The dense co-occurrence of psychiatric disorders questions the categorical classification tradition and motivates efforts to establish dimensional constructs with neurobiological foundations that transcend diagnostic boundaries. In this study, we examined the genetic liability for eight major psychiatric disorder phenotypes under both a disorder-specific and a transdiagnostic framework. The study sample (n = 513) was deeply phenotyped, consisting of 452 patients from tertiary care with mood disorders, anxiety disorders (ANX), attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders, and/or substance use disorders (SUD) and 61 unaffected comparison individuals. We computed subject-specific polygenic risk score (PRS) profiles and assessed their associations with psychiatric diagnoses, comorbidity status, as well as cross-disorder behavioral dimensions derived from a rich battery of psychopathology assessments. High PRSs for depression were unselectively associated with the diagnosis of SUD, ADHD, ANX, and mood disorders (p < 1e-4). In the dimensional approach, four distinct functional domains were uncovered, namely the negative valence, social, cognitive, and regulatory systems, closely matching the major functional domains proposed by the Research Domain Criteria (RDoC) framework. Critically, the genetic predisposition for depression was selectively reflected in the functional aspect of negative valence systems (R² = 0.041, p = 5e-4) but not others. This study adds evidence to the ongoing discussion about the misalignment between current psychiatric nosology and the underlying psychiatric genetic etiology and underscores the effectiveness of the dimensional approach in both the functional characterization of psychiatric patients and the delineation of the genetic liability for psychiatric disorders.

中文翻译：

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精神病学中的多基因评分：从特定疾病到跨诊断视角

精神疾病的密集共现对分类传统提出了质疑，并激励人们努力建立具有超越诊断界限的神经生物学基础的维度结构。在这项研究中，我们在疾病特异性和跨诊断框架下检查了八种主要精神疾病表型的遗传倾向。研究样本 (n = 513) 具有深度表型，由来自三级医疗机构的 452 名患有情绪障碍、焦虑症 (ANX)、注意力缺陷的患者组成/多动症 (ADHD)、自闭症谱系障碍和/或物质使用障碍 (SUD) 以及 61 名未受影响的对照个体。我们计算了受试者特定的多基因风险评分（PRS）概况，并评估了它们与精神病学诊断、合并症状态以及源自丰富的精神病理学评估的跨疾病行为维度的关联。抑郁症的高 PRS 与 SUD、ADHD、ANX 和情绪障碍的诊断无选择性地相关 (p < 1e-4)。在维度方法中，发现了四个不同的功能域，即负价、社会、认知和调节系统，与研究领域标准（RDoC）框架提出的主要功能域密切匹配。至关重要的是，抑郁症的遗传倾向选择性地反映在负价系统的功能方面（R² = 0.041 ，p = 5e-4），但不是其他。这项研究为正在进行的关于当前精神病学分类学与潜在精神病遗传病因学之间不一致的讨论提供了证据，并强调了维度方法在精神病患者功能表征和精神疾病遗传倾向描述方面的有效性。