Analysis of human neuronal cells carrying ASTN2 deletion: A cross-disorder risk variant of psychiatric disorders

Recent genetic studies have found common genomic risk variants among psychiatric disorders, 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 using genome-edited iPSC cells with the loss of function variants on both alleles 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. A total of 6 iPS cell lines, including healthy control (N=3) and homozygous ASTN2 deletion (N=3), were induced to neurosphere, respectively. Each of the healthy control and homozygous ASTN2 deletion iPS cell lines is the same clone and has a different number of passages.