Fine Mapping on Chromosome 13q32–34 and Brain Expression Analysis Implicates MYO16 in Schizophrenia

Rodríguez-Murillo, Laura; Xu, Bin; Roos, J.L.; Abecasis, Gonçalo R.; Gogos, Joseph A.; Karayiorgou, Maria

doi:10.1038/npp.2013.293

Cited by 36 publications

(28 citation statements)

References 48 publications

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“…MYO16 is expressed predominantly in hippocampal neurons to regulate synaptic cytoskeleton in neurocognitive developmental disorders (Liu et al, 2015). Previous evidence suggested that common variants within the MYO16 gene contribute to the genetic liability of schizophrenia (Rodriguez-Murillo et al, 2014). It is known that schizophrenia and BP might share some common pathophysiology (Konopaske et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…In particular, large scale genome-wide association (GWA) studies are commonly employed in the last decade to search susceptibility loci for complex human traits (McCarthy et al, 2008). Several GWA studies have identified many loci for the risk of developing BP (The Wellcome Trust Case Control Consortium, 2007; Baum et al, 2008; Ferreira et al, 2008; Sklar et al, 2008; Lee et al, 2011; Kuo et al, 2014; Muhleisen et al, 2014; Xu et al, 2014); however, conclusive and replicated findings are relatively scattered. Some examples are the ANK3 and CACNA1C genes (Ferreira et al, 2008; Muhleisen et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Identification of Susceptible Loci and Enriched Pathways for Bipolar II Disorder Using Genome-Wide Association Studies

Kao

Chen

et al. 2016

IJNPPY

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Background:This study aimed to identify susceptible loci and enriched pathways for bipolar disorder subtype II.Methods:We conducted a genome-wide association scan in discovery samples with 189 bipolar disorder subtype II patients and 1773 controls, and replication samples with 283 bipolar disorder subtype II patients and 500 controls in a Taiwanese Han population using Affymetrix Axiom Genome-Wide CHB1 Array. We performed single-marker and gene-based association analyses, as well as calculated polygeneic risk scores for bipolar disorder subtype II. Pathway enrichment analyses were employed to reveal significant biological pathways.Results:Seven markers were found to be associated with bipolar disorder subtype II in meta-analysis combining both discovery and replication samples (P<5.0×10–6), including markers in or close to MYO16, HSP90AB3P, noncoding gene LOC100507632, and markers in chromosomes 4 and 10. A novel locus, ETF1, was associated with bipolar disorder subtype II (P<6.0×10–3) in gene-based association tests. Results of risk evaluation demonstrated that higher genetic risk scores were able to distinguish bipolar disorder subtype II patients from healthy controls in both discovery (P=3.9×10–4~1.0×10–3) and replication samples (2.8×10–4~1.7×10–3). Genetic variance explained by chip markers for bipolar disorder subtype II was substantial in the discovery (55.1%) and replication (60.5%) samples. Moreover, pathways related to neurodevelopmental function, signal transduction, neuronal system, and cell adhesion molecules were significantly associated with bipolar disorder subtype II.Conclusion:We reported novel susceptible loci for pure bipolar subtype II disorder that is less addressed in the literature. Future studies are needed to confirm the roles of these loci for bipolar disorder subtype II.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of Susceptible Loci and Enriched Pathways for Bipolar II Disorder Using Genome-Wide Association Studies

Kao

Chen

et al. 2016

IJNPPY

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“…In humans, a naturally occurring F145S mutation in the FGF14 gene is implicated in the development of spinocerebellar ataxia 27 (SCA27), a severe motor and cognitive neurodegenerative disorder (Laezza et al, 2009; Brusse et al, 2006; Wozniak et al, 2007; Coebergh et al, 2014), and SNPs in the Fgf14 gene have been associated with depression and schizophrenia (Hsu et al, 2014; Verbeek et al, 2012; Rodriguez-Murillo et al, 2014; Di Re et al, 2017). Recent transcriptomics studies from human post-mortem brains identify FGF14 as a new schizophrenia risk gene, a finding that is corroborated by fgf14 −/− mice which exhibit phenotypes including changes in network activity, decreased gamma frequency, and cognitive impairments that mimic the human disease (Alshammari et al, 2016b).…”

Section: Introductionmentioning

confidence: 99%

PPARgamma agonists rescue increased phosphorylation of FGF14 at S226 in the Tg2576 mouse model of Alzheimer's disease

Hsu

Wildburger

Haidacher

et al. 2017

Experimental Neurology

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Background Cognitive impairment in humans with Alzheimer's disease (AD) and in animal models of Aβ-pathology can be ameliorated by treatments with the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARγ) agonists, such as rosiglitazone (RSG). Previously, we demonstrated that in the Tg2576 animal model of AD, RSG treatment rescued cognitive deficits and reduced aberrant activity of granule neurons in the dentate gyrus (DG), an area critical for memory formation. Methods We used a combination of mass spectrometry, confocal imaging, electrophysiology and split-luciferase assay and in vitro phosphorylation and Ingenuity Pathway Analysis. Results Using an unbiased, quantitative nano-LC-MS/MS screening, we searched for potential molecular targets of the RSG-dependent rescue of DG granule neurons. We found that S226 phosphorylation of fibroblast growth factor 14 (FGF14), an accessory protein of the voltage-gated Na+ (Nav) channels required for neuronal firing, was reduced in Tg2576 mice upon treatment with RSG. Using confocal microscopy, we confirmed that the Tg2576 condition decreased PanNav channels at the AIS of the DG, and that RSG treatment of Tg2576 mice reversed the reduction in PanNav channels. Analysis from previously published data sets identified correlative changes in action potential kinetics in RSG-treated T2576 compared to untreated and wildtype controls. In vitro phosphorylation and mass spectrometry confirmed that the multifunctional kinase GSK–3β, a downstream target of insulin signaling highly implicated in AD, phosphorylated FGF14 at S226. Assembly of the FGF14:Nav1.6 channel complex and functional regulation of Nav1.6-mediated currents by FGF14 was impaired by a phosphosilent S226A mutation. Bioinformatics pathway analysis of mass spectrometry and biochemistry data revealed a highly interconnected network encompassing PPARγ, FGF14, SCN8A (Nav 1.6), and the kinases GSK–3 β, casein kinase 2β, and ERK1/2. Conclusions These results identify FGF14 as a potential PPARγ-sensitive target controlling Aβ-induced dysfunctions of neuronal activity in the DG underlying memory loss in early AD.

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“…In searching for PPI surfaces that could lead to the development of probes and drug-like molecules targeting Nav channels, we have identified FGF14, a member of the iFGF family, as a physiologically relevant accessory protein with implications for brain function and pathology in both animal models and humans (46 -48). FGF14 is an emerging diseaserelevant protein that was initially associated with neurological disorders such as ataxia (49) and, from more recent genomewide association studies (GWAS), as a potential risk factor for schizophrenia (47) and depression (46). Binding of FGF14 to Nav1.1, Nav1.2, and Nav1.6 exerts powerful effects on Na ϩ currents, producing phenotypes that are Nav isoform-dependent and distinct from those associated with other iFGFs (39 -41, 50 -53).…”

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confidence: 99%

Identification of Amino Acid Residues in Fibroblast Growth Factor 14 (FGF14) Required for Structure-Function Interactions with Voltage-gated Sodium Channel Nav1.6

Ali

Singh

Laezza

2016

Journal of Biological Chemistry

111

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The voltage-gated Na ؉ (Nav) channel provides the basis for electrical excitability in the brain. This channel is regulated by a number of accessory proteins including fibroblast growth factor 14 (FGF14), a member of the intracellular FGF family. In addition to forming homodimers, FGF14 binds directly to the Nav1.6 channel C-tail, regulating channel gating and expression, properties that are required for intrinsic excitability in neurons. Seeking amino acid residues with unique roles at the protein-protein interaction interface (PPI) of FGF14⅐Nav1.6, we engineered model-guided mutations of FGF14 and validated their impact on the FGF14⅐Nav1.6 complex and the FGF14: FGF14 dimer formation using a luciferase assay. Divergence was found in the ␤-9 sheet of FGF14 where an alanine (Ala) mutation of Val-160 impaired binding to Nav1.6 but had no effect on FGF14:FGF14 dimer formation. . Altogether these studies indicate that the ␤-9 sheet and the N terminus of FGF14 are well positioned targets for drug development of PPI-based allosteric modulators of Nav channels.Voltage-gated sodium (Nav) 2 channels are responsible for the initiation and propagation of the action potential in excitable cells. Nine isoforms of Nav channels (Nav1.1-Nav1.9) have been characterized functionally, and evidence for a tenth one (Na x ) has been provided (1-12). Nav channels are differentially expressed in organs, with Nav1.1, -1.2, -1.3, and -1.6 found primarily in the central and peripheral nervous systems, Nav1.4 in the adult skeletal muscle, Nav1.5 in cardiac muscle, and Nav1.7, -1.8, and -1.9 primarily in the peripheral nervous system (3,4,7,12,13). With such widespread expression, it is not surprising that numerous diseases have been ascribed to mutations of specific Nav channel isoforms (4, 14). These include the Dravet syndrome and other types of epilepsy (15-17); pain-related syndromes, such as congenital insensitivity to pain (18, 19), primary erythromelalgia (20), and paroxysmal extreme pain disorder (21, 22); and cardiac arrhythmias with congenital long QT syndrome (LQTS) type 3 (23, 24); and Brugada syndrome (25). Furthermore, SNPs and/or copy variants within Nav channel genes have been associated recently with autism (Nav1.2) (26). Nav channels blockers are currently used in combined therapy for bipolar disorder (27, 28), depression (29, 30), and schizophrenia (31), extending the role of Nav channels to virtually all brain disorders both neurological and psychiatric (14,26,32). Their centrality in the pathophysiology of so many disruptive diseases has made Nav channels key pharmacological target sites for antiepileptic, analgesic, antiarrhythmic, and psychiatric drugs (11,14,33,34). Unfortunately, current Nav channel blockers lack specificity, as they are directed against molecular domains conserved across all Nav isoforms. As such, therapies based on these medications can result in severe side effects, such as Stevens-Johnson syndrome, blood dyscrasias, and ataxia (35). Although some success has been achieved in developing more ta...

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Fine Mapping on Chromosome 13q32–34 and Brain Expression Analysis Implicates MYO16 in Schizophrenia

Cited by 36 publications

References 48 publications

Identification of Susceptible Loci and Enriched Pathways for Bipolar II Disorder Using Genome-Wide Association Studies

Identification of Susceptible Loci and Enriched Pathways for Bipolar II Disorder Using Genome-Wide Association Studies

PPARgamma agonists rescue increased phosphorylation of FGF14 at S226 in the Tg2576 mouse model of Alzheimer's disease

Identification of Amino Acid Residues in Fibroblast Growth Factor 14 (FGF14) Required for Structure-Function Interactions with Voltage-gated Sodium Channel Nav1.6

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