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Cross-disorder risk gene CACNA1C differentially modulates susceptibility to psychiatric disorders during development and adulthood.

ABSTRACT: Single-nucleotide polymorphisms (SNPs) in CACNA1C, the ?1C subunit of the voltage-gated L-type calcium channel Cav1.2, rank among the most consistent and replicable genetics findings in psychiatry and have been associated with schizophrenia, bipolar disorder and major depression. However, genetic variants of complex diseases often only confer a marginal increase in disease risk, which is additionally influenced by the environment. Here we show that embryonic deletion of Cacna1c in forebrain glutamatergic neurons promotes the manifestation of endophenotypes related to psychiatric disorders including cognitive decline, impaired synaptic plasticity, reduced sociability, hyperactivity and increased anxiety. Additional analyses revealed that depletion of Cacna1c during embryonic development also increases the susceptibility to chronic stress, which suggest that Cav1.2 interacts with the environment to shape disease vulnerability. Remarkably, this was not observed when Cacna1c was deleted in glutamatergic neurons during adulthood, where the later deletion even improved cognitive flexibility, strengthened synaptic plasticity and induced stress resilience. In a parallel gene × environment design in humans, we additionally demonstrate that SNPs in CACNA1C significantly interact with adverse life events to alter the risk to develop symptoms of psychiatric disorders. Overall, our results further validate Cacna1c as a cross-disorder risk gene in mice and humans, and additionally suggest a differential role for Cav1.2 during development and adulthood in shaping cognition, sociability, emotional behavior and stress susceptibility. This may prompt the consideration for pharmacological manipulation of Cav1.2 in neuropsychiatric disorders with developmental and/or stress-related origins.

SUBMITTER: Dedic N

PROVIDER: S-EPMC5822460 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Cross-disorder risk gene CACNA1C differentially modulates susceptibility to psychiatric disorders during development and adulthood.

Dedic N N Pöhlmann M L ML Richter J S JS Mehta D D Czamara D D Metzger M W MW Dine J J Bedenk B T BT Hartmann J J Wagner K V KV Jurik A A Almli L M LM Lori A A Moosmang S S Hofmann F F Wotjak C T CT Rammes G G Eder M M Chen A A Ressler K J KJ Wurst W W Schmidt M V MV Binder E B EB Deussing J M JM

Molecular psychiatry 20170711 3

Single-nucleotide polymorphisms (SNPs) in CACNA1C, the α1C subunit of the voltage-gated L-type calcium channel Ca<sub>v</sub>1.2, rank among the most consistent and replicable genetics findings in psychiatry and have been associated with schizophrenia, bipolar disorder and major depression. However, genetic variants of complex diseases often only confer a marginal increase in disease risk, which is additionally influenced by the environment. Here we show that embryonic deletion of Cacna1c in for ...[more]

PMID: 28696432

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Project description:ObjectiveTo investigate whether anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder (BED), and other specified feeding and eating disorders (OSFED), including purging disorder (PD), subthreshold BN, and BED at ages 14 and 16 years, are prospectively associated with later depression, anxiety disorders, alcohol and substance use, and self-harm.MethodEating disorders were ascertained at ages 14 and 16 years in 6,140 youth at age 14 (58% of those eligible) and 5,069 at age 16 (52% of those eligible) as part of the prospective Avon Longitudinal Study of Parents and Children (ALSPAC). Outcomes (depression, anxiety disorders, binge drinking, drug use, deliberate self-harm, weight status) were measured using interviews and questionnaires about 2 years after predictors. Generalized estimating equation models adjusting for gender, socio-demographic variables, and prior outcome were used to examine prospective associations between eating disorders and each outcome.ResultsAll eating disorders were predictive of later anxiety disorders. AN, BN, BED, PD, and OSFED were prospectively associated with depression (respectively AN: odds ratio [OR] = 1.39, 95% CI = 1.00-1.94; BN: OR = 3.39, 95% CI = 1.25-9.20; BED: OR = 2.00, 95% CI = 1.06-3.75; and PD: OR = 2.56, 95% CI = 1.38-4.74). All eating disorders but AN predicted drug use and deliberate self-harm (BN: OR = 5.72, 95% CI = 2.22-14.72; PD: OR = 4.88, 95% CI = 2.78-8.57; subthreshold BN: OR = 3.97, 95% CI = 1.44-10.98; and subthreshold BED: OR = 2.32, 95% CI = 1.43-3.75). Although BED and BN predicted obesity (respectively OR = 3.58, 95% CI = 1.06-12.14 and OR = 6.42, 95% CI = 1.69-24.30), AN was prospectively associated with underweight.ConclusionsAdolescent eating disorders, including subthreshold presentations, predict negative outcomes, including mental health disorders, substance use, deliberate self-harm, and weight outcomes. This study highlights the high public health and clinical burden of eating disorders among adolescents.

Dataset Information

Cross-disorder risk gene CACNA1C differentially modulates susceptibility to psychiatric disorders during development and adulthood.

Publications

Cross-disorder risk gene CACNA1C differentially modulates susceptibility to psychiatric disorders during development and adulthood.

Similar Datasets

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