title: Genome-Wide Association Study Identifies ZNF354C Variants Associated with Depression from Interferon-Based Therapy for Chronic Hepatitis C.
abstract: The therapeutic use of interferon (IFN) is known to cause depression that frequently interrupts treatment. To identify genetic variants associated with IFN-induced depression, we conducted a genome-wide association study (GWAS) of 224 Japanese chronic hepatitis C patients receiving IFN-based therapy in a multicenter prospective study and stratified them into two groups according to the Beck Depression Inventory, Second Edition (BDI-II) score. In the GWAS stage, we selected 42 candidate single nucleotide polymorphisms (SNPs) to perform replication analysis in an independent set of 160 subjects. The SNP rs1863918 in strong linkage disequilibrium with SNPs located around the Zinc finger 354C (ZNF354C) gene on chromosome 5 showed a significant association when the results of GWAS and replication were combined (odds ratio = 2.55, P = 7.89×10-8 in the allele frequency model), suggesting that the rs1863918 T allele was associated with IFN-induced depression. Furthermore, logistic regression analysis showed that rs1863918 T allele, a history of depression, and younger age were independent predictive factors for IFN-induced depression. Interestingly, western blotting and immunofluorescence showed that ZNF354C was highly expressed in the hippocampus in mice, a region implicated in the pathology of psychiatric symptoms. In conclusion, we identified rs1863918 as significantly associated with IFN-induced depression, and revealed that the candidate gene ZNF354C is highly expressed in the hippocampus of mice. Our data might be useful for elucidating the pathogenic mechanisms of depression induced by drugs including IFN.
authors.affiliation: Department of Virology & Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.|Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Matsunami
authors.affiliation: The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.|Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Nao
authors.initials: N
authors.lastname: Nishida
authors.affiliation: Department of Developmental and Regenerative Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Kaneko
authors.affiliation: Laboratory for DNA Data Analysis Center for Information Biology and DNA Data Bank of Japan, National Institute of Genetics, Mishima, Japan.
authors.forename: Kazuho
authors.initials: K
authors.lastname: Ikeo
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Licht
authors.initials: L
authors.lastname: Toyo-Oka
authors.affiliation: Department of Psychiatry, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takeuchi
authors.affiliation: Department of Virology & Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.|Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Matsuura
authors.affiliation: Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tamori
authors.affiliation: The Center for Liver Disease, Shin-Kokura Hospital, Kitakyushu, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Nomura
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yoshiji
authors.affiliation: Kohnodai Hospital, National Center for Global Health and Medicine, Ichikawa, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Imamura
authors.affiliation: Kohnodai Hospital, National Center for Global Health and Medicine, Ichikawa, Japan.
authors.forename: Naohiko
authors.initials: N
authors.lastname: Masaki
authors.affiliation: Kohnodai Hospital, National Center for Global Health and Medicine, Ichikawa, Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Hayakawa
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University, Kurume, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ide
authors.affiliation: Division of Gastroenterology and Hepatology, Ootakanomori Hospital, Kashiwa, Japan.
authors.forename: Noritomo
authors.initials: N
authors.lastname: Shimada
authors.affiliation: Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Fusao
authors.initials: F
authors.lastname: Ikeda
authors.affiliation: Division of Hepatology and Pancreatology, Kawasaki Medical College, Kurashiki, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Hino
authors.affiliation: Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Nishiguchi
authors.affiliation: Department of Gastroenterology and Hepatology, St. Marianna University School of Medicine, Kawasaki, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Okuse
authors.affiliation: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Nojiri
authors.affiliation: Department of Developmental and Regenerative Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Sawamoto
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 Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Joh
authors.affiliation: Department of Virology & Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Tanaka
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D003863:Depression / Q000139:chemically induced / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects*; D015810:Linkage Disequilibrium; D008297:Male; D051379:Mice; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects*; D020641:Polymorphism, Single Nucleotide; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: D016898:Interferon-alpha; D011994:Recombinant Proteins; D012097:Repressor Proteins; C485805:ZNF354C protein, human; D011092:Polyethylene Glycols; C100416:peginterferon alfa-2a