Kato Hidekazu, Kimura Hiroki, Kushima Itaru, Takahashi Nagahide, Aleksic Branko, Ozaki Norio
Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Medical Genomics Center, Nagoya University Hospital, Nagoya, Japan.
J Hum Genet. 2023 Mar;68(3):175-182. doi: 10.1038/s10038-022-01059-4. Epub 2022 Jul 12.
Schizophrenia is a complex and often chronic psychiatric disorder with high heritability. Diagnosis of schizophrenia is still made clinically based on psychiatric symptoms; no diagnostic tests or biomarkers are available. Pathophysiology-based diagnostic scheme and treatments are also not available. Elucidation of the pathogenesis is needed for development of pathology-based diagnostics and treatments. In the past few decades, genetic research has made substantial advances in our understanding of the genetic architecture of schizophrenia. Rare copy number variations (CNVs) and rare single-nucleotide variants (SNVs) detected by whole-genome CNV analysis and whole-genome/-exome sequencing analysis have provided the great advances. Common single-nucleotide polymorphisms (SNPs) detected by large-scale genome-wide association studies have also provided important information. Large-scale genetic studies have been revealed that both rare and common genetic variants play crucial roles in this disorder. In this review, we focused on CNVs, SNVs, and SNPs, and discuss the latest research findings on the pathogenesis of schizophrenia based on these genetic variants. Rare variants with large effect sizes can provide mechanistic hypotheses. CRISPR-based genetics approaches and induced pluripotent stem cell technology can facilitate the functional analysis of these variants detected in patients with schizophrenia. Recent advances in long-read sequence technology are expected to detect variants that cannot be detected by short-read sequence technology. Various studies that bring together data from common variant and transcriptomic datasets provide biological insight. These new approaches will provide additional insight into the pathophysiology of schizophrenia and facilitate the development of pathology-based therapeutics.
精神分裂症是一种复杂且往往为慢性的精神疾病，具有高度遗传性。精神分裂症的诊断目前仍基于临床精神症状进行；尚无诊断测试或生物标志物可用。基于病理生理学的诊断方案和治疗方法也不存在。要开发基于病理学的诊断方法和治疗手段，需要阐明其发病机制。在过去几十年里，基因研究在我们对精神分裂症基因结构的理解方面取得了重大进展。通过全基因组拷贝数变异（CNV）分析和全基因组/外显子组测序分析检测到的罕见拷贝数变异和罕见单核苷酸变异取得了巨大进展。大规模全基因组关联研究检测到的常见单核苷酸多态性（SNP）也提供了重要信息。大规模基因研究表明，罕见和常见基因变异在这种疾病中都起着关键作用。在本综述中，我们重点关注CNV、SNV和SNP，并基于这些基因变异讨论精神分裂症发病机制的最新研究结果。具有大效应量的罕见变异可以提供机制假说。基于CRISPR的遗传学方法和诱导多能干细胞技术可以促进对精神分裂症患者中检测到的这些变异的功能分析。长读长序列技术的最新进展有望检测到短读长序列技术无法检测到的变异。汇集来自常见变异和转录组数据集的数据的各种研究提供了生物学见解。这些新方法将为精神分裂症的病理生理学提供更多见解，并促进基于病理学的治疗方法的开发。
