36 results on '"Schulze, Thomas"'
Search Results
2. Autorenverzeichnis
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Becker, Thomas, primary, Falkai, Peter, additional, Falkenberg, Irina, additional, Fallgatter, Andreas J., additional, Förstl, Hans, additional, Gaebel, Wolfgang, additional, Görtz, Philipp, additional, Hasan, Alkomiet, additional, Janssen, Birgit, additional, Kircher, Tilo, additional, Lang, Fabian U., additional, Leucht, Stefan, additional, Lincoln, Tania, additional, Mehl, Stephanie, additional, Plewnia, Christian, additional, Schimmelmann, Benno G., additional, Schmitt, Andrea, additional, Schulze, Thomas G., additional, Wobrock, Thomas, additional, Wolff-Menzler, Claus, additional, and Zielasek, Jürgen, additional
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- 2016
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3. Translating big data to better treatment in bipolar disorder - a manifesto for coordinated action
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Manchia, Mirko, Vieta i Pascual, Eduard, 1963, Smeland, Olav B., Altimus, Cara, Bechdolf, Andreas, Bellivier, Frank, Bergink, Veerle, Fagiolini, Andrea, Geddes, John R., Hajek, Tomas, Henry, Chantal, Kupka, Ralph, Lagerberg, Trine V., Licht, Rasmus W., Martinez-Cengotitabengoa, Monica, Morken, Gunnar, Nielsen, René E., González-Pinto, Ana, Reif, Andreas, Rietschel, Marcella, Ritter, Phillip, Schulze, Thomas G., Scott, Jan, Severus, Emanuel, Yildiz, Aysegul, Kessing, Lars Vedel, Bauer, Michael, Goodwin, Guy M., Andreassen, Ole A., European College of Neuropsychopharmacology (ECNP) Bipolar Disorders Network, Psychiatry, European Commission, and APH - Mental Health
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Big Data ,Manifesto ,Open science ,Bipolar Disorder ,precision medicine ,Psychological intervention ,Global Health ,Translational Research, Biomedical ,03 medical and health sciences ,risk prediction ,Big data ,0302 clinical medicine ,Health care ,open science ,Machine learning ,Humans ,Manic-depressive illness ,Pharmacology (medical) ,philanthropy ,Biological Psychiatry ,Pharmacology ,Clinical Trials as Topic ,Government ,Trastorn bipolar ,business.industry ,Precision medicine ,Dades massives ,Public relations ,Risk prediction ,030227 psychiatry ,3. Good health ,Psychiatry and Mental health ,Treatment Outcome ,machine learning ,Neurology ,Action (philosophy) ,Common cause and special cause ,Philanthropy ,Neurology (clinical) ,business ,Psychology ,030217 neurology & neurosurgery - Abstract
[EN] Bipolar disorder (BD) is a major healthcare and socio-economic challenge. Despite its substan- tial burden on society, the research activity in BD is much smaller than its economic impact appears to demand. There is a consensus that the accurate identification of the underlying pathophysiology for BD is fundamental to realize major health benefits through better treat- ment and preventive regimens. However, to achieve these goals requires coordinated action and innovative approaches to boost the discovery of the neurobiological underpinnings of BD, and rapid translation of research findings into development and testing of better and more spe- cific treatments. To this end, we here propose that only a large-scale coordinated action can be successful in integrating international big-data approaches with real-world clinical inter- ventions. This could be achieved through the creation of a Global Bipolar Disorder Foundation, which could bring government, industry and philanthropy together in common cause. A global initiative for BD research would come at a highly opportune time given the seminal advances promised for our understanding of the genetic and brain basis of the disease and the obvious areas of unmet clinical need. Such an endeavour would embrace the principles of open science and see the strong involvement of user groups and integration of dissemination and public involvement with the research programs. We believe the time is right for a step change in our approach to understanding, treating and even preventing BD effectively. We thank Chris Chang for input on the description of the ENIGMA project. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health in the UK. Ole A. Andreassen is together with Paolo Fusar-Poli co-chairing the Prevention of Severe Mental Disorders (PSMD) cluster, which is supported by the European Brain Research Area project. EBRA has re- ceived funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 825348 .
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- 2020
4. Association between schizophrenia and common variation in neurocan (NCAN), a genetic risk factor for bipolar disorder
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Mühleisen, Thomas W, Mattheisen, Manuel, Rivandeneira, Fernando, Hofman, Albert, Uitterlinden, André G, Moebus, Susanne, Gieger, Christian, Emeny, Rebecca, Ladwig, Karl-Heinz, Wichmann, H-Erich, Schwarz, Markus, Kammerer-Ciernioch, Jutta, Strohmaier, Jana, Schlösser, Ralf G M, Nenadic, Igor, Sauer, Heinrich, Mössner, Rainald, Maier, Wolfgang, Rujescu, Dan, Lange, Christoph, Ophoff, Roel A, Schulze, Thomas G, Rietschel, Marcella, Degenhardt, Franziska, Nöthen, Markus M, Priebe, Lutz, Schultz, C Christoph, Kahn, René S, Linszen, Don H, van Os, Jim, Wiersma, Durk, Bruggeman, Richard, Cahn, Wiepke, de Haan, Lieuwe, Krabbendam, Lydia, Myin-Germeys, Inez, Breuer, René, Wichmann, H -Erich, Breuer, Rene, Meier, Sandra, Hoffmann, Per, Cichon, Sven, Investigators, GROUP, Psychiatrie & Neuropsychologie, RS: MHeNs School for Mental Health and Neuroscience, Adult Psychiatry, Amsterdam Neuroscience, Epidemiology, and Internal Medicine
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Oncology ,NCAN protein, human ,medicine.medical_specialty ,Bipolar Disorder ,Genotype ,Psychotic disorder ,Medizin ,Genetic overlap ,Genome-wide association study ,Nerve Tissue Proteins ,Polymorphism, Single Nucleotide ,Hippocampus ,Association ,03 medical and health sciences ,0302 clinical medicine ,Gene Frequency ,Neurocan ,Internal medicine ,Genetic variation ,mental disorders ,medicine ,Humans ,genetics [Schizophrenia] ,Genetic Predisposition to Disease ,Lectins, C-Type ,ddc:610 ,Bipolar disorder ,Risk factor ,genetics [Nerve Tissue Proteins] ,Biological Psychiatry ,genetics [Lectins, C-Type] ,030304 developmental biology ,Genetics ,genetics [Chondroitin Sulfate Proteoglycans] ,0303 health sciences ,Case-control study ,Odds ratio ,medicine.disease ,Psychiatry and Mental health ,Manic depression ,Chondroitin Sulfate Proteoglycans ,Schizophrenia ,Case-Control Studies ,Cortex ,Psychology ,genetics [Bipolar Disorder] ,030217 neurology & neurosurgery - Abstract
A recent study found genome-wide significant association between common variation in the gene neurocan (NCAN, rs1064395) and bipolar disorder (BD). In view of accumulating evidence that BD and schizophrenia partly share genetic risk factors, we tested this single-nucleotide polymorphism for association with schizophrenia in three independent patient-control samples of European ancestry, totaling 5061 patients and 9655 controls. The rs1064395 A-allele, which confers risk for BD, was significantly over-represented in schizophrenia patients compared to controls (p=2.28x10(-3); odds ratio=1.11). Follow-up in non-overlapping samples from the Schizophrenia Psychiatric GWAS Consortium (5537 patients, 8043 controls) provided further support for our finding (p=0.0239, odds ratio=1.07). Our data suggest that genetic variation in NCAN is a common risk factor for BD and schizophrenia. (C) 2012 Elsevier B.V. All rights reserved.
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- 2012
5. Therapeutic effectiveness of anti-inflammatory monoclonal antibodies in psychiatric disorders: Challenges with an imbalanced immune system.
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Oraki Kohshour M and Schulze TG
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Competing Interests: Declaration of competing interest The authors report no conflict of interest related to this manuscript.
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- 2024
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6. Lithium response in bipolar disorder: Epigenome-wide DNA methylation signatures and epigenetic aging.
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Zafrilla-López M, Acosta-Díez M, Mitjans M, Giménez-Palomo A, Saiz PA, Barrot-Feixat C, Jiménez E, Papiol S, Ruiz V, Gavín P, García-Portilla MP, González-Blanco L, Bobes J, Schulze TG, Vieta E, Benabarre A, and Arias B
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- Humans, Female, Male, Adult, Middle Aged, Epigenome genetics, Antimanic Agents therapeutic use, Lithium Compounds therapeutic use, Lithium Compounds pharmacology, Bipolar Disorder genetics, Bipolar Disorder drug therapy, DNA Methylation drug effects, Epigenesis, Genetic drug effects, Epigenesis, Genetic genetics, Aging genetics
- Abstract
Lithium (Li) is the first-line treatment for bipolar disorder (BD) even though only 30 % of BD patients are considered excellent responders. The mechanisms by which Li exerts its action are not clearly understood, but it has been suggested that specific epigenetic mechanisms, such as methylation processes, may play a role. In this regard, DNA methylation patterns can be used to estimate epigenetic age (EpiAge), which is accelerated in BD patients and reversed by Li treatment. Our first aim was to compare the DNA methylation profile in peripheral blood between BD patients categorized as excellent responders to Li (Ex-Rp) and non-responders (N-Rp). Secondly, EpiAge was estimated to detect differential age acceleration between the two groups. A total of 130 differentially methylated positions (DMPs) and 16 differentially methylated regions (DMRs) between Ex-Rp (n = 26) and N-Rp (n = 37) were identified (FDR adjusted p-value < 0.05). We found 122 genes mapping the DMPs and DMRs, nine of which (HOXB6, HOXB3, HOXB-AS3, TENM2, CACNA1B, ANK3, EEF2K, CYP1A1, and SORCS2) had previously been linked to Li response. We found genes related to the GSK3β pathway to be highly represented. Using FUMA, we found enrichment in Gene Ontology Cell Component for the synapse. Gene network analysis highlighted functions related to the cell cycle, nervous system development and function, and gene expression. No significant differences in age acceleration were found between Ex-Rp and N-Rp for any of the epigenetic clocks analysed. Our findings indicate that a specific methylation pattern could determine the response to Li in BD patients. We also found that a significant portion of the differentially methylated genes are closely associated with the GSK3β pathway, reinforcing the role of this system in Li response. Future longitudinal studies with larger samples will help to elucidate the epigenetic mechanisms underlying Li response., Competing Interests: Declaration of competing interest AGP has received CME-related honoraria, or consulting fees unrelated to the present work from Angelini, Janssen-Cilag, Casen Recordati, Rovi, LCN and Lundbeck. EV has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, AbbVie, Adamed, Angelini, Biogen, Biohaven, Boehringer-Ingelheim, Celon Pharma, Compass, Dainippon Sumitomo Pharma, Ethypharm, Ferrer, Gedeon Richter, GH Research, Glaxo-Smith Kline, HMNC, Idorsia, Janssen, Lundbeck, Medincell, Merck, Novartis, Orion Corporation, Organon, Otsuka, Roche, Rovi, Sage, Sanofi-Aventis, Sunovion, Takeda, and Viatris, outside the submitted work. The rest of authors have nothing to disclose., (Copyright © 2024. Published by Elsevier B.V.)
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- 2024
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7. How do lipids fit into the picture of severe mental health disorders? A missing pathophysiologic link or just a consequence of behavior and treatment.
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Schulte EC and Schulze TG
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- Humans, Lipids blood, Mental Disorders psychology
- Abstract
Competing Interests: Declaration of competing interest The authors report no relevant conflicts of interest with regard to the content of this manuscript.
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- 2024
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8. Engineered extracellular vesicles and their promising therapeutic potential in neuropsychiatric disorders.
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Schulze TG and Delalle I
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- Extracellular Vesicles
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- 2022
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9. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors.
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Mullins N, Kang J, Campos AI, Coleman JRI, Edwards AC, Galfalvy H, Levey DF, Lori A, Shabalin A, Starnawska A, Su MH, Watson HJ, Adams M, Awasthi S, Gandal M, Hafferty JD, Hishimoto A, Kim M, Okazaki S, Otsuka I, Ripke S, Ware EB, Bergen AW, Berrettini WH, Bohus M, Brandt H, Chang X, Chen WJ, Chen HC, Crawford S, Crow S, DiBlasi E, Duriez P, Fernández-Aranda F, Fichter MM, Gallinger S, Glatt SJ, Gorwood P, Guo Y, Hakonarson H, Halmi KA, Hwu HG, Jain S, Jamain S, Jiménez-Murcia S, Johnson C, Kaplan AS, Kaye WH, Keel PK, Kennedy JL, Klump KL, Li D, Liao SC, Lieb K, Lilenfeld L, Liu CM, Magistretti PJ, Marshall CR, Mitchell JE, Monson ET, Myers RM, Pinto D, Powers A, Ramoz N, Roepke S, Rozanov V, Scherer SW, Schmahl C, Sokolowski M, Strober M, Thornton LM, Treasure J, Tsuang MT, Witt SH, Woodside DB, Yilmaz Z, Zillich L, Adolfsson R, Agartz I, Air TM, Alda M, Alfredsson L, Andreassen OA, Anjorin A, Appadurai V, Soler Artigas M, Van der Auwera S, Azevedo MH, Bass N, Bau CHD, Baune BT, Bellivier F, Berger K, Biernacka JM, Bigdeli TB, Binder EB, Boehnke M, Boks MP, Bosch R, Braff DL, Bryant R, Budde M, Byrne EM, Cahn W, Casas M, Castelao E, Cervilla JA, Chaumette B, Cichon S, Corvin A, Craddock N, Craig D, Degenhardt F, Djurovic S, Edenberg HJ, Fanous AH, Foo JC, Forstner AJ, Frye M, Fullerton JM, Gatt JM, Gejman PV, Giegling I, Grabe HJ, Green MJ, Grevet EH, Grigoroiu-Serbanescu M, Gutierrez B, Guzman-Parra J, Hamilton SP, Hamshere ML, Hartmann A, Hauser J, Heilmann-Heimbach S, Hoffmann P, Ising M, Jones I, Jones LA, Jonsson L, Kahn RS, Kelsoe JR, Kendler KS, Kloiber S, Koenen KC, Kogevinas M, Konte B, Krebs MO, Landén M, Lawrence J, Leboyer M, Lee PH, Levinson DF, Liao C, Lissowska J, Lucae S, Mayoral F, McElroy SL, McGrath P, McGuffin P, McQuillin A, Medland SE, Mehta D, Melle I, Milaneschi Y, Mitchell PB, Molina E, Morken G, Mortensen PB, Müller-Myhsok B, Nievergelt C, Nimgaonkar V, Nöthen MM, O'Donovan MC, Ophoff RA, Owen MJ, Pato C, Pato MT, Penninx BWJH, Pimm J, Pistis G, Potash JB, Power RA, Preisig M, Quested D, Ramos-Quiroga JA, Reif A, Ribasés M, Richarte V, Rietschel M, Rivera M, Roberts A, Roberts G, Rouleau GA, Rovaris DL, Rujescu D, Sánchez-Mora C, Sanders AR, Schofield PR, Schulze TG, Scott LJ, Serretti A, Shi J, Shyn SI, Sirignano L, Sklar P, Smeland OB, Smoller JW, Sonuga-Barke EJS, Spalletta G, Strauss JS, Świątkowska B, Trzaskowski M, Turecki G, Vilar-Ribó L, Vincent JB, Völzke H, Walters JTR, Shannon Weickert C, Weickert TW, Weissman MM, Williams LM, Wray NR, Zai CC, Ashley-Koch AE, Beckham JC, Hauser ER, Hauser MA, Kimbrel NA, Lindquist JH, McMahon B, Oslin DW, Qin X, Agerbo E, Børglum AD, Breen G, Erlangsen A, Esko T, Gelernter J, Hougaard DM, Kessler RC, Kranzler HR, Li QS, Martin NG, McIntosh AM, Mors O, Nordentoft M, Olsen CM, Porteous D, Ursano RJ, Wasserman D, Werge T, Whiteman DC, Bulik CM, Coon H, Demontis D, Docherty AR, Kuo PH, Lewis CM, Mann JJ, Rentería ME, Smith DJ, Stahl EA, Stein MB, Streit F, Willour V, and Ruderfer DM
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- Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Risk Factors, Suicide, Attempted, Depressive Disorder, Major genetics, Mental Disorders genetics
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Background: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders., Methods: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors., Results: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged., Conclusions: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders., (Copyright © 2021 Society of Biological Psychiatry. All rights reserved.)
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- 2022
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10. Outcomes associated with different vaccines in individuals with bipolar disorder and impact on the current COVID-19 pandemic- a systematic review.
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Reininghaus EZ, Manchia M, Dalkner N, Bonkat N, Squassina A, Hodl I, Vieta E, Reif A, Hajek T, Landén M, Correll CU, Scott J, Etain B, Rietschel M, Bergink V, Martinez-Cengotitabengoa M, Kessing LV, Fagiolini A, Bauer M, Goodwin G, Gonzalez-Pinto A, Kupka RW, Schulze TG, Lagerberg TV, Yildiz A, Henry C, Morken G, Ritter P, Nieslen RE, Licht RW, Bechdolf A, Andreassen OA, and Fellendorf FT
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- Communicable Disease Control, Communicable Diseases, Humans, Pandemics, SARS-CoV-2, Bipolar Disorder epidemiology, COVID-19, Vaccines administration & dosage, Vaccines adverse effects
- Abstract
Bipolar disorder (BD) might be associated with higher infection rates of coronavirus disease (COVID-19) which in turn could result in worsening the clinical course and outcome. This may be due to a high prevalence of somatic comorbidities and an increased risk of delays in and poorer treatment of somatic disease in patients with severe mental illness in general. Vaccination is the most important public health intervention to tackle the ongoing pandemic. We undertook a systematic review regarding the data on vaccinations in individuals with BD. Proportion of prevalence rates, efficacy and specific side effects of vaccinations and in individuals with BD were searched. Results show that only five studies have investigated vaccinations in individuals with BD, which substantially limits the interpretation of overall findings. Studies on antibody production after vaccinations in BD are very limited and results are inconsistent. Also, the evidence-based science on side effects of vaccinations in individuals with BD so far is poor., Competing Interests: Declaration of Competing Interest As the article is a review on the literature, there is generally no conflict of interest in respect to this article. Nevertheless, some of the authors had relationships with different companies or served as consultants in the last three years. MM has served as consultant, or CME speaker for Angelini. EV has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, Abbott, AbbVie, Angelini, Boehringer-Ingelheim, Dainippon Sumitomo Pharma, Ferrer, Gedeon Richter, GH Research, Janssen, Lundbeck, Novartis, Otsuka, Sage, Sanofi-Aventis, Sunovion, and Takeda, outside the submitted work. LM declares that he has received lecture honoraria from Lundbeck pharmaceutical. No other equity ownership, profit-sharing agreements, royalties, or patent. CC has been a consultant and/or advisor to or has received honoraria from: Acadia, Alkermes, Allergan, Angelini, Axsome, Gedeon Richter, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Medscape, Merck, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Servier, Sumitomo Dainippon, Sunovion, Supernus, Takeda, and Teva. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Lundbeck, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He is also a stock option holder of LB Pharma. AF is /has been a consultant and/or a speaker and/or has received research grants from Angelini, Apsen, Boheringer Ingelheim, Daiichi Sankyo, Doc Generici, Glaxo Smith Kline, Italfarmaco, Lundbeck, Janssen, Mylan, Neuraxpharm, Otsuka, Pfizer, Recordati, Sanofi Aventis, Sunovion, Vifor. MB has received institutional grants from Deutsche Forschungsgemeinschaft (DFG), Bundesministerium für Bildung und Forschung (BMBF), and European Commission. He served in advisory boards for GH Research, Janssen-Cilag, neuraxpharm, Novartis, Sandoz, Shire International, Sumitomo Dainippon, Sunovion, and Takeda, and received speaker honoraria for Aristo, Hexal, Janssen Pharmaceutica NV, Janssen-Cilag, and Sunovion, outside the submitted work. REN has received research grants from H. Lundbeck and Otsuka Pharmaceuticals for clinical trials, received speaking fees from Bristol-Myers Squibb, Astra Zeneca, Janssen & Cilag, Lundbeck, Servier, Otsuka Pharmaceuticals, Teva A/S, and Eli Lilly and has acted as advisor to Astra Zeneca, Eli Lilly, Lundbeck, Otsuka Pharmaceuticals, Takeda, and Medivir, and has acted as investigator for Janssen-Cilag, Lundbeck, Boehringer, Compass and Sage. RW Licht has within the preceding three years served an advisory board of Janssen Cilag and Sage and has received speaker honorarium from Astra-Zeneca, Jannsen-Cilag, Servier, Lundbeck and Teva. No known conflicts of interest in respect to this article from all other authors., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)
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- 2022
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11. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders.
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Blokland GAM, Grove J, Chen CY, Cotsapas C, Tobet S, Handa R, St Clair D, Lencz T, Mowry BJ, Periyasamy S, Cairns MJ, Tooney PA, Wu JQ, Kelly B, Kirov G, Sullivan PF, Corvin A, Riley BP, Esko T, Milani L, Jönsson EG, Palotie A, Ehrenreich H, Begemann M, Steixner-Kumar A, Sham PC, Iwata N, Weinberger DR, Gejman PV, Sanders AR, Buxbaum JD, Rujescu D, Giegling I, Konte B, Hartmann AM, Bramon E, Murray RM, Pato MT, Lee J, Melle I, Molden E, Ophoff RA, McQuillin A, Bass NJ, Adolfsson R, Malhotra AK, Martin NG, Fullerton JM, Mitchell PB, Schofield PR, Forstner AJ, Degenhardt F, Schaupp S, Comes AL, Kogevinas M, Guzman-Parra J, Reif A, Streit F, Sirignano L, Cichon S, Grigoroiu-Serbanescu M, Hauser J, Lissowska J, Mayoral F, Müller-Myhsok B, Świątkowska B, Schulze TG, Nöthen MM, Rietschel M, Kelsoe J, Leboyer M, Jamain S, Etain B, Bellivier F, Vincent JB, Alda M, O'Donovan C, Cervantes P, Biernacka JM, Frye M, McElroy SL, Scott LJ, Stahl EA, Landén M, Hamshere ML, Smeland OB, Djurovic S, Vaaler AE, Andreassen OA, Baune BT, Air T, Preisig M, Uher R, Levinson DF, Weissman MM, Potash JB, Shi J, Knowles JA, Perlis RH, Lucae S, Boomsma DI, Penninx BWJH, Hottenga JJ, de Geus EJC, Willemsen G, Milaneschi Y, Tiemeier H, Grabe HJ, Teumer A, Van der Auwera S, Völker U, Hamilton SP, Magnusson PKE, Viktorin A, Mehta D, Mullins N, Adams MJ, Breen G, McIntosh AM, Lewis CM, Hougaard DM, Nordentoft M, Mors O, Mortensen PB, Werge T, Als TD, Børglum AD, Petryshen TL, Smoller JW, and Goldstein JM
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- Endothelial Cells, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Receptors, Vascular Endothelial Growth Factor, Sulfurtransferases, Bipolar Disorder genetics, Depressive Disorder, Major genetics, Psychotic Disorders genetics, Schizophrenia genetics, Sex Characteristics
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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., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
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12. A GWAS top hit for circulating leptin is associated with weight gain but not with leptin protein levels in lithium-augmented patients with major depression.
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Bopp SK, Heilbronner U, Schlattmann P, Buspavanich PJ, Lang UE, Heinz A, Schulze TG, Adli M, Mühleisen TW, and Ricken R
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- Body Mass Index, Depression, Genome-Wide Association Study, Humans, Leptin genetics, Lithium adverse effects, Polymorphism, Single Nucleotide genetics, Weight Gain genetics, Depressive Disorder, Major drug therapy, Depressive Disorder, Major genetics
- Abstract
Lithium-treated patients often suffer from weight gain as a common adverse event. In an earlier investigation, we found an impact of two single-nucleotide polymorphisms (rs10487506 and rs2278815) at the leptin gene on weight gain but not on leptin protein levels in serum under lithium augmentation. A recent genome-wide association study identified a polymorphism at the leptin gene locus (rs10487505) associated with circulating leptin protein levels. To characterize potential effects of this variant in acute major depressive disorder, we investigated body mass indices from 180 lithium-augmented patients and serum concentrations of leptin protein from 89 patients using linear mixed model analyses and rs6979832, a proxy SNP of rs10487505. Body mass index was measured before and after 4 weeks of lithium augmentation, in a subsample also after 4 and 7 months. Leptin serum levels were measured before and during lithium augmentation. G-allele homozygotes of rs6979832 had a significantly lower body mass index increase during observation compared to A-allele hetero- and homozygotes. However, we found no influence on leptin serum levels. Joint analyses of rs6979832 with the previously investigated polymorphisms rs10487506 and rs2278815, and expressed quantitative trait data, suggest a complex interplay between SNP alleles at the leptin locus. These results strongly support our earlier findings that common genetic variation at the leptin gene locus may be involved in lithium augmentation-associated weight gain in major depressive disorder., (Copyright © 2021. Published by Elsevier B.V.)
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- 2021
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13. DSM-5 and ICD-11 criteria for bipolar disorder: Implications for the prevalence of bipolar disorder and validity of the diagnosis - A narrative review from the ECNP bipolar disorders network.
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Kessing LV, González-Pinto A, Fagiolini A, Bechdolf A, Reif A, Yildiz A, Etain B, Henry C, Severus E, Reininghaus EZ, Morken G, Goodwin GM, Scott J, Geddes JR, Rietschel M, Landén M, Manchia M, Bauer M, Martinez-Cengotitabengoa M, Andreassen OA, Ritter P, Kupka R, Licht RW, Nielsen RE, Schulze TG, Hajek T, Lagerberg TV, Bergink V, and Vieta E
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- Delayed Diagnosis, Diagnostic and Statistical Manual of Mental Disorders, Humans, International Classification of Diseases, Prevalence, Bipolar Disorder diagnosis, Bipolar Disorder epidemiology
- Abstract
This narrative review summarizes and discusses the implications of the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 and the upcoming International Classification of Diseases (ICD)-11 classification systems on the prevalence of bipolar disorder and on the validity of the DSM-5 diagnosis of bipolar disorder according to the Robin and Guze criteria of diagnostic validity. Here we review and discuss current data on the prevalence of bipolar disorder diagnosed according to DSM-5 versus DSM-IV, and data on characteristics of bipolar disorder in the two diagnostic systems in relation to extended Robin and Guze criteria: 1) clinical presentation, 2) associations with para-clinical data such as brain imaging and blood-based biomarkers, 3) delimitation from other disorders, 4) associations with family history / genetics, 5) prognosis and long-term follow-up, and 6) treatment effects. The review highlights that few studies have investigated consequences for the prevalence of the diagnosis of bipolar disorder and for the validity of the diagnosis. Findings from these studies suggest a substantial decrease in the point prevalence of a diagnosis of bipolar with DSM-5 compared with DSM-IV, ranging from 30-50%, but a smaller decrease in the prevalence during lifetime, corresponding to a 6% reduction. It is concluded that it is likely that the use of DSM-5 and ICD-11 will result in diagnostic delay and delayed early intervention in bipolar disorder. Finally, we recommend areas for future research., (Copyright © 2021. Published by Elsevier B.V.)
- Published
- 2021
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14. Corrigendum to "Translating big data to better treatment in bipolar disorder - a manifesto for coordinated action [European Neuropsychopharmacology (2020) 36, 121-136]".
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Manchia M, Vieta E, Smeland OB, Altimus C, Bechdolf A, Bellivier F, Bergink V, Fagiolini A, Geddes JR, Hajek T, Henry C, Kupka R, Lagerberg TV, Licht RW, Martinez-Cengotitabengoa M, Morken G, Nielsen RE, González-Pinto A, Reif A, Rietschel M, Ritter P, Schulze TG, Scott J, Severus E, Yildiz A, Kessing LV, Bauer M, Goodwin GM, and Andreassen OA
- Published
- 2021
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15. The ongoing torture and medical neglect of Julian Assange.
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Hogan W, Frost S, Johnson L, Schulze TG, Nelson EAS, and Frost W
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- Ethics, Medical, Human Rights, Longitudinal Studies, Torture
- Published
- 2020
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16. Clinical application of genomic high-throughput data: Infrastructural, ethical, legal and psychosocial aspects.
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Umbach N, Beißbarth T, Bleckmann A, Duttge G, Flatau L, König A, Kuhn J, Perera-Bel J, Roschauer J, Schulze TG, Schweda M, Urban A, Zimmermann A, and Sax U
- Subjects
- Genetic Counseling legislation & jurisprudence, Genetic Counseling standards, Genetic Testing legislation & jurisprudence, Genetic Testing standards, Genomics legislation & jurisprudence, Genomics standards, High-Throughput Screening Assays standards, Humans, Psychology, Genetic Counseling ethics, Genetic Testing ethics, Genomics ethics, High-Throughput Screening Assays ethics
- Abstract
Genomic high-throughput technologies (GHTT) such as next-generation sequencing represent a fast and cost-effective tool toward a more comprehensive understanding of the molecular background of complex diseases. However, technological advances contrast with insufficient application in clinical practice. Thus, patients, physicians, and other professionals are faced with tough challenges that forestall the efficient and effective implementation. With the increasing application of genetic testing, it is of paramount importance that physicians and other professionals in healthcare recognize the restrictions and potential of GHTT, in order to understand and interpret the complex data in the context of health and disease. At the same time, the growing volume and complexity of data is forever increasing the need for sustainable infrastructure and state-of-the-art tools for efficient data management, including their analysis and integration. The large pool of sensitive information remains difficult to interpret and fundamental questions spanning from billing to legal, social, and ethical issues have still not been resolved. Here we summarize and discuss these obstacles in an interdisciplinary context and suggest ways to overcome them. Continuous discussion with clinicians, data managers, biostatisticians, systems medicine experts, ethicists, legal scholars, and patients illuminates the strengths, weakness, and current practices in the pipeline from biomaterial to sequencing and data management. This discussion also highlights the new, cross-disciplinary working collaborations to realize the wide-ranging challenges in clinical genomics including the exceptional demands placed on the staff preparing and presenting the data, as well as the question as to how to report the data and results to patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2019. Published by Elsevier B.V.)
- Published
- 2020
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17. Leptin gene polymorphisms are associated with weight gain during lithium augmentation in patients with major depression.
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Bopp SK, Heilbronner U, Schlattmann P, Mühleisen TW, Bschor T, Richter C, Steinacher B, Stamm TJ, Merkl A, Herms S, Köhler S, Sterzer P, Hellweg R, Heinz A, Cichon S, Lang UE, Schulze TG, Adli M, and Ricken R
- Subjects
- Adult, Depressive Disorder, Major blood, Female, Genotype, Humans, Ideal Body Weight, Leptin blood, Male, Middle Aged, Psychiatric Status Rating Scales, Retrospective Studies, Depressive Disorder, Major drug therapy, Depressive Disorder, Major genetics, Leptin genetics, Lithium adverse effects, Polymorphism, Single Nucleotide genetics, Weight Gain drug effects, Weight Gain genetics
- Abstract
Weight gain is a common adverse effect of lithium augmentation. Previous studies indicate an impact of genetic variants at the leptin gene on weight gain as a consequence of psychopharmacological treatment. The primary aim of our study was to identify variants at the leptin locus that might predict lithium-induced weight gain. The secondary aim was to investigate if these variants modulate leptin levels. In 180 patients with acute major depressive disorder, body mass index was measured before and after 4 weeks of lithium augmentation, in a subsample also after 4 and/or 7 months. In a subsample of 89 patients, leptin serum concentrations were measured before and during lithium augmentation. We used linear mixed model analyzes to investigate the effects of 2 polymorphisms at the leptin locus (rs4731426 and rs7799039, employing the respective proxy SNPs rs2278815 and rs10487506) on changes in body mass index and leptin levels. For both polymorphisms, which are in high linkage disequilibrium, body mass index was significantly lower in homozygous A-allele carriers than in carriers of other genotypes at baseline. Over the follow-up period, body mass index increased less in homozygous A-allele carriers of rs4731426 than in carriers of other genotypes. This was not the case for rs7799039. Neither polymorphism modulated leptin protein expression. Our study strongly supports the hypothesis that genetic variability at the leptin locus is involved in lithium augmentation-associated weight gain in major depressive disorder. Furthermore, Genotype-Tissue Expression data provide strong evidence that rs4731426 influences the expression of leptin messenger ribonucleic acid in fibroblasts., (Copyright © 2018. Published by Elsevier B.V.)
- Published
- 2019
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18. Efficient region-based test strategy uncovers genetic risk factors for functional outcome in bipolar disorder.
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Budde M, Friedrichs S, Alliey-Rodriguez N, Ament S, Badner JA, Berrettini WH, Bloss CS, Byerley W, Cichon S, Comes AL, Coryell W, Craig DW, Degenhardt F, Edenberg HJ, Foroud T, Forstner AJ, Frank J, Gershon ES, Goes FS, Greenwood TA, Guo Y, Hipolito M, Hood L, Keating BJ, Koller DL, Lawson WB, Liu C, Mahon PB, McInnis MG, McMahon FJ, Meier SM, Mühleisen TW, Murray SS, Nievergelt CM, Nurnberger JI Jr, Nwulia EA, Potash JB, Quarless D, Rice J, Roach JC, Scheftner WA, Schork NJ, Shekhtman T, Shilling PD, Smith EN, Streit F, Strohmaier J, Szelinger S, Treutlein J, Witt SH, Zandi PP, Zhang P, Zöllner S, Bickeböller H, Falkai PG, Kelsoe JR, Nöthen MM, Rietschel M, Schulze TG, and Malzahn D
- Subjects
- Adolescent, Adult, Aged, Bipolar Disorder physiopathology, Bipolar Disorder psychology, Case-Control Studies, Female, Genome-Wide Association Study, Genotype, Haplotypes, Humans, Linkage Disequilibrium genetics, Male, Middle Aged, Models, Statistical, Polymorphism, Single Nucleotide genetics, Prognosis, Psychiatric Status Rating Scales, White People genetics, Young Adult, Bipolar Disorder diagnosis, Bipolar Disorder genetics, Genetic Predisposition to Disease genetics
- Abstract
Genome-wide association studies of case-control status have advanced the understanding of the genetic basis of psychiatric disorders. Further progress may be gained by increasing sample size but also by new analysis strategies that advance the exploitation of existing data, especially for clinically important quantitative phenotypes. The functionally-informed efficient region-based test strategy (FIERS) introduced herein uses prior knowledge on biological function and dependence of genotypes within a powerful statistical framework with improved sensitivity and specificity for detecting consistent genetic effects across studies. As proof of concept, FIERS was used for the first genome-wide single nucleotide polymorphism (SNP)-based investigation on bipolar disorder (BD) that focuses on an important aspect of disease course, the functional outcome. FIERS identified a significantly associated locus on chromosome 15 (hg38: chr15:48965004 - 49464789 bp) with consistent effect strength between two independent studies (GAIN/TGen: European Americans, BOMA: Germans; n = 1592 BD patients in total). Protective and risk haplotypes were found on the most strongly associated SNPs. They contain a CTCF binding site (rs586758); CTCF sites are known to regulate sets of genes within a chromatin domain. The rs586758 - rs2086256 - rs1904317 haplotype is located in the promoter flanking region of the COPS2 gene, close to microRNA4716, and the EID1, SHC4, DTWD1 genes as plausible biological candidates. While implication with BD is novel, COPS2, EID1, and SHC4 are known to be relevant for neuronal differentiation and function and DTWD1 for psychopharmacological side effects. The test strategy FIERS that enabled this discovery is equally applicable for tag SNPs and sequence data., (Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2019
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19. Areas of uncertainties and unmet needs in bipolar disorders: clinical and research perspectives.
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Bauer M, Andreassen OA, Geddes JR, Vedel Kessing L, Lewitzka U, Schulze TG, and Vieta E
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- Bipolar Disorder psychology, Humans, Recurrence, Time-to-Treatment, Bipolar Disorder diagnosis, Bipolar Disorder drug therapy, Disease Management, Research, Uncertainty
- Abstract
This Review discusses crucial areas related to the identification, clinical presentation, course, and therapeutic management of bipolar disorder, a major psychiatric illness. Bipolar disorder is often misdiagnosed, leading to inappropriate, inadequate, or delayed treatment. Even when bipolar disorder is successfully diagnosed, its clinical management presents several major challenges, including how best to optimise treatment for an individual patient, and how to balance the benefits and risks of polypharmacy. We discuss the major unmet needs in the diagnosis and management of bipolar disorder in this Review, including improvement of adequate recognition and intervention in at-risk and early-disease stages, identification of reliable warning signs and prevention of relapses in unstable and rapid cycling patients, treatment of refractory depression, and prevention of suicide. Taken together, there are several promising opportunities for improving treatment of bipolar disorder to deliver medical care that is more personalised., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2018
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20. An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype.
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Direk N, Williams S, Smith JA, Ripke S, Air T, Amare AT, Amin N, Baune BT, Bennett DA, Blackwood DHR, Boomsma D, Breen G, Buttenschøn HN, Byrne EM, Børglum AD, Castelao E, Cichon S, Clarke TK, Cornelis MC, Dannlowski U, De Jager PL, Demirkan A, Domenici E, van Duijn CM, Dunn EC, Eriksson JG, Esko T, Faul JD, Ferrucci L, Fornage M, de Geus E, Gill M, Gordon SD, Grabe HJ, van Grootheest G, Hamilton SP, Hartman CA, Heath AC, Hek K, Hofman A, Homuth G, Horn C, Jan Hottenga J, Kardia SLR, Kloiber S, Koenen K, Kutalik Z, Ladwig KH, Lahti J, Levinson DF, Lewis CM, Lewis G, Li QS, Llewellyn DJ, Lucae S, Lunetta KL, MacIntyre DJ, Madden P, Martin NG, McIntosh AM, Metspalu A, Milaneschi Y, Montgomery GW, Mors O, Mosley TH Jr, Murabito JM, Müller-Myhsok B, Nöthen MM, Nyholt DR, O'Donovan MC, Penninx BW, Pergadia ML, Perlis R, Potash JB, Preisig M, Purcell SM, Quiroz JA, Räikkönen K, Rice JP, Rietschel M, Rivera M, Schulze TG, Shi J, Shyn S, Sinnamon GC, Smit JH, Smoller JW, Snieder H, Tanaka T, Tansey KE, Teumer A, Uher R, Umbricht D, Van der Auwera S, Ware EB, Weir DR, Weissman MM, Willemsen G, Yang J, Zhao W, Tiemeier H, and Sullivan PF
- Subjects
- Acid Anhydride Hydrolases genetics, Genome-Wide Association Study, Humans, Neoplasm Proteins genetics, Phenotype, White People genetics, Depression genetics, Depressive Disorder genetics, Genetic Loci, Genetic Predisposition to Disease
- Abstract
Background: The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder., Methods: We analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures., Results: The SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 × 10
-9 ) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 × 10-9 )., Conclusions: This large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)- Published
- 2017
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21. Genome-wide Regional Heritability Mapping Identifies a Locus Within the TOX2 Gene Associated With Major Depressive Disorder.
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Zeng Y, Navarro P, Shirali M, Howard DM, Adams MJ, Hall LS, Clarke TK, Thomson PA, Smith BH, Murray A, Padmanabhan S, Hayward C, Boutin T, MacIntyre DJ, Lewis CM, Wray NR, Mehta D, Penninx BWJH, Milaneschi Y, Baune BT, Air T, Hottenga JJ, Mbarek H, Castelao E, Pistis G, Schulze TG, Streit F, Forstner AJ, Byrne EM, Martin NG, Breen G, Müller-Myhsok B, Lucae S, Kloiber S, Domenici E, Deary IJ, Porteous DJ, Haley CS, and McIntosh AM
- Subjects
- Cohort Studies, Female, Genetic Loci, Genome-Wide Association Study, Humans, Ireland, Male, Middle Aged, United Kingdom, Depressive Disorder, Major genetics, Genetic Predisposition to Disease, HMGB Proteins genetics, Haplotypes, Polymorphism, Single Nucleotide
- Abstract
Background: Major depressive disorder (MDD) is the second largest cause of global disease burden. It has an estimated heritability of 37%, but published genome-wide association studies have so far identified few risk loci. Haplotype-block-based regional heritability mapping (HRHM) estimates the localized genetic variance explained by common variants within haplotype blocks, integrating the effects of multiple variants, and may be more powerful for identifying MDD-associated genomic regions., Methods: We applied HRHM to Generation Scotland: The Scottish Family Health Study, a large family- and population-based Scottish cohort (N = 19,896). Single-single nucleotide polymorphism (SNP) and haplotype-based association tests were used to localize the association signal within the regions identified by HRHM. Functional prediction was used to investigate the effect of MDD-associated SNPs within the regions., Results: A haplotype block across a 24-kb region within the TOX2 gene reached genome-wide significance in HRHM. Single-SNP- and haplotype-based association tests demonstrated that five of nine genotyped SNPs and two haplotypes within this block were significantly associated with MDD. The expression of TOX2 and a brain-specific long noncoding RNA RP1-269M15.3 in frontal cortex and nucleus accumbens basal ganglia, respectively, were significantly regulated by MDD-associated SNPs within this region. Both the regional heritability and single-SNP associations within this block were replicated in the UK-Ireland group of the most recent release of the Psychiatric Genomics Consortium (PGC), the PGC2-MDD (Major Depression Dataset). The SNP association was also replicated in a depressive symptom sample that shares some individuals with the PGC2-MDD., Conclusions: This study highlights the value of HRHM for MDD and provides an important target within TOX2 for further functional studies., (Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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22. The inverse link between genetic risk for schizophrenia and migraine through NMDA (N-methyl-D-aspartate) receptor activation via D-serine.
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Van der Auwera S, Teumer A, Hertel J, Homuth G, Völker U, Lucht MJ, Degenhardt F, Schulze T, Rietschel M, Nöthen MM, John U, Nauck M, and Grabe HJ
- Subjects
- Epistasis, Genetic, Female, Genetic Association Studies, Humans, Male, Middle Aged, Migraine Disorders metabolism, Multifactorial Inheritance, Quantitative Trait Loci, Receptors, N-Methyl-D-Aspartate metabolism, Schizophrenia metabolism, Serine metabolism, Genetic Predisposition to Disease, Migraine Disorders genetics, Polymorphism, Single Nucleotide, Racemases and Epimerases genetics, Schizophrenia genetics
- Abstract
Schizophrenia has a considerable genetic background. Epidemiological studies suggest an inverse clinical association between schizophrenia and migraine. However, it is unclear to what extent this inverse comorbidity can be explained by genetic mechanisms or by schizophrenia-related behavioral factors. For both disorders hypotheses of glutamate N-methyl-D-aspartate (NMDA) receptor dysfunction have been developed in the past. We hypothesized that both conditions share common genetic factors with inverse effects, primary in the glutamatergic system and genes involved in NMDA activation. Data from the population based Study of Health in Pomerania (N=3973) were used. Based on the results from the recent genome-wide association study for schizophrenia, we calculated polygenic scores (PRS) for subsets of SNPs with different p-value cutoffs and for biological sub-entities. These scores were tested for an association of distinct biological pathways with migraine. The PRS for schizophrenia was inversely associated with migraine in our sample. This association was exclusively based on the genome-wide hits and on single nucleotide polymorphisms near or within genes encoding proteins involved in glutamatergic neurotransmission. This association could be attributed to a single intronic variant rs4523957 in SRR encoding serine-racemase. Additional expression quantitative trait loci analyses of functional variants in SRR and gene-by-gene interaction analyses further supported the validity of this finding. SRR represents the rate limiting enzyme for the synthesis of D-serine, an important co-agonist of the NMDA receptor. According to our results, a decreased versus increased activation of NMDA receptors may play a role in the etiology of schizophrenia, as well as in migraine., (Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.)
- Published
- 2016
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23. Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study.
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Hou L, Heilbronner U, Degenhardt F, Adli M, Akiyama K, Akula N, Ardau R, Arias B, Backlund L, Banzato CEM, Benabarre A, Bengesser S, Bhattacharjee AK, Biernacka JM, Birner A, Brichant-Petitjean C, Bui ET, Cervantes P, Chen GB, Chen HC, Chillotti C, Cichon S, Clark SR, Colom F, Cousins DA, Cruceanu C, Czerski PM, Dantas CR, Dayer A, Étain B, Falkai P, Forstner AJ, Frisén L, Fullerton JM, Gard S, Garnham JS, Goes FS, Grof P, Gruber O, Hashimoto R, Hauser J, Herms S, Hoffmann P, Hofmann A, Jamain S, Jiménez E, Kahn JP, Kassem L, Kittel-Schneider S, Kliwicki S, König B, Kusumi I, Lackner N, Laje G, Landén M, Lavebratt C, Leboyer M, Leckband SG, Jaramillo CAL, MacQueen G, Manchia M, Martinsson L, Mattheisen M, McCarthy MJ, McElroy SL, Mitjans M, Mondimore FM, Monteleone P, Nievergelt CM, Nöthen MM, Ösby U, Ozaki N, Perlis RH, Pfennig A, Reich-Erkelenz D, Rouleau GA, Schofield PR, Schubert KO, Schweizer BW, Seemüller F, Severino G, Shekhtman T, Shilling PD, Shimoda K, Simhandl C, Slaney CM, Smoller JW, Squassina A, Stamm T, Stopkova P, Tighe SK, Tortorella A, Turecki G, Volkert J, Witt S, Wright A, Young LT, Zandi PP, Potash JB, DePaulo JR, Bauer M, Reininghaus EZ, Novák T, Aubry JM, Maj M, Baune BT, Mitchell PB, Vieta E, Frye MA, Rybakowski JK, Kuo PH, Kato T, Grigoroiu-Serbanescu M, Reif A, Del Zompo M, Bellivier F, Schalling M, Wray NR, Kelsoe JR, Alda M, Rietschel M, McMahon FJ, and Schulze TG
- Subjects
- Bipolar Disorder drug therapy, Female, Genetic Variation, Genome-Wide Association Study, Genotype, Glial Cell Line-Derived Neurotrophic Factor Receptors genetics, Humans, Male, Middle Aged, Phenotype, Prospective Studies, Treatment Outcome, Bipolar Disorder genetics, Lithium Compounds therapeutic use, Polymorphism, Single Nucleotide genetics
- Abstract
Background: Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified., Methods: Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis., Findings: A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37 × 10(-8); rs78015114, p=1·31 × 10(-8); rs74795342, p=3·31 × 10(-9); and rs75222709, p=3·50 × 10(-9)). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1-13·0)., Interpretation: The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings., Funding: Deutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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24. Going longitudinal in biological psychiatric research: All things considered.
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Gould TD, Hashimoto R, and Schulze TG
- Subjects
- Biomedical Research, Humans, Longitudinal Studies, Mental Disorders genetics, Mental Disorders pathology, Mental Disorders physiopathology
- Published
- 2016
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25. A common risk variant in CACNA1C supports a sex-dependent effect on longitudinal functioning and functional recovery from episodes of schizophrenia-spectrum but not bipolar disorder.
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Heilbronner U, Malzahn D, Strohmaier J, Maier S, Frank J, Treutlein J, Mühleisen TW, Forstner AJ, Witt SH, Cichon S, Falkai P, Nöthen MM, Rietschel M, and Schulze TG
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Female, Genetic Predisposition to Disease, Humans, Longitudinal Studies, Male, Middle Aged, Phenotype, Psychiatric Status Rating Scales, Sex Factors, Young Adult, Bipolar Disorder genetics, Calcium Channels, L-Type genetics, Polymorphism, Single Nucleotide genetics, Schizophrenia genetics
- Abstract
Sex is a powerful modulator of disease susceptibility, course and outcome. The gene CACNA1C is among the best replicated vulnerability genes of bipolar disorder and schizophrenia. The aim of the present study was to investigate whether sex and a variant in CACNA1C (rs10774035 as a proxy for the well-acknowledged risk variant rs1006737) influence psychosocial adaptation in a large German patient sample with schizophrenia-spectrum (n=297) and bipolar (n=516) disorders. We analyzed Global Assessment of Functioning (GAF) scores, retrospectively collected for different time points during disease course. We investigated whether CACNA1C sex-dependently modulates longitudinal GAF scores and recovery from episodes of psychiatric disturbance in the above mentioned disorders. Psychosocial recovery was measured as difference score between the current GAF score (assessing the last remission) and the worst GAF score ever during an illness episode. Covariate- adjusted association analyses revealed a sex × rs10774035 genotype interaction on longitudinal GAF and recovery from illness episodes only in schizophrenia-spectrum but not in bipolar disorders. In schizophrenia-spectrum affected males, rs10774035 minor allele (T) carriers had higher GAF scores at three time points (premorbid, worst ever, current). In contrast, females carrying rs10774035 minor alleles had impaired recovery from schizophrenia-spectrum episodes. These results encourage further investigations of gene × sex interactions and longitudinal quantitative phenotypes to unravel the rich variety of behavioral consequences of genetic individuality., (Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.)
- Published
- 2015
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26. Molecular actions and clinical pharmacogenetics of lithium therapy.
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Can A, Schulze TG, and Gould TD
- Subjects
- Humans, Lithium Compounds pharmacology, Manganese metabolism, Neuroprotective Agents pharmacology, Neuroprotective Agents therapeutic use, Lithium Compounds therapeutic use, Mood Disorders drug therapy, Pharmacogenetics
- Abstract
Mood disorders, including bipolar disorder and depression, are relatively common human diseases for which pharmacological treatment options are often not optimal. Among existing pharmacological agents and mood stabilizers used for the treatment of mood disorders, lithium has a unique clinical profile. Lithium has efficacy in the treatment of bipolar disorder generally, and in particular mania, while also being useful in the adjunct treatment of refractory depression. In addition to antimanic and adjunct antidepressant efficacy, lithium is also proven effective in the reduction of suicide and suicidal behaviors. However, only a subset of patients manifests beneficial responses to lithium therapy and the underlying genetic factors of response are not exactly known. Here we discuss preclinical research suggesting mechanisms likely to underlie lithium's therapeutic actions including direct targets inositol monophosphatase and glycogen synthase kinase-3 (GSK-3) among others, as well as indirect actions including modulation of neurotrophic and neurotransmitter systems and circadian function. We follow with a discussion of current knowledge related to the pharmacogenetic underpinnings of effective lithium therapy in patients within this context. Progress in elucidation of genetic factors that may be involved in human response to lithium pharmacology has been slow, and there is still limited conclusive evidence for the role of a particular genetic factor. However, the development of new approaches such as genome-wide association studies (GWAS), and increased use of genetic testing and improved identification of mood disorder patients sub-groups will lead to improved elucidation of relevant genetic factors in the future., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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27. SCN1A affects brain structure and the neural activity of the aging brain.
- Author
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Meier S, Demirakca T, Brusniak W, Wolf I, Liebsch K, Tunc-Skarka N, Nieratschker V, Witt SH, Matthäus F, Ende G, Flor H, Rietschel M, Diener C, and Schulze TG
- Subjects
- Adult, Age Factors, Aged, Aged, 80 and over, Brain blood supply, Female, Genome-Wide Association Study, Genotype, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Memory, Short-Term physiology, Middle Aged, Neuropsychological Tests, Oxygen blood, Young Adult, Aging genetics, Brain anatomy & histology, Brain Mapping, NAV1.1 Voltage-Gated Sodium Channel genetics, Polymorphism, Single Nucleotide genetics
- Abstract
Background: The aging of the human brain is accompanied by changes in cortical structure as well as functional activity and variable degrees of cognitive decline. One-third of the observable inter-individual differences in cognitive decline are thought to be heritable. SCN1A encodes the sodium channel α subunit and is considered to be a susceptibility gene for several neurological disorders with prominent cognitive deficits. In a recent genome-wide association study the C allele of the SCN1A variant rs10930201 was observed to be significantly associated with poor short-term memory performance. rs10930201 was further observed to be related to differences in neural activity during a working memory task., Methods: The aim of the present study was to explore whether SCN1A modifies the vulnerability to aging processes of the human brain. Therefore we assessed the interacting effects of the SCN1A vulnerability allele rs10930201 and age in terms of brain activity and brain morphology in 62 healthy volunteers between 21 and 82 years of age., Results: In C allele carriers, activity in the right inferior frontal cortex and the posterior cingulate cortex increased with age. Moreover, exploratory analysis revealed regional effects of rs10930201 on brain structure, indicating reduced gray matter densities in the frontal and insular regions in the C allele carriers., Conclusions: Collectively, the present results suggest that the SCN1A polymorphism has modulatory effects on brain morphology and vulnerability to age-related alterations in brain activity of cortical regions that subserve working memory., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
- Published
- 2012
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28. The complement control-related genes CSMD1 and CSMD2 associate to schizophrenia.
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Håvik B, Le Hellard S, Rietschel M, Lybæk H, Djurovic S, Mattheisen M, Mühleisen TW, Degenhardt F, Priebe L, Maier W, Breuer R, Schulze TG, Agartz I, Melle I, Hansen T, Bramham CR, Nöthen MM, Stevens B, Werge T, Andreassen OA, Cichon S, and Steen VM
- Subjects
- Adult, Case-Control Studies, Female, Genotype, Humans, Major Histocompatibility Complex genetics, Male, Polymorphism, Single Nucleotide, Tumor Suppressor Proteins, Complement System Proteins genetics, Genetic Association Studies methods, Membrane Proteins genetics, Schizophrenia genetics
- Abstract
Background: Patients with schizophrenia often suffer from cognitive dysfunction, including impaired learning and memory. We recently demonstrated that long-term potentiation in rat hippocampus, a mechanistic model of learning and memory, is linked to gene expression changes in immunity-related processes involved in complement activity and antigen presentation. We therefore aimed to examine whether key regulators of these processes are genetic susceptibility factors in schizophrenia., Methods: Analysis of genetic association was based on data mining of genotypes from a German genome-wide association study and a multiplex GoldenGate tag single nucleotide polymorphism (SNP)-based assay of Norwegian and Danish case-control samples (Scandinavian Collaboration on Psychiatric Etiology), including 1133 patients with schizophrenia and 2444 healthy control subjects., Results: Allelic associations were found across all three samples for eight common SNPs in the complement control-related gene CSMD2 (CUB and Sushi Multiple Domains 2) on chromosome 1p35.1-34.3, of which rs911213 reached a statistical significance comparable to that of a genome wide threshold (p value = 4.0 × 10(-8); odd ratio = .73, 95% confidence interval = .65-.82). The second most significant gene was CSMD1 on chromosome 8p23.2, a homologue to CSMD2. In addition, we observed replicated associations in the complement surface receptor CD46 as well as the major histocompatibility complex genes HLA-DMB and HLA-DOA., Conclusions: These data demonstrate a significant role of complement control-related genes in the etiology of schizophrenia and support disease mechanisms that involve the activity of immunity-related pathways in the brain., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
- Published
- 2011
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29. The new HNO donor, 1-nitrosocyclohexyl acetate, increases contractile force in normal and β-adrenergically desensitized ventricular myocytes.
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El-Armouche A, Wahab A, Wittköpper K, Schulze T, Böttcher F, Pohlmann L, King SB, DuMond JF, Gerloff C, Böger RH, Eschenhagen T, Carrier L, and Donzelli S
- Subjects
- Animals, Cells, Cultured, Heart Ventricles cytology, Male, Mice, Mice, Inbred C57BL, Myocytes, Cardiac physiology, Nitrogen Oxides metabolism, Acetates pharmacology, Heart Ventricles drug effects, Muscle Contraction drug effects, Myocytes, Cardiac drug effects, Nitric Oxide Donors pharmacology, Nitroso Compounds pharmacology
- Abstract
Contractile dysfunction and diminished response to β-adrenergic agonists are characteristics for failing hearts. Chemically donated nitroxyl (HNO) improves contractility in failing hearts and thus may have therapeutic potential. Yet, there is a need for pharmacologically suitable donors. In this study we tested whether the pure and long acting HNO donor, 1-nitrosocyclohexyl acetate (NCA), affects contractile force in normal and pathological ventricular myocytes (VMs) as well as in isolated hearts. VMs were isolated from mice either subjected to isoprenaline-infusion (ISO; 30 μg/g per day) or to vehicle (0.9% NaCl) for 5 days. Sarcomere shortening and Ca2+ transients were simultaneously measured using the IonOptix system. Force of contraction of isolated hearts was measured by a Langendorff-perfusion system. NCA increased peak sarcomere shortening by+40-200% in a concentration-dependent manner (EC50 ∼55 μM). Efficacy and potency did not differ between normal and chronic ISO VMs, despite the fact that the latter displayed a markedly diminished inotropic response to acute β-adrenergic stimulation with ISO (1 μM). NCA (60 μM) increased peak sarcomere shortening and Ca2+ transient amplitude by ∼200% and ∼120%, respectively, suggesting effects on both myofilament Ca2+ sensitivity and sarcoplasmic reticulum (SR) Ca2+ cycling. Importantly, NCA did not affect diastolic Ca2+ or SR Ca2+ content, as assessed by rapid caffeine application. NCA (45 μM) increased force of contraction by 30% in isolated hearts. In conclusion, NCA increased contractile force in normal and β-adrenergically desensitized VMs as well as in isolated mouse hearts. This profile warrants further investigations of this HNO donor in the context of heart failure., (Copyright © 2010 Elsevier Inc. All rights reserved.)
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- 2010
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30. Genome-wide association-, replication-, and neuroimaging study implicates HOMER1 in the etiology of major depression.
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Rietschel M, Mattheisen M, Frank J, Treutlein J, Degenhardt F, Breuer R, Steffens M, Mier D, Esslinger C, Walter H, Kirsch P, Erk S, Schnell K, Herms S, Wichmann HE, Schreiber S, Jöckel KH, Strohmaier J, Roeske D, Haenisch B, Gross M, Hoefels S, Lucae S, Binder EB, Wienker TF, Schulze TG, Schmäl C, Zimmer A, Juraeva D, Brors B, Bettecken T, Meyer-Lindenberg A, Müller-Myhsok B, Maier W, Nöthen MM, and Cichon S
- Subjects
- Adult, Carrier Proteins physiology, Depressive Disorder, Major physiopathology, Depressive Disorder, Major psychology, Female, Homer Scaffolding Proteins, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Psychomotor Performance physiology, Brain physiopathology, Carrier Proteins genetics, Depressive Disorder, Major genetics, Genome-Wide Association Study methods
- Abstract
Background: Genome-wide association studies are a powerful tool for unravelling the genetic background of complex disorders such as major depression., Methods: We conducted a genome-wide association study of 604 patients with major depression and 1364 population based control subjects. The top hundred findings were followed up in a replication sample of 409 patients and 541 control subjects., Results: Two SNPs showed nominally significant association in both the genome-wide association study and the replication samples: 1) rs9943849 (p(combined) = 3.24E-6) located upstream of the carboxypeptidase M (CPM) gene and 2) rs7713917 (p(combined) = 1.48E-6), located in a putative regulatory region of HOMER1. Further evidence for HOMER1 was obtained through gene-wide analysis while conditioning on the genotypes of rs7713917 (p(combined) = 4.12E-3). Homer1 knockout mice display behavioral traits that are paradigmatic of depression, and transcriptional variants of Homer1 result in the dysregulation of cortical-limbic circuitry. This is consistent with the findings of our subsequent human imaging genetics study, which revealed that variation in single nucleotide polymorphism rs7713917 had a significant influence on prefrontal activity during executive cognition and anticipation of reward., Conclusion: Our findings, combined with evidence from preclinical and animal studies, suggest that HOMER1 plays a role in the etiology of major depression and that the genetic variation affects depression via the dysregulation of cognitive and motivational processes., (2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
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- 2010
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31. Reduction of the internal capsule in families affected with schizophrenia.
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Wobrock T, Kamer T, Roy A, Vogeley K, Schneider-Axmann T, Wagner M, Maier W, Rietschel M, Schulze TG, Scherk H, Schild HH, Block W, Träber F, Tepest R, Honer WG, and Falkai P
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- Adult, Analysis of Variance, Case-Control Studies, Female, Humans, Magnetic Resonance Imaging methods, Male, Middle Aged, Neuropsychological Tests, Psychiatric Status Rating Scales, Statistics as Topic, Family Health, Internal Capsule pathology, Schizophrenia genetics, Schizophrenia pathology
- Abstract
Background: The anterior limb of the internal capsule (ALIC), connecting cortical and subcortical structures, is involved in functional important circuits. To detect volumetric changes in ALIC, including the influence of genetic factors, a magnetic resonance imaging (MRI) study of families affected with schizophrenia was performed., Methods: The study sample comprised 22 family members with schizophrenia (FM-SZ), 34 family members without schizophrenia (FM-NSZ), and 43 control subjects. In addition to manual tracing of ALIC, subjects underwent proton magnetic resonance spectroscopy in the left prefrontal cortex, psychopathological rating, and neuropsychological assessment of frontal lobe function., Results: Compared with controls, a significant reduction of right ALIC volume was seen in all family members (12%-16% reduction, p < .01) and a reduction of left ALIC volume in FM-NSZ (10% reduction, p = .028) was also observed. Both groups of family members showed a bilateral reduction in maximal cross sectional area of the ALIC. FM-SZ performed significantly worse on neurocognitive measures (Subject Ordered Pointing Task [SOPT] and Wisconsin Card Sorting Test), and performance correlated negatively with the ALIC volume (SOPT, r = -.6, p = .03)., Conclusions: A reduced volume of ALIC in affected families supports the hypothesis of disturbed frontothalamic connectivity in schizophrenia and demonstrates functional relevance by an association with reduced neurocognitive performance.
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- 2008
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32. Evidence for a relationship between genetic variants at the brain-derived neurotrophic factor (BDNF) locus and major depression.
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Schumacher J, Jamra RA, Becker T, Ohlraun S, Klopp N, Binder EB, Schulze TG, Deschner M, Schmäl C, Höfels S, Zobel A, Illig T, Propping P, Holsboer F, Rietschel M, Nöthen MM, and Cichon S
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- Adult, Aged, Bipolar Disorder genetics, Case-Control Studies, Dinucleotide Repeats, Gene Frequency, Genotype, Humans, Male, Middle Aged, Polymorphism, Genetic, Schizophrenia genetics, Brain-Derived Neurotrophic Factor genetics, Depressive Disorder, Major genetics, Genetic Predisposition to Disease, Genetic Variation genetics
- Abstract
Background: Previous genetic studies investigating a possible involvement of variations at the brain derived neurotrophic factor (BDNF) gene locus in major depressive disorder (MDD), bipolar affective disorder (BPAD), and schizophrenia have provided inconsistent results., Methods: We performed single-marker and haplotype analyses using three BDNF polymorphisms in 2,376 individuals (465 MDD, 281 BPAD, 533 schizophrenia, and 1,097 control subjects)., Results: Single-marker analysis did not provide strong evidence for association. Haplotype analysis of marker combination rs988748-(GT)n-rs6265 produced nominally significant associations for all investigated phenotypes (global p values: MDD p = .00006, BPAD p = .0057, schizophrenia p = .016). Association with MDD was the most robust finding and could be replicated in a second German sample of MDD patients and control subjects (p = .0092, uncorrected). Stratification of our schizophrenia sample according to the presence or absence of a lifetime history of depressive symptoms showed that our finding in schizophrenia might be attributable mainly to the presence of depressive symptoms., Conclusions: Association studies of genetic variants of the BDNF gene with various psychiatric disorders have been published with reports of associations and nonreplications. Our findings suggest that BDNF may be a susceptibility gene for MDD and schizophrenia-in particular, in a subgroup of patients with schizophrenia with a lifetime history of depressive symptoms.
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- 2005
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33. No association between the putative functional ZDHHC8 single nucleotide polymorphism rs175174 and schizophrenia in large European samples.
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Glaser B, Schumacher J, Williams HJ, Jamra RA, Ianakiev N, Milev R, Ohlraun S, Schulze TG, Czerski PM, Hauser J, Jönsson EG, Sedvall GC, Klopp N, Illig T, Becker T, Propping P, Williams NM, Cichon S, Kirov G, Rietschel M, Murphy KC, O'Donovan MC, Nöthen MM, and Owen MJ
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- Alleles, Bulgaria ethnology, Child, Chromosomes, Human, Pair 22, Female, Genetic Predisposition to Disease genetics, Genetic Variation, Humans, Linkage Disequilibrium, Male, Reverse Transcriptase Polymerase Chain Reaction, Risk Factors, Schizophrenia enzymology, Sex Factors, Zinc Fingers genetics, Acyltransferases genetics, Membrane Proteins genetics, Polymorphism, Single Nucleotide genetics, Schizophrenia genetics, White People genetics
- Abstract
Background: It has been recently reported that a functional variant in the ZDHHC8 gene encoding a putative palmitoyltransferase directly confers susceptibility to schizophrenia in females ()., Methods: We investigated the putative risk allele (rs175174) in four schizophrenia association samples including a Bulgarian proband and parent sample (474 trios) and three case-control panels of European origin (1028 patients/1253 control subjects) in an attempt to replicate these findings., Results: Our results do not support the hypothesis that genetic variation at rs175174 is associated with increased risk for schizophrenia nor do they suggest the presence of gender-specific differences., Conclusions: Our data suggest that the reported genetic association by either represents type I error resulting from sampling variance or that rs175174 is in linkage disequilibrium (LD) with the functional variant for schizophrenia and different LD patterns obscure the detection of association.
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- 2005
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34. The power of sample size and homogenous sampling: association between the 5-HTTLPR serotonin transporter polymorphism and major depressive disorder.
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Hoefgen B, Schulze TG, Ohlraun S, von Widdern O, Höfels S, Gross M, Heidmann V, Kovalenko S, Eckermann A, Kölsch H, Metten M, Zobel A, Becker T, Nöthen MM, Propping P, Heun R, Maier W, and Rietschel M
- Subjects
- Adult, Aged, Case-Control Studies, Female, Gene Frequency, Genotype, Humans, Linkage Disequilibrium, Male, Middle Aged, Phenotype, Serotonin Plasma Membrane Transport Proteins, Depressive Disorder, Major genetics, Membrane Glycoproteins genetics, Membrane Transport Proteins genetics, Nerve Tissue Proteins genetics, Polymorphism, Genetic
- Abstract
Background: Several lines of evidence indicate that abnormalities in the functioning of the central serotonergic system are involved in the pathogenesis of affective illness. A 44-base-pair insertion/deletion polymorphism in the 5' regulatory region of the serotonin transporter gene (5-HTTLPR), which influences expression of the serotonin transporter, has been the focus of intensive research since an initial report on an association between 5-HTTLPR and depression-related personality traits. Consistently replicated evidence for an involvement of this polymorphism in the etiology of mood disorders, particularly in major depressive disorder (MDD), remains scant., Methods: We assessed a potential association between 5-HTTLPR and MDD, using the largest reported sample to date (466 patients, 836 control subjects). Individuals were all of German descent. Patients were systematically recruited from consecutive inpatient admissions. Control subjects were drawn from random lists of the local Census Bureau and screened for psychiatric disorders., Results: The short allele of 5-HTTLPR was significantly more frequent in patients than in control subjects (45.5% vs. 39.9%; p = .006; odds ratio = 1.26)., Conclusions: These results support an involvement of 5-HTTLPR in the etiology of MDD. They also demonstrate that the detection of small genetic effects requires very large and homogenous samples.
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- 2005
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35. Loci on chromosomes 6q and 6p interact to increase susceptibility to bipolar affective disorder in the national institute of mental health genetics initiative pedigrees.
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Schulze TG, Buervenich S, Badner JA, Steele CJ, Detera-Wadleigh SD, Dick D, Foroud T, Cox NJ, MacKinnon DF, Potash JB, Berrettini WH, Byerley W, Coryell W, DePaulo JR Jr, Gershon ES, Kelsoe JR, McInnis MG, Murphy DL, Reich T, Scheftner W, Nurnberger JI Jr, and McMahon FJ
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- Bipolar Disorder epidemiology, Epistasis, Genetic, Female, Humans, Lod Score, Male, National Institute of Mental Health (U.S.), Pedigree, Psychotic Disorders genetics, Schizophrenia genetics, United States epidemiology, Bipolar Disorder genetics, Chromosomes, Human, Pair 6, Genetic Linkage, Genetic Predisposition to Disease
- Abstract
Background: We have reported genetic linkage between bipolar disorder and markers on chromosome 6q16.3-22.1 in the National Institute of Mental Health Genetics Initiative wave 3 pedigrees. Here we test for: 1) robustness of the linkage to differing analysis methods, genotyping error, and gender-specific maps; 2) parent-of-origin effects; and 3) interaction with markers within the schizophrenia linkage region on chromosome 6p., Methods: Members of 245 families ascertained through a sibling pair affected with bipolar I or schizoaffective-bipolar disorder were genotyped with 18 markers spanning chromosome 6. Nonparametric linkage analysis was performed., Results: Linkage to 6q is robust to analysis method, gender-specific map differences, and genotyping error. The locus confers a 1.4-fold increased risk. Affected siblings share the maternal more often than the paternal chromosome (p =.006), which could reflect a maternal parent-of-origin effect. There is a positive correlation between family-specific linkage scores on 6q and those on 6p22.2 (r =.26; p <.0001). Linkage analysis for each locus conditioned on evidence of linkage to the other increases the evidence for linkage at both loci (p <.0005). Logarithm of the odds (LOD) scores increased from 2.26 to 5.42 on 6q and from.35 to 2.26 on 6p22.2., Conclusions: These results support linkage of bipolar disorder to 6q, uncover a maternal parent-of-origin effect, and demonstrate an interaction of this locus with one on chromosome 6p22.2, previously linked only to schizophrenia.
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- 2004
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36. Additional, physically ordered markers increase linkage signal for bipolar disorder on chromosome 18q22.
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Schulze TG, Chen YS, Badner JA, McInnis MG, DePaulo JR Jr, and McMahon FJ
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- Adult, Bipolar Disorder diagnosis, Female, Gene Frequency, Genetic Predisposition to Disease genetics, Humans, Lod Score, Male, Statistics, Nonparametric, Bipolar Disorder genetics, Chromosome Mapping, Chromosomes, Human, Pair 18, Microsatellite Repeats genetics
- Abstract
Background: We recently reported evidence of linkage of bipolar disorder to chromosome 18q, with a paternal logarithm of odds (LOD) score of 4.67 (p =.004) in a clinically defined subset of families. Like other linkage studies, we had to rely on imprecise genetic maps to establish the marker order. Here, we test for linkage in the same sample with a denser set of markers, now physically ordered according to the draft sequence of the human genome., Methods: Families were ascertained through probands with bipolar I disorder and diagnosed with reliable methods. Genotypes were generated for 12 microsatellite markers within an 11-centimorgan (cM) region of chromosome 18q22. Multipoint affected sib-pair linkage analysis was performed in a set of 16 nuclear families., Results: The additional markers significantly increased the total genetic information extracted from our sample. We also observed an increase in the LOD score (to 5.42, p =.0066) and linkage resolution. The approximate 1-LOD support interval is now 9 male cM., Conclusions: The results strengthen our previous findings and further define a region suitable for genetic fine-mapping analysis on chromosome 18q. Our data suggest that a dense set of markers, when physically ordered, can increase the informational value of genetic linkage signals.
- Published
- 2003
- Full Text
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