Pharmacogenomics of Mood Stabilizer Response in Bipolar Disorder

双相情感障碍情绪稳定剂反应的药物基因组学

• 批准号: 8695486
• 负责人: John R. Kelsoe
• 金额: $ 113.17万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-10 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8695486
• 关键词: Algorithm Design; Biopsy; Bipolar Disorder; Cell Culture Techniques; Cells; Collaborations; Collection; Data; Disease; Fibroblasts; Gene Expression; Genes; Genetic; Genetic Crossing Over; Genomics; Genotype; Goals; Human; In Vitro; Individual; Instruction; Lead; Lithium; Maintenance; Meta-Analysis; Modeling; Molecular Profiling; Mood stabilizers; Multicenter Trials; NTRK2 gene; Neurons; Outcome Measure; Pathway Analysis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenomics; Phase; Phenotype; Physicians; Process; Prospective Studies; Recontacts; Recording of previous events; Recruitment Activity; Relapse; Relative (related person); Research Institute; Retrospective Studies; Sampling; Site; Skin; Surveys; Testing; Time; Treatment outcome; Valproic Acid; arm; design; disorder later incidence prevention; genetic variant; genome wide association study; genome-wide; human data; induced pluripotent stem cell; nerve stem cell; phosphodiesterase 11a; primary outcome; prospective; response; treatment as usual

DESCRIPTION (provided by applicant): Mood stabilizer treatment is central to the pharmacological management of patients with bipolar disorder. However, response to such agents is highly variable between individuals often resulting in a lengthy trial and error process of medication optimization that can last years. There is a great need for a better predictor of response which would guide physicians to the optimum medication in a more efficient fashion. Genetic differences likely explain a substantial portion of this variability. The goal of this project is to identify genetic variants that are associated with response to mood stabilizer medications that might ultimately be useful as a predictive test. Studies to date by our group have implicated two genes, NTRK2 and PDE11A as predicting response to lithium. In this project, we propose a two pronged approach: genes will first be sought in an exploratory fashion in a larger retrospective sample and then tested for replication in a smaller prospective sample. Larger samples are more easily obtainable in a retrospective study, however, prospective designs though more difficult, provide better and more quantitative data. Our 11 site consortium has recently completed collection of over 4,500 bipolar subjects for a large genetic study. 2,000 retrospective subjects will be collected from both recontact of these previous cases and recruitment of new retrospective cases. The prospective sample of 960 subjects will be collected through an eight site multicenter trial. Patients will be recruited, screened and stabilized first on lithium monotherapy over a 3 month period. After one month observation, they will enter the maintenance phase and followed for 2 years. The primary outcome measure will be time to relapse. Patients who fail lithium will be crossed over to valproic acid, those failing both drugs will enter the treatment as usual arm. Genomewide association will be performed on the retrospective sample and positive SNPs replicated in the prospective sample. Secondary analyses will include genomewide association ofthe prospective sample alone and in meta-analysis with the retrospective sample. These analyses will be guided in part by studies of lithium's mechanism of action in neuronal cells derived from induced pluripotent stem cells in turn derived from skin fibroblasts from lithium responders and non-responders. RELEVANCE (See instructions): This multi-site collaborative project aims to identify genetic variants in individuals with bipolar disorder that predict response to lithium. We will do this with a combination of retrospective assessment of lithium response in 1600 individuals with BP disorder and analysis of genotype data, as well as a prospective study of 1000 BP individuals who begin an open trial with lithium. Our hypothesis is that genetic variants at several loci predict treatment outcomes with lithium.

描述（由申请人提供）：

项目成果

A gene co-expression module implicating the mitochondrial electron transport chain is associated with long-term response to lithium treatment in bipolar affective disorder.

• DOI: 10.1038/s41398-018-0237-0
• 发表时间: 2018-09-05
• 期刊: Translational psychiatry
• 影响因子: 6.8
• 作者: Stacey D;Schubert KO;Clark SR;Amare AT;Milanesi E;Maj C;Leckband SG;Shekhtman T;Kelsoe JR;Gurwitz D;Baune BT
• 通讯作者: Baune BT

Unraveling the biology of bipolar disorder using induced pluripotent stem-derived neurons.

• DOI: 10.1111/bdi.12535
• 发表时间: 2017-11
• 期刊: Bipolar disorders
• 影响因子: 5.4
• 作者: Miller ND;Kelsoe JR
• 通讯作者: Kelsoe JR

The Pharmacogenomics of Bipolar Disorder study (PGBD): identification of genes for lithium response in a prospective sample.

• DOI: 10.1186/s12888-016-0732-x
• 发表时间: 2016-05-05
• 期刊: BMC psychiatry
• 影响因子: 4.4
• 作者: Oedegaard KJ;Alda M;Anand A;Andreassen OA;Balaraman Y;Berrettini WH;Bhattacharjee A;Brennand KJ;Burdick KE;Calabrese JR;Calkin CV;Claasen A;Coryell WH;Craig D;DeModena A;Frye M;Gage FH;Gao K;Garnham J;Gershon E;Jakobsen P;Leckband SG;McCarthy MJ;McInnis MG;Maihofer AX;Mertens J;Morken G;Nievergelt CM;Nurnberger J;Pham S;Schoeyen H;Shekhtman T;Shilling PD;Szelinger S;Tarwater B;Yao J;Zandi PP;Kelsoe JR
• 通讯作者: Kelsoe JR

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

致力于在躁郁症中进行药物遗传学的临床实施。

• DOI: 10.1186/1741-7015-12-90
• 发表时间: 2014-05-30
• 期刊: BMC medicine
• 影响因子: 9.3
• 作者: Salloum NC;McCarthy MJ;Leckband SG;Kelsoe JR
• 通讯作者: Kelsoe JR

Patch-Seq Protocol to Analyze the Electrophysiology, Morphology and Transcriptome of Whole Single Neurons Derived From Human Pluripotent Stem Cells.

• DOI: 10.3389/fnmol.2018.00261
• 发表时间: 2018
• 期刊: Frontiers in molecular neuroscience
• 影响因子: 4.8
• 作者: van den Hurk M;Erwin JA;Yeo GW;Gage FH;Bardy C
• 通讯作者: Bardy C