Schizophrenia case-control study of neonatal and post onset methylomes

新生儿和发病后甲基化的精神分裂症病例对照研究

• 批准号: 9238825
• 负责人: Karolina Anna Aberg
• 金额: $ 61.22万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-06 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9238825
• 关键词: Address; Affect; Affinity; Algorithms; Antipsychotic Agents; Autopsy; Binding; Bioinformatics; Biological; Biological Assay; Biological Markers; Birth; Blood; Blood specimen; Brain; Caring; Case-Control Studies; Cell division; Clinic; Clinical; Collection; Complex; Computer software; Cost Measures; DNA; DNA Methylation; Data; Development; Diagnosis; Diagnostic; Diet; Disease; Disease remission; Early Diagnosis; Ethics; Etiology; Event; Gene Expression; Genetic; Genetic Transcription; Genomic DNA; Genomics; Goals; Gold; Hematological Disease; Histones; Human; Human Genome; Individual Differences; Investigation; Knowledge; Life; Life Style; Light; Measures; Mental disorders; Methods; Methylation; Neonatal; Pathogenicity; Pathway Analysis; Pathway interactions; Patients; Pattern; Performance; Phenylketonurias; Predisposition; Process; Protein Binding Domain; Psychological Stress; Relapse; Risk; Sampling; Schizophrenia; Site; Smoking; Spottings; Symptoms; Testing; Tissues; Transcript; Validation; Variant; Work; base; bisulfite sequencing; brain tissue; case control; cell type; clinical application; cost; design; disorder risk; experimental study; follow-up; improved; innovation; insight; methylation biomarker; methylation pattern; methylome; novel; outcome forecast; risk variant; screening; theories; transcriptome; transcriptome sequencing; transcriptomics; whole genome

PROJECT SUMMARY Schizophrenia (SZ) is a devastating psychiatric illness with a complex etiology. While genetic sequence variation clearly contributes to SZ development, knowledge of DNA methylation patterns may provide complementary information. First, methylation studies may provide additional insights into disease processes. For example, as methylation may directly regulate gene expression and is mutable in postmitotic tissues, it provides functional information unobtainable by sequence alone and can account for clinical phenomena such as the dynamic course of illness including cycles of remissions and relapses. Second, the translational potential of methylation studies is profound. For example, pathogenic environmental events may leave methylation signatures in blood, traces of which can be preserved during cell division. As methylation marks can be measured cost-effectively in (histone-free) genomic DNA, they can potentially increase the predictive power of algorithms based on sequence variation. Two complications hamper inferences in methylation studies of SZ. First, there are many possible differences between SZ cases and controls that may affect the methylome including lifestyle differences, disease induced psychological stress, smoking and antipsychotic use. Rather than methylation affecting SZ susceptibility, the direction of effect could be reversed with the disease causing methylation changes. Second, the procurement of brain tissue is not possible in living patients. It is therefore important to study the methylome using a combination of blood samples, which can reveal useful biomarkers, and in brain tissue, which can help identify biologically relevant functions regulated by methylation. To address these complications we propose to study the methylomic profiles of SZ cases/controls in blood samples collected at birth. Because these samples were collected years prior to any SZ symptoms, it is logically impossible for SZ disease related confounders to cause the associations. Next, to generate causal hypotheses that can potentially be followed up with functional experiments, we integrate the pre SZ onset findings with methylation and transcription data from post SZ onset blood and brain samples using a logically rigorous analytical framework. As detailed knowledge is lacking about disease relevant methylation sites, we propose to assay all ~27 million CpGs in the human genome in all our samples. Successful completion of this proposal will identify biomarkers and functional methylation marks for SZ generally, and may specifically identify markers with potential to predict SZ risk. Such findings would be of considerable value for improving SZ treatment and care.

项目摘要 精神分裂症（SZ）是一种具有复杂病因的毁灭性精神疾病。虽然基因序列 变异显然有助于SZ的发展，DNA甲基化模式的知识可以提供 补充信息。首先，甲基化研究可以为疾病过程提供更多的见解。 例如，由于甲基化可以直接调节基因表达，并且在有丝分裂后组织中是可变的，因此甲基化可能会影响基因表达。 提供了单独通过序列无法获得的功能信息，并且可以解释临床现象， 疾病的动态过程包括缓解和复发的周期。第二，翻译 甲基化研究的潜力是深远的。例如，致病性环境事件可能会使 血液中的甲基化特征，其痕迹可以在细胞分裂期间保留。作为甲基化标记 可以在（无组蛋白）基因组DNA中经济有效地测量，它们可以潜在地增加预测 基于序列变化的算法的能力。 两个并发症妨碍SZ甲基化研究的推论。首先，有很多可能的 SZ病例和对照之间可能影响甲基化的差异，包括生活方式差异， 疾病引起的心理压力，吸烟和抗精神病药物的使用。而不是甲基化影响SZ 易感性，影响的方向可以与疾病引起的甲基化改变相反。第二、 在活体患者中获取脑组织是不可能的。因此，研究 使用血液样品的组合进行甲基化组，其可以揭示有用的生物标志物，并且在脑组织中， 这可以帮助识别由甲基化调控的生物学相关功能。 为了解决这些并发症，我们建议研究SZ病例/对照组血液中的甲基化谱 出生时采集的样本。因为这些样本是在任何SZ症状出现前几年收集的， SZ疾病相关混杂因素在逻辑上不可能导致相关性。接下来，为了生成因果关系 假设，可以潜在地跟进与功能实验，我们整合了前SZ发病 使用逻辑分析方法，从SZ发作后的血液和脑样本中获得甲基化和转录数据， 严格的分析框架。由于缺乏关于疾病相关甲基化位点的详细知识，我们 建议在我们所有的样本中检测人类基因组中的所有~ 2700万个CpG。 成功完成此提案将确定SZ的生物标志物和功能性甲基化标记 一般来说，可以特异性地识别具有预测SZ风险潜力的标志物。这样的结果将是 对于改善SZ治疗和护理具有相当大的价值。