Brain Proteome-Wide Association Study Identifies Candidate Genes that Regulate Protein Abundance Associated with Post-Traumatic Stress Disorder

Zhang, Zhen; Meng, Peilin; Zhang, Huijie; Jia, Yumeng; Wen, Yan; Zhang, Jingxi; Chen, Yujing; Li, Chune; Pan, Chuyu; Cheng, Shiqiang; Yang, Xuena; Yao, Yao; Liu, Li; Zhang, Na

doi:10.3390/genes13081341

Cited by 9 publications

(5 citation statements)

References 52 publications

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“…We determined that ten genes (PROC, KNG1, THBS2, SERPINA1, RARRES2, GP6, SERPINE2, SERPINA10, EFEMP1, and MSR1) (Supplementary Table 8), implying that these genes could not be significant in GWAS of VTE. These findings are consistent with observations from other PWAS studies that found the novel genes from regions below genome-wide significant P values [32][33][34].…”

Section: Significance Of the Protein Findingssupporting

confidence: 92%

Proteome-wide mendelian randomization identifies causal plasma proteins in venous thromboembolism development

Zhang

Qiu

et al. 2023

J Hum Genet

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Genome-wide association studies (GWAS) have identified numerous risk loci for venous thromboembolism (VTE), but it is challenging to decipher the underlying mechanisms. We employed an integrative analytical pipeline to transform genetic associations to identify novel plasma proteins for VTE. Proteome-wide association studies (PWAS) were determined by functional summary-based imputation leveraging data from a genome-wide association analysis (14,429 VTE patients, 267,037 controls), blood proteomes (1348 cases), followed by Mendelian randomization, Bayesian colocalization, protein-protein interaction, and pathway enrichment analysis. Twenty genetically regulated circulating protein abundances (F2, F11, ABO, PLCG2, LRP4, PLEK, KLKB1, PROC, KNG1, THBS2, SERPINA1, RARRES2, CEL, GP6, SERPINE2, SERPINA10, OBP2B, EFEMP1, F5, and MSR1) were associated with VTE. Of these 13 proteins demonstrated Mendelian randomized correlations. Six proteins (F2, F11, PLEK, SERPINA1, RARRES2, and SERPINE2) had strong support in colocalization analysis. Utilizing multidimensional data, this study suggests PLEK, SERPINA1, and SERPINE2 as compelling proteins that may provide key hints for future research and possible diagnostic and therapeutic targets for VTE.

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Section: Significance Of the Protein Findingssupporting

confidence: 92%

Proteome-wide mendelian randomization identifies causal plasma proteins in venous thromboembolism development

Zhang

Qiu

et al. 2023

J Hum Genet

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“…De novo mutations associated with ASDs are found in transcription factor 20 (Tcf20) 82 and Tcf20 knockdown mice display impairments in social novelty recognition and pup communication 83 . Moreover, Rbfox1, one of the plasticity genes identified in the enrichment analyses is also linked to risk for ASDs 84 , TRANK1 is a susceptibility gene for bipolar disorder 85 , and RIMS1 was identified in a PTSD TWAS 86 . Together, these findings suggest that TrkB knockdown in the LS decreases expression of genes that control synaptic signaling, which may alter LS function to give rise to behavioral impairments that are relevant for disorders where social communication is affected.…”

Section: Trkb Knockdown In the Ls Regulates Genes Associated With Soc...mentioning

confidence: 99%

TrkB-dependent regulation of molecular signaling across septal cell types

Rodriguez

Tran

Garcia-Flores

et al. 2023

Preprint

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The lateral septum (LS), a GABAergic structure located in the basal forebrain, is implicated in social behavior, learning and memory. We previously demonstrated that expression of tropomyosin kinase receptor B (TrkB) in LS neurons is required for social novelty recognition. To better understand molecular mechanisms by which TrkB signaling controls behavior, we locally knocked down TrkB in LS and used bulk RNA-sequencing to identify changes in gene expression downstream of TrkB. TrkB knockdown induces upregulation of genes associated with inflammation and immune responses, and downregulation of genes associated with synaptic signaling and plasticity. Next, we generated one of the first atlases of molecular profiles for LS cell types using single nucleus RNA-sequencing (snRNA-seq). We identified markers for the septum broadly, and the LS specifically, as well as for all neuronal cell types. We then investigated whether the differentially expressed genes (DEGs) induced by TrkB knockdown map to specific LS cell types. Enrichment testing identified that downregulated DEGs are broadly expressed across neuronal clusters. Enrichment analyses of these DEGs demonstrated that downregulated genes are uniquely expressed in the LS, and associated with either synaptic plasticity or neurodevelopmental disorders. Upregulated genes are enriched in LS microglia, associated with immune response and inflammation, and linked to both neurodegenerative disease and neuropsychiatric disorders. In addition, many of these genes are implicated in regulating social behaviors. In summary, the findings implicate TrkB signaling in the LS as a critical regulator of gene networks associated with psychiatric disorders that display social deficits, including schizophrenia and autism, and with neurodegenerative diseases, including Alzheimer's.

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“…Another gene, MAP kinase-activating Death Domain protein ( MADD ) showed increased expression with depressive symptom in inhibitory neuron subtype 11 (FDR=0.03). This gene plays a survival-promoting role against TNF mediated apoptosis (33), and it has been found associated with post-traumatic stress disorder (34).…”

Section: Resultsmentioning

confidence: 99%

“…The copyright holder for this preprint this version posted March 29, 2023. ; https://doi.org/10.1101/2023.03.27.23286844 doi: medRxiv preprint Five genes (MADD, TAOK3, SCAI, C11orf58 and CHUK) were both identified by the TWAS and differential expression analysis. MADD plays a survival-promoting role against TNF mediated apoptosis (33), it has been found associated with post-traumatic stress disorder (34). A previous study found individuals suffering from bipolar disorder and schizophrenia showed that a microdeletion that affects TAOK3 (and PEBP1) is present in schizophrenia patients (31), and a GWAS analysis suggested that TAOK3 alone may contribute to neurodevelopmental disorders, at least in schizophrenia (32).…”

Section: (Which Was Not Certified By Peer Review)mentioning

confidence: 99%

A single-nucleus transcriptome-wide association study implicates novel genes in depression pathogenesis

Fujita

Gao

et al. 2023

Preprint

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Background: Depression is a common psychiatric illness and global public health problem. However, our limited understanding of the biological basis of depression has hindered the development of novel treatments and interventions. Methods: To identify new candidate genes for therapeutic development, we examined single-nucleus RNA sequencing (snucRNAseq) data from the dorsolateral prefrontal cortex (N=424) in relation to ante-mortem depressive symptoms. To complement these direct analyses, we also used genome-wide association study (GWAS) results for depression (N=500,199) along with genetic tools for inferring the expression of 22,159 genes in 7 cell types and 55 cell subtypes to perform transcriptome-wide association studies (TWAS) of depression followed by Mendelian randomization (MR). Results: Our single-nucleus TWAS analysis identified 71 causal genes in depression that have a role in specific neocortical cell subtypes; 59 of 71 genes were novel compared to previous studies. Depression TWAS genes showed a cell type specific pattern, with the greatest enrichment being in both excitatory and inhibitory neurons as well as astrocytes. Gene expression in different neuron subtypes have different directions of effect on depression risk. Compared to lower genetically correlated traits (e.g. body mass index) with depression, higher correlated traits (e.g., neuroticism) have more common TWAS genes with depression. In parallel, we performed differential gene expression analysis in relation to depression in 55 cortical cell subtypes, and we found that genes such as ANKRD36, MADD, TAOK3, SCAI and CHUK are associated with depression in specific cell subtypes. Conclusions: These two sets of analyses illustrate the utility of large snucRNAseq data to uncover both genes whose expression is altered in specific cell subtypes in the context of depression and to enhance the interpretation of well-powered GWAS so that we can prioritize specific susceptibility genes for further analysis and therapeutic development.

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Brain Proteome-Wide Association Study Identifies Candidate Genes that Regulate Protein Abundance Associated with Post-Traumatic Stress Disorder

Cited by 9 publications

References 52 publications

Proteome-wide mendelian randomization identifies causal plasma proteins in venous thromboembolism development

Proteome-wide mendelian randomization identifies causal plasma proteins in venous thromboembolism development

TrkB-dependent regulation of molecular signaling across septal cell types

A single-nucleus transcriptome-wide association study implicates novel genes in depression pathogenesis

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