CACNA1C rs1006737 genotype and bipolar disorder: Focus on intermediate phenotypes and cardiovascular comorbidity

Ou, Xiao-Ming; Crane, David; MacIntosh, Bradley J.; Young, L. Trevor; Arnold, Paul; Ameis, Stephanie H.; Goldstein, Benjamin I.

doi:10.1016/j.neubiorev.2015.04.022

Cited by 34 publications

(29 citation statements)

References 83 publications

(99 reference statements)

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“…Previous studies have linked this haplotype to changes in CACNA1C expression, with decreases reported in brain (Gershon et al, 2014) and increases reported in cultured neurons (Yoshimizu et al, 2015). Brain imaging studies of CACNA1C show a variety of results that vary with the specific measure and brain region (Ou et al, 2015). The lack of consensus in findings is not necessarily surprising.…”

Section: Discussionmentioning

confidence: 99%

Calcium channel genes associated with bipolar disorder modulate lithium's amplification of circadian rhythms

et al. 2016

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Bipolar disorder (BD) is associated with mood episodes and low amplitude circadian rhythms. Previously, we demonstrated that fibroblasts grown from BD patients show weaker amplification of circadian rhythms by lithium compared to control cells. Since calcium signals impact upon the circadian clock, and L-type calcium channels (LTCC) have emerged as genetic risk factors for BD, we examined whether loss of function in LTCCs accounts for the attenuated response to lithium in BD cells. We used fluorescent dyes to measure Ca2+ changes in BD and control fibroblasts after lithium treatment, and bioluminescent reporters to measure Per2∷luc rhythms in fibroblasts from BD patients, human controls, and mice while pharmacologically or genetically manipulating calcium channels. Longitudinal expression of LTCC genes (CACNA1C, CACNA1D and CACNB3) was then measured over 12-24 hr in BD and control cells. Our results indicate that independently of LTCCs, lithium stimulated intracellular Ca2+ less effectively in BD vs. control fibroblasts. In longitudinal studies, pharmacological inhibition of LTCCs or knockdown of CACNA1A, CACNA1C, CACNA1D and CACNB3 altered circadian rhythm amplitude. Diltiazem and knockdown of CACNA1C or CACNA1D eliminated lithium's ability to amplify rhythms. Knockdown of CACNA1A or CACNB3 altered baseline rhythms, but did not affect rhythm amplification by lithium. In human fibroblasts, CACNA1C genotype predicted the amplitude response to lithium, and the expression profiles of CACNA1C, CACNA1D and CACNB3 were altered in BD vs. controls. We conclude that in cells from BD patients, calcium signaling is abnormal, and that LTCCs underlie the failure of lithium to amplify circadian rhythms.

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Section: Discussionmentioning

confidence: 99%

Calcium channel genes associated with bipolar disorder modulate lithium's amplification of circadian rhythms

et al. 2016

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“…Cell sizes (averaging 19.2 subjects) are shown in Table S1. The grouping of genotype groups had the purpose of maximising counterbalance for the rs1006737 CACNA1C SNP, as commonly practiced in the literature (Backes et al ; Dietsche et al ; Nieratschker et al ; Ou et al ; Woon et al ) given the much lower frequency counts of allele A, compared to C, in the Caucasian population. The SNPs reported in this manuscript are the only SNPs analysed in this imaging data set.…”

Section: Methodsmentioning

confidence: 99%

The impact of CACNA1C gene, and its epistasis with ZNF804A, on white matter microstructure in health, schizophrenia and bipolar disorder¹

Mallas

Carletti

Chaddock

et al. 2016

Genes Brain and Behavior

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“…[15][16][17][18] CACNA1C encodes the α1C subunit of the voltage-gated L-type calcium ion (Ca 2+ ) channel Ca v 1.2. 19 CACNA1C is ranked as a prime candidate susceptibility gene, [20][21][22] most notably because single-nucleotide polymorphisms (SNPs) within CACNA1C belong to the best replicated and most robust genetic findings from genome-wide association studies in psychiatry. Ca v 1.2 accounts for~90% of all voltage-gated L-type Ca 2+ channels in the brain and represents a promising therapeutic target.…”

mentioning

confidence: 99%

“…Ca v 1.2 accounts for~90% of all voltage-gated L-type Ca 2+ channels in the brain and represents a promising therapeutic target. 19 CACNA1C is ranked as a prime candidate susceptibility gene, [20][21][22] most notably because single-nucleotide polymorphisms (SNPs) within CACNA1C belong to the best replicated and most robust genetic findings from genome-wide association studies in psychiatry. [23][24][25] Further evidence from clinical studies links rs1006737, the primary CACNA1C risk allele associated with neuropsychiatric disorders, to alterations in brain structure and function, both in patients [26][27][28][29] and healthy individuals.…”

mentioning

confidence: 99%

Sex‐dependent effects of Cacna1c haploinsufficiency on juvenile social play behavior and pro‐social 50‐kHz ultrasonic communication in rats

Kisko

Braun

Michels

et al. 2019

Genes Brain and Behavior

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As cross‐disorder risk gene, CACNA1C is implicated in the etiology of all major neuropsychiatric disorders characterized by deficits in social behavior and communication and there is evidence for sex‐dependent influences of single‐nucleotide polymorphisms within CACNA1C on diagnosis, course, and recovery in humans. In this study, we aimed, therefore, at further exploring the role of Cacna1c in regulating behavioral phenotypes, focusing on sex‐specific differences in social behavior and communication during the critical developmental period of adolescence in rats. Specifically, we compared rough‐and‐tumble play, concomitant emission of pro‐social 50‐kHz ultrasonic vocalizations, and social approach behavior in response to playback of 50‐kHz ultrasonic vocalizations between constitutive heterozygous Cacna1c +/− females and wildtype Cacna1c +/+ littermate controls, and contrasted present female findings to data previously reported in males. Our results show for the first time that partial depletion of Cacna1c leads to sex‐dependent alterations in social behavior and communication in rats. In females, Cacna1c haploinsufficiency led to hypermasculinization, with rough‐and‐tumble play behavior, in general, and pinning behavior, in particular, being even higher than in males without affecting concomitant 50‐kHz ultrasonic vocalizations. In males, in contrast, rough‐and‐tumble play behavior was not altered, yet emission of 50‐kHz ultrasonic vocalizations was diminished following partial Cacna1c depletion. The behavioral responses elicited by playback of 50‐kHz ultrasonic vocalizations were reduced upon partial Cacna1c depletion in both sexes. It thus can be concluded that Cacna1c plays a prominent sex‐dependent role in regulating juvenile rat social play behavior and pro‐social 50‐kHz ultrasonic communication with relevance to sex‐specific effects seen in neuropsychiatric disorders.

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CACNA1C rs1006737 genotype and bipolar disorder: Focus on intermediate phenotypes and cardiovascular comorbidity

Cited by 34 publications

References 83 publications

Calcium channel genes associated with bipolar disorder modulate lithium's amplification of circadian rhythms

Calcium channel genes associated with bipolar disorder modulate lithium's amplification of circadian rhythms

The impact of CACNA1C gene, and its epistasis with ZNF804A, on white matter microstructure in health, schizophrenia and bipolar disorder¹

Sex‐dependent effects of Cacna1c haploinsufficiency on juvenile social play behavior and pro‐social 50‐kHz ultrasonic communication in rats

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CACNA1C rs1006737 genotype and bipolar disorder: Focus on intermediate phenotypes and cardiovascular comorbidity

Cited by 34 publications

References 83 publications

Calcium channel genes associated with bipolar disorder modulate lithium's amplification of circadian rhythms

Calcium channel genes associated with bipolar disorder modulate lithium's amplification of circadian rhythms

The impact of CACNA1C gene, and its epistasis with ZNF804A, on white matter microstructure in health, schizophrenia and bipolar disorder1

Sex‐dependent effects of Cacna1c haploinsufficiency on juvenile social play behavior and pro‐social 50‐kHz ultrasonic communication in rats

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The impact of CACNA1C gene, and its epistasis with ZNF804A, on white matter microstructure in health, schizophrenia and bipolar disorder¹