rs1006737

Meta-analysis of 9 case-control studies (12,744 schizophrenia cases, 16,460 controls) examining CACNA1C rs1006737 found significant association with schizophrenia across recessive, dominant, additive, and allele models (all p<0.05, overall OR: 0.85, 95% CI: 0.81-0.90 for G vs. A allele model). Association was significant in European populations for all models and in Asian populations for recessive and allele models; A-allele conferring risk.

This study demonstrates that the CACNA1C rs1006737 risk allele (A) is associated with increased bilateral amygdala volume in 258 healthy individuals (p_CORR = .027), with significant effects in both left (p = .008) and right (p = .021) amygdala. The association was stronger under a recessive genetic model. This finding supports the hypothesis that genetic variation in CACNA1C confers psychiatric risk via alterations in limbic brain structures.

Study of 1086 Finnish infants from the CHILD-SLEEP cohort examined associations between seven CACNA1C variants previously linked to psychiatric disorders and infant sleep parameters. Three variants (rs4765913, rs4765914, rs2239063) were significantly associated with prolonged sleep latency (permuted P < 0.05), with rs2239063 showing the strongest dominant model association (beta = -0.4023, P = 0.0037). No significant associations were found with sleep duration or night awakenings.

This paper presents CalPen, a web-based tool for calculating penetrance (disease likelihood given a mutation) in complex genetic disorders. The authors validated CalPen against published penetrance calculations for schizophrenia-associated copy number variants (CNVs) and single nucleotide polymorphisms (SNPs). They analyzed 15 CNVs in 39,059 schizophrenia patients and 55,084 controls (average penetrance 7%, ranging from ~1.4% for 15q11.2 deletions to ~20% for 22q11.21 CNVs) and 145 SNPs in 45,405 patients and 122,761 controls (average penetrance 0.7%, with rs1801028 showing the highest at 1.6%).

A perspective article examining schizophrenia as an oscillopathy rooted in language evolution. The authors argue that schizophrenia-related genes are overrepresented among genes important for human language evolution, with many involved in brain rhythmicity and neural oscillations. They propose that language deficits in schizophrenia arise from disruptions in oscillatory neural dynamics and suggest specific brain rhythm patterns (delta, theta, alpha, beta, gamma) correlate with linguistic impairments.

A case-control association study of 1,237 Pakistani subjects (479 with major depression, 222 with bipolar disorder, 146 with schizophrenia, 390 controls) examined 11 dopaminergic system gene variants. Significant risk associations were found for rs1006737 and rs2238056 (CACNA1c) with bipolar disorder (OR=1.14-1.15), while rs10033951 (DRD5), rs2388334 (POU3F2), and the DRD4 120bp VNTR showed protective effects across disorders (OR=0.81-0.86).

This fMRI study examined how the NCAN SNP rs1064395 (a genome-wide supported psychiatric risk variant) influences brain function and cognitive performance in 110 healthy individuals. Risk allele (A) carriers showed poorer verbal memory performance (p=0.002 for immediate recall, p=0.002 for delayed recall) and a lack of task-related deactivation in the left middle temporal gyrus/temporal pole during semantic verbal fluency tasks, compared to GG homozygotes. Greater deactivation in this region was significantly associated with better verbal memory performance in GG subjects (r=-0.28, p=0.012).

This imaging genetics study examined 94 healthy subjects to investigate the association of rs1006737 in CACNA1C (a bipolar disorder and schizophrenia susceptibility locus) with brain activation and connectivity during working memory tasks. The rs1006737 A (risk) allele was associated with reduced right dorsolateral prefrontal cortex (DLPFC) activation during the 2-back task, contrary to previous findings of increased activation. The study found increased functional connectivity between the right DLPFC and bilateral hippocampal formations in A allele carriers, supporting a fronto-hippocampal dysconnectivity phenotype linked to genetic susceptibility for psychosis.

This genetic association study identified ADRB2 SNP rs2400707 as protective against PTSD symptoms in the context of childhood adversity (β=0.243, P=1.02×10^-5 in discovery cohort; P=0.0009 in replication cohort). The AA homozygotes showed lower PTSD severity with ≥2 categories of adverse childhood experiences across two independent cohorts (n=810 soldiers and n=2,083 civilians), with combined interaction effect P=3.97×10^-7. The protective A allele tags the H1 haplotype, hypothesized to represent low-transcription ADRB2 variant.

This fMRI study examined how two bipolar disorder risk variants (CACNA1C rs1006737 and ANK3 rs10994336) affect brain activation and connectivity during facial affect processing in 41 BD patients and 46 healthy controls. Both risk alleles independently increased activation throughout the facial affect-processing network in healthy carriers, but in BD patients, they were associated with reduced ventral prefrontal cortical activation and visual-prefrontal connectivity, suggesting a mechanistic link between these GWAS-identified variants and BD pathophysiology.

Genome-wide association study of 2,323 Australian twins identified several associations with sleep phenotypes including sleep latency, sleep quality, sleep duration, and insomnia, but no genome-wide significant variants. Most notable finding: SNPs in CACNA1C intron 3 (rs7316184, rs7304986, rs7301906, and others) showed strongest association with sleep latency (p = 1.3 × 10⁻⁶), though this did not replicate in independent Chronogen Consortium sample. Additional associations with insomnia factor score (rs11174478 in SLC2A13, p = 1.92 × 10⁻⁶) and sleep duration (rs4780805, p = 2.66 × 10⁻⁶) were identified but remain unreplicated.

This systematic review and validation study examined psychosis-associated SNPs and their effects on brain volumetry in 113 subjects (schizophrenia, bipolar disorder, at-risk mental state, and healthy controls). Of 25 studies identified in the systematic review implicating 7 SNPs in 5 genes, the authors tested these variants using voxel-based morphometry. They found FWER-corrected associations for CACNA1C rs769087-A with larger bilateral hippocampus and thalamus white matter (p = 0.026 and p = 0.036) and with larger superior frontal gyrus volume. Higher replication concordance was found for CACNA1C, ZNF804A, and BDNF variants, supporting their involvement in psychosis and brain structure.

This review article examines the link between genes and language deficits in schizophrenia through the lens of neural oscillations and brain rhythmicity. The authors argue that candidate genes for schizophrenia are overrepresented among genes important for human language evolution, and propose that schizophrenia can be understood as an oscillopathy affecting language-relevant brain circuits, particularly those involving GABAergic inhibitory interneurons and oscillatory dynamics in the hippocampus and prefrontal cortex. The paper presents evidence that genes like ZNF804A, NRG1, ERBB4, CACNA1C, and GRIN2A are involved in both brain rhythmicity and schizophrenia susceptibility.

This review comprehensively summarizes the latest genetic studies on schizophrenia, including family studies (heritability ~80%), genome-wide association studies, epigenetic mechanisms, candidate gene investigations, and next-generation sequencing findings. Key GWAS findings identified 108 schizophrenia-associated loci including variants in MIR137 (rs1625579), TCF4 (rs12966547), CSMD1 (rs10503253), CACNA1C (rs4765905), ANK3 (rs10761482), and MHC region variants, with evidence for polygenetic inheritance involving both common SNPs and rare copy number variations.

This comprehensive review examines the genomics of schizophrenia and pharmacogenomics of antipsychotic drugs, synthesizing evidence on over 200 genes associated with psychotic disorders. The authors discuss five categories of genes relevant to antipsychotic response: disease-associated genes, mechanism-of-action genes, drug metabolism genes (particularly CYP2D6, CYP2C19, CYP2C9, CYP3A4), drug transporter genes, and pleiotropic genes. The review details pharmacogenomic profiles of 20+ antipsychotic drugs and demonstrates significant ethnic and interindividual variation in drug metabolism phenotypes, with examples including CYP2D6 extensive metabolizers (55.71% of population), intermediate metabolizers (34.7%), poor metabolizers (2.28%), and ultra-rapid metabolizers (7.31%).

This study examined two CACNA1C SNPs (rs10848635 and rs1006737) previously associated with bipolar disorder in 1,213 depressed participants from the STAR*D treatment trial. The rs10848635 risk allele was associated with lower baseline agitation (β = -0.09, P = 0.03), and rs1006737 with lower baseline depression severity (β = -0.4, P = 0.04) and reduced insomnia (β = -0.22, P = 0.047). Both SNPs were significantly associated with increased risk of citalopram-emergent suicidality (rs10848635: OR = 1.29, P = 0.04; rs1006737: OR = 1.34, P = 0.02), suggesting bipolar liability genes may influence treatment-related adverse effects in major depression.

Functional neuroimaging and post-mortem brain expression analysis showing that the rs1006737 risk allele in CACNA1C (calcium channel gene) is associated with increased hippocampal activity during emotional memory encoding (p=0.001) and increased prefrontal cortex activity during working memory (p=2.8e-05), with increased CACNA1C mRNA expression (p=0.0017). Case-control analysis confirmed association with schizophrenia (OR=1.77, p=0.026). The findings suggest calcium channel dysfunction contributes to psychiatric genetic risk through altered brain circuit function.

A PhD dissertation investigating the cell type-specific effects of CACNA1C, a cross-disorder psychiatric risk gene encoding the α1 subunit of the L-type voltage-gated calcium channel Cav1.2. The dissertation reviews human genetic studies showing associations between multiple CACNA1C SNPs (including rs1006737, rs1024582, rs2007044) and psychiatric disorders (bipolar disorder, schizophrenia, major depression, autism), then presents preclinical studies using conditional knockout mouse models to elucidate the neurobiological mechanisms underlying these genetic associations through behavioral testing, electrophysiology, and molecular analyses.

This comprehensive review synthesizes genomic and pharmacogenomic research in schizophrenia, discussing over 200 candidate genes associated with psychotic disorders, genetic mechanisms including copy number variants and microRNA alterations, and pharmacogenomic factors affecting antipsychotic efficacy and safety. Key genes covered include dopamine receptors (DRD1-5), dysbindin (DTNBP1), DISC1, neurotrophic factors, and metabolic enzymes such as CYP2D6, CYP3A4, and COMT, with emphasis on genotype-phenotype correlations in antipsychotic response and side effects.