MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.
JAMA Psychiatry. 2022 Mar 1;79(3):260-269. doi: 10.1001/jamapsychiatry.2021.3799.
About 20% to 30% of people with schizophrenia have psychotic symptoms that do not respond adequately to first-line antipsychotic treatment. This clinical presentation, chronic and highly disabling, is known as treatment-resistant schizophrenia (TRS). The causes of treatment resistance and their relationships with causes underlying schizophrenia are largely unknown. Adequately powered genetic studies of TRS are scarce because of the difficulty in collecting data from well-characterized TRS cohorts.
To examine the genetic architecture of TRS through the reassessment of genetic data from schizophrenia studies and its validation in carefully ascertained clinical samples.
DESIGN, SETTING, AND PARTICIPANTS: Two case-control genome-wide association studies (GWASs) of schizophrenia were performed in which the case samples were defined as individuals with TRS (n = 10 501) and individuals with non-TRS (n = 20 325). The differences in effect sizes for allelic associations were then determined between both studies, the reasoning being such differences reflect treatment resistance instead of schizophrenia. Genotype data were retrieved from the CLOZUK and Psychiatric Genomics Consortium (PGC) schizophrenia studies. The output was validated using polygenic risk score (PRS) profiling of 2 independent schizophrenia cohorts with TRS and non-TRS: a prevalence sample with 817 individuals (Cardiff Cognition in Schizophrenia [CardiffCOGS]) and an incidence sample with 563 individuals (Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances [STRATA-G]).
GWAS of treatment resistance in schizophrenia. The results of the GWAS were compared with complex polygenic traits through a genetic correlation approach and were used for PRS analysis on the independent validation cohorts using the same TRS definition.
The study included a total of 85 490 participants (48 635 [56.9%] male) in its GWAS stage and 1380 participants (859 [62.2%] male) in its PRS validation stage. Treatment resistance in schizophrenia emerged as a polygenic trait with detectable heritability (1% to 4%), and several traits related to intelligence and cognition were found to be genetically correlated with it (genetic correlation, 0.41-0.69). PRS analysis in the CardiffCOGS prevalence sample showed a positive association between TRS and a history of taking clozapine (r2 = 2.03%; P = .001), which was replicated in the STRATA-G incidence sample (r2 = 1.09%; P = .04).
In this GWAS, common genetic variants were differentially associated with TRS, and these associations may have been obscured through the amalgamation of large GWAS samples in previous studies of broadly defined schizophrenia. Findings of this study suggest the validity of meta-analytic approaches for studies on patient outcomes, including treatment resistance.
约 20%至 30%的精神分裂症患者存在精神病症状，对一线抗精神病药物治疗反应不足。这种临床表现为慢性且高度致残，被称为治疗抵抗性精神分裂症（TRS）。治疗抵抗的原因及其与精神分裂症潜在原因的关系在很大程度上尚不清楚。由于难以从特征明确的 TRS 队列中收集数据，充分有力的 TRS 遗传研究相对较少。
通过重新评估精神分裂症研究中的遗传数据，并在精心确定的临床样本中对其进行验证，来研究 TRS 的遗传结构。
设计、设置和参与者：对精神分裂症进行了两项病例对照全基因组关联研究（GWAS），病例样本定义为 TRS 个体（n=10501）和非 TRS 个体（n=20325）。然后确定了两项研究之间等位基因关联效应大小的差异，其推理是这种差异反映了治疗抵抗而不是精神分裂症。从 CLOZUK 和精神分裂症基因组学联盟（PGC）精神分裂症研究中检索基因型数据。使用具有 TRS 和非 TRS 的 2 个独立精神分裂症队列的多基因风险评分（PRS）分析对结果进行验证：一个具有 817 名个体的患病率样本（卡迪夫精神分裂症认知[卡迪夫 COGS]）和一个具有 563 名个体的发病率样本（精神分裂症治疗抵抗和治疗进展的遗传学工作流[STRATA-G]）。
精神分裂症治疗抵抗的 GWAS。通过遗传相关性方法将 GWAS 的结果与复杂的多基因特征进行比较，并使用相同的 TRS 定义在独立验证队列中进行 PRS 分析。
该研究在 GWAS 阶段共纳入 85490 名参与者（48635[56.9%]名男性），在 PRS 验证阶段纳入 1380 名参与者（859[62.2%]名男性）。精神分裂症的治疗抵抗是一种具有可检测遗传性的多基因特征（1%至 4%），与智力和认知相关的几个特征被发现与其具有遗传相关性（遗传相关性，0.41-0.69）。在卡迪夫 COGS 患病率样本中的 PRS 分析显示，TRS 与氯氮平（r2=2.03%；P=.001）的使用史之间存在正相关，这在 STRATA-G 发病率样本中得到了复制（r2=1.09%；P=.04）。
在这项 GWAS 中，常见的遗传变异与 TRS 有差异关联，这些关联可能因先前对广义定义的精神分裂症进行的大型 GWAS 样本合并而被掩盖。本研究的结果表明，荟萃分析方法在包括治疗抵抗在内的患者结局研究中的有效性。
