Identification of shared risk loci and pathways for bipolar disorder and schizophrenia.
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.
Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.|Department of Psychiatry (UPK), University of Basel, Basel, Switzerland.|Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland.|Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
Andreas J
AJ
Forstner
Institute for Genomics Mathematics, University of Bonn, Bonn, Germany.
Julian
J
Hecker
Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.|Institute of Medical Microbiology, Immunology and Parasitology, University of Bonn, Bonn, Germany.
Andrea
A
Hofmann
Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
Anna
http://orcid.org/0000-0002-9440-0712
A
Maaser
Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland.|Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
Céline S
http://orcid.org/0000-0002-3394-3158
CS
Reinbold
Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.|Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland.|Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.|Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany.
Thomas W
TW
Mühleisen
Department of Psychiatry & Psychotherapy, University of Cologne, Cologne, Germany.
Markus
M
Leber
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/University of Heidelberg, Mannheim, Germany.
Jana
J
Strohmaier
Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
Franziska
F
Degenhardt
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/University of Heidelberg, Mannheim, Germany.
Jens
J
Treutlein
Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Biomedicine and Centre for integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.|The Lundbeck Foundation Initiative for integrative Psychiatric Research, iPSYCH, Aarhus and Copenhagen, Denmark.
Manuel
M
Mattheisen
Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
Johannes
J
Schumacher
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/University of Heidelberg, Mannheim, Germany.
Fabian
http://orcid.org/0000-0003-1080-4339
F
Streit
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/University of Heidelberg, Mannheim, Germany.|The Lundbeck Foundation Initiative for integrative Psychiatric Research, iPSYCH, Aarhus and Copenhagen, Denmark.|National Centre Register-Based Research, Aarhus University, Aarhus, Denmark.
Sandra
S
Meier
Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.|Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland.|Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
Stefan
http://orcid.org/0000-0002-2786-8200
S
Herms
Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.|Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland.|Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
Per
P
Hoffmann
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
André
A
Lacour
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/University of Heidelberg, Mannheim, Germany.
Stephanie H
http://orcid.org/0000-0002-1571-1468
SH
Witt
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt am Main, Frankfurt am Main, Germany.
Andreas
A
Reif
Max Planck Institute of Psychiatry, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.|University of Liverpool, Institute of Translational Medicine, Liverpool, United Kingdom.
Bertram
B
Müller-Myhsok
Max Planck Institute of Psychiatry, Munich, Germany.
Susanne
S
Lucae
Department of Psychiatry, University of Bonn, Bonn, Germany.
Wolfgang
W
Maier
Psychiatric Center Nordbaden, Wiesloch, Germany.
Markus
M
Schwarz
Psychiatric Center Nordbaden, Wiesloch, Germany.
Helmut
H
Vedder
Center of Psychiatry Weinsberg, Weinsberg, Germany.
Jutta
J
Kammerer-Ciernioch
Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany.
Andrea
A
Pfennig
Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany.
Michael
M
Bauer
Department of Psychology, Clinical Psychology and Psychotherapy, Eberhard Karls University Tübingen, Tübingen, Germany.
Martin
M
Hautzinger
Institute of Medical Informatics, Biometry and Epidemiology, University Duisburg-Essen, Essen, Germany.
Susanne
S
Moebus
Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
Lorena M
LM
Schenk
Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland.|Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
Sascha B
http://orcid.org/0000-0003-0336-0784
SB
Fischer
Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
Sugirthan
http://orcid.org/0000-0001-5239-5137
S
Sivalingam
Laboratory of Psychiatric Genetics, Department of Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
Piotr M
PM
Czerski
Laboratory of Psychiatric Genetics, Department of Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
Joanna
http://orcid.org/0000-0002-6621-3493
J
Hauser
Department of Cancer Epidemiology and Prevention, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology Warsaw, Warsaw, Poland.
Jolanta
J
Lissowska
Department of Epidemiology, Nofer Institute of Occupational Medicine, Lodz, Poland.
Neonila
N
Szeszenia-Dabrowska
Genetic Epidemiology Group, International Agency for Research on Cancer (IARC), Lyon, France.
Paul
P
Brennan
Genetic Cancer Susceptibility Group, International Agency for Research on Cancer (IARC), Lyon, France.
James D
JD
McKay
School of Psychiatry, University of New South Wales, Randwick, Australia.|Black Dog Institute, Prince of Wales Hospital, Randwick, Australia.
Adam
A
Wright
School of Psychiatry, University of New South Wales, Randwick, Australia.|Black Dog Institute, Prince of Wales Hospital, Randwick, Australia.
Philip B
http://orcid.org/0000-0002-7954-5235
PB
Mitchell
Neuroscience Research Australia, Sydney, Australia.|School of Medical Sciences Faculty of Medicine, University of New South Wales, Sydney, Australia.
Janice M
JM
Fullerton
Neuroscience Research Australia, Sydney, Australia.|School of Medical Sciences Faculty of Medicine, University of New South Wales, Sydney, Australia.
Peter R
http://orcid.org/0000-0003-2967-9662
PR
Schofield
Queensland Institute of Medical Research (QIMR), Brisbane, Australia.
Grant W
GW
Montgomery
Queensland Institute of Medical Research (QIMR), Brisbane, Australia.
Sarah E
SE
Medland
Queensland Institute of Medical Research (QIMR), Brisbane, Australia.
Scott D
http://orcid.org/0000-0001-7623-328X
SD
Gordon
Queensland Institute of Medical Research (QIMR), Brisbane, Australia.
Nicholas G
NG
Martin
Moscow Research Institute of Psychiatry, Moscow, Russian Federation.
Valery
V
Krasnov
Institute of Pulmonology, Russian State Medical University, Moscow, Russian Federation.
Alexander
A
Chuchalin
Institute of Pulmonology, Russian State Medical University, Moscow, Russian Federation.
Gulja
G
Babadjanova
Russian Academy of Medical Sciences, Mental Health Research Center, Moscow, Russian Federation.
Galina
G
Pantelejeva
Russian Academy of Medical Sciences, Mental Health Research Center, Moscow, Russian Federation.
Lilia I
LI
Abramova
Russian Academy of Medical Sciences, Mental Health Research Center, Moscow, Russian Federation.
Alexander S
AS
Tiganov
Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, Kursk, Russian Federation.|Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, Kursk, Russian Federation.
Alexey
A
Polonikov
Institute of Biochemistry and Genetics, Ufa Scientific Center of Russian Academy of Sciences, Ufa, Russian Federation.|Department of Genetics and Fundamental Medicine of Bashkir State University, Ufa, Russian Federation.
Elza
E
Khusnutdinova
Department of Psychiatry, Dalhousie University, Halifax, Canada.|National Institute of Mental Health, Klecany, Czech Republic.
Martin
http://orcid.org/0000-0001-9544-3944
M
Alda
Montreal Neurological Institute, McGill University, Montreal, Canada.|Department of Human Genetics, McGill University, Montreal, Canada.|McGill Group for Suicide Studies & Douglas Research Institute, Montreal, Canada.
Cristiana
http://orcid.org/0000-0002-7799-5531
C
Cruceanu
Montreal Neurological Institute, McGill University, Montreal, Canada.
Guy A
GA
Rouleau
Department of Human Genetics, McGill University, Montreal, Canada.|McGill Group for Suicide Studies & Douglas Research Institute, Montreal, Canada.|Department of Psychiatry, McGill University, Montreal, Canada.
Gustavo
G
Turecki
Département des sciences fondamentales, Université du Québec à Chicoutimi (UQAC), Saguenay, Canada.
Catherine
C
Laprise
Department of Psychiatry, Hospital Regional Universitario, Biomedical Institute of Malaga, Malaga, Spain.
Fabio
F
Rivas
Department of Psychiatry, Hospital Regional Universitario, Biomedical Institute of Malaga, Malaga, Spain.
Fermin
http://orcid.org/0000-0002-9710-9672
F
Mayoral
Center for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.
Manolis
M
Kogevinas
Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
Maria
M
Grigoroiu-Serbanescu
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.|Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
Tim
T
Becker
Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University Munich, Munich, Germany.
Thomas G
TG
Schulze
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/University of Heidelberg, Mannheim, Germany.
Marcella
http://orcid.org/0000-0002-5236-6149
M
Rietschel
Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.|Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland.|Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.|Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany.
Sven
S
Cichon
Institute for Genomics Mathematics, University of Bonn, Bonn, Germany.
Heide
H
Fier
Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
Markus M
MM
Nöthen
D001714:Bipolar Disorder / Q000235:genetics* / Q000378:metabolism*; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012306:Risk; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction