title: A genome-wide association study identifies two novel susceptibility loci and trans population polygenicity associated with bipolar disorder.
abstract: Genome-wide association studies (GWASs) have identified several susceptibility loci for bipolar disorder (BD) and shown that the genetic architecture of BD can be explained by polygenicity, with numerous variants contributing to BD. In the present GWAS (Phase I/II), which included 2964 BD and 61 887 control subjects from the Japanese population, we detected a novel susceptibility locus at 11q12.2 (rs28456, P=6.4 × 10-9), a region known to contain regulatory genes for plasma lipid levels (FADS1/2/3). A subsequent meta-analysis of Phase I/II and the Psychiatric GWAS Consortium for BD (PGC-BD) identified another novel BD gene, NFIX (Pbest=5.8 × 10-10), and supported three regions previously implicated in BD susceptibility: MAD1L1 (Pbest=1.9 × 10-9), TRANK1 (Pbest=2.1 × 10-9) and ODZ4 (Pbest=3.3 × 10-9). Polygenicity of BD within Japanese and trans-European-Japanese populations was assessed with risk profile score analysis. We detected higher scores in BD cases both within (Phase I/II) and across populations (Phase I/II and PGC-BD). These were defined by (1) Phase II as discovery and Phase I as target, or vice versa (for 'within Japanese comparisons', Pbest~10-29, R2~2%), and (2) European PGC-BD as discovery and Japanese BD (Phase I/II) as target (for 'trans-European-Japanese comparison,' Pbest~10-13, R2~0.27%). This 'trans population' effect was supported by estimation of the genetic correlation using the effect size based on each population (liability estimates~0.7). These results indicate that (1) two novel and three previously implicated loci are significantly associated with BD and that (2) BD 'risk' effect are shared between Japanese and European populations.
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ikeda
authors.affiliation: Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.|Laboratory for Omics Informatics, Omics Research Center, National Cerebral and Cardiovascular Center, Osaka, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kamatani
authors.affiliation: Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Okahisa
authors.affiliation: Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kunugi
authors.affiliation: Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Mori
authors.affiliation: Laboratory of Health Education, Graduate School of Education, the University of Tokyo, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Department of Psychiatry, Course of Integrated Brain Sciences, Medical Informatics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ohmori
authors.affiliation: Department of Psychiatry and Neurosciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Okamoto
authors.affiliation: Department of Psychiatry, Fukuoka University, Faculty of Medicine, Fukuoka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kawasaki
authors.affiliation: Department of Neuropsychiatry, Kochi Medical School, Kochi University, Nankoku, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Shimodera
authors.affiliation: Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kato
authors.affiliation: Department of Neuropsychiatry, Osaka Medical College, Takatsuki, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yoneda
authors.affiliation: Department of Psychiatry, University of Occupational and Environmental Health, Kitakyusyu, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Yoshimura
authors.affiliation: Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Iyo
authors.affiliation: Laboratory of Clinical Sequence, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Matsuda
authors.affiliation: Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Akiyama
authors.affiliation: Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ashikawa
authors.affiliation: Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kashiwase
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Tokunaga
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kondo
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Saito
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Shimasaki
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kawase
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kitajima
authors.affiliation: Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Matsuo
authors.affiliation: Center for Medical Cooperation, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Itokawa
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Someya
authors.affiliation: Department of Psychiatry, Nagoya University, Graduate School of Medicine, Nagoya, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Inada
authors.affiliation: Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Suita, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Hashimoto
authors.affiliation: Department of Psychiatry, Tokyo Medical University, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Mibu, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Akiyama
authors.affiliation: Department of Neuropsychiatry, Mie University, Graduate School of Medicine, Tsu, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Tanii
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Juntendo Graduate School of Medicine, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Arai
authors.affiliation: Department of Neuropsychiatry, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kanba
authors.affiliation: Department of Psychiatry, Nagoya University, Graduate School of Medicine, Nagoya, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Ozaki
authors.affiliation: Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Kusumi
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yoshikawa
authors.affiliation: RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Iwata
mesh_terms: D000328:Adult; D001714:Bipolar Disorder / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D000090943:Delta-5 Fatty Acid Desaturase; D044943:Fatty Acid Desaturases / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008875:Middle Aged; D020412:Multifactorial Inheritance / Q000235:genetics; D051839:NFI Transcription Factors / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D016207:Cytokines; D000090943:Delta-5 Fatty Acid Desaturase; C501384:MAD1L1 protein, human; D008562:Membrane Glycoproteins; D051839:NFI Transcription Factors; C000594474:NFIX protein, human; D009687:Nuclear Proteins; C576539:TENM4 protein, human; C112841:TRANK1 protein, human; D044943:Fatty Acid Desaturases; C000716847:FADS1 protein, human; C533241:FADS2 protein, human