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.
| Original language | English |
|---|---|
| Pages (from-to) | 400-412 |
| Number of pages | 13 |
| Journal | Molecular Psychiatry |
| Volume | 23 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Feb 1 2018 |
Bibliographical note
Funding Information:We are grateful to all the voluntary donors of DNA samples in this study. We thank members of the Psychiatric Genomics Consortium, who shared the PGC GWAS data. This work was supported by CAS Pioneer Hundred Talents Program (to ML). This work was also supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med Programme (grant 01ZX1314A to SC and MMN, grant 01ZX1314G to MR). MMN is a member of the DFG-funded Excellence-Cluster ImmunoSensation. The study was also supported by the German Research Foundation (DFG; grant FOR2107, RI908/11-1 to MR, NO246/10-1 to MMN). The Romanian sample recruitment and genotyping was funded by UEFISCDI, Bucharest, Romania, grant no. 89/2012 to MGS and by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (grant 01ZX1314A to MMN and SC). Funding for the Swedish collection was provided by the Stanley Center for Psychiatric Research, Broad Institute from a grant from Stanley Medical Research Institute. We thank the Okinawa Institute of Science and Technology Graduate University for generous support to TY and NH. We also wish to thank the BBMRI.se and KI Biobank at Karolinska Institutet for professional biobank service. We are grateful to Sue O'Shea Ph.D., and Melvin McInnis MD, of the University of Michigan for providing detailed expression data on PCDH17, which was generated with the support of the Steven Schwartzberg Memorial Fund and Prechter Bipolar Research Fund. The ERF study as a part of EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant number 018947 (LSHG-CT-2006-01947) and also received funding from the European Community's Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F4-2007-201413 by the European Commission under the programme 'Quality of Life and Management of the Living Resources' of 5th Framework Programme (no. QLG2-CT-2002-01254). High-throughput analysis of the ERF data was supported by joint grant from The Netherlands Organization for Scientific Research and the Russian Foundation for Basic Research (NWO-RFBR 047.017.043). Exome sequencing was supported by the ZonMw grant (project 91111025). We are grateful to all study participants and their relatives, general practitioners and neurologists for their contributions and to P Veraart for her help in genealogy, J Vergeer for the supervision of the laboratory work and P. Snijders for his help in data collection. Najaf Amin is supported by the Hersenstichting Nederland (project number F2013(1)-28). The data in USA BPD sample used for the analyses described in this manuscript were obtained from dbGaP accession number phs000979.v1.p1 on May 25, 2016.
Funding Information:
We are grateful to all the voluntary donors of DNA samples in this study. We thank members of the Psychiatric Genomics Consortium, who shared the PGC GWAS data. This work was supported by CAS Pioneer Hundred Talents Program (to ML). This work was also supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med Programme (grant 01ZX1314A to SC and MMN, grant 01ZX1314G to MR). MMN is a member of the DFG-funded Excellence-Cluster ImmunoSensation. The study was also supported by the German Research Foundation (DFG; grant FOR2107, RI908/11-1 to MR, NO246/10-1 to MMN). The Romanian sample recruitment and genotyping was funded by UEFISCDI, Bucharest, Romania, grant no. 89/2012 to MGS and by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (grant 01ZX1314A to MMN and SC). Funding for the Swedish collection was provided by the Stanley Center for Psychiatric Research, Broad Institute from a grant from Stanley Medical Research Institute. We thank the Okinawa Institute of Science and Technology Graduate University for generous support to TY and NH. We also wish to thank the BBMRI.se and KI Biobank at Karolinska Institutet for professional biobank service. We are grateful to Sue O’Shea Ph.D., and Melvin McInnis MD, of the University of Michigan for providing detailed expression data on PCDH17, which was generated with the support of the Steven Schwartzberg Memorial Fund and Prechter Bipolar Research Fund. The ERF study as a part of EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant number 018947 (LSHG-CT-2006-01947) and also received funding from the European Community's Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F4-2007-201413 by the European Commission under the programme ‘Quality of Life and Management of the Living Resources’ of 5th Framework Programme (no. QLG2-CT-2002-01254). High-throughput analysis of the ERF data was supported by joint grant from The Netherlands Organization for Scientific Research and the Russian Foundation for Basic Research (NWO-RFBR 047.017.043). Exome sequencing was supported by the ZonMw grant (project 91111025). We are grateful to all study participants and their relatives, general practitioners and neurologists for their contributions and to P Veraart for her help in genealogy, J Vergeer for the supervision of the laboratory work and P. Snijders for his help in data collection. Najaf Amin is supported by the Hersenstichting Nederland (project number F2013(1)-28). The data in USA BPD sample used for the analyses described in this manuscript were obtained from dbGaP accession number phs000979.v1.p1 on May 25, 2016.
ASJC Scopus Subject Areas
- Molecular Biology
- Cellular and Molecular Neuroscience
- Psychiatry and Mental health
