Multiple Rare Risk Coding Variants in Postsynaptic Density-Related Genes Associated With Schizophrenia Susceptibility

Tsung-Ming Hu; Ying-Chieh Wang; Chia-Liang Wu; Shih-Hsin Hsu; Hsin-Yao Tsai; Min-Chih Cheng

doi:10.3389/fgene.2020.524258

Multiple Rare Risk Coding Variants in Postsynaptic Density-Related Genes Associated With Schizophrenia Susceptibility

Front Genet. 2020 Dec 4:11:524258. doi: 10.3389/fgene.2020.524258. eCollection 2020.

Authors

Tsung-Ming Hu^{1

2}, Ying-Chieh Wang¹, Chia-Liang Wu^{1

3}, Shih-Hsin Hsu¹, Hsin-Yao Tsai¹, Min-Chih Cheng¹

Affiliations

¹ Department of Psychiatry, Yuli Branch, Taipei Veterans General Hospital, Hualien, Taiwan.
² Department of Future Studies and LOHAS Industry, Fo Guang University, Jiaosi, Taiwan.
³ Institute of Medical Sciences, Tzu Chi University, Hualien City, Taiwan.

Abstract

Objective: Schizophrenia is a chronic debilitating neurobiological disorder of aberrant synaptic connectivity and synaptogenesis. Postsynaptic density (PSD)-related proteins in N-methyl-D-aspartate receptor-postsynaptic signaling complexes are crucial to regulating the synaptic transmission and functions of various synaptic receptors. This study examined the role of PSD-related genes in susceptibility to schizophrenia.

Methods: We resequenced 18 genes encoding the disks large-associated protein (DLGAP), HOMER, neuroligin (NLGN), neurexin, and SH3 and multiple ankyrin repeat domains (SHANK) protein families in 98 schizophrenic patients with family psychiatric history using semiconductor sequencing. We analyzed the protein function of the identified rare schizophrenia-associated mutants via immunoblotting and immunocytochemistry.

Results: We identified 50 missense heterozygous mutations in 98 schizophrenic patients with family psychiatric history, and in silico analysis revealed some as damaging or pathological to the protein function. Ten missense mutations were absent from the dbSNP database, the gnomAD (non-neuro) dataset, and 1,517 healthy controls from Taiwan BioBank. Immunoblotting revealed eight missense mutants with altered protein expressions in cultured cells compared with the wild type.

Conclusion: Our findings suggest that PSD-related genes, especially the NLGN, SHANK, and DLGAP families, harbor rare functional mutations that might alter protein expression in some patients with schizophrenia, supporting contributing rare coding variants into the genetic architecture of schizophrenia.

Keywords: PSD gene; in vitro; rare mutation; resequencing; schizophrenia.