Axon guidance pathway genes are associated with schizophrenia risk

Wang, Zhichao; Li, Ping; Wu, Tie; Zhu, Shuangyue; Deng, Libin; Cui, Guangcheng

doi:10.3892/etm.2018.6781

Cited by 27 publications

(28 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Transcriptomic analysis of these cortical neuroids also identified AP-specific dysregulation of pathways involved in multiple aspects of neurodevelopmental signaling, including axonal guidance, integrins and gap junctions, Wnt signaling, and GABA receptor function, with most genes in these pathways exhibiting reduced expression in the AP relative to controls. Accumulating evidence from both imaging and high content genomic studies of post-mortem brain has identified aberrations in axonal growth and correspondingly disrupted expression of genes that mediate axonal growth in ASD and in other psychiatric disorders, including altered expression of Slit, Robo, Ephrin, and Semaphorin family genes (45,51,52). Here, the AP model exhibited altered expression of multiple axonal guidance molecules (SLIT2, EPHA8, EPHA5, EPHB4, and ROBO2).…”

Section: Discussionmentioning

confidence: 87%

Alterations in neuronal physiology, development, and function associated with a common duplication of chromosome 15 involvingCHRNA7

Meganathan¹,

Prakasam²,

Baldridge³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Copy number variants at chromosome 15q13.3 contribute to liability for multiple intellectual and developmental disabilities (IDDs) including Autism Spectrum Disorder (ASD). Individuals with duplications of this interval, which includes the gene CHRNA7, have IDDs with variable penetrance. However, the basis of such differential affectation remains uncharacterized. Methods:Induced pluripotent stem cell (iPSC) models were generated from two first degree relatives with the same 15q13.3 duplication, a boy with distinct features of autism and emotional dysregulation (the affected proband, AP) and his clinically unaffected mother (the UM). These models were compared to unrelated control subjects lacking this duplication (UC, male and female). iPSC-derived neural progenitors and cortical neuroids consisting of cortical excitatory and inhibitory neurons were used to model potential contributors to neuropsychiatric impairment. Results:The AP-derived model uniquely exhibited disruptions of cellular physiology and neurodevelopment not observed in either the UM or in unrelated male and female controls. These included enhanced neural progenitor proliferation but impaired neuronal differentiation, maturation, and migration, and increased endoplasmic reticulum (ER) stress in neural progenitors. Both the AP model's neuronal migration deficit and elevated ER stress could be selectively rescued by different pharmacologic agents. Neuronal gene expression was also specifically dysregulated in the AP, including altered expression of genes related to behavior, psychological disorders, neuritogenesis, neuronal migration, and WNT signaling. By contrast with these AP-specific phenotypes, both the AP-and UM-derived neurons exhibited shared alterations of neuronal function, including elevated cholinergic activity consistent with increased homomeric CHRNA7 channel activity. Conclusion:Together, these data define both affectation-specific phenotypes seen only in the AP, as well as abnormalities observed in both individuals with CHRNA7 duplication, the AP and UM, but not in UC-derived neurons. This is, to our knowledge, the first study to use a human stem cell-based platform to study the basis of variable affectation in cases of 15q13.3 duplication at the cellular, molecular, and functional levels. This work suggests potential approaches for suppressing abnormal neurodevelopment or physiology that may contribute to severity of affectation in this proband. Some of these AP-specific neurodevelopmental anomalies, or the functional anomalies observed in both 15q13.3 duplication carriers (the AP and UM), could also contribute to the variable phenotypic penetrance seen in other individuals with 15q13.3 duplication. Ethics approval and consent to participateSubjects were consented for biobanking and iPSC line generation by the Washington University Institutional

show abstract

Section: Discussionmentioning

confidence: 87%

Alterations in neuronal physiology, development, and function associated with a common duplication of chromosome 15 involvingCHRNA7

Meganathan¹,

Prakasam²,

Baldridge³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Clinically, this is consistent with the general consensus that SCZ is strictly neuropsychiatric as opposed to degenerative. In this same vein, axonogenesis (p_microglia<2.91e-5, p_oligodencrocytes<4.56e-12, p_excitatory<5.27e-17, p_inhibitory<7.91e-16) [68], regulation of cell morphogenesis (p_microglia<1.01e-8, p_oligodencrocytes<9.11e-10, p_excitatory<1.56e-8, p_inhibitory<2.65e-9) [69], neuronal cell synapses (p_oligodencrocytes<7.26e-11, p_excitatory<2.28e-25, p_inhibitory<2.17e-26) [49] were all enriched. Multiple axon guidance pathways associated with general axon growth in axonogenesis have been heavily implicated in the broad mechanism of SCZ pathology; elucidating this mechanism has remained difficult in part due to the polygenic nature of the disease.…”

Section: Revealing Disease Related Functions Involving Multiple Cell-mentioning

confidence: 89%

“…Multiple axon guidance pathways associated with general axon growth in axonogenesis have been heavily implicated in the broad mechanism of SCZ pathology; elucidating this mechanism has remained difficult in part due to the polygenic nature of the disease. Broadly, it is thought that missteps in guidance cues can lead to eventual presentation and disease onset, but the underlying pathway remains unclear [68]. On the front of cell morphogenesis, early life neurodevelopmental genetic markers may suggest causal links with alterations in hippocampal cell differentiation points leading to cascades of downstream effects [69].…”

Section: Revealing Disease Related Functions Involving Multiple Cell-mentioning

confidence: 99%

scGRNom: a computational pipeline of integrative multi-omics analyses for predicting cell-type disease genes and regulatory networks

Jin

Rehani

Ying

et al. 2020

Preprint

View full text Add to dashboard Cite

Strong phenotype-genotype associations have been reported across brain diseases. However, understanding underlying gene regulatory mechanisms remains challenging, especially at the cellular level. To address this, we integrated the multi-omics data at the cellular resolution of the human brain: cell-type chromatin interactions, epigenomics and single cell transcriptomics, and predicted cell-type gene regulatory networks linking transcription factors, distal regulatory elements and target genes (e.g., excitatory and inhibitory neurons, microglia, oligodendrocyte). Using these cell-type networks and disease risk variants, we further identified the cell-type disease genes and regulatory networks for schizophrenia and Alzheimer's disease. The celltype regulatory elements (e.g., enhancers) in the networks were also found to be potential pleiotropic regulatory loci for a variety of diseases. Further enrichment analyses including gene ontology and KEGG pathways revealed potential novel cross-disease and disease-specific molecular functions, advancing knowledge on the interplays among genetic, transcriptional and epigenetic risks at the cellular resolution between neurodegenerative and neuropsychiatric diseases. Finally, we summarized our computational analyses as a general-purpose pipeline for predicting gene regulatory networks via multi-omics data.Recent analyses have also revealed that brain disease risk variants are located in non-coding regulatory elements (e.g., enhancers) and that the risk genes likely have cell-type specific effects including neuronal and non-neuronal types [25,26]. In addition, recent single-cell studies 68 TFs,

show abstract

“…Finally, on chromosome 18, DCC (the most significant hit) encodes a netrin 1 receptor with a role in axon guidance, and has been previously reported to be associated with anhedonic phenotypes in mice and humans 62 and potentially with schizophrenia pathogenesis 63 . We have previously identified DCC in GWAS of mood instability 64 , suicidality 65 and multisite chronic pain 66 .…”

Section: Genes Within Anhedonia-associated Locimentioning

confidence: 99%

32 Novel Genome-Wide Associations for Anhedonia, Genetic Correlation With Psychiatric Disorders, and Polygenic Association With Brain Structure

Lyall

Bethlehem

Strawbridge

et al. 2019

European Neuropsychopharmacology

View full text Add to dashboard Cite

Anhedonia is a core symptom of several psychiatric disorders but its biological underpinnings are poorly understood. We performed a genome-wide association study of state anhedonia in 375,275 UK Biobank participants and assessed for genetic correlation between anhedonia and neuropsychiatric conditions (major depressive disorder, schizophrenia, bipolar disorder, obsessive compulsive disorder and Parkinson's Disease). We then used a polygenic risk score approach to test for association between genetic loading for anhedonia and both brain structure and brain function. This included: magnetic resonance imaging (MRI) assessments of total grey matter volume, white matter volume, cerebrospinal fluid volume, and 15 cortical/subcortical regions of interest; diffusion tensor imaging (DTI) measures of white matter tract integrity; and functional MRI activity during an emotion processing task. We identified 11 novel loci associated at genome-wide significance with anhedonia, with a SNP heritability estimate (h 2 SNP) of 5.6%. Strong positive genetic correlations were found between anhedonia and major depressive disorder, schizophrenia and bipolar disorder; but not with obsessive compulsive disorder or Parkinson's Disease. Polygenic risk for anhedonia was associated with poorer brain white matter integrity, smaller total grey matter volume, and smaller volumes of brain regions linked to reward and pleasure processing, including orbito-frontal cortex. In summary, the identification of novel anhedoniaassociated loci substantially expands our current understanding of the biological basis of state anhedonia and genetic correlations with several psychiatric disorders confirm the utility of this phenotype as a transdiagnostic marker of vulnerability to mental illness. We also provide the first evidence that genetic risk for state anhedonia influences brain structure, including in regions associated with reward and pleasure processing.

show abstract

Axon guidance pathway genes are associated with schizophrenia risk

Cited by 27 publications

References 42 publications

Alterations in neuronal physiology, development, and function associated with a common duplication of chromosome 15 involvingCHRNA7

Alterations in neuronal physiology, development, and function associated with a common duplication of chromosome 15 involvingCHRNA7

scGRNom: a computational pipeline of integrative multi-omics analyses for predicting cell-type disease genes and regulatory networks

32 Novel Genome-Wide Associations for Anhedonia, Genetic Correlation With Psychiatric Disorders, and Polygenic Association With Brain Structure

Contact Info

Product

Resources

About