title: Immune-related pathways including HLA-DRB1(∗)13:02 are associated with panic disorder.
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.
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Mihoko
authors.initials: M
authors.lastname: Shimada-Sugimoto
authors.affiliation: Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: totowa-psy@umin.org.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Otowa
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Miyagawa
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Seik-Soon
authors.initials: SS
authors.lastname: Khor
authors.affiliation: Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kashiwase
authors.affiliation: Department of Epidemiology and Public Health, Graduate School of Medicine, Yokohama City University, Kanagawa, Japan.
authors.forename: Nagisa
authors.initials: N
authors.lastname: Sugaya
authors.affiliation: Department of Psychiatry, Sakae Seijinkai Hospital, Kanagawa, Japan.
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Kawamura
authors.affiliation: Division for Environment, Health and Safety, The University of Tokyo, Tokyo, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Umekage
authors.affiliation: HLA Foundation Laboratory, Kyoto, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Kojima
authors.affiliation: HLA Foundation Laboratory, Kyoto, Japan.
authors.forename: Hiroh
authors.initials: H
authors.lastname: Saji
authors.affiliation: Department of Molecular Genetics, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Miyashita
authors.affiliation: Department of Molecular Genetics, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Ryozo
authors.initials: R
authors.lastname: Kuwano
authors.affiliation: Panic Disorder Research Center, Warakukai Med. Corp., Tokyo, Japan.
authors.forename: Hisanobu
authors.initials: H
authors.lastname: Kaiya
authors.affiliation: Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Kiyoto
authors.initials: K
authors.lastname: Kasai
authors.affiliation: Department of Psychiatry, Institute of Medical Life Science, Graduate School of Medicine, Mie University, Mie, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Tanii
authors.affiliation: Tokyo Metropolitan Matsuzawa Hospital, Tokyo, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Okazaki
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Katsushi
authors.initials: K
authors.lastname: Tokunaga
authors.affiliation: Department of Physical and Health Education, Graduate School of Education, The University of Tokyo, Tokyo, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Sasaki
mesh_terms: D000328:Adult; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D016584:Panic Disorder / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D059811:HLA-DRB1 Chains
keywords: Genome-wide association study; HLA-B; HLA-DRB1; Human Leukocyte Antigen; Immunity; Panic disorder; Pathway analysis