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 主动诊断和治疗在场接受评估的青年与关注之间的紧张关系 关于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) 已经开始揭示了一系列精神病理学的风险的多基因成分，反映了 数千个小效等位基因的综合影响。在医学的其他分支中，这样的分数 有助于改进对高危个人的诊断和识别。最近，我们团队的成员 领导了第一个治疗注意力缺陷/多动障碍(ADHD)的重要GWA。在目前的R01中，我们的目标是 从本研究和重症成人GWA中确定多基因风险评分(PR)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 布景。为此，我们将增加连续接受神经精神病学评估的青年队列。 实现样本N=2500名儿童精神科门诊患者。我们将研究这个青年群体与以下方面的关系 发育期(儿童/青春期)和性别，也研究了来自生物库的约15,000名成年人 同样的集水区。从生命的角度来看，我们的目标将有序地解决文学中的空白 以促进基因组风险分数的真实临床转换。首先，确定ADHD PRS的效用 作为客观的风险指标，我们将确认它们相对于核心的收敛和区分有效性 患有一系列精神病的个体中的ADHD表型。其次，我们将检查该实用程序 通过将分数与具有功能暗示的个体表型相关联来进行ADHD PR的风险分层， 到患者的多变量症状描述，以及从基于表型的潜伏期衍生的患者组 阶级分析。第三，我们将确定SMI和相关生物途径的PR的程度 单独使用这些标准以及与ADHD-PR结合使用。我们在1,294名青年和 5,140名成年人支持我们的目标，并强调了不同情况下PR的潜力 影响将其用作风险指标和风险分层工具的发展差异。 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)强调了在我们的更大样本中开展工作的前景，以奠定坚实的经验基础 将基因组发现转化为儿童精神病学，以改善青年心理健康结果。

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 ~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.