Genetic Risk for Serious Mental Illness and Development

严重精神疾病和发育的遗传风险

基本信息

批准号：
10443282
负责人：
Jennifer Katherine Forsyth
金额：
$ 69.01万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10443282
关键词：
15 year old Adolescent Adult Andean Anxiety Attention deficit hyperactivity disorder Biological Markers Bipolar Disorder Characteristics Child Childhood Clinical Cognitive Colombia Complex Computerized Medical Record DNA Databases Development Diagnosis Diagnostic Disease Early Intervention Emotional Ensure Epidemiology Etiology Future Gene Frequency Genetic Genetic Risk Genetic study Genotype Goals Individual Infrastructure Intellectual functioning disability Interview Knowledge Manic Maps Mental Depression Mental disorders Motor Neurobehavioral Manifestations Onset of illness Outcome Pathogenesis Pattern Phenotype Population Psychiatric Diagnosis Psychiatric Hospitals Psychiatry Psychopathology Psychoses Risk Sampling Schizophrenia Sensory Severities Specificity Staging Structure Symptoms Syndrome Time Traction Undifferentiated United States National Institutes of Health Variant Virulence Factors Work autism spectrum disorder base clinical development clinical phenotype cohort disease classification emotional functioning follow-up genetic architecture genetic risk factor genetic variant genome-wide high risk improved lens mental development neurobehavioral polygenic risk score predictive marker prevent psychologic rare variant schizophrenia risk severe mental illness trait

项目摘要

PROJECT SUMMARY/ABSTRACT Clinical staging is gaining traction as a potentially powerful framework for understanding the pathogenesis and emergence of serious mental illnesses (SMI), such as schizophrenia (SCZ), bipolar disorder (BP), and severe depression (severe-DEP), across development, and for guiding early interventions that aim to alter disease trajectory. However, realizing the full potential of this approach requires overcoming a number of challenges. These challenges include the imprecise boundaries between psychiatric disorders; unclear validity and specificity of early clinical and neurobehavioral markers for predicting later illness onset; and growing recognition that current psychiatric nosology may not map onto differences in underlying etiology in an optimal way. Indeed, as large-scale genetic studies continue to unravel the genetic architecture of psychiatric disorders, it has become clear that genetic risk for each disorder is complex and highly polygenic; involves variants that span the allelic frequency range; and that individual genetic variants frequently confer risk for multiple disorders. Leveraging genetic risk profiles to define groups of at-risk individuals and map the progression of clinical phenotypes across development may therefore offer a more biologically valid approach for defining the nosology of psychiatric disorders, identifying biomarkers with the greatest predictive validity and specificity for different clinical outcomes, and optimizing early intervention. Towards this end, the current project will investigate the relationships between genetic risk profiles and early markers of psychopathology in the “Paisa,” a genetically and culturally homogenous population that predominates in the Andean Mountains of Colombia. Specifically, we will build upon our existing infrastructure for large-scale studies of SMI in the region to establish a new cohort of 3,000 children and early adolescents at elevated (n = 2,700) or low risk (n = 300) for SMI. We will obtain DNA samples and comprehensive clinical and neurobehavioral phenotyping and will generate common-variant based polygenic risk scores (PRS) for major psychiatric disorders, as well as rare variant scores summarizing burden of rare damaging variants and copy number deletions. We will characterize relationships between clinical syndromes and neurobehavioral traits in childhood (Aim 1). We will then map relationships between common variant-based genetic risk for SMI, rare damaging variant burden, and psychiatric diagnoses in childhood (Aim 2), as well as cognitive, motor, sensory, and psychological markers of functioning (Aim 3). Finally, using existing state-of-the-art psychiatric electronic medical record (EMR) databases to obtain longitudinal outcomes, we will explore genetic and clinical and neurobehavioral characteristics associated with poor clinical outcome within 2 years. Study findings will clarify trans-diagnostic vs. disorder-specific neurobehavioral profiles in childhood, identify clinical syndromes and neurobehavioral traits in childhood associated with genetic liability for SMI, and quantify the relative power of genetic versus clinical and neurobehavioral characteristics for predicting proximal psychiatric outcomes.

项目概要/摘要临床分期作为了解发病机制和潜在的强大框架而受到关注。严重精神疾病 (SMI) 的出现，例如精神分裂症 (SCZ)、双向情感障碍 (BP) 和严重精神疾病 (SMI) 抑郁症（重度 DEP）、跨发育以及旨在改变疾病的早期指导干预措施然而，要充分发挥这种方法的潜力需要克服许多挑战。这些挑战包括精神疾病之间的界限不明确；有效性和不明确；早期临床和神经行为标志物的特异性，用于预测后期疾病的发作和生长；认识到当前的精神病学分类学可能无法以最佳方式映射潜在病因学的差异事实上，随着大规模的遗传学研究不断揭示精神病学的遗传结构。疾病，很明显，每种疾病的遗传风险都是复杂且高度多基因的；跨越等位基因频率范围的变异；以及个体遗传变异经常面临的风险利用遗传风险概况来定义高危个体群体并绘制地图。因此，临床表型在发育过程中的进展可能提供一种生物学上更有效的方法用于定义精神疾病的疾病分类学，识别具有最大预测有效性的生物标志物和针对不同临床结果的特异性，并优化早期干预。项目将调查遗传风险概况与精神病理学早期标志之间的关系 “Paisa”，一个在遗传和文化上同质的群体，在安第斯山脉中占主导地位具体来说，我们将利用现有基础设施在该地区进行大规模 SMI 研究。建立一个由 3,000 名处于高风险 (n = 2,700) 或低风险 (n = 300) 的儿童和青少年组成的新队列对于 SMI，我们将获得 DNA 样本以及全面的临床和神经行为表型分析。为主要精神疾病以及罕见疾病生成基于常见变异的多基因风险评分 (PRS) 变异分数总结了罕见的破坏性变异和拷贝数缺失的负担。然后我们将绘制临床综合征与儿童神经行为特征之间的关系（目标 1）。 SMI 常见的基于变异的遗传风险、罕见的破坏性变异负担和儿童时期的精神病学诊断（目标 2），以及认知、运动、感觉和心理标记最后，使用现有的最先进的精神科电子病历（EMR）。为了获得纵向结果，我们将探索遗传、临床和神经行为数据库与两年内不良临床结果相关的特征研究结果将澄清跨诊断。与儿童时期特定疾病的神经行为特征相比，识别临床综合征和神经行为与 SMI 遗传倾向相关的童年特征，并量化遗传与 SMI 的相对力量用于预测近端精神病结果的临床和神经行为特征。