Analysis of human neuronal cells carrying ASTN2 deletion: A cross-disorder risk variant of schizophrenia, autism spectrum disorder, and bipolar disorder

Abstract

Abstract Recent genetic studies have found common genomic risk variants among schizophrenia (SCZ), autism spectrum disorder (ASD), and bipolar disorder (BP), strongly suggesting the overlaps in their molecular and cellular mechanism. Our research group identified the variant in ASTN2 as one of the candidate risk factors across these psychiatric disorders by whole-genome copy number variation analysis. However, the alterations in the human neuronal cells resulting from ASTN2 variants identified in patients remain unknown. To address this, we used patient-derived and genome-edited iPS cells with ASTN2 deletion; cells were further differentiated into neuronal cells. A comprehensive gene expression analysis revealed that the expression level of ZNF558, a gene specifically expressed in human forebrain neural progenitor cells, was greatly reduced in ASTN2-deleted neuronal cells. Furthermore, the expression of the mitophagy-related gene SPATA18, which is repressed by ZNF558, and mitophagy activity were increased in ASTN2-deleted neuronal cells. These phenotypes were detected in both neuronal cells from patient-derived and genome-edited iPS cells with ASTN2 deletion. Our results suggest that ASTN2 deletion is related to the common pathogenic mechanism of SCZ, ASD, and BP by regulating mitophagy via ZNF558.