A high proportion of those with schizophrenia experience treatment non-response, placing them at higher risk for mortality and suicide attempts, compared to treatment responders. The clinical, social, and economic burden of treatment-resistant schizophrenia (TRS) are substantial. Previous genomic and epidemiological studies of TRS were often limited by sample size or lack of comprehensive genomic data. We aimed to systematically understand the clinical, demographic, and genomic correlates of TRS using epidemiological and genetic epidemiological modelling in a Swedish national population sample (n = 24,706) and then in a subgroup with common variant genetic risk scores, rare copy-number variant burden, and rare exonic burden (n = 4936). Population-based analyses identified increasing schizophrenia family history to be significantly associated with TRS (highest quartile of familial burden vs. lowest: adjusted odds ratio (aOR): 1.31, P = 4.8 × 10^-8). In males, a decrease of premorbid IQ of one standard deviation was significantly associated with greater risk of TRS (minimal aOR: 0.94, P = 0.002). In a subset of cases with extensive genomic data, we found no significant association between the genetic risk scores of four psychiatric disorders and two cognitive traits with TRS (schizophrenia genetic risk score: aOR = 1.07, P = 0.067). The association between copy number variant and rare variant burden measures and TRS did not reach the pre-defined statistical significance threshold (all P ≥ 0.005). In conclusion, direct measures of genomic risk were not associated with TRS; however, premorbid IQ in males and schizophrenia family history were significantly correlated with TRS and points to new insights into the architecture of TRS.

与治疗有反应者相比，很大一部分精神分裂症患者对治疗无反应，这使他们面临更高的死亡和自杀未遂风险。难治性精神分裂症 (TRS) 的临床、社会和经济负担是巨大的。以前的 TRS 基因组和流行病学研究通常受到样本量或缺乏全面基因组数据的限制。我们旨在系统地了解 TRS 的临床、人口统计学和基因组相关性，在瑞典全国人口样本 ( n  = 24,706) 中使用流行病学和遗传流行病学模型，然后在具有常见变异遗传风险评分、罕见拷贝数变异负担的亚组中, 和罕见的外显子负担 ( n = 4936）。基于人群的分析确定增加的精神分裂症家族史与 TRS 显着相关（家庭负担的最高四分位数与最低：调整后的比值比 (aOR)：1.31，P  = 4.8 × 10 ^-8）。在男性中，病前智商降低一个标准差与 TRS 风险增加显着相关（最小 aOR：0.94，P  = 0.002）。在具有大量基因组数据的病例子集中，我们发现四种精神疾病的遗传风险评分与 TRS 的两种认知特征之间没有显着关联（精神分裂症遗传风险评分：aOR = 1.07，P = 0.067）。拷贝数变异和罕见变异负荷测量与 TRS 之间的关联未达到预定义的统计显着性阈值（所有P  ≥ 0.005）。总之，基因组风险的直接测量与 TRS 无关；然而，男性病前智商和精神分裂症家族史与 TRS 显着相关，并指出了对 TRS 结构的新见解。