title: The protocadherin 17 gene affects cognition, personality, amygdala structure and function, synapse development and risk of major mood disorders.
abstract: Major mood disorders, which primarily include bipolar disorder and major depressive disorder, are the leading cause of disability worldwide and pose a major challenge in identifying robust risk genes. Here, we present data from independent large-scale clinical data sets (including 29 557 cases and 32 056 controls) revealing brain expressed protocadherin 17 (PCDH17) as a susceptibility gene for major mood disorders. Single-nucleotide polymorphisms (SNPs) spanning the PCDH17 region are significantly associated with major mood disorders; subjects carrying the risk allele showed impaired cognitive abilities, increased vulnerable personality features, decreased amygdala volume and altered amygdala function as compared with non-carriers. The risk allele predicted higher transcriptional levels of PCDH17 mRNA in postmortem brain samples, which is consistent with increased gene expression in patients with bipolar disorder compared with healthy subjects. Further, overexpression of PCDH17 in primary cortical neurons revealed significantly decreased spine density and abnormal dendritic morphology compared with control groups, which again is consistent with the clinical observations of reduced numbers of dendritic spines in the brains of patients with major mood disorders. Given that synaptic spines are dynamic structures which regulate neuronal plasticity and have crucial roles in myriad brain functions, this study reveals a potential underlying biological mechanism of a novel risk gene for major mood disorders involved in synaptic function and related intermediate phenotypes.
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China.
authors.forename: H
authors.initials: H
authors.lastname: Chang
authors.affiliation: Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan.|Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Hoshina
authors.affiliation: Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: C
authors.initials: C
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cognitive Neuroscience and Learning, IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
authors.forename: D-D
authors.initials: DD
authors.lastname: Wu
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Bergen
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.|Section of Psychiatry and Neurochemistry, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Landén
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: C M
authors.initials: CM
authors.lastname: Hultman
authors.affiliation: Department of Psychiatry, Centre Hospitalier Universitaire Vaudois, Prilly, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Preisig
authors.affiliation: Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.|Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Z
authors.initials: Z
authors.lastname: Kutalik
authors.affiliation: Department of Psychiatry, Centre Hospitalier Universitaire Vaudois, Prilly, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Castelao
authors.affiliation: Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
authors.forename: M
authors.initials: M
authors.lastname: Grigoroiu-Serbanescu
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: A J
authors.initials: AJ
authors.lastname: Forstner
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Strohmaier
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Institute of Genomic Mathematics, University of Bonn, Bonn, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Hecker
authors.affiliation: Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: T G
authors.initials: TG
authors.lastname: Schulze
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.|University of Liverpool, Institute of Translational Medicine, Liverpool, UK.
authors.forename: B
authors.initials: B
authors.lastname: Müller-Myhsok
authors.affiliation: Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Reif
authors.affiliation: School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.|Black Dog Institute, Sydney, NSW, Australia.
authors.forename: P B
authors.initials: PB
authors.lastname: Mitchell
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: N G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: Neuroscience Research Australia, Sydney, NSW, Australia.|School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
authors.forename: P R
authors.initials: PR
authors.lastname: Schofield
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.|Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, Basel, Switzerland.|Institute of Neuroscience and Medicine (INM-1), Structural and Functional Organization of the Brain, Genomic Imaging, Research Centre Jülich, Jülich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Cichon
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: M M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Department of Psychiatry and Psychotherapy, Universitätsmedizin Charité, Berlin, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Walter
authors.affiliation: Department of Psychiatry and Psychotherapy, Universitätsmedizin Charité, Berlin, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Erk
authors.affiliation: Department of Psychiatry and Psychotherapy, Universitätsmedizin Charité, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Heinz
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: Amin
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: C M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Meyer-Lindenberg
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Tost
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China.
authors.forename: X
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Rietschel
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China.
authors.forename: M
authors.initials: M
authors.lastname: Li
mesh_terms: D000328:Adult; D000679:Amygdala / Q000503:physiopathology; D001714:Bipolar Disorder / Q000235:genetics; D001921:Brain / Q000503:physiopathology; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D003071:Cognition / Q000502:physiology; D003712:Dendrites; D049229:Dendritic Spines; D003865:Major Depressive Disorder / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D019964:Mood Disorders / Q000235:genetics*; D009473:Neuronal Plasticity; D009474:Neurons; D010551:Personality / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D013569:Synapses / Q000235:genetics / Q000378:metabolism
chemical_list: D015820:Cadherins; C529349:PCDH17 protein, human