Diverse types of genomic evidence converge on alcohol use disorder risk genes

Dai, Yulin; Hu, Ruifeng; Pei, Guangsheng; Zhang, Huiping; Zhao, Zhongming; Jia, Peilin

doi:10.1136/jmedgenet-2019-106490

Cited by 12 publications

(10 citation statements)

References 60 publications

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“…In recent years, large consortia like GTEx (Genotype-Tissue Expression), eQTLGen Consortium, and DICE (database of immune cell expression) have generated rich eQTLs resources in diverse tissues and immune-related cell types (GTEx Consortium 2020 ; Schmiedel et al 2018 ; Võsa et al 2018a ). A variety of statistical approaches, such as transcriptome-wide association study (TWAS) analysis and colocalization analysis, have successfully interpreted the target genes of non-coding variants by integrating the context-specific eQTLs (Dai et al 2020 ; Dai et al 2019 ; Gamazon et al 2015; Giambartolomei et al 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Association of CXCR6 with COVID-19 severity: delineating the host genetic factors in transcriptomic regulation

et al. 2021

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The coronavirus disease 2019 (COVID-19) is an infectious disease that mainly affects the host respiratory system with ~ 80% asymptomatic or mild cases and ~ 5% severe cases. Recent genome-wide association studies (GWAS) have identified several genetic loci associated with the severe COVID-19 symptoms. Delineating the genetic variants and genes is important for better understanding its biological mechanisms. We implemented integrative approaches, including transcriptome-wide association studies (TWAS), colocalization analysis, and functional element prediction analysis, to interpret the genetic risks using two independent GWAS datasets in lung and immune cells. To understand the context-specific molecular alteration, we further performed deep learning-based single-cell transcriptomic analyses on a bronchoalveolar lavage fluid (BALF) dataset from moderate and severe COVID-19 patients. We discovered and replicated the genetically regulated expression of CXCR6 and CCR9 genes. These two genes have a protective effect on lung, and a risk effect on whole blood, respectively. The colocalization analysis of GWAS and cis -expression quantitative trait loci highlighted the regulatory effect on CXCR6 expression in lung and immune cells. In the lung-resident memory CD8 + T (T RM ) cells, we found a 2.24-fold decrease of cell proportion among CD8 + T cells and lower expression of CXCR6 in the severe patients than moderate patients. Pro-inflammatory transcriptional programs were highlighted in the T RM cellular trajectory from moderate to severe patients. CXCR6 from the 3p21.31 locus is associated with severe COVID-19. CXCR6 tends to have a lower expression in lung T RM cells of severe patients, which aligns with the protective effect of CXCR6 from TWAS analysis. Supplementary Information The online version contains supplementary material available at 10.1007/s00439-021-02305-z.

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Section: Introductionmentioning

confidence: 99%

Association of CXCR6 with COVID-19 severity: delineating the host genetic factors in transcriptomic regulation

et al. 2021

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“…Previous studies have discovered that genetic variants tend to regulate the gene expression or function in specific tissues and cell types ( 1 , 2 ). The accurate assessment of disease-associated tissues or cell types becomes a critical step to understanding the etiology of these human complex diseases and traits ( 3 , 4 ). Recently, we successfully developed a t-statistics-based method ‘decoding the tissue-specificity’ (deTS) to measure the tissue-specific enrichment of 26 human complex diseases utilizing GWAS summary statistics and tissue gene expression profiling ( 5 ).…”

Section: Introductionmentioning

confidence: 99%

CSEA-DB: an omnibus for human complex trait and cell type associations

Dai

Manuel

et al. 2020

Nucleic Acids Research

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During the past decade, genome-wide association studies (GWAS) have identified many genetic variants with susceptibility to several thousands of complex diseases or traits. The genetic regulation of gene expression is highly tissue-specific and cell type-specific. Recently, single-cell technology has paved the way to dissect cellular heterogeneity in human tissues. Here, we present a reference database for GWAS trait-associated cell type-specificity, named Cell type-Specific Enrichment Analysis DataBase (CSEA-DB, available at https://bioinfo.uth.edu/CSEADB/). Specifically, we curated total of 5120 GWAS summary statistics data for a wide range of human traits and diseases followed by rigorous quality control. We further collected >900 000 cells from the leading consortia such as Human Cell Landscape, Human Cell Atlas, and extensive literature mining, including 752 tissue cell types from 71 adult and fetal tissues across 11 human organ systems. The tissues and cell types were annotated with Uberon and Cell Ontology. By applying our deTS algorithm, we conducted 10 250 480 times of trait-cell type associations, reporting a total of 598 (11.68%) GWAS traits with at least one significantly associated cell type. In summary, CSEA-DB could serve as a repository of association map for human complex traits and their underlying cell types, manually curated GWAS, and single-cell transcriptome resources.

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“…In recent years, large consortia like GTEx (Genotype-Tissue Expression), eQTLGen Consortium, and DICE (database of immune cell expression) have generated rich eQTLs resources in diverse tissues and immune-related cell types [7][8][9]. A variety of statistical approaches such as transcriptome-wide association study (TWAS) analysis and colocalization analysis have successfully interpreted the target genes of non-coding variants by integrating the context-specific eQTLs [10][11][12][13].…”

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confidence: 99%

Association ofCXCR6with COVID-19 severity: Delineating the host genetic factors in transcriptomic regulation

Dai

Wang

Jeong

et al. 2021

Preprint

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Background: The coronavirus disease 2019 (COVID-19) is an infectious disease that mainly affects the host respiratory system with ~80% asymptomatic or mild cases and ~5% severe cases. Recent genome-wide association studies (GWAS) have identified several genetic loci associated with the severe COVID-19 symptoms. Delineating the genetic variants and genes is important for better understanding its biological mechanisms. Methods: We implemented integrative approaches, including transcriptome-wide association studies (TWAS) and colocalization analysis, to interpret the genetic risks using two independent GWAS datasets in lung and immune cells. We further performed single cell transcriptomic analysis on a bronchoalveolar lavage fluid (BALF) dataset from moderate and severe COVID-19 patients. Results: We discovered and replicated the genetically regulated expression of CXCR6 and CCR9 genes. These two genes have a protective effect on the lung and a risk effect on whole blood, respectively. The colocalization analysis of GWAS and cis-expression quantitative trait loci highlighted the regulatory effect on CXCR6 expression in lung and immune cells. In the lung resident memory CD8+ T (TRM) cells, we found a 3.32-fold decrease of cell proportion and lower expression of CXCR6 in the severe than moderate patients using the BALF transcriptomic dataset. Conclusion: CXCR6 from the 3p21.31 locus is associated with severe COVID-19. CXCR6 tends to have a lower expression in lung TRM cells of severe patients, which aligns with the protective effect of CXCR6 from TWAS analysis. We illustrate one potential mechanism of host genetic factor impacting the severity of COVID-19 through regulating the expression of CXCR6 and TRM cell proportion. Our results shed light on potential therapeutic targets for severe COVID-19.

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Diverse types of genomic evidence converge on alcohol use disorder risk genes

Cited by 12 publications

References 60 publications

Association of CXCR6 with COVID-19 severity: delineating the host genetic factors in transcriptomic regulation

Association of CXCR6 with COVID-19 severity: delineating the host genetic factors in transcriptomic regulation

CSEA-DB: an omnibus for human complex trait and cell type associations

Association ofCXCR6with COVID-19 severity: Delineating the host genetic factors in transcriptomic regulation

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