Translational Study of Copy Number Variations in Schizophrenia.

Min-Chih Cheng,Wei-Hsien Chien,Chia-Hsiang Chen,Ting-Hsuan Fang,Yu-Shu Huang

doi:10.3390/ijms23010457

Abstract

Rare copy number variations (CNVs) are part of the genetics of schizophrenia; they are highly heterogeneous and personalized. The CNV Analysis Group of the Psychiatric Genomic Consortium (PGC) conducted a large-scale analysis and discovered that recurrent CNVs at eight genetic loci were pathogenic to schizophrenia, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.23, 15q13.3, distal 16p11.2, proximal 16p11.2, and 22q11.2. We adopted a two-stage strategy to translate this knowledge into clinical psychiatric practice. As a screening test, we first developed a real-time quantitative PCR (RT-qPCR) panel that simultaneously detected these pathogenic CNVs. Then, we tested the utility of this screening panel by investigating a sample of 557 patients with schizophrenia. Chromosomal microarray analysis (CMA) was used to confirm positive cases from the screening test. We detected and confirmed thirteen patients who carried CNVs at these hot loci, including two patients at 1q21.1, one patient at 7q11.2, three patients at 15q13.3, two patients at 16p11.2, and five patients at 22q11.2. The detection rate in this sample was 2.3%, and the concordance rate between the RT-qPCR test panel and CMA was 100%. Our results suggest that a two-stage approach is cost-effective and reliable in achieving etiological diagnosis for some patients with schizophrenia and improving the understanding of schizophrenia genetics.

Highlights

Schizophrenia is a complex mental disorder affecting approximately 1% of the general population worldwide
Copy number variations (CNVs) are genetic variations resulting from the rearrangements of DNA segments
For each target CNV locus, we designed an optimal pair of primers that could detect the dose changes in the gene encompassed by the target CNV

Summary

Introduction

Schizophrenia is a complex mental disorder affecting approximately 1% of the general population worldwide. Genetic factors play a major role in its etiology [1]. The genetic landscapes of schizophrenia include common variants with minimal clinical effects, rare variations with high penetrance and large clinical impact, and epigenomic dysregulation [1,2]. Copy number variations (CNVs) are genetic variations resulting from the rearrangements of DNA segments. Accumulating studies show that rare CNVs (including microduplications and microdeletions) contribute a significant part to the genetic etiology of schizophrenia [3,4]. Identifying the genetic bases of psychiatric disorders can aid in achieving the etiological diagnosis of patients with psychiatric disorders and may help elucidate the pathophysiology of psychiatric disorders and hopefully improve psychiatric treatment in the future [5,6]

Methods

Results

Conclusion