Immune-related pathways including HLA-DRB1(∗)13:02 are associated with panic disorder

Mihoko Shimada-Sugimoto; Takeshi Otowa; Taku Miyagawa; Seik-Soon Khor; Koichi Kashiwase; Nagisa Sugaya; Yoshiya Kawamura; Tadashi Umekage; Hiroto Kojima; Hiroh Saji; Akinori Miyashita; Ryozo Kuwano; Hisanobu Kaiya; Kiyoto Kasai; Hisashi Tanii; Yuji Okazaki; Katsushi Tokunaga; Tsukasa Sasaki

doi:10.1016/j.bbi.2015.01.002

Immune-related pathways including HLA-DRB1(∗)13:02 are associated with panic disorder

Brain Behav Immun. 2015 May:46:96-103. doi: 10.1016/j.bbi.2015.01.002. Epub 2015 Jan 9.

Authors

Mihoko Shimada-Sugimoto¹, Takeshi Otowa², Taku Miyagawa¹, Seik-Soon Khor¹, Koichi Kashiwase³, Nagisa Sugaya⁴, Yoshiya Kawamura⁵, Tadashi Umekage⁶, Hiroto Kojima⁷, Hiroh Saji⁷, Akinori Miyashita⁸, Ryozo Kuwano⁸, Hisanobu Kaiya⁹, Kiyoto Kasai¹⁰, Hisashi Tanii¹¹, Yuji Okazaki¹², Katsushi Tokunaga¹, Tsukasa Sasaki¹³

Affiliations

¹ Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
² Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: totowa-psy@umin.org.
³ Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan.
⁴ Department of Epidemiology and Public Health, Graduate School of Medicine, Yokohama City University, Kanagawa, Japan.
⁵ Department of Psychiatry, Sakae Seijinkai Hospital, Kanagawa, Japan.
⁶ Division for Environment, Health and Safety, The University of Tokyo, Tokyo, Japan.
⁷ HLA Foundation Laboratory, Kyoto, Japan.
⁸ Department of Molecular Genetics, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan.
⁹ Panic Disorder Research Center, Warakukai Med. Corp., Tokyo, Japan.
¹⁰ Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
¹¹ Department of Psychiatry, Institute of Medical Life Science, Graduate School of Medicine, Mie University, Mie, Japan.
¹² Tokyo Metropolitan Matsuzawa Hospital, Tokyo, Japan.
¹³ Department of Physical and Health Education, Graduate School of Education, The University of Tokyo, Tokyo, Japan.

PMID: 25582808
DOI: 10.1016/j.bbi.2015.01.002

Abstract

Panic disorder (PD) is an anxiety disorder characterized by panic attacks and anticipatory anxiety. Both genetic and environmental factors are thought to trigger PD onset. Previously, we performed a genome-wide association study (GWAS) for PD and focused on candidate SNPs with the lowest P values. However, there seemed to be a number of polymorphisms which did not reach genome-wide significance threshold due to their low allele frequencies and odds ratios, even though they were truly involved in pathogenesis. Therefore we performed pathway analyses in order to overcome the limitations of conventional single-marker analysis and identify associated SNPs with modest effects. Each pathway analysis indicated that pathways related to immunity showed the strongest association with PD (DAVID, P=2.08×10(-6); i-GSEA4GWAS, P<10(-3); ICSNPathway, P<10(-3)). Based on the results of pathway analyses and the previously performed GWAS for PD, we focused on and investigated HLA-B and HLA-DRB1 as candidate susceptibility genes for PD. We typed HLA-B and HLA-DRB1 in 744 subjects with PD and 1418 control subjects. Patients with PD were significantly more likely to carry HLA-DRB1(∗)13:02 (P=2.50×10(-4), odds ratio=1.54). Our study provided initial evidence that HLA-DRB1(∗)13:02 and genes involved in immune-related pathways are associated with PD. Future studies are necessary to confirm these results and clarify the underlying mechanisms causing PD.

Keywords: Genome-wide association study; HLA-B; HLA-DRB1; Human Leukocyte Antigen; Immunity; Panic disorder; Pathway analysis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Female
Gene Frequency
Genetic Predisposition to Disease*
Genome-Wide Association Study
HLA-DRB1 Chains / genetics*
Haplotypes
Humans
Male
Middle Aged
Panic Disorder / genetics*
Polymorphism, Single Nucleotide*

Substances

HLA-DRB1 Chains