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

在儿童精神病学中，生物标记物的缺乏一直是有效患者护理的障碍。虽然高效和 准确描述求助青年是该领域的优先事项，也是目前列举的战略 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 不同的情况，以及严重的成人起病神经精神疾病的隐蔽速度。 此外，越来越多的证据表明，传统的诊断界限并不反映生物学上的 精神病理学的基础。因此，在没有客观指标的情况下，很难解决 积极主动地诊断和治疗在场接受评估的青年与周围的关切之间的紧张关系 过度用药和过度贴标签。在过去的十年里，全基因组关联研究(GWAS)已经开始 揭示一系列精神病理学的风险的多基因成分，反映出 成千上万的小效应等位基因。在医学的其他分支中，这样的分数有助于提高 高危个体的诊断和识别。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)。在目前的R01中，我们的目标是确定 本研究和严重成人精神疾病(SMI)多基因风险评分(PR)的可能性 作为儿童临床环境中风险分层的客观风险指标和工具。要做到这一点，我们将 扩大我们连续转诊进行神经精神病学评估的青年队列，以实现 N=2500名儿童精神科门诊病人。我们将研究这一青年群体与发育阶段的关系。 (童年/青春期)和性别，还研究了来自同一流域的生物库中的约30,000名成年人 区域。从生命的角度来看，我们的目标将解决文学中的空白，以促进现实世界 基因组风险评分的临床换算。首先，将ADHD-PR的效用确定为客观风险 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 所有患有一系列精神病态的人。其次，我们将检查ADHD-PR的风险效用 通过将分数与具有功能含义的个体表型和多变量症状相关联进行分层 从基于表型的潜伏期分析得出的患者和患者组的概况。第三，我们 将确定SMI和相关生物通路的PR与这些标准的关联程度 单独使用或与ADHD-PRS结合使用。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和 强调不同条件下的发展潜力，以显示有影响的发展差异 将其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 精神病学遗传学、发展精神病理学和生物库/大数据)突出了在 我们更大的样本为基因组发现向儿童的转化奠定了坚实的经验基础 精神病学，以改善青少年的心理健康结果。

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.