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，生物标志物的缺乏一直是有效患者护理的障碍。在高效且 准确描述寻求帮助的青少年是该领域的一个优先事项，目前的战略是列举 体征和症状受到评估工具的主观性、共病和共同特征的限制 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，很难解决问题。 积极诊断和治疗接受评估的青少年的努力与周围的担忧之间存在紧张关系 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组成部分，反映了以下因素的总体影响 数千个小效应等位基因。在医学的其他分支中，这些分数有助于提高 诊断和识别高危人群。最近，我们团队的成员领导了第一个重大的 针对注意力缺陷/多动障碍 (ADHD) 的 GWAS。在当前的 R01 中，我们的目标是确定 本研究和严重成人精神疾病 (SMI) 的 GWAS 的多基因风险评分 (PRS) 的潜力 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 扩大我们连续转介接受神经精神病学评估的年轻人群体，以获得样本 N=2500 名儿童精神科门诊患者。我们将研究这个青年群体与发展时期的关系 （童年/青春期）和性，还研究来自同一流域生物库的约 30,000 名成年人 区域。从生命周期的角度来看，我们的目标将解决文献中的空白，以促进现实世界 基因组风险评分的临床转化。首先，确定 ADHD PRS 作为客观风险的效用 指标，我们将确认它们与核心 ADHD 表型相关的收敛和判别有效性 跨越具有一系列精神病理学的个体。其次，我们将检查 ADHD PRS 对风险的效用 通过将分数与具有功能意义的个体表型、多变量症状相关联来进行分层 跨患者以及从基于表型的潜在类别分析得出的患者组的概况。第三，我们 将确定 SMI 的 PRS 和相关生物途径与这些标准的关联程度 单独使用或与 ADHD PRS 联合使用。我们对 1,294 名青少年和 5,140 名成年人进行的试点数据支持了我们的目标， 强调 PRS 在不同条件下的潜力，以显示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 精神遗传学、发展精神病理学和生物库/大数据）强调了该领域工作的前景 我们更大的样本为将基因组发现转化为儿童奠定了坚实的经验基础 精神病学以改善青少年心理健康结果。