A mega-analysis of expression quantitative trait loci (eQTL) provides insight into the regulatory architecture of gene expression variation in liver

Strunz, Tobias; Graßmann, Felix; Gayán, Javier; Nahkuri, Satu; Souza-Costa, Debora C.; Maugeais, Cyrille; Fauser, Sascha; Nogoceke, Everson; Weber, Bernhard H. F.

doi:10.1038/s41598-018-24219-z

Cited by 56 publications

(79 citation statements)

References 75 publications

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“…In large eQTL data, there were no significant eQTLs in the APOA1 locus in the liver or small intestine. 26,39 According to mQTL data 40 , rs12225230 is associated with the methylation status of nearby CpG methylation sites. Furthermore, rs12225230 is in LD with rs625145 (top SNP in our apoA-I GWAS), and methylation status of CpG sites associated with this SNP was previously reported to be causally associated with apoA-I concentrations.…”

Section: Identification Of Genetic Variants Associated With Circulatimentioning

confidence: 99%

Genetic variation in apolipoprotein A-I concentrations and risk of coronary artery disease

Karjalainen

Holmes

Wang

et al. 2019

Preprint

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Rationale: Apolipoprotein A-I (apoA-I) infusions represent a potential novel therapeutic approach for the prevention of coronary artery disease (CAD) with phase III cardiovascular outcome trials currently underway. Although circulating apoA-I levels inversely associate with risk of CAD, the evidence base of this representing a causal relationship is lacking.Objective: To assess the causal role of apoA-I in CAD using human genetics. Methods and Results:We identified a variant (rs12225230) in APOA1 locus that associated with circulating apoA-I concentrations at GWAS significance (P<5x10 -8 ) in 20,370 Finnish participants and meta-analyzed our data with a previous genome-wide association study of apoA-I. We obtained genetic estimates of CAD from UK Biobank and CARDIoGRAMplusC4D (totaling 122,733 CAD cases) and conducted a two-sample Mendelian randomization analysis. We compared our genetic findings to observational associations of apoA-I with risk of CAD in 918 incident CAD cases among 11,535 individuals from population-based prospective cohorts. We also summarized the available evidence from randomized controlled trials (RCTs) of apoA-I infusion therapies reporting CAD events. ApoA-I was associated with a lower risk of CAD in observational analyses (HR 0.81; 95%CI: 0.75, 0.88; per 1-SD higher apoA-I), with the association showing a dose-response relationship. Rs12225230 associated with apoA-I concentrations (per-C allele beta 0.076 SD; SE: 0.013; P=1.5x10 -9 ) but not with potential confounders. In Mendelian randomization analyses, apoA-I was not related to risk of CAD (OR 1.13; 95%CI: 0.98, 1.30 per 1-SD higher apoA-I), which was different to the observational association (P-het<0.001). RCTs of apoA-I infusions did not show an effect on the risk of CAD.

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Section: Identification Of Genetic Variants Associated With Circulatimentioning

confidence: 99%

Genetic variation in apolipoprotein A-I concentrations and risk of coronary artery disease

Karjalainen

Holmes

Wang

et al. 2019

Preprint

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“…A recent GWAS identified an intronic variant in CFHR4 that associated with increased systemic complement activation and AMD risk 39 . Furthermore, it has recently been reported that the top AMD-associated CFH variant rs10922109 5 is associated with altered CFHR4 expression in the liver 40 . Taken together, these studies propose that, as well as FH, FHR-4 may also be involved in AMD.…”

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confidence: 99%

Increased circulating levels of Factor H-Related Protein 4 are strongly associated with age-related macular degeneration

et al. 2020

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Age-related macular degeneration (AMD) is a leading cause of blindness. Genetic variants at the chromosome 1q31.3 encompassing the complement factor H (CFH, FH) and CFH related genes (CFHR1-5) are major determinants of AMD susceptibility, but their molecular consequences remain unclear. Here we demonstrate that FHR-4 plays a prominent role in AMD pathogenesis. We show that systemic FHR-4 levels are elevated in AMD (P-value = 7.1 × 10 −6 ), whereas no difference is seen for FH. Furthermore, FHR-4 accumulates in the choriocapillaris, Bruch's membrane and drusen, and can compete with FH/FHL-1 for C3b binding, preventing FI-mediated C3b cleavage. Critically, the protective allele of the strongest AMD-associated CFH locus variant rs10922109 has the highest association with reduced FHR-4 levels (P-value = 2.2 × 10 −56 ), independently of the AMD-protective CFHR1-3 deletion, and even in those individuals that carry the high-risk allele of rs1061170 (Y402H). Our findings identify FHR-4 as a key molecular player contributing to complement dysregulation in AMD.

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“…We focused on identifying cis-eQTMs (i.e., CpGs regulating transcription of neighboring genes), 241 due to limited power to perform a trans analysis (i.e., CpGs regulating distant genes) 23 . Thus, we 242 only considered methylation probes within 1 Mb from the TSS of a gene.…”

Section: Study Population 205mentioning

confidence: 99%

Expression quantitative trait methylation analysis reveals methylomic associations with gene expression in childhood asthma

Kim

Forno

Zhang

et al. 2020

Preprint

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findings, we were interested in examining whether methylation of specific CpG sites is 67 associated with expression of non-nearby cis-genes. We thus conducted an expression 68 quantitative trait methylation (eQTM) analysis in nasal airway epithelium from 455 Puerto 69Ricans ages 9 to 20 years, including 219 subjects with asthma (cases) and 236 control subjects. 70 71 Results 72Location of eQTM-methylation probes relative to paired genes 73 By testing associations between methylation probes within 1 Mb of transcription start sites (TSS) 74 of genes and gene expression, we identified 16,867 significant methylation-expression pairs 75 (FDR-P < 0.01, see Methods), comprising 9,103 methylation probes associated with expression 76 of 3,512 genes. We then investigated the position of significant methylation probes in this eQTM 77 analysis in relation to their paired genes. If a methylation probe was associated with expression 78 of multiple genes, we counted such probe for each gene. We found that 11% and 89% of 79 significant eQTM probes were located within and outside genes, respectively -including 4% of 80 eQTM probes in promoter regions (Figure 1a). Most eQTM methylation probes were distant 81 from their target genes (371,840 bp on average) (Figure 1b). 82 83 Because we found distant relationships between methylation and their target genes, we assessed 84 whether eQTM methylation probes in nasal epithelium are enriched in the enhancer regions of 85 their paired genes. For this, we checked the enhancer database for lung tissue 86 (http://enhanceratlas.org/) 3 , since nasal epithelial tissue was not available in that database, and 87 nasal and bronchial epithelial methylation and expression are well correlated 1 . We found that 88 eQTM methylation probes are more likely to be located in enhancer regions of their paired genes 89 than randomly selected control probes (p-value: 1.3x10 -213 ) (Figure 1c, Table 1). 90 91 While most methylation probes near TSS were negatively correlated with gene expression, more 92 distant pairs tended to be positively correlated (Figure 1d). Of the eQTM methylation probes 93 associated with expression of the gene they were located in, 81.9% were negatively correlated 94 with expression (85.3% if in promoter regions) (Figure 1e). In contrast, only 40.2 % of eQTM 95 methylation probes associated with expression of a distant gene (i.e. methylation probes outside 96 of the associated gene) were negatively correlated with expression levels (Figure 1f). 97 98 Most of the top eQTM genes (by eQTM P-value) have been implicated in lung disease (Figure 99 2). PAX8 is associated with bronchodilator response in children with asthma 4 , ECHDC3 is 100 associated with obesity and asthma in children 5 , LSP1 is associated with acute lung inflammation 101 6 , HLA-DQB1 is associated with asthma 7 and total IgE 8 , FRG1B is highly mutated in lung 102 adenocarcinoma 9 , and KANSL1 is associated with pulmonary function 10 . 103 104 Gene Ontology enrichment analysis 105We performed a Gene Ontology enrichment ...

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A mega-analysis of expression quantitative trait loci (eQTL) provides insight into the regulatory architecture of gene expression variation in liver

Cited by 56 publications

References 75 publications

Genetic variation in apolipoprotein A-I concentrations and risk of coronary artery disease

Genetic variation in apolipoprotein A-I concentrations and risk of coronary artery disease

Increased circulating levels of Factor H-Related Protein 4 are strongly associated with age-related macular degeneration

Expression quantitative trait methylation analysis reveals methylomic associations with gene expression in childhood asthma

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