, Jean-Luc;McDonald, Colm;Mitchell, Philip B.;Muetzel, Ryan L.;Murray, Robin M.;Nees, Frauke;Nenadic, Igor;Oosterlaan, Jaap;Ophoff, Roel A.;Pan, Pedro M.;Penninx, Brenda W. J. H.;Poustka, Luise;Sachdev, Perminder S.;Salum, Giovanni A.;Schofield, Peter R.;Schumann, Gunter;Shaw, Philip;Sim, Kang;Smolka, Michael N.;Stein, Dan J.;Trollor, Julian N.;van den Berg, Leonard H.;Veldink, Jan H.;Walter, Henrik;Westlye, Lars T.;Whelan, Robert;White, Tonya;Wright, Margaret J.;Medland, Sarah E.;Franke, Barbara;Thompson, Paul M.;Hulshoff Pol, Hilleke E.
• 通讯作者: Hulshoff Pol, Hilleke E.

Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers.

• DOI: 10.1016/j.biopsych.2023.08.018
• 发表时间: 2024-01-15
• 期刊: Biological psychiatry
• 影响因子: 10.6
• 作者: Boen R;Kaufmann T;van der Meer D;Frei O;Agartz I;Ames D;Andersson M;Armstrong NJ;Artiges E;Atkins JR;Bauer J;Benedetti F;Boomsma DI;Brodaty H;Brosch K;Buckner RL;Cairns MJ;Calhoun V;Caspers S;Cichon S;Corvin AP;Crespo-Facorro B;Dannlowski U;David FS;de Geus EJC;de Zubicaray GI;Desrivières S;Doherty JL;Donohoe G;Ehrlich S;Eising E;Espeseth T;Fisher SE;Forstner AJ;Fortaner-Uyà L;Frouin V;Fukunaga M;Ge T;Glahn DC;Goltermann J;Grabe HJ;Green MJ;Groenewold NA;Grotegerd D;Grøntvedt GR;Hahn T;Hashimoto R;Hehir-Kwa JY;Henskens FA;Holmes AJ;Håberg AK;Haavik J;Jacquemont S;Jansen A;Jockwitz C;Jönsson EG;Kikuchi M;Kircher T;Kumar K;Le Hellard S;Leu C;Linden DE;Liu J;Loughnan R;Mather KA;McMahon KL;McRae AF;Medland SE;Meinert S;Moreau CA;Morris DW;Mowry BJ;Mühleisen TW;Nenadić I;Nöthen MM;Nyberg L;Ophoff RA;Owen MJ;Pantelis C;Paolini M;Paus T;Pausova Z;Persson K;Quidé Y;Marques TR;Sachdev PS;Sando SB;Schall U;Scott RJ;Selbæk G;Shumskaya E;Silva AI;Sisodiya SM;Stein F;Stein DJ;Straube B;Streit F;Strike LT;Teumer A;Teutenberg L;Thalamuthu A;Tooney PA;Tordesillas-Gutierrez D;Trollor JN;van 't Ent D;van den Bree MBM;van Haren NEM;Vázquez-Bourgon J;Völzke H;Wen W;Wittfeld K;Ching CRK;Westlye LT;Thompson PM;Bearden CE;Selmer KK;Alnæs D;Andreassen OA;Sønderby IE;ENIGMA-CNV Working Group
• 通讯作者: ENIGMA-CNV Working Group