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

• Published in: Molecular Psychiatry Vol. 23; no. 2; pp. 400 - 412
• Main Authors: Chang, H, Hoshina, N, Zhang, C, Ma, Y, Cao, H, Wang, Y, Wu, D-d, Bergen, S E, Landén, M, Hultman, C M, Preisig, M, Kutalik, Z, Castelao, E, Grigoroiu-Serbanescu, M, Forstner, A J, Strohmaier, J, Hecker, J, Schulze, T G, Müller-Myhsok, B, Reif, A, Mitchell, P B, Martin, N G, Schofield, P R, Cichon, S, Nöthen, M M, Walter, H, Erk, S, Heinz, A, Amin, N, van Duijn, C M, Meyer-Lindenberg, A, Tost, H, Xiao, X, Yamamoto, T, Rietschel, M, Li, M
• Format: Journal Article
• Language: English
• Published: London Springer Science and Business Media LLC 01.02.2018; Nature Publishing Group UK; Nature Publishing Group
• Subjects: 1312 Molecular Biology; 2738 Psychiatry and Mental health; 2804 Cellular and Molecular Neuroscience; 631/208; 631/378; 692/699/476/1333; 692/699/476/1414; Adult; Adult; Amygdala/physiopathology; Bipolar Disorder/genetics; Brain/physiopathology; Cadherins/genetics; Cadherins/metabolism; Cognition/physiology; Dendrites; Dendritic Spines; Depressive Disorder, Major/genetics; Female; Genetic Predisposition to Disease/genetics; Genotype; Humans; Male; Middle Aged; Mood Disorders/genetics; Neuronal Plasticity; Neurons; Personality/genetics; Polymorphism, Single Nucleotide/genetics; Risk Factors; Synapses/genetics; Synapses/metabolism; Alleles; Amygdala; Amygdala (Brain); Amygdala - physiopathology; Analysis; Behavioral Sciences; Biochemistry & Molecular Biology; Biological Psychology; bipolar affective-disorder; Bipolar Disorder; Bipolar Disorder - genetics; Brain; Brain - physiopathology; cadherin; Cadherins; Cadherins - genetics; Cadherins - metabolism; Cellular and Molecular Neuroscience; Cognition; Cognition & reasoning; Cognition - physiology; Cognitive ability; ddc:610; Dendrites; dendritic spine; Dendritic Spines; Depressive Disorder, Major; Depressive Disorder, Major - genetics; Development and progression; Disease susceptibility; educational-attainment; EMC NIHES-01-64-02; Emotional disorders; expression; Female; Gene expression; Genetic aspects; Genetic Predisposition to Disease; Genetic Predisposition to Disease - genetics; genome-wide association; Genotype; hippocampal structure; Humans; Male; Medicine; Medicine & Public Health; Mental depression; Middle Aged; Molecular Biology; Molekylärbiologi; Mood; Mood Disorders; Mood Disorders - genetics; Neuronal Plasticity; Neurons; Neuroplasticity; Neurosciences; Neurosciences & Neurology; Neurovetenskaper; Original; Original Article; pathology; Personality; Personality - genetics; Pharmacotherapy; Polymorphism, Single Nucleotide; Polymorphism, Single Nucleotide - genetics; Protocadherin; Psychiatry; Psychiatry and Mental health; Psykiatri; Risk Factors; schizophrenia; Single-nucleotide polymorphism; Structure; Structure-function relationships; superfamily; susceptibility; Synapses; Synapses - genetics; Synapses - metabolism; Synaptic plasticity; Transcription; unipolar depression
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2016.231

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.