WNT/β-Catenin Pathway and Epigenetic Mechanisms Regulate the Pitt-Hopkins Syndrome and Schizophrenia Risk Gene TCF4

Hennig, Krista M.; Zhao, Wen-Ning; Sheridan, Steven D.; Fu, Ting; Erdin, Serkan; Stortchevoi, Alexei; Lucente, Diane; Cody, Jannine D.; Sweetser, David A.; Gusella, James F.; Talkowski, Michael E.; Haggarty, Stephen J.

doi:10.1159/000475666

Cited by 20 publications

(23 citation statements)

References 79 publications

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“…In fact, the strongest locus identified in our secondary GxS interaction analyses for SCZ (using the PGC dataset) (rs13270586; p=1.55×10 −7 ) was near C8orf4 (aka TCIM), which functions as a positive regulator of the Wnt/ß-catenin signaling pathway that has a central role in fundamental neuronal processes-including synaptogenesis, axon guidance, and dendrite development (59)-and a pathway previously implicated in SCZ, BIP, and MDD (60)(61)(62)(63).…”

Section: Discussionmentioning

confidence: 92%

Sex-Dependent Shared and Non-Shared Genetic Architecture Across Mood and Psychotic Disorders

Blokland¹,

Grove²,

Chen³

et al. 2020

Preprint

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BACKGROUND: Sex differences in the incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across these disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (GxS) interaction analysis of risk for these disorders, using data from 85,735 cases (33,403 SCZ, 19,924 BIP, 32,408 MDD) and 109,946 controls from the Psychiatric Genomics Consortium (PGC) and iPSYCH. RESULTS: Across disorders, genome-wide significant SNP-by-sex interaction was detected for a locus encompassing NKAIN2 gene (rs117780815; p=3.2x10-8), that interacts with sodium/potassium-transporting ATPase enzymes important for neuronal excitability. Three additional loci showed evidence (p<1x10-6) for cross-disorder GxS interaction (rs7302529, p=1.6x10-7; rs73033497, p=8.8x10-7; rs7914279, p=6.4x10-7) with various potential functions. Gene-based analyses identified GxS interaction across disorders (p=8.97x10-7) with transcriptional inhibitor SLTM. Most significant in SCZ was a locus in the MOCOS gene (rs11665282; p=1.5x10-7), implicating vascular endothelial cells. Secondary analysis of the SCZ PGC dataset detected a noteworthy interaction (rs13265509; p=1.1x10-7) in a locus containing IDO2, a kynurenine pathway enzyme with an immunoregulatory function previously implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant GxS of genes regulating vascular endothelial growth factor (VEGF) receptor signaling in MDD (pFDR<0.05). CONCLUSIONS: In the largest genome-wide GxS analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development, immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway enrichment levels.

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Section: Discussionmentioning

confidence: 92%

Sex-Dependent Shared and Non-Shared Genetic Architecture Across Mood and Psychotic Disorders

Blokland¹,

Grove²,

Chen³

et al. 2020

Preprint

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“…The impaired learning phenotype could be explained by neurodevelopmental issues resulting from lowered levels of Da protein during development or, alternatively, by the contribution of cells outside the mushroom body. Da mammalian orthologue TCF4 is also associated with learning and memory, as when TCF4 is downregulated in the mouse hippocampus, pathways associated with neuronal plasticity are dysregulated (Kennedy et al, 2016), and silencing of TCF4 in human pluripotent stem cell-derived neurons results in downregulated signalling pathways that are important for learning and memory (Hennig et al, 2017). In TCF4 conditional knockout mice, the neurons in the cortex and hippocampus have reduced numbers of dendritic spines, which also suggests that synaptic plasticity is altered (Crux et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…In multiple PTHS mouse models, spatial learning is defective probably as a result of hippocampal N-methyl-D-aspartate receptor (NMDA) hyperfunction (Thaxton et al, 2018). Furthermore, many genes that code for synaptic proteins and have been linked to autism, intellectual disability, or psychiatric diseases, are direct targets of TCF4 (Forrest et al, 2018;Hennig et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…We also found that Da is a direct regulator of dlg1, as in adult Drosophila heads, Da binds to multiple areas in the dlg1 gene and dlg1 expression is upregulated when da is overexpressed. The gene coding for discs large MAGUK scaffold protein 2 [DLG2; also called postsynaptic density protein 93 (PSD-93)], which is a homologue of Drosophila dlg1, is a direct target of TCF4 (Hennig et al, 2017), which indicates that Da and TCF4 share at least some common mechanisms in regulating learning and memory.…”

Section: Discussionmentioning

confidence: 99%

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Daughterless, the Drosophila orthologue of TCF4, is required for associative learning and maintenance of the synaptic proteome

Tamberg

Jaago

Saalik

et al. 2020

Disease Models &Amp; Mechanisms

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Mammalian transcription factor 4 (TCF4) has been linked to schizophrenia and intellectual disabilities, such as Pitt–Hopkins syndrome (PTHS). Here, we show that similarly to mammalian TCF4, fruit fly orthologue Daughterless (Da) is expressed widely in the Drosophila brain. Furthermore, silencing of da, using several central nervous system-specific Gal4 driver lines, impairs appetitive associative learning of the larvae and leads to decreased levels of the synaptic proteins Synapsin (Syn) and Discs large 1 (Dlg1), suggesting the involvement of Da in memory formation. Here, we demonstrate that Syn and dlg1 are direct target genes of Da in adult Drosophila heads, as Da binds to the regulatory regions of these genes and the modulation of Da levels alter the levels of Syn and dlg1 mRNA. Silencing of da also affects negative geotaxis of the adult flies, suggesting the impairment of locomotor function. Overall, our findings suggest that Da regulates Drosophila larval memory and adult negative geotaxis, possibly via its synaptic target genes Syn and dlg1. These behavioural phenotypes can be further used as a PTHS model to screen for therapeutics.This article has an associated First Person interview with the first author of the paper.

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“…Second, the risk SNP rs10489202 was not associated with schizophrenia in European populations 3 , suggesting that there are potential genetic heterogeneities on this locus between different ethnic backgrounds. Thus, before we conclude that rs10489202 is a common schizophrenia risk variant in general world populations, further analyses revealing the genetic mechanism of this genomic locus in the risk of schizophrenia in Europeans are necessary 56 . Third, we also tested a limited number of SNPs in this genomic region, and it is unlikely that rs10489202 is the functional variant; whether there are underlying causative variants that explain the overall risk of associations in East Asians is still unclear.…”

Section: Discussionmentioning

confidence: 96%

Genetic association and meta-analysis of a schizophrenia GWAS variant rs10489202 in East Asian populations

Yang

Wang

et al. 2018

Transl Psychiatry

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Previous genome-wide association studies (GWAS) suggest that rs10489202 in the intron of MPC2 (mitochondrial pyruvate carrier 2) is a risk locus for schizophrenia in Han Chinese populations. To validate this discovery, we conducted a replication analysis in an independent case-control sample of Han Chinese ancestry (437 cases and 2031 controls), followed by a meta-analytic investigation in multiple East Asian samples. In the replication analysis, rs10489202 showed marginal association with schizophrenia (two-tailed P = 0.071, OR = 1.192 for T allele); in the meta-analysis using a total of 14,340 cases and 20,349 controls from ten East Asian samples, rs10489202 was genome-wide significantly associated with schizophrenia (two-tailed P = 3.39 × 10–10, OR = 1.161 for T allele, under the fixed-effect model). We then performed an explorative investigation of the association between this SNP and bipolar disorder, as well as a major depressive disorder, and the schizophrenia-predisposing allele was associated with an increased risk of major depressive disorder in East Asians (two-tailed P = 2.49 × 10–2, OR = 1.103 for T allele). Furthermore, expression quantitative trait loci (eQTL) analysis in lymphoblastoid cell lines from East Asian donors (N = 85 subjects) revealed that rs10489202 was specifically and significantly associated with the expression of TIPRL gene (P = 5.67 × 10–4). Taken together, our data add further support for the genetic involvement of this genomic locus in the susceptibility to schizophrenia in East Asian populations, and also provide preliminary evidence for the underlying molecular mechanisms.

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WNT/β-Catenin Pathway and Epigenetic Mechanisms Regulate the Pitt-Hopkins Syndrome and Schizophrenia Risk Gene TCF4

Cited by 20 publications

References 79 publications

Sex-Dependent Shared and Non-Shared Genetic Architecture Across Mood and Psychotic Disorders

Sex-Dependent Shared and Non-Shared Genetic Architecture Across Mood and Psychotic Disorders

Daughterless, the Drosophila orthologue of TCF4, is required for associative learning and maintenance of the synaptic proteome

Genetic association and meta-analysis of a schizophrenia GWAS variant rs10489202 in East Asian populations

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