Ruderfer Douglas M, Charney Alexander W, Readhead Ben, Kidd Brian A, Kähler Anna K, Kenny Paul J, Keiser Michael J, Moran Jennifer L, Hultman Christina M, Scott Stuart A, Sullivan Patrick F, Purcell Shaun M, Dudley Joel T, Sklar Pamela
Division of Psychiatric Genomics, Department of Psychiatry, New York, NY, USA; Institute for Genomics and Multiscale Biology, New York, NY, USA; Icahn School of Medicine at Mount Sinai, New York, NY, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Division of Psychiatric Genomics, Department of Psychiatry, New York, NY, USA; Institute for Genomics and Multiscale Biology, New York, NY, USA.
Lancet Psychiatry. 2016 Apr;3(4):350-7. doi: 10.1016/S2215-0366(15)00553-2. Epub 2016 Feb 23.
Therapeutic treatments for schizophrenia do not alleviate symptoms for all patients and efficacy is limited by common, often severe, side-effects. Genetic studies of disease can identify novel drug targets, and drugs for which the mechanism has direct genetic support have increased likelihood of clinical success. Large-scale genetic studies of schizophrenia have increased the number of genes and gene sets associated with risk. We aimed to examine the overlap between schizophrenia risk loci and gene targets of a comprehensive set of medications to potentially inform and improve treatment of schizophrenia.
We defined schizophrenia risk loci as genomic regions reaching genome-wide significance in the latest Psychiatric Genomics Consortium schizophrenia genome-wide association study (GWAS) of 36 989 cases and 113 075 controls and loss of function variants observed only once among 5079 individuals in an exome-sequencing study of 2536 schizophrenia cases and 2543 controls (Swedish Schizophrenia Study). Using two large and orthogonally created databases, we collated drug targets into 167 gene sets targeted by pharmacologically similar drugs and examined enrichment of schizophrenia risk loci in these sets. We further linked the exome-sequenced data with a national drug registry (the Swedish Prescribed Drug Register) to assess the contribution of rare variants to treatment response, using clozapine prescription as a proxy for treatment resistance.
We combined results from testing rare and common variation and, after correction for multiple testing, two gene sets were associated with schizophrenia risk: agents against amoebiasis and other protozoal diseases (106 genes, p=0·00046, pcorrected =0·024) and antipsychotics (347 genes, p=0·00078, pcorrected=0·046). Further analysis pointed to antipsychotics as having independent enrichment after removing genes that overlapped these two target sets. We noted significant enrichment both in known targets of antipsychotics (70 genes, p=0·0078) and novel predicted targets (277 genes, p=0·019). Patients with treatment-resistant schizophrenia had an excess of rare disruptive variants in gene targets of antipsychotics (347 genes, p=0·0067) and in genes with evidence for a role in antipsychotic efficacy (91 genes, p=0·0029).
Our results support genetic overlap between schizophrenia pathogenesis and antipsychotic mechanism of action. This finding is consistent with treatment efficacy being polygenic and suggests that single-target therapeutics might be insufficient. We provide evidence of a role for rare functional variants in antipsychotic treatment response, pointing to a subset of patients where their genetic information could inform treatment. Finally, we present a novel framework for identifying treatments from genetic data and improving our understanding of therapeutic mechanism.
US National Institutes of Health.
精神分裂症的治疗方法并非对所有患者都能缓解症状，且疗效受常见且往往严重的副作用限制。疾病的遗传学研究可识别新的药物靶点，而其作用机制有直接遗传学支持的药物临床成功的可能性更大。大规模的精神分裂症遗传学研究增加了与风险相关的基因和基因集的数量。我们旨在研究精神分裂症风险位点与一整套药物的基因靶点之间的重叠情况，以潜在地为精神分裂症的治疗提供信息并加以改善。
我们将精神分裂症风险位点定义为在最新的精神疾病基因组学联盟对36989例病例和113075例对照进行的精神分裂症全基因组关联研究（GWAS）中达到全基因组显著性的基因组区域，以及在对2536例精神分裂症病例和2543例对照进行的外显子测序研究（瑞典精神分裂症研究）中，在5079名个体中仅出现一次的功能丧失变异。利用两个大型且相互独立创建的数据库，我们将药物靶点整理成167个由药理相似药物靶向的基因集，并研究这些基因集中精神分裂症风险位点的富集情况。我们还将外显子测序数据与国家药物登记处（瑞典处方药登记处）相联系，以评估罕见变异对治疗反应的贡献，将氯氮平处方作为治疗抵抗的替代指标。
我们综合了检测罕见和常见变异的结果，经过多重检验校正后，有两个基因集与精神分裂症风险相关：抗阿米巴病和其他原生动物疾病的药物（106个基因，p = 0.00046，校正后p = 0.024）和抗精神病药物（347个基因，p = 0.00078，校正后p = 0.046）。进一步分析表明，去除与这两个靶点集重叠的基因后，抗精神病药物具有独立的富集。我们注意到在抗精神病药物的已知靶点（70个基因，p = 0.0078）和新预测靶点（277个基因，p = 0.019）中均有显著富集。治疗抵抗性精神分裂症患者在抗精神病药物的基因靶点（347个基因，p = 0.0067）和有证据表明在抗精神病疗效中起作用的基因（91个基因，p = 0.0029）中存在过多的罕见破坏性变异。
我们的结果支持精神分裂症发病机制与抗精神病药物作用机制之间的遗传重叠。这一发现与治疗效果是多基因的观点一致，并表明单靶点治疗可能不足。我们提供了罕见功能变异在抗精神病治疗反应中起作用的证据，指出了一部分患者，其遗传信息可为治疗提供参考。最后，我们提出了一个从遗传数据中识别治疗方法并增进我们对治疗机制理解的新框架。
美国国立卫生研究院。
