Whole-exome sequencing and gene-based rare variant association tests suggest that PLA2G4E might be a risk gene for panic disorder

Yoshiro Morimoto,Jürgen Deckert,T Mori ,Hiroki Ozawa,Katharina Domschke,Shintaro Yoshida,Mihoko Shimada-Sugimoto,Akira Kinoshita,Naohiro Kurotaki,Mamoru Tochigi,Katsushi Tokunaga,Tadashi Umekage,Takeshi Otowa,Hiroyuki Mishima,Yuji Okazaki,Tsukasa Sasaki,Christiane Ziegler,Naohiro Yamaguchi,Koh-Ichiro Yoshiura,Hisanobu Kaiya,Akira Imamura,Shinji Ono

doi:10.1038/s41398-017-0088-0

Abstract

Panic disorder (PD) is characterized by recurrent and unexpected panic attacks, subsequent anticipatory anxiety, and phobic avoidance. Recent epidemiological and genetic studies have revealed that genetic factors contribute to the pathogenesis of PD. We performed whole-exome sequencing on one Japanese family, including multiple patients with panic disorder, which identified seven rare protein-altering variants. We then screened these genes in a Japanese PD case–control group (384 sporadic PD patients and 571 controls), resulting in the detection of three novel single nucleotide variants as potential candidates for PD (chr15: 42631993, T>C in GANC; chr15: 42342861, G>T in PLA2G4E; chr20: 3641457, G>C in GFRA4). Statistical analyses of these three genes showed that PLA2G4E yielded the lowest p value in gene-based rare variant association tests by Efficient and Parallelizable Association Container Toolbox algorithms; however, the p value did not reach the significance threshold in the Japanese. Likewise, in a German case–control study (96 sporadic PD patients and 96 controls), PLA2G4E showed the lowest p value but again did not reach the significance threshold. In conclusion, we failed to find any significant variants or genes responsible for the development of PD. Nonetheless, our results still leave open the possibility that rare protein-altering variants in PLA2G4E contribute to the risk of PD, considering the function of this gene.

Highlights

Panic disorder (PD) is characterized by recurrent and unexpected panic attacks, subsequent anticipatory anxiety, and phobic avoidance
Whole-exome sequencing and Sanger sequencing We identified 127 functionally significant variants shared by the two affected individuals subjected to WES
In this study, we focused on rare protein-altering variants in a Japanese family, including multiple patients, with PD to identify genetic variants contributing to the risk of this disorder

Summary

Introduction

Panic disorder (PD) is characterized by recurrent and unexpected panic attacks, subsequent anticipatory anxiety, and phobic avoidance. Whole-exome sequencing (WES) is a powerful tool to detect genes causative of single-gene disorders, and. Regarding PD, to the best of our knowledge, only a few studies have explored genes causative of this condition using next-generation sequencing (NGS)[8,9,10]. To identify genes related to PD, we performed WES in a Japanese family including several members with PD and identified variants linked to this disorder in this family. After identifying the genes that were candidates for causing PD in this family, the frequencies of all variants of these genes were compared between larger groups of PD cases and controls not related to this family. We describe the results of NGS and the assessment of rare protein-altering variants of potential candidate genes in patients with PD and ethnically matched controls

Methods

Results

Conclusion