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

Andreas J. Forstner, Julian Hecker, Andrea Hofmann, Anna Maaser, Céline S. Reinbold, Thomas W. Mühleisen, Markus Leber, Jana Strohmaier, Franziska Degenhardt, Jens Treutlein, Manuel Mattheisen, Johannes Schumacher, Fabian Streit, Sandra Meier, Stefan Herms, Per Hoffmann, André Lacour, Stephanie H. Witt, Andreas Reif, Bertram Müller-MyhsokSusanne Lucae, Wolfgang Maier, Markus Schwarz, Helmut Vedder, Jutta Kammerer-Ciernioch, Andrea Pfennig, Michael Bauer, Martin Hautzinger, Susanne Moebus, Lorena M. Schenk, Sascha B. Fischer, Sugirthan Sivalingam, Piotr M. Czerski, Joanna Hauser, Jolanta Lissowska, Neonila Szeszenia-Dabrowska, Paul Brennan, James D. McKay, Adam Wright, Philip B. Mitchell, Janice M. Fullerton, Peter R. Schofield, Grant W. Montgomery, Sarah E. Medland, Scott D. Gordon, Nicholas G. Martin, Valery Krasnov, Alexander Chuchalin, Gulja Babadjanova, Galina Pantelejeva, Lilia I. Abramova, Alexander S. Tiganov, Alexey Polonikov, Elza Khusnutdinova, Martin Alda, Cristiana Cruceanu, Guy A. Rouleau, Gustavo Turecki, Catherine Laprise, Fabio Rivas, Fermin Mayoral, Manolis Kogevinas, Maria Grigoroiu-Serbanescu, Tim Becker, Thomas G. Schulze, Marcella Rietschel, Sven Cichon, Heide Fier, Markus M. Nöthen

Research output: Contribution to journalArticle

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 SCZassociated 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.

Original languageEnglish (US)
Article numbere0171595
JournalPLoS One
Volume12
Issue number2
DOIs
StatePublished - Feb 1 2017
Externally publishedYes

Fingerprint

Bipolar Disorder
single nucleotide polymorphism
Schizophrenia
Polymorphism
Genes
loci
Nucleotides
Single Nucleotide Polymorphism
behavior disorders
genes
Psychiatry
Genome-Wide Association Study
genome
calmodulin
schizophrenia
glutamates
Genome
pain
Posterior Horn Cells
Calmodulin

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Forstner, A. J., Hecker, J., Hofmann, A., Maaser, A., Reinbold, C. S., Mühleisen, T. W., ... Nöthen, M. M. (2017). Identification of shared risk loci and pathways for bipolar disorder and schizophrenia. PLoS One, 12(2), [e0171595]. https://doi.org/10.1371/journal.pone.0171595

Identification of shared risk loci and pathways for bipolar disorder and schizophrenia. / Forstner, Andreas J.; Hecker, Julian; Hofmann, Andrea; Maaser, Anna; Reinbold, Céline S.; Mühleisen, Thomas W.; Leber, Markus; Strohmaier, Jana; Degenhardt, Franziska; Treutlein, Jens; Mattheisen, Manuel; Schumacher, Johannes; Streit, Fabian; Meier, Sandra; Herms, Stefan; Hoffmann, Per; Lacour, André; Witt, Stephanie H.; Reif, Andreas; Müller-Myhsok, Bertram; Lucae, Susanne; Maier, Wolfgang; Schwarz, Markus; Vedder, Helmut; Kammerer-Ciernioch, Jutta; Pfennig, Andrea; Bauer, Michael; Hautzinger, Martin; Moebus, Susanne; Schenk, Lorena M.; Fischer, Sascha B.; Sivalingam, Sugirthan; Czerski, Piotr M.; Hauser, Joanna; Lissowska, Jolanta; Szeszenia-Dabrowska, Neonila; Brennan, Paul; McKay, James D.; Wright, Adam; Mitchell, Philip B.; Fullerton, Janice M.; Schofield, Peter R.; Montgomery, Grant W.; Medland, Sarah E.; Gordon, Scott D.; Martin, Nicholas G.; Krasnov, Valery; Chuchalin, Alexander; Babadjanova, Gulja; Pantelejeva, Galina; Abramova, Lilia I.; Tiganov, Alexander S.; Polonikov, Alexey; Khusnutdinova, Elza; Alda, Martin; Cruceanu, Cristiana; Rouleau, Guy A.; Turecki, Gustavo; Laprise, Catherine; Rivas, Fabio; Mayoral, Fermin; Kogevinas, Manolis; Grigoroiu-Serbanescu, Maria; Becker, Tim; Schulze, Thomas G.; Rietschel, Marcella; Cichon, Sven; Fier, Heide; Nöthen, Markus M.

In: PLoS One, Vol. 12, No. 2, e0171595, 01.02.2017.

Research output: Contribution to journalArticle

Forstner, AJ, Hecker, J, Hofmann, A, Maaser, A, Reinbold, CS, Mühleisen, TW, Leber, M, Strohmaier, J, Degenhardt, F, Treutlein, J, Mattheisen, M, Schumacher, J, Streit, F, Meier, S, Herms, S, Hoffmann, P, Lacour, A, Witt, SH, Reif, A, Müller-Myhsok, B, Lucae, S, Maier, W, Schwarz, M, Vedder, H, Kammerer-Ciernioch, J, Pfennig, A, Bauer, M, Hautzinger, M, Moebus, S, Schenk, LM, Fischer, SB, Sivalingam, S, Czerski, PM, Hauser, J, Lissowska, J, Szeszenia-Dabrowska, N, Brennan, P, McKay, JD, Wright, A, Mitchell, PB, Fullerton, JM, Schofield, PR, Montgomery, GW, Medland, SE, Gordon, SD, Martin, NG, Krasnov, V, Chuchalin, A, Babadjanova, G, Pantelejeva, G, Abramova, LI, Tiganov, AS, Polonikov, A, Khusnutdinova, E, Alda, M, Cruceanu, C, Rouleau, GA, Turecki, G, Laprise, C, Rivas, F, Mayoral, F, Kogevinas, M, Grigoroiu-Serbanescu, M, Becker, T, Schulze, TG, Rietschel, M, Cichon, S, Fier, H & Nöthen, MM 2017, 'Identification of shared risk loci and pathways for bipolar disorder and schizophrenia', PLoS One, vol. 12, no. 2, e0171595. https://doi.org/10.1371/journal.pone.0171595
Forstner AJ, Hecker J, Hofmann A, Maaser A, Reinbold CS, Mühleisen TW et al. Identification of shared risk loci and pathways for bipolar disorder and schizophrenia. PLoS One. 2017 Feb 1;12(2). e0171595. https://doi.org/10.1371/journal.pone.0171595
Forstner, Andreas J. ; Hecker, Julian ; Hofmann, Andrea ; Maaser, Anna ; Reinbold, Céline S. ; Mühleisen, Thomas W. ; Leber, Markus ; Strohmaier, Jana ; Degenhardt, Franziska ; Treutlein, Jens ; Mattheisen, Manuel ; Schumacher, Johannes ; Streit, Fabian ; Meier, Sandra ; Herms, Stefan ; Hoffmann, Per ; Lacour, André ; Witt, Stephanie H. ; Reif, Andreas ; Müller-Myhsok, Bertram ; Lucae, Susanne ; Maier, Wolfgang ; Schwarz, Markus ; Vedder, Helmut ; Kammerer-Ciernioch, Jutta ; Pfennig, Andrea ; Bauer, Michael ; Hautzinger, Martin ; Moebus, Susanne ; Schenk, Lorena M. ; Fischer, Sascha B. ; Sivalingam, Sugirthan ; Czerski, Piotr M. ; Hauser, Joanna ; Lissowska, Jolanta ; Szeszenia-Dabrowska, Neonila ; Brennan, Paul ; McKay, James D. ; Wright, Adam ; Mitchell, Philip B. ; Fullerton, Janice M. ; Schofield, Peter R. ; Montgomery, Grant W. ; Medland, Sarah E. ; Gordon, Scott D. ; Martin, Nicholas G. ; Krasnov, Valery ; Chuchalin, Alexander ; Babadjanova, Gulja ; Pantelejeva, Galina ; Abramova, Lilia I. ; Tiganov, Alexander S. ; Polonikov, Alexey ; Khusnutdinova, Elza ; Alda, Martin ; Cruceanu, Cristiana ; Rouleau, Guy A. ; Turecki, Gustavo ; Laprise, Catherine ; Rivas, Fabio ; Mayoral, Fermin ; Kogevinas, Manolis ; Grigoroiu-Serbanescu, Maria ; Becker, Tim ; Schulze, Thomas G. ; Rietschel, Marcella ; Cichon, Sven ; Fier, Heide ; Nöthen, Markus M. / Identification of shared risk loci and pathways for bipolar disorder and schizophrenia. In: PLoS One. 2017 ; Vol. 12, No. 2.
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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 SCZassociated 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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AU - Forstner, Andreas J.

AU - Hecker, Julian

AU - Hofmann, Andrea

AU - Maaser, Anna

AU - Reinbold, Céline S.

AU - Mühleisen, Thomas W.

AU - Leber, Markus

AU - Strohmaier, Jana

AU - Degenhardt, Franziska

AU - Treutlein, Jens

AU - Mattheisen, Manuel

AU - Schumacher, Johannes

AU - Streit, Fabian

AU - Meier, Sandra

AU - Herms, Stefan

AU - Hoffmann, Per

AU - Lacour, André

AU - Witt, Stephanie H.

AU - Reif, Andreas

AU - Müller-Myhsok, Bertram

AU - Lucae, Susanne

AU - Maier, Wolfgang

AU - Schwarz, Markus

AU - Vedder, Helmut

AU - Kammerer-Ciernioch, Jutta

AU - Pfennig, Andrea

AU - Bauer, Michael

AU - Hautzinger, Martin

AU - Moebus, Susanne

AU - Schenk, Lorena M.

AU - Fischer, Sascha B.

AU - Sivalingam, Sugirthan

AU - Czerski, Piotr M.

AU - Hauser, Joanna

AU - Lissowska, Jolanta

AU - Szeszenia-Dabrowska, Neonila

AU - Brennan, Paul

AU - McKay, James D.

AU - Wright, Adam

AU - Mitchell, Philip B.

AU - Fullerton, Janice M.

AU - Schofield, Peter R.

AU - Montgomery, Grant W.

AU - Medland, Sarah E.

AU - Gordon, Scott D.

AU - Martin, Nicholas G.

AU - Krasnov, Valery

AU - Chuchalin, Alexander

AU - Babadjanova, Gulja

AU - Pantelejeva, Galina

AU - Abramova, Lilia I.

AU - Tiganov, Alexander S.

AU - Polonikov, Alexey

AU - Khusnutdinova, Elza

AU - Alda, Martin

AU - Cruceanu, Cristiana

AU - Rouleau, Guy A.

AU - Turecki, Gustavo

AU - Laprise, Catherine

AU - Rivas, Fabio

AU - Mayoral, Fermin

AU - Kogevinas, Manolis

AU - Grigoroiu-Serbanescu, Maria

AU - Becker, Tim

AU - Schulze, Thomas G.

AU - Rietschel, Marcella

AU - Cichon, Sven

AU - Fier, Heide

AU - Nöthen, Markus M.

PY - 2017/2/1

Y1 - 2017/2/1

N2 - 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 SCZassociated 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.

AB - 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 SCZassociated 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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