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。虽然高效 准确表征寻求帮助青年是该领域的优先事项，即当前列举的策略 体征和症状受评估工具的主观性，合并症和共同特征的限制 不同的条件以及严重的成人神经精神疾病的阴险速度。 此外，越来越多的证据表明，传统的诊断边界不能反映生物学 心理病理学的基础。因此，在没有客观指标的情况下，很难解决 积极努力诊断和治疗在出席评估的年轻人和围绕疑虑的青年之间的紧张关系 过度用药和标签过度。在过去的十年中，全基因组协会研究（GWAS）已经开始 揭示一系列心理病理学风险的多基因组成部分，反映了 成千上万的小等位基因。在其他医学分支中，这种分数有助于改善 诊断和处于危险中的个人。最近，我们团队的成员领导了第一个重要的 注意力缺陷/多动症（ADHD）的GWA。在当前R01中，我们旨在确定 这项研究的多基因风险评分（PR）以及严重的成人精神疾病（SMI）的潜力 在儿童临床环境中充当客观风险指标和风险分层的工具。为此，我们会 增强我们连续参考神经精神病学评估的青年队列，以获得一个样本 n = 2500名儿童精神病学院门诊病人。我们将研究与发展时期有关的青年队列 （儿童/青春期）和性别，还从同一流域的生物库中学习约30,000名成年人 区域。在一生的观点中，我们的目标将解决文献中的差距，以促进现实世界 基因组风险评分的临床翻译。首先，确定ADHD PR的效用为客观风险 指标，我们将确认它们相对于核心ADHD表型的收敛性和判别有效性 跨多种心理病理学的人。其次，我们将检查ADHD PRS的效用是否有风险 分层通过将分数与单个表型与功能含义的分层相关联，与多元症状相关 跨患者的剖面，以及基于表型的潜在类别分析的患者群体。第三，我们 将确定与这些标准相关的SMI和相关生物途径的PR的程度 单独并与多动症PR相结合。我们的1,294名青年和5,140名成年人的试点数据支持我们的目标 突出显示不同条件下PR的潜力显示出具有影响的发育差异 用作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，发育心理病理学和生物库/大数据）突出了工作的希望 我们更大的样本为将基因组发现转化为儿童奠定了强大的经验基础 改善青年心理健康成果的精神病学。