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1. Cerebrospinal fluid flow cytometry distinguishes psychosis spectrum disorders from differential diagnoses

Author

Gerd Meyer zu Hörste, Saskia Räuber, Tillmann Ruland, Tim Hahn, Andreas Schulte-Mecklenbeck, Sven G. Meuth, Jonathan Repple, Catharina C. Gross, Heinz Wiendl, Rebecca Kuelby, Udo Dannlowski, Nico Melzer, Michael Heming, Volker Arolt, and Bernhard T. Baune

Subjects
Autoimmune encephalitis, Psychosis, medicine.diagnostic_test, business.industry, Retrospective cohort study, Flow Cytometry, medicine.disease, Flow cytometry, Diagnosis, Differential, Cellular and Molecular Neuroscience, Psychiatry and Mental health, Cerebrospinal fluid, Immune system, Psychotic Disorders, Immunology, medicine, Encephalitis, Humans, Medical diagnosis, business, Molecular Biology, Cytometry, Cerebrospinal Fluid, Retrospective Studies
Abstract

Psychotic disorders are common and disabling mental conditions. The relative importance of immune-related mechanisms in psychotic disorders remains subject of debate. Here, we present a large-scale retrospective study of blood and cerebrospinal fluid (CSF) immune cell profiles of psychosis spectrum patients. We performed basic CSF analysis and multi-dimensional flow cytometry of CSF and blood cells from 59 patients with primary psychotic disorders (F20, F22, F23, and F25) in comparison to inflammatory (49 RRMS and 16 NMDARE patients) and non-inflammatory controls (52 IIH patients). We replicated the known expansion of monocytes in the blood of psychosis spectrum patients, that we identified to preferentially affect classical monocytes. In the CSF, we found a relative shift from lymphocytes to monocytes, increased protein levels, and evidence of blood–brain barrier disruption in psychosis. In fact, these CSF features confidently distinguished autoimmune encephalitis from psychosis despite similar (initial) clinical features. We then constructed machine learning models incorporating blood and CSF parameters and demonstrated their superior ability to differentiate psychosis from non-inflammatory controls compared to individual parameters. Multi-dimensional and multi-compartment immune cell signatures can thus support the diagnosis of psychosis spectrum disorders with the potential to accelerate diagnosis and initiation of therapy.

Published
2021
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2. Variation of HbA1c affects cognition and white matter microstructure in healthy, young adults

Author

Greta Karliczek, Dominik Grotegerd, Jonathan Repple, Janik Goltermann, Udo Dannlowski, Bernhard T. Baune, Nils Opel, Ronny Redlich, Susanne Meinert, Katharina Förster, and Volker Arolt

Subjects
0301 basic medicine, business.industry, Cognition, Affect (psychology), White matter, 03 medical and health sciences, Cellular and Molecular Neuroscience, Psychiatry and Mental health, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Fractional anisotropy, Connectome, Medicine, Effects of sleep deprivation on cognitive performance, Young adult, business, Molecular Biology, Body mass index, 030217 neurology & neurosurgery, Clinical psychology
Abstract

The metabolic serum marker HbA1c has been associated with both impaired cognitive performance and altered white matter integrity in patients suffering from diabetes mellitus. However, it remains unclear if higher levels of HbA1c might also affect brain structure and function in healthy subjects. With the present study we therefore aimed to investigate the relationship between HbA1c levels and cognitive performance as well as white matter microstructure in healthy, young adults. To address this question, associations between HbA1c and cognitive measures (NIH Cognition Toolbox) as well as DTI-derived imaging measures of white matter microstructure were investigated in a publicly available sample of healthy, young adults as part of the Humane Connectome Project (n = 1206, mean age = 28.8 years, 45.5% male). We found that HbA1c levels (range 4.1-6.3%) were significantly inversely correlated with measures of cognitive performance. Higher HbA1c levels were associated with significant and widespread reductions in fractional anisotropy (FA) controlling for age, sex, body mass index, ethnicity, and education. FA reductions were furthermore found to covary with measures of cognitive performance. The same pattern of results could be observed in analyses restricted to participants with HBA1c levels below 5.7%. The present study demonstrates that low-grade HbA1c variation below diagnostic threshold for diabetes is related to both cognitive performance and white matter integrity in healthy, young adults. These findings highlight the detrimental impact of metabolic risk factors on brain physiology and underscore the importance of intensified preventive measures independent of the currently applied diagnostic HbA1c cutoff scores.

Published
2019
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3. Cortical surface area alterations shaped by genetic load for neuroticism

Author

Elisabeth J. Leehr, David Wilhelms, Andreas Jansen, Jochen Bauer, Katharina Förster, Verena Enneking, Daniel Emden, Axel Krug, Markus M. Nöthen, Joscha Böhnlein, Ronny Redlich, Walter Heindel, Udo Dannlowski, Katharina Dohm, Jonathan Repple, Igor Nenadic, Nils Opel, Dominik Grotegerd, Tim Hahn, Tilo Kircher, Susanne Meinert, Azmeraw T. Amare, Nils R. Winter, Stephanie H. Witt, Christian Bürger, Marcella Rietschel, Volker Arolt, Bernhard T. Baune, Claas Kaehler, Dario Zaremba, Andreas J. Forstner, Simon Schmitt, and Ramona Leenings

Subjects
0301 basic medicine, Cingulate cortex, medicine.medical_specialty, Precuneus, Inferior frontal gyrus, Biology, medicine.disease, Neuroticism, 03 medical and health sciences, Cellular and Molecular Neuroscience, Psychiatry and Mental health, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Endocrinology, Neuroimaging, Cerebral cortex, Internal medicine, Cortex (anatomy), mental disorders, medicine, Major depressive disorder, Molecular Biology, 030217 neurology & neurosurgery
Abstract

Neuroticism has been shown to act as an important risk factor for major depressive disorder (MDD). Genetic and neuroimaging research has independently revealed biological correlates of neurotic personality including cortical alterations in brain regions of high relevance for affective disorders. Here we investigated the influence of a polygenic score for neuroticism (PGS) on cortical brain structure in a joint discovery sample of n = 746 healthy controls (HC) and n = 268 MDD patients. Findings were validated in an independent replication sample (n = 341 HC and n = 263 MDD). Subgroup analyses stratified for case-control status and analyses of associations between neurotic phenotype and cortical measures were carried out. PGS for neuroticism was significantly associated with a decreased cortical surface area of the inferior parietal cortex, the precuneus, the rostral cingulate cortex and the inferior frontal gyrus in the discovery sample. Similar associations between PGS and surface area of the inferior parietal cortex and the precuneus were demonstrated in the replication sample. Subgroup analyses revealed negative associations in the latter regions between PGS and surface area in both HC and MDD subjects. Neurotic phenotype was negatively correlated with surface area in similar cortical regions including the inferior parietal cortex and the precuneus. No significant associations between PGS and cortical thickness were detected. The morphometric overlap of associations between both PGS and neurotic phenotype in similar cortical regions closely related to internally focused cognition points to the potential relevance of genetically shaped cortical alterations in the development of neuroticism.

Published
2018
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4. Cortical abnormalities in bipolar disorder: an MRI analysis of 6503 individuals from the ENIGMA Bipolar Disorder Working Group

Author

T.G.M. van Erp, Martin Alda, Harald Kugel, Salvador Sarró, Eduard Vieta, Lucija Abramovic, Jair C. Soares, Theodore D. Satterthwaite, Sarah Trost, René S. Kahn, M F Ponteduro, Michael Bauer, M. Fatjó-Vilas, Rhoshel K. Lenroot, Amy C. Bilderbeck, Christopher R.K. Ching, Janusz K. Rybakowski, Danai Dima, Volker Arolt, Udo Dannlowski, Thomas Nickson, Henricus G. Ruhé, Christian Simhandl, Guy M. Goodwin, Edith Pomarol-Clotet, Chantal Henry, Saskia P. Hagenaars, Neil Horn, Benson Mwangi, M Bonnin, Matthew J. Kempton, Erlend Bøen, Daniel H. Wolf, Christoph Abé, Ingrid Agartz, Wayne C. Drevets, Marcus V. Zanetti, Bernhard T. Baune, Mary L. Phillips, Amelia Versace, Fabiano G. Nery, Nhat Trung Doan, Carrie E. Bearden, Fleur M. Howells, Derrek P. Hibar, Nefize Yalin, Oliver Gruber, Lars T. Westlye, Henk Temmingh, Janice M. Fullerton, Jose Manuel Goikolea, David C. Glahn, Godfrey D. Pearlson, Roel A. Ophoff, Josselin Houenou, C J Ekman, Anne Uhlmann, Rodrigo Machado-Vieira, Adrian J. Lloyd, Nelson B. Freimer, Andrew M. McIntosh, Lisa Rauer, Neda Jahanshad, Aart H. Schene, Cecilie B. Hartberg, Allison C. Nugent, Tomas Hajek, Bernd Kramer, Esther Jiménez, P. G. P. Rosa, Emma Sprooten, G. Delvecchio, Khallil T. Chaim, Allan H. Young, Silvia Alonso-Lana, Maria M. Rive, Paul M. Thompson, Erick J. Canales-Rodríguez, Maristela S. Schaufelberger, Nailin Yao, Mikael Landén, Wagner F. Gattaz, Heather C. Whalley, Torbjørn Elvsåshagen, Scott C. Fears, Beny Lafer, Dan J. Stein, Jonathan Savitz, L M Beard, Maria Concepcion Garcia Otaduy, Sophia Frangou, Dominik Grotegerd, Ulrik Fredrik Malt, Marco P. Boks, C Bourne, Ronny Redlich, J Starke, Anders M. Dale, Geraldo F. Busatto, Andrea Pfennig, Martin Ingvar, Peter R. Schofield, Dara M. Cannon, Carlos A. Zarate, Tiffany M. Chaim-Avancini, Fábio L.S. Duran, Dick J. Veltman, Bronwyn Overs, Unn K. Haukvik, Philip B. Mitchell, Márcio Gerhardt Soeiro-de-Souza, Colm McDonald, Maria Keil, Jorge R. C. Almeida, Timothy B. Meier, Joshua W. Cheung, Gloria Roberts, Xavier Caseras, Won Hee Lee, N.E.M. van Haren, Ole A. Andreassen, Pablo Najt, Natalia Lawrence, Anatomy and neurosciences, Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Adult Psychiatry, and Graduate School

Subjects
Male, Bipolar Disorder, Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13], Audiology, 0302 clinical medicine, Gray Matter, Prefrontal cortex, Cerebral Cortex, Age Factors, Brain, Middle Aged, Magnetic Resonance Imaging, Temporal Lobe, Frontal Lobe, 3. Good health, Psychiatry and Mental health, medicine.anatomical_structure, Frontal lobe, cerebral-cortex, Schizophrenia, Cerebral cortex, Female, Original Article, antipsychotic treatment, Psychology, Adult, emotion regulation, Psychosis, medicine.medical_specialty, Adolescent, Prefrontal Cortex, BF, Neuroimaging, thickness abnormalities, Temporal lobe, Young Adult, 03 medical and health sciences, Cellular and Molecular Neuroscience, Sex Factors, Journal Article, medicine, Humans, Bipolar disorder, unipolar depression, human brain, Molecular Biology, DEPRESSÃO, Cerebral atrophy, anterior cingulate, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], major depressive disorder, treatment response, medicine.disease, R1, 030227 psychiatry, Psychotic Disorders, Case-Control Studies, RC0321, gray-matter volume, Neuroscience, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 191289.pdf (Publisher’s version ) (Open Access) Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis (Cohen's d=-0.293; P=1.71 x 10(-21)), left fusiform gyrus (d=-0.288; P=8.25 x 10(-21)) and left rostral middle frontal cortex (d=-0.276; P=2.99 x 10(-19)). Longer duration of illness (after accounting for age at the time of scanning) was associated with reduced cortical thickness in frontal, medial parietal and occipital regions. We found that several commonly prescribed medications, including lithium, antiepileptic and antipsychotic treatment showed significant associations with cortical thickness and surface area, even after accounting for patients who received multiple medications. We found evidence of reduced cortical surface area associated with a history of psychosis but no associations with mood state at the time of scanning. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD.

Published
2017
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5. Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression

Author

Andreas J, Forstner, Swapnil, Awasthi, Christiane, Wolf, Eduard, Maron, Angelika, Erhardt, Darina, Czamara, Elias, Eriksson, Catharina, Lavebratt, Christer, Allgulander, Nina, Friedrich, Jessica, Becker, Julian, Hecker, Stefanie, Rambau, Rupert, Conrad, Franziska, Geiser, Francis J, McMahon, Susanne, Moebus, Timo, Hess, Benedikt C, Buerfent, Per, Hoffmann, Stefan, Herms, Stefanie, Heilmann-Heimbach, Ingrid, Kockum, Tomas, Olsson, Lars, Alfredsson, Heike, Weber, Georg W, Alpers, Volker, Arolt, Lydia, Fehm, Thomas, Fydrich, Alexander L, Gerlach, Alfons, Hamm, Tilo, Kircher, Christiane A, Pané-Farré, Paul, Pauli, Winfried, Rief, Andreas, Ströhle, Jens, Plag, Thomas, Lang, Hans-Ulrich, Wittchen, Manuel, Mattheisen, Sandra, Meier, Andres, Metspalu, Katharina, Domschke, Andreas, Reif, Iiris, Hovatta, Nils, Lindefors, Evelyn, Andersson, Martin, Schalling, Hamdi, Mbarek, Yuri, Milaneschi, Eco J C, de Geus, Dorret I, Boomsma, Brenda W J H, Penninx, Thorgeir E, Thorgeirsson, Stacy, Steinberg, Kari, Stefansson, Hreinn, Stefansson, Bertram, Müller-Myhsok, Thomas Folkmann, Hansen, Anders D, Børglum, Thomas, Werge, Preben Bo, Mortensen, Merete, Nordentoft, David M, Hougaard, Christina M, Hultman, Patrick F, Sullivan, Markus M, Nöthen, David P D, Woldbye, Ole, Mors, Elisabeth B, Binder, Christian, Rück, Stephan, Ripke, Jürgen, Deckert, and Johannes, Schumacher

Subjects
Estonia, Neuroticism, Sweden, Depressive Disorder, Major, Depression, Denmark, Germany, Humans, Panic Disorder, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study
Abstract

Panic disorder (PD) has a lifetime prevalence of 2-4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0-34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p 1 × 10

Published
2019

6. Variation of HbA1c affects cognition and white matter microstructure in healthy, young adults

Author

Jonathan, Repple, Greta, Karliczek, Susanne, Meinert, Katharina, Förster, Dominik, Grotegerd, Janik, Goltermann, Ronny, Redlich, Volker, Arolt, Bernhard T, Baune, Udo, Dannlowski, and Nils, Opel

Subjects
Adult, Glycated Hemoglobin, Male, Young Adult, Cognition, Diffusion Tensor Imaging, Anisotropy, Brain, Humans, Female, White Matter
Abstract

The metabolic serum marker HbA1c has been associated with both impaired cognitive performance and altered white matter integrity in patients suffering from diabetes mellitus. However, it remains unclear if higher levels of HbA1c might also affect brain structure and function in healthy subjects. With the present study we therefore aimed to investigate the relationship between HbA1c levels and cognitive performance as well as white matter microstructure in healthy, young adults. To address this question, associations between HbA1c and cognitive measures (NIH Cognition Toolbox) as well as DTI-derived imaging measures of white matter microstructure were investigated in a publicly available sample of healthy, young adults as part of the Humane Connectome Project (n = 1206, mean age = 28.8 years, 45.5% male). We found that HbA1c levels (range 4.1-6.3%) were significantly inversely correlated with measures of cognitive performance. Higher HbA1c levels were associated with significant and widespread reductions in fractional anisotropy (FA) controlling for age, sex, body mass index, ethnicity, and education. FA reductions were furthermore found to covary with measures of cognitive performance. The same pattern of results could be observed in analyses restricted to participants with HBA1c levels below 5.7%. The present study demonstrates that low-grade HbA1c variation below diagnostic threshold for diabetes is related to both cognitive performance and white matter integrity in healthy, young adults. These findings highlight the detrimental impact of metabolic risk factors on brain physiology and underscore the importance of intensified preventive measures independent of the currently applied diagnostic HbA1c cutoff scores.

Published
2019

7. Correction: Variation of HbA1c affects cognition and white matter microstructure in healthy, young adults

Author

Jonathan Repple, Volker Arolt, Bernhard T. Baune, Ronny Redlich, Udo Dannlowski, Susanne Meinert, Nils Opel, Katharina Förster, Greta Karliczek, Dominik Grotegerd, and Janik Goltermann

Subjects
Gerontology, Cellular and Molecular Neuroscience, Psychiatry and Mental health, Variation (linguistics), Cognition, Young adult, Psychology, Molecular Biology, White matter microstructure
Published
2020
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8. Cortical surface area alterations shaped by genetic load for neuroticism

Author

Nils, Opel, Azmeraw T, Amare, Ronny, Redlich, Jonathan, Repple, Claas, Kaehler, Dominik, Grotegerd, Katharina, Dohm, Dario, Zaremba, Elisabeth J, Leehr, Joscha, Böhnlein, Katharina, Förster, Christian, Bürger, Susanne, Meinert, Verena, Enneking, Daniel, Emden, Ramona, Leenings, Nils, Winter, Tim, Hahn, Walter, Heindel, Jochen, Bauer, David, Wilhelms, Simon, Schmitt, Andreas, Jansen, Axel, Krug, Igor, Nenadic, Marcella, Rietschel, Stephanie, Witt, Andreas J, Forstner, Markus M, Nöthen, Tilo, Kircher, Volker, Arolt, Bernhard T, Baune, and Udo, Dannlowski

Subjects
Cerebral Cortex, Neuroticism, Depressive Disorder, Major, Multifactorial Inheritance, Humans, Genetic Load, Magnetic Resonance Imaging
Abstract

Neuroticism has been shown to act as an important risk factor for major depressive disorder (MDD). Genetic and neuroimaging research has independently revealed biological correlates of neurotic personality including cortical alterations in brain regions of high relevance for affective disorders. Here we investigated the influence of a polygenic score for neuroticism (PGS) on cortical brain structure in a joint discovery sample of n = 746 healthy controls (HC) and n = 268 MDD patients. Findings were validated in an independent replication sample (n = 341 HC and n = 263 MDD). Subgroup analyses stratified for case-control status and analyses of associations between neurotic phenotype and cortical measures were carried out. PGS for neuroticism was significantly associated with a decreased cortical surface area of the inferior parietal cortex, the precuneus, the rostral cingulate cortex and the inferior frontal gyrus in the discovery sample. Similar associations between PGS and surface area of the inferior parietal cortex and the precuneus were demonstrated in the replication sample. Subgroup analyses revealed negative associations in the latter regions between PGS and surface area in both HC and MDD subjects. Neurotic phenotype was negatively correlated with surface area in similar cortical regions including the inferior parietal cortex and the precuneus. No significant associations between PGS and cortical thickness were detected. The morphometric overlap of associations between both PGS and neurotic phenotype in similar cortical regions closely related to internally focused cognition points to the potential relevance of genetically shaped cortical alterations in the development of neuroticism.

Published
2018

9. Allelic variation in CRHR1 predisposes to panic disorder: evidence for biased fear processing

Author

Thomas Lang, Alfons O. Hamm, Bettina Pfleiderer, Claus-Jürgen Scholz, Jan Richter, Christiane A. Pané-Farré, Jürgen Deckert, Benjamin Straube, Hans-Ulrich Wittchen, Volker Arolt, Heike Weber, Alexander L. Gerlach, Andreas Ströhle, Paul Pauli, Benedikt Klauke, Christian Jacob, Tilo Kircher, Lydia Fehm, Carsten Konrad, Lindsey Kent, Thomas Fydrich, Andreas Jansen, Peter Zwanzger, Christian Baumann, Ulrike Lueken, André Wittmann, Katharina Domschke, C. Schartner, Andreas Reif, Georg W. Alpers, University of St Andrews. School of Medicine, and University of St Andrews. Institute of Behavioural and Neural Sciences

Subjects
Male, 0301 basic medicine, Avoidance test, Candidate gene, Hydrocortisone, Corticotropin-Releasing Hormone, Pituitary-Adrenal System, Anxiety, 0302 clinical medicine, Risk Factors, Medicine, R2C, Panic disorder, fMRI, ~DC~, Fear, Middle Aged, Anxiety Disorders, Association study, Psychiatry and Mental health, Phenotype, Schizophrenia, Panic Disorder, Female, medicine.symptom, BDC, RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry, Adult, Hypothalamo-Hypophyseal System, medicine.medical_specialty, Genotype, NDAS, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Receptors, Corticotropin-Releasing Hormone, 03 medical and health sciences, Cellular and Molecular Neuroscience, Bias, Internal medicine, Humans, Genetic Predisposition to Disease, Allele, Molecular Biology, Alleles, business.industry, Genetic Variation, CRHR1, medicine.disease, Minor allele frequency, 030104 developmental biology, Endocrinology, MCP, RC0321, Anxiety sensitivity, business, Neuroscience, 030217 neurology & neurosurgery
Abstract

This work is part of the German multicenter trial ‘Mechanisms of Action in CBT (MAC)’. The MAC study is funded by the German Federal Ministry of Education and Research (BMBF; project no. 01GV0615) as part of the BMBF Psychotherapy Research Funding Initiative. The study was further supported by the DFG (Grant RE1632/5-1 and KFO 125 to AR; SFB TRR 58 Z02 to JD, PP and AR; C02 to JD and KD; DE357/4-1 to JD, AR, JR and AH; RTG 1256 to AR, JD and PP; IZKF-Würzburg Z-6 to HW). Corticotropin releasing hormone (CRH) is a major regulator of the hypothalamicpituitary-adrenal (HPA) axis. Binding to its receptor CRHR1 triggers the downstream release of cortisol, a hormone needed for regulation of stress responses. Biochemical, behavioral and genetic studies revealed CRHR1 as a possible candidate gene for mood and anxiety disorders. Here, we aimed to evaluate CRHR1 as a candidate molecule in panic disorder (PD). Allelic variation throughout the CRHR1 gene was captured by 9 selected single nucleotide polymorphisms (SNPs); these were genotyped in 531 matched case/control pairs (discovery sample (n=239); replication sample (n=292)). Four SNPs were found to be associated with PD, in at least one sub-sample. The minor alleles of rs17689918 and rs17689966 were found to significantly increase risk for PD in females of the discovery, the replication and the combined sample, both withstanding correction for multiple testing (prs17689918=1.3*10-4; prs17689966=0.042). Expressional analysis demonstrated that both minor alleles of rs17689918 and rs17689966 significantly decreased CRHR1 mRNA in the forebrain and amygdala. Bioinformatical analysis revealed a high proportion of differential neuro-relevant transcription factor binding possibly underlying expression changes. When investigating the neural correlates underlying this association, risk allele carriers of rs17689918 and rs17689966 showed aberrant differential conditioning and safety signal processing arguing for predominant generalization of fear and hence anxious apprehension. Furthermore, the minor risk (A) allele of rs17689918 led to less flight behavior during fear provoking situations, but rather increased anxious apprehension and went along with increased anxiety sensitivity. Thus, reduced CRHR1 expression driven by CRHR1 risk allele leads to a phenotype characterized by a fear bias and hence sustained fear. These results strengthen the role of CRHR1 in PD and clarify the mechanisms by which genetic variation in CRHR1 is linked to this disorder. Postprint

Published
2015
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10. GLRB allelic variation associated with agoraphobic cognitions, increased startle response and fear network activation: a potential neurogenetic pathway to panic disorder

Author

Hans-Ulrich Wittchen, Peter Zwanzger, Alejandro Arias-Vasquez, Johannes Schumacher, Andreas Mühlberger, Andreas J. Forstner, Tina B. Lonsdorf, Sven Cichon, Miriam A. Schiele, Georg W. Alpers, Tilo Kircher, Christian Baumann, Marcel Romanos, Paul Pauli, Christoph Schartner, Agnieszka Gajewska, Volker Arolt, Jürgen Deckert, Swantje Notzon, Raffael Kalisch, Christian Büchel, Marta Andreatta, Thomas Fydrich, Leif Hommers, Lydia Fehm, Heike Weber, Lambertus A. Kiemeney, Katharina Domschke, Dirk Schümann, Alexander L. Gerlach, Jan Richter, Robert Scharfenort, Robert Blum, Natascha Schaefer, C. R. von Collenberg, Christiane Wolf, Andreas Reif, Alfons O. Hamm, Joost G. E. Janzing, Thomas Lang, Evelyn Glotzbach-Schoon, Andreas Ströhle, Lindsey Kent, M. M. Nöthen, Britta Wachter, Tessel E. Galesloot, Carmen Villmann, University of St Andrews. School of Medicine, and University of St Andrews. Institute of Behavioural and Neural Sciences

Subjects
0301 basic medicine, Male, Startle response, Reflex, Startle, QH301 Biology, Genome-wide association study, Gene mutation, Anxiety, 0302 clinical medicine, Cognition, Receptors, Glycine, Gene Frequency, Germany, GWAS, Hyperekplexia, Genetics, Panic disorder, medicine.diagnostic_test, Startle, Brain, Fear, GLRB, Anxiety Disorders, Psychiatry and Mental health, Schizophrenia, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Panic Disorder, Female, medicine.symptom, Psychology, BDC, RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry, Clinical psychology, Adult, Genotype, NDAS, QH426 Genetics, 03 medical and health sciences, Cellular and Molecular Neuroscience, QH301, Fear network, Spastic mouse, medicine, Humans, Genetic Predisposition to Disease, Molecular Biology, QH426, Agoraphobia, Alleles, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Other Research Radboud Institute for Health Sciences [Radboudumc 0], medicine.disease, Startle reaction, 030104 developmental biology, MCP, Case-Control Studies, Mutation, RC0321, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Contains fulltext : 177350.pdf (Publisher’s version ) (Closed access) The molecular genetics of panic disorder (PD) with and without agoraphobia (AG) are still largely unknown and progress is hampered by small sample sizes. We therefore performed a genome-wide association study with a dimensional, PD/AG-related anxiety phenotype based on the Agoraphobia Cognition Questionnaire (ACQ) in a sample of 1370 healthy German volunteers of the CRC TRR58 MEGA study wave 1. A genome-wide significant association was found between ACQ and single non-coding nucleotide variants of the GLRB gene (rs78726293, P=3.3 x 10-8; rs191260602, P=3.9 x 10-8). We followed up on this finding in a larger dimensional ACQ sample (N=2547) and in independent samples with a dichotomous AG phenotype based on the Symptoms Checklist (SCL-90; N=3845) and a case-control sample with the categorical phenotype PD/AG (Ncombined =1012) obtaining highly significant P-values also for GLRB single-nucleotide variants rs17035816 (P=3.8 x 10-4) and rs7688285 (P=7.6 x 10-5). GLRB gene expression was found to be modulated by rs7688285 in brain tissue, as well as cell culture. Analyses of intermediate PD/AG phenotypes demonstrated increased startle reflex and increased fear network, as well as general sensory activation by GLRB risk gene variants rs78726293, rs191260602, rs17035816 and rs7688285. Partial Glrb knockout mice demonstrated an agoraphobic phenotype. In conjunction with the clinical observation that rare coding GLRB gene mutations are associated with the neurological disorder hyperekplexia characterized by a generalized startle reaction and agoraphobic behavior, our data provide evidence that non-coding, although functional GLRB gene polymorphisms may predispose to PD by increasing startle response and agoraphobic cognitions.

Published
2016

11. Neuropeptide S receptor gene — converging evidence for a role in panic disorder

Author

Thomas Lang, Christian Baumann, Jürgen Fritze, Angelika Erhardt, Alexander L. Gerlach, Patricia Ohrmann, Andrew T. Gloster, Lydia Fehm, Katharina Domschke, Thomas Suslow, Andreas Ströhle, Jochen Bauer, Petra Krakowitzky, Tilo Kircher, Alfons O. Hamm, Anya Pedersen, Wolfgang Maier, Georg W. Alpers, Andreas Reif, Borwin Bandelow, Jürgen Deckert, Jan Richter, Florian Holsboer, Volker Arolt, Heike Weber, Benedikt Klauke, Walter Heindel, Harald Kugel, Hans-Ulrich Wittchen, Matthias Rothermundt, Paul Pauli, Elisabeth B. Binder, Christa Hohoff, and Christian Jacob

Subjects
Adult, Male, medicine.medical_specialty, Genotype, Anxiety, Polymorphism, Single Nucleotide, Receptors, G-Protein-Coupled, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Heart Rate, Neuropeptide S, Avoidance Learning, medicine, Humans, Allele, Psychiatry, Agoraphobia, Molecular Biology, Neuropeptide S receptor, Alleles, Anterior cingulate cortex, 030304 developmental biology, Sex Characteristics, 0303 health sciences, Functional Neuroimaging, Panic disorder, medicine.disease, Anxiety Disorders, Magnetic Resonance Imaging, Psychiatry and Mental health, medicine.anatomical_structure, Case-Control Studies, Anxiety sensitivity, Panic Disorder, Female, medicine.symptom, Arousal, Psychology, Neuroscience, 030217 neurology & neurosurgery
Abstract

Animal studies have suggested neuropeptide S (NPS) and its receptor (NPSR) to be involved in the pathogenesis of anxiety-related behavior. In this study, a multilevel approach was applied to further elucidate the role of NPS in the etiology of human anxiety. The functional NPSR A/T (Asn 107 Ile) variant (rs324981) was investigated for association with (1) panic disorder with and without agoraphobia in two large, independent case–control studies, (2) dimensional anxiety traits, (3) autonomic arousal level during a behavioral avoidance test and (4) brain activation correlates of anxiety-related emotional processing in panic disorder. The more active NPSR rs324981 T allele was found to be associated with panic disorder in the female subgroup of patients in both samples as well as in a meta-analytic approach. The T risk allele was further related to elevated anxiety sensitivity, increased heart rate and higher symptom reports during a behavioral avoidance test as well as decreased activity in the dorsolateral prefrontal, lateral orbitofrontal and anterior cingulate cortex during processing of fearful faces in patients with panic disorder. The present results provide converging evidence for a female-dominant role of NPSR gene variation in panic disorder potentially through heightened autonomic arousal and distorted processing of anxiety-relevant emotional stimuli. Molecular Psychiatry (2011) 16, 938–948; doi:10.1038/mp.2010.81; published online 6 July 2010

Published
2010
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12. Genome-wide association for major depressive disorder: a possible role for the presynaptic protein piccolo

Author

Volker Arolt, Maurizio Fava, Willem A. Nolen, Markus M. Nöthen, Alexandra Schosser, R. van Dyck, D. H. R. Blackwood, Katharina Domschke, K. Pirlo, S.D. Gordon, Michael R. James, N. G. Martin, Wolfgang Maier, Marcella Rietschel, A. C. Heath, Yi Hu, Martin A. Kohli, Grant W. Montgomery, Susanne Lucae, Jordan W. Smoller, August B. Smit, Bernhard T. Baune, Donald J. MacIntyre, Qianchuan He, Anne Farmer, Kevin A. McGhee, Jouke-Jan Hottenga, Frans G. Zitman, Peter McGuffin, B.W.J.H. Penninx, Florian Holsboer, Dorret I. Boomsma, Patrick F. Sullivan, Jan Smit, Danielle Posthuma, Witte J.G. Hoogendijk, Danyu Lin, T. Zandbelt, Naomi R. Wray, Matthijs Verhage, Gonneke Willemsen, Jung-Ying Tzeng, Peter Heutink, E.J.C. de Geus, Walter J. Muir, Patrizia Rizzu, Roy H. Perlis, Sven Cichon, William L. Coventry, Biological Psychology, Molecular and Cellular Neurobiology, Functional Genomics, Neuroscience Campus Amsterdam - Anxiety & Depression, Psychiatry, Human genetics, and NCA - Anxiety & Depression

Subjects
Male, Netherlands Twin Register (NTR), Genetic Linkage, Genome-wide association study, Cohort Studies, NATIONAL-COMORBIDITY-SURVEY, 0302 clinical medicine, Copy-number variation, Genetics, GENERAL-POPULATION, 0303 health sciences, PSYCHIATRIC-DISORDERS, SINGLE-NUCLEOTIDE POLYMORPHISMS, Middle Aged, 3. Good health, FALSE DISCOVERY RATE, Psychiatry and Mental health, Female, Psychology, SAMPLE-SIZE REQUIREMENTS, Presynaptic active zone, Adult, GENETIC-ASSOCIATION, Netherlands study of depression and anxiety, Single-nucleotide polymorphism, Protein Piccolo, COPY-NUMBER VARIATION, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, SDG 3 - Good Health and Well-being, Humans, SNP, Genetic Predisposition to Disease, Molecular Biology, Gene, 030304 developmental biology, Genetic association, Depressive Disorder, Major, SELECTION BIAS, major depressive disorder, Neuropeptides, Netherlands twin registry, Cytoskeletal Proteins, HARDY-WEINBERG EQUILIBRIUM, Case-Control Studies, genome-wide association, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Major depressive disorder (MDD) is a common complex trait with enormous public health significance. As part of the Genetic Association Information Network initiative of the US Foundation for the National Institutes of Health, we conducted a genome-wide association study of 435 291 single nucleotide polymorphisms (SNPs) genotyped in 1738 MDD cases and 1802 controls selected to be at low liability for MDD. Of the top 200, 11 signals localized to a 167 kb region overlapping the gene piccolo (PCLO, whose protein product localizes to the cytomatrix of the presynaptic active zone and is important in monoaminergic neurotransmission in the brain) with P-values of 7.7 x 10(-7) for rs2715148 and 1.2 x 10(-6) for rs2522833. We undertook replication of SNPs in this region in five independent samples (6079 MDD independent cases and 5893 controls) but no SNP exceeded the replication significance threshold when all replication samples were analyzed together. However, there was heterogeneity in the replication samples, and secondary analysis of the original sample with the sample of greatest similarity yielded P=6.4 x 10(-8) for the nonsynonymous SNP rs2522833 that gives rise to a serine to alanine substitution near a C2 calcium-binding domain of the PCLO protein. With the integrated replication effort, we present a specific hypothesis for further studies.

Published
2009
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13. Decreased in vitro production of interferon-gamma and interleukin-2 in whole blood of patients with schizophrenia during treatment

Author

Holger Kirchner, Klaus-Peter Wandinger, Matthias Rothermundt, and Volker Arolt

Subjects
Adult, Male, Interleukin 2, medicine.medical_specialty, Adolescent, Exacerbation, Chlorpromazine, medicine.medical_treatment, Interferon-gamma, Cellular and Molecular Neuroscience, Reference Values, Internal medicine, medicine, Humans, Interferon gamma, Clozapine, Molecular Biology, business.industry, Receptors, Interleukin-2, Middle Aged, medicine.disease, Psychiatry and Mental health, Cytokine, Endocrinology, Schizophrenia, Immunology, Interleukin-2, Regression Analysis, Female, business, Antipsychotic Agents, medicine.drug, Psychopathology
Abstract

A pattern of aberrations in the T-cell cytokine system that is typical for autoimmune disorders has also been reported in patients with schizophrenia, namely a decreased interleukin-2 (IL-2) production and increased levels of the soluble IL-2 receptor (sIL-2R). It has also been reported that the production of interferon-gamma (IFN-gamma) may be lowered. In a longitudinal design, we studied the production of both IFN-gamma and IL-2 and their correlation in patients with schizophrenia during treatment and investigated whether associations exist between cytokine production and clinical variables. The production of IFN-gamma and IL-2 was measured in equal numbers (n = 29) of patients with schizophrenia (DSM-IV) and controls who were matched for age and gender. Patients were measured 1 day after admission (T1), after 14 (T2) and 28 (T2) days of treatment. Psychopathology was assessed after these times. The production of both IFN-gamma and IL-2 was significantly lower in patients than in controls throughout the whole investigation period (T1-T3). The productions of both cytokines were significantly correlated in controls (r = 0.60, P

Published
2000
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14. Glial cell dysfunction in schizophrenia indicated by increased S100B in the CSF

Author

Peter Falkai, Anya Pedersen, H Bürkle, Matthias Rothermundt, S. Abel, Wolfgang Maier, Thomas Suslow, Volker Arolt, G. Hetzel, Markus Diedrich, Gerald Ponath, J. Schramm, Patricia Ohrmann, Ansgar Siegmund, and Marion Peters

Subjects
Cellular and Molecular Neuroscience, Psychiatry and Mental health, medicine.anatomical_structure, Nerve growth factor, Schizophrenia, Cell, medicine, medicine.disease, Psychology, Molecular Biology, Neuroscience, S100 Calcium Binding Protein beta Subunit
Published
2004
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15. MAOA and mechanisms of panic disorder revisited: from bench to molecular psychotherapy

Author

Katharina Domschke, Paul Pauli, Lydia Fehm, Thomas Lang, Bettina Pfleiderer, Andreas Ströhle, Isabelle Reinhardt, Alexander L. Gerlach, Ulrike Lueken, André Wittmann, Hermann Weber, Michael Höfler, Andrew T. Gloster, Hans-Ulrich Wittchen, Jürgen Deckert, Benjamin Straube, Georg W. Alpers, Jan Richter, Alfons O. Hamm, Andreas Reif, Andreas Jansen, Christoph Konrad, Martin Pyka, Tilo Kircher, and Volker Arolt

Subjects
Male, Psychotherapist, Panic Disorder with Agoraphobia, Genotype, medicine.medical_treatment, Conditioning, Classical, Minisatellite Repeats, Cellular and Molecular Neuroscience, Electrocardiography, Gene Frequency, medicine, Image Processing, Computer-Assisted, Humans, Fear conditioning, Molecular Biology, Allele frequency, Agoraphobia, Monoamine Oxidase, Anterior cingulate cortex, Psychiatric Status Rating Scales, biology, Cognitive Behavioral Therapy, Panic disorder, Panic, Brain, medicine.disease, Magnetic Resonance Imaging, Cognitive behavioral therapy, Oxygen, Psychiatry and Mental health, medicine.anatomical_structure, biology.protein, Panic Disorder, Female, medicine.symptom, Monoamine oxidase A, Psychology, Follow-Up Studies
Abstract

Panic disorder with agoraphobia (PD/AG) is a prevalent mental disorder featuring a substantial complex genetic component. At present, only a few established risk genes exist. Among these, the gene encoding monoamine oxidase A (MAOA) is noteworthy given that genetic variation has been demonstrated to influence gene expression and monoamine levels. Long alleles of the MAOA-uVNTR promoter polymorphism are associated with PD/AG and correspond with increased enzyme activity. Here, we have thus investigated the impact of MAOA-uVNTR on therapy response, behavioral avoidance and brain activity in fear conditioning in a large controlled and randomized multicenter study on cognitive behavioral therapy (CBT) in PD/AG. The study consisted of 369 PD/AG patients, and genetic information was available for 283 patients. Carriers of the risk allele had significantly worse outcome as measured by the Hamilton Anxiety scale (46% responders vs 67%, P=0.017). This was accompanied by elevated heart rate and increased fear during an anxiety-provoking situation, that is, the behavioral avoidance task. All but one panic attack that happened during this task occurred in risk allele carriers and, furthermore, risk allele carriers did not habituate to the situation during repetitive exposure. Finally, functional neuroimaging during a classical fear conditioning paradigm evidenced that the protective allele is associated with increased activation of the anterior cingulate cortex upon presentation of the CS+ during acquisition of fear. Further differentiation between high- and low-risk subjects after treatment was observed in the inferior parietal lobes, suggesting differential brain activation patterns upon CBT. Taken together, we established that a genetic risk factor for PD/AG is associated with worse response to CBT and identify potential underlying neural mechanisms. These findings might govern how psychotherapy can include genetic information to tailor individualized treatment approaches.

Published
2012

16. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine

Author

B. Goldstein-Müller, Hans-Jürgen Möller, A. Douhe, Volker Arolt, G. Hetzel, A. Cerovecki, Sandra Dehning, Michael Riedel, Ilja Spellmann, Markus J. Schwarz, N. Kleindienst, Norbert Müller, and Katja Maino

Subjects
Adult, Male, medicine.medical_specialty, Serotonin, Patient Dropouts, Morpholines, Pilot Projects, Pharmacology, Placebo, Lorazepam, Gastroenterology, Severity of Illness Index, Dinoprostone, Cellular and Molecular Neuroscience, Reboxetine, Double-Blind Method, Internal medicine, Severity of illness, medicine, Humans, Molecular Biology, Inflammation, Depressive Disorder, Psychological Tests, Sulfonamides, biology, Adrenergic Uptake Inhibitors, Cyclooxygenase 2 Inhibitors, Interleukin-6, Therapeutic effect, Middle Aged, Antidepressive Agents, Psychiatry and Mental health, Anti-Anxiety Agents, Celecoxib, biology.protein, Pyrazoles, Drug Therapy, Combination, Female, Psychopharmacology, Cyclooxygenase, Reuptake inhibitor, Psychology, medicine.drug
Abstract

Signs of an inflammatory process, in particular increased pro-inflammatory cytokines and increased levels of prostaglandine E(2) (PGE(2)), have repeatedly been described in major depression (MD). As cyclooxygenase-2 (COX-2) inhibitors inhibit the PGE(2) production and the production of pro-inflammatory cytokines, we performed a therapeutic trial with the COX-2 inhibitor celecoxib. In a prospective, double-blind, add-on study, 40 patients suffering from an acute depressive episode were randomly assigned to either reboxetine and celecoxib or to reboxetine plus placebo. After a wash-out period, 20 patients received 4-10 mg reboxetine plus placebo and 20 received reboxetine plus 400 mg celecoxib for 6 weeks. The treatment effect was calculated by analysis of variance. There were no significant differences between groups in age, sex, duration or severity of disease or psychopathology, or reboxetine dose or plasma levels. Over 6 weeks, both groups of patients showed significant improvement in scores of the Hamilton Depression Scale. However, the celecoxib group showed significantly greater improvement compared to the reboxetine-alone group. Additional treatment with celecoxib has significant positive effects on the therapeutic action of reboxetine with regard to depressive symptomatology. Moreover, the fact that treatment with an anti-inflammatory drug showed beneficial effects on MD indicates that inflammation is related to the pathomechanism of the disorder, although the exact mechanisms remain to become elucidated.

Published
2006

17. Increased S100B blood levels in unmedicated and treated schizophrenic patients are correlated with negative symptomatology

Author

Sebastian Rudolf, Holger Kirchner, Klaus-Peter Wandinger, Martin Wiesmann, J. Leadbeater, Ulrich Missler, Volker Arolt, Marion Peters, and Matthias Rothermundt

Subjects
Adult, Male, medicine.medical_specialty, Psychosis, Time Factors, Acute schizophrenia, Brain damage, S100 Calcium Binding Protein beta Subunit, Autoantigens, Cellular and Molecular Neuroscience, Reference Values, Internal medicine, medicine, Humans, Nerve Growth Factors, Psychiatry, Molecular Biology, Negative symptom, Psychological Tests, Schizophrenia, Paranoid, Neurodegeneration, Calcium-Binding Proteins, S100 Proteins, Reproducibility of Results, Middle Aged, medicine.disease, Psychiatry and Mental health, Schizophrenia, Female, Schizophrenic Psychology, medicine.symptom, Psychology, Biomarkers, Psychopathology, Antipsychotic Agents
Abstract

S100B, a calcium-binding protein produced by astroglial cells, is a marker of astroglial cellular integrity. It has been shown to be increased in acute brain damage and neurodegeneration. A recent study showed increased S100B levels in medicated acutely psychotic patients with schizophrenia. The study presented here included 26 drug-free patients with acute schizophrenia and 26 matched healthy controls. S100B blood concentrations were determined using a quantitative immunoassay upon admission and after 6 weeks of neuroleptic treatment. The PANSS was used to investigate psychopathology. Unmedicated schizophrenic patients showed significantly increased S100B levels compared to matched healthy controls. After 6 weeks of treatment, 11 patients showed normal S100B levels while in 15 patients the levels remained increased. These patients showed significantly higher PANSS negative scores upon admission and after 6 weeks of treatment. Schizophrenic patients display a loss of astroglial integrity which is not caused by neuroleptic medication. Continuously increased S100B levels are associated with negative symptomatology.

Published
2000

18. Association of polygenic score for major depression with response to lithium in patients with bipolar disorder

Author

Amare, Azmeraw T., Schubert, Klaus Oliver, Hou, Liping, Clark, Scott R., Papiol, Sergi, Cearns, Micah, Heilbronner, Urs, Degenhardt, Franziska, Tekola-Ayele, Fasil, Hsu, Yi Hsiang, Shekhtman, Tatyana, Adli, Mazda, Akula, Nirmala, Akiyama, Kazufumi, Ardau, Raffaella, Arias, Bárbara, Aubry, Jean Michel, Backlund, Lena, Bhattacharjee, Abesh Kumar, Bellivier, Frank, Benabarre, Antonio, Bengesser, Susanne, Biernacka, Joanna M., Birner, Armin, Brichant-Petitjean, Clara, Cervantes, Pablo, Chen, Hsi Chung, Chillotti, Caterina, Cichon, Sven, Cruceanu, Cristiana, Czerski, Piotr M., Dalkner, Nina, Dayer, Alexandre, Del Zompo, Maria, DePaulo, J. Raymond, Étain, Bruno, Jamain, Stephane, Falkai, Peter, Forstner, Andreas J., Frisen, Louise, Frye, Mark A., Fullerton, Janice M., Gard, Sébastien, Garnham, Julie S., Goes, Fernando S., Grigoroiu-Serbanescu, Maria, Grof, Paul, Hashimoto, Ryota, Hauser, Joanna, Herms, Stefan, Hoffmann, Per, Hofmann, Andrea, Jiménez, Esther, Kahn, Jean Pierre, Kassem, Layla, Kuo, Po Hsiu, Kato, Tadafumi, Kelsoe, John R., Kittel-Schneider, Sarah, Kliwicki, Sebastian, König, Barbara, Kusumi, Ichiro, Laje, Gonzalo, Landén, Mikael, Lavebratt, Catharina, Leboyer, Marion, Leckband, Susan G., Tortorella, Alfonso, Manchia, Mirko, Martinsson, Lina, McCarthy, Michael J., McElroy, Susan L., Colom, Francesc, Mitjans, Marina, Mondimore, Francis M., Monteleone, Palmiero, Nievergelt, Caroline M., Nöthen, Markus M., Novák, Tomas, O’Donovan, Claire, Ozaki, Norio, Ösby, Urban, Pfennig, Andrea, Potash, James B., Reif, Andreas, Wray, Naomi R., Ripke, Stephan, Mattheisen, Manuel, Trzaskowski, Maciej, Byrne, Enda M., Abdellaoui, Abdel, Adams, Mark J., Agerbo, Esben, Air, Tracy M., Andlauer, Till F.M., Bacanu, Silviu Alin, Bækvad-Hansen, Marie, Beekman, Aartjan T.F., Bigdeli, Tim B., Binder, Elisabeth B., Blackwood, Douglas H.R., Bryois, Julien, Buttenschøn, Henriette N., Bybjerg-Grauholm, Jonas, Cai, Na, Castelao, Enrique, Christensen, Jane varregaard, Clarke, Toni Kim, Coleman, Jonathan R.I., Colodro-Conde, Lucía, Couvy-Duchesne, Baptiste, Craddock, Nick, Crawford, Gregory E., Davies, Gail, Deary, Ian J., Derks, Eske M., Direk, Nese, Dolan, Conor V., Dunn, Erin C., Eley, Thalia C., Escott-Price, Valentina, Kiadeh, Farnush Farhadi Hassan, Finucane, Hilary K., Frank, Josef, Gaspar, Héléna A., Gill, Michael, Gordon, Scott D., Grove, Jakob, Hall, Lynsey S., Hansen, Christine Søholm, Hansen, Thomas F., Hickie, Ian B., Homuth, Georg, Horn, Carsten, Hottenga, Jouke Jan, Hougaard, David M., Ising, Marcus, Jansen, Rick, Jorgenson, Eric, Knowles, James A., Kohane, Isaac S., Kraft, Julia, Kretzschmar, Warren W., Krogh, Jesper, Kutalik, Zoltán, Li, Yihan, Lind, Penelope A., MacIntyre, Donald J., MacKinnon, Dean F., Maier, Robert M., Maier, Wolfgang, Marchini, Jonathan, Mbarek, Hamdi, McGrath, Patrick, McGuffin, Peter, Medland, Sarah E., Mehta, Divya, Middeldorp, Christel M., Mihailov, Evelin, Milaneschi, Yuri, Milani, Lili, Montgomery, Grant W., Mostafavi, Sara, Mullins, Niamh, Nauck, Matthias, Ng, Bernard, Nivard, Michel G., Nyholt, Dale R., O’Reilly, Paul F., Oskarsson, Hogni, Owen, Michael J., Painter, Jodie N., Pedersen, Carsten Bøcker, Pedersen, Marianne Giørtz, Peterson, Roseann E., Pettersson, Erik, Peyrot, Wouter J., Pistis, Giorgio, Posthuma, Danielle, Quiroz, Jorge A., Qvist, Per, Rice, John P., Riley, Brien P., Rivera, Margarita, Mirza, Saira Saeed, Schoevers, Robert, Schulte, Eva C., Shen, Ling, Shi, Jianxin, Shyn, Stanley I., Sigurdsson, Engilbert, Sinnamon, Grant C.B., Smit, Johannes H., Smith, Daniel J., Stefansson, Hreinn, Steinberg, Stacy, Streit, Fabian, Strohmaier, Jana, Tansey, Katherine E., Teismann, Henning, Teumer, Alexander, Thompson, Wesley, Thomson, Pippa A., Thorgeirsson, Thorgeir E., Traylor, Matthew, Treutlein, Jens, Trubetskoy, Vassily, Uitterlinden, André G., Umbricht, Daniel, Van der Auwera, Sandra, van Hemert, Albert M., Viktorin, Alexander, Visscher, Peter M., Wang, Yunpeng, Webb, Bradley T., Weinsheimer, Shantel Marie, Wellmann, Jürgen, Willemsen, Gonneke, Witt, Stephanie H., Wu, Yang, Xi, Hualin S., Yang, Jian, Zhang, Futao, Arolt, Volker, Baune, Bernhard T., Berger, Klaus, Boomsma, Dorret I., Dannlowski, Udo, de Geus, E. J.C., Domenici, Enrico, Domschke, Katharina, Esko, Tõnu, Grabe, Hans J., Hamilton, Steven P., Hayward, Caroline, Heath, Andrew C., Kendler, Kenneth S., Kloiber, Stefan, Lewis, Glyn, Li, Qingqin S., Lucae, Susanne, Madden, Pamela A.F., Magnusson, Patrik K., Martin, Nicholas G., McIntosh, Andrew M., Metspalu, Andres, Mors, Ole, Mortensen, Preben Bo, Müller-Myhsok, Bertram, Nordentoft, Merete, O’Donovan, Michael C., Paciga, Sara A., Pedersen, Nancy L., Penninx, Brenda W.J.H., Perlis, Roy H., Porteous, David J., Preisig, Martin, Rietschel, Marcella, Schaefer, Catherine, Schulze, Thomas G., Smoller, Jordan W., Stefansson, Kari, Tiemeier, Henning, Uher, Rudolf, Völzke, Henry, Weissman, Myrna M., Werge, Thomas, Lewis, Cathryn M., Levinson, Douglas F., Breen, Gerome, Børglum, Anders D., Sullivan, Patrick F., Reininghaus, Eva, Rouleau, Guy A., Rybakowski, Janusz K., Schalling, Martin, Schofield, Peter R., Schweizer, Barbara W., Severino, Giovanni, Shilling, Paul D., Shimoda, Katzutaka, Simhandl, Christian, Slaney, Claire M., Squassina, Alessio, Stamm, Thomas, Stopkova, Pavla, Maj, Mario, Turecki, Gustavo, Vieta, Eduard, Veeh, Julia, Wright, Adam, Zandi, Peter P., Mitchell, Philip B., Bauer, Michael, Alda, Martin, McMahon, Francis J., APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Human genetics, APH - Digital Health, APH - Methodology, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Complex Trait Genetics, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Jamain, Stéphane, University of Adelaide, South Australian Health and Medical Research Institute [ Adelaide] (SAHMRI), Mental Health Services [Adelaide, SA, Australia], National Institute of Mental Health (NIMH), Ludwig Maximilian University [Munich] (LMU), Georg-August-University = Georg-August-Universität Göttingen, Institut für Genetik - Universität Bonn / Institute of Genetics - University of Bonn, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Harvard Medical School [Boston] (HMS), Harvard School of Public Health, University of California [San Diego] (UC San Diego), University of California (UC), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Dokkyo Medical University, Università degli Studi di Cagliari = University of Cagliari (UniCa), Universitat Autònoma de Barcelona (UAB), Centro de Investigación Biomédica en Red de Salud Mental [Barcelona, Spain] (CIBERSAM), Hospital Sant Joan de Déu [Barcelona], Geneva University Hospital (HUG), Karolinska Institutet [Stockholm], Karolinska University Hospital [Stockholm], Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Karl-Franzens-Universität Graz, Mayo Clinic [Rochester], McGill University Health Center [Montreal] (MUHC), National Taiwan University [Taiwan] (NTU), University Hospital Basel [Basel], Poznan University of Medical Sciences [Poland] (PUMS), Johns Hopkins University (JHU), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Fondation FondaMental [Créteil], IMRB - 'Neuropsychiatrie translationnelle' [Créteil] (U955 Inserm - UPEC), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), University of Basel (Unibas), Neuroscience Research Australia [Sydney, NSW, Australia] (NRA), University of New South Wales [Sydney] (UNSW), Psychiatrie de l'enfant et de l'adolescent [CH C. Perrens, Bordeaux], SECOP - centre hospitalier Charles Perrens, Dalhousie University [Halifax], 'Prof. Dr. Alexandru Obregia' Clinical Hospital of Psychiatry [Bucharest, Romania], Mood Disorders Center of Ottawa (MDCO), University of Ottawa [Ottawa], Osaka University [Osaka], Graduate School of Medicine [Osaka], Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Psychiatrie et Psychologie Clinique de Liaison [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Psychothérapique de Nancy (CPN), National Institutes of Health [Bethesda] (NIH), Environmental Molecular Biology Laboratory (RIKEN), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Goethe-University Frankfurt am Main, Landesklinikum Neunkirchen (LK Neunkirchen), Hokkaido University Graduate School of Medicine [Sapporo, Japan], Sahlgrenska Academy at University of Gothenburg [Göteborg], Research Service VA San Diego Healthcare System, Università degli Studi di Perugia = University of Perugia (UNIPG), University of Cincinnati (UC), IMIM-Hospital del Mar, Generalitat de Catalunya, Max Planck Institute of Experimental Medicine [Göttingen] (MPI), Max-Planck-Gesellschaft, University of Salerno (UNISA), University of the Study of Campania Luigi Vanvitelli, National Institute of Mental Health [Klecany, Czech Republic] (NIMH), Nagoya University Graduate School of Medicine [Japon], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Medical University Graz, Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Sigmund Freud University (SFU), Douglas Mental Health University Institute [Montréal], University of Heidelberg, Medical Faculty, Black Dog Institute [Sydney, Australia], Johns Hopkins Bloomberg School of Public Health [Baltimore], Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Melbourne Medical School [Melbourne], Faculty of Medicine, Dentistry and Health Sciences [Melbourne], University of Melbourne-University of Melbourne, The Florey Institute of Neuroscience and Mental Health [Parkville, VIC, Australie], University of Melbourne, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium: Naomi R Wray, Stephan Ripke, Manuel Mattheisen, Maciej Trzaskowski, Enda M Byrne, Abdel Abdellaoui, Mark J Adams, Esben Agerbo, Tracy M Air, Till F M Andlauer, Silviu-Alin Bacanu, Marie Bækvad-Hansen, Aartjan T F Beekman, Tim B Bigdeli, Elisabeth B Binder, Douglas H R Blackwood, Julien Bryois, Henriette N Buttenschøn, Jonas Bybjerg-Grauholm, Na Cai, Enrique Castelao, Jane Varregaard Christensen, Toni-Kim Clarke, Jonathan R I Coleman, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Nick Craddock, Gregory E Crawford, Gail Davies, Ian J Deary, Franziska Degenhardt, Eske M Derks, Nese Direk, Conor V Dolan, Erin C Dunn, Thalia C Eley, Valentina Escott-Price, Farnush Farhadi Hassan Kiadeh, Hilary K Finucane, Andreas J Forstner, Josef Frank, Héléna A Gaspar, Michael Gill, Fernando S Goes, Scott D Gordon, Jakob Grove, Lynsey S Hall, Christine Søholm Hansen, Thomas F Hansen, Stefan Herms, Ian B Hickie, Per Hoffmann, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, David M Hougaard, Marcus Ising, Rick Jansen, Eric Jorgenson, James A Knowles, Isaac S Kohane, Julia Kraft, Warren W Kretzschmar, Jesper Krogh, Zoltán Kutalik, Yihan Li, Penelope A Lind, Donald J MacIntyre, Dean F MacKinnon, Robert M Maier, Wolfgang Maier, Jonathan Marchini, Hamdi Mbarek, Patrick McGrath, Peter McGuffin, Sarah E Medland, Divya Mehta, Christel M Middeldorp, Evelin Mihailov, Yuri Milaneschi, Lili Milani, Francis M Mondimore, Grant W Montgomery, Sara Mostafavi, Niamh Mullins, Matthias Nauck, Bernard Ng, Michel G Nivard, Dale R Nyholt, Paul F O'Reilly, Hogni Oskarsson, Michael J Owen, Jodie N Painter, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Roseann E Peterson, Erik Pettersson, Wouter J Peyrot, Giorgio Pistis, 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Subjects
0301 basic medicine, Netherlands Twin Register (NTR), Lithium (medication), [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Genome-wide association study, Logistic regression, THERAPY, ddc:616.89, 0302 clinical medicine, Medicine, Major depression, PREDICTORS, Depression (differential diagnoses), RISK, Depression, Psychiatry and Mental health, Quartile, Cohort, AUGMENTATION, medicine.drug, POLARITY, medicine.medical_specialty, GENETICS, Bipolar disorder, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Lithium, PROPHYLACTIC LITHIUM, 03 medical and health sciences, Cellular and Molecular Neuroscience, SDG 3 - Good Health and Well-being, Internal medicine, Humans, ddc:610, AGENTS, Molecular Biology, Genetic association, Depressive Disorder, Major, business.industry, medicine.disease, EFFICACY, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, PHARMACOLOGICAL-TREATMENTS, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

© 2020, The Author(s), under exclusive licence to Springer Nature Limited.Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi+Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18–2.01) and European sample: OR = 1.75 (95% CI: 1.30–2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61–4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.

Published
2021
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