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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：
10674065
负责人：
Jennifer Katherine Forsyth
金额：
$ 67.48万
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/10674065
关键词：
15 year old Adolescent Adult Andean Anxiety Attention deficit hyperactivity disorder 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 Populations at Risk 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 biomarker identification clinical development clinical phenotype cohort disease classification emotional functioning follow-up genetic architecture genetic risk factor genetic variant genome-wide high risk population 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.

项目总结/文摘