Further Evidence of an Association between &lt;b&gt;&lt;i&gt;NCAN&lt;/i&gt;&lt;/b&gt; rs1064395 and Bipolar Disorder

Wang, Lu; Liu, Weiqing; Li, Xingxing; Xiao, Xiao; Li, Lingyi; Liu, Fang; He, Yuanfang; Bai, Yan; Chang, Hong; Zhou, Dongsheng; Li, Ming

doi:10.1159/000488590

Cited by 10 publications

(11 citation statements)

References 39 publications

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“…We find it very interesting that the network analysis of our transcriptomic study and genes associated with BPI led to the identification of NCAN as a central hub for the differentially expressed genes. GWAS data show that NCAN is one of the common variants that are significantly associated with BPI risk [21,22,46,47]. NCAN is a proteoglycan that is involved in cell adhesion and neuronal migration, processes that are pivotal during neurodevelopment [42][43][44][45]84].…”

Section: Discussionmentioning

confidence: 99%

“…NCAN is a proteoglycan that is a component of the neuronal extracellular matrix that is expressed during the modeling and remodeling of neuronal tissue and modulates neural adhesion and migration [42][43][44][45]. Genome-wide association studies have implicated common variation in NCAN as a risk for BPI [21,22,46,47]. Functional magnetic resonance imaging (fMRI) studies in humans show that the risk allele affects neural processing and cognitive performance in humans [48].…”

Section: Analysis Of Protein-protein Interaction (Ppi) Networkmentioning

confidence: 99%

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Transcriptome analysis and functional characterization of cerebral organoids in bipolar disorder

et al. 2020

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Background: Reprogramming human induced pluripotent stem cells (iPSCs) from somatic cells and generating three-dimensional brain organoids from these iPSCs provide access to live human neuronal tissue with diseasespecific genetic backgrounds. Methods: Cerebral organoids were generated from iPSCs of eight bipolar disorder (BPI) patients and eight healthy control individuals. RNA-seq experiments were undertaken using RNA isolated from the cerebral organoids. Functional activity in the cerebral organoids was studied using microelectrode arrays.Results: RNA-seq data comparing gene expression profiles in the cerebral organoids showed downregulation of pathways involved in cell adhesion, neurodevelopment, and synaptic biology in bipolar disorder along with upregulation of genes involved in immune signaling. The central hub in the network analysis was neurocan (NCAN), which is located in a locus with evidence for genome-wide significant association in BPI. Gene ontology analyses suggested deficits related to endoplasmic reticulum biology in BPI, which was supported by cellular characterization of ER-mitochondria interactions. Functional studies with microelectrode arrays revealed specific deficits in response to stimulation and depolarization in BPI cerebral organoids.Conclusions: Our studies in cerebral organoids from bipolar disorder showed dysregulation in genes involved in cell adhesion, immune signaling, and endoplasmic reticulum biology; implicated a central role for the GWAS hit NCAN in the biology of BPI; and showed evidence of deficits in neurotransmission.

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Section: Discussionmentioning

confidence: 99%

Section: Analysis Of Protein-protein Interaction (Ppi) Networkmentioning

confidence: 99%

Transcriptome analysis and functional characterization of cerebral organoids in bipolar disorder

et al. 2020

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“…Intriguingly, the significant associations between these two genes with the risk of depression were again observed in Europeans (P MAGMA = 1.01 × 10 −11 for LRFN5, P MAGMA = 2.85 × 10 −12 for DCC, Table 1). Given the emerging evidence supporting the notion that vital genetic markers for psychiatric disorders are normally associated with the disease across different ethnic populations 65 (e.g., psychiatric risk loci in ZNF804A, FADS1, and VRK2 show significant associations in both Europeans and East Asians [66][67][68][69][70][71] ), we then examined whether LRFN5 and DCC were also associated with depression in Han Chinese subjects through MAGMA gene-level analyses using a published Han Chinese GWAS dataset (5303 cases and 5337 controls) 24 . Notably, DCC was associated with depression as well in Han Chinese despite the lower level of statistical significance compared with that in Europeans (P MAGMA = 3.21 × 10 −4 , Table 1), but LRFN5 was not associated with depression in Han Chinese (P MAGMA = 0.406, Table 1).…”

Section: Independent Replications Across Populations Further Confirmementioning

confidence: 99%

Further confirmation of netrin 1 receptor (DCC) as a depression risk gene via integrations of multi-omics data

et al. 2020

Transl Psychiatry

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Genome-wide association studies (GWAS) of major depression and its relevant biological phenotypes have been extensively conducted in large samples, and transcriptome-wide analyses in the tissues of brain regions relevant to pathogenesis of depression, e.g., dorsolateral prefrontal cortex (DLPFC), have also been widely performed recently. Integrating these multi-omics data will enable unveiling of depression risk genes and even underlying pathological mechanisms. Here, we employ summary data-based Mendelian randomization (SMR) and integrative risk gene selector (iRIGS) approaches to integrate multi-omics data from GWAS, DLPFC expression quantitative trait loci (eQTL) analyses and enhancer-promoter physical link studies to prioritize high-confidence risk genes for depression, followed by independent replications across distinct populations. These integrative analyses identify multiple high-confidence depression risk genes, and numerous lines of evidence supporting pivotal roles of the netrin 1 receptor (DCC) gene in this illness across different populations. Our subsequent explorative analyses further suggest that DCC significantly predicts neuroticism, well-being spectrum, cognitive function and putamen structure in general populations. Gene expression correlation and pathway analyses in DLPFC further show that DCC potentially participates in the biological processes and pathways underlying synaptic plasticity, axon guidance, circadian entrainment, as well as learning and long-term potentiation. These results are in agreement with the recent findings of this gene in neurodevelopment and psychiatric disorders, and we thus further confirm that DCC is an important susceptibility gene for depression, and might be a potential target for new antidepressants.

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“…1315 BPD patients of Han Chinese origin were recruited from several provinces of Mainland China (e.g., Henan, Hunan, Shanghai, Zhejiang and Sichuan). Part of the samples have been previously described elsewhere [21, 31]. To minimize the impact of confounding variables, patients were excluded if they (i) had a history of mental retardation, drug/alcohol abuse, or schizophrenia; or (ii) had comorbid diagnosis of other brain injury.…”

Section: Methodsmentioning

confidence: 99%

“…Majority of the follow-up efforts have been put into understanding whether genes highlighted in these GWAS are indeed susceptibility genes of BPD in populations other than Europeans [16–21], and such cross-population replications were not limited to BPD [22–25]. For example, Gonzalez et al conducted replication analysis of the European GWAS risk loci in a Latino BPD cohort [16], and Zeng et al replicated the associations between DGKH SNPs and haplotypes with BPD in Chinese populations [18].…”

Section: Introductionmentioning

confidence: 99%

Association of SYNE1 locus with bipolar disorder in Chinese population

Yang

Luo

et al. 2019

Hereditas

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Objectives Genome-wide association studies (GWAS) suggest that rs9371601 in the SYNE1 gene is a risk SNP for bipolar disorder (BPD) in populations of European ancestry, but further replication analyses across distinct populations are needed. Methods We analyzed the association between rs9371601 and BPD in a Han Chinese sample of 1315 BPD cases and 1956 controls. Results We observed a significant association between rs9371601 and BPD in Han Chinese ( p = 0.0121, OR = 0.859). However, further examinations revealed that the Europeans and Chinese subjects had different BPD risk alleles at the locus. We then found that rs9371601 had different “minor alleles” and distinct linkage disequilibrium (LD) patterns surrounding itself in Europeans and Han Chinese, which might be the explanation of the observed inconsistent association signals for this locus in different populations. Our explorative analyses of the biological impact of rs9371601 suggested that this SNP was significantly associated with the methylation of a CpG site (cg01844274, p = 5.05⨯10 − 6 ) within SYNE1 in human dorsal lateral prefrontal cortex (DLPFC) tissues. Conclusions Our data confirms the association between rs9371601 and BPD, but the underlying biological mechanism remains to be fully elucidated in further studies. Electronic supplementary material The online version of this article (10.1186/s41065-019-0095-7) contains supplementary material, which is available to authorized users.

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Further Evidence of an Association between <b><i>NCAN</i></b> rs1064395 and Bipolar Disorder

Cited by 10 publications

References 39 publications

Transcriptome analysis and functional characterization of cerebral organoids in bipolar disorder

Transcriptome analysis and functional characterization of cerebral organoids in bipolar disorder

Further confirmation of netrin 1 receptor (DCC) as a depression risk gene via integrations of multi-omics data

Association of SYNE1 locus with bipolar disorder in Chinese population

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