HomeClinical White PapersGet to know a gene: CACNA1C Get to know a gene: CACNA1C August 16, 2018Clinical White Papers Summary: Minimal evidence exists linking CACNA1C as a pharmacogenomic marker, and CACNA1C shows little clinical utility as a disease marker. While there is an association between CACNA1C and bipolar disorder and schizophrenia, the absolute contribution of CACNA1C to disease risk is very small. Therefore, genetic testing for CACNA1C is not recommended at this time. What is CACNA1C? CACNA1C encodes the α-1C subunit of the voltage-gated L-type Ca2+ channel, which plays a critical role in neurotransmission, gene expression, synaptic plasticity, and memory processes in the brain.1-7 While CACNA1C has been studied as a potential disease marker for schizophrenia (SCZ), bipolar disorder (BPD), and major depressive disorder (MDD), concrete evidence is lacking to associate genetic variation in CACNA1C with psychiatric medication response. Is CACNA1C a risk factor for bipolar disorder, schizophrenia, and major depressive disorder? Single nucleotide polymorphisms (SNPs) within CACNA1C repeatedly reached genome-wide significance (p<5 x 10-8) for an association with SCZ or BPD.8-14 However, the effect size is small (OR = 1.07-1.18), and CACNA1C is only one of many susceptibility genes that impact the risk for these disorders. Some of the other genes associated with SCZ and BPD include ANK3, TRANK1, ODZ4, and MHC.13, 15, 16 Additionally, CACNA1C has been linked to MDD, but these results are less consistent.17 What do the data say about CACNA1C variation and psychiatric treatment response? There are currently only four studies that have evaluated the effect of CACNA1C variants on response to psychiatric medications. One study found two SNPs (rs1006737 and rs10848635) were associated with an increased risk of suicidality and worsening of concentration among Caucasians taking citalopram. However, there was no association between CACNA1C genotype and treatment response or rates of remission.18 A second study that evaluated response to antidepressants found that the risk allele of rs1006737 was associated with better treatment response and rate of remission in one European group (n = 357), but the same allele was associated with an increased rate of treatment-resistant depression in a second European group (n = 218). No associations were found in a third group of Italian ancestry (n = 96).19 In another study that evaluated response to olanzapine in a Korean population (n = 502), five novel SNPs were associated with improvement of SCZ symptoms in the Positive and Negative Syndrome Scale (PANSS) subscales. However, rs1006737 was found to have no association with treatment and total PANSS score improvements.20 Lastly, in a Han Chinese population, another polymorphism in CACNA1C (rs2239063) was associated with better treatment response in SCZ patients treated with olanzapine for 6 weeks (n = 884). There were no associations with treatment response and other antipsychotics (n = 2,908).21 What is the clinical significance of CACNA1C genotyping? The actual level of risk conferred by CACNA1C variants is very small. For example, a recent meta-analysis in SCZ determined the odds ratio for a common SNP (rs1006737) to be 1.20 in an Asian population.22 Based on this data, a pooled relative risk was calculated to be 1.10. Therefore, given a lifetime prevalence of SCZ being ~0.60% 23-26, carriers would be expected to have a 0.64% risk of lifetime SCZ diagnosis, compared to a 0.58% risk for non-carriers.27 In effect, the CACNA1C variant confers a 0.06% absolute increase in the risk of developing SCZ. Thus, while the diagnostic association appears to be consistent, the absolute contribution of CACNA1C to disease risk is very small, and CACNA1C is only one of many susceptibility genes. Without a proper understanding of the modest clinical impact of CACNA1C variation, testing for CACNA1C may lead to overestimation of disease risk, unnecessary use of psychotropic medications, and undue patient anxiety regarding the development of serious conditions. Furthermore, the limited studies investigating the effect of CACNA1C variants on psychiatric treatment response have not produced any consistent findings. Additional well-designed, independently replicated pharmacogenomic studies are needed to verify whether CACNA1C variation predicts response to psychiatric medications. While CACNA1C remains an intriguing research target, genetic testing for CACNA1C is not recommended at this time. References Ban TA, Morey L, Aguglia E et al. Nimodipine in the treatment of old age dementias. Prog Neuropsychopharmacol Biol Psychiatry. 1990;14:525-551. Trompet S, Westendorp RG, Kamper AM et al. Use of calcium antagonists and cognitive decline in old age. The Leiden 85-plus study. Neurobiol Aging. 2008;29:306-308. DOI: 10.1016/j.neurobiolaging.2006.10.006 Deyo RA, Straube KT, Disterhoft JF. Nimodipine facilitates associative learning in aging rabbits. Science. 1989;243:809-811. Levy A, Kong RM, Stillman MJ et al. Nimodipine improves spatial working memory and elevates hippocampal acetylcholine in young rats. Pharmacol Biochem Behav. 1991;39:781-786. Bito H, Deisseroth K, Tsien RW. CREB phosphorylation and dephosphorylation: a Ca(2+)- and stimulus duration-dependent switch for hippocampal gene expression. Cell. 1996;87:1203-1214. Dolmetsch RE, Pajvani U, Fife K et al. Signaling to the nucleus by an L-type calcium channel-calmodulin complex through the MAP kinase pathway. Science. 2001;294:333-339. DOI: 10.1126/science.1063395 Sinnegger-Brauns MJ, Huber IG, Koschak A et al. Expression and 1,4-dihydropyridine-binding properties of brain L-type calcium channel isoforms. Mol Pharmacol. 2009;75:407-414. DOI: 10.1124/mol.108.049981 Ferreira MA, O’Donovan MC, Meng YA et al. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet. 2008;40:1056-1058. DOI: 10.1038/ng.209 Cross-Disorder Group of the Psychiatric Genomics C. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet. 2013;381:1371-1379. DOI: 10.1016/S0140-6736(12)62129-1 Bergen SE, O’Dushlaine CT, Ripke S et al. Genome-wide association study in a Swedish population yields support for greater CNV and MHC involvement in schizophrenia compared with bipolar disorder. Mol Psychiatry. 2012;17:880-886. DOI: 10.1038/mp.2012.73 Ripke S, O’Dushlaine C, Chambert K et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet. 2013;45:1150-1159. DOI: 10.1038/ng.2742 Schizophrenia Working Group of the Psychiatric Genomics C. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421-427. DOI: 10.1038/nature13595 Ruderfer DM, Fanous AH, Ripke S et al. Polygenic dissection of diagnosis and clinical dimensions of bipolar disorder and schizophrenia. Mol Psychiatry. 2014;19:1017-1024. DOI: 10.1038/mp.2013.138 Psychiatric GCBDWG. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet. 2011;43:977-983. DOI: 10.1038/ng.943 Chen DT, Jiang X, Akula N et al. Genome-wide association study meta-analysis of European and Asian-ancestry samples identifies three novel loci associated with bipolar disorder. Mol Psychiatry. 2013;18:195-205. DOI: 10.1038/mp.2011.157 Muhleisen TW, Leber M, Schulze TG et al. Genome-wide association study reveals two new risk loci for bipolar disorder. Nat Commun. 2014;5:3339. DOI: 10.1038/ncomms4339 Green EK, Grozeva D, Jones I et al. The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia. Mol Psychiatry. 2010;15:1016-1022. DOI: 10.1038/mp.2009.49 Casamassima F, Huang J, Fava M et al. Phenotypic effects of a bipolar liability gene among individuals with major depressive disorder. Am J Med Genet B Neuropsychiatr Genet. 2010;153B:303-309. DOI: 10.1002/ajmg.b.30962 Fabbri C, Corponi F, Albani D et al. Pleiotropic genes in psychiatry: Calcium channels and the stress-related FKBP5 gene in antidepressant resistance. Prog Neuropsychopharmacol Biol Psychiatry. 2018;81:203-210. DOI: 10.1016/j.pnpbp.2017.10.005 Porcelli S, Lee SJ, Han C et al. CACNA1C gene and schizophrenia: a case-control and pharmacogenetic study. Psychiatr Genet. 2015;25:163- 167. DOI: 10.1097/YPG.0000000000000092 Yu H, Yan H, Wang L et al. Five novel loci associated with antipsychotic treatment response in patients with schizophrenia: a genome-wide association study. Lancet Psychiatry. 2018. DOI: 10.1016/S2215-0366(18)30049-X Jiang H, Qiao F, Li Z et al. Evaluating the association between CACNA1C rs1006737 and schizophrenia risk: A meta-analysis. Asia Pac Psychiatry. 2015;7:260-267. DOI: 10.1111/appy.12173 Reeves WC, Strine TW, Pratt LA et al. Mental illness surveillance among adults in the United States. MMWR Suppl. 2011;60:1-29. McGrath J, Saha S, Chant D et al. Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epidemiol Rev. 2008;30:67-76. DOI: 10.1093/epirev/mxn001 Goldner EM, Hsu L, Waraich P et al. Prevalence and incidence studies of schizophrenic disorders: a systematic review of the literature. Can J Psychiatry. 2002;47:833-843. DOI: 10.1177/070674370204700904 NIMH. Statistics-Schizophrenia. https://www.nimh.nih.gov/health/statistics/schizophrenia.shtml. (last accessed March 1, 2018). Wang Z. Converting Odds Ratio to Relative Risk in Cohort Studies with Partial Data Information. Journal of Statistical Software. 2013;55:1-11. Patient Movement as Medicine: Solutions for Anxiety Moving forward. It sounds like a nice idea, especially when you’re feeling stuck deep in the throes of an anxiety spiral. But it turns out that physically m... Read more Patient Weight-Loss Drugs and Mental Health: What You Need to Know New medications for weight loss seem to be flying off pharmacy shelves these days. But could they be linked to mental health conditions? Researchers are ... Read more Patient 3 million patients (and counting!) have now taken the GeneSight test! We’re thrilled to share that 3 million patients (and counting!) have now taken the GeneSight test! We're so grateful to the dedicated healthcare providers who... 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If you or someone you know has suicidal thoughts, please call the National Suicide Prevention Lifeline at 988. ... Read more Patient Stress Relief Methods for Family Caregivers Caring for a loved one can be a rewarding and meaningful experience. However, the day in and day out of taking care of someone who is unwell also can be challen... Read more Healthcare Provider Healthcare Professional Burnout and Links to Depression When Dr. Lorna Breen, an ER doc in Manhattan, died by suicide in April 2020, it opened up a public discussion about the burdens faced by healthcare professi... Read more Healthcare Provider Antidepressant Withdrawal or Depression Reoccurrence? What Healthcare Providers Should Know People who stop taking antidepressants may do so for many reasons: they may feel like it isn’t working, may feel unable to cope with side effects, or may not fe... Read more Learn more Learn more about GeneSight How to talk to your provider View our clinical studies
Patient Movement as Medicine: Solutions for Anxiety Moving forward. It sounds like a nice idea, especially when you’re feeling stuck deep in the throes of an anxiety spiral. But it turns out that physically m... Read more
Patient Weight-Loss Drugs and Mental Health: What You Need to Know New medications for weight loss seem to be flying off pharmacy shelves these days. But could they be linked to mental health conditions? Researchers are ... Read more
Patient 3 million patients (and counting!) have now taken the GeneSight test! We’re thrilled to share that 3 million patients (and counting!) have now taken the GeneSight test! We're so grateful to the dedicated healthcare providers who... Read more
Patient The Model Minority Myth and Mental Health The model minority myth stereotypes one cultural group, typically Asian Americans, as “intelligent, hard-working, and diligent and therefore more academically, ... Read more
Healthcare Provider How Clinicians Can Help Support Their Patients Who Are Being Bullied How Clinicians Can Help Support Their Patients Who Are Being Bullied Acts of bullying can cause feelings of fear, loneliness and sadness, as well as depressi... Read more
Patient Cyberbullying: Unique Challenges and Impacts ‘We lost our daughter to cyberbullying.’ McKenna Brown was an accomplished hockey player and scholar, known for her kindness, when she became the target of int... Read more
Going Beyond Green, Yellow, Red on the GeneSight Report This blog summarizes key points discussed during the March 2024 GeneSight® Engage webinar Participants: Bernie Ranchero, MD, MS, MBA, medical direc... Read more
Healthcare Provider Top 5 Reasons Patients Stop Their Mood Disorder Treatment Mood disorder treatment for depression can be challenging – and patients may become frustrated when treatments don’t work. In fact, when people with depres... Read more
Patient The Impact of Gratitude on Depression and Anxiety “Say ‘Thank you,” a mother reminds her young kiddo. “T.G.I.F.!” we cheer at the end of a long week. We know it’s important to be thankful. But do we ... Read more
Patient The Silent Thief: The 5 Things Depression Can Steal “Depression is a thief,” writes Abhinav Chaurasia, a marketing automation specialist in an essay on LinkedIn. “It steals your joy, your motivation, and your abi... Read more
Patient How to Talk to Your Doctor about Anxiety Medication “When I was 27, I felt bad all the time,” writes Joanna Goddard on the popular Cup of Jo blog. She describes her initial experience with anxiety in detail. ... Read more
Healthcare Provider Building Trust by Reducing Bias: The GeneSight Test as a Tool for Mental Health Equity This blog summarizes key points discussed during Myriad Mental Health’s July 2022 Webinar: Building Trust by Reducing Bias: The GeneSight Test as a Tool for Men... Read more
Patient Anxiety and older adults: What to look for and how to help “It’s not how old you are. It’s how you are, old.” - French author Jules Renard Mental health is important at every age. But when people experience an a... Read more
Patient Adult ADHD: Symptoms, treatment, where to start Many people may incorrectly think ADHD, or attention-deficit/hyperactivity disorder, only impacts children. After all, according to the Centers for Disease C... Read more
Healthcare Provider It’s time to talk suicide: addressing stigma around a difficult topic Trigger Warning: This webinar discusses suicide. If you or someone you know has suicidal thoughts, please call the National Suicide Prevention Lifeline at 988. ... Read more
Patient Stress Relief Methods for Family Caregivers Caring for a loved one can be a rewarding and meaningful experience. However, the day in and day out of taking care of someone who is unwell also can be challen... Read more
Healthcare Provider Healthcare Professional Burnout and Links to Depression When Dr. Lorna Breen, an ER doc in Manhattan, died by suicide in April 2020, it opened up a public discussion about the burdens faced by healthcare professi... Read more
Healthcare Provider Antidepressant Withdrawal or Depression Reoccurrence? What Healthcare Providers Should Know People who stop taking antidepressants may do so for many reasons: they may feel like it isn’t working, may feel unable to cope with side effects, or may not fe... Read more