Pleiotropic Association of CACNA1C Variants With Neuropsychiatric Disorders

Abstract

Background Neuropsychiatric disorders are highly heritable and have overlapping genetic underpinnings. Single nucleotide polymorphisms (SNPs) in the gene CACNA1C have been associated with several neuropsychiatric disorders, across multiple genome-wide association studies. Method A total of 70,711 subjects from 37 independent cohorts with 13 different neuropsychiatric disorders were meta-analyzed to identify overlap of disorder-associated SNPs within CACNA1C. The differential expression of CACNA1C mRNA in five independent postmortem brain cohorts was examined. Finally, the associations of disease-sharing risk alleles with total intracranial volume (ICV), gray matter volumes (GMVs) of subcortical structures, cortical surface area (SA), and average cortical thickness (TH) were tested. Results Eighteen SNPs within CACNA1C were nominally associated with more than one neuropsychiatric disorder (P < .05); the associations shared among schizophrenia, bipolar disorder, and alcohol use disorder survived false discovery rate correction (five SNPs with P < 7.3 × 10−4 and q < 0.05). CACNA1C mRNA was differentially expressed in brains from individuals with schizophrenia, bipolar disorder, and Parkinson’s disease, relative to controls (three SNPs with P < .01). Risk alleles shared by schizophrenia, bipolar disorder, substance dependence, and Parkinson’s disease were significantly associated with ICV, GMVs, SA, or TH (one SNP with P ≤ 7.1 × 10−3 and q < 0.05). Conclusion Integrating multiple levels of analyses, we identified CACNA1C variants associated with multiple psychiatric disorders, and schizophrenia and bipolar disorder were most strongly implicated. CACNA1C variants may contribute to shared risk and pathophysiology in these conditions.

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

“…However, the same variants have also been found to be associated with schizophrenia and not just BD [ 55 ]. Current methods estimate that the cumulative impact of many frequent alleles may explain only 38% of the BD phenotypic variance [ 56 ].…”

MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway: Role in lateral ventricles and corpus callosum volume

“…Partial MIR137 loss in mice causes repetitive behavior, lack of sociability and impaired learning ( Yan et al, 2019 ), while overexpression in transgenic mice causes behavioral deficits and transcriptome profiles related to SZ ( Arakawa et al, 2019 ). Gene sets of potential MIR137 targets ( Hill et al, 2014 ) are enriched with variants associated with SZ risk, including TCF4, involved with enlargement of LV, hypoplasia of CC and mental delays ( Goodspeed et al, 2018 ; Kim et al, 2020 ; Zollino et al, 2019 ; Zweier et al, 2007 ); cortical expansion and neuronal differentiation ( Tomasello et al, 2022 ); GRIN2A, involved in the NMDA receptor pathway ( Gandal et al, 2012 ; Harrison & Bannerman, 2023 ) and possibly associated with negative symptoms ( Coyle & Tsai, 2004 ; Javitt et al, 1994 ; Poltavskaya et al, 2023 ); CACNA1C, a risk factor also for bipolar disorder and major depression ( Green et al, 2010 ; Wang et al, 2023 ); and ZNF804A, central to cognition ( del Re et al, 2014 ; Novaes de Oliveira Roldan et al, 2023 ). Many of these MIR137-regulated and SZ-associated risk genes demonstrate genetic overlap with syndromes such as Pitt-Hopkins (TCF4) ( Jung et al, 2018 ; Peippo & Ignatius, 2012 ; Teixeira et al, 2021 ), in which LV enlargement, CC hypoplasia and mental delays are present.…”