Identification of Pathways for Bipolar Disorder: A Meta-analysis
Open accessAbstract
IMPORTANCE: Genome-wide investigations provide systematic information regarding the neurobiology of psychiatric disorders. OBJECTIVE: To identify biological pathways that contribute to risk for bipolar disorder (BP) using genes with consistent evidence for association in multiple genome-wide association studies (GWAS). DATA SOURCES: Four independent data sets with individual genome-wide data available in July 2011 along with all data sets contributed to the Psychiatric Genomics Consortium Bipolar Group by May 2012. A prior meta-analysis was used as a source for brain gene expression data. STUDY SELECTION: The 4 published GWAS were included in the initial sample. All independent BP data sets providing genome-wide data in the Psychiatric Genomics Consortium were included as a replication sample. DATA EXTRACTION AND SYNTHESIS: We identified 966 genes that contained 2 or more variants associated with BP at P < .05 in 3 of 4 GWAS data sets (n = 12,127 [5253 cases, 6874 controls]). Simulations using 10,000 replicates of these data sets corrected for gene size and allowed the calculation of an empirical P value for each gene; empirically significant genes were entered into a pathway analysis. Each of these pathways was then tested in the replication sample (n = 8396 [3507 cases, 4889 controls]) using gene set enrichment analysis for single-nucleotide polymorphisms. The 226 genes were also compared with results from a meta-analysis of gene expression in the dorsolateral prefrontal cortex. MAIN OUTCOMES AND MEASURES: Empirically significant genes and biological pathways. RESULTS Among 966 genes, 226 were empirically significant (P < .05). Seventeen pathways were overrepresented in analyses of the initial data set. Six of the 17 pathways were associated with BP in both the initial and replication samples: corticotropin-releasing hormone signaling, cardiac β-adrenergic signaling, phospholipase C signaling, glutamate receptor signaling, endothelin 1 signaling, and cardiac hypertrophy signaling. Among the 226 genes, 9 differed in expression in the dorsolateral prefrontal cortex in patients with BP: CACNA1C, DTNA, FOXP1, GNG2, ITPR2, LSAMP, NPAS3, NCOA2, and NTRK3. CONCLUSIONS AND RELEVANCE: Pathways involved in the genetic predisposition to BP include hormonal regulation, calcium channels, second messenger systems, and glutamate signaling. Gene expression studies implicate neuronal development pathways as well. These results tend to reinforce specific hypotheses regarding BP neurobiology and may provide clues for new approaches to treatment and prevention.
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Subsequent studies have linked NPAS3 to multiple human psychiatric and neurodevelopmental disorders, including bipolar disorder, schizophrenia, attention-deficit/hyperactivity disorder, major depression, and intellectual disability.
“Subsequent studies have further linked NPAS3 to multiple human psychiatric and neurodevelopmental disorders, including bipolar disorder (Pickard et al. 2009; Huang et al. 2010; Nurnberger et al. 2014), schizophrenia (Pickard et al. 2005, 2006, 2009; Huang et al. 2010; Macintyre et al. 2010; Yu et al. 2014)”
From The Human Accelerated Region HAR202 Controls <i>NPAS3</i> Expression in the Developing Forebrain Displaying Differential Enhancer Activity Between Modern and Archaic Human Sequences (2024) · cites this paper as Nurnberger et al. 2014
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- Authors
- Nurnberger, J. I., Koller, D. L., Jung, J., Edenberg, H. J., Foroud, T., Guella, I., Vawter, M. P., & Kelsoe, J. R.
- Affiliations
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis2Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Indianapolis
- Indiana University School of Medicine (US)
- National Institutes of Health (US)
- Indiana University Indianapolis (US)
- University of California, Irvine (US)
- University of California San Diego (US)
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2014-06-01
- Volume
- 71
- Issue
- 6
- Pages
- 657
- ISSN
- 2168-622X (ISSN-L)
- PMC
- PMC4523227
- OpenAlex
- W2095094363
- Cited by
- 234
- References
- 41
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 13 · 2023: 10 · 2022: 19 · 2021: 23 · 2020: 24 · 2019: 23 · 2018: 16 · 2017: 27 · 2016: 25 · 2015: 31 · 2014: 10
- FWCI
- 23.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
- Worcester Research and Publications (University of Worcester) (submittedVersion)
- UNSWorks (UNSW Sydney) (submittedVersion, cc-by-nc-nd)
- UCL Discovery (University College London) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Purdue University Indianapolis (Indiana University) (submittedVersion)
- Funders
- GlaxoSmithKline
- Wellcome Trust
- NorthShore University HealthSystem
- Fondation FondaMental
- European Commission
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Lundbeckfonden (R155-2014-1724)
- Norges Forskningsråd (#167153/V50, #163070/V50, #175345/V50, 167153)
- Assistance publique-Hôpitaux de Paris
- National Institutes of Health (UL1TR001108)
- University of California, Irvine
- National Institute of Mental Health (R01 MH61675, R01 MH-59571, R01MH085801, R01MH59588, R01MH059553, R01-MH59566, R01-MH60879, R01-MH60870, R01-MH59586, R01MH059566, R01MH59587, MH094483, R01-MH59565, R01MH059571, MH081804, R01MH078151, R01MH059545, R01MH060879, R01MH059565, MH 59553, R01 MH-67257, R01MH060870, MH085801, R01MH061675, R01MH059567, R01MH059586, MH59571, R01MH059588, MH078151, R01MH094483, R01MH067257, R01MH081804, MH080372, K08MH080372, R01MH059587, MH059567)
- U.S. National Library of Medicine
- National Center for Research Resources (1U54RR025204)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- bipolar disorder, gene pathways, single nucleotide polymorphisms, phospholipase C signaling, glutamate receptor signaling, endothelin-1 signaling, CACNA1C, calcium channels, second messenger signaling, hormonal regulation
- MeSH terms
- Bipolar Disorder, Humans, Signal Transduction, Gene Expression, Case-Control Studies, Prefrontal Cortex, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study
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