CACNA1C: Association With Psychiatric Disorders, Behavior, and Neurogenesis.
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ABSTRACT:
SUBMITTER: Moon AL
PROVIDER: S-EPMC6101623 | biostudies-literature | 2018 Aug
REPOSITORIES: biostudies-literature
Publications
CACNA1C: Association With Psychiatric Disorders, Behavior, and Neurogenesis.
Moon Anna L AL Haan Niels N Wilkinson Lawrence S LS Thomas Kerrie L KL Hall Jeremy J
Schizophrenia bulletin 20180801 5
Large-scale genome-wide association studies have consistently shown that genetic variation in CACNA1C, a gene that encodes calcium voltage-gated channel subunit alpha1C, increases risk for psychiatric disorders. CACNA1C encodes the Cav1.2 subunit of voltage-gated calcium channels, which themselves have been functionally implicated in a broad spectrum of neuropsychiatric syndromes. Research has concentrated on uncovering the underlying biological mechanisms that could be responsible for this incr ...[more]
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Project description:Single-nucleotide polymorphisms (SNPs) in CACNA1C, the α1C 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.
| S-EPMC5822460 | biostudies-literature
Project description:ImportanceMaternal immune activation (MIA) leading to altered neurodevelopment in utero is a hypothesized risk factor for psychiatric outcomes in offspring. Primary antibody immunodeficiencies (PIDs) constitute a unique natural experiment to test the MIA hypothesis of mental disorders.ObjectiveTo assess the association of maternal and paternal PIDs with psychiatric disorders and suicidal behavior in offspring.Design, setting, and participantsCohort study of 4 294 169 offspring of parents with and without PIDs living in Sweden at any time between 1973 and 2013. Data were extracted from Swedish nationwide health and administrative registers and were analyzed from May 5 to September 30, 2022. All individuals with diagnoses of PIDs identified between 1973 and 2013 from the National Patient Register were included. Offspring were included if born before 2003. Parent-offspring pairs in which both parents had a history of PIDs were excluded.ExposuresLifetime records of parental PIDs according to the International Classification of Diseases, Eighth Revision (ICD-8); International Classification of Diseases, Ninth Revision (ICD-9); and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnostic codes.Main outcomes and measuresLifetime records of 10 psychiatric disorders and suicidal behavior identified using ICD-8, ICD-9, and ICD-10 diagnostic codes, including suicide attempts and death by suicide, among offspring. Covariates included sex, birth year, parental psychopathology, suicide attempts, and autoimmune diseases. Additional analyses excluded offspring with their own PIDs and autoimmune diseases. Poisson regression models were fitted separately for mothers and fathers to estimate incidence rate ratios (IRRs) and 95% CIs for the risk of psychiatric and suicidal behavior outcomes in the offspring of PID-exposed vs PID-unexposed mothers or fathers.ResultsThe cohort included 4 294 169 offspring (2 207 651 males [51.4%]) and 3 954 937 parents (1 987 972 females [50.3%]). A total of 7270 offspring (0.17%) had parents with PIDs, and 4 286 899 offspring had parents without PIDs. In fully adjusted models, offspring of mothers with PIDs had an increased risk of any psychiatric disorder, while no such risks were observed in offspring of fathers with PIDs (IRR, 1.17; 95% CI, 1.10-1.25 vs IRR, 1.03; 95% CI, 0.94-1.14; P < .001). Likewise, an increased risk of suicidal behavior was observed among offspring of mothers with PIDs but not offspring of fathers with PIDs (IRR, 1.20; 95% CI, 1.06-1.36 vs IRR, 1.10; 95% CI, 0.91-1.34; P = .01). For the offspring of mothers with PIDs, the risk of developing any psychiatric disorder was significantly higher for those with mothers with 6 of 10 individual disorders, with IRRs ranging from 1.15 (95% CI, 1.04-1.26) for anxiety and stress-related disorders and 1.15 (95% CI, 1.03-1.30) for substance use disorders to 1.71 (95% CI, 1.37-2.14) for bipolar disorders. Offspring of mothers with both PIDs and autoimmune diseases had the highest risk for any psychiatric disorder (IRR, 1.24; 95% CI, 1.11-1.38) and suicidal behavior (IRR, 1.44; 95% CI, 1.17-1.78).Conclusions and relevanceFindings of this cohort study suggest that maternal, but not paternal, PIDs were associated with a statistically significant increased risk of psychiatric disorders and suicidal behavior in the offspring, particularly when PIDs co-occur with autoimmune diseases. These findings align with the MIA hypothesis of mental disorders, but the precise mechanisms remain to be elucidated.
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Project description:It is well known that only a small proportion of the human genome code for proteins; the rest belong to the family of RNAs that do not code for protein and are known as non-coding RNAs (ncRNAs). ncRNAs are further divided into two subclasses based on size: 1) long non-coding RNAs (lncRNAs; >200 nucleotides) and 2) small RNAs (<200 nucleotides). Small RNAs contain various family members that include microRNAs (miRNAs), small interfering RNAs (siRNAs), piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), and small nuclear RNAs (snRNAs). The roles of ncRNAs, especially lncRNAs and miRNAs, are well documented in brain development, homeostasis, stress responses, and neural plasticity. It has also been reported that ncRNAs can influence the development of psychiatric disorders including schizophrenia, major depressive disorder, and bipolar disorder. More recently, their roles are being investigated in suicidal behavior. In this article, we have comprehensively reviewed the findings of lncRNA and miRNA expression changes and their functions in various psychiatric disorders including suicidal behavior. We primarily focused on studies that have been done in postmortem human brain. In addition, we have briefly reviewed the role of other small RNAs (e.g. piwiRNA, siRNA, snRNA, and snoRNAs) and their expression changes in psychiatric illnesses.
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Project description:Suicide is a leading cause of death worldwide. In 2020, some 12.2 million Americans seriously contemplated suicide, 3.2 million planned suicide attempts, and 1.2 million attempted suicide. Traditionally, the approach to treating suicidal behavior (SB) has been to treat the "underlying" psychiatric disorder. However, the number of diagnoses associated with SB is considerable. We could find no studies describing the range of disorders reported to be comorbid with SB. This narrative review summarizes literature documenting the occurrence of SB across the lifespan and the full range of psychiatric diagnoses, not only BPD and those that comprise MDE, It also describes the relevance of these observations to clinical practice, research, and nosology. The literature searches contained the terms "suicid*" and each individual psychiatric diagnosis and identified 587 studies. We did not include case reports, case series, studies only addressing suicidal ideation or non-suicidal self-injury (NSSI), studies on self-harm, not distinguishing between SB and NSSI and studies that did not include any individuals that met criteria for a specific DSM-5 diagnosis (n = 366). We found that SB (suicide and/or suicide attempt) was reported to be associated with 72 out of 145 diagnoses, although data quality varied. Thus, SB is not exclusively germane to Major Depressive Episode (MDE) and Borderline Personality Disorder (BPD), the only conditions for which it is a diagnostic criterion. That SB co-occurs with so many diagnoses reinforces the need to assess current and past SB regardless of diagnosis, and supports the addition of charting codes to the DSM-5 to indicate current or past SB. It also comports with new data that specific genes are associated with SB independent of psychiatric diagnoses, and suggests that SB should be managed with specific suicide prevention interventions in addition to treatments indicated for co-occurring diagnoses. SB diagnostic codes would help researchers and clinicians document and measure SB's trajectory and response to treatment over time, and, ultimately, help develop secondary and tertiary prevention strategies. As a separate diagnosis, SB would preclude situations in which a potentially life-threatening behavior is not accounted for by a diagnosis, a problem that is particularly salient when no mental disorder is present, as is sometimes the case.
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Project description:Importance:The hypothesis that disrupted immune function is implicated in the pathophysiology of psychiatric disorders and suicide is gaining traction, but the underlying mechanisms are largely unknown. Primary humoral immunodeficiencies (PIDs) are rare deficiencies of the immune system-mainly dysfunction of antibody production-and are associated with adverse health problems, such as recurrent infections and autoimmune diseases. Objective:To establish whether PIDs that affect antibody function and level are associated with lifetime psychiatric disorders and suicidal behavior and whether this association is explained by the co-occurrence of autoimmune diseases. Design, Setting, and Participants:This population- and sibling-based cohort study included more than 14 million individuals living in Sweden from January 1, 1973, through December 31, 2013. Register-based data on exposure, outcomes, and covariates were collected through December 31, 2013. Individuals with a record of PID were linked to their full siblings, and a family identification number was created. Data were analyzed from May 17, 2019, to February 21, 2020. Exposures:Lifetime records of PID and autoimmune disease. Main Outcomes and Measures:Lifetime records of 12 major psychiatric disorders and suicidal behavior, including suicide attempts and death by suicide. Results:A lifetime diagnosis of PID affecting immunoglobulin levels was identified in 8378 patients (4947 women [59.0%]; median age at first diagnosis, 47.8 [interquartile range, 23.8-63.4] years). A total of 4776 clusters of full siblings discordant for PID was identified. After adjusting for comorbid autoimmune diseases, PIDs were associated with greater odds of any psychiatric disorder (adjusted odds ratio [AOR],?1.91; 95% CI, 1.81-2.01) and any suicidal behavior (AOR,?1.84; 95% CI, 1.66-2.04). The associations were also significant for all individual psychiatric disorders (range of AORs, 1.34 [95% CI, 1.17-1.54] for schizophrenia and other psychotic disorders to 2.99 [95% CI, 2.42-3.70] for autism spectrum disorders), death by suicide (AOR, 1.84; 95% CI, 1.25-2.71), and suicide attempts (AOR, 1.84; 95% CI, 1.66-2.04). In the sibling comparisons, the associations were attenuated but remained significant for aggregated outcomes (AOR for any psychiatric disorder, 1.64 [95% CI, 1.48-1.83]; AOR for any suicidal behavior, 1.37 [95% CI, 1.14-1.66]), most individual disorders (range of AORs, 1.46 [95% CI, 1.23-1.73] for substance use disorders to 2.29 [95% CI, 1.43-3.66] for autism spectrum disorders), and suicide attempts (AOR, 1.41; 95% CI, 1.17-1.71). Joint exposure for PID and autoimmune disease resulted in the highest odds for any psychiatric disorder (AOR,?2.77; 95% CI, 2.52-3.05) and any suicidal behavior (AOR,?2.75; 95% CI, 2.32-3.27). The associations with psychiatric outcomes (AORs, 2.42 [95% CI, 2.24-2.63] vs 1.65 [95% CI, 1.48-1.84]) and suicidal behavior (AORs, 2.43 [95% CI, 2.09-2.82] vs 1.40 [95% CI, 1.12-1.76]) were significantly stronger for women than for men with PID. Conclusions and Relevance:Primary humoral immunodeficiencies were robustly associated with psychopathology and suicidal behavior, particularly in women. The associations could not be fully explained by co-occurring autoimmune diseases, suggesting that antibody dysfunction may play a role, although other mechanisms are possible. Individuals with both PID and autoimmune disease had the highest risk of psychiatric disorders and suicide, suggesting an additive effect. Future studies should explore the underlying mechanisms of these associations.
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Project description:Although there are pronounced sex differences for psychiatric disorders, relatively little has been published on the heterogeneity of sex-specific genetic effects for these traits until very recently for adults. Much less is known about children because most psychiatric disorders will not manifest until later in life and existing studies for children on psychiatric traits such as cognitive functions are underpowered. We used results from publicly available genome-wide association studies for six psychiatric disorders and individual-level data from the Adolescent Brain Cognitive Development (ABCD) study and the UK Biobank (UKB) study to evaluate the associations between the predicted polygenic risk scores (PRS) of these six disorders and observed cognitive functions, behavioral and brain imaging traits. We further investigated the mediation effects of the brain structure and function, which showed heterogeneity between males and females on the correlation between genetic risk of schizophrenia and fluid intelligence. There was significant heterogeneity in genetic associations between the cognitive traits and psychiatric disorders between sexes. Specifically, the PRSs of schizophrenia of boys showed stronger correlation with eight of the ten cognitive functions in the ABCD data set; whereas the PRSs of autism of females showed a stronger correlation with fluid intelligence in the UKB data set. Besides cognitive traits, we also found significant sexual heterogeneity in genetic associations between psychiatric disorders and behavior and brain imaging. These results demonstrate the underlying early etiology of psychiatric disease and reveal a shared and unique genetic basis between the disorders and cognition traits involved in brain functions between the sexes.
| S-EPMC9418275 | biostudies-literature
Project description:Immune dysregulation due to chronic inflammation is a hypothesized risk factor underlying psychiatric disorders and suicidal behavior. Whether tonsillectomy and acute appendicitis used, respectively, as proxies for chronic and acute inflammation within the mucosa-associated lymphoid tissue (MALT) are associated with psychiatric disorders and suicidal behavior is currently unknown. A birth cohort study was conducted including 3,052,875 individuals born in Sweden between 1973 and 2003. We identified 210,686 individuals ever exposed to tonsillectomy and 86,928 individuals ever exposed to acute appendicitis, as well as 317,214 clusters of siblings discordant for tonsillectomy, and 160,079 sibling clusters discordant for acute appendicitis. Outcomes were an aggregate risk of 'any psychiatric disorder', 'any suicidal behavior', 12 individual psychiatric disorders, suicide attempts and deaths by suicide. Tonsillectomy was associated with increased odds of 'any psychiatric disorder' (adjusted odds ratio [aOR] = 1.39; 95% confidence interval (CI) = 1.38-1.41) and 'any suicidal behavior' (aOR = 1.41; 95% CI = 1.37-1.44), and most individual disorders. Acute appendicitis also increased the odds of 'any psychiatric disorder' and 'any suicidal behavior' (aOR = 1.23; 95% CI = 1.20-1.25, and aOR = 1.32; 95% CI = 1.28-1.37, respectively). Exposure to both tonsillectomy and appendicitis was associated with the highest odds of 'any psychiatric disorder' (aOR = 1.70; 95% CI = 1.59-1.82) and 'any suicidal behavior' (aOR = 1.90; 95% CI = 1.70-2.12). In sibling comparisons, the associations were attenuated but remained significant. We conclude that inflammation within the MALT, particularly when chronic, is robustly associated with a broad range of psychiatric disorders and suicidal behavior.
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