Long-read sequencing reveals structural variants underlying schizophrenia in the Chinese population

key source of human genomic diversity and a major contributor to disease susceptibility. Recent studies have highlighted the critical roles of rare SVs, including copy-number variations and tandem repeat expansions, in the genetic architecture and mechanism of schizophrenia. However, conventional short-read sequencing has limited power to detect large SVs, particularly those in the repetitive regions of the genome.

To overcome these limitations, researchers at Fudan University established a long-read sequencing (LRS)–based cohort of 141 Chinese schizophrenia cases (termed CN_SCZ), and developed a comprehensive analytical framework to identify potentially pathogenic SVs in both unique and repetitive genomic regions. This study refined the genomic landscape of SVs in schizophrenia, providing new insights into its genetic mechanisms.

Highlights of this article:
The analysis revealed that the schizophrenia-specific SVs were significantly enriched in genomic hotspots previously associated with schizophrenia. For example, a striking enrichment was observed within the 16p12.1 region, a locus repeatedly linked to schizophrenia and other neurodevelopmental phenotypes. Interestingly, many of these schizophrenia-specific SVs seemed to have emerged from tandem repeat expansions in both coding and regulatory regions—areas notoriously difficult to resolve with short-read sequencing.

Using their novel pathogenicity scoring tool designed for both coding and noncoding SVs, termed SVJudge, researchers identified 358 potentially pathogenic SVs (ppSVs), many of which overlapped with genomic regulatory elements and repeat-rich regions. Functional analyses revealed that 197 ppSVs significantly altered transcription factor binding activity, potentially disturbing regulatory networks active in brain tissues and affecting multiple known schizophrenia risk genes and therapeutic targets. For example, insertions were detected in the promoter regions of CBL and RAC1, which are genes known to be critical for neurodevelopment, and they were predicted to enhance local transcription-factor binding and impact known schizophrenia drug targets.

Further analyses prioritized 82 candidate risk genes, including 59 previously reported schizophrenia genes and 23 newly implicated ones. These genes were significantly enriched in neurodevelopmental and synaptic functional pathways, underscoring their relevance to the disease pathology.

Summary and Outlook:
This work established among the first cohort-scale long-read sequencing resources for schizophrenia, and offered a powerful framework to uncover disease-relevant structural variants and decipher their gene regulatory impacts. The findings refined the genetic architecture of schizophrenia and provided new insights for future therapeutic explorations.

This work was supported by the National Key R&D Program of China (2023YFF1204800, 2020YFA0712403); the National Natural Science Foundation of China (T2225015, 62433008, 32200537), the Shanghai Science and Technology Commission Program (23JS1410100, 24JS2810100), the Shanghai Municipal Education Commission (24KXZNA11), the Key Science and Technology Project of Hainan Province (ZDYF2024SHFZ058), the Major Project of Guangzhou National Laboratory (GZNL2024A01003). The related results have been published in Science Bulletin.

Zhengyu An, a Ph.D student from the School of Biomedical Engineering at Fudan University, is the first author of this paper. Professor Xing-Ming Zhao from the School of Biomedical Engineering at Fudan University and Associate Professor Jingqi Chen from the Institute of Science and Technology for Brain-inspired Intelligence at Fudan University are the co-corresponding authors.

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