. 2017 Feb 6;12(2):e0171595.

doi: 10.1371/journal.pone.0171595. eCollection 2017.

Identification of shared risk loci and pathways for bipolar disorder and schizophrenia

Andreas J Forstner^{1

2

3

4

5}, Julian Hecker⁶, Andrea Hofmann^{1

2

7}, Anna Maaser^{1

2}, Céline S Reinbold^{4

5}, Thomas W Mühleisen^{1

2

4

5

8}, Markus Leber⁹, Jana Strohmaier¹⁰, Franziska Degenhardt^{1

2}, Jens Treutlein¹⁰, Manuel Mattheisen^{1

11

12}, Johannes Schumacher^{1

2}, Fabian Streit¹⁰, Sandra Meier^{10

12

13}, Stefan Herms^{1

2

4

5}, Per Hoffmann^{1

2

4

5}, André Lacour¹⁴, Stephanie H Witt¹⁰, Andreas Reif¹⁵, Bertram Müller-Myhsok^{16

17

18}, Susanne Lucae¹⁶, Wolfgang Maier¹⁹, Markus Schwarz²⁰, Helmut Vedder²⁰, Jutta Kammerer-Ciernioch²¹, Andrea Pfennig²², Michael Bauer²², Martin Hautzinger²³, Susanne Moebus²⁴, Lorena M Schenk^{1

2}, Sascha B Fischer^{4

5}, Sugirthan Sivalingam^{1

2}, Piotr M Czerski²⁵, Joanna Hauser²⁵, Jolanta Lissowska²⁶, Neonila Szeszenia-Dabrowska²⁷, Paul Brennan²⁸, James D McKay²⁹, Adam Wright^{30

31}, Philip B Mitchell^{30

31}, Janice M Fullerton^{32

33}, Peter R Schofield^{32

33}, Grant W Montgomery³⁴, Sarah E Medland³⁴, Scott D Gordon³⁴, Nicholas G Martin³⁴, Valery Krasnov³⁵, Alexander Chuchalin³⁶, Gulja Babadjanova³⁶, Galina Pantelejeva³⁷, Lilia I Abramova³⁷, Alexander S Tiganov³⁷, Alexey Polonikov^{38

39}, Elza Khusnutdinova^{40

41}, Martin Alda^{42

43}, Cristiana Cruceanu^{44

45

46}, Guy A Rouleau⁴⁴, Gustavo Turecki^{45

46

47}, Catherine Laprise⁴⁸, Fabio Rivas⁴⁹, Fermin Mayoral⁴⁹, Manolis Kogevinas⁵⁰, Maria Grigoroiu-Serbanescu⁵¹, Tim Becker^{14

52}, Thomas G Schulze⁵³, Marcella Rietschel¹⁰, Sven Cichon^{1

2

4

5

8}, Heide Fier⁶, Markus M Nöthen^{1

2}

Affiliations

¹ Institute of Human Genetics, University of Bonn, Bonn, Germany.
² Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
³ Department of Psychiatry (UPK), University of Basel, Basel, Switzerland.
⁴ Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland.
⁵ Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
⁶ Institute for Genomics Mathematics, University of Bonn, Bonn, Germany.
⁷ Institute of Medical Microbiology, Immunology and Parasitology, University of Bonn, Bonn, Germany.
⁸ Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany.
⁹ Department of Psychiatry & Psychotherapy, University of Cologne, Cologne, Germany.
¹⁰ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/University of Heidelberg, Mannheim, Germany.
¹¹ Department of Biomedicine and Centre for integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.
¹² The Lundbeck Foundation Initiative for integrative Psychiatric Research, iPSYCH, Aarhus and Copenhagen, Denmark.
¹³ National Centre Register-Based Research, Aarhus University, Aarhus, Denmark.
¹⁴ German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
¹⁵ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt am Main, Frankfurt am Main, Germany.
¹⁶ Max Planck Institute of Psychiatry, Munich, Germany.
¹⁷ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
¹⁸ University of Liverpool, Institute of Translational Medicine, Liverpool, United Kingdom.
¹⁹ Department of Psychiatry, University of Bonn, Bonn, Germany.
²⁰ Psychiatric Center Nordbaden, Wiesloch, Germany.
²¹ Center of Psychiatry Weinsberg, Weinsberg, Germany.
²² Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany.
²³ Department of Psychology, Clinical Psychology and Psychotherapy, Eberhard Karls University Tübingen, Tübingen, Germany.
²⁴ Institute of Medical Informatics, Biometry and Epidemiology, University Duisburg-Essen, Essen, Germany.
²⁵ Laboratory of Psychiatric Genetics, Department of Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
²⁶ Department of Cancer Epidemiology and Prevention, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology Warsaw, Warsaw, Poland.
²⁷ Department of Epidemiology, Nofer Institute of Occupational Medicine, Lodz, Poland.
²⁸ Genetic Epidemiology Group, International Agency for Research on Cancer (IARC), Lyon, France.
²⁹ Genetic Cancer Susceptibility Group, International Agency for Research on Cancer (IARC), Lyon, France.
³⁰ School of Psychiatry, University of New South Wales, Randwick, Australia.
³¹ Black Dog Institute, Prince of Wales Hospital, Randwick, Australia.
³² Neuroscience Research Australia, Sydney, Australia.
³³ School of Medical Sciences Faculty of Medicine, University of New South Wales, Sydney, Australia.
³⁴ Queensland Institute of Medical Research (QIMR), Brisbane, Australia.
³⁵ Moscow Research Institute of Psychiatry, Moscow, Russian Federation.
³⁶ Institute of Pulmonology, Russian State Medical University, Moscow, Russian Federation.
³⁷ Russian Academy of Medical Sciences, Mental Health Research Center, Moscow, Russian Federation.
³⁸ Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, Kursk, Russian Federation.
³⁹ Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, Kursk, Russian Federation.
⁴⁰ Institute of Biochemistry and Genetics, Ufa Scientific Center of Russian Academy of Sciences, Ufa, Russian Federation.
⁴¹ Department of Genetics and Fundamental Medicine of Bashkir State University, Ufa, Russian Federation.
⁴² Department of Psychiatry, Dalhousie University, Halifax, Canada.
⁴³ National Institute of Mental Health, Klecany, Czech Republic.
⁴⁴ Montreal Neurological Institute, McGill University, Montreal, Canada.
⁴⁵ Department of Human Genetics, McGill University, Montreal, Canada.
⁴⁶ McGill Group for Suicide Studies & Douglas Research Institute, Montreal, Canada.
⁴⁷ Department of Psychiatry, McGill University, Montreal, Canada.
⁴⁸ Département des sciences fondamentales, Université du Québec à Chicoutimi (UQAC), Saguenay, Canada.
⁴⁹ Department of Psychiatry, Hospital Regional Universitario, Biomedical Institute of Malaga, Malaga, Spain.
⁵⁰ Center for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.
⁵¹ Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
⁵² Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
⁵³ Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University Munich, Munich, Germany.

PMID: 28166306
PMCID: PMC5293228
DOI: 10.1371/journal.pone.0171595

Identification of shared risk loci and pathways for bipolar disorder and schizophrenia

Andreas J Forstner et al. PLoS One. 2017.

. 2017 Feb 6;12(2):e0171595.

doi: 10.1371/journal.pone.0171595. eCollection 2017.

Authors

Affiliations

¹ Institute of Human Genetics, University of Bonn, Bonn, Germany.
² Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
³ Department of Psychiatry (UPK), University of Basel, Basel, Switzerland.
⁴ Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland.
⁵ Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
⁶ Institute for Genomics Mathematics, University of Bonn, Bonn, Germany.
⁷ Institute of Medical Microbiology, Immunology and Parasitology, University of Bonn, Bonn, Germany.
⁸ Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany.
⁹ Department of Psychiatry & Psychotherapy, University of Cologne, Cologne, Germany.
¹⁰ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/University of Heidelberg, Mannheim, Germany.
¹¹ Department of Biomedicine and Centre for integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.
¹² The Lundbeck Foundation Initiative for integrative Psychiatric Research, iPSYCH, Aarhus and Copenhagen, Denmark.
¹³ National Centre Register-Based Research, Aarhus University, Aarhus, Denmark.
¹⁴ German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
¹⁵ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt am Main, Frankfurt am Main, Germany.
¹⁶ Max Planck Institute of Psychiatry, Munich, Germany.
¹⁷ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
¹⁸ University of Liverpool, Institute of Translational Medicine, Liverpool, United Kingdom.
¹⁹ Department of Psychiatry, University of Bonn, Bonn, Germany.
²⁰ Psychiatric Center Nordbaden, Wiesloch, Germany.
²¹ Center of Psychiatry Weinsberg, Weinsberg, Germany.
²² Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany.
²³ Department of Psychology, Clinical Psychology and Psychotherapy, Eberhard Karls University Tübingen, Tübingen, Germany.
²⁴ Institute of Medical Informatics, Biometry and Epidemiology, University Duisburg-Essen, Essen, Germany.
²⁵ Laboratory of Psychiatric Genetics, Department of Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
²⁶ Department of Cancer Epidemiology and Prevention, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology Warsaw, Warsaw, Poland.
²⁷ Department of Epidemiology, Nofer Institute of Occupational Medicine, Lodz, Poland.
²⁸ Genetic Epidemiology Group, International Agency for Research on Cancer (IARC), Lyon, France.
²⁹ Genetic Cancer Susceptibility Group, International Agency for Research on Cancer (IARC), Lyon, France.
³⁰ School of Psychiatry, University of New South Wales, Randwick, Australia.
³¹ Black Dog Institute, Prince of Wales Hospital, Randwick, Australia.
³² Neuroscience Research Australia, Sydney, Australia.
³³ School of Medical Sciences Faculty of Medicine, University of New South Wales, Sydney, Australia.
³⁴ Queensland Institute of Medical Research (QIMR), Brisbane, Australia.
³⁵ Moscow Research Institute of Psychiatry, Moscow, Russian Federation.
³⁶ Institute of Pulmonology, Russian State Medical University, Moscow, Russian Federation.
³⁷ Russian Academy of Medical Sciences, Mental Health Research Center, Moscow, Russian Federation.
³⁸ Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, Kursk, Russian Federation.
³⁹ Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, Kursk, Russian Federation.
⁴⁰ Institute of Biochemistry and Genetics, Ufa Scientific Center of Russian Academy of Sciences, Ufa, Russian Federation.
⁴¹ Department of Genetics and Fundamental Medicine of Bashkir State University, Ufa, Russian Federation.
⁴² Department of Psychiatry, Dalhousie University, Halifax, Canada.
⁴³ National Institute of Mental Health, Klecany, Czech Republic.
⁴⁴ Montreal Neurological Institute, McGill University, Montreal, Canada.
⁴⁵ Department of Human Genetics, McGill University, Montreal, Canada.
⁴⁶ McGill Group for Suicide Studies & Douglas Research Institute, Montreal, Canada.
⁴⁷ Department of Psychiatry, McGill University, Montreal, Canada.
⁴⁸ Département des sciences fondamentales, Université du Québec à Chicoutimi (UQAC), Saguenay, Canada.
⁴⁹ Department of Psychiatry, Hospital Regional Universitario, Biomedical Institute of Malaga, Malaga, Spain.
⁵⁰ Center for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.
⁵¹ Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
⁵² Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
⁵³ Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University Munich, Munich, Germany.

PMID: 28166306
PMCID: PMC5293228
DOI: 10.1371/journal.pone.0171595

Abstract

Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. BD shows substantial clinical and genetic overlap with other psychiatric disorders, in particular schizophrenia (SCZ). The genes underlying this etiological overlap remain largely unknown. A recent SCZ genome wide association study (GWAS) by the Psychiatric Genomics Consortium identified 128 independent genome-wide significant single nucleotide polymorphisms (SNPs). The present study investigated whether these SCZ-associated SNPs also contribute to BD development through the performance of association testing in a large BD GWAS dataset (9747 patients, 14278 controls). After re-imputation and correction for sample overlap, 22 of 107 investigated SCZ SNPs showed nominal association with BD. The number of shared SCZ-BD SNPs was significantly higher than expected (p = 1.46x10-8). This provides further evidence that SCZ-associated loci contribute to the development of BD. Two SNPs remained significant after Bonferroni correction. The most strongly associated SNP was located near TRANK1, which is a reported genome-wide significant risk gene for BD. Pathway analyses for all shared SCZ-BD SNPs revealed 25 nominally enriched gene-sets, which showed partial overlap in terms of the underlying genes. The enriched gene-sets included calcium- and glutamate signaling, neuropathic pain signaling in dorsal horn neurons, and calmodulin binding. The present data provide further insights into shared risk loci and disease-associated pathways for BD and SCZ. This may suggest new research directions for the treatment and prevention of these two major psychiatric disorders.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

**Fig 1. Results of the Ingenuity Pathway Analysis.**
Results of the Ingenuity Pathway Analysis (IPA) are shown in bar plot format. The x-axis shows negative logarithmic enrichment p-values for all associated pathways containing two and more genes prior to- (gray) and after- (blue) Benjamini Hochberg correction for multiple testing. The red horizontal line indicates a p-value of 0.05.

**Fig 2. IPA pathway synaptic long term potentiation.**
Results of the Ingenuity pathway analysis (IPA) for the pathway “Synaptic Long Term Potentiation” are shown. Shared schizophrenia-bipolar disorder associated genes (*GRIN2A*, *GRM3*, *CACNA1C*) are highlighted in purple.

**Fig 3. Results of the INRICH pathway analysis.**
Results of the INRICH pathway analysis are shown in bar plot format. The x-axis shows negative logarithmic enrichment p-values for all nominally associated pathways containing two and more genes prior to- (gray) and after- (blue) correction for multiple testing. The red horizontal line indicates a p-value of 0.05.

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Identification of shared risk loci and pathways for bipolar disorder and schizophrenia

Affiliations

Identification of shared risk loci and pathways for bipolar disorder and schizophrenia

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Abstract

Conflict of interest statement

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