From Genotypes to Phenotypes in Schizophrenia: A Developmental Functional Genomics Approach

从精神分裂症的基因型到表型：发育功能基因组学方法

• 批准号: 10490530
• 负责人: Jennifer Katherine Forsyth
• 金额: $ 18.33万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-12 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10490530
• 关键词: Bioinformatics; Biological; Biological Process; Brain; Characteristics; Clinical; Cognitive; Data; Development; Disease; Etiology; Genes; Genetic Heterogeneity; Genetic Risk; Genomic approach; Genomics; Genotype; Human; Individual; Infrastructure; Intervention; Knowledge; Link; Magnetic Resonance Imaging; Maps; Mentors; National Institute of Mental Health; Neurodevelopmental Disorder; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Phenotype; Population; Process; Psychoses; Research; Research Personnel; Research Training; Schizophrenia; Scientist; Structure; Subgroup; Testing; Time; Training; Variant; Work; base; burden of illness; clinical heterogeneity; cognitive function; cohort; exome sequencing; functional genomics; genetic architecture; genetic variant; genome wide association study; insight; neuroimaging; rare variant; schizophrenia risk; transcriptomics; whole genome

PROJECT SUMMARY Efforts to understand the core biological processes underlying schizophrenia (SCZ) have been hampered by the clinical and genetic heterogeneity of the disorder. However, large-scale genomic studies have begun to yield major insights into the genetic architecture of SCZ. Applying a developmental functional genomics approach to characterize findings from large-scale genomic studies of SCZ and related disorders, and examine relationships between genotypes and phenotypes in well-characterized cohorts may therefore help determine which neurotypical processes are most impacted by genetic risk for SCZ, and facilitate the discovery of links between specific genotypes and phenotypes in SCZ. In line with NIMH Strategic Objective 1, the PI therefore aims to: 1) integrate large-scale genomic findings for schizophrenia and related neurodevelopmental disorders with gene co-expression networks derived from the developing human brain to understand the impact of polygenic risk for schizophrenia on brain development at the clinical population level; and 2) using a unique cohort of 650 predominantly recent-onset SCZ patients with rich clinical, cognitive, and structural magnetic resonance imaging phenotyping, determine whether specific genetic risk profiles predict distinct phenotypes among SCZ patients. In particular, the PI will evaluate the extent to which common and rare variants associated with SCZ and related neurodevelopmental disorders converge on developmentally regulated biological pathways (Aim 1), derived from applying weighted gene co-expression network analyses (WGCNA) to BrainSpan transcriptomic data. Then, using common and rare variant data derived from genome-wide association study (GWAS) chips and whole exome sequencing in a cohort of 650 SCZ patients, the PI will test whether common variants, rare variants, and/or their combination in biologically-partitioned genetic risk profiles (partitioned based on BrainSpan modules developed in Aim 1) predict current and premorbid clinical and cognitive phenotypes (Aim 2); and/or specific neuroanatomic characteristics (Aim 3). Through structured coursework, mentoring from a team of distinguished scientists (Drs. Bearden, Ophoff, Nuechterlein, and Eichler), and UCLA and UW’s outstanding infrastructure for genomics, neuroimaging, and psychosis research, the proposed research and training plan will allow the PI to extend her training to work with whole-genome genotyping and exome sequencing data; deepen her knowledge of bioinformatics, neurodevelopmental disorders, and neuroimaging; and ultimately, transition to an independent investigator able to integrate genomic, clinical, and neuroimaging data to help map the pathogenesis of SCZ through development. Successful completion of this project will provide mechanistic insights into the neurotypical processes impacted by genetic risk for SCZ and has the potential to inform biologically valid subtypes of SCZ with distinct developmental trajectories, in line with NIMH Strategic Objective 2.

项目总结 精神分裂症(SCZ)的核心生物学过程一直受到以下因素的阻碍 这种疾病的临床和遗传异质性。然而，大规模的基因组研究已经开始 对SCZ的遗传结构有了重大的见解。应用发育功能基因组学 对SCZ和相关疾病的大规模基因组研究结果进行表征的方法，并检查 因此，在特征良好的队列中，基因类型和表型之间的关系可能有助于确定 哪些神经典型过程受SCZ的遗传风险影响最大，并有助于发现联系 SCZ中特定的基因类型和表型之间的差异。根据NIMH的战略目标1，PI因此 目的是：1)整合精神分裂症和相关神经发育障碍的大规模基因组研究结果 利用来自发育中的人脑的基因共表达网络来了解影响 在临床人群水平上精神分裂症对大脑发育的多基因风险；以及2)使用独特的 650例临床、认知和结构磁性丰富的新发SCZ患者的队列研究 磁共振成像表型分型，确定特定的遗传风险特征是否预测不同的表型 在SCZ患者中。特别是，PI将评估常见和罕见变种的程度 与SCZ和相关神经发育障碍相关的集中在发育调节上 生物途径(目标1)，源自应用加权基因共表达网络分析(WGCNA) 到BrainSpan转录数据。然后，使用来自全基因组的常见和罕见的变异数据 在650名SCZ患者的队列中，关联研究(Gwas)芯片和整个外显子组测序，PI将测试 无论是常见的变异，还是罕见的变异，和/或它们在生物分区的遗传风险概况中的组合 (根据在AIM 1中开发的BrainSpan模块进行分区)预测当前和发病前的临床和 认知表型(目标2)；和/或特定神经解剖特征(目标3)。通过结构化 课程工作，来自杰出科学家团队的指导(比尔登博士、奥弗夫博士、努切特莱因博士和 以及加州大学洛杉矶分校和华盛顿大学在基因组学、神经成像和精神病研究方面的卓越基础设施， 拟议的研究和培训计划将允许PI将她的培训扩展到全基因组工作 基因分型和外显子组测序数据；加深她对生物信息学、神经发育的知识 障碍和神经成像；最终过渡到能够整合的独立调查人员 基因组、临床和神经影像数据，以帮助绘制SCZ的发病机制图。 该项目的成功完成将提供对受影响的神经典型过程的机械性洞察 与SCZ的遗传风险有关，并有可能通知SCZ的生物有效亚型具有不同的 发展轨迹，符合NIMH战略目标2。

项目成果

Developmental trajectories of premorbid functioning predict cognitive remediation treatment response in first-episode schizophrenia.

• DOI: 10.1017/s0033291722003312
• 发表时间: 2023-10
• 期刊: PSYCHOLOGICAL MEDICINE
• 影响因子: 6.9
• 作者: Kuo, Susan S.;Ventura, Joseph;Forsyth, Jennifer K.;Subotnik, Kenneth L.;Turner, Luana R.;Nuechterlein, Keith H.
• 通讯作者: Nuechterlein, Keith H.