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The genetic architecture of schizophrenia: review of large-scale genetic studies

Journal of Human Genetics volume 68, pages 175–182 (2023)Cite this article

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Abstract

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.

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Funding

This work was supported in part by research grants from the Japan Agency for Medical Research and Development (AMED) under grant numbers JP19km0405216, JP21wm0425007, JP21dm0207075, JP21dk0307103, JP21ak0101113, JP22dk0307113, and JP22tm0424222; and the Japan Society for the Promotion of Science (JSPS) KAKENHI under grant numbers 20K20602, 21H04815, 21H02848, 21K20866, and 22K15748.

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Authors and Affiliations

  1. Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Hidekazu Kato, Hiroki Kimura, Itaru Kushima, Nagahide Takahashi, Branko Aleksic & Norio Ozaki

  2. Medical Genomics Center, Nagoya University Hospital, Nagoya, Japan

    Itaru Kushima & Norio Ozaki

  3. Institute for Glyco-core Research (iGCORE), Nagoya University, Nagoya, Japan

    Norio Ozaki

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  1. Hidekazu Kato
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  2. Hiroki Kimura
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HK, HK, IK and NT wrote the article. BA and ON reviewed and edited the manuscript before submission.

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Correspondence to Branko Aleksic.

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HK, HK, IK, NT and BA declare no competing interest. NO has received research support or speakers’ honoraria from, or has served as a joint researcher with, or a consultant to, Sumitomo Dainippon, Eisai, Otsuka, KAITEKI, Mitsubishi Tanabe, Shionogi, Eli Lilly, Mochida, DAIICHI SANKYO, TSUMURA, Takeda, Meiji Seika Pharma, Kyowa, EA Pharma, Viatris, Kyowa Kirin, MSD, Janssen, Yoshitomi, Ricoh, Taisho, and Nippon Boehringer Ingelheim outside the submitted work.

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Kato, H., Kimura, H., Kushima, I. et al. The genetic architecture of schizophrenia: review of large-scale genetic studies. J Hum Genet 68, 175–182 (2023). https://doi.org/10.1038/s10038-022-01059-4

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