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: 10628282
• 负责人: ALYSA E DOYLE
• 金额: $ 51.61万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10628282
• 关键词: Address; Adolescence; Adult; Alleles; Assessment tool; Attention deficit hyperactivity disorder; Big Data; Biological; Biological Markers; Catchment Area; Child; Child Psychiatry; Childhood; Clinical; Data; Development; Diagnosis; Diagnostic; Evaluation; Foundations; Genomics; Individual; Label; Literature; Longevity; Medicine; Mental Health; Mental disorders; Outcome; Outpatients; Pathway interactions; Patient Care; Patients; Pharmaceutical Preparations; Phenotype; Psychopathology; Risk; Sampling; Signs and Symptoms; Symptoms; Translations; Work; Youth; base; biobank; clinical care; clinical translation; clinically relevant; cohort; comorbidity; genome wide association study; help-seeking behavior; improved; member; neuropsychiatry; polygenic risk score; psychogenetics; risk stratification; sex; tool

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 ~30,000 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， 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，传统的诊断边界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， 积极主动地诊断和治疗接受评估的青年人， 过度用药和过度标签。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成分，反映了以下因素的综合影响： 成千上万的小效应等位基因在医学的其他分支，这样的分数有助于改善 诊断和识别有风险的个人。最近，我们团队的成员领导了第一个重要的 注意力缺陷多动障碍（ADHD）的GWAS。在当前的R 01中，我们的目标是确定 本研究和严重成人精神疾病（SMI）GWAS的潜在多基因风险评分（PRS） 作为儿童临床环境中风险分层的客观风险指标和工具。为此，我们将 增加我们的青少年队列连续转介神经精神评估，以实现样本， N=2500名儿童精神科门诊患者。我们将研究这一青年群体的发展时期 （儿童/青少年）和性别，并研究来自同一流域生物银行的约30，000名成年人 区从生命周期的角度来看，我们的目标是解决文献中的空白，以促进真实的世界 基因组风险评分的临床翻译。首先，确定ADHD PRS作为客观风险的效用 指标，我们将确认他们的收敛和判别效度的核心ADHD表型 在不同的精神病患者中其次，我们将研究ADHD PRS的风险效用 通过将评分与具有功能意义的个体表型、多变量症状 跨患者的特征，以及来自基于表型的潜在类别分析的患者组。三是 将确定SMI的PRS和相关生物学途径与这些标准相关的程度 单独和与ADHD PRS组合。我们在1，294名青年和5，140名成年人中的试点数据支持我们的目标， 强调不同条件下PRS显示具有影响的发育差异的潜力 作为风险指标和风险分层工具。这些发现和我们团队的专业知识（在 精神病遗传学、发育性精神病理学和生物库/大数据）突出了 我们更大的样本为基因组发现转化为儿童奠定了坚实的经验基础 精神病学，以改善青年心理健康的结果。