Suggestive evidence for association of the circadian genes PERIOD3 and ARNTL with bipolar disorder
Open accessAbstract
Bipolar affective disorder (BPAD) is suspected to arise in part from malfunctions of the circadian system, a system that enables adaptation to a daily and seasonally cycling environment. Genetic variations altering functions of genes involved with the input to the circadian clock, in the molecular feedback loops constituting the circadian oscillatory mechanism itself, or in the regulatory output systems could influence BPAD as a result. Several human circadian system genes have been identified and localized recently, and a comparison with linkage hotspots for BPAD has revealed some correspondences. We have assessed evidence for linkage and association involving polymorphisms in 10 circadian clock genes (ARNTL, CLOCK, CRY2, CSNK1epsilon, DBP, GSK3beta, NPAS2, PER1, PER2, and PER3) to BPAD. Linkage analysis in 52 affected families showed suggestive evidence for linkage to CSNK1epsilon. This finding was not substantiated in the association study. Fifty-two SNPs in 10 clock genes were genotyped in 185 parent proband triads. Single SNP TDT analyses showed no evidence for association to BPAD. However, more powerful haplotype analyses suggest two candidates deserving further studies. Haplotypes in ARNTL and PER3 were found to be significantly associated with BPAD via single-gene permutation tests (PG = 0.025 and 0.008, respectively). The most suggestive haplotypes in PER3 showed a Bonferroni-corrected P-value of PGC = 0.07. These two genes have previously been implicated in circadian rhythm sleep disorders and affective disorders. With correction for the number of genes considered and tests conducted, these data do not provide statistically significant evidence for association. However, the trends for ARNTL and PER3 are suggestive of their involvement in bipolar disorder and warrant further study in a larger sample.
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Haplotypes in BMAL1 and Per3 significantly associate with bipolar disorder in one study.
“Haplotypes in BMAL1 and Per3 were found to significantly associate with BPD in one study (Nievergelt et al., 2006).”
From Circadian genes, rhythms and the biology of mood disorders (2007) · cites this paper as Nievergelt et al., 2006
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- Authors
- Nievergelt, C. M., Kripke, D. F., Barrett, T. B., Burg, E., Remick, R. A., Sadovnick, A. D., McElroy, S. L., Keck, P. E., Schork, N. J., & Kelsoe, J. R.
- Affiliations
- University of California San Diego (US)
- St. Paul's Hospital (CA)
- University of British Columbia (CA)
- University of Cincinnati (US)
- Corresponding author
- Kelsoe, John R.
- ORCID
- Venue
- American Journal of Medical Genetics Part B Neuropsychiatric Genetics
- Publisher
- Wiley
- Published
- 2006-03-27
- Volume
- 141B
- Issue
- 3
- Pages
- 234-241
- ISSN
- 1552-4841 (ISSN-L)
- 1552-485X
- PMC
- PMC2651679
- OpenAlex
- W2099766655
- Cited by
- 294
- References
- 53
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 6 · 2023: 4 · 2022: 4 · 2021: 10 · 2020: 7 · 2019: 10 · 2018: 17 · 2017: 17 · 2016: 25 · 2015: 22 · 2014: 23 · 2013: 13 · 2012: 18
- FWCI
- 8.27
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Medical Genetics Part B Neuropsychiatric Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Science Foundation
- U.S. Department of Veterans Affairs
- Johns Hopkins University
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- National Institutes of Health (5u01mh046280-08, 5r29mh047612-05, 5r01da013769-02, 5u01mh046274-08, AG023122)
- U.S. Public Health Service (HLMH065571-02)
- University of California, San Diego
- National Institute on Aging (AG 15763, R01AG012364, AG-12364, R01AG015763, AG023122-01, U19AG023122)
- National Heart, Lung, and Blood Institute (R56HL071123, HL074730-02, U01HL064777, R01HL070137, HL071123, U01HL069758, HL054998-09, P50HL054998, HL064777-06, HL61280, HL070137-01A1, R01HL071123, R01HL061280, HL069758-03, R01HL074730)
- National Institute of Mental Health (MH-47612, MH068503-01A1, R01MH068503, UO1 MH46282, MH-59567, MH059567-05A2, MH68503, K08MH067959, U01MH046282, R01MH059567, MH067959, UO1 MH46280, U01 MH 46274)
- National Institute on Drug Abuse (DA13769)
- National Center for Research Resources (M-01RR00827, M01RR000827)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- bipolar disorder, clock genes, Per3, Bmal1, genetic association, haplotype analysis, single nucleotide polymorphisms, linkage analysis, circadian rhythm sleep disorders, mood disorders
- MeSH terms
- Bipolar Disorder, Chromosome Mapping, Circadian Rhythm, Family Health, Female, Genotype, Haplotypes, Humans, Male, Nuclear Proteins, Transcription Factors, Linkage Disequilibrium, Microsatellite Repeats, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, ARNTL Transcription Factors, Period Circadian 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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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