Genomic copy number variations in the risk of schizophrenia

Abstract

In the first half of this article, we will outline the large genomic copy number variants (CNVs) that are strongly implicated in the risk of schizophrenia. Although individual CNVs account for less than 1% of the patient population, some, such as the 22q11.2 deletion, the 3q29 deletion, and the 15q11‐q13 duplication, increase the risk of developing the disorder more than tenfold. These CNVs are involved not only in schizophrenia but also in the risk of neurodevelopmental disorders such as intellectual disability, autism spectrum disorder, and attention deficit hyperactivity disorder, making them cross‐disease risk variants. In the latter half of the article, we will introduce the ARHGAP10 gene, which we found to be associated with schizophrenia based on our CNV study. We found developmental abnormalities in ARHGAP10 variant based model mice and patient‐derived iPS cells. We hypothesize that the abnormal activation of RhoA and Rho kinase caused by the loss‐of‐function variant of ARHGAP10 gene underlines these abnormalities. We will describe our drug discovery research for schizophrenia targeting this signal.