CACNG2 Gene Nominally Associated With Lithium Response in Bipolar Disorder

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Recent study results confirm previous findings that the CACNG2 gene is associated with both bipolar disorder and lithium responsiveness.

The CACNG2 gene may be associated with lithium response in patients with bipolar disorder, according to study data published in the Journal of Affective Disorders.

Investigators recruited participants from 2 independent studies: 1 with retrospective assessment of lithium response and 1 with prospective trial design. Only patients with bipolar disorder type I were selected for inclusion. All participants underwent diagnostic assessment at baseline with the Diagnostic Interview for Genetic Studies. Patients in the retrospective sample (n=286) were queried on lifetime lithium response; those who reported a >50% reduction in symptoms on lithium were classified as “good” responders, and those with self-reported negative (<50% reduction) response were classified as “poor” responders. Patients in the prospective sample (n=68) were placed on lithium monotherapy for a maintenance period of 2 years, and assessed every 2 months for relapse.

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Participants were classified as either responders or nonresponders, based on their ability to stabilize on lithium monotherapy and enter maintenance. Investigators selected 45 genes for analysis, based on prior associations with lithium pathways or bipolar disorder. Single-nucleotide polymorphisms (SNPs) were genotyped in each study cohort. In the retrospective study, analysis was completed on 684 directly genotyped SNPs within the 45 selected genes.

After correcting for multiple comparisons in the retrospective analysis, several SNPs with nominal significance were identified. The SNP most significantly associated with a positive response to lithium was found in the CACNG2 gene (odds ratio [OR], 1.728; P =.0026). A gene-based set analysis identified 10 genes with at least 1 SNP with statistical significance; the most significant gene in this analysis was also CACNG2 (P =.0725). The CACNG2 gene also displayed greatest significance in the prospective analysis. Several SNPs in the NRG1 gene displayed nominally significant association with lithium response. These data are consistent with prior findings that have identified CACNG2 as associated with lithium response and bipolar disorder. The second best association with lithium response was seen with the NRG1 gene, which has previously been associated with schizophrenia.

The study was limited by its sample size, particularly in the prospective cohort, and a lack of significant SNPs that met the multiple comparisons threshold.

These data corroborate with prior literature on the role of the CACNG2 gene in lithium response. Further research on the role of CACNG2 in lithium response may elucidate better modes of treatment for patients with bipolar disorder.


Miranda A, Shekhtman T, McCarthy M, DeModena A, Leckband SG, Kelsoe JR. Study of 45 candidate genes suggests CACNG2 may be associated with lithium response in bipolar disorder. J Affect Disord. 2019;248:175-179.