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

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、合并症和共同特征的限制 不同情况的不同，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和关注的青少年之间的紧张关系 围绕过度用药和过度标签。过去十年，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 数千个小效应等位基因的总体影响。在医学的其他分支中，这样的分数 有助于改善高危人群的诊断和识别。近期，我们团队的成员 领导了第一个针对注意力缺陷/多动障碍（ADHD）的重大 GWAS。在当前的R01中，我们的目标是 确定本研究和重症成人 GWAS 的多基因风险评分 (PRS) 的潜力 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 设置。为此，我们将扩大连续转介接受神经精神评估的青少年群体 获得 N=2500 名儿童精神病学门诊患者的样本。我们将研究这个青年群体的相关问题 发育时期（童年/青春期）和性别，还研究了来自生物库的约 15,000 名成年人 同一集水区。从生命周期的角度来看，我们的目标将解决文献中的空白，以便 促进基因组风险评分的现实世界临床转化。首先，确定 ADHD PRS 的效用 作为客观风险指标，我们将确认其与核心风险相关的收敛有效性和区分有效性。 患有一系列精神病理学的个体的多动症表型。其次，我们将检查实用性 ADHD PRS 通过将分数与具有功能意义的个体表型相关联来进行风险分层， 跨患者的多变量症状概况，以及源自基于表型的潜伏的患者组 类分析。第三，我们将确定 SMI 和相关生物途径的 PRS 的程度 单独使用这些标准并与 ADHD PRS 结合使用。我们针对 1,294 名青少年和 5,140 名成年人支持我们的目标，并强调 PRS 在不同条件下的潜力 发展差异对其用作风险指标和风险分层工具产生影响。 这些发现和我们团队的专业知识（精神遗传学、发育精神病理学和 生物样本库/大数据）强调了我们在更大样本中的工作前景，为以下方面奠定了坚实的经验基础： 将基因组发现转化为儿童精神病学，以改善青少年心理健康结果。

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.