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Discoveries in ADHD genomics: Help or hype in clinical settings?

ADHD 基因组学的发现：在临床环境中是帮助还是炒作？

基本信息

批准号：
10458514
负责人：
ALYSA E DOYLE
金额：
$ 69.38万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10458514
关键词：
Address Adolescence Adolescent Adult Aggressive behavior Alleles Assessment tool Attention Attention deficit hyperactivity disorder Big Data Biological Biological Markers Caregivers Catchment Area Child Child Mental Health Child Psychiatry Childhood Clinic Clinical Cognition Complement Critical Illness Data Development Diagnosis Diagnostic Early Intervention Enrollment Etiology Evaluation Foundations Genetic Genetic Markers Genetic Variation Genomics Goals Healthcare Individual Investigation Label Lead Literature Longevity Longitudinal Studies Major Depressive Disorder Medicine Mental Health Mental disorders Modeling Molecular National Institute of Mental Health Outcome Outpatients Pathway interactions Patient Care Patients Pharmaceutical Preparations Phase Phenotype Population Control Predisposition Process Prognosis Psychopathology Recommendation Reporting Research Research Domain Criteria Resources Risk Sampling Scientific Inquiry Severities Signs and Symptoms Source Symptoms Tail Time Translational Research Translations Variant Work Youth base behavior observation biobank case control clinical care clinical practice clinical risk clinical translation cohort comorbidity evidence base genetic variant genome wide association study help-seeking behavior improved indexing insight knowledge base member middle age neuropsychiatry patient subsets polygenic risk score preventive intervention psychogenetics risk sharing risk stratification severe mental illness sex substance use tool translational genomics young adult

项目摘要

In child psychiatry, the lack of biomarkers has been a hurdle to effective patient care. While efficient and accurate characterization of help-seeking youth is a priority for the field, the current strategy of enumerating signs and symptoms is limited by the subjectivity of assessment tools, the comorbidity and shared features of different conditions, and the insidious pace at which severe, adult-onset neuropsychiatric illness unfolds. Moreover, growing evidence suggests that traditional diagnostic boundaries do not reflect the biological underpinnings of psychopathology. Thus, in the absence of objective indicators, it is difficult to resolve the tension between proactive efforts to diagnose and treat youth who present for evaluation and concerns around over-medication and over-labeling. In the past decade, genomewide association studies (GWAS) have begun to reveal a polygenic component of risk for a range of psychopathology, reflecting the aggregate influence of thousands of small-effect alleles. In other branches of medicine, such scores have contributed to improved diagnostics and identification of at-risk individuals. Recently, members of our team led the first significant GWAS for attention-deficit/ hyperactivity disorder (ADHD). In the current R01, we aim to determine the potential for polygenic risk scores (PRS) from this study and from GWAS of severe adult mental illness (SMI) to serve as objective risk indicators and tools for risk stratification in the child clinical setting. To do so, we will augment our cohort of youth consecutively referred for neuropsychiatric evaluation to achieve a sample of N=2500 child psychiatry outpatients. We will study this youth cohort in relation to developmental period (childhood/ adolescence) and sex and also study ~15,000 adults from a biobank from the same catchment area. Within a lifespan perspective, our aims will address gaps in the literature in order to facilitate real world clinical translation of genomic risk scores. First, to determine the utility of ADHD PRS as objective risk indicators, we will confirm their convergent and discriminant validity in relation to core ADHD phenotypes across individuals with a range of psychopathology. Second, we will examine the utility of ADHD PRS for risk stratification by relating scores to individual phenotypes with functional implications, to multivariate symptom profiles across patients, and to patient groups derived from phenotype-based latent class analysis. Third, we will determine the extent to which PRS for SMI and relevant biological pathways associate with these criteria alone and in combination with ADHD PRS. Our pilot data in 1,294 youth and 5,140 adults support our aims and highlight the potential for PRS for different conditions to show developmental differences that have implications for their use as risk indicators and risk stratification tools. These findings and the expertise of our team (in psychiatric genetics, developmental psychopathology and biobank/ big data) highlight the promise of work in our larger sample to lay a strong empirical foundation for the translation of genomic discoveries to child psychiatry to improve youth mental health outcomes.

在儿童精神病学中，缺乏生物标志物一直是有效治疗患者的障碍。虽然效率高