Cross-Disorder Analysis of Genic and Regulatory Copy Number Variations in Bipolar Disorder, Schizophrenia, and Autism Spectrum Disorder

Biol Psychiatry. 2022 Sep 1;92(5):362-374. doi: 10.1016/j.biopsych.2022.04.003. Epub 2022 Apr 22.


Background: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD).

Methods: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD.

Results: In genic CNVs, we found an increased burden of smaller (<100 kb) exonic deletions in BD, which contrasted with the highest burden of larger (>500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25-0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue.

Conclusions: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD.

Keywords: Autism spectrum disorder; Bipolar disorder; Chromatin biology; Copy number variation; Cross-disorder analysis; Schizophrenia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autism Spectrum Disorder* / genetics
  • Bipolar Disorder* / genetics
  • Chromatin
  • DNA Copy Number Variations / genetics
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study / methods
  • Humans
  • Schizophrenia* / genetics


  • Chromatin