pathQTL: Integrative Multi-Omics Causal Inference of Molecular Mechanisms Leading to Neuropsychiatric Illness

pathQTL：导致神经精神疾病的分子机制的综合多组学因果推断

• 批准号: 10550143
• 负责人: Michael Isaiah Love
• 金额: $ 47.18万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-10 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10550143
• 关键词: Adult; Affect; Alzheimer' s Disease; Bayesian Modeling; Bioconductor; Biological; Biology; Brain; Brain region; CRISPR-mediated transcriptional activation; Cells; Chromatin; Complex; Computer Models; Computer software; Computing Methodologies; Data; Data Set; Development; Disease; Engineering; Epigenetic Process; Gene Expression; Genes; Genetic; Genetic Variation; Genome; Genotype; Goals; Human; Human Development; Individual; Link; Love; Major Depressive Disorder; Measures; Mediating; Modeling; Molecular; Morphology; Multiomic Data; Neurons; Nonsense Mutation; Pathogenesis; Pathway interactions; Phenotype; Probability; Productivity; Quantitative Trait Loci; Regulator Genes; Regulatory Element; Regulatory Pathway; Risk; Schizophrenia; Statistical Distributions; Stream; Structure; System; Testing; Therapeutic Effect; Time; Update; Validation; Variant; Viral; Visualization; Work; brain abnormalities; causal model; cell type; cost; disorder risk; epigenome; experimental study; fetal; genetic association; genetic variant; genome wide association study; genomic locus; histone modification; inhibitor; multiple datasets; multiple omics; nerve stem cell; neurogenetics; neuropsychiatric disorder; neuropsychiatry; novel; open source; overexpression; risk variant; skills; statistics; success; therapeutic target; tool; trait; transcriptome; user-friendly; web interface

Project Summary A multitude of common genetic variants influencing risk for neuropsychiatric disorders (e.g., schizophrenia, major depressive disorder, and Alzheimer’s disease) have recently been identified and replicated, providing a foothold into the causes of these disorders. The critical next step in neuropsychiatric genetics is to move from a risk locus in the genome to an understanding of how this genetic variation influences molecules, cells, and circuits of the brain, leading to complex disorders. Many datasets, including those generated by our own labs, have established direct links between genotype and human brain traits at multiple levels of biology (molecular: chromatin accessibility, expression; cellular: morphology; circuit: gross brain structure), termed quantitative trait loci (QTLs). Here, we will integrate QTLs across multiple levels of biology in order to statistically prioritize causal pathways by which genetic variation creates risk for complex neuropsychiatric disorders. Causal modeling goes well beyond previous co-localization work, as it allows the prioritization of expensive functional validation experiments for cellular or molecular changes that are a cause of the disorder, rather than those that are a consequence or independent of the disorder. It additionally allows inference of key experimental parameters including cell-type and developmental time period. Finally, causal inference when combined across multiple levels of biology and multiple disorder risk loci allows for assessment of convergence at a biological level, cell-type, or developmental time period, which is critical information for therapeutic targeting. We will leverage the computational and statistical frameworks of Bayesian probabilistic networks and causal inference in a new framework that utilizes association summary statistics, as well-powered multi-level data collected on the same individuals is almost always infeasible. Subsequently, we will experimentally validate the molecular predictions of our model using epigenetic engineering in primary human neural progenitor cells, and in turn revising the computational models. Prioritizing causal molecular pathways of disorder associated variants, and identifying the relevant cell-type and developmental stage will increase the success rate of validation experiments and shed light on mechanisms of neuropsychiatric disorders in an unbiased manner.

项目总结

项目成果

The Evolutionary History of Common Genetic Variants Influencing Human Cortical Surface Area.

• DOI: 10.1093/cercor/bhaa327
• 发表时间: 2021-03-05
• 期刊: Cerebral cortex (New York, N.Y. : 1991)
• 作者: Tilot AK;Khramtsova EA;Liang D;Grasby KL;Jahanshad N;Painter J;Colodro-Conde L;Bralten J;Hibar DP;Lind PA;Liu S;Brotman SM;Thompson PM;Medland SE;Macciardi F;Stranger BE;Davis LK;Fisher SE;Stein JL
• 通讯作者: Stein JL

Chromatin loop dynamics during cellular differentiation are associated with changes to both anchor and internal regulatory features.

• DOI: 10.1101/gr.277397.122
• 发表时间: 2023-08
• 期刊: GENOME RESEARCH
• 影响因子: 7
• 作者: Bond, Marielle L.;Davis, Eric S.;Quiroga, Ivana Y.;Dey, Anubha;Kiran, Manjari;Love, Michael I.;Won, Hyejung;Phanstiel, Douglas H.
• 通讯作者: Phanstiel, Douglas H.

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.

MRLocus: Identifying causal genes mediating a trait through Bayesian estimation of allelic heterogeneity.

• DOI: 10.1371/journal.pgen.1009455
• 发表时间: 2021-04
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Zhu A;Matoba N;Wilson EP;Tapia AL;Li Y;Ibrahim JG;Stein JL;Love MI
• 通讯作者: Love MI