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The association of genetic variation in CACNA1C with structure and function of a frontotemporal system.

ABSTRACT: A single nucleotide polymorphism at the CACNA1C gene (rs1006737) has been reported in genome-wide association studies to be associated with bipolar disorder (BD) with genome-wide significance. However, the neural system effects of CACNA1C that mediate the association are not known. In this study, we assessed associations between rs1006737 variation and both morphology and functional connectivity within a corticolimbic frontotemporal neural system implicated in BD.A total of 55 European Americans were divided into two groups: a GG group homozygous for the 'G' allele (n = 30) and carriers of the high risk A allele ('A-carrier' group, AA/AG genotypes; n = 25). The subjects participated in both high-resolution structural magnetic resonance imaging (MRI) scans and functional MRI scans during emotional face-processing. Voxel-based morphometry and functional connectivity analyses were performed.Compared to the GG group, the A-carrier group showed significantly increased gray matter volume and reduced functional connectivity within a corticolimbic frontotemporal neural system (p < 0.05, corrected).The findings support effects of the rs1006737 variation on the frontotemporal neural system implicated in BD, both in gray matter morphology and in functional connectivity. This suggests that influence of CACNA1C variation on corticolimbic structure and function may be a mechanism contributing to the neural circuitry of BD.

SUBMITTER: Wang F

PROVIDER: S-EPMC3233238 | biostudies-literature | 2011 Nov-Dec

REPOSITORIES: biostudies-literature

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The association of genetic variation in CACNA1C with structure and function of a frontotemporal system.

Wang Fei F McIntosh Andrew M AM He Yong Y Gelernter Joel J Blumberg Hilary P HP

Bipolar disorders 20111101 7-8

<h4>Objectives</h4>A single nucleotide polymorphism at the CACNA1C gene (rs1006737) has been reported in genome-wide association studies to be associated with bipolar disorder (BD) with genome-wide significance. However, the neural system effects of CACNA1C that mediate the association are not known. In this study, we assessed associations between rs1006737 variation and both morphology and functional connectivity within a corticolimbic frontotemporal neural system implicated in BD.<h4>Methods</ ...[more]

PMID: 22085483

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Project description:Genome-wide association studies have identified allelic variation in CACNA1C as a risk factor for multiple psychiatric disorders associated with limbic system dysfunction, including bipolar disorder, schizophrenia, and depression. The CACNA1C gene codes for a subunit of L-type voltage-gated calcium channels, which modulate amygdala function. Although CACNA1C genotype appears to be associated with amygdala morphology and function in adults with and without psychopathology, whether genetic variation influences amygdala structure and function earlier in development has not been examined.In this first investigation of the neural correlates of CACNA1C in young individuals, we examined associations between two single nucleotide polymorphisms in CACNA1C (rs1006737 and rs4765914) with amygdala volume and activation during an emotional processing task in 58 adolescents and young adults 13-20 years of age.Minor (T) allele carriers of rs4765914 exhibited smaller amygdala volume than major (C) allele homozygotes (?=-0.33, p=0.006). Furthermore, minor (A) allele homozygotes of rs1006737 exhibited increased blood-oxygen-level-dependent (BOLD) signal in the amygdala when viewing negative (vs. neutral) stimuli (?=0.29, p=0.040) and decreased BOLD signal in the amygdala when instructed to downregulate their emotional response to negative stimuli (?=-0.38, p=0.009). Follow-up analyses indicated that childhood trauma did not moderate the associations of CACNA1C variation with amygdala structure and function (ps>0.170).Findings indicate that CACNA1C-related differences in amygdala structure and function are present by adolescence. However, population stratification is a concern, given the racial/ethnic heterogeneity of our sample, and our findings do not have direct clinical implications currently. Nevertheless, these results suggest that developmentally informed research can begin to shed light on the time course by which genetic liability may translate into neural differences associated with vulnerability to psychopathology.

Project description:CONTEXT:The CACNA1C gene (alpha-1C subunit of the L-type voltage-gated calcium channel) has been identified as a risk gene for bipolar disorder and schizophrenia, but the mechanism of association has not been explored. OBJECTIVE:To identify the neural system mechanism that explains the genetic association between the CACNA1C gene and psychiatric illness using neuroimaging and human brain expression. DESIGN:We used blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to measure brain activation in circuitries related to bipolar disorder and schizophrenia by comparing CACNA1C genotype groups among healthy subjects. We tested the effect of genotype on messenger RNA (mRNA) levels of CACNA1C in postmortem human brain. A case-control analysis was used to determine the association of CACNA1C genotype with schizophrenia. SETTING:National Institutes of Health Clinical Center. PATIENTS:Healthy men and women of white race/ethnicity participated in the fMRI study. Postmortem samples from normal human brains were used for the brain expression study. Patients with schizophrenia and healthy subjects were used in the case-control analysis. MAIN OUTCOME MEASURES:BOLD fMRI, mRNA levels in postmortem brain samples, and genetic association with schizophrenia. RESULTS:The risk-associated single-nucleotide polymorphism (SNP rs1006737) in CACNA1C predicted increased hippocampal activity during emotional processing (P = .001 uncorrected, P((false recovery rate [FDR])) = .05, z = 3.20) and increased prefrontal activity during executive cognition (P = 2.8e-05 uncorrected, P(FDR) = .01, z = 4.03). The risk-associated SNP also predicted increased expression of CACNA1C mRNA in human brain (P = .002). CACNA1C was associated with schizophrenia in our case-control sample (odds ratio, 1.77; P = .03). CONCLUSIONS:The risk-associated SNP in CACNA1C maps to circuitries implicated in genetic risk for bipolar disorder and schizophrenia. Its effects in human brain expression implicate a molecular and neural system mechanism for the clinical genetic association.

Project description:ImportanceKeratoconus is a condition in which the cornea progressively thins and protrudes in a conical shape, severely affecting refraction and vision. It is a major indication for corneal transplant. To discover new genetic loci associated with keratoconus and better understand the causative mechanism of this disease, we performed a genome-wide association study on patients with keratoconus.ObjectiveTo identify genetic susceptibility regions for keratoconus in the human genome.Design, setting, and participantsThis study was conducted with data from eye clinics in Australia, the United States, and Northern Ireland. The discovery cohort of individuals with keratoconus and control participants from Australia was genotyped using the Illumina HumanCoreExome single-nucleotide polymorphism array. After quality control and data cleaning, genotypes were imputed against the 1000 Genomes Project reference panel (phase III; version 5), and association analyses were completed using PLINK version 1.90. Single-nucleotide polymorphisms with P < 1.00 × 10-6 were assessed for replication in 3 additional cohorts. Control participants were drawn from the cohorts of the Blue Mountains Eye Study and a previous study of glaucoma. Replication cohorts were from a previous keratoconus genome-wide association study data set from the United States, a cohort of affected and control participants from Australia and Northern Ireland, and a case-control cohort from Victoria, Australia. Data were collected from January 2006 to March 2019.Main outcomes and measuresAssociations between keratoconus and 6 252 612 genetic variants were estimated using logistic regression after adjusting for ancestry using the first 3 principal components.ResultsThe discovery cohort included 522 affected individuals and 655 control participants, while the replication cohorts included 818 affected individuals (222 from the United States, 331 from Australia and Northern Ireland, and 265 from Victoria, Australia) and 3858 control participants (2927 from the United States, 229 from Australia and Northern Ireland, and 702 from Victoria, Australia). Two novel loci reached genome-wide significance (defined as P < 5.00 × 10-8), with a P value of 7.46 × 10-9 at rs61876744 in patatin-like phospholipase domain-containing 2 gene (PNPLA2) on chromosome 11 and a P value of 6.35 × 10-12 at rs138380, 2.2 kb upstream of casein kinase I isoform epsilon gene (CSNK1E) on chromosome 22. One additional locus was identified with a P value less than 1.00 × 10-6 in mastermind-like transcriptional coactivator 2 (MAML2) on chromosome 11 (P = 3.91 × 10-7). The novel locus in PNPLA2 reached genome-wide significance in an analysis of all 4 cohorts (P = 2.45 × 10-8).Conclusions and relevanceIn this relatively large keratoconus genome-wide association study, we identified a genome-wide significant locus for keratoconus in the region of PNPLA2 on chromosome 11.

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The association of genetic variation in CACNA1C with structure and function of a frontotemporal system.

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The association of genetic variation in CACNA1C with structure and function of a frontotemporal system.

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