Eur Arch Psychiatry Clin Neurosci DOI 10.1007/s00406-015-0609-x
SHORT COMMUNICATION
CACNA1C risk variant is associated with increased amygdala volume T. M. Lancaster1,2 · S. Foley2,3 · K. E. Tansey3 · D. E. J. Linden1,2,3 · X. Caseras2,3
Received: 18 February 2015 / Accepted: 28 May 2015 © Springer-Verlag Berlin Heidelberg 2015
Abstract Genome-wide association studies suggest that genetic variation within L-type calcium channel subunits confer risk to psychosis. The single nucleotide polymorphism at rs1006737 in CACNA1C has been associated with both schizophrenia and bipolar disorder and with several intermediate phenotypes that may serve as neurobiological antecedents, linking psychosis to genetic aetiology. Amongst others, it has been implicated in alterations in amygdala structure and function. In the present study, we show that the risk allele (A) is associated with increased amygdala volume in healthy individuals (n = 258). This observation reinforces a hypothesis that genetic variation may confer risk to psychosis via alterations in limbic structures. Further study of CACNA1C using intermediate phenotypes for psychosis will determine the mechanisms by which variation in this gene confers risk. Keywords Bipolar · CACNA1C · Amygdala · rs1006737
* T. M. Lancaster [email protected] 1
Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, Wales, UK
2
Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, 70 Park Place, Cardiff CF10 3AT, Wales, UK
3
MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff School of Medicine, Cardiff University, Cardiff, Wales, UK
Introduction Recent genome-wide association studies (GWAS) suggest that variations in L-type calcium channel genes are part of the genetic architecture that confers susceptibility to schizophrenia [1, 2] and bipolar disorder [3–5]. A growing body of evidence suggests that variation within the CACNA1C gene may confer susceptibility to psychosis. Variation within CACNA1C identified via GWAS for bipolar disorder and schizophrenia may increase susceptibility via molecular mechanism as single nucleotide polymorphisms (SNP) (such as rs1006737) may have functional consequences that effect gene expression [6], lead to increases in mRNA expression in cortical tissue [7] and affect L-type voltage-gated calcium channel current density [8]. Recent research also suggests that allelic variation within the CACNA1C gene might be associated with psychopathology via modification of the brain’s function and structure. For example, the rs1006737 risk allele (A) has been associated with altered behaviour [9– 11], brain structure [12–15] as well as brain circuits involving working memory [7, 16, 17], episodic memory [18–21], learning [22, 23] and emotion processing [15, 24, 25]. One common finding implicates the rs1006737 risk allele (A) with alterations in amygdala structure and function [12, 14, 22, 24]. Several studies have demonstrated associations between rs1006737 and amygdala volume [12, 14]; however, one large study failed to find associations between rs1006737 and subcortical structures, but instead found associations between CACNA1C SNPs and brain stem volume [26]. As replication in imaging genetics is of critical importance, we attempt to address any discrepancies within the previous literature that have linked rs1006737 to variation in volumetric brain measures. In the present study, we aim to confirm putative associations/negative findings between rs1006737 and global brain structures. Using a well-validated cortical
13
reconstruction technique [27–29], frequently used in largescale imaging genetic studies [30, 31], we aim to confirm any putative associations between rs1006737 and cortical/ subcortical/brainstem volumes. Based upon prior work, we anticipate linking the rs1006737 risk allele (A) to increased amygdala volume and/or alterations in brain stem volume, as previously observed [12, 14, 26].
Eur Arch Psychiatry Clin Neurosci
Centre (CUBRIC), School of Psychology, Cardiff University. High-resolution three-dimensional T1-weighted images were acquired using a three-dimensional fast spoiled gradient echo sequence (FSPGR) with contiguous sagittal slices of 1 mm thickness (TR 7.9 s, TE 3.0 ms, TI 450 ms, flip angle 20°, FOV 256 × 256 × 176 mm to yield 1 mm isotropic voxel resolution images). Image processing
Methods and materials Sample demographics Two hundred and seventy-two Caucasian individuals consisting of university undergraduates, postgraduates, members of staff and the public were recruited from Cardiff University. All individuals in the sample either were in or had completed higher education or underwent a standardised IQ test to ensure they were of average or above-average intelligence. Individuals were only included in the absence of a personal history of psychiatric disorders, including alcohol and substance abuse. Similarly, psychotropic medication, neurological or chronic medical conditions were also exclusion criteria. The mean age was 24.57 (±6.77) years with 73 male and 185 female. One-way ANOVA demonstrated that age did not differ between rs1006737 genotypes (F2,257 = .139, p = .870). Chi-square test confirmed that rs1006737 genotype frequencies did not differ between genders (χ2 = . 048, p = . 976). The study was approved by the local ethics committee and Cardiff University, and all participants gave written informed consent. Genotyping Genomic DNA was obtained from saliva using Oragene OG-500 saliva kits. Genotyping was performed using custom SNP genotyping arrays from Illumina (Illumina, Inc., San Diego, CA). Quality control was implemented in PLINK [32]. Individuals were excluded for ambiguous sex, cryptic relatedness up to third-degree relatives by identity of descent, genotyping completeness
SHORT COMMUNICATION
CACNA1C risk variant is associated with increased amygdala volume T. M. Lancaster1,2 · S. Foley2,3 · K. E. Tansey3 · D. E. J. Linden1,2,3 · X. Caseras2,3
Received: 18 February 2015 / Accepted: 28 May 2015 © Springer-Verlag Berlin Heidelberg 2015
Abstract Genome-wide association studies suggest that genetic variation within L-type calcium channel subunits confer risk to psychosis. The single nucleotide polymorphism at rs1006737 in CACNA1C has been associated with both schizophrenia and bipolar disorder and with several intermediate phenotypes that may serve as neurobiological antecedents, linking psychosis to genetic aetiology. Amongst others, it has been implicated in alterations in amygdala structure and function. In the present study, we show that the risk allele (A) is associated with increased amygdala volume in healthy individuals (n = 258). This observation reinforces a hypothesis that genetic variation may confer risk to psychosis via alterations in limbic structures. Further study of CACNA1C using intermediate phenotypes for psychosis will determine the mechanisms by which variation in this gene confers risk. Keywords Bipolar · CACNA1C · Amygdala · rs1006737
* T. M. Lancaster [email protected] 1
Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, Wales, UK
2
Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, 70 Park Place, Cardiff CF10 3AT, Wales, UK
3
MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff School of Medicine, Cardiff University, Cardiff, Wales, UK
Introduction Recent genome-wide association studies (GWAS) suggest that variations in L-type calcium channel genes are part of the genetic architecture that confers susceptibility to schizophrenia [1, 2] and bipolar disorder [3–5]. A growing body of evidence suggests that variation within the CACNA1C gene may confer susceptibility to psychosis. Variation within CACNA1C identified via GWAS for bipolar disorder and schizophrenia may increase susceptibility via molecular mechanism as single nucleotide polymorphisms (SNP) (such as rs1006737) may have functional consequences that effect gene expression [6], lead to increases in mRNA expression in cortical tissue [7] and affect L-type voltage-gated calcium channel current density [8]. Recent research also suggests that allelic variation within the CACNA1C gene might be associated with psychopathology via modification of the brain’s function and structure. For example, the rs1006737 risk allele (A) has been associated with altered behaviour [9– 11], brain structure [12–15] as well as brain circuits involving working memory [7, 16, 17], episodic memory [18–21], learning [22, 23] and emotion processing [15, 24, 25]. One common finding implicates the rs1006737 risk allele (A) with alterations in amygdala structure and function [12, 14, 22, 24]. Several studies have demonstrated associations between rs1006737 and amygdala volume [12, 14]; however, one large study failed to find associations between rs1006737 and subcortical structures, but instead found associations between CACNA1C SNPs and brain stem volume [26]. As replication in imaging genetics is of critical importance, we attempt to address any discrepancies within the previous literature that have linked rs1006737 to variation in volumetric brain measures. In the present study, we aim to confirm putative associations/negative findings between rs1006737 and global brain structures. Using a well-validated cortical
13
reconstruction technique [27–29], frequently used in largescale imaging genetic studies [30, 31], we aim to confirm any putative associations between rs1006737 and cortical/ subcortical/brainstem volumes. Based upon prior work, we anticipate linking the rs1006737 risk allele (A) to increased amygdala volume and/or alterations in brain stem volume, as previously observed [12, 14, 26].
Eur Arch Psychiatry Clin Neurosci
Centre (CUBRIC), School of Psychology, Cardiff University. High-resolution three-dimensional T1-weighted images were acquired using a three-dimensional fast spoiled gradient echo sequence (FSPGR) with contiguous sagittal slices of 1 mm thickness (TR 7.9 s, TE 3.0 ms, TI 450 ms, flip angle 20°, FOV 256 × 256 × 176 mm to yield 1 mm isotropic voxel resolution images). Image processing
Methods and materials Sample demographics Two hundred and seventy-two Caucasian individuals consisting of university undergraduates, postgraduates, members of staff and the public were recruited from Cardiff University. All individuals in the sample either were in or had completed higher education or underwent a standardised IQ test to ensure they were of average or above-average intelligence. Individuals were only included in the absence of a personal history of psychiatric disorders, including alcohol and substance abuse. Similarly, psychotropic medication, neurological or chronic medical conditions were also exclusion criteria. The mean age was 24.57 (±6.77) years with 73 male and 185 female. One-way ANOVA demonstrated that age did not differ between rs1006737 genotypes (F2,257 = .139, p = .870). Chi-square test confirmed that rs1006737 genotype frequencies did not differ between genders (χ2 = . 048, p = . 976). The study was approved by the local ethics committee and Cardiff University, and all participants gave written informed consent. Genotyping Genomic DNA was obtained from saliva using Oragene OG-500 saliva kits. Genotyping was performed using custom SNP genotyping arrays from Illumina (Illumina, Inc., San Diego, CA). Quality control was implemented in PLINK [32]. Individuals were excluded for ambiguous sex, cryptic relatedness up to third-degree relatives by identity of descent, genotyping completeness
