The Protocadherin 17 Gene Affects Cognition, Personality, Amygdala Structure and Function, Synapse Development and Risk of Major Mood Disorders
作者单位：Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province Kunming Institute of Zoology Cell Signal Unit Okinawa Institute of Science and Technology Graduate University State Key Laboratory of Cognitive Neuroscience and Learning IDG/McGovern Institute for Brain Research Beijing Normal University Department of Psychiatry and Psychotherapy Central Institute of Mental Health Medical Faculty Mannheim University of Heidelberg
会议名称：《中国神经科学学会第十二届全国学术会议》
会议日期：2017年
学科分类：1002[医学-临床医学] 100205[医学-精神病与精神卫生学] 10[医学]
关 键 词：PCDH17 mood disorders amygdala expression dendritic spines
摘 要：Objective: 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. Methods: An integrative analysis involving genetics, m RNA expression, cognitive performance, neuroimaging and neurobiology was performed. Results: We present data from independent large-scale clinical datasets（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 m RNA 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. Conclusions: Given that synaptic spines are dynamic structures which regulate neuronal plasticity and play 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.