Analysis of <i>ANK3</i> and <i>CACNA1C</i> variants identified in bipolar disorder whole genome sequence data

Fiorentino, Alessia; O’Brien, Niamh; Locke, Devin P.; McQuillin, Andrew; Jarram, A; Anjorin, Adebayo; Kandaswamy, Radhika; Curtis, David; Blizard, Robert; Gurling, Hugh

doi:10.1111/bdi.12203

Cited by 49 publications

(50 citation statements)

References 71 publications

(90 reference statements)

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“…Although carefully screened, the control group was selected from the general population, thus some subjects may have a disposition for BPD not yet revealed. Of note, investigations on 3 of the SNPs analyzed, rs1016388 [56], rs2337980 [44], and rs6494223 [12,45], respectively, were previously reported on larger GWAS analyses. The cited GWAS reported no significant associations on the sample analyzed; thus, the data we obtained should be carefully considered.…”

Section: Discussionmentioning

confidence: 99%

Genes Involved in Neurodevelopment, Neuroplasticity, and Bipolar Disorder: CACNA1C, CHRNA1, and MAPK1

Calabrò¹,

Mandelli²,

Crisafulli³

et al. 2016

Neuropsychobiology

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Background: Bipolar disorder (BPD) is a common and severe mental disorder. The involvement of genetic factors in the pathophysiology of BPD is well known. In the present study, we tested the association of several single-nucleotide polymorphisms (SNPs) within 3 strong candidate genes (CACNA1C, CHRNA7, and MAPK1) with BPD. These genes are involved in monoamine-related pathways, as well as in dendrite development, neuronal survival, synaptic plasticity, and memory/learning. Methods: One hundred and thirty-two subjects diagnosed with BPD and 326 healthy controls of Korean ancestry were genotyped for 40 SNPs within CACNA1C, CHRNA17, and MAPK1. Distribution of alleles and block of haplotypes within each gene were compared in cases and controls. Interactions between variants in different loci were also tested. Results: Significant differences in the distribution of alleles between the cases and controls were detected for rs1016388 within CACNA1C, rs1514250, rs2337980, rs6494223, rs3826029 and rs4779565 within CHRNA7, and rs8136867 within MAPK1. Haplotype analyses also confirmed an involvement of variations within these genes in BPD. Finally, exploratory epistatic analyses demonstrated potential interactive effects, especially regarding variations in CACNA1C and CHRNA7. Limitations: Limited sample size and risk of false-positive findings. Discussion: Our data suggest a possible role of these 3 genes in BPD. Alterations of 1 or more common brain pathways (e.g., neurodevelopment and neuroplasticity, calcium signaling) may explain the obtained results.

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Section: Discussionmentioning

confidence: 99%

Genes Involved in Neurodevelopment, Neuroplasticity, and Bipolar Disorder: CACNA1C, CHRNA1, and MAPK1

Calabrò¹,

Mandelli²,

Crisafulli³

et al. 2016

Neuropsychobiology

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“…It is possible that one or a few rare variants of large effect dramatically increase disease risk, resulting in an inheritance model resembling monogenic inheritance in a given family. However, four exomesequencing and whole-genome sequencing (WGS) studies of BD pedigrees have detected few, if any, plausible variants of large effect (6)(7)(8)(9). An alternative oligogenic model posits that different combinations of several uncommon or rare variants of moderate effect cluster in affected individuals and collectively cause disease.…”

mentioning

confidence: 99%

Rare variants in neuronal excitability genes influence risk for bipolar disorder

Ament

Szelinger

Glusman

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

162

135

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We sequenced the genomes of 200 individuals from 41 families multiply affected with bipolar disorder (BD) to identify contributions of rare variants to genetic risk. We initially focused on 3,087 candidate genes with known synaptic functions or prior evidence from genomewide association studies. BD pedigrees had an increased burden of rare variants in genes encoding neuronal ion channels, including subunits of GABA A receptors and voltage-gated calcium channels. Four uncommon coding and regulatory variants also showed significant association, including a missense variant in GABRA6. Targeted sequencing of 26 of these candidate genes in an additional 3,014 cases and 1,717 controls confirmed rare variant associations in ANK3, CACNA1B, CACNA1C, CACNA1D, CACNG2, CAMK2A, and NGF. Variants in promoters and 5′ and 3′ UTRs contributed more strongly than coding variants to risk for BD, both in pedigrees and in the case-control cohort. The genes and pathways identified in this study regulate diverse aspects of neuronal excitability. We conclude that rare variants in neuronal excitability genes contribute to risk for BD. by episodes of mania and depression (1). Episodes of mania are marked by elevated or alternatively irritable mood, grandiosity, racing thoughts, rapid speech, diminished need for sleep, and risk-taking behavior. Depression includes sadness, low energy and motivation, decreased ability to experience pleasure, insomnia, and appetite changes. Psychosis with hallucinations and delusions can occur in either state. BD affects 1-2% of the US population, and if untreated, up to 15% of patients die from suicide. Twin and family studies suggest that heritable causes explain 60-80% of lifetime risk for BD (2), with an approximate eightfold relative risk in the siblings of BD probands (3). Several common genetic markers have shown significant and replicable associations in genome-wide association studies (GWASs), including a region near a voltage-gated calcium channel, CACNA1C, and another near a synaptic scaffolding gene, ANK3 (4). Additive effects of common loci detectable on commercially available genomic arrays may be used to predict about 25% of the risk for BD (5), but typically the function and exact location of the causative variants linked to these loci is unknown.Rare variants may explain additional risk for BD. It is possible that one or a few rare variants of large effect dramatically increase disease risk, resulting in an inheritance model resembling monogenic inheritance in a given family. However, four exomesequencing and whole-genome sequencing (WGS) studies of BD pedigrees have detected few, if any, plausible variants of large effect (6-9). An alternative oligogenic model posits that different combinations of several uncommon or rare variants of moderate effect cluster in affected individuals and collectively cause disease.To test the hypothesis that rare variants contribute to risk for BD, we sequenced the genomes of 200 individuals from 41 multiply affected BD pedigrees of European ancestry. We seque...

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“…Based on the phenotypic observations of BD, in which there is full recovery between two states, it was suggested that the etiological base-pair changes could be affecting gene expression and mRNA translation rather than causing structural changes in proteins. Potential novel variants identified further need replication and validation in independent samples (27).…”

Section: Whole Genome Sequencingmentioning

confidence: 99%

Update on Research into the Genetics and Pharmacogenetics of Bipolar Disorder

Schulze¹,

Özkan²

2017

Dusunen Adam

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Analysis of ANK3 and CACNA1C variants identified in bipolar disorder whole genome sequence data

Cited by 49 publications

References 71 publications

Genes Involved in Neurodevelopment, Neuroplasticity, and Bipolar Disorder: CACNA1C, CHRNA1, and MAPK1

Genes Involved in Neurodevelopment, Neuroplasticity, and Bipolar Disorder: CACNA1C, CHRNA1, and MAPK1

Rare variants in neuronal excitability genes influence risk for bipolar disorder

Update on Research into the Genetics and Pharmacogenetics of Bipolar Disorder

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