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

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 con-trasted with the highest burden of larger (.500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neuro-developmental 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 neuro-developmental 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.

Automated summary

This study aimed to compare the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). High-resolution CNV data from 8708 Japanese samples were used to perform the largest cross-disorder analysis of genic and regulatory CNVs in these disorders. The results showed differences in CNV burden, characteristics of CNVs associated with neurodevelopmental disorders, and regulatory CNVs between BD and SCZ/ASD. However, there were also shared molecular mechanisms, particularly in chromatin biology. The study identified specific risk genes for BD that could contribute to understanding the pathogenesis of the disorder.