The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Melanie P Leussis - One of the best experts on this subject based on the ideXlab platform.
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disruption of the psychiatric risk gene ankyrin 3 enhances microtubule dynamics through gsk3 crmp2 signaling
Translational Psychiatry, 2018Co-Authors: Jacob C Garza, Xiaoli Qi, Klaudio Gjeluci, Himanish Basu, Melanie P Leussis, Surya A ReisAbstract:The ankyrin 3 gene (ANK3) is a well-established risk gene for psychiatric illness, but the mechanisms underlying its pathophysiology remain elusive. We examined the molecular effects of disrupting brain-specific ANK3 isoforms in mouse and neuronal model systems. RNA sequencing of hippocampus from ANK3+/− and ANK3+/+ mice identified altered expression of 282 genes that were enriched for microtubule-related functions. Results were supported by increased expression of microtubule end-binding protein 3 (EB3), an indicator of microtubule dynamics, in ANK3+/− mouse hippocampus. Live-cell imaging of EB3 movement in primary neurons from ANK3+/− mice revealed impaired elongation of microtubules. Using a CRISPR-dCas9-KRAB transcriptional repressor in mouse neuro-2a cells, we determined that repression of brain-specific ANK3 increased EB3 expression, decreased tubulin acetylation, and increased the soluble:polymerized tubulin ratio, indicating enhanced microtubule dynamics. These changes were rescued by inhibition of glycogen synthase kinase 3 (GSK3) with lithium or CHIR99021, a highly selective GSK3 inhibitor. Brain-specific ANK3 repression in neuro-2a cells increased GSK3 activity (reduced inhibitory phosphorylation) and elevated collapsin response mediator protein 2 (CRMP2) phosphorylation, a known GSK3 substrate and microtubule-binding protein. Pharmacological inhibition of CRMP2 activity attenuated the rescue of EB3 expression and tubulin polymerization in ANK3-repressed cells by lithium or CHIR99021, suggesting microtubule instability induced by ANK3 repression is dependent on CRMP2 activity. Taken together, our data indicate that ANK3 functions in neuronal microtubule dynamics through GSK3 and its downstream substrate CRMP2. These findings reveal cellular and molecular mechanisms underlying brain-specific ANK3 disruption that may be related to its role in psychiatric illness.
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disruption of the psychiatric risk gene ankyrin 3 enhances microtubule dynamics through gsk3 crmp2 signaling
bioRxiv, 2018Co-Authors: Jacob C Garza, Xiaoli Qi, Klaudio Gjeluci, Himanish Basu, Surya A Reis, Wenning Zhao, Nicolas H Piguel, Peter Penzes, Melanie P Leussis, Stephen J HaggartyAbstract:The ankyrin 3 gene (ANK3) is a well-established risk gene for psychiatric illness, but the mechanisms underlying its pathophysiology remain elusive. We examined the molecular effects of disrupting brain-specific ANK3 isoforms in mouse and neuronal model systems. RNA sequencing of hippocampus from ANK3+/- and ANK3+/+ mice identified altered expression of 282 genes that were enriched for microtubule-related functions. Results were supported by increased expression of microtubule end-binding protein 3 (EB3), an indicator of microtubule dynamics, in ANK3+/- mouse hippocampus. Live-cell imaging of EB3 movement in primary neurons from ANK3+/- mice revealed stunted polymerization at microtubule plus-ends. Using a CRISPR-dCas9-KRAB transcriptional repressor in mouse neuro-2a cells, we determined that repression of brain-specific ANK3 increased EB3 expression, decreased tubulin acetylation, and increased the soluble:polymerized tubulin ratio, indicating enhanced microtubule dynamics. These changes were rescued by inhibition of glycogen synthase kinase 3 (GSK3) with lithium or CHIR99021, a highly selective GSK3 inhibitor. Brain-specific ANK3 repression in neuro-2a cells increased GSK3 activity (reduced inhibitory phosphorylation) and elevated collapsin response mediator protein 2 (CRMP2) phosphorylation, a known GSK3 substrate and microtubule-binding protein. Pharmacological inhibition of CRMP2 activity attenuated the rescue of EB3 expression and tubulin polymerization in ANK3 repressed cells by lithium or CHIR99021, suggesting microtubule instability induced by ANK3 repression is dependent on CRMP2 activity. Taken together, our data indicate that ANK3 functions in neuronal microtubule dynamics through GSK3 and its downstream substrate CRMP2. These findings reveal cellular and molecular mechanisms underlying brain-specific ANK3 disruption that may be related to its role in psychiatric illness.
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lithium reverses behavioral and axonal transport related changes associated with ANK3 bipolar disorder gene disruption
European Neuropsychopharmacology, 2017Co-Authors: Michael G Gottschalk, Klaudio Gjeluci, Melanie P Leussis, Tillmann Ruland, Tracey L PetryshenAbstract:Ankyrin 3 (ANK3) has been implicated as a genetic risk factor for bipolar disorder (BD), however the resulting pathophysiological and treatment implications remain elusive. In a preclinical systems biological approach, we aimed to characterize the behavioral and proteomic effects of ANK3 haploinsufficiency and chronic mood-stabilizer treatment in mice. Psychiatric-related behavior was evaluated with the novelty-suppressed feeding (NSF) paradigm, elevated plus maze (EPM) and a passive avoidance task (PAT). Tandem mass spectrometry (MSE) was employed for hippocampal proteome profiling. A functional enrichment approach based on protein-protein interactions (PPIs) was performed to outline which biological processes in the hippocampus were affected by ANK3 haploinsufficiency and lithium treatment. Proteomic abundance changes as detected by MSE or highlighted by PPI network modelling were followed up by targeted selected reaction monitoring (SRM). Increased psychiatric-related behavior in ANK3+/- mice was ameliorated by lithium in all assessments (NSF, EPM, PAT). MSE followed by modular PPI clustering and functional annotation enrichment pointed towards kinesin-related axonal transport and glutamate signaling as mediators of ANK3+/- pathophysiology and lithium treatment. SRM validated this hypothesis and further confirmed abundance changes of ANK3 interaction partners. We propose that psychiatric-related behavior in ANK3+/- mice is connected to a disturbance of the kinesin cargo system, resulting in a dysfunction of neuronal ion channel and glutamate receptor transport. Lithium reverses this molecular signature, suggesting the promotion of anterograde kinesin transport as part of its mechanism of action in ameliorating ANK3-related psychiatric-related behavior.
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the ankyrin 3 gene is associated with posttraumatic stress disorder and externalizing comorbidity
Psychoneuroendocrinology, 2013Co-Authors: Mark W Logue, Melanie P Leussis, Nadia Solovieff, Erika J Wolf, Efthymia Melista, Clinton T BaldwinAbstract:Summary Background The ankyrin 3 gene ( ANK3 ) produces the ankyrin G protein that plays an integral role in regulating neuronal activity. Previous studies have linked ANK3 to bipolar disorder and schizophrenia. A recent mouse study suggests that ANK3 may regulate behavioral disinhibition and stress reactivity. This led us to hypothesize that ANK3 might also be associated with stress-related psychopathology such as posttraumatic stress disorder (PTSD), as well as disorders of the externalizing spectrum such as antisocial personality disorder and substance-related disorders that are etiologically linked to impulsivity and temperamental disinhibition. Methods We examined the possibility of association between ANK3 SNPs and both PTSD and externalizing (defined by a factor score representing a composite of adult antisociality and substance abuse) in a cohort of white non-Hispanic combat veterans and their intimate partners ( n = 554). Initially, we focused on rs9804190—a SNP previously reported to be associated with bipolar disorder, schizophrenia, and ankyrin G expression in brain. Then we examined 358 additional ANK3 SNPs utilizing a multiple-testing correction. Results rs9804190 was associated with both externalizing and PTSD ( p = 0.028 and p = 0.042 respectively). Analysis of other ANK3 SNPs identified several that were more strongly associated with either trait. The most significant association with externalizing was observed at rs1049862 ( p = 0.00040, p corrected = 0.60). The most significant association with PTSD ( p = 0.00060, p corrected = 0.045) was found with three SNPs in complete linkage disequilibrium (LD)—rs28932171, rs11599164, and rs17208576. Conclusions These findings support a role of ANK3 in risk of stress-related and externalizing disorders, beyond its previous associations with bipolar disorder and schizophrenia.
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the ANK3 bipolar disorder gene regulates psychiatric related behaviors that are modulated by lithium and stress
Biological Psychiatry, 2013Co-Authors: Melanie P Leussis, Erin Berryscott, Mai Saito, Hueihan Jhuang, Georgius De Haan, Ozan AlkanAbstract:Background Ankyrin 3 ( ANK3 ) has been strongly implicated as a risk gene for bipolar disorder (BD) by recent genome-wide association studies of patient populations. However, the genetic variants of ANK3 contributing to BD risk and their pathological function are unknown. Methods To gain insight into the potential disease relevance of ANK3 , we examined the function of mouse ANK3 in the regulation of psychiatric-related behaviors using genetic, neurobiological, pharmacological, and gene-environment interaction (G×E) approaches. ANK3 expression was reduced in mouse brain either by viral-mediated RNA interference or through disruption of brain-specific ANK3 in a heterozygous knockout mouse. Results RNA interference of ANK3 in hippocampus dentate gyrus induced a highly specific and consistent phenotype marked by decreased anxiety-related behaviors and increased activity during the light phase, which were attenuated by chronic treatment with the mood stabilizer lithium. Similar behavioral alterations of reduced anxiety and increased motivation for reward were also exhibited by ANK3+/– heterozygous mice compared with wild-type ANK3+/+ mice. Remarkably, the behavioral traits of ANK3 +/– mice transitioned to depression-related features after chronic stress, a trigger of mood episodes in BD. ANK3 +/– mice also exhibited elevated serum corticosterone, suggesting that reduced ANK3 expression is associated with elevated stress reactivity. Conclusions This study defines a new role for ANK3 in the regulation of psychiatric-related behaviors and stress reactivity that lends support for its involvement in BD and establishes a general framework for determining the disease relevance of genes implicated by patient genome-wide association studies.
Vann Bennett - One of the best experts on this subject based on the ideXlab platform.
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ankyrin g regulates forebrain connectivity and network synchronization via interaction with gabarap
Molecular Psychiatry, 2020Co-Authors: Andrew D L Nelson, Vann Bennett, Rene N Caballerofloran, J Rodriguez C Diaz, Jacob M Hull, Yukun Yuan, Keyu Chen, Kathryn Walder, Luis F LopezsantiagoAbstract:GABAergic circuits are critical for the synchronization and higher order function of brain networks. Defects in this circuitry are linked to neuropsychiatric diseases, including bipolar disorder, schizophrenia, and autism. Work in cultured neurons has shown that ankyrin-G plays a key role in the regulation of GABAergic synapses on the axon initial segment and somatodendritic domain of pyramidal neurons, where it interacts directly with the GABAA receptor-associated protein (GABARAP) to stabilize cell surface GABAA receptors. Here, we generated a knock-in mouse model expressing a mutation that abolishes the ankyrin-G/GABARAP interaction (ANK3 W1989R) to understand how ankyrin-G and GABARAP regulate GABAergic circuitry in vivo. We found that ANK3 W1989R mice exhibit a striking reduction in forebrain GABAergic synapses resulting in pyramidal cell hyperexcitability and disruptions in network synchronization. In addition, we identified changes in pyramidal cell dendritic spines and axon initial segments consistent with compensation for hyperexcitability. Finally, we identified the ANK3 W1989R variant in a family with bipolar disorder, suggesting a potential role of this variant in disease. Our results highlight the importance of ankyrin-G in regulating forebrain circuitry and provide novel insights into how ANK3 loss-of-function variants may contribute to human disease.
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giant ankyrin g a critical innovation in vertebrate evolution of fast and integrated neuronal signaling
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Paul M Jenkins, Namsoo Kim, Steven L Jones, Wei Chou Tseng, Tatyana Svitkina, Henry H Yin, Vann BennettAbstract:Axon initial segments (AISs) and nodes of Ranvier are sites of clustering of voltage-gated sodium channels (VGSCs) in nervous systems of jawed vertebrates that facilitate fast long-distance electrical signaling. We demonstrate that proximal axonal polarity as well as assembly of the AIS and normal morphogenesis of nodes of Ranvier all require a heretofore uncharacterized alternatively spliced giant exon of ankyrin-G (AnkG). This exon has sequence similarity to I-connectin/Titin and was acquired after the first round of whole-genome duplication by the ancestral ANK2/ANK3 gene in early vertebrates before development of myelin. The giant exon resulted in a new nervous system-specific 480-kDa polypeptide combining previously known features of ANK repeats and β-spectrin–binding activity with a fibrous domain nearly 150 nm in length. We elucidate previously undescribed functions for giant AnkG, including recruitment of β4 spectrin to the AIS that likely is regulated by phosphorylation, and demonstrate that 480-kDa AnkG is a major component of the AIS membrane “undercoat’ imaged by platinum replica electron microscopy. Surprisingly, giant AnkG-knockout neurons completely lacking known AIS components still retain distal axonal polarity and generate action potentials (APs), although with abnormal frequency. Giant AnkG-deficient mice live to weaning and provide a rationale for survival of humans with severe cognitive dysfunction bearing a truncating mutation in the giant exon. The giant exon of AnkG is required for assembly of the AIS and nodes of Ranvier and was a transformative innovation in evolution of the vertebrate nervous system that now is a potential target in neurodevelopmental disorders.
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cysteine 70 of ankyrin g is s palmitoylated and is required for function of ankyrin g in membrane domain assembly
Journal of Biological Chemistry, 2012Co-Authors: Paul M Jenkins, Vann BennettAbstract:Ankyrin-G (AnkG) coordinates protein composition of diverse membrane domains, including epithelial lateral membranes and neuronal axon initial segments. However, how AnkG itself localizes to these membrane domains is not understood. We report that AnkG remains on the plasma membrane in Madin-Darby canine kidney (MDCK) cells grown in low calcium, although these cells lack apical-basal polarity and exhibit loss of plasma membrane association of AnkG partners, E-cadherin and β2-spectrin. We subsequently demonstrate using mutagenesis and mass spectrometry that AnkG is S-palmitoylated exclusively at Cys-70, which is located in a loop of the first ankyrin repeat and is conserved in the vertebrate ankyrin family. Moreover, C70A mutation abolishes membrane association of 190-kDa AnkG in MDCK cells grown in low calcium. C70A 190-kDa AnkG fails to restore biogenesis of epithelial lateral membranes in MDCK cells depleted of endogenous AnkG. In addition, C70A 270-kDa AnkG fails to cluster at the axon initial segment of AnkG-depleted cultured hippocampal neurons and fails to recruit neurofascin as well as voltage-gated sodium channels. These effects of C70A mutation combined with evidence for its S-palmitoylation are consistent with a requirement of palmitoylation for targeting and function of AnkG in membrane domain biogenesis at epithelial lateral membranes and neuronal axon initial segments.
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ANK3 dependent svz niche assembly is required for the continued production of new neurons
Neuron, 2011Co-Authors: Patricia Paezgonzalez, Vann Bennett, Khadar Abdi, Dominic Luciano, Yan Liu, Mario Sorianonavarro, Emma L Rawlins, Jose Manuel Garciaverdugo, Chay T KuoAbstract:The rodent subventricular/subependymal zone (SVZ/SEZ) houses neural stem cells (NSCs) that generate olfactory bulb interneurons. It is unclear how the SVZ environment sustains neuronal production into adulthood. We discovered that the adapter molecule Ankyrin-3 (ANK3) is specifically upregulated in ventricular progenitors destined to become ependymal cells, but not in NSCs, and is required for SVZ niche assembly through progenitor lateral adhesion. Furthermore, we found that ANK3 expression is controlled by Foxj1, a transcriptional regulator of multicilia formation, and genetic deletion of this pathway led to complete loss of SVZ niche structure. Interestingly, radial glia continued to transition into postnatal NSCs without this niche. However, inducible deletion of Foxj1-ANK3 from mature SVZ ependyma resulted in dramatic depletion of neurogenesis. Targeting a pathway regulating ependymal organization/assembly and showing its requirement for new neuron production, our results have important implications for environmental control of adult neurogenesis and harvesting NSCs for replacement therapy.
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chromosomal localization of the ankyring gene ANK3 ANK3 to human 10q21 and mouse 10
Genomics, 1995Co-Authors: David Kapfhamer, Vann Bennett, Diane E Miller, Stephen Lambert, Thomas W Glover, Margit BurmeisterAbstract:The ankyrin3 gene encodes a novel form of ankyrin, AnkyrinG, expressed in multiple tissues but characteristically present at the axonal initial segment and nodes of Ranvier of neurons in the central and peripheral nervous systems. We have localized ANK3 to human Chromosome 10q21 by fluorescence in situ hybridization. The position of the murine homologue was determined by intersubspecific backcross analysis, mapping ANK3 to mouse Chromosome 10, between microsatellite marker D10Mit31 and the Bcr gene. This interval is known to comprise a region syntenic to human 10q. The localization of ANK3 is a preliminary step in identifying neurological disorders potentially associated with the gene.
Sophia Frangou - One of the best experts on this subject based on the ideXlab platform.
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epa 1035 the ANK3 risk gene for bipolar disorder modulates brain regional activity during a working memory task
European Psychiatry, 2014Co-Authors: G Delvecchio, Danai Dima, Sophia FrangouAbstract:Introduction Genome-wide association studies indicate that two single-nucleotide polymorphisms (SNPs) in the ANK3 gene, rs10994336 and rs9804190, increase the risk for bipolar disorder (BD). The ANK3 gene encodes the ankyrin-G protein and influences neuronal firing by changing sodium channel functions, thus impacting on brain regional activation. Objectives We examined the effect of the two ANK3 SNPs on brain activation during a working memory task. Aims The aim of our study is to investigate whether the genetic risk associated with the two SNPs is coupled with abnormal activation in the working memory network. Methods We used functional magnetic resonance imaging data to investigate the impact of ANK3 rs10994336 and ANK3 rs9804190, on brain activity during a 3-back working memory task in 41 BD patients, 25 unaffected first-degree relatives and 46 healthy individuals (HI). Results For the ANK3 rs10994336 (risk allele T), significant diagnosis x genotype interactions were observed in the left prefrontal (BA10/BA11), anterior cingulate (BA32/BA25) and posterior cingulate (BA31) cortex. These regions, risk allele carriers who were either patients or unaffected relatives showed increased activation compared to healthy controls carrying the risk allele. For the ANK3 rs9804190 (risk allele C) a significant effect of genotype was found in the right anterior cingulate (BA24), where subjects carrying the risk allele showed decreased activation compared to subjects carrying the protective allele. Conclusions Our data demonstrate that the effect of ANK3 rs10994336 and ANK3 rs9804190 on the brain converges on key regions involved in working memory processing.
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independent modulation of engagement and connectivity of the facial network during affect processing by cacna1c and ANK3 risk genes for bipolar disorder
JAMA Psychiatry, 2013Co-Authors: Danai Dima, Evangelos Vassos, David A Collier, Jigar Jogia, Katherine E Burdick, Sophia FrangouAbstract:IMPORTANCE Genome-wide association studies (GWASs) indicate that single-nucleotide polymorphisms in the CACNA1C and ANK3 genes increase the risk for bipolar disorder (BD). The genes influence neuronal firing by modulating calcium and sodium channel functions, respectively. Both genes modulate ?-aminobutyric acid-transmitting interneuron function and can thus affect brain regional activation and interregional connectivity. OBJECTIVE To determine whether the genetic risk for BD associated with 2 GWAS-supported risk single-nucleotide polymorphisms at CACNA1C rs1006737 and ANK3 rs10994336 is mediated through changes in regional activation and interregional connectivity of the facial affect-processing network. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional functional magnetic resonance imaging study at a research institute of 41 euthymic patients with BD and 46 healthy participants, all of British white descent. MAIN OUTCOMES AND MEASURES Blood oxygen level-dependent signal and effective connectivity measures during the facial affect-processing task. RESULTS In healthy carriers, both genetic risk variants were independently associated with increased regional engagement throughout the facial affect-processing network and increased effective connectivity between the visual and ventral prefrontal cortical regions. In contrast, BD carriers of either genetic risk variant exhibited pronounced reduction in ventral prefrontal cortical activation and visual-prefrontal effective connectivity. CONCLUSIONS AND RELEVANCE Our data demonstrate that the effect of CACNA1C rs1006737 and ANK3 rs10994336 (or genetic variants in linkage disequilibrium) on the brain converges on the neural circuitry involved in affect processing and provides a mechanism linking BD to genome-wide genetic risk variants.
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the cognitive impact of the ANK3 risk variant for bipolar disorder initial evidence of selectivity to signal detection during sustained attention
PLOS ONE, 2011Co-Authors: G Ruberto, Evangelos Vassos, Cathryn M Lewis, Roberto Tatarelli, Paolo Girardi, David A Collier, Sophia FrangouAbstract:Background Abnormalities in cognition have been reported in patients with Bipolar Disorder (BD) and their first degree relatives, suggesting that susceptibility genes for BD may impact on cognitive processes. Recent genome-wide genetic studies have reported a strong association with BD in a single nucleotide polymorphism (SNP) (rs10994336) within ANK3, which codes for Ankyrin 3. This protein is involved in facilitating the propagation of action potentials by regulating the assembly of sodium gated ion channels. Since ANK3 influences the efficiency of transmission of neuronal impulses, allelic variation in this gene may have widespread cognitive effects. Preclinical data suggest that this may principally apply to sequential signal detection, a core process of sustained attention.
Zhong Sheng Sun - One of the best experts on this subject based on the ideXlab platform.
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mutations of ANK3 identified by exome sequencing are associated with autism susceptibility
Human Mutation, 2012Co-Authors: Tao Jiang, Yonghui Jiang, Qi Liu, Wanshi Cai, Tao Cai, Mei Zhao, Zhong Sheng SunAbstract:Autism spectrum disorders (ASDs) are common neurodevelopmental disorders with a strong genetic etiology. However, due to the extreme genetic heterogeneity of ASDs, traditional approaches for gene discovery are challenging. Next-generation sequencing technologies offer an opportunity to accelerate the identification of the genetic causes of ASDs. Here, we report the results of whole-exome sequence in a cohort of 20 ASD patients. By extensive bioinformatic analysis, we identified novel mutations in seven genes that are implicated in synaptic function and neurodevelopment. After sequencing an additional 47 ASD samples, we identified three different missense mutations in ANK3 in four unrelated ASD patients, one of which, c.4705T>G (p.S1569A), is a de novo mutation. Given the fact that ANK3 has been shown to strongly associate with schizophrenia and bipolar disorder, our findings support an association between ANK3 mutations and ASD susceptibility and imply a shared molecular pathophysiology between ASDs and other neuropsychiatric disorders. Hum Mutat 33:16351638, 2012. (c) 2012 Wiley Periodicals, Inc.
Timothy P Hughes - One of the best experts on this subject based on the ideXlab platform.
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elevated expression of a minor isoform of ANK3 is a risk factor for bipolar disorder
Translational Psychiatry, 2018Co-Authors: Timothy P Hughes, Ida E Sonderby, Tatiana Polushina, Lars Johan Axel Hansson, Asbjorn Holmgren, Lavinia AthanasiuAbstract:Ankyrin-3 (ANK3) is one of the few genes that have been consistently identified as associated with bipolar disorder by multiple genome-wide association studies. However, the exact molecular basis of the association remains unknown. A rare loss-of-function splice-site SNP (rs41283526*G) in a minor isoform of ANK3 (incorporating exon ENSE00001786716) was recently identified as protective of bipolar disorder and schizophrenia. This suggests that an elevated expression of this isoform may be involved in the etiology of the disorders. In this study, we used novel approaches and data sets to test this hypothesis. First, we strengthen the statistical evidence supporting the allelic association by replicating the protective effect of the minor allele of rs41283526 in three additional large independent samples (meta-analysis p-values: 6.8E–05 for bipolar disorder and 8.2E–04 for schizophrenia). Second, we confirm the hypothesis that both bipolar and schizophrenia patients have a significantly higher expression of this isoform than controls (p-values: 3.3E–05 for schizophrenia and 9.8E–04 for bipolar type I). Third, we determine the transcription start site for this minor isoform by Pacific Biosciences sequencing of full-length cDNA and show that it is primarily expressed in the corpus callosum. Finally, we combine genotype and expression data from a large Norwegian sample of psychiatric patients and controls, and show that the risk alleles in ANK3 identified by bipolar disorder GWAS are located near the transcription start site of this isoform and are significantly associated with its elevated expression. Together, these results point to the likely molecular mechanism underlying ANK3´s association with bipolar disorder.
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a loss of function variant in a minor isoform of ANK3 protects against bipolar disorder and schizophrenia
Biological Psychiatry, 2016Co-Authors: Timothy P Hughes, Martin Tesli, Lavinia Athanasiu, Lars Hansson, Ida E Sonderby, Verena Zuber, Jie SongAbstract:Abstract Background Ankyrin-3 ( ANK3 ) was one of the first genes to reach significance in a bipolar disorder genome-wide association study. Many subsequent association studies confirmed this finding and implicated this gene in schizophrenia. However, the exact nature of the role of ANK3 in the pathophysiology remains elusive. In particular, the specific isoforms involved and the nature of the imbalance are unknown. Methods We genotyped a Norwegian sample of 402 patients with bipolar disorder, 293 patients with schizophrenia, and 330 healthy control subjects genome-wide with the Illumina Human Exome BeadChip. We performed allelic association tests at the genome-wide and gene levels and found a significantly associated single nucleotide polymorphism in a splice site of ANK3 . We replicated this finding in two other samples and studied the functional effect of this single nucleotide polymorphism by performing quantitative polymerase chain reaction on the affected exon junction in complementary DNA from blood total RNA. Results The splice site single nucleotide polymorphism (rs41283526) is located in an alternatively spliced exon of ANK3 and has a strong and significant protective effect against bipolar disorder (odds ratio=.31) and schizophrenia (odds ratio=.21). The minor allele of rs41283526 is a loss-of-function variant that disables the correct splicing of the transcript. Data from the BrainSpan human developmental transcriptome show that the exon bearing this variant is expressed only in a minor isoform of ANK3 , the transcription of which is initiated in early adolescence. Conclusions Our results suggest that an elevated expression of this transcript starting in adolescence may be an important factor in the pathophysiology of schizophrenia and bipolar disorder.
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ANK3 gene expression in bipolar disorder and schizophrenia
British Journal of Psychiatry, 2014Co-Authors: Katrine V Wirgenes, Martin Tesli, Elin Inderhaug, Lavinia Athanasiu, Ingrid Agartz, Ingrid Melle, Timothy P Hughes, Ole A Andreassen, Srdjan DjurovicAbstract:ANK3 gene variants have consistently been associated with bipolar spectrum disorder and schizophrenia spectrum disorder. However, the relevance of its encoded protein, ankyrin-3, in these disorders remains elusive. Here, we show that ANK3 gene expression in blood is significantly increased in bipolar disorder and schizophrenia compared with healthy controls. Additionally, we identified potential cis-acting expression quantitative trait loci located close to the transcription start site of one of the isoforms of the gene. These findings suggest that ANK3 mRNA is an interesting marker for further investigation of the underlying mechanisms in psychotic disorders.