Autoimmune risk variants in ERAP2 are associated with gene-expression levels in thymus

Gabrielsen, Ingvild; Viken, Marte K.; Amundsen, Silja Svanstrøm; Helgeland, Hanna; Holm, Kristian; Flåm, Siri Tennebø; Lie, Benedicte A.

doi:10.1038/gene.2016.39

Cited by 8 publications

(8 citation statements)

References 169 publications

(251 reference statements)

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“…However, the haplotype with this variant contains hundreds of other linked variants with significant population variation and harbors a second conditional ERAP2 eQTL in GTEx v8 LCLs. Moreover, several prior studies have demonstrated associations between ERAP2 expression and cis-variation independently of NMD, although linkage limited the resolution of functional studies ( 33, 45, 49, 50 ). Taken together, these results suggest that ERAP2 is regulated by a complex multi-allelic structure which operates via both gene expression and splicing.…”

Section: Resultsmentioning

confidence: 99%

“…One of the most complex multi-variant colocalizations was identified at the ERAP2 locus, which is an aminopeptidase that has been functionally implicated in both Irritable Bowel Disease and Crohn's Disease and for which we observe strong eQTL-GWAS colocalization (45)(46)(47). However, unlike AHI1, we detected six putative causal variants of which five are directionally concordant with eQTL effect along with a significant haplotype effect.…”

Section: Experimental Fine-mapping Of Complex Trait Associationsmentioning

confidence: 97%

“…Prior work has shown that a common splice variant at this locus results in nonsense-mediated decay (NMD) and allele-specific expression, which can cause an eQTL signal (48). However, the haplotype with this variant contains hundreds of other linked variants with significant population variation, harbors a second conditional ERAP2 eQTL in GTEx v8 LCLs, and is also regulated by surrounding variation independently of NMD though linkage has limited the resolution of functional studies (34,45,49,50). Notably, all but one of the variants identified in this study had allelic effects in the same direction as the predicted effect of NMD and are linked on the same haplotype.…”

Section: Experimental Fine-mapping Of Complex Trait Associationsmentioning

confidence: 99%

See 2 more Smart Citations

Multiple Causal Variants Underlie Genetic Associations in Humans

DeGorter

Gloudemans

Greenwald

et al. 2021

Preprint

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The majority of associations between genetic variation and human traits and diseases are non-coding and in strong linkage disequilibrium (LD) with surrounding genetic variation. In these cases, a single causal variant is often assumed to underlie the association, however no systematic assessment of the number of causal variants has been performed. In this study, we applied a massively parallel reporter assay (MPRA) in lymphoblastoid cells to functionally evaluate 49,256 allelic pairs, representing 30,893 genetic variants in high, local linkage disequilibrium for 744 independent cis-expression quantitative trait loci (eQTL) and assessed each for colocalization across 114 traits. We identified 3,536 allele-independent regulatory regions containing 907 allele-specific regulatory variants, and found that 17.3% of eQTL contained more than one significant allelic effect. We show that detected regulatory variants are highly and specifically enriched for activating chromatin structures and allelic transcription factor binding, for which ETS-domain family members are a large driver. Integration of MPRA profiles with eQTL/complex trait colocalizations identified causal variant sets for associations with blood cell measurements, Multiple Sclerosis, Irritable Bowel Disease, and Crohns Disease. These results demonstrate that a sizable number of association signals are manifest through multiple, tightly-linked causal variants requiring high-throughput functional assays for fine-mapping.

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Section: Resultsmentioning

confidence: 99%

Section: Experimental Fine-mapping Of Complex Trait Associationsmentioning

confidence: 97%

Section: Experimental Fine-mapping Of Complex Trait Associationsmentioning

confidence: 99%

See 1 more Smart Citation

Multiple Causal Variants Underlie Genetic Associations in Humans

DeGorter

Gloudemans

Greenwald

et al. 2021

Preprint

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“…ERAP2 encodes for endoplasmic reticulum aminopeptidase 2, which is responsible for trimming peptides to optimal sizes for antigen presentation by MHC class I [53]. ERAP2 variants are associated with various immune diseases, including psoriasis [54,55]. Together, these results showed that the protective haplotype (rs2549797-G and rs2248374-G) almost certainly caused NMD to decrease ERAP2 gene expression, which appeared to reduce the risk of psoriasis.…”

Section: Candidate Functional Variants Newly Identified In Gene Regionsmentioning

confidence: 87%

An integrated analysis of public genomic data unveils a possible functional mechanism of psoriasis risk via a long-range ERRFI1 enhancer

Kubota

Suyama

2020

BMC Med Genomics

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Background: Psoriasis is a chronic inflammatory skin disease, for which genome-wide association studies (GWAS) have identified many genetic variants as risk markers. However, the details of underlying molecular mechanisms, especially which variants are functional, are poorly understood. Methods: We utilized a computational approach to survey psoriasis-associated functional variants that might affect protein functions or gene expression levels. We developed a pipeline by integrating publicly available datasets provided by GWAS Catalog, FANTOM5, GTEx, SNP2TFBS, and DeepBlue. To identify functional variants on exons or splice sites, we used a web-based annotation tool in the Ensembl database. To search for noncoding functional variants within promoters or enhancers, we used eQTL data calculated by GTEx. The data of variants lying on transcription factor binding sites provided by SNP2TFBS were used to predict detailed functions of the variants. Results: We discovered 22 functional variant candidates, of which 8 were in noncoding regions. We focused on the enhancer variant rs72635708 (T > C) in the 1p36.23 region; this variant is within the enhancer region of the ERRFI1 gene, which regulates lipid metabolism in the liver and skin morphogenesis via EGF signaling. Further analysis showed that the ERRFI1 promoter spatially contacts with the enhancer, despite the 170 kb distance between them. We found that this variant lies on the AP-1 complex binding motif and may modulate binding levels. Conclusions: The minor allele rs72635708 (rs72635708-C) might affect the ERRFI1 promoter activity, which results in unstable expression of ERRFI1, enhancing the risk of psoriasis via disruption of lipid metabolism and skin cell proliferation. Our study represents a successful example of predicting molecular pathogenesis by integration and reanalysis of public data.

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“…We have previously reported autoimmune disease associated expression quantitative trait loci (eQTL) in whole human thymus [27, 28]. As the thymic tissue is composed of 98% thymocytes and only 2% APCs [29], it is conceivable that the expression of these eQTL genes (eGenes) originated from the developing T cells.…”

Section: Resultsmentioning

confidence: 99%

Transcriptomes of antigen presenting cells in human thymus

et al. 2019

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Antigen presenting cells (APCs) in the thymus play an essential role in the establishment of central tolerance, i.e. the generation of a repertoire of functional and self-tolerant T cells to prevent autoimmunity. In this study, we have compared the transcriptomes of four primary APCs from human thymus (mTECs, CD19 + B cells, CD141 + and CD123 + DCs). We investigated a set of genes including the HLA genes, genes encoding transcriptional regulators and finally, tissue-enriched genes, i.e, genes with a five-fold higher expression in a particular human tissue. We show that thymic CD141 + DCs express the highest levels of all classical HLA genes and 67% (14/21) of the HLA class I and II pathway genes investigated in this study. CD141 + DCs also expressed the highest levels of the transcriptional regulator DEAF1 , whereas AIRE and FEZF2 expression were mainly found in primary human mTECs. We found expression of “tissue enriched genes” from the Human Protein Atlas (HPA) in all four APC types, but the mTECs were clearly dominating in the number of uniquely expressed tissue enriched genes (20% in mTECs, 7% in CD19 + B cells, 4% in CD123 + DCs and 2% in CD141 + DCs). The tissue enriched genes also overlapped with reported human autoantigens. This is, to our knowledge, the first study that performs RNA sequencing of mTECs, CD19 + B cells, CD141 + and CD123 + DCs isolated from the same individuals and provides insight into the transcriptomes of these human thymic APCs.

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Autoimmune risk variants in ERAP2 are associated with gene-expression levels in thymus

Cited by 8 publications

References 169 publications

Multiple Causal Variants Underlie Genetic Associations in Humans

Multiple Causal Variants Underlie Genetic Associations in Humans

An integrated analysis of public genomic data unveils a possible functional mechanism of psoriasis risk via a long-range ERRFI1 enhancer

Transcriptomes of antigen presenting cells in human thymus

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