L-type calcium channels and neuropsychiatric diseases: Insights into genetic risk variant-associated genomic regulation and impact on brain development

Baker, Madelyn R.; Lee, Andrew S; Rajadhyaksha, Anjali M.

doi:10.1080/19336950.2023.2176984

Cited by 6 publications

(1 citation statement)

References 160 publications

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“…This mutation has been associated with an odds ratio of 1,7 for BD, according to the clinical genetics database SNPedia. At the same time, this database associates this mutation with a trait for autism spectrum disorder, attention-deficit/hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia—in particular, reporting different publications through genome-wide association studies (GWAS) [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

Screening, Genetic Variants, and Bipolar Disorders: Can Useful Hypotheses Arise from the Sum of Partial Failures?

Carta,

Kalcev,

Scano

et al. 2023

Clinics and Practice

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Bipolar disorder (BD) is a relevant public health issue, therefore accurate screening tools could be useful. The objective of this study is to verify the accuracy of the Mood Disorder Questionnaire (MDQ) and genetic risk as screeners, and their comparison in terms of reliability. Older adults (N = 61, ≥60 years) received a clinical psychiatric evaluation, the MDQ, and were evaluated according to the presence of the genetic variant RS1006737 of CACNA1C. MDQ+ versus the diagnosis of BD as a gold standard shows a sensitivity of 0.286 (Cl 95% 0.14–0.39); a specificity of 0.925 (Cl 95% 0.85–0.08); a predictive positive value (PPV) of 0.667 (Cl 95% 0.33–0.91); and a predictive negative value (PNV) of 0.702 (Cl 95% 0.65–0.75). The positivity for the variant RS1006737 of the CACNA1C against the diagnosis of BD as a gold standard shows a sensitivity of 0.750 (Cl 95% 0.55–0.90); a specificity of 0.375 (Cl 95% 0.28–0.45); a PPV of 0.375 (Cl 95% 0.28–0.45); and a PNV of 0.750 (Cl 95% 0.55–0.90). The reliability between the MDQ+ and positivity for the variant RS1006737 of the CACNA1C was very low (K = −0.048, Cl 95% −0.20–0.09). The study found that both the genetic and the paper and pencil test were quite accurate, but were not reliable in case finding. In fact, despite some validity, albeit specular (in the case of a positive genetic test, the probability of having the disorder is very high, whereas in the case of a negative score on the paper and pencil test, the probability of not having the disorder is very high), the unreliability of the two tests (i.e., they certainly do not measure the same underlying dimension) opens the door to the need for an interpretation and the possibility of a synergistic use for screening. From a heuristic perspective, which obviously requires all of the necessary verifications, this study seems to suggest the hypothesis that a condition of hyperactivation common to disorders and stress conditions, and identified by a positive score on the MDQ (which is common to BD, post-traumatic stress disorder (PTSD), and anxiety disorders and whose genetic basis has not yet been clarified) can trigger BD in people with a predisposition to hyperactivity (i.e., in people with the condition identified by the analyzed genetic variant).

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Section: Discussionmentioning

confidence: 99%

Screening, Genetic Variants, and Bipolar Disorders: Can Useful Hypotheses Arise from the Sum of Partial Failures?

Carta,

Kalcev,

Scano

et al. 2023

Clinics and Practice

View full text Add to dashboard Cite

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Advances in Alzheimer's disease: A multifaceted review of potential therapies and diagnostic techniques for early detection

Sharma,

Pal,

Gupta

2024

Neurochemistry International

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Single-nucleus transcriptome-wide association study of human brain disorders

Venkatesh,

Wu,

Anyfantakis

et al. 2024

Preprint

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Neuropsychiatric and neurodegenerative disorders exhibit cell–type–specific characteristics1–8, yet most transcriptome–wide association studies have been constrained by the use of homogenate brain tissue9–11, limiting their resolution and power. Here, we present a single–nucleus transcriptome–wide association study (snTWAS) leveraging single–nucleus RNA sequencing of over 6 million nuclei from the dorsolateral prefrontal cortex of 1,494 donors across three ancestries–European, African, and Admixed American. We constructed ancestry–specific single–nucleus–derived transcriptomic imputation models (snTIMs) including up to 27 non–overlapping cellular populations, enhancing the resolution of genetically regulated gene expression (GReX) in the brain and uncovering novel gene–trait associations across 12 neuropsychiatric and neurodegenerative traits. Our snTWAS framework revealed cell–type–specific dysregulation of GReX, identifying over 4,000 novel gene–trait associations not detected by bulk tissue approaches. By applying these snTIMs to the Million Veteran Program, we validated major findings and explored the pleiotropy of cell–type–specific GReX, revealing cross–ancestry concordance and fine–mapping causal genes. This approach enhances the discovery of biologically relevant pathways and gene targets, highlighting the importance of cell–type resolution and ancestry–specific models in understanding the genetic architecture of complex brain disorders.

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L-type calcium channels and neuropsychiatric diseases: Insights into genetic risk variant-associated genomic regulation and impact on brain development

Cited by 6 publications

References 160 publications

Screening, Genetic Variants, and Bipolar Disorders: Can Useful Hypotheses Arise from the Sum of Partial Failures?

Screening, Genetic Variants, and Bipolar Disorders: Can Useful Hypotheses Arise from the Sum of Partial Failures?

Advances in Alzheimer's disease: A multifaceted review of potential therapies and diagnostic techniques for early detection

Single-nucleus transcriptome-wide association study of human brain disorders

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