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Study of 45 candidate genes suggests CACNG2 may be associated with lithium response in bipolar disorder
Open accessAbstract
Background Bipolar disorder is a neuropsychiatric disorder that is characterized by fluctuations between manic and depressive phases. Lithium is the original and best mood stabilizing treatment for bipolar disorder. While its mechanism is not well understood, it is believed to have a strong genetic component, as several studies suggest that lithium responsiveness, in bipolar disorder, is heritable. In this study we aimed to identify genetic variants that are associated with lithium responsiveness in bipolar disorder.Methods Here we present two cohorts; a retrospective cohort in which patients were surveyed about their response to lithium, and a prospective cohort, in which patients were placed on a lithium monotherapy and monitored for their response to lithium. In both cohorts, patients were stratified into two categories in terms of lithium response; good responders and poor responders. 45 genes were selected based on previous associations with lithium pathways or bipolar disorder and 684 SNPs within these genes were selected to test for association with lithium response.Results While no single SNP was significant after correcting for multiple comparisons, there were several that were nominally significant (p < 0.05). Of these nominally significant SNPs, the most highly significant SNP in both the prospective and retrospective cohorts were found to be in CACNG2, or Stargazin. The second best association with lithium response was several SNPs in NRG1, a gene that has previously been associated with schizophrenia.Conclusions Evidence for the association of lithium response with SNPs in CACNG2 is consistent with previous findings that have identified CACNG2 as associated with both bipolar disorder and lithium responsiveness.
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The CACNG2 gene, encoding a voltage-gated calcium channel, has repeatedly been implicated in mood regulation and impulsivity across cohorts.
“The CACNG2 gene, encoding voltage-gated calcium channel, has repeatedly been implicated in mood regulation and impulsivity across cohorts (39).”
From Exploring the neurobiological markers of suicidal behaviors in pediatric population: a narrative review (2026) · cites this paper as [39]
The Discussion (page unavailable) reports CACNG2 associations with bipolar disorder and nominal associations with lithium response in two cohorts, but it does not report an association with impulsivity. It describes stargazin as structurally similar to a voltage-gated calcium-channel subunit while emphasizing its demonstrated role as an AMPA-receptor auxiliary subunit; calling it a voltage-gated calcium channel overstates that description. (LLM, conf=0.88)
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Metadata
- Authors
- Miranda, A., Shekhtman, T., McCarthy, M., DeModena, A., Leckband, S. G., & Kelsoe, J. R.
- Affiliations
- University of California San Diego (US)
- VA San Diego Healthcare System (US)
- Corresponding author
- Kelsoe, John R.
- Venue
- Journal of Affective Disorders
- Publisher
- Elsevier BV
- Published
- 2019-04
- Volume
- 248
- Pages
- 175-179
- ISSN
- 0165-0327 (ISSN-L)
- PMC
- PMC7292366
- OpenAlex
- W2910587240
- Cited by
- 18
- References
- 24
- Citations by year
- 2026: 3 · 2024: 2 · 2023: 1 · 2022: 6 · 2021: 2 · 2020: 2 · 2019: 2
- FWCI
- 2.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Affective Disorders (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- UCSD (T32 GM008666)
- Department of Veterans Affairs (I01CX000363)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- bipolar disorder, lithium response, stargazin, neuregulin-1, single nucleotide polymorphisms, candidate genes, genetic association, mood stabilizers, genetic susceptibility
- MeSH terms
- Pharmacogenomic Variants, Adolescent, Adult, Aged, Bipolar Disorder, Female, Humans, Male, Middle Aged, Prospective Studies, Retrospective Studies, Calcium Channels, Lithium Compounds, Antimanic Agents, Polymorphism, Single Nucleotide, Young Adult
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