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1. Neurotransmission-related gene expression in the frontal pole is altered in subjects with bipolar disorder and schizophrenia

Author

Adriana M. Medina, Megan Hastings Hagenauer, David M. Krolewski, Evan Hughes, Liam Cannon Thew Forrester, David M. Walsh, Maria Waselus, Evelyn Richardson, Cortney A. Turner, P. Adolfo Sequeira, Preston M. Cartagena, Robert C. Thompson, Marquis P. Vawter, Blynn G. Bunney, Richard M. Myers, Jack D. Barchas, Francis S. Lee, Alan F. Schatzberg, William E. Bunney, Huda Akil, and Stanley J. Watson

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract The frontal pole (Brodmann area 10, BA10) is the largest cytoarchitectonic region of the human cortex, performing complex integrative functions. BA10 undergoes intensive adolescent grey matter pruning prior to the age of onset for bipolar disorder (BP) and schizophrenia (SCHIZ), and its dysfunction is likely to underly aspects of their shared symptomology. In this study, we investigated the role of BA10 neurotransmission-related gene expression in BP and SCHIZ. We performed qPCR to measure the expression of 115 neurotransmission-related targets in control, BP, and SCHIZ postmortem samples (n = 72). We chose this method for its high sensitivity to detect low-level expression. We then strengthened our findings by performing a meta-analysis of publicly released BA10 microarray data (n = 101) and identified sources of convergence with our qPCR results. To improve interpretation, we leveraged the unusually large database of clinical metadata accompanying our samples to explore the relationship between BA10 gene expression, therapeutics, substances of abuse, and symptom profiles, and validated these findings with publicly available datasets. Using these convergent sources of evidence, we identified 20 neurotransmission-related genes that were differentially expressed in BP and SCHIZ in BA10. These results included a large diagnosis-related decrease in two important therapeutic targets with low levels of expression, HTR2B and DRD4, as well as other findings related to dopaminergic, GABAergic and astrocytic function. We also observed that therapeutics may produce a differential expression that opposes diagnosis effects. In contrast, substances of abuse showed similar effects on BA10 gene expression as BP and SCHIZ, potentially amplifying diagnosis-related dysregulation.

Published
2023
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3. Jack D. Barchas, MD, Recognized for Contributions to Psychiatry and Neuroscience

Subjects
College faculty -- Achievements and awards, Medical centers, Neurosciences, Psychiatric hospitals, Psychiatrists -- Achievements and awards, General interest, News, opinion and commentary, National Academy of Medicine
Abstract

NEW YORK, NY: Marquis Who's Who Ventures LLC has issued the following press release: Dr. Barchas is the Barklie McKee Henry Professor and Chair of the Department of Psychiatry, and [...]

Published
2018

4. Jack D. Barchas, MD, Recognized for Contributions to Psychiatry and Neuroscience

Subjects
Medical centers, Medical policy, Neurosciences, College teachers -- Achievements and awards, Psychiatrists -- Achievements and awards, Business, News, opinion and commentary
Abstract

As a scientist and scientific leader, he is credited with fundamental studies of brain neurotransmitters as well as significant educational roles, major editing and writing, and transforming clinical and health [...]

Published
2018

5. Mitochondria DNA copy number, mitochondria DNA total somatic deletions, Complex I activity, synapse number, and synaptic mitochondria number are altered in schizophrenia and bipolar disorder

Author

Sujan C. Das, Brooke E. Hjelm, Brandi L. Rollins, Adolfo Sequeira, Ling Morgan, Audrey A. Omidsalar, Alan F. Schatzberg, Jack D. Barchas, Francis S. Lee, Richard M. Myers, Stanley J. Watson, Huda Akil, William E. Bunney, and Marquis P. Vawter

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Mitochondrial dysfunction is a neurobiological phenomenon implicated in the pathophysiology of schizophrenia and bipolar disorder that can synergistically affect synaptic neurotransmission. We hypothesized that schizophrenia and bipolar disorder share molecular alterations at the mitochondrial and synaptic levels. Mitochondria DNA (mtDNA) copy number (CN), mtDNA common deletion (CD), mtDNA total deletion, complex I activity, synapse number, and synaptic mitochondria number were studied in the postmortem human dorsolateral prefrontal cortex (DLPFC), superior temporal gyrus (STG), primary visual cortex (V1), and nucleus accumbens (NAc) of controls (CON), and subjects with schizophrenia (SZ), and bipolar disorder (BD). The results showed (i) the mtDNA CN is significantly higher in DLPFC of both SZ and BD, decreased in the STG of BD, and unaltered in V1 and NAc of both SZ and BD; (ii) the mtDNA CD is significantly higher in DLPFC of BD while unaltered in STG, V1, and NAc of both SZ and BD; (iii) The total deletion burden is significantly higher in DLPFC in both SZ and BD while unaltered in STG, V1, and NAc of SZ and BD; (iv) Complex I activity is significantly lower in DLPFC of both SZ and BD, which is driven by the presence of medications, with no alteration in STG, V1, and NAc. In addition, complex I protein concentration, by ELISA, was decreased across three cortical regions of SZ and BD subjects; (v) The number of synapses is decreased in DLPFC of both SZ and BD, while the synaptic mitochondria number was significantly lower in female SZ and female BD compared to female controls. Overall, these findings will pave the way to understand better the pathophysiology of schizophrenia and bipolar disorder for therapeutic interventions.

Published
2022
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6. Profile of Director Jack D. Barchas, M.D. of Brain & Behavior Research Foundation

Subjects
Brain, Physicians, College faculty, Brain research, General interest, News, opinion and commentary
Abstract

New York, NY: Following is the Profile of Director Jack D. Barchas, M.D. of Brain & Behavior Research Foundation: Founding Member of the Scientific Council Chair and Barklie McKee Henry [...]

Published
2016

10. WEDDINGS; Jack D. Barchas, Rosemary A. Stevens

Subjects
Yale University, Weddings
Abstract

Rosemary A. Stevens, the dean of the School of Arts and Sciences at the University of Pennsylvania in Philadelphia, was married on Tuesday to Jack D. Barchas, a professor and […]

Published
1994

12. The Third Editor of the ARCHIVES—Jack D. Barchas, MD

Author

Michael D. Springer and George D. Lundberg

Subjects
Psychiatry and Mental health, medicine.medical_specialty, Arts and Humanities (miscellaneous), Internship, media_common.quotation_subject, medicine, Psychology, Psychiatry, Classics, Freedman, Irony, media_common
Abstract

THE JULY 1993 issue of the Archives of General Psychiatry contained a sad irony for friends of the journal. That issue carried a memorial to the founding editor of theArchives, Roy R. Grinker, Sr, MD, written by his successor, Daniel X. Freedman, MD. 1 In that same issue was the news that Dr Freedman had died suddenly. We are pleased to announce the appointment of the third editor of the Archives of General Psychiatry : Jack D. Barchas, MD. Jack David Barchas is an outstanding choice to succeed the two eminent psychiatrists who have edited the journal. A graduate of Yale University School of Medicine, Dr Barchas completed his medical internship at the University of Chicago Pritzker School of Medicine and his psychiatric residency at Stanford University. From 1966 to 1990 he was based at Stanford where he rose to professor of psychiatry and behavioral sciences, director of the

Published
1994
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13. Post-mortem molecular profiling of three psychiatric disorders

Author

Ryne C. Ramaker, Kevin M. Bowling, Brittany N. Lasseigne, Megan H. Hagenauer, Andrew A. Hardigan, Nicholas S. Davis, Jason Gertz, Preston M. Cartagena, David M. Walsh, Marquis P. Vawter, Edward G. Jones, Alan F. Schatzberg, Jack D. Barchas, Stanley J. Watson, Blynn G. Bunney, Huda Akil, William E. Bunney, Jun Z. Li, Sara J. Cooper, and Richard M. Myers

Subjects
Schizophrenia, Bipolar disorder, Major depressive disorder, RNA sequencing, Metabolomics, EGR1, Medicine, Genetics, QH426-470
Abstract

Abstract Background Psychiatric disorders are multigenic diseases with complex etiology that contribute significantly to human morbidity and mortality. Although clinically distinct, several disorders share many symptoms, suggesting common underlying molecular changes exist that may implicate important regulators of pathogenesis and provide new therapeutic targets. Methods We performed RNA sequencing on tissue from the anterior cingulate cortex, dorsolateral prefrontal cortex, and nucleus accumbens from three groups of 24 patients each diagnosed with schizophrenia, bipolar disorder, or major depressive disorder, and from 24 control subjects. We identified differentially expressed genes and validated the results in an independent cohort. Anterior cingulate cortex samples were also subjected to metabolomic analysis. ChIP-seq data were used to characterize binding of the transcription factor EGR1. Results We compared molecular signatures across the three brain regions and disorders in the transcriptomes of post-mortem human brain samples. The most significant disease-related differences were in the anterior cingulate cortex of schizophrenia samples compared to controls. Transcriptional changes were assessed in an independent cohort, revealing the transcription factor EGR1 as significantly down-regulated in both cohorts and as a potential regulator of broader transcription changes observed in schizophrenia patients. Additionally, broad down-regulation of genes specific to neurons and concordant up-regulation of genes specific to astrocytes was observed in schizophrenia and bipolar disorder patients relative to controls. Metabolomic profiling identified disruption of GABA levels in schizophrenia patients. Conclusions We provide a comprehensive post-mortem transcriptome profile of three psychiatric disorders across three brain regions. We highlight a high-confidence set of independently validated genes differentially expressed between schizophrenia and control patients in the anterior cingulate cortex and integrate transcriptional changes with untargeted metabolite profiling.

Published
2017
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14. Genetic Overlap Between Alzheimer’s Disease and Bipolar Disorder Implicates the MARK2 and VAC14 Genes

Author

Ole Kristian Drange, Olav Bjerkehagen Smeland, Alexey A. Shadrin, Per Ivar Finseth, Aree Witoelar, Oleksandr Frei, Psychiatric Genomics Consortium Bipolar Disorder Working Group, Yunpeng Wang, Sahar Hassani, Srdjan Djurovic, Anders M. Dale, Ole A. Andreassen, Eli A Stahl, Gerome Breen, Andreas J Forstner, Andrew McQuillin, Stephan Ripke, Vassily Trubetskoy, Manuel Mattheisen, Jonathan R I Coleman, Heìleìna A Gaspar, Christiaan A de Leeuw, Stacy Steinberg, Jennifer M Whitehead Pavlides, Maciej Trzaskowski, Tune H Pers, Peter A Holmans, Liam Abbott, Esben Agerbo, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Thomas D Als, Adebayo Anjorin, Verneri Antilla, Swapnil Awasthi, Judith A Badner, Marie Bækvad-Hansen, Jack D Barchas, Nicholas Bass, Michael Bauer, Richard Belliveau, Sarah E Bergen, Carsten Bøcker Pedersen, Erlend Bøen, Marco Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Jonas Bybjerg-Grauholm, William Byerley, Miquel Casas, Felecia Cerrato, Pablo Cervantes, Kimberly Chambert, Alexander W Charney, Danfeng Chen, Claire Churchhouse, Toni-Kim Clarke, William Coryell, David W Craig, Cristiana Cruceanu, David Curtis, Piotr M Czerski, Anders M Dale, Simone de Jong, Franziska Degenhardt, Jurgen Del-Favero, J Raymond DePaulo, Amanda L Dobbyn, Ashley Dumont, Torbjørn Elvsåshagen, Valentina Escott-Price, Chun Chieh Fan, Sascha B Fischer, Matthew Flickinger, Tatiana M Foroud, Liz Forty, Josef Frank, Christine Fraser, Nelson B Freimer, Louise Friseìn, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Marianne Giørtz Pedersen, Jaqueline Goldstein, Scott D Gordon, Katherine Gordon-Smith, Elaine K Green, Melissa J Green, Tiffany A Greenwood, Jakob Grove, Weihua Guan, Joseì Guzman Parra, Marian L Hamshere, Martin Hautzinger, Urs Heilbronner, Stefan Herms, Maria Hipolito, Per Hoffmann, Dominic Holland, Laura Huckins, Steìphane Jamain, Jessica S Johnson, Anders Jureìus, Radhika Kandaswamy, Robert Karlsson, James L Kennedy, Sarah Kittel-Schneider, Sarah V Knott, James A Knowles, Manolis Kogevinas, Anna C Koller, Ralph Kupka, Catharina Lavebratt, Jacob Lawrence, William B Lawson, Markus Leber, Phil H Lee, Shawn E Levy, Jun Z Li, Chunyu Liu, Susanne Lucae, Anna Maaser, Donald J MacIntyre, Pamela B Mahon, Wolfgang Maier, Lina Martinsson, Steve McCarroll, Peter McGuffin, Melvin G McInnis, James D McKay, Helena Medeiros, Sarah E Medland, Fan Meng, Lili Milani, Grant W Montgomery, Derek W Morris, Thomas W Mühleisen, Niamh Mullins, Hoang Nguyen, Caroline M Nievergelt, Annelie Nordin Adolfsson, Evaristus A Nwulia, Claire O’Donovan, Loes M Olde Loohuis, Anil P S Ori, Lilijana Oruc, Urban Ösby, Roy H Perlis, Amy Perry, Andrea Pfennig, James B Potash, Shaun M Purcell, Eline J Regeer, Andreas Reif, Ceìline S Reinbold, John P Rice, Fabio Rivas, Margarita Rivera, Panos Roussos, Douglas M Ruderfer, Euijung Ryu, Cristina Saìnchez-Mora, Alan F Schatzberg, William A Scheftner, Nicholas J Schork, Cynthia Shannon Weickert, Tatyana Shehktman, Paul D Shilling, Engilbert Sigurdsson, Claire Slaney, Olav B Smeland, Janet L Sobell, Christine Søholm Hansen, Anne T Spijker, David St Clair, Michael Steffens, John S Strauss, Fabian Streit, Jana Strohmaier, Szabolcs Szelinger, Robert C Thompson, Thorgeir E Thorgeirsson, Jens Treutlein, Helmut Vedder, Weiqing Wang, Stanley J Watson, Thomas W Weickert, Stephanie H Witt, Simon Xi, Wei Xu, Allan H Young, Peter Zandi, Peng Zhang, Sebastian Zollner, Rolf Adolfsson, Ingrid Agartz, Martin Alda, Lena Backlund, Bernhard T Baune, Frank Bellivier, Wade H Berrettini, Joanna M Biernacka, Douglas H R Blackwood, Michael Boehnke, Anders D Børglum, Aiden Corvin, Nicholas Craddock, Mark J Daly, Udo Dannlowski, ToÞnu Esko, Bruno Etain, Mark Frye, Janice M Fullerton, Elliot S Gershon, Michael Gill, Fernando Goes, Maria Grigoroiu-Serbanescu, Joanna Hauser, David M Hougaard, Christina M Hultman, Ian Jones, Lisa A Jones, Reneì S Kahn, George Kirov, Mikael Landeìn, Marion Leboyer, Cathryn M Lewis, Qingqin S Li, Jolanta Lissowska, Nicholas G Martin, Fermin Mayoral, Susan L McElroy, Andrew M McIntosh, Francis J McMahon, Ingrid Melle, Andres Metspalu, Philip B Mitchell, Gunnar Morken, Ole Mors, Preben Bo Mortensen, Bertram Müller-Myhsok, Richard M Myers, Benjamin M Neale, Vishwajit Nimgaonkar, Merete Nordentoft, Markus M Nöthen, Michael C O’Donovan, Ketil J Oedegaard, Michael J Owen, Sara A Paciga, Carlos Pato, Michele T Pato, Danielle Posthuma, Josep Antoni Ramos-Quiroga, Marta Ribaseìs, Marcella Rietschel, Guy A Rouleau, Martin Schalling, Peter R Schofield, Thomas G Schulze, Alessandro Serretti, Jordan W Smoller, Hreinn Stefansson, Kari Stefansson, Eystein Stordal, Patrick F Sullivan, Gustavo Turecki, Arne E Vaaler, Eduard Vieta, John B Vincent, Thomas Werge, John I Nurnberger, Naomi R Wray, Arianna Di Florio, Howard J Edenberg, Sven Cichon, Roel A Ophoff, Laura J Scott, Ole A Andreassen, John Kelsoe, and Pamela Sklar

Subjects
Alzheimer’s disease, bipolar disorder, GWAS, pleiotropy, cognitive symptoms, affective symptoms, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Background: Alzheimer’s disease (AD) and bipolar disorder (BIP) are complex traits influenced by numerous common genetic variants, most of which remain to be detected. Clinical and epidemiological evidence suggest that AD and BIP are related. However, it is not established if this relation is of genetic origin. Here, we applied statistical methods based on the conditional false discovery rate (FDR) framework to detect genetic overlap between AD and BIP and utilized this overlap to increase the power to identify common genetic variants associated with either or both traits.Methods: We obtained genome wide association studies data from the International Genomics of Alzheimer’s Project part 1 (17,008 AD cases and 37,154 controls) and the Psychiatric Genetic Consortium Bipolar Disorder Working Group (20,352 BIP cases and 31,358 controls). We used conditional QQ-plots to assess overlap in common genetic variants between AD and BIP. We exploited the genetic overlap to re-rank test-statistics for AD and BIP and improve detection of genetic variants using the conditional FDR framework.Results: Conditional QQ-plots demonstrated a polygenic overlap between AD and BIP. Using conditional FDR, we identified one novel genomic locus associated with AD, and nine novel loci associated with BIP. Further, we identified two novel loci jointly associated with AD and BIP implicating the MARK2 gene (lead SNP rs10792421, conjunctional FDR = 0.030, same direction of effect) and the VAC14 gene (lead SNP rs11649476, conjunctional FDR = 0.022, opposite direction of effect).Conclusion: We found polygenic overlap between AD and BIP and identified novel loci for each trait and two jointly associated loci. Further studies should examine if the shared loci implicating the MARK2 and VAC14 genes could explain parts of the shared and distinct features of AD and BIP.

Published
2019
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16. Large Common Mitochondrial DNA Deletions Are Associated with a Mitochondrial SNP T14798C Near the 3′ Breakpoints

Author

Brooke E. Hjelm, Christian Ramiro, Brandi L. Rollins, Audrey A. Omidsalar, Daniel S. Gerke, Sujan C. Das, Adolfo Sequeira, Ling Morgan, Alan F. Schatzberg, Jack D. Barchas, Francis S. Lee, Richard M. Myers, Stanley J. Watson, Huda Akil, William E. Bunney, and Marquis P. Vawter

Subjects
General Medicine
Abstract

Introduction: Large somatic deletions of mitochondrial DNA (mtDNA) accumulate with aging in metabolically active tissues such as the brain. We have cataloged the breakpoints and frequencies of large mtDNA deletions in the human brain. Methods: We quantified 112 high-frequency mtDNA somatic deletions across four human brain regions with the Splice-Break2 pipeline. In addition, we utilized PLINK/Seq to test the association of mitochondrial genotypes with the abundance of these high-frequency mtDNA deletions. A conservative p value threshold of 5E−08 was used to find the significant loci. Results: One mtDNA SNP (T14798C) was significantly associated with mtDNA deletions in two brain regions, the dorsolateral prefrontal cortex (DLPFC) and the superior temporal gyrus. Since the DLPFC showed the most robust association between T14798C and two deletion breakpoints (7816–14807 and 5462–14807), this association was tested in the DLPFC of a replication sample and validated the first results. Incorporating the C allele at 14,798 bp increased the perfect/imperfect length of the repeat at the 3′ breakpoint of the two associated deletions. Conclusion: This is the first study to identify the association of mtDNA SNP with large mtDNA deletions in the human brain. The T14798C allele located in the MT-CYB gene is a common polymorphism that occurs in several mitochondrial haplogroups. We hypothesize that the T14798C association with two deletions occurs by extending the repeat length around the 3′ deletion breakpoints. This simple mechanism suggests that mtDNA SNPs can affect the mitochondrial genome structure, especially in brain where high levels of reactive oxygen species lead to deletion accumulation with aging.

Published
2022
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17. Inference of cell type content from human brain transcriptomic datasets illuminates the effects of age, manner of death, dissection, and psychiatric diagnosis.

Author

Megan Hastings Hagenauer, Anton Schulmann, Jun Z Li, Marquis P Vawter, David M Walsh, Robert C Thompson, Cortney A Turner, William E Bunney, Richard M Myers, Jack D Barchas, Alan F Schatzberg, Stanley J Watson, and Huda Akil

Subjects
Medicine, Science
Abstract

Psychiatric illness is unlikely to arise from pathology occurring uniformly across all cell types in affected brain regions. Despite this, transcriptomic analyses of the human brain have typically been conducted using macro-dissected tissue due to the difficulty of performing single-cell type analyses with donated post-mortem brains. To address this issue statistically, we compiled a database of several thousand transcripts that were specifically-enriched in one of 10 primary cortical cell types in previous publications. Using this database, we predicted the relative cell type content for 833 human cortical samples using microarray or RNA-Seq data from the Pritzker Consortium (GSE92538) or publicly-available databases (GSE53987, GSE21935, GSE21138, CommonMind Consortium). These predictions were generated by averaging normalized expression levels across transcripts specific to each cell type using our R-package BrainInABlender (validated and publicly-released on github). Using this method, we found that the principal components of variation in the datasets strongly correlated with the predicted neuronal/glial content of the samples. This variability was not simply due to dissection-the relative balance of brain cell types appeared to be influenced by a variety of demographic, pre- and post-mortem variables. Prolonged hypoxia around the time of death predicted increased astrocytic and endothelial gene expression, illustrating vascular upregulation. Aging was associated with decreased neuronal gene expression. Red blood cell gene expression was reduced in individuals who died following systemic blood loss. Subjects with Major Depressive Disorder had decreased astrocytic gene expression, mirroring previous morphometric observations. Subjects with Schizophrenia had reduced red blood cell gene expression, resembling the hypofrontality detected in fMRI experiments. Finally, in datasets containing samples with especially variable cell content, we found that controlling for predicted sample cell content while evaluating differential expression improved the detection of previously-identified psychiatric effects. We conclude that accounting for cell type can greatly improve the interpretability of transcriptomic data.

Published
2018
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18. Neurotransmission-Related Gene Expression in the Frontal Pole (Brodmann Area 10) is Altered in Subjects with Bipolar Disorder and Schizophrenia

Author

Adriana M. Medina, Megan Hastings Hagenauer, David M. Krolewski, Evan Hughes, Liam Cannon Thew Forrester, David M. Walsh, Maria Waselus, Evelyn Richardson, Cortney A. Turner, P. Adolfo Sequeira, Preston M. Cartagena, Robert C. Thompson, Marquis P. Vawter, Blynn G. Bunney, Richard M. Myers, Jack D. Barchas, Francis S.Y. Lee, Alan F. Schatzberg, William E. Bunney, Huda Akil, and Stanley J. Watson

Abstract

Brodmann Area 10 (BA10) is the largest cytoarchitectonic region of the human cortex, performing complex integrative functions. BA10 undergoes intensive adolescent grey matter pruning around the average age of onset for Bipolar disorder (BP) and Schizophrenia (SCHIZ), and its dysfunction is likely to underly aspects of their shared symptomology. In this study, we investigated the role of BA10 neurotransmission-related gene expression in BP and SCHIZ. We performed qPCR to measure the expression of 115 neurotransmission-related targets in control, BP, and SCHIZ post-mortem samples (n=72). We chose this method for its high sensitivity to detect low-level expression. We then bolstered our findings by performing a meta-analysis of publicly-released BA10 microarray data (n=101) and identified sources of convergence with our qPCR results. To improve interpretation, we compiled an unusually large database of clinical metadata for our samples. We used this data to explore the relationship between BA10 gene expression, therapeutics, substances of abuse, and symptom profiles, and validated these findings with publicly-available datasets. Using these convergent sources of evidence, we identified 20 neurotransmission-related genes that were differentially expressed in BP and SCHIZ in BA10. These results included a large diagnosis-related decrease in two important therapeutic targets with low-levels of expression, HTR2B and DRD4, as well as other findings related to dopaminergic, GABA-ergic and astrocytic function. We also observed that therapeutics may produce differential expression that opposes the effects of diagnosis. In contrast, substances of abuse showed similar effects on BA10 gene expression as BP and SCHIZ, potentially amplifying diagnosis-related dysregulation.

Published
2022
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19. Rare coding variants in ten genes confer substantial risk for schizophrenia

Author

Tarjinder Singh, Timothy Poterba, David Curtis, Huda Akil, Mariam Al Eissa, Jack D. Barchas, Nicholas Bass, Tim B. Bigdeli, Gerome Breen, Evelyn J. Bromet, Peter F. Buckley, William E. Bunney, Jonas Bybjerg-Grauholm, William F. Byerley, Sinéad B. Chapman, Wei J. Chen, Claire Churchhouse, Nicholas Craddock, Caroline M. Cusick, Lynn DeLisi, Sheila Dodge, Michael A. Escamilla, Saana Eskelinen, Ayman H. Fanous, Stephen V. Faraone, Alessia Fiorentino, Laurent Francioli, Stacey B. Gabriel, Diane Gage, Sarah A. Gagliano Taliun, Andrea Ganna, Giulio Genovese, David C. Glahn, Jakob Grove, Mei-Hua Hall, Eija Hämäläinen, Henrike O. Heyne, Matti Holi, David M. Hougaard, Daniel P. Howrigan, Hailiang Huang, Hai-Gwo Hwu, René S. Kahn, Hyun Min Kang, Konrad J. Karczewski, George Kirov, James A. Knowles, Francis S. Lee, Douglas S. Lehrer, Francesco Lescai, Dolores Malaspina, Stephen R. Marder, Steven A. McCarroll, Andrew M. McIntosh, Helena Medeiros, Lili Milani, Christopher P. Morley, Derek W. Morris, Preben Bo Mortensen, Richard M. Myers, Merete Nordentoft, Niamh L. O’Brien, Ana Maria Olivares, Dost Ongur, Willem H. Ouwehand, Duncan S. Palmer, Tiina Paunio, Digby Quested, Mark H. Rapaport, Elliott Rees, Brandi Rollins, F. Kyle Satterstrom, Alan Schatzberg, Edward Scolnick, Laura J. Scott, Sally I. Sharp, Pamela Sklar, Jordan W. Smoller, Janet L. Sobell, Matthew Solomonson, Eli A. Stahl, Christine R. Stevens, Jaana Suvisaari, Grace Tiao, Stanley J. Watson, Nicholas A. Watts, Douglas H. Blackwood, Anders D. Børglum, Bruce M. Cohen, Aiden P. Corvin, Tõnu Esko, Nelson B. Freimer, Stephen J. Glatt, Christina M. Hultman, Andrew McQuillin, Aarno Palotie, Carlos N. Pato, Michele T. Pato, Ann E. Pulver, David St. Clair, Ming T. Tsuang, Marquis P. Vawter, James T. Walters, Thomas M. Werge, Roel A. Ophoff, Patrick F. Sullivan, Michael J. Owen, Michael Boehnke, Michael C. O’Donovan, Benjamin M. Neale, Mark J. Daly, Psychiatry, HUS Psychiatry, Clinicum, University of Helsinki, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Department of Psychiatry, Centre of Excellence in Complex Disease Genetics, Research Programs Unit, and Aarno Palotie / Principal Investigator

Subjects
Multidisciplinary, Schizophrenia/genetics, MUTATIONS, Receptors, N-Methyl-D-Aspartate/genetics, Genetic Predisposition to Disease/genetics, 3112 Neurosciences, ASSOCIATION, Neurodevelopmental Disorders/genetics, Receptors, N-Methyl-D-Aspartate, INDIVIDUALS, Neurodevelopmental Disorders, Case-Control Studies, Mutation, Schizophrenia, Humans, Genetic Predisposition to Disease, Exome, 3111 Biomedicine, BURDEN
Abstract

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3–50, P < 2.14 × 10−6) and 32 genes at a false discovery rate of 1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach.

Published
2022
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20. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

Author

Gabriëlla A.M. Blokland, Jakob Grove, Chia-Yen Chen, Chris Cotsapas, Stuart Tobet, Robert Handa, David St Clair, Todd Lencz, Bryan J. Mowry, Sathish Periyasamy, Murray J. Cairns, Paul A. Tooney, Jing Qin Wu, Brian Kelly, George Kirov, Patrick F. Sullivan, Aiden Corvin, Brien P. Riley, Tõnu Esko, Lili Milani, Erik G. Jönsson, Aarno Palotie, Hannelore Ehrenreich, Martin Begemann, Agnes Steixner-Kumar, Pak C. Sham, Nakao Iwata, Daniel R. Weinberger, Pablo V. Gejman, Alan R. Sanders, Joseph D. Buxbaum, Dan Rujescu, Ina Giegling, Bettina Konte, Annette M. Hartmann, Elvira Bramon, Robin M. Murray, Michele T. Pato, Jimmy Lee, Ingrid Melle, Espen Molden, Roel A. Ophoff, Andrew McQuillin, Nicholas J. Bass, Rolf Adolfsson, Anil K. Malhotra, Nicholas G. Martin, Janice M. Fullerton, Philip B. Mitchell, Peter R. Schofield, Andreas J. Forstner, Franziska Degenhardt, Sabrina Schaupp, Ashley L. Comes, Manolis Kogevinas, José Guzman-Parra, Andreas Reif, Fabian Streit, Lea Sirignano, Sven Cichon, Maria Grigoroiu-Serbanescu, Joanna Hauser, Jolanta Lissowska, Fermin Mayoral, Bertram Müller-Myhsok, Beata Świątkowska, Thomas G. Schulze, Markus M. Nöthen, Marcella Rietschel, John Kelsoe, Marion Leboyer, Stéphane Jamain, Bruno Etain, Frank Bellivier, John B. Vincent, Martin Alda, Claire O’Donovan, Pablo Cervantes, Joanna M. Biernacka, Mark Frye, Susan L. McElroy, Laura J. Scott, Eli A. Stahl, Mikael Landén, Marian L. Hamshere, Olav B. Smeland, Srdjan Djurovic, Arne E. Vaaler, Ole A. Andreassen, Bernhard T. Baune, Tracy Air, Martin Preisig, Rudolf Uher, Douglas F. Levinson, Myrna M. Weissman, James B. Potash, Jianxin Shi, James A. Knowles, Roy H. Perlis, Susanne Lucae, Dorret I. Boomsma, Brenda W.J.H. Penninx, Jouke-Jan Hottenga, Eco J.C. de Geus, Gonneke Willemsen, Yuri Milaneschi, Henning Tiemeier, Hans J. Grabe, Alexander Teumer, Sandra Van der Auwera, Uwe Völker, Steven P. Hamilton, Patrik K.E. Magnusson, Alexander Viktorin, Divya Mehta, Niamh Mullins, Mark J. Adams, Gerome Breen, Andrew M. McIntosh, Cathryn M. Lewis, David M. Hougaard, Merete Nordentoft, Ole Mors, Preben B. Mortensen, Thomas Werge, Thomas D. Als, Anders D. Børglum, Tracey L. Petryshen, Jordan W. Smoller, Jill M. Goldstein, Stephan Ripke, Benjamin M. Neale, James T.R. Walters, Kai-How Farh, Peter A. Holmans, Phil Lee, Brendan Bulik-Sullivan, David A. Collier, Hailiang Huang, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Richard A. Belliveau, Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberly D. Chambert, Raymond C.K. Chan, Ronald Y.L. Chen, Eric Y.H. Chen, Wei Cheng, Eric F.C. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, David Curtis, Michael Davidson, Kenneth L. Davis, Jurgen Del Favero, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H. Fanous, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Giulio Genovese, Lyudmila Georgieva, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, Masashi Ikeda, Inge Joa, Antonio Julià, René S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kähler, Claudine Laurent, Jimmy Lee Chee Keong, S. Hong Lee, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Carmel M. Loughland, Jan Lubinski, Jouko Lönnqvist, Milan Macek, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Sandra Meier, Carin J. Meijer, Bela Melegh, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Vihra Milanova, Younes Mokrab, Derek W. Morris, Kieran C. Murphy, Inez Myin-Germeys, Mari Nelis, Igor Nenadic, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Eadbhard O’Callaghan, Colm O’Dushlaine, F. Anthony O’Neill, Sang-Yun Oh, Ann Olincy, Line Olsen, Jim Van Os, Christos Pantelis, George N. Papadimitriou, Sergi Papiol, Elena Parkhomenko, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietiläinen, Jonathan Pimm, Andrew J. Pocklington, John Powell, Alkes Price, Ann E. Pulver, Shaun M. Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander L. Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Ulrich Schall, Christian R. Schubert, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Hon-Cheong So, Chris C.A. Spencer, Hreinn Stefansson, Stacy Steinberg, Elisabeth Stogmann, Richard E. Straub, Eric Strengman, Jana Strohmaier, T. Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Svrakic, Jin P. Szatkiewicz, Erik Söderman, Srinivas Thirumalai, Draga Toncheva, Sarah Tosato, Juha Veijola, John Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer, Nigel M. Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily H.M. Wong, Brandon K. Wormley, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Naomi R. Wray, Kari Stefansson, Peter M. Visscher, Douglas H.R. Blackwood, Ariel Darvasi, Enrico Domenici, Michael Gill, Hugh Gurling, Christina M. Hultman, Assen V. Jablensky, Kenneth S. Kendler, Jo Knight, Qingqin S. Li, Jianjun Liu, Steven A. McCarroll, Jennifer L. Moran, Michael J. Owen, Carlos N. Pato, Danielle Posthuma, Pamela Sklar, Jens R. Wendland, Mark J. Daly, Michael C. O’Donovan, Peter Donnelly, Ines Barroso, Jenefer M. Blackwell, Matthew A. Brown, Juan P. Casas, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh S. Markus, Christopher G. Mathew, Colin N.A. Palmer, Robert Plomin, Anna Rautanen, Stephen J. Sawcer, Richard C. Trembath, Ananth C. Viswanathan, Nicholas W. Wood, Gavin Band, Céline Bellenguez, Colin Freeman, Eleni Giannoulatou, Garrett Hellenthal, Richard Pearson, Matti Pirinen, Amy Strange, Zhan Su, Damjan Vukcevic, Cordelia Langford, Hannah Blackburn, Suzannah J. Bumpstead, Serge Dronov, Sarah Edkins, Matthew Gillman, Emma Gray, Rhian Gwilliam, Naomi Hammond, Sarah E. Hunt, Alagurevathi Jayakumar, Jennifer Liddle, Owen T. McCann, Simon C. Potter, Radhi Ravindrarajah, Michelle Ricketts, Avazeh Tashakkori-Ghanbaria, Matthew Waller, Paul Weston, Pamela Whittaker, Sara Widaa, Mark I. McCarthy, Maria J. Arranz, Steven Bakker, Stephan Bender, Benedicto Crespo-Facorro, Jeremy Hall, Conrad Iyegbe, Stephen Lawrie, Kuang Lin, Don H. Linszen, Ignacio Mata, Muriel Walshe, Matthias Weisbrod, Durk Wiersma, Vassily Trubetskoy, Yunpeng Wang, Jonathan R.I. Coleman, Héléna A. Gaspar, Christiaan A. de Leeuw, Jennifer M. Whitehead Pavlides, Maciej Trzaskowski, Enda M. Byrne, Liam Abbott, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Adebayo Anjorin, Verneri Antilla, Swapnil Awasthi, Judith A. Badner, Marie Bækvad-Hansen, Jack D. Barchas, Nicholas Bass, Michael Bauer, Richard Belliveau, Carsten Bøcker Pedersen, Erlend Bøen, Marco P. Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Jonas Bybjerg-Grauholm, Miquel Casas, Felecia Cerrato, Kimberly Chambert, Alexander W. Charney, Danfeng Chen, Claire Churchhouse, Toni-Kim Clarke, William Coryell, David W. Craig, Cristiana Cruceanu, Piotr M. Czerski, Anders M. Dale, Simone de Jong, Jurgen Del-Favero, J. Raymond DePaulo, Amanda L. Dobbyn, Ashley Dumont, Torbjørn Elvsåshagen, Chun Chieh Fan, Sascha B. Fischer, Matthew Flickinger, Tatiana M. Foroud, Liz Forty, Christine Fraser, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Marianne Giørtz Pedersen, Jaqueline Goldstein, Scott D. Gordon, Katherine Gordon-Smith, Elaine K. Green, Melissa J. Green, Tiffany A. Greenwood, Weihua Guan, Martin Hautzinger, Urs Heilbronner, Maria Hipolito, Dominic Holland, Laura Huckins, Jessica S. Johnson, Radhika Kandaswamy, Robert Karlsson, Sarah Kittel-Schneider, Anna C. Koller, Ralph Kupka, Catharina Lavebratt, Jacob Lawrence, William B. Lawson, Markus Leber, Phil H. Lee, Shawn E. Levy, Jun Z. Li, Chunyu Liu, Anna Maaser, Donald J. MacIntyre, Pamela B. Mahon, Lina Martinsson, Steve McCarroll, Peter McGuffin, Melvin G. McInnis, James D. McKay, Helena Medeiros, Sarah E. Medland, Fan Meng, Grant W. Montgomery, Thomas W. Mühleisen, Hoang Nguyen, Caroline M. Nievergelt, Annelie Nordin Adolfsson, Evaristus A. Nwulia, Claire O'Donovan, Loes M. Olde Loohuis, Anil P.S. Ori, Lilijana Oruc, Urban Ösby, Amy Perry, Andrea Pfennig, Eline J. Regeer, Céline S. Reinbold, John P. Rice, Fabio Rivas, Margarita Rivera, Euijung Ryu, Cristina Sánchez-Mora, Alan F. Schatzberg, William A. Scheftner, Nicholas J. Schork, Cynthia Shannon Weickert, Tatyana Shehktman, Paul D. Shilling, Claire Slaney, Janet L. Sobell, Christine Søholm Hansen, Anne T. Spijker, Michael Steffens, John S. Strauss, Szabolcs Szelinger, Robert C. Thompson, Thorgeir E. Thorgeirsson, Jens Treutlein, Helmut Vedder, Weiqing Wang, Stanley J. Watson, Thomas W. Weickert, Simon Xi, Wei Xu, Allan H. Young, Peter Zandi, Peng Zhang, Sebastian Zöllner, Abdel Abdellaoui, Tracy M. Air, Till F.M. Andlauer, Silviu-Alin Bacanu, Aartjan T.F. Beekman, Elisabeth B. Binder, Julien Bryois, Henriette N. Buttenschøn, Na Cai, Enrique Castelao, Jane Hvarregaard Christensen, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Gregory E. Crawford, Gail Davies, Ian J. Deary, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Jerome C. Foo, Fernando S. Goes, Lynsey S. Hall, Thomas F. Hansen, Ian B. Hickie, Georg Homuth, Carsten Horn, David M. Howard, Marcus Ising, Rick Jansen, Ian Jones, Lisa A. Jones, Eric Jorgenson, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Dean F. MacKinnon, Robert M. Maier, Jonathan Marchini, Hamdi Mbarek, Patrick McGrath, Christel M. Middeldorp, Evelin Mihailov, Francis M. Mondimore, Sara Mostafavi, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O'Reilly, Hogni Oskarsson, Jodie N. Painter, Roseann E. Peterson, Wouter J. Peyrot, Giorgio Pistis, Jorge A. Quiroz, Per Qvist, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Stanley I. Shyn, Grant C.B. Sinnamon, Johannes H. Smit, Daniel J. Smith, Katherine E. Tansey, Henning Teismann, Wesley Thompson, Pippa A. Thomson, Matthew Traylor, André G. Uitterlinden, Daniel Umbricht, Albert M. van Hemert, Shantel Marie Weinsheimer, Jürgen Wellmann, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Volker Arolt, Klaus Berger, Udo Dannlowski, Katharina Domschke, Caroline Hayward, Andrew C. Heath, Stefan Kloiber, Glyn Lewis, Pamela AF. Madden, Patrik K. Magnusson, Preben Bo Mortensen, Michael C. O'Donovan, Sara A. Paciga, Nancy L. Pedersen, David J. Porteous, Catherine Schaefer, Henry Völzke, Marco Bortolato, Janita Bralten, Cynthia M. Bulik, Christie L. Burton, Caitlin E. Carey, Lea K. Davis, Laramie E. Duncan, Howard J. Edenberg, Lauren Erdman, Stephen V. Faraone, Slavina B. Goleva, Wei Guo, Christopher Hübel, Laura M. Huckins, Ekaterina A. Khramtsova, Joanna Martin, Carol A. Mathews, Elise Robinson, Eli Stahl, Barbara E. Stranger, Michela Traglia, Raymond K. Walters, Lauren A. Weiss, Stacey J. Winham, Yin Yao, Kristjar Skajaa, Markus Nöthen, Michael Owen, Robert H. Yolken, Niels Plath, Jonathan Mill, Daniel Geschwind, Psychiatry 1, RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, Centre of Excellence in Complex Disease Genetics, Research Programme of Molecular Medicine, Research Programs Unit, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Functional Genomics, Biological Psychology, APH - Mental Health, APH - Methodology, Sociology and Social Gerontology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Blokland, Gabriella AM, Grove, Jakob, Chen, Chia Yen, Cotsapas, Chris, Tobet, Stuart, Handa, Robert, Lee, Sang Hong, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium, iPSYCH, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), Child and Adolescent Psychiatry / Psychology, Adult Psychiatry, ANS - Complex Trait Genetics, and ANS - Mood, Anxiety, Psychosis, Stress & Sleep

Subjects
0301 basic medicine, Male, Bipolar Disorder, Schizophrenia/genetics, LD SCORE REGRESSION, Genome-wide association study, 0302 clinical medicine, Receptors, SCHIZOPHRENIA, Psychotic Disorders/genetics, KYNURENINE PATHWAY METABOLISM, Genetics, RISK, Sex Characteristics, Vascular Endothelial Growth Factor, Bipolar Disorder/genetics, Major/genetics, Single Nucleotide, AFFECTIVE STIMULI IMPACT, Schizophrenia, Sulfurtransferases, Major depressive disorder, Female, Depressive Disorder, Major/genetics, Bipolar disorder, Locus (genetics), Genomics, Biology, Polymorphism, Single Nucleotide, Article, DYSPHORIC MOOD, 03 medical and health sciences, Sex differences, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Polymorphism, GENOME-WIDE ASSOCIATION, Genotype-by-sex interaction, Biological Psychiatry, Depressive Disorder, Major, Depressive Disorder, GENDER-DIFFERENCES, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], PARAVENTRICULAR NUCLEUS, 3112 Neurosciences, Endothelial Cells, MAJOR DEPRESSION, medicine.disease, Genetic architecture, 030104 developmental biology, Mood, Receptors, Vascular Endothelial Growth Factor, Psychotic Disorders, 3111 Biomedicine, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Contains fulltext : 248656.pdf (Publisher’s version ) (Closed access) BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10(-8)), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10(-6)) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10(-7); rs73033497, p = 8.8 × 10(-7); rs7914279, p = 6.4 × 10(-7)), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10(-7)) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10(-7)), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10(-7)) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.

Published
2022
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27. Mitochondrial mutations in subjects with psychiatric disorders.

Author

Adolfo Sequeira, Brandi Rollins, Christophe Magnan, Mannis van Oven, Pierre Baldi, Richard M Myers, Jack D Barchas, Alan F Schatzberg, Stanley J Watson, Huda Akil, William E Bunney, and Marquis P Vawter

Subjects
Medicine, Science
Abstract

A considerable body of evidence supports the role of mitochondrial dysfunction in psychiatric disorders and mitochondrial DNA (mtDNA) mutations are known to alter brain energy metabolism, neurotransmission, and cause neurodegenerative disorders. Genetic studies focusing on common nuclear genome variants associated with these disorders have produced genome wide significant results but those studies have not directly studied mtDNA variants. The purpose of this study is to investigate, using next generation sequencing, the involvement of mtDNA variation in bipolar disorder, schizophrenia, major depressive disorder, and methamphetamine use. MtDNA extracted from multiple brain regions and blood were sequenced (121 mtDNA samples with an average of 8,800x coverage) and compared to an electronic database containing 26,850 mtDNA genomes. We confirmed novel and rare variants, and confirmed next generation sequencing error hotspots by traditional sequencing and genotyping methods. We observed a significant increase of non-synonymous mutations found in individuals with schizophrenia. Novel and rare non-synonymous mutations were found in psychiatric cases in mtDNA genes: ND6, ATP6, CYTB, and ND2. We also observed mtDNA heteroplasmy in brain at a locus previously associated with schizophrenia (T16519C). Large differences in heteroplasmy levels across brain regions within subjects suggest that somatic mutations accumulate differentially in brain regions. Finally, multiplasmy, a heteroplasmic measure of repeat length, was observed in brain from selective cases at a higher frequency than controls. These results offer support for increased rates of mtDNA substitutions in schizophrenia shown in our prior results. The variable levels of heteroplasmic/multiplasmic somatic mutations that occur in brain may be indicators of genetic instability in mtDNA.

Published
2015
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28. Electrophysiological evaluation of extracellular spermine and alkaline pH on synaptic human GABAA receptors

Author

D. Pandya, Francis S. Lee, S.J. Watson, E. Delbruck, Huda Akil, Adolfo Sequeira, Marquis P. Vawter, Richard M. Myers, Schatzberg, A. Yassine, Jack D. Barchas, Agenor Limon, and William E. Bunney

Subjects
0301 basic medicine, Diazepam binding, GABAA receptor, Spermine, Long-term potentiation, Inhibitory postsynaptic potential, Cell biology, lcsh:RC321-571, 03 medical and health sciences, Cellular and Molecular Neuroscience, Psychiatry and Mental health, chemistry.chemical_compound, 030104 developmental biology, 0302 clinical medicine, chemistry, Extracellular, Premovement neuronal activity, Polyamine, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, 030217 neurology & neurosurgery, Biological Psychiatry
Abstract

Polyamines have fundamental roles in brain homeostasis as key modulators of cellular excitability. Several studies have suggested alterations in polyamine metabolism in stress related disorders, suicide, depression, and neurodegeneration, making the pharmacological modulation of polyamines a highly appealing therapeutic strategy. Polyamines are small aliphatic molecules that can modulate cationic channels involved in neuronal excitability. Previous indirect evidence has suggested that polyamines can modulate anionic GABAA receptors (GABAARs), which mediate inhibitory signaling and provide a direct route to reduce hyperexcitability. Here, we attempted to characterize the effect that spermine, the polyamine with the strongest reported effect on GABAARs, has on human postmortem native GABAARs. We microtransplanted human synaptic membranes from the dorsolateral prefrontal cortex of four cases with no history of mental or neurological disorders, and directly recorded spermine effects on ionic GABAARs responses on microtransplanted oocytes. We show that in human synapses, inhibition of GABAARs by spermine was better explained by alkalization of the extracellular solution. Additionally, spermine had no effect on the potentiation of GABA-currents by diazepam, indicating that even if diazepam binding is enhanced by spermine, it does not translate to changes in functional activity. Our results clearly demonstrate that while extracellular spermine does not have direct effects on human native synaptic GABAARs, spermine-mediated shifts of pH inhibit GABAARs. Potential spermine-mediated increase of pH in synapses in vivo may therefore participate in increased neuronal activity observed during physiological and pathological states, and during metabolic alterations that increase the release of spermine to the extracellular milieu.

Published
2019
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29. Altered choroid plexus gene expression in major depressive disorder

Author

Cortney Ann Turner, Robert C Thompson, William eBunney, Alan F Schatzberg, Jack D Barchas, Richard M Myers, Huda eAkil, and Stanley J Watson

Subjects
Brain, Cytoskeleton, Depression, Hippocampus, mRNA, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Given the emergent interest in biomarkers for mood disorders, we assessed gene expression in the choroid plexus, the region that produces cerebrospinal fluid (CSF), in individuals with major depressive disorder (MDD). Genes that are expressed in the choroid plexus (CP) can be secreted into the CSF and may be potential biomarker candidates. Given that we have previously shown that fibroblast growth factor family members are differentially expressed in post-mortem brain of subjects with MDD and the CP is a known source of growth factors in the brain, we posed the question whether growth factor dysregulation would be found in the CP of subjects with MDD. We performed laser capture microscopy of the choroid plexus at the level of the hippocampus in subjects with MDD and psychiatrically normal controls. We then extracted, amplified, labeled and hybridized the cRNA to Illumina BeadChips to assess gene expression. In controls, the most highly abundant known transcript was transthyretin. Moreover, half of the 14 most highly expressed transcripts in controls encode ribosomal proteins. Using BeadStudio software, we identified 169 transcripts differentially expressed (p< 0.05) between control and MDD samples. Using pathway analysis we noted that the top network altered in subjects with MDD included multiple members of the transforming growth factor-beta (TGFβ) pathway. Quantitative real-time PCR (qRT-PCR) confirmed downregulation of several transcripts that interact with the extracellular matrix in subjects with MDD. These results suggest that there may be an altered cytoskeleton in the choroid plexus in MDD subjects that may lead to a disrupted blood-CSF-brain barrier.

Published
2014
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32. G Protein-Linked Signaling Pathways in Bipolar and Major Depressive Disorders

Author

Hiroaki eTomita, Mary E Ziegler, Helen B Kim, Simon J Evans, Prabhakara V Choudary, Jun Z Li, Fan eMeng, Manhong eDai, Charles R Neal, Richard M Myers, Terry P Speed, Jack D Barchas, Alan F Schatzberg, Stanley J Watson, Huda eAkil, Edward G Jones, William E Bunney, and Marquis P Vawter

Subjects
Microarray, Effectors, postmortem brain, G-protein, G-protein coupled receptor (GPCR), G-protein linked signaling, Genetics, QH426-470
Abstract

The G-protein linked signaling system (GPLS) comprises a large number of G-proteins, G protein-coupled receptors (GPCRs), GPCR ligands, and downstream effector molecules. G-proteins interact with both GPCRs and downstream effectors such as cyclic adenosine monophosphate (cAMP), phosphatidylinositols, and ion channels. The GPLS is implicated in the pathophysiology and pharmacology of both major depressive disorder (MDD) and bipolar disorder (BPD). This study evaluated whether GPLS is altered at the transcript level. The gene expression in the dorsolateral prefrontal (DLPFC) and anterior cingulate (ACC) were compared from MDD, BPD, and control subjects using Affymetrix Gene Chips and real time quantitative PCR. High quality brain tissue was used in the study to control for confounding effects of agonal events, tissue pH, RNA integrity, gender, and age. GPLS signaling transcripts were altered especially in the ACC of BPD and MDD subjects. Transcript levels of molecules which repress cAMP activity were increased in BPD and decreased in MDD. Two orphan GPCRs, GPRC5B and GPR37, showed significantly decreased expression levels in MDD, and significantly increased expression levels in BPD. Our results suggest opposite changes in BPD and MDD in the GPLS, ‘activated’ cAMP signaling activity in BPD and ‘blunted’ cAMP signaling activity in MDD. GPRC5B and GPR37 both appear to have behavioral effects, and are also candidate genes for neurodegenerative disorders. In the context of the opposite changes observed in BPD and MDD, these GPCRs warrant further study of their brain effects.

Published
2013
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33. The Genetics of the Mood Disorder Spectrum: Genome-wide Association Analyses of More Than 185,000 Cases and 439,000 Controls

Author

Jonathan R.I. Coleman, Héléna A. Gaspar, Julien Bryois, Gerome Breen, Enda M. Byrne, Andreas J. Forstner, Peter A. Holmans, Christiaan A. de Leeuw, Manuel Mattheisen, Andrew McQuillin, Jennifer M. Whitehead Pavlides, Tune H. Pers, Stephan Ripke, Eli A. Stahl, Stacy Steinberg, Vassily Trubetskoy, Maciej Trzaskowski, Yunpeng Wang, Liam Abbott, Abdel Abdellaoui, Mark J. Adams, Annelie Nordin Adolfsson, Esben Agerbo, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Thomas D. Als, Till F.M. Andlauer, Adebayo Anjorin, Verneri Antilla, Sandra Van der Auwera, Swapnil Awasthi, Silviu-Alin Bacanu, Judith A. Badner, Marie Bækvad-Hansen, Jack D. Barchas, Nicholas Bass, Michael Bauer, Aartjan T.F. Beekman, Richard Belliveau, Sarah E. Bergen, Tim B. Bigdeli, Elisabeth B. Binder, Erlend Bøen, Marco Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, William Byerley, Na Cai, Miquel Casas, Enrique Castelao, Felecia Cerrato, Pablo Cervantes, Kimberly Chambert, Alexander W. Charney, Danfeng Chen, Jane Hvarregaard Christensen, Claire Churchhouse, David St Clair, Toni-Kim Clarke, Lucía Colodro-Conde, William Coryell, Baptiste Couvy-Duchesne, David W. Craig, Gregory E. Crawford, Cristiana Cruceanu, Piotr M. Czerski, Anders M. Dale, Gail Davies, Ian J. Deary, Franziska Degenhardt, Jurgen Del-Favero, J Raymond DePaulo, Eske M. Derks, Nese Direk, Srdjan Djurovic, Amanda L. Dobbyn, Conor V. Dolan, Ashley Dumont, Erin C. Dunn, Thalia C. Eley, Torbjørn Elvsåshagen, Valentina Escott-Price, Chun Chieh Fan, Hilary K. Finucane, Sascha B. Fischer, Matthew Flickinger, Jerome C. Foo, Tatiana M. Foroud, Liz Forty, Josef Frank, Christine Fraser, Nelson B. Freimer, Louise Frisén, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Fernando S. Goes, Jaqueline Goldstein, Scott D. Gordon, Katherine Gordon-Smith, Elaine K. Green, Melissa J. Green, Tiffany A. Greenwood, Jakob Grove, Weihua Guan, Lynsey S. Hall, Marian L. Hamshere, Christine Søholm Hansen, Thomas F. Hansen, Martin Hautzinger, Urs Heilbronner, Albert M. van Hemert, Stefan Herms, Ian B. Hickie, Maria Hipolito, Per Hoffmann, Dominic Holland, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, Laura Huckins, Marcus Ising, Stéphane Jamain, Rick Jansen, Jessica S. Johnson, Simone de Jong, Eric Jorgenson, Anders Juréus, Radhika Kandaswamy, Robert Karlsson, James L. Kennedy, Farnush Farhadi Hassan Kiadeh, Sarah Kittel-Schneider, James A. Knowles, Manolis Kogevinas, Isaac S. Kohane, Anna C. Koller, Julia Kraft, Warren W. Kretzschmar, Jesper Krogh, Ralph Kupka, Zoltán Kutalik, Catharina Lavebratt, Jacob Lawrence, William B. Lawson, Markus Leber, Phil H. Lee, Shawn E. Levy, Jun Z. Li, Yihan Li, Penelope A. Lind, Chunyu Liu, Loes M. Olde Loohuis, Anna Maaser, Donald J. MacIntyre, Dean F. MacKinnon, Pamela B. Mahon, Wolfgang Maier, Robert M. Maier, Jonathan Marchini, Lina Martinsson, Hamdi Mbarek, Steve McCarroll, Patrick McGrath, Peter McGuffin, Melvin G. McInnis, James D. McKay, Helena Medeiros, Sarah E. Medland, Divya Mehta, Fan Meng, Christel M. Middeldorp, Evelin Mihailov, Yuri Milaneschi, Lili Milani, Saira Saeed Mirza, Francis M. Mondimore, Grant W. Montgomery, Derek W. Morris, Sara Mostafavi, Thomas W. Mühleisen, Niamh Mullins, Matthias Nauck, Bernard Ng, Hoang Nguyen, Caroline M. Nievergelt, Michel G. Nivard, Evaristus A. Nwulia, Dale R. Nyholt, Claire O'Donovan, Paul F. O'Reilly, Anil P.S. Ori, Lilijana Oruc, Urban Ösby, Hogni Oskarsson, Jodie N. Painter, José Guzman Parra, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Amy Perry, Roseann E. Peterson, Erik Pettersson, Wouter J. Peyrot, Andrea Pfennig, Giorgio Pistis, Shaun M. Purcell, Jorge A. Quiroz, Per Qvist, Eline J. Regeer, Andreas Reif, Céline S. Reinbold, John P. Rice, Brien P. Riley, Fabio Rivas, Margarita Rivera, Panos Roussos, Douglas M. Ruderfer, Euijung Ryu, Cristina Sánchez-Mora, Alan F. Schatzberg, William A. Scheftner, Robert Schoevers, Nicholas J. Schork, Eva C. Schulte, Tatyana Shehktman, Ling Shen, Jianxin Shi, Paul D. Shilling, Stanley I. Shyn, Engilbert Sigurdsson, Claire Slaney, Olav B. Smeland, Johannes H. Smit, Daniel J. Smith, Janet L. Sobell, Anne T. Spijker, Michael Steffens, John S. Strauss, Fabian Streit, Jana Strohmaier, Szabolcs Szelinger, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Robert C. Thompson, Wesley Thompson, Pippa A. Thomson, Thorgeir E. Thorgeirsson, Matthew Traylor, Jens Treutlein, André G. Uitterlinden, Daniel Umbricht, Helmut Vedder, Alexander Viktorin, Peter M. Visscher, Weiqing Wang, Stanley J. Watson, Bradley T. Webb, Cynthia Shannon Weickert, Thomas W. Weickert, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Stephanie H. Witt, Yang Wu, Hualin S. Xi, Wei Xu, Jian Yang, Allan H. Young, Peter Zandi, Peng Zhang, Futao Zhang, Sebastian Zollner, Rolf Adolfsson, Ingrid Agartz, Martin Alda, Volker Arolt, Lena Backlund, Bernhard T. Baune, Frank Bellivier, Klaus Berger, Wade H. Berrettini, Joanna M. Biernacka, Douglas H.R. Blackwood, Michael Boehnke, Dorret I. Boomsma, Aiden Corvin, Nicholas Craddock, Mark J. Daly, Udo Dannlowski, Enrico Domenici, Katharina Domschke, Tõnu Esko, Bruno Etain, Mark Frye, Janice M. Fullerton, Elliot S. Gershon, E.J.C. de Geus, Michael Gill, Fernando Goes, Hans J. Grabe, Maria Grigoroiu-Serbanescu, Steven P. Hamilton, Joanna Hauser, Caroline Hayward, Andrew C. Heath, David M. Hougaard, Christina M. Hultman, Ian Jones, Lisa A. Jones, René S. Kahn, Kenneth S. Kendler, George Kirov, Stefan Kloiber, Mikael Landén, Marion Leboyer, Glyn Lewis, Qingqin S. Li, Jolanta Lissowska, Susanne Lucae, Pamela A.F. Madden, Patrik K. Magnusson, Nicholas G. Martin, Fermin Mayoral, Susan L. McElroy, Andrew M. McIntosh, Francis J. McMahon, Ingrid Melle, Andres Metspalu, Philip B. Mitchell, Gunnar Morken, Ole Mors, Preben Bo Mortensen, Bertram Müller-Myhsok, Richard M. Myers, Benjamin M. Neale, Vishwajit Nimgaonkar, Merete Nordentoft, Markus M. Nöthen, Michael C. O'Donovan, Ketil J. Oedegaard, Michael J. Owen, Sara A. Paciga, Carlos Pato, Michele T. Pato, Nancy L. Pedersen, Brenda W.J. H. Penninx, Roy H. Perlis, David J. Porteous, Danielle Posthuma, James B. Potash, Martin Preisig, Josep Antoni Ramos-Quiroga, Marta Ribasés, Marcella Rietschel, Guy A. Rouleau, Catherine Schaefer, Martin Schalling, Peter R. Schofield, Thomas G. Schulze, Alessandro Serretti, Jordan W. Smoller, Hreinn Stefansson, Kari Stefansson, Eystein Stordal, Henning Tiemeier, Gustavo Turecki, Rudolf Uher, Arne E. Vaaler, Eduard Vieta, John B. Vincent, Henry Völzke, Myrna M. Weissman, Thomas Werge, Ole A. Andreassen, Anders D. Børglum, Sven Cichon, Howard J. Edenberg, Arianna Di Florio, John Kelsoe, Douglas F. Levinson, Cathryn M. Lewis, John I. Nurnberger, Roel A. Ophoff, Laura J. Scott, Pamela Sklar, Patrick F. Sullivan, Naomi R. Wray, APH - Methodology, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, Complex Trait Genetics, Epidemiology, Erasmus MC other, Urology, Psychiatry, Internal Medicine, Medical Informatics, Immunology, Child and Adolescent Psychiatry / Psychology, Adult Psychiatry, Coleman J.R.I., Gaspar H.A., Bryois J., Byrne E.M., Forstner A.J., Holmans P.A., de Leeuw C.A., Mattheisen M., McQuillin A., Whitehead Pavlides J.M., Pers T.H., Ripke S., Stahl E.A., Steinberg S., Trubetskoy V., Trzaskowski M., Wang Y., Abbott L., Abdellaoui A., Adams M.J., Adolfsson A.N., Agerbo E., Akil H., Albani D., Alliey-Rodriguez N., Als T.D., Andlauer T.F.M., Anjorin A., Antilla V., Van der Auwera S., Awasthi S., Bacanu S.-A., Badner J.A., Baekvad-Hansen M., Barchas J.D., Bass N., Bauer M., Beekman A.T.F., Belliveau R., Bergen S.E., Bigdeli T.B., Binder E.B., Boen E., Boks M., Boocock J., Budde M., Bunney W., Burmeister M., Buttenschon H.N., Bybjerg-Grauholm J., Byerley W., Cai N., Casas M., Castelao E., Cerrato F., Cervantes P., Chambert K., Charney A.W., Chen D., Christensen J.H., Churchhouse C., St Clair D., Clarke T.-K., Colodro-Conde L., Coryell W., Couvy-Duchesne B., Craig D.W., Crawford G.E., Cruceanu C., Czerski P.M., Dale A.M., Davies G., Deary I.J., Degenhardt F., Del-Favero J., DePaulo J.R., Derks E.M., Direk N., Djurovic S., Dobbyn A.L., Dolan C.V., Dumont A., Dunn E.C., Eley T.C., Elvsashagen T., Escott-Price V., Fan C.C., Finucane H.K., Fischer S.B., Flickinger M., Foo J.C., Foroud T.M., Forty L., Frank J., Fraser C., Freimer N.B., Frisen L., Gade K., Gage D., Garnham J., Giambartolomei C., Goes F.S., Goldstein J., Gordon S.D., Gordon-Smith K., Green E.K., Green M.J., Greenwood T.A., Grove J., Guan W., Hall L.S., Hamshere M.L., Hansen C.S., Hansen T.F., Hautzinger M., Heilbronner U., van Hemert A.M., Herms S., Hickie I.B., Hipolito M., Hoffmann P., Holland D., Homuth G., Horn C., Hottenga J.-J., Huckins L., Ising M., Jamain S., Jansen R., Johnson J.S., de Jong S., Jorgenson E., Jureus A., Kandaswamy R., Karlsson R., Kennedy J.L., Hassan Kiadeh F.F., Kittel-Schneider S., Knowles J.A., Kogevinas M., Kohane I.S., Koller A.C., Kraft J., Kretzschmar W.W., Krogh J., Kupka R., Kutalik Z., Lavebratt C., Lawrence J., Lawson W.B., Leber M., Lee P.H., Levy S.E., Li J.Z., Li Y., Lind P.A., Liu C., Olde Loohuis L.M., Maaser A., MacIntyre D.J., MacKinnon D.F., Mahon P.B., Maier W., Maier R.M., Marchini J., Martinsson L., Mbarek H., McCarroll S., McGrath P., McGuffin P., McInnis M.G., McKay J.D., Medeiros H., Medland S.E., Mehta D., Meng F., Middeldorp C.M., Mihailov E., Milaneschi Y., Milani L., Mirza S.S., Mondimore F.M., Montgomery G.W., Morris D.W., Mostafavi S., Muhleisen T.W., Mullins N., Nauck M., Ng B., Nguyen H., Nievergelt C.M., Nivard M.G., Nwulia E.A., Nyholt D.R., O'Donovan C., O'Reilly P.F., Ori A.P.S., Oruc L., Osby U., Oskarsson H., Painter J.N., Parra J.G., Pedersen C.B., Pedersen M.G., Perry A., Peterson R.E., Pettersson E., Peyrot W.J., Pfennig A., Pistis G., Purcell S.M., Quiroz J.A., Qvist P., Regeer E.J., Reif A., Reinbold C.S., Rice J.P., Riley B.P., Rivas F., Rivera M., Roussos P., Ruderfer D.M., Ryu E., Sanchez-Mora C., Schatzberg A.F., Scheftner W.A., Schoevers R., Schork N.J., Schulte E.C., Shehktman T., Shen L., Shi J., Shilling P.D., Shyn S.I., Sigurdsson E., Slaney C., Smeland O.B., Smit J.H., Smith D.J., Sobell J.L., Spijker A.T., Steffens M., Strauss J.S., Streit F., Strohmaier J., Szelinger S., Tansey K.E., Teismann H., Teumer A., Thompson R.C., Thompson W., Thomson P.A., Thorgeirsson T.E., Traylor M., Treutlein J., Uitterlinden A.G., Umbricht D., Vedder H., Viktorin A., Visscher P.M., Wang W., Watson S.J., Webb B.T., Weickert C.S., Weickert T.W., Weinsheimer S.M., Wellmann J., Willemsen G., Witt S.H., Wu Y., Xi H.S., Xu W., Yang J., Young A.H., Zandi P., Zhang P., Zhang F., Zollner S., Adolfsson R., Agartz I., Alda M., Arolt V., Backlund L., Baune B.T., Bellivier F., Berger K., Berrettini W.H., Biernacka J.M., Blackwood D.H.R., Boehnke M., Boomsma D.I., Corvin A., Craddock N., Daly M.J., Dannlowski U., Domenici E., Domschke K., Esko T., Etain B., Frye M., Fullerton J.M., Gershon E.S., de Geus E.J.C., Gill M., Goes F., Grabe H.J., Grigoroiu-Serbanescu M., Hamilton S.P., Hauser J., Hayward C., Heath A.C., Hougaard D.M., Hultman C.M., Jones I., Jones L.A., Kahn R.S., Kendler K.S., Kirov G., Kloiber S., Landen M., Leboyer M., Lewis G., Li Q.S., Lissowska J., Lucae S., Madden P.A.F., Magnusson P.K., Martin N.G., Mayoral F., McElroy S.L., McIntosh A.M., McMahon F.J., Melle I., Metspalu A., Mitchell P.B., Morken G., Mors O., Mortensen P.B., Muller-Myhsok B., Myers R.M., Neale B.M., Nimgaonkar V., Nordentoft M., Nothen M.M., O'Donovan M.C., Oedegaard K.J., Owen M.J., Paciga S.A., Pato C., Pato M.T., Pedersen N.L., Penninx B.W.J.H., Perlis R.H., Porteous D.J., Posthuma D., Potash J.B., Preisig M., Ramos-Quiroga J.A., Ribases M., Rietschel M., Rouleau G.A., Schaefer C., Schalling M., Schofield P.R., Schulze T.G., Serretti A., Smoller J.W., Stefansson H., Stefansson K., Stordal E., Tiemeier H., Turecki G., Uher R., Vaaler A.E., Vieta E., Vincent J.B., Volzke H., Weissman M.M., Werge T., Andreassen O.A., Borglum A.D., Cichon S., Edenberg H.J., Di Florio A., Kelsoe J., Levinson D.F., Lewis C.M., Nurnberger J.I., Ophoff R.A., Scott L.J., Sklar P., Sullivan P.F., Wray N.R., and Breen G.

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), Genetic correlation, Genome-wide association study, Mood Disorder, Bipolar disorder, Population, BF, Genomics, Major depressive disorder, Affective disorder, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, mental disorders, medicine, Animals, ddc:610, education, Depression (differential diagnoses), Biological Psychiatry, 030304 developmental biology, Genetic association, Genetics, Depressive Disorder, Major, 0303 health sciences, education.field_of_study, Animal, business.industry, Risk Factor, medicine.disease, 3. Good health, Affective disorders, 030104 developmental biology, Mood, Mood disorders, RC0321, Biological psychiatry, business, 030217 neurology & neurosurgery, Clinical psychology
Abstract

BackgroundMood disorders (including major depressive disorder and bipolar disorder) affect 10-20% of the population. They range from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Despite their diagnostic distinction, multiple approaches have shown considerable sharing of risk factors across the mood disorders.MethodsTo clarify their shared molecular genetic basis, and to highlight disorder-specific associations, we meta-analysed data from the latest Psychiatric Genomics Consortium (PGC) genome-wide association studies of major depression (including data from 23andMe) and bipolar disorder, and an additional major depressive disorder cohort from UK Biobank (total: 185,285 cases, 439,741 controls; non-overlapping N = 609,424).ResultsSeventy-three loci reached genome-wide significance in the meta-analysis, including 15 that are novel for mood disorders. More genome-wide significant loci from the PGC analysis of major depression than bipolar disorder reached genome-wide significance. Genetic correlations revealed that type 2 bipolar disorder correlates strongly with recurrent and single episode major depressive disorder. Systems biology analyses highlight both similarities and differences between the mood disorders, particularly in the mouse brain cell types implicated by the expression patterns of associated genes. The mood disorders also differ in their genetic correlation with educational attainment – positive in bipolar disorder but negative in major depressive disorder.ConclusionsThe mood disorders share several genetic associations, and can be combined effectively to increase variant discovery. However, we demonstrate several differences between these disorders. Analysing subtypes of major depressive disorder and bipolar disorder provides evidence for a genetic mood disorders spectrum.

Published
2020
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38. Quantitative validation of immunofluorescence and lectin staining using reduced CLARITY acrylamide formulations

Author

Vivek Kumar, Stanley J. Watson, Karl Deisseroth, Jack D. Barchas, Ben R. Martin, Richard M. Myers, Alan F. Schatzberg, David M. Krolewski, Francis S. Lee, Raju Tomer, William E. Bunney, and Huda Akil

Subjects
Male, 0301 basic medicine, Time Factors, Histology, Confocal, Fluorescent Antibody Technique, Immunofluorescence, Article, Mice, 03 medical and health sciences, chemistry.chemical_compound, Imaging, Three-Dimensional, Lectins, medicine, Animals, Sodium dodecyl sulfate, Acrylamide, Microscopy, Confocal, Chromatography, Dose-Response Relationship, Drug, Staining and Labeling, medicine.diagnostic_test, biology, General Neuroscience, Brain, Lectin, Fluorescence, Staining, Mice, Inbred C57BL, Parvalbumins, 030104 developmental biology, Monomer, chemistry, biology.protein, Anatomy
Abstract

The CLARITY technique enables three-dimensional visualization of fluorescent-labeled biomolecules in clarified intact brain samples, affording a unique view of molecular neuroanatomy and neurocircuitry. It is therefore, essential to find the ideal combination for clearing tissue and detecting the fluorescent-labeled signal. This method requires the formation of a formaldehyde-acrylamide fixative-generated hydrogel mesh through which cellular lipid is removed with sodium dodecyl sulfate. Several laboratories have used differential acrylamide and detergent concentrations to achieve better tissue clearing and antibody penetration, but the potential effects upon fluorescent signal retention is largely unknown. In an effort to optimize CLARITY processing procedures we performed quantitative parvalbumin immunofluorescence and lectin-based vasculature staining using either 4 or 8% sodium dodecyl sulfate detergent in combination with different acrylamide formulas in mouse brain slices. Using both confocal and CLARITY-optimized lightsheet microscope-acquired images, we demonstrate that 2% acrylamide monomer combined with 0.0125% bis-acrylamide and cleared with 4% sodium dodecyl sulfate generally provides the most optimal signal visualization amongst various hydrogel monomer concentrations, lipid removal times, and detergent concentrations.

Published
2017
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39. Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder

Author

Peter P. Zandi, Lisa Jones, Aartjan T.F. Beekman, Christine Fraser, Andreas J. Forstner, Nese Direk, Mark Lathrop, Jesper Krogh, Merete Nordentoft, Bradley T. Webb, Yihan Li, Michael Bauer, Qingqin S. Li, Daniel J. Smith, Carsten Horn, Robert C. Thompson, René Breuer, Eli A. Stahl, David A. Collier, Richard Williamson, Boomsma, Dorret, I, Céline S. Reinbold, Laura J. Scott, Manolis Kogevinas, Jacob Lawrence, Caroline Hayward, Nicholas J. Schork, Penelope A. Lind, Wade H. Berrettini, John B. Vincent, Toni-Kim Clarke, Henry Voelzke, Stacy Steinberg, Hreinn Stefansson, Dean F. MacKinnon, Thorgeir E. Thorgeirsson, Niamh Mullins, Esben Agerbo, Rudolf Uher, Christina M. Hultman, Pamela A. F. Madden, Eva C. Schulte, Matthew Flickinger, Sebastian Zöllner, Kenneth S. Kendler, Urban Ösby, Enrique Castelao, Michael John Owen, Colm O'Dushlaine, Jens Treutlein, Joanna Hauser, Markus M. Noethen, Erin N. Smith, James McKay, Sandra Van der Auwera, Erin C. Dunn, Steven P. Hamilton, Martin Schalling, Helmut Vedder, Katherine Gordon-Smith, Fabio Rivas, Matthias Nauck, James B. Potash, Morten Mattingsdal, Ling Shen, Tim B. Bigdeli, Kimberly Chambert, Volker Arolt, Daniel L. Koller, Annelie Nordin Adolfsson, Na Cai, Nicholas G. Martin, Carlos N. Pato, Georg Homuth, Jonas Bybjerg-Grauholm, Alexander Teumer, Wesley K. Thompson, Hamel Patel, Jian Yang, Margit Burmeister, Frank Bellivier, Jodie N. Painter, Enda M. Byrne, Margarita Rivera, Nicholas John Craddock, Tatiana Foroud, Shaun Purcell, Paul D. Shilling, David Craig, Vanessa Kiyomi Ota, Michael Boehnke, Devin Absher, Stéphane Jamain, Anne Farmer, Yunpeng Wang, Ole Mors, William A. Scheftner, Jack D. Barchas, Robert Maier, Stanley J. Watson, Allan H. Young, Baptiste Couvy-Duchesne, Jakob Grove, Rick Jansen, John P. Rice, Gerome Breen, Eske M. Derks, Ingrid Melle, Tiffany A. Greenwood, Manuel Mattheisen, Bernard Ng, Edward M. Scolnick, Stefan Kloiber, Lili Milani, Yuri Milaneschi, Fermín Mayoral, Engilbert Sigurdsson, Sarah E. Medland, Wolfgang Maier, Alan F. Schatzberg, Myrna M. Weissman, Jun Li, John R. Kelsoe, Eric Jorgenson, Grant C.B. Sinnamon, Preben Bo Mortensen, Jana Strohmaier, William Byerley, Michel G. Nivard, Richard M. Myers, Evelin Mihailov, Gustavo Turecki, Benjamin S. Pickard, Ian J. Deary, Bernhard T. Baune, Marian L. Hamshere, Stephanie H. Witt, Patrick F. Sullivan, Jennifer L. Moran, Farnush Farhadi Hassan Kiadeh, Cathryn M. Lewis, Srdjan Djurovic, Ian B. Hickie, Hans J. Grabe, Helena Gaspar, Francis J. McMahon, Catherine Schaefer, Guy A. Rouleau, Sandra Meier, Derek W. Morris, Tõnu Esko, Wouter J. Peyrot, Markus Schwarz, Silviu-Alin Bacanu, Adam Wright, Melvin G. McInnis, Elaine K. Green, Douglas M. Ruderfer, Danielle Posthuma, Franziska Degenhardt, Per Qvist, Henriette N. Buttenschøn, Jolanta Lissowska, Stephan Ripke, Nicholas Bass, Giorgio Pistis, Emma M. Quinn, Shantel Weinsheimer, Howard J. Edenberg, Sintia Iole Belangero, Charles Curtis, Ashley R. Winslow, Tracy M. Air, Johannes H. Smit, Isaac S. Kohane, Wei Xu, Pamela B. Mahon, Neonila Szeszenia-Dabrowska, Gonneke Willemsen, Ivan Nikolov, Sven Cichon, Gregory E. Crawford, David M. Hougaard, E.J.C. de Geus, Klaus Berger, Evaristus A. Nwulia, Fernando S. Goes, Pablo Cervantes, Udo Dannlowski, Rolf Adolfsson, Thomas G. Schulze, Bruno Etain, Mark J. Adams, Thomas Hansen, Hugh Gurling, Fan Guo Meng, Judith A. Badner, Julien Bryois, Mateus Jose Abdalla Diniz, Rodrigo A. Bressan, Radhika Kandaswamy, Josef Frank, I. Nicol Ferrier, Bertram Mueller-Myhsok, Manuel A. R. Ferreira, Marion Leboyer, Futao Zhang, Valentina Moskvina, Patrik K. E. Magnusson, Laura M. Huckins, Douglas Blackwood, Michael Gill, Jianxin Shi, Dale R. Nyholt, Nancy L. Pedersen, André G. Uitterlinden, Henning Tiemeier, Vassily Trubetskoy, Scott D. Gordon, Ian Jones, Grant W. Montgomery, Martin Preisig, Cristiana Cruceanu, Sara A. Paciga, Lena Backlund, Abdel Abdellaoui, Andres Metspalu, Gunnar Morken, Marcus Ising, Sascha B. Fischer, Lilijana Oruc, Sian Caesar, Sarah Kittel-Schneider, Thalia C. Eley, Vihra Milanova, Thomas Werge, Andrew Heath, Katherine E. Tansey, Thomas W. Muehleisen, Jane H. Christensen, Chunyu Liu, Mikael Landén, Douglas F. Levinson, Julia Kraft, Juergen Wellmann, Coleman, Jonathan R., I, Peng Zhang, Glyn Lewis, Henning Teismann, Hamdi Mbarek, Carsten Bøcker Pedersen, Szabolcs Szelinger, Alexander Viktorin, Paul Brennan, Brenda W.J.H. Penninx, Maciej Trzaskowski, Yang Wu, Katharina Domschke, John Strauss, Hilary K. Finucane, Detelina Grozeva, Peter Holmans, Saira Saeed Mirza, Ole A. Andreassen, John I. Nurnberger, Lynsey S Hall, Till F. M. Andlauer, Sara Mostafavi, Andreas Reif, Joanna M. Biernacka, Christine Søholm Hansen, Hualin S. Xi, Stephen Newhouse, William E. Bunney, Andrew M. McIntosh, Anna Maaser, Enrico Domenici, Shyn, Stanley, I, Gail Davies, Warren W. Kretzschmar, Simone de Jong, Lucía Colodro-Conde, Pippa A. Thomson, Francis M. Mondimore, Martin Hautzinger, Cinnamon S. Bloss, Fabian Streit, James L. Kennedy, Erik Pettersson, Peter M. Visscher, Valentina Escott-Price, Donald J. MacIntyre, Johannes Schumacher, Kevin A. McGhee, Divya Mehta, Naomi R. Wray, Robert A. Schoevers, John A. Rice, Jordan W. Smoller, Anders D. Børglum, Susanne Lucae, Jorge A. Quiroz, Daniel Umbricht, Jouke-Jan Hottenga, Kari Stefansson, Marcella Rietschel, Zoltán Kutalik, Sarah E. Bergen, Paul F. O'Reilly, Amanda Dobbyn, Michael Conlon O'Donovan, Falk W. Lohoff, Caroline M. Nievergelt, David J. Porteous, Matthew Traylor, Brien P. Riley, Roy H. Perlis, J. Raymond DePaulo, Martin Alda, James A. Knowles, Cristiano Noto, Keith Matthews, Mark A. Frye, Patrick J. McGrath, Roseann E. Peterson, David St Clair, Roel A. Ophoff, William Coryell, Peter McGuffin, Andiara Calado Saloma Rodrigues, Elliot S. Gershon, Conor V. Dolan, Janice M. Fullerton, Weihua Guan, Niklas Långström, Pamela Sklar, Paul Lichtenstein, Per Hoffmann, Ary Gadelha, Alan W. McLean, Andrew McQuillin, Philip B. Mitchell, Huda Akil, Piotr M. Czerski, Michael Steffens, Hogni Oskarsson, Soumya Raychaudhuri, Marcos L. Santoro, Elisabeth B. Binder, Christel M. Middeldorp, Jose G. Para, Jurgen Del-Favero, Vishwajit L. Nimgaonkar, Peter R. Schofield, Stefan Herms, Marie Bækvad-Hansen, Andrea Pfennig, Albert M. van Hemert, Jutta Kammerer-Ciernioch, Adebayo Anjorin, Sara Paciga, William Lawson, George Kirov, Aiden Corvin, Maria Grigoroiu-Serbanescu, Marianne Giørtz Pedersen, Jonathan Marchini, Markus Leber, Maria Hipolito, Louise Frisén, Margitta Borrmann-Hassenbach, Amanda Elkin, Major Depressive Disorder and Bipolar Disorder Working Groups of the Psychiatric Genomics Consortium, Wray, N.R., Ripke, S., Mattheisen, M., Trzaskowski, M., Byrne, E.M., Abdellaoui, A., Adams, M.J., Agerbo, E., Air, T.M., Andlauer, TFM, Bacanu, S.A., Bækvad-Hansen, M., Beekman, ATF, Bigdeli, T.B., Binder, E.B., Blackwood, DHR, Bryois, J., Buttenschøn, H.N., Bybjerg-Grauholm, J., Cai, N., Castelao, E., Christensen, J.H., Clarke, T.K., Coleman, JRI, Colodro-Conde, L., Couvy-Duchesne, B., Craddock, N., Crawford, G.E., Davies, G., Deary, I.J., Degenhardt, F., Derks, E.M., Direk, N., Dolan, C.V., Dunn, E.C., Eley, T.C., Escott-Price, V., Kiadeh, FFH, Finucane, H.K., Forstner, A.J., Frank, J., Gaspar, H.A., Gill, M., Goes, F.S., Gordon, S.D., Grove, J., Hansen, C.S., Hansen, T.F., Herms, S., Hickie, I.B., Hoffmann, P., Homuth, G., Horn, C., Hottenga, J.J., Hougaard, D.M., Ising, M., Jansen, R., Jones, I., Jones, L.A., Jorgenson, E., Knowles, J.A., Kohane, I.S., Kraft, J., Kretzschmar, W.W., Krogh, J., Kutalik, Z., Li, Y., Lind, P.A., MacIntyre, D.J., MacKinnon, D.F., Maier, R.M., Maier, W., Marchini, J., Mbarek, H., McGrath, P., McGuffin, P., Medland, S.E., Mehta, D., Middeldorp, C.M., Mihailov, E., Milaneschi, Y., Milani, L., Mondimore, F.M., Montgomery, G.W., Mostafavi, S., Mullins, N., Nauck, M., Ng, B., Nivard, M.G., Nyholt, D.R., Oskarsson, H., Owen, M.J., Painter, J.N., Pedersen, C.B., Pedersen, M.G., Peterson, R.E., Pettersson, E., Peyrot, W.J., Pistis, G., Posthuma, D., Quiroz, J.A., Qvist, P., Rice, J.P., Riley, B.P., Rivera, M., Mirza, S.S., Schoevers, R., Schulte, E.C., Shen, L., Shyn, S.I., Sigurdsson, E., Sinnamon, GCB, Smit, J.H., Smith, D.J., Stefansson, H., Steinberg, S., Streit, F., Strohmaier, J., Tansey, K.E., Teismann, H., Teumer, A., Thompson, W., Thomson, P.A., Thorgeirsson, T.E., Traylor, M., Treutlein, J., Trubetskoy, V., Uitterlinden, A.G., Umbricht, D., Van der Auwera, S., van Hemert, A.M., Viktorin, A., Visscher, P.M., Wang, Y., Webb, B.T., Weinsheimer, S.M., Wellmann, J., Willemsen, G., Witt, S.H., Wu, Y., Xi, H.S., Yang, J., Zhang, F., Arolt, V., Baune, B.T., Berger, K., Boomsma, D.I., Cichon, S., Dannlowski, U., de Geus, EJC, DePaulo, J.R., Domenici, E., Domschke, K., Esko, T., Grabe, H.J., Hamilton, S.P., Hayward, C., Heath, A.C., Kendler, K.S., Kloiber, S., Lewis, G., Li, Q.S., Lucae, S., Madden, PAF, Magnusson, P.K., Martin, N.G., McIntosh, A.M., Metspalu, A., Mors, O., Mortensen, P.B., Müller-Myhsok, B., Nordentoft, M., Nöthen, M.M., O'Donovan, M.C., Paciga, S.A., Pedersen, N.L., Penninx, BWJH, Perlis, R.H., Porteous, D.J., Potash, J.B., Preisig, M., Rietschel, M., Schaefer, C., Schulze, T.G., Smoller, J.W., Stefansson, K., Tiemeier, H., Uher, R., Völzke, H., Weissman, M.M., Werge, T., Lewis, C.M., Levinson, D.F., Børglum, A.D., Sullivan, P.F., Meier, S., Strauss, J., Xu, W., Vincent, J.B., Matthews, K., Ferreira, M., O'Dushlaine, C., Purcell, S., Raychaudhuri, S., Ruderfer, D.M., Sklar, P., Scott, L.J., Flickinger, M., Burmeister, M., Li, J., Guan, W., Absher, D., Thompson, R.C., Meng, F.G., Schatzberg, A.F., Bunney, W.E., Barchas, J.D., Watson, S.J., Myers, R.M., Akil, H., Boehnke, M., Chambert, K., Moran, J., Scolnick, E., Djurovic, S., Melle, I., Morken, G., Corvin, A., Anjorin, A., Kandaswamy, R., Lawrence, J., McLean, A.W., Pickard, B.S., Bergen, S.E., Nimgaonkar, V., Landén, M., Schalling, M., Osby, U., Backlund, L., Frisén, L., Langstrom, N., Stahl, E., Dobbyn, A., Jamain, S., Etain, B., Bellivier, F., Leber, M., Maaser, A., Fischer, S.B., Reinbold, C.S., Kittel-Schneider, S., Fullerton, J.M., Oruč, L., Para, J.G., Mayoral, F., Rivas, F., Czerski, P.M., Kammerer-Ciernioch, J., Vedder, H., Borrmann-Hassenbach, M., Pfennig, A., Brennan, P., McKay, J.D., Kogevinas, M., Schwarz, M., Schofield, P.R., Mühleisen, T.W., Schumacher, J., Bauer, M., Wright, A., Mitchell, P.B., Hautzinger, M., Kelsoe, J.R., Greenwood, T.A., Nievergelt, C.M., Shilling, P.D., Smith, E.N., Bloss, C.S., Edenberg, H.J., Koller, D.L., Gershon, E.S., Liu, C., Badner, J.A., Scheftner, W.A., Lawson, W.B., Nwulia, E.A., Hipolito, M., Coryell, W., Rice, J., Byerley, W., McMahon, F.J., Lohoff, F.W., Zandi, P.P., Mahon, P.B., McInnis, M.G., Zöllner, S., Zhang, P., Szelinger, S., St Clair, D., Caesar, S., Gordon-Smith, K., Fraser, C., Green, E.K., Grozeva, D., Hamshere, M.L., Kirov, G., Nikolov, I., Collier, D.A., Elkin, A., Williamson, R., Young, A.H., Ferrier, I.N., Milanova, V., Alda, M., Cervantes, P., Cruceanu, C., Rouleau, G.A., Turecki, G., Paciga, S., Winslow, A.R., Grigoroiu-Serbanescu, M., Ophoff, R., Adolfsson, R., Adolfsson, A.N., Del-Favero, J., Pato, C., Biernacka, J.M., Frye, M.A., Morris, D., Schork, N.J., Reif, A., Lissowska, J., Hauser, J., Szeszenia-Dabrowska, N., McGhee, K., Quinn, E., Moskvina, V., Holmans, P.A., Farmer, A., Kennedy, J.L., Andreassen, O.A., Mattingsdal, M., Bass, N.J., Gurling, H., McQuillin, A., Breuer, R., Hultman, C., Lichtenstein, P., Huckins, L.M., Leboyer, M., Lathrop, M., Nurnberger, J., Steffens, M., Foroud, T.M., Berrettini, W.H., Craig, D.W., Shi, J., Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Perceptual and Cognitive Neuroscience (PCN), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Major Depressive Disorder Bipolar, Biological Psychology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Methodology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, Pediatric Surgery, Epidemiology, Child and Adolescent Psychiatry / Psychology, Psychiatry, and Internal Medicine

Subjects
Netherlands Twin Register (NTR), 0301 basic medicine, Major Depressive Disorder and Bipolar Disorder Working Groups of the Psychiatric Genomics Consortium, Bipolar Disorder, SAMPLE, Medicine (miscellaneous), Pedigree chart, Disease, 0302 clinical medicine, SCHIZOPHRENIA, 2.1 Biological and endogenous factors, Medicine, Aetiology, ANTICIPATION, lcsh:QH301-705.5, Psychiatry, 0303 health sciences, Depression, ASSOCIATION, Serious Mental Illness, Mental Health, Schizophrenia, Major depressive disorder, General Agricultural and Biological Sciences, Engineering sciences. Technology, medicine.medical_specialty, Context (language use), Article, Psykiatri, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, AGE, SDG 3 - Good Health and Well-being, ddc:570, Behavioral and Social Science, Genetics, PLINK, Genetic Testing, Bipolar disorder, Biology, 030304 developmental biology, business.industry, Prevention, Human Genome, Assortative mating, medicine.disease, Brain Disorders, 030104 developmental biology, Mood, lcsh:Biology (General), Mood disorders, Anticipation (genetics), ONSET, Human medicine, business, 030217 neurology & neurosurgery
Abstract

Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders., Simone de Jong et al. examine the balance of common and rare risk for psychiatric disorders in a large family with high incidence of Bipolar Disorder and Major Depressive Disorder. They find that increased polygenic risk over generations could be partially due to assortative mating, which may explain the observation of anticipation in mood disorders.

Published
2018
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40. Connective Tissue Growth Factor Is a Novel Prodepressant

Author

Angela M. O’Connor, Richard M. Myers, Cortney A. Turner, Megan Hastings Hagenauer, Robert C. Thompson, Jack D. Barchas, Stanley J. Watson, Vikram Sharma, William E. Bunney, Elaine K. Hebda-Bauer, Sraboni Chaudhury, Francis S. Lee, Huda Akil, and Alan F. Schatzberg

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, medicine.medical_treatment, Hippocampus, Anxiety, Fibroblast growth factor, Antibodies, Monoclonal, Humanized, Article, Social defeat, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Internal medicine, medicine, Animals, Humans, Biological Psychiatry, Depressive Disorder, Major, integumentary system, business.industry, Growth factor, Dentate gyrus, Gene Expression Profiling, Connective Tissue Growth Factor, Antibodies, Monoclonal, Middle Aged, medicine.disease, Amygdala, Rats, CTGF, Disease Models, Animal, 030104 developmental biology, Endocrinology, Dentate Gyrus, Exploratory Behavior, Major depressive disorder, Female, Fibroblast Growth Factor 2, business, 030217 neurology & neurosurgery
Abstract

Background While downregulation of several growth factors in major depressive disorder is well established, less attention has been paid to the upregulation of other growth factors. Yet, upregulated growth factors may offer better therapeutic targets. We show that connective tissue growth factor (CTGF) represents a target based on its upregulation in major depressive disorder and studies in animal models implicating it in negative affect. Methods CTGF gene expression was first evaluated in the postmortem human amygdala. The findings were followed up in outbred rats and in two rat lines that were selectively bred for differences in novelty-seeking and anxiety behavior (bred low responders and bred high responders). We studied the impact of social defeat and early-life treatment with fibroblast growth factor 2 on CTGF expression. Finally, we assessed the ability of an anti-CTGF antibody (FG-3019) to alter CTGF expression and emotionality. Results In the human amygdala, CTGF expression was significantly increased in major depressive disorder compared with control subjects. CTGF expression was also significantly increased in the dentate gyrus of adult bred low responders compared with bred high responders. Social defeat stress in bred low responders significantly increased CTGF expression in the dentate gyrus. Early-life fibroblast growth factor 2, a treatment that reduces anxiety-like behavior throughout life, decreased CTGF expression in the adult dentate gyrus. In outbred rats, CTGF administration increased depression-like behavior. Chronic treatment with FG-3019 decreased CTGF expression, and acute and chronic treatment was antidepressant. Conclusions This study is the first to implicate CTGF as a prodepressant molecule that could serve as a target for the development of novel therapeutics.

Published
2018

41. Fibroblast growth factor 9 is a novel modulator of negative affect

Author

Jun Li, Stanley J. Watson, Megan Hastings Hagenauer, Jack D. Barchas, William E. Bunney, Richard M. Myers, Katherine E. Prater, Alan F. Schatzberg, Najmul Shah, Peter Blandino, Cortney A. Turner, Edny Gula Inui, Huda Akil, Devin Absher, and Elyse L. Aurbach

Subjects
Adult, Fibroblast Growth Factor 9, Male, Microinjections, Hippocampus, Anxiety, Hippocampal formation, Rats, Sprague-Dawley, Social defeat, Young Adult, FGF9, Avoidance Learning, medicine, Animals, Humans, Receptor, Fibroblast Growth Factor, Type 1, RNA, Small Interfering, Aged, Demography, Aged, 80 and over, Depressive Disorder, Major, Multidisciplinary, Dentate gyrus, Lentivirus, Human brain, Middle Aged, Biological Sciences, medicine.disease, Rats, Gene expression profiling, Affect, stomatognathic diseases, medicine.anatomical_structure, Gene Expression Regulation, Case-Control Studies, Gene Knockdown Techniques, Postmortem Changes, Dentate Gyrus, Major depressive disorder, Female, Psychology, Neuroscience, Stress, Psychological
Abstract

Both gene expression profiling in postmortem human brain and studies using animal models have implicated the fibroblast growth factor (FGF) family in affect regulation and suggest a potential role in the pathophysiology of major depressive disorder (MDD). FGF2, the most widely characterized family member, is down-regulated in the depressed brain and plays a protective role in rodent models of affective disorders. By contrast, using three microarray analyses followed by quantitative RT-PCR confirmation, we show that FGF9 expression is up-regulated in the hippocampus of individuals with MDD, and that FGF9 expression is inversely related to the expression of FGF2. Because little is known about FGF9's function in emotion regulation, we used animal models to shed light on its potential role in affective function. We found that chronic social defeat stress, an animal model recapitulating some aspects of MDD, leads to a significant increase in hippocampal FGF9 expression, paralleling the elevations seen in postmortem human brain tissue. Chronic intracerebroventricular administration of FGF9 increased both anxiety- and depression-like behaviors. In contrast, knocking down FGF9 expression in the dentate gyrus of the hippocampus using a lentiviral vector produced a decrease in FGF9 expression and ameliorated anxiety-like behavior. Collectively, these results suggest that high levels of hippocampal FGF9 play an important role in the development or expression of mood and anxiety disorders. We propose that the relative levels of FGF9 in relation to other members of the FGF family may prove key to understanding vulnerability or resilience in affective disorders.

Published
2015
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42. Perspectives on depression-past, present, futurea

Author

Jack D. Barchas and Benjamin D. Brody

Subjects
Psychotherapist, General Neuroscience, Behavioural sciences, Context (language use), Neuropsychiatry, Mental illness, medicine.disease, Mental health, General Biochemistry, Genetics and Molecular Biology, DSM-5, History and Philosophy of Science, medicine, Psychology, Depression (differential diagnoses), Research Domain Criteria
Abstract

Depression presents a wide canvas for considering some approaches, issues, and problems in the study of major categories of mental illness in the context of current behavioral and molecular neurobiology. The study of depression encompasses multiple interactions among psychiatry, neurology, and neuroscience, as well as interactions with a host of other disciplines. This paper considers issues from an American perspective and discusses topics including historical aspects of the ways humanity has struggled with depression; the growth of approaches, and the "wars" in psychiatry in the middle of the 20th century between different ideologies; the development of psychiatry as a behavioral science inclusive of many disciplines; current diagnostic systems such as the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) of the American Psychiatric Association, and the ICD-10 Classification of Mental and Behavioral Disorders of the World Health Organization; the efforts to delineate subtypes of depression; the search for new neurobiological and behavioral targets in the context of the National Institute of Mental Health's Research Domain Criteria framework; and examples of potential future discoveries and disciplines that may ultimately improve treatment.

Published
2015
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43. Mitochondrial Complex I Deficiency in Schizophrenia and Bipolar Disorder and Medication Influence

Author

Ling Morgan, Marquis P. Vawter, Jack D. Barchas, Francis S. Lee, Brandi Rollins, Stanley J. Watson, William E. Bunney, Richard M. Myers, Adolfo Sequeira, Brooke E. Hjelm, Huda Akil, Alan F. Schatzberg, and Steven G. Potkin

Subjects
0301 basic medicine, medicine.medical_specialty, Mitochondrial DNA, Psychosis, Original Paper, business.industry, medicine.medical_treatment, General Medicine, Mitochondrion, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Endocrinology, Schizophrenia, Internal medicine, medicine, Antidepressant, Bipolar disorder, Psychiatry, Prefrontal cortex, business, Antipsychotic, 030217 neurology & neurosurgery
Abstract

Subjects with schizophrenia (SZ) and bipolar disorder (BD) show decreased protein and transcript levels for mitochondrial complex I. In vitro results suggest antipsychotic and antidepressant drugs may be responsible. We measured complex I activity in BD, SZ, and controls and presence of antipsychotic and antidepressant medications, mitochondrial DNA (mtDNA) copy number, and the mtDNA “common deletion” in the brain. Complex I activity in the prefrontal cortex was decreased by 45% in SZ compared to controls (p = 0.02), while no significant difference was found in BD. Complex I activity was significantly decreased (p = 0.01) in pooled cases (SZ and BD) that had detectable psychotropic medications and drugs compared to pooled cases with no detectable levels. Subjects with age at onset in their teens and psychotropic medications showed decreased (p < 0.05) complex I activity compared to subjects with an adult age at onset. Both SZ and BD groups displayed significant increases (p < 0.05) in mtDNA copy number compared to controls; however, common deletion burden was not altered. Complex I deficiency is found in SZ brain tissue, and psychotropic medications may play a role in mitochondrial dysfunction. Studies of medication-free first-episode psychosis patients are needed to elucidate whether mitochondrial pathophysiology occurs independent of medication effects.

Published
2017

44. Transcriptomic Imputation of Bipolar Disorder and Bipolar subtypes reveals 29 novel associated genes

Author

Thomas G. Schulze, Eduard Vieta, Melissa J. Green, Jakob Grove, Ingrid Melle, Preben Bo Mortensen, Nicholas J. Schork, Thorgeir E. Thorgeirsson, Jonas Bybjerg-Grauholm, Margit Burmeister, Peter R. Schofield, Szabolcs Szelinger, Fermín Mayoral, Katherine Gordon-Smith, Qingqin S. Li, Claire O'Donovan, Josep Antoni Ramos-Quiroga, Derek W. Morris, Douglas M. Ruderfer, Stefan Herms, Huckins Lm, Martin Hautzinger, Eline J. Regeer, Sebastian Zöllner, Gustavo Turecki, Christine Søholm Hansen, Helena Medeiros, Laura J. Scott, Annelie Nordin Adolfsson, Helmut Vedder, Thomas W. Weickert, Nelson B. Freimer, Céline S. Reinbold, James McKay, Cathryn M. Lewis, Eric R. Gamazon, Frank Bellivier, Marie B¾kvad-Hansen, Srdjan Djurovic, Chun Chieh Fan, Ole A. Andreassen, Solveig K. Sieberts, Jack D. Barchas, David Curtis, Elaine K. Green, Tatiana Foroud, Shaun Purcell, Mette A. Peters, Joanna M. Biernacka, Fabian Streit, Alan F. Schatzberg, James L. Kennedy, Tiffany A. Greenwood, Bertram Müller-Myhsok, Robin Kramer, Swapnil Awasthi, Jordan W. Smoller, Cristina Sánchez-Mora, George Kirov, Ulrik Fredrik Malt, Gabriel E. Hoffman, Liz Forty, Pablo Cervantes, Jose Guzman Parra, Nicholas G. Martin, William Byerley, J. Raymond DePaulo, Martin Alda, Anil P.S. Ori, Menachem Fromer, William E. Bunney, Valentina Escott-Price, Judith A. Badner, Danielle Posthuma, Judith Allardyce, M. Ribasés, Manolis Kogevinas, Stephanie H. Witt, Anne T. Spijker, James A. Knowles, Simon Xi, Jun Li, Francis J. McMahon, Nancy J. Cox, Marcella Rietschel, Markus Leber, Laura M. Huckins, John I. Nurnberger, M. Casas, Marco P. Boks, Maria Hipolito, Evaristus A. Nwulia, Gerome Breen, Franziska Degenhardt, Janice M. Fullerton, Carlos N. Pato, Urs Heilbronner, Piotr M. Czerski, Michael Steffens, Monika Budde, Nicholas John Craddock, Katrin Gade, Bernie Devlin, Sarah Kittel-Schneider, Enrico Domenci, Weihua Guan, Sarah E. Bergen, Fan Meng, Eystein Stordal, Janet L. Sobell, Naomi R. Wray, Engilbert Sigurdsson, Marion Leboyer, Sven Cichon, Pamela Sklar, Bruno Etain, Richard M. Myers, Melvin G. McInnis, Steve McCarroll, Nicholas Bass, Christine Fraser, Thomas W. Mühleisen, Anna Maaser, Patrick F. Sullivan, Mark A. Frye, Amanda Dobbyn, John P. Rice, Amy Perry, Wei Xu, Thomas Damm Als, Anders D. Børglum, Anna C. Koller, Michael Conlon O'Donovan, Pamela B. Mahon, Sara A. Paciga, Douglas Blackwood, Michael Bauer, Fernando S. Goes, Susanne Lucae, Markus M. Nöthen, Josef Frank, Grant W. Montgomery, Scott D. Gordon, Philip B. Mitchell, Hoang T. Nguyen, Huda Akil, Chunyu Liu, Stanley J. Watson, Allan H. Young, Roel A. Ophoff, Caroline M. Nievergelt, John B. Vincent, Robert Karlsson, Kari Stefansson, Thomas Werge, Niamh Mullins, William A. Scheftner, Elliot S. Gershon, Peter McGuffin, Ralph Kupka, Mikael Landén, Matthew Flickinger, Claudia Giambartolomei, Carsten Bøcker Pedersen, Michael John Owen, Diego Albani, Hae Kyung Im, Andres Metspalu, Gunnar Morken, Panos Roussos, Tõnu Esko, Andrew M. McIntosh, Vishwajit L. Nimgaonkar, Per Hoffmann, Olav B. Smeland, Stéphane Jamain, Ole Mors, Vahram Haroutunian, Anders Juréus, Shawn Levy, Roy H. Perlis, Whitney McFadden, James Boocock, Ney Alliey-Rodriguez, Stacy Steinberg, Paul D. Shilling, Arne E. Vaaler, David Craig, Sarah E. Medland, Donald J. MacIntyre, William Coryell, Jens Treutlein, Joanna Hauser, Cynthia Shannon Weickert, Jana Strohmaier, Guy A. Rouleau, Michele T. Pato, John R. Kelsoe, Arianna Di Florio, Radhika Kandaswamy, David M. Hougaard, Toni-Kim Clarke, Susan L. McElroy, Ian Jones, Sarah Knott, Tatyana Shehktman, Wade H. Berrettini, John Strauss, Anders M. Dale, Peter P. Zandi, Andreas Reif, Claire Slaney, Julie Garnham, Margarita Rivera, Michael Gill, Lisa Jones, Cristiana Cruceanu, Sascha B. Fischer, Marian L. Hamshere, Lilijana Oruc, Weiqing Wang, Eli A. Stahl, Wolfgang Maier, Peng Zhang, Hreinn Stefansson, Ingrid Agartz, Bernhard T. Baune, Esben Agerbo, Alessandro Serretti, Robert C. Thompson, Ketil J. Oedegaard, William Lawson, Merete Nordentoft, Jacob Lawrence, Fabio Rivas, James B. Potash, Aiden Corvin, Christina M. Hultman, Maria Grigoroiu-Serbanescu, Marianne Giørtz Pedersen, Michael Boehnke, René S. Kahn, Lili Milani, Jurgen Del-Favero, Veera M. Rajagopal, Jolanta Lissowska, Howard J. Edenberg, Udo Dannlowski, Rolf Adolfsson, Andrea Pfennig, Adebayo Anjorin, and Torbjørn Elvsåshagen

Subjects
Genotype, Expression quantitative trait loci, medicine, Genome-wide association study, Locus (genetics), Bipolar disorder, Computational biology, Biology, medicine.disease, Phenotype, Genetic architecture, Imputation (genetics)
Abstract

Bipolar disorder is a complex neuropsychiatric disorder presenting with episodic mood disturbances. In this study we use a transcriptomic imputation approach to identify novel genes and pathways associated with bipolar disorder, as well as three diagnostically and genetically distinct subtypes. Transcriptomic imputation approaches leverage well-curated and publicly available eQTL reference panels to create gene-expression prediction models, which may then be applied to “impute” genetically regulated gene expression (GREX) in large GWAS datasets. By testing for association between phenotype and GREX, rather than genotype, we hope to identify more biologically interpretable associations, and thus elucidate more of the genetic architecture of bipolar disorder.We applied GREX prediction models for 13 brain regions (derived from CommonMind Consortium and GTEx eQTL reference panels) to 21,488 bipolar cases and 54,303 matched controls, constituting the largest transcriptomic imputation study of bipolar disorder (BPD) to date. Additionally, we analyzed three specific BPD subtypes, including 14,938 individuals with subtype 1 (BD-I), 3,543 individuals with subtype 2 (BD-II), and 1,500 individuals with schizoaffective subtype (SAB).We identified 125 gene-tissue associations with BPD, of which 53 represent independent associations after FINEMAP analysis. 29/53 associations were novel; i.e., did not lie within 1Mb of a locus identified in the recent PGC-BD GWAS. We identified 37 independent BD-I gene-tissue associations (10 novel), 2 BD-II associations, and 2 SAB associations. Our BPD, BD-I and BD-II associations were significantly more likely to be differentially expressed in post-mortem brain tissue of BPD, BD-I and BD-II cases than we might expect by chance. Together with our pathway analysis, our results support long-standing hypotheses about bipolar disorder risk, including a role for oxidative stress and mitochondrial dysfunction, the post-synaptic density, and an enrichment of circadian rhythm and clock genes within our results.

Published
2017
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45. Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder

Author

Eli A Stahl, Gerome Breen, Andreas J Forstner, Andrew McQuillin, Stephan Ripke, Vassily Trubetskoy, Manuel Mattheisen, Yunpeng Wang, Jonathan R I Coleman, Héléna A Gaspar, Christiaan A de Leeuw, Stacy Steinberg, Jennifer M Whitehead Pavlides, Maciej Trzaskowski, Tune H Pers, Peter A Holmans, Liam Abbott, Esben Agerbo, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Thomas D Als, Adebayo Anjorin, Verneri Antilla, Swapnil Awasthi, Judith A Badner, Marie Bækvad-Hansen, Jack D Barchas, Nicholas Bass, Michael Bauer, Richard Belliveau, Sarah E Bergen, Carsten Bøcker Pedersen, Erlend Bøen, Marco Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Jonas Bybjerg-Grauholm, William Byerley, Miquel Casas, Felecia Cerrato, Pablo Cervantes, Kimberly Chambert, Alexander W Charney, Danfeng Chen, Claire Churchhouse, Toni-Kim Clarke, William Coryell, David W Craig, Cristiana Cruceanu, David Curtis, Piotr M Czerski, Anders M Dale, Simone de Jong, Franziska Degenhardt, Jurgen Del-Favero, J Raymond DePaulo, Srdjan Djurovic, Amanda L Dobbyn, Ashley Dumont, Torbjørn Elvsåshagen, Valentina Escott-Price, Chun Chieh Fan, Sascha B Fischer, Matthew Flickinger, Tatiana M Foroud, Liz Forty, Josef Frank, Christine Fraser, Nelson B Freimer, Louise Frisén, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Marianne Giørtz Pedersen, Jaqueline Goldstein, Scott D Gordon, Katherine Gordon-Smith, Elaine K Green, Melissa J Green, Tiffany A Greenwood, Jakob Grove, Weihua Guan, JoséGuzman Parra, Marian L Hamshere, Martin Hautzinger, Urs Heilbronner, Stefan Herms, Maria Hipolito, Per Hoffmann, Dominic Holland, Laura Huckins, Stéphane Jamain, Jessica S Johnson, Anders Juréus, Radhika Kandaswamy, Robert Karlsson, James L Kennedy, Sarah Kittel-Schneider, Sarah V Knott, James A Knowles, Manolis Kogevinas, Anna C Koller, Ralph Kupka, Catharina Lavebratt, Jacob Lawrence, William B Lawson, Markus Leber, Phil H Lee, Shawn E Levy, Jun Z Li, Chunyu Liu, Susanne Lucae, Anna Maaser, Donald J MacIntyre, Pamela B Mahon, Wolfgang Maier, Lina Martinsson, Steve McCarroll, Peter McGuffin, Melvin G McInnis, James D McKay, Helena Medeiros, Sarah E Medland, Fan Meng, Lili Milani, Grant W Montgomery, Derek W Morris, Thomas W Mühleisen, Niamh Mullins, Hoang Nguyen, Caroline M Nievergelt, Annelie Nordin Adolfsson, Evaristus A Nwulia, Claire O’Donovan, Loes M Olde Loohuis, Anil P S Ori, Lilijana Oruc, Urban Ösby, Roy H Perlis, Amy Perry, Andrea Pfennig, James B Potash, Shaun M Purcell, Eline J Regeer, Andreas Reif, Céline S Reinbold, John P Rice, Fabio Rivas, Margarita Rivera, Panos Roussos, Douglas M Ruderfer, Euijung Ryu, Cristina Sánchez-Mora, Alan F Schatzberg, William A Scheftner, Nicholas J Schork, Cynthia Shannon Weickert, Tatyana Shehktman, Paul D Shilling, Engilbert Sigurdsson, Claire Slaney, Olav B Smeland, Janet L Sobell, Christine Søholm Hansen, Anne T Spijker, David St Clair, Michael Steffens, John S Strauss, Fabian Streit, Jana Strohmaier, Szabolcs Szelinger, Robert C Thompson, Thorgeir E Thorgeirsson, Jens Treutlein, Helmut Vedder, Weiqing Wang, Stanley J Watson, Thomas W Weickert, Stephanie H Witt, Simon Xi, Wei Xu, Allan H Young, Peter Zandi, Peng Zhang, Sebastian Zollner, Rolf Adolfsson, Ingrid Agartz, Martin Alda, Lena Backlund, Bernhard T Baune, Frank Bellivier, Wade H Berrettini, Joanna M Biernacka, Douglas H R Blackwood, Michael Boehnke, Anders D Børglum, Aiden Corvin, Nicholas Craddock, Mark J Daly, Udo Dannlowski, Tõnu Esko, Bruno Etain, Mark Frye, Janice M Fullerton, Elliot S Gershon, Michael Gill, Fernando Goes, Maria Grigoroiu-Serbanescu, Joanna Hauser, David M Hougaard, Christina M Hultman, Ian Jones, Lisa A Jones, RenéS Kahn, George Kirov, Mikael Landén, Marion Leboyer, Cathryn M Lewis, Qingqin S Li, Jolanta Lissowska, Nicholas G Martin, Fermin Mayoral, Susan L McElroy, Andrew M McIntosh, Francis J McMahon, Ingrid Melle, Andres Metspalu, Philip B Mitchell, Gunnar Morken, Ole Mors, Preben Bo Mortensen, Bertram Müller-Myhsok, Richard M Myers, Benjamin M Neale, Vishwajit Nimgaonkar, Merete Nordentoft, Markus M Nöthen, Michael C O’Donovan, Ketil J Oedegaard, Michael J Owen, Sara A Paciga, Carlos Pato, Michele T Pato, Danielle Posthuma, Josep Antoni Ramos-Quiroga, Marta Ribasés, Marcella Rietschel, Guy A Rouleau, Martin Schalling, Peter R Schofield, Thomas G Schulze, Alessandro Serretti, Jordan W Smoller, Hreinn Stefansson, Kari Stefansson, Eystein Stordal, Patrick F Sullivan, Gustavo Turecki, Arne E Vaaler, Eduard Vieta, John B Vincent, Thomas Werge, John I Nurnberger, Naomi R Wray, Arianna Di Florio, Howard J Edenberg, Sven Cichon, Roel A Ophoff, Laura J Scott, Ole A Andreassen, John Kelsoe, and Pamela Sklar

Subjects
0303 health sciences, medicine.medical_specialty, business.industry, medicine.disease, European descent, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Genomewide association, medicine, Bipolar disorder, medicine.symptom, Psychiatry, business, Mania, 030217 neurology & neurosurgery, Depression (differential diagnoses), 030304 developmental biology
Abstract

Bipolar disorder is a highly heritable psychiatric disorder that features episodes of mania and depression. We performed the largest genome-wide association study to date, including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 sentinel variants at loci with P-4 in an independent sample of 9,412 cases and 137,760 controls. In the combined analysis, 30 loci reached genome-wide significant evidence for association, of which 20 were novel. These significant loci contain genes encoding ion channels and neurotransmitter transporters (CACNA1C, GRIN2A, SCN2A, SLC4A1), synaptic components (RIMS1, ANK3), immune and energy metabolism components. Bipolar disorder type I (depressive and manic episodes; ~73% of our cases) is strongly genetically correlated with schizophrenia whereas bipolar disorder type II (depressive and hypomanic episodes; ~17% of our cases) is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential new biological mechanisms for bipolar disorder.

Published
2017
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46. Genome-wide association study identifies 30 loci associated with bipolar disorder

Author

Euijung Ryu, Danfeng Chen, Allan H. Young, Olav B. Smeland, James McKay, Frank Bellivier, Qingqin S. Li, Yunpeng Wang, Tõnu Esko, Bertram Müller-Myhsok, Weiqing Wang, Thomas W. Weickert, Joanna M. Biernacka, Ralph W. Kupka, Claire O'Donovan, Josep Antoni Ramos-Quiroga, Marian L. Hamshere, Derek W. Morris, Douglas M. Ruderfer, Stephan Ripke, Nelson B. Freimer, Tatiana Foroud, Shaun Purcell, Ashley Dumont, Shawn Levy, Dominic Holland, Joanna Hauser, Anders D. Børglum, Liz Forty, Alan F. Schatzberg, Christine Fraser, Jennifer M. Whitehead Pavlides, William E. Bunney, Merete Nordentoft, Andres Metspalu, Gunnar Morken, Susanne Lucae, Roy H. Perlis, Anne T. Spijker, Richard A. Belliveau, Sarah E. Bergen, Fan Meng, Eduard Vieta, Cynthia Shannon Weickert, J. Raymond DePaulo, Martin Alda, Lina Martinsson, Melvin G. McInnis, Jacob Lawrence, Markus Leber, James A. Knowles, Franziska Degenhardt, Melissa J. Green, Jaqueline Goldstein, Amanda Dobbyn, Radhika Kandaswamy, Steve McCarroll, Katrin Gade, Jack D. Barchas, Christina M. Hultman, Sarah Kittel-Schneider, Martin Hautzinger, Maria Hipolito, Louise Frisén, Kari Stefansson, Michael Conlon O'Donovan, Markus M. Nöthen, Eline J. Regeer, Jens Treutlein, Robert Karlsson, Ian Jones, Nicholas G. Martin, William A. Scheftner, Caroline M. Nievergelt, Marta Ribasés, Simone de Jong, Szabolcs Szelinger, Thomas W. Mühleisen, Michele T. Pato, Manuel Mattheisen, Maciej Trzaskowski, Urs Heilbronner, Diane Gage, Jakob Grove, Ingrid Melle, Ole A. Andreassen, Claudia Giambartolomei, Kimberly Chambert, Arne E. Vaaler, William Coryell, Peter R. Schofield, Preben Bo Mortensen, Roel A. Ophoff, Fabian Streit, Manolis Kogevinas, Ingrid Agartz, John Strauss, James L. Kennedy, Anders M. Dale, Stefan Herms, Douglas Blackwood, Torbjørn Elvsåshagen, Bernhard T. Baune, Grant W. Montgomery, Andreas Reif, Fabio Rivas, Andrew McQuillin, Jordan W. Smoller, Chun Chieh Fan, James B. Potash, Jun Li, Ketil J. Oedegaard, David Curtis, Martin Schalling, John R. Kelsoe, Valentina Escott-Price, Sascha B. Fischer, Tatyana Shehktman, Jonathan R. I. Coleman, Stanley J. Watson, Donald J. MacIntyre, Tune H. Pers, Eystein Stordal, Richard M. Myers, Jose Guzman-Parra, Danielle Posthuma, John I. Nurnberger, William Lawson, Janet L. Sobell, Felecia Cerrato, Judith A. Badner, Elliot S. Gershon, Gerome Breen, Naomi R. Wray, Thomas Werge, Lilijana Oruc, Claire Slaney, Anil P.S. Ori, Alexander W. Charney, Marianne Giørtz Pedersen, Marie Bækvad-Hansen, Michael Boehnke, Marcella Rietschel, George Kirov, Aiden Corvin, Piotr M. Czerski, Peter Holmans, Michael Steffens, Margarita Rivera, Maria Grigoroiu-Serbanescu, René S. Kahn, Laura M. Huckins, Monika Budde, Michael Gill, Lili Milani, Christiaan de Leeuw, Peng Zhang, Nicholas Bass, Jana Strohmaier, John P. Rice, Wei Xu, Cristiana Cruceanu, Vassily Trubetskoy, Philip B. Mitchell, Helena Medeiros, Thomas Damm Als, Anna C. Koller, Huda Akil, Jessica S. Johnson, Toni-Kim Clarke, Janice M. Fullerton, Guy A. Rouleau, Fernando S. Goes, Weihua Guan, Wolfgang Maier, Pamela Sklar, Diego Albani, Laura J. Scott, Pamela B. Mahon, Anna Maaser, Katherine Gordon-Smith, Urban Ösby, Jurgen Del-Favero, Jolanta Lissowska, Howard J. Edenberg, Sven Cichon, Annelie Nordin Adolfsson, Julie Garnham, Josef Frank, Hoang T. Nguyen, Michael Bauer, Helmut Vedder, Vishwajit L. Nimgaonkar, Loes M. Olde Loohuis, Thomas G. Schulze, Cristina Sánchez-Mora, Udo Dannlowski, Rolf Adolfsson, Benjamin M. Neale, Verneri Antilla, Andrea Pfennig, John B. Vincent, Niamh Mullins, Per Hoffmann, Peter McGuffin, Erlend Bøen, Ney Alliey-Rodriguez, Adebayo Anjorin, Fermín Mayoral, Arianna Di Florio, Claire Churchhouse, David M. Hougaard, Nicholas J. Schork, Tiffany A. Greenwood, Carlos N. Pato, Thorgeir E. Thorgeirsson, Nicholas John Craddock, Stephanie H. Witt, Liam Abbott, Swapnil Awasthi, Miquel Casas, Jonas Bybjerg-Grauholm, Cathryn M. Lewis, Srdjan Djurovic, Bruno Etain, Margit Burmeister, Phil Lee, Elaine K. Green, Sara A. Paciga, Lena Backlund, Engilbert Sigurdsson, Patrick F. Sullivan, Amy Perry, Pablo Cervantes, Marco P. Boks, Catharina Lavebratt, Andrew M. McIntosh, Panos Roussos, Enda M. Byrne, Alexander Richards, Eli A. Stahl, Stéphane Jamain, Hreinn Stefansson, Ole Mors, Esben Agerbo, Susan L. McElroy, Wade H. Berrettini, Peter P. Zandi, Lisa Jones, Andreas J. Forstner, Alessandro Serretti, Céline S. Reinbold, Robert C. Thompson, Matthew Flickinger, William Byerley, Michael John Owen, Helena Gaspar, Francis J. McMahon, David St Clair, Mark A. Frye, Christine Søholm Hansen, Scott D. Gordon, Mikael Landén, Gustavo Turecki, Simon Xi, Evaristus A. Nwulia, Anders Juréus, James Boocock, Stacy Steinberg, Paul D. Shilling, David Craig, Mark J. Daly, Sarah E. Medland, Marion Leboyer, Chunyu Liu, Carsten Bøcker Pedersen, Sebastian Zöllner, APH - Mental Health, Psychiatry, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Stahl E.A., Breen G., Forstner A.J., McQuillin A., Ripke S., Trubetskoy V., Mattheisen M., Wang Y., Coleman J.R.I., Gaspar H.A., de Leeuw C.A., Steinberg S., Pavlides J.M.W., Trzaskowski M., Byrne E.M., Pers T.H., Holmans P.A., Richards A.L., Abbott L., Agerbo E., Akil H., Albani D., Alliey-Rodriguez N., Als T.D., Anjorin A., Antilla V., Awasthi S., Badner J.A., Baekvad-Hansen M., Barchas J.D., Bass N., Bauer M., Belliveau R., Bergen S.E., Pedersen C.B., Boen E., Boks M.P., Boocock J., Budde M., Bunney W., Burmeister M., Bybjerg-Grauholm J., Byerley W., Casas M., Cerrato F., Cervantes P., Chambert K., Charney A.W., Chen D., Churchhouse C., Clarke T.-K., Coryell W., Craig D.W., Cruceanu C., Curtis D., Czerski P.M., Dale A.M., de Jong S., Degenhardt F., Del-Favero J., DePaulo J.R., Djurovic S., Dobbyn A.L., Dumont A., Elvsashagen T., Escott-Price V., Fan C.C., Fischer S.B., Flickinger M., Foroud T.M., Forty L., Frank J., Fraser C., Freimer N.B., Frisen L., Gade K., Gage D., Garnham J., Giambartolomei C., Pedersen M.G., Goldstein J., Gordon S.D., Gordon-Smith K., Green E.K., Green M.J., Greenwood T.A., Grove J., Guan W., Guzman-Parra J., Hamshere M.L., Hautzinger M., Heilbronner U., Herms S., Hipolito M., Hoffmann P., Holland D., Huckins L., Jamain S., Johnson J.S., Jureus A., Kandaswamy R., Karlsson R., Kennedy J.L., Kittel-Schneider S., Knowles J.A., Kogevinas M., Koller A.C., Kupka R., Lavebratt C., Lawrence J., Lawson W.B., Leber M., Lee P.H., Levy S.E., Li J.Z., Liu C., Lucae S., Maaser A., MacIntyre D.J., Mahon P.B., Maier W., Martinsson L., McCarroll S., McGuffin P., McInnis M.G., McKay J.D., Medeiros H., Medland S.E., Meng F., Milani L., Montgomery G.W., Morris D.W., Muhleisen T.W., Mullins N., Nguyen H., Nievergelt C.M., Adolfsson A.N., Nwulia E.A., O'Donovan C., Loohuis L.M.O., Ori A.P.S., Oruc L., Osby U., Perlis R.H., Perry A., Pfennig A., Potash J.B., Purcell S.M., Regeer E.J., Reif A., Reinbold C.S., Rice J.P., Rivas F., Rivera M., Roussos P., Ruderfer D.M., Ryu E., Sanchez-Mora C., Schatzberg A.F., Scheftner W.A., Schork N.J., Shannon Weickert C., Shehktman T., Shilling P.D., Sigurdsson E., Slaney C., Smeland O.B., Sobell J.L., Soholm Hansen C., Spijker A.T., St Clair D., Steffens M., Strauss J.S., Streit F., Strohmaier J., Szelinger S., Thompson R.C., Thorgeirsson T.E., Treutlein J., Vedder H., Wang W., Watson S.J., Weickert T.W., Witt S.H., Xi S., Xu W., Young A.H., Zandi P., Zhang P., Zollner S., Adolfsson R., Agartz I., Alda M., Backlund L., Baune B.T., Bellivier F., Berrettini W.H., Biernacka J.M., Blackwood D.H.R., Boehnke M., Borglum A.D., Corvin A., Craddock N., Daly M.J., Dannlowski U., Esko T., Etain B., Frye M., Fullerton J.M., Gershon E.S., Gill M., Goes F., Grigoroiu-Serbanescu M., Hauser J., Hougaard D.M., Hultman C.M., Jones I., Jones L.A., Kahn R.S., Kirov G., Landen M., Leboyer M., Lewis C.M., Li Q.S., Lissowska J., Martin N.G., Mayoral F., McElroy S.L., McIntosh A.M., McMahon F.J., Melle I., Metspalu A., Mitchell P.B., Morken G., Mors O., Mortensen P.B., Muller-Myhsok B., Myers R.M., Neale B.M., Nimgaonkar V., Nordentoft M., Nothen M.M., O'Donovan M.C., Oedegaard K.J., Owen M.J., Paciga S.A., Pato C., Pato M.T., Posthuma D., Ramos-Quiroga J.A., Ribases M., Rietschel M., Rouleau G.A., Schalling M., Schofield P.R., Schulze T.G., Serretti A., Smoller J.W., Stefansson H., Stefansson K., Stordal E., Sullivan P.F., Turecki G., Vaaler A.E., Vieta E., Vincent J.B., Werge T., Nurnberger J.I., Wray N.R., Di Florio A., Edenberg H.J., Cichon S., Ophoff R.A., Scott L.J., Andreassen O.A., Kelsoe J., Sklar P., eQTLGen Consortium, BIOS Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, and Complex Trait Genetics

Subjects
Male, Bipolar Disorder, Bipolar I disorder, Schizophrenia/genetics, LD SCORE REGRESSION, Genome-wide association study, VARIANTS, Bipolar II disorder, 0302 clinical medicine, SCHIZOPHRENIA, GWAS, Psychotic Disorders/genetics, Non-U.S. Gov't, RISK, Genetics, 0303 health sciences, HERITABILITY, Research Support, Non-U.S. Gov't, Systems Biology, Major/genetics, Single Nucleotide, 3. Good health, Schizophrenia, Major depressive disorder, Female, Case-Control Studie, Depressive Disorder, Major/genetics, Human, Psychosis, GENES, Biology, Psychotic Disorder, Research Support, Polymorphism, Single Nucleotide, Article, Bipolar Disorder/classification, N.I.H, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, Journal Article, POLYGENICITY, Humans, Genetic Predisposition to Disease, Bipolar disorder, Polymorphism, METAANALYSIS, 030304 developmental biology, Intramural, Depressive Disorder, Major, Depressive Disorder, Genetic heterogeneity, Research Support, N.I.H., Intramural, medicine.disease, INDIVIDUALS, Psychotic Disorders, Genetic Loci, Case-Control Studies, Human medicine, 030217 neurology & neurosurgery, Genome-Wide Association Study, Meta-Analysis
Abstract

This paper is dedicated to the memory of Psychiatric Genomics Consortium (PGC) founding member and Bipolar disorder working group co-chair Pamela Sklar. We thank the participants who donated their time, experiences and DNA to this research, and to the clinical and scientific teams that worked with them. We are deeply indebted to the investigators who comprise the PGC. The views expressed are those of the authors and not necessarily those of any funding or regulatory body. Analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org ) hosted by SURFsara, and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu)., Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P, This work was funded in part by the Brain and Behavior Research Foundation, Stanley Medical Research Institute, University of Michigan, Pritzker Neuropsychiatric Disorders Research Fund L.L.C., Marriot Foundation and the Mayo Clinic Center for Individualized Medicine, the NIMH Intramural Research Program; Canadian Institutes of Health Research; the UK Maudsley NHS Foundation Trust, NIHR, NRS, MRC, Wellcome Trust; European Research Council; German Ministry for Education and Research, German Research Foundation IZKF of Münster, Deutsche Forschungsgemeinschaft, ImmunoSensation, the Dr. Lisa-Oehler Foundation, University of Bonn; the Swiss National Science Foundation; French Foundation FondaMental and ANR; Spanish Ministerio de Economía, CIBERSAM, Industria y Competitividad, European Regional Development Fund (ERDF), Generalitat de Catalunya, EU Horizon 2020 Research and Innovation Programme; BBMRI-NL; South-East Norway Regional Health Authority and Mrs. Throne-Holst; Swedish Research Council, Stockholm County Council, Söderström Foundation; Lundbeck Foundation, Aarhus University; Australia NHMRC, NSW Ministry of Health, Janette M O'Neil and Betty C Lynch.

Published
2019
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47. Splice-Break: exploiting an RNA-seq splice junction algorithm to discover mitochondrial DNA deletion breakpoints and analyses of psychiatric disorders

Author

Marquis P. Vawter, Elizabeth C. Chao, Filipe Pereira, William E. Bunney, Jack D. Barchas, Richard M. Myers, Adolfo Sequeira, Joana Damas, Ling Morgan, Firoza Mamdani, Francis S. Lee, Brooke E. Hjelm, Alan F. Schatzberg, Brandi Rollins, Michelle Webb, Huda Akil, Virginia Kimonis, Matthieu D Weber, Stanley J. Watson, and Peter M. Thompson

Subjects
Male, Mitochondrial DNA, Sequence analysis, Biology, DNA, Mitochondrial, Polymerase Chain Reaction, Genome, law.invention, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, law, Genetics, Humans, splice, Polymerase chain reaction, Sequence Deletion, 030304 developmental biology, Depressive Disorder, Major, 0303 health sciences, Base Sequence, Sequence Analysis, RNA, DNA Breaks, Breakpoint, Brain, Computational Biology, RNA, chemistry, Methods Online, Female, RNA Splice Sites, Algorithm, Algorithms, 030217 neurology & neurosurgery, DNA
Abstract

Deletions in the 16.6 kb mitochondrial genome have been implicated in numerous disorders that often display muscular and/or neurological symptoms due to the high-energy demands of these tissues. We describe a catalogue of 4489 putative mitochondrial DNA (mtDNA) deletions, including their frequency and relative read rate, using a combinatorial approach of mitochondria-targeted PCR, next-generation sequencing, bioinformatics, post-hoc filtering, annotation, and validation steps. Our bioinformatics pipeline uses MapSplice, an RNA-seq splice junction detection algorithm, to detect and quantify mtDNA deletion breakpoints rather than mRNA splices. Analyses of 93 samples from postmortem brain and blood found (i) the 4977 bp ‘common deletion’ was neither the most frequent deletion nor the most abundant; (ii) brain contained significantly more deletions than blood; (iii) many high frequency deletions were previously reported in MitoBreak, suggesting they are present at low levels in metabolically active tissues and are not exclusive to individuals with diagnosed mitochondrial pathologies; (iv) many individual deletions (and cumulative metrics) had significant and positive correlations with age and (v) the highest deletion burdens were observed in major depressive disorder brain, at levels greater than Kearns–Sayre Syndrome muscle. Collectively, these data suggest the Splice-Break pipeline can detect and quantify mtDNA deletions at a high level of resolution.

Published
2019
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49. Circadian patterns of gene expression in the human brain and disruption in major depressive disorder

Author

Prabhakara V. Choudary, David M. Walsh, Fan Meng, Jack D. Barchas, Preston M. Cartagena, Simon J. Evans, Huda Akil, Blynn G. Bunney, Richard M. Myers, Edward G. Jones, Jun Li, William E. Bunney, Alan F. Schatzberg, Megan Hastings Hagenauer, Marquis P. Vawter, and Stanley J. Watson

Subjects
Adult, Male, medicine.medical_specialty, Circadian clock, Biology, Circadian Clocks, Internal medicine, Basic Helix-Loop-Helix Transcription Factors, medicine, Humans, Circadian rhythm, Aged, Oligonucleotide Array Sequence Analysis, Homeodomain Proteins, Depressive Disorder, Major, Multidisciplinary, Suprachiasmatic nucleus, Gene Expression Profiling, ARNTL Transcription Factors, Brain, Period Circadian Proteins, Human brain, Middle Aged, Biological Sciences, Circadian Rhythm, CLOCK, ARNTL, Dorsolateral prefrontal cortex, medicine.anatomical_structure, Endocrinology, Nuclear Receptor Subfamily 1, Group D, Member 1, Female, Autopsy, Neuroscience
Abstract

A cardinal symptom of major depressive disorder (MDD) is the disruption of circadian patterns. However, to date, there is no direct evidence of circadian clock dysregulation in the brains of patients who have MDD. Circadian rhythmicity of gene expression has been observed in animals and peripheral human tissues, but its presence and variability in the human brain were difficult to characterize. Here, we applied time-of-death analysis to gene expression data from high-quality postmortem brains, examining 24-h cyclic patterns in six cortical and limbic regions of 55 subjects with no history of psychiatric or neurological illnesses (“controls”) and 34 patients with MDD. Our dataset covered ∼12,000 transcripts in the dorsolateral prefrontal cortex, anterior cingulate cortex, hippocampus, amygdala, nucleus accumbens, and cerebellum. Several hundred transcripts in each region showed 24-h cyclic patterns in controls, and >100 transcripts exhibited consistent rhythmicity and phase synchrony across regions. Among the top-ranked rhythmic genes were the canonical clock genes BMAL1(ARNTL), PER1-2-3, NR1D1(REV-ERBa), DBP, BHLHE40 (DEC1) , and BHLHE41(DEC2) . The phasing of known circadian genes was consistent with data derived from other diurnal mammals. Cyclic patterns were much weaker in the brains of patients with MDD due to shifted peak timing and potentially disrupted phase relationships between individual circadian genes. This transcriptome-wide analysis of the human brain demonstrates a rhythmic rise and fall of gene expression in regions outside of the suprachiasmatic nucleus in control subjects. The description of its breakdown in MDD suggests potentially important molecular targets for treatment of mood disorders.

Published
2013
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50. Variable telomere length across post-mortem human brain regions and specific reduction in the hippocampus of major depressive disorder

Author

Firoza Mamdani, Jack D. Barchas, Ling Morgan, Richard M. Myers, Steven G. Potkin, William E. Bunney, Huda Akil, Alan F. Schatzberg, S.J. Watson, Barrett J. Rollins, Marquis P. Vawter, and P.A. Sequeira

Subjects
Male, medicine.medical_specialty, Hippocampus, Hippocampal formation, Polymerase Chain Reaction, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Internal medicine, medicine, Cadaver, Humans, Biological Psychiatry, 030304 developmental biology, 0303 health sciences, Analysis of Variance, Depressive Disorder, Major, Dissection, Brain, Human brain, Middle Aged, Telomere, medicine.disease, Dorsolateral prefrontal cortex, Psychiatry and Mental health, Endocrinology, medicine.anatomical_structure, Mood disorders, Genetic Techniques, Schizophrenia, Major depressive disorder, Original Article, Female, Erratum, Psychology, Cell aging, Neuroscience, 030217 neurology & neurosurgery
Abstract

Stress can be a predisposing factor to psychiatric disorders and has been associated with decreased neurogenesis and reduced hippocampal volume especially in depression. Similarly, in white blood cells chronic psychological stress has been associated with telomere shortening and with mood disorders and schizophrenia (SZ). However, in previous post-mortem brain studies from occipital cortex and cerebellum, no difference in telomere length was observed in depression. We hypothesized that in psychiatric disorders, stress-driven accelerated cellular aging can be observed in brain regions particularly sensitive to stress. Telomere length was measured by quantitative-PCR in five brain regions (dorsolateral prefrontal cortex, hippocampus (HIPP), amygdala, nucleus accumbens and substantia nigra (SN)) in major depressive disorder (MDD), bipolar disorder, SZ and normal control subjects (N=40, 10 subjects per group). We observed significant differences in telomere length across brain regions suggesting variable levels of cell aging, with SN and HIPP having the longest telomeres and the dorsolateral prefrontal cortex the shortest. A significant decrease (P

Published
2016

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