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Mol Psychiatry. 2018 Feb;23(2):400-412. doi: 10.1038/mp.2016.231. Epub 2017 Jan 10.

The protocadherin 17 gene affects cognition, personality, amygdala structure and function, synapse development and risk of major mood disorders.

Author information

1
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.
2
Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan.
3
Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
4
Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
5
State Key Laboratory of Cognitive Neuroscience and Learning, IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China.
6
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
7
State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
8
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
9
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
10
Section of Psychiatry and Neurochemistry, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.
11
Department of Psychiatry, Centre Hospitalier Universitaire Vaudois, Prilly, Switzerland.
12
Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
13
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
14
Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
15
Institute of Human Genetics, University of Bonn, Bonn, Germany.
16
Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
17
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
18
Institute of Genomic Mathematics, University of Bonn, Bonn, Germany.
19
Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University Munich, Munich, Germany.
20
Max Planck Institute of Psychiatry, Munich, Germany.
21
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
22
University of Liverpool, Institute of Translational Medicine, Liverpool, UK.
23
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
24
School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
25
Black Dog Institute, Sydney, NSW, Australia.
26
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
27
Neuroscience Research Australia, Sydney, NSW, Australia.
28
School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
29
Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, Basel, Switzerland.
30
Institute of Neuroscience and Medicine (INM-1), Structural and Functional Organization of the Brain, Genomic Imaging, Research Centre Jülich, Jülich, Germany.
31
Department of Psychiatry and Psychotherapy, Universitätsmedizin Charité, Berlin, Germany.
32
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.

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.

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