Al Eissa Mariam M, Fiorentino Alessia, Sharp Sally I, O'Brien Niamh L, Wolfe Kate, Giaroli Giovanni, Curtis David, Bass Nicholas J, McQuillin Andrew
Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK.
Current address: Institute of Opthalmology, University College London, London, UK.
Ann Hum Genet. 2018 Mar;82(2):88-92. doi: 10.1111/ahg.12226. Epub 2017 Nov 17.
Schizophrenia (SCZ) is a severe, highly heritable psychiatric disorder. Elucidation of the genetic architecture of the disorder will facilitate greater understanding of the altered underlying neurobiological mechanisms. The aim of this study was to identify likely aetiological variants in subjects affected with SCZ. Exome sequence data from a SCZ cas-control sample from Sweden was analysed for likely aetiological variants using a weighted burden test. Suggestive evidence implicated the UNC-51-like kinase (ULK1) gene, and it was observed that four rare variants that were more common in the Swedish SCZ cases were also more common in UK10K SCZ cases, as compared to obesity cases. These three missense variants and one intronic variant were genotyped in the University College London cohort of 1304 SCZ cases and 1348 ethnically matched controls. All four variants were more common in the SCZ cases than controls and combining them produced a result significant at P = 0.02. The results presented here demonstrate the importance of following up exome sequencing studies using additional datasets. The roles of ULK1 in autophagy and mTOR signalling strengthen the case that these pathways may be important in the pathophysiology of SCZ. The findings reported here await independent replication.
精神分裂症（SCZ）是一种严重的、高度可遗传的精神障碍。阐明该疾病的遗传结构将有助于更深入地理解潜在的神经生物学机制改变。本研究的目的是在患有SCZ的受试者中识别可能的病因变异。使用加权负担测试分析了来自瑞典的SCZ病例对照样本的外显子组序列数据，以寻找可能的病因变异。有提示性证据表明与UNC-51样激酶（ULK1）基因有关，并且观察到在瑞典SCZ病例中更常见的四个罕见变异，与肥胖病例相比，在UK10K SCZ病例中也更常见。在伦敦大学学院的1304例SCZ病例和1348例种族匹配对照的队列中对这三个错义变异和一个内含子变异进行了基因分型。所有四个变异在SCZ病例中比对照中更常见，将它们合并后得到的结果在P = 0.02时具有显著性。此处呈现的结果证明了使用额外数据集跟进外显子组测序研究的重要性。ULK1在自噬和mTOR信号传导中的作用进一步证明了这些途径可能在SCZ的病理生理学中起重要作用。此处报告的研究结果有待独立验证。
