Association study of 21 circadian genes with bipolar I disorder, schizoaffective disorder, and schizophrenia
Open accessAbstract
Objective: Published studies suggest associations between circadian gene polymorphisms and bipolar I disorder (BPI), as well as schizoaffective disorder (SZA) and schizophrenia (SZ). The results are plausible, based on prior studies of circadian abnormalities. As replications have not been attempted uniformly, we evaluated representative, common polymorphisms in all three disorders. Methods: We assayed 276 publicly available ‘tag’ single nucleotide polymorphisms (SNPs) at 21 circadian genes among 523 patients with BPI, 527 patients with SZ/SZA, and 477 screened adult controls. Detected associations were evaluated in relation to two published genome‐wide association studies (GWAS). Results: Using gene‐based tests, suggestive associations were noted between EGR3 and BPI (p = 0.017), and between NPAS2 and SZ/SZA (p = 0.034). Three SNPs were associated with both sets of disorders (NPAS2: rs13025524 and rs11123857; RORB: rs10491929; p < 0.05). None of the associations remained significant following corrections for multiple comparisons. Approximately 15% of the analyzed SNPs overlapped with an independent study that conducted GWAS for BPI; suggestive overlap between the GWAS analyses and ours was noted at ARNTL. Conclusions: Several suggestive, novel associations were detected with circadian genes and BPI and SZ/SZA, but the present analyses do not support associations with common polymorphisms that confer risk with odds ratios greater than 1.5. Additional analyses using adequately powered samples are warranted to further evaluate these results.
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In a study examining 276 single nucleotide polymorphisms at 21 circadian genes, significant associations were detected for 8 SNPs from 4 circadian-related genes (RORβ, Per2, Per3, and NPAS2), however, no associations remained significant after correcting for multiple comparisons, suggesting these individual polymorphisms in clock genes are unlikely to confer sizeable (>1.5 OR) risk for SZ.
“In a study that examined 276 single nucleotide polymorphisms (SNPs) at 21 circadian genes, significant associations were detected for 8 SNPs from 4 circadian-related genes (Retinoic acid-related orphan receptor (RORβ), Per2, Per3, and Neuronal Pas domain protein 2), however, no associations remained significant after correcting for multiple comparisons, suggesting these individual polymorphisms in”
From Circadian rhythm disruption and mental health (2020) · cites this paper as [162]
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Experimental — accuracy not yet measuredEgr3 has been implicated in both schizophrenia and circadian organization.
“Another gene that has been implicated in both SZ and circadian organization is immediate early gene growth response 3 (Egr3)162,165–168.”
From Circadian rhythm disruption and mental health (2020) · cites this paper as [162]
The Discussion describes EGR3 as involved in regulating genes that mediate biological rhythms, supporting its connection to circadian organization. But the Results report a nominal EGR3 association with bipolar I disorder, not schizophrenia or schizoaffective disorder; the reported associations with those conditions involve other genes. No page numbers are available in our copy. (LLM, conf=0.88)
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- Authors
- Mansour, H. A., Talkowski, M. E., Wood, J., Chowdari, K. V., McClain, L., Prasad, K., Montrose, D., Fagiolini, A., Friedman, E. S., Allen, M. H., Bowden, C. L., Calabrese, J., El‐Mallakh, R. S., Escamilla, M., Faraone, S. V., Fossey, M. D., Gyulai, L., Loftis, J. M., Hauser, P., Ketter, T. A., Marangell, L. B., Miklowitz, D. J., Nierenberg, A. A., Patel, J., Sachs, G. S., Sklar, P., Smoller, J. W., Laird, N., Keshavan, M., Thase, M. E., Axelson, D., Birmaher, B., Lewis, D., Monk, T., Frank, E., Kupfer, D. J., Devlin, B., & Nimgaonkar, V. L.
- Affiliations
- University of Pittsburgh (US)
- University of Siena (IT)
- University of Colorado Denver (US)
- The University of Texas at San Antonio Health Science Center (US)
- University Hospitals of Cleveland (US)
- University of Louisville (US)
- SUNY Upstate Medical University (US)
- University of Oklahoma - Tulsa (US)
- University of Pennsylvania (US)
- Portland VA Medical Center (US)
- Stanford Medicine (US)
- Eli Lilly (United States) (US)
- University of Colorado Boulder (US)
- Harvard University (US)
- University of Massachusetts Chan Medical School (US)
- Massachusetts General Hospital (US)
- Philadelphia VA Medical Center (US)
- Corresponding author
- Nimgaonkar, Vishwajit L
- ORCID
- Talkowski, Michael E
- Wood, Joel
- Prasad, Konasale
- Fagiolini, Andrea
- Calabrese, Joseph
- El‐Mallakh, Rif S
- Escamilla, Michael
- Faraone, Stephen V
- Loftis, Jennifer M
- Ketter, Terence A
- Miklowitz, David J
- Nierenberg, Andrew A
- Sklar, Pamela
- Smoller, Jordan W
- Laird, Nan
- Keshavan, Matcheri
- Thase, Michael E
- Axelson, David
- Birmaher, Boris
- Lewis, David
- Frank, Ellen
- Kupfer, David J
- Devlin, Bernie
- Nimgaonkar, Vishwajit L
- Venue
- Bipolar Disorders
- Publisher
- Wiley
- Published
- 2009-10-14
- Volume
- 11
- Issue
- 7
- Pages
- 701-710
- ISSN
- 1398-5647 (ISSN-L)
- 1399-5618
- PMC
- PMC3401899
- OpenAlex
- W2049188227
- Cited by
- 161
- References
- 108
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 10 · 2023: 3 · 2022: 4 · 2021: 9 · 2020: 5 · 2019: 3 · 2018: 7 · 2017: 11 · 2016: 17 · 2015: 17 · 2014: 16 · 2013: 13 · 2012: 11
- FWCI
- 8.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Bipolar Disorders (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Use Siena air (University of Siena) (submittedVersion)
- Funders
- National Institutes of Health (UL1TR000005)
- National Institute of Mental Health (P 20 MH-66054, P20MH066054, MH56242, MH 45156, R10MH056242, R01MH060952, R01MH063420, K23MH072995, R01MH056242, MH63420, P30MH030915, P50MH045156, MH30915)
- Fogarty International Center (D43TW009114)
- National Center for Research Resources (M01-RR00056, M01RR000056, UL1RR024153)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- circadian genes, bipolar I disorder, schizoaffective disorder, schizophrenia, single nucleotide polymorphisms, genetic association, EGR3, NPAS2, RORB, Bmal1, gene-based association tests, psychiatric genetics
- MeSH terms
- Adult, Bipolar Disorder, Circadian Rhythm, Female, Gene Frequency, Genotype, Humans, Male, Middle Aged, Psychiatric Status Rating Scales, Psychotic Disorders, Schizophrenia, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Databases, Genetic, Genome-Wide Association Study, Young Adult, Circadian Rhythm Signaling Peptides and Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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