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？

• 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
• 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

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患者护理的障碍。虽然效率高， 准确描述寻求帮助的青年是该领域的一个优先事项，目前的战略是 体征和症状的评估工具的主观性，共病性和共同特征的限制 不同的条件，以及严重的，成人发病的神经精神疾病的发展速度。 此外，越来越多的证据表明，传统的诊断界限并不能反映生物学特征。 精神病理学的基础因此，在缺乏客观指标的情况下， 积极努力诊断和治疗接受评价的青年与关切问题之间的紧张关系 过度用药和过度贴标签在过去的十年中，全基因组关联研究（GWAS） 已经开始揭示一系列精神病理学风险的多基因组成部分，反映了 数千个小效应等位基因的聚集影响。在其他医学分支中，这样的分数 有助于改进诊断和查明高危个人。最近，我们的团队成员 领导了第一个针对注意力缺陷多动障碍（ADHD）的重大GWAS。在当前的R 01中，我们的目标是 确定本研究和重度成人GWAS中多基因风险评分（PRS）的可能性 精神疾病（SMI）作为儿童临床风险分层的客观风险指标和工具 设置.为了做到这一点，我们将增加我们的青少年队列连续转介神经精神评估 以获得N=2500名儿童精神病学门诊患者的样本。我们将从以下方面研究这一青年群体： 发育期（儿童/青少年）和性别，并研究了来自生物银行的约15，000名成年人， 相同的集水区。从生命周期的角度来看，我们的目标将解决文献中的空白， 以促进基因组风险评分的真实的临床翻译。首先，确定ADHD PRS的效用 作为客观的风险指标，我们将确认它们的收敛和判别有效性， ADHD表型在不同精神病理学个体中的分布。第二，我们将考察 通过将分数与具有功能意义的个体表型相关联， 患者间的多变量症状特征，以及从基于表型的潜在 阶级分析第三，我们将确定PRS对SMI和相关生物学途径的影响程度， 与这些标准单独或与ADHD PRS组合。我们在1,294名青年和 5，140名成年人支持我们的目标，并强调PRS在不同条件下的潜力 发展差异对它们作为风险指标和风险分层工具的使用具有影响。 这些发现和我们团队的专业知识（精神遗传学、发育精神病理学和 生物库/大数据）突出了我们在更大样本中工作的承诺，为以下方面奠定了坚实的经验基础： 将基因组发现转化为儿童精神病学，以改善青少年心理健康结果。