Genetic factors contribute to the susceptibility of psychotic disorders, but less is known how they affect psychotic disease-course development. Utilizing polygenic scores (PGSs) in combination with longitudinal healthcare data with decades of follow-up we investigated the contributing genetics to psychotic disease-course severity and diagnostic shifts in the SUPER-Finland study, encompassing 10 403 genotyped individuals with a psychotic disorder. To longitudinally track the study participants’ past disease-course severity, we created a psychiatric hospitalization burden metric using the full-coverage and nation-wide Finnish in-hospital registry (data from 1969 and onwards). Using a hierarchical model, ranking the psychotic diagnoses according to clinical severity, we show that high schizophrenia PGS (SZ-PGS) was associated with progression from lower ranked psychotic disorders to schizophrenia (OR = 1.32 [1.23–1.43], p = 1.26e-12). This development manifested already at psychotic illness onset as a higher psychiatric hospitalization burden, the proxy for disease-course severity. In schizophrenia (n = 5 479), both a high SZ-PGS and a low educational attainment PGS (EA-PGS) were associated with increased psychiatric hospitalization burden (p = 1.00e-04 and p = 4.53e-10). The SZ-PGS and the EA-PGS associated with distinct patterns of hospital usage. In individuals with high SZ-PGS, the increased hospitalization burden was composed of longer individual hospital stays, while low EA-PGS associated with shorter but more frequent hospital visits. The negative effect of a low EA-PGS was found to be partly mediated via substance use disorder, a major risk factor for hospitalizations. In conclusion, we show that high SZ-PGS and low EA-PGS both impacted psychotic disease-course development negatively but resulted in different disease-course trajectories.

遗传因素导致精神障碍的易感性，但人们对它们如何影响精神病病程的发展知之甚少。在 SUPER-Finland 研究中，我们利用多基因评分 (PGS) 结合纵向医疗保健数据和数十年的随访，调查了遗传因素对精神病病程严重程度和诊断变化的影响，该研究涵盖了 10 403 名患有精神障碍的基因型个体。为了纵向跟踪研究参与者过去的病程严重程度，我们使用全覆盖的全国性芬兰住院登记系统（1969 年及以后的数据）创建了精神科住院负担指标。使用分层模型，根据临床严重程度对精神病诊断进行排名，我们发现高精神分裂症 PGS (SZ-PGS) 与从排名较低的精神病到精神分裂症的进展相关（OR = 1.32 [1.23–1.43]，p  = 1.26e -12）。这种发展在精神病发作时就已经表现为较高的精神病住院负担，这是病程严重程度的代表。在精神分裂症患者中 ( n  = 5 479)，高 SZ-PGS 和低教育程度 PGS (EA-PGS) 均与精神科住院负担增加相关（p  = 1.00e-04 和p  = 4.53e-10）。 SZ-PGS 和 EA-PGS 与不同的医院使用模式相关。在 SZ-PGS 高的个体中，住院负担的增加是由较长的个人住院时间组成的，而低 EA-PGS 则与较短但更频繁的医院就诊有关。研究发现，低 EA-PGS 的负面影响部分是通过物质使用障碍介导的，物质使用障碍是住院的主要危险因素。总之，我们表明高 SZ-PGS 和低 EA-PGS 均对精神病病程发展产生负面影响，但导致不同的病程轨迹。