A genetics-led approach defines the drug target landscape of 30 immune-related traits

Fang, Hai; Wolf, Hans; Knezevic, Bogdan; Burnham, Katie L; Osgood, Julie; Sanniti, Anna; Lara, Alicia Lledó; Kasela, Silva; Cesco, Stéphane De; Wegner, Jörg K.; Handunnetthi, Lahiru; McCann, Fiona E.; Chen, L; Sekine, Takuya; Brennan, P.E.; Marsden, Brian D.; Damerell, David; O’Callaghan, C A; Bountra, C.; Bowness, Paul; Sundström, Yvonne; Milani, Lili; Berg, Louise; Göhlmann, Hinrick W. H.; Peeters, Pieter J.; Fairfax, Benjamin P.; Sundström, M.; Knight, Julian C.

doi:10.1038/s41588-019-0456-1

Cited by 182 publications

(206 citation statements)

References 68 publications

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“…Phenotypically, psoriasis, is a disease primarily affecting skin barrier and this locus possibly explain some of the genetic background that leads to developing the disease. These novel connections have the potential to be used as therapeutic targets in drug repurposing and discovery, as recently applied for other diseases (Fang et al 2019;Martin et al 2019).…”

Section: Discussionmentioning

confidence: 99%

An active chromatin interactome in relevant cell lines elucidates biological mechanisms at genetic risk loci for dermatological traits

Shi

Ray-Jones

Ding

et al. 2020

Preprint

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In the last 15 years Genome wide association studies (GWAS) have uncovered the genetic factors that contribute to disease risk for many disorders, yet the biological significance of many of these associations remain unclear. This is because about 90% of these variants are predicted to affect regulatory elements that are highly cell-type specific and can affect distal genes through chromatin interaction mechanisms and, therefore, understanding their role in disease is challenging.Previous studies have attempted to use chromatin conformation methods to describe the functional mechanism in disease associated loci. However, the majority of these studies have focused on cell lines derived from blood, which might not be the most relevant cell lines for dermatological conditions.Here, we generated HiChIP for H3K27ac, Hi-C and RNA-seq datasets from a keratinocyte and a skinplaque derived CD8+ T cell line. We studied their active chromatin conformation with the aim to identify biological mechanisms that could be affected by variants associated with skin related diseases: psoriasis (Ps), psoriatic arthritis (PsA), systemic sclerosis (SSc), melanoma and atopic dermatitis.In our analysis we show that HiChIP interactions provide functional evidence for gene regulation by showing that enhancers linked to genes that respond to IFN-γ stimulation are strongly enriched for motifs for TFs related to the stimulation. We also show that by using chromatin conformation we can recall 53% of eQTLs identified by GTEx in skin.In addition to our datasets, we integrated public datasets for a B cell-like lymphoblastoid cell line and primary CD4+ T cells to expand our analysis to include GWAS variants associated with the aforementioned diseases likely to be mediated specifically by B cells and CD4+ T cells (such as in systemic sclerosis and melanoma). We then identified the numerous genes that interact with GWAS variants associated and show that these genes strongly enrich for pathways that are related to the trait studied. For example, the top enriched pathways for autoimmune conditions such as PsA and psoriasis included responses to cytokines and T cell regulation, whereas for melanoma they were related to replicative senescence.We show examples of how our analysis can inform changes in the current description of a few psoriasis associated risk loci. For example, the variant rs10794648, which had previously been assigned to IFNLR1, was linked to GRHL3 in our dataset, a gene essential in skin repair and development. This can indicate a renewed importance of skin related factors in the risk of disease.In conclusion, this study allows us to further characterize disease risk loci by using novel chromatin conformation techniques, which can help identify the genes that are putatively involved in disease and has the potential to identify therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

An active chromatin interactome in relevant cell lines elucidates biological mechanisms at genetic risk loci for dermatological traits

Shi

Ray-Jones

Ding

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…We extend this analysis with the use of a larger, more highly powered GWAS and network-based methods to implicate additional genes with potential relevance in AD pathology. A recently published study used genetic information and network-based methods to develop a priority index for drug target validation in immune-mediated traits [28].…”

Section: Discussionmentioning

confidence: 99%

An Integrative Network-based Analysis Reveals Gene Networks, Biological Mechanisms, and Novel Drug Targets in Alzheimer’s Disease

Gerring

Gamazon

White

et al. 2019

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Alzheimer's disease is a highly heritable and severe neuropsychiatric condition. Genomewide association studies have identified multiple genetic risk factors underlying susceptibility to Alzheimer's disease, however their functional impact remains poorly understood. To overcome this shortcoming, we integrated genome-wide association summary statistics (71,880 cases, 338,378 controls) with tissue-specific gene co-expression networks derived from GTEx to identify functional gene co-expression networks underlying the disease. We found genetic variants associated with Alzheimer's disease are enriched in gene coexpression networks involved in immune response-related biological processes. The implicated gene co-expression networks are preserved across multiple brain and peripheral tissues, highlighting the potential utility of peripheral tissues in genetic studies of Alzheimer's disease. We also performed a computational drug repositioning analysis by integrating gene expression changes within Alzheimer's disease modules with drug-gene signatures from the Connectivity Map, and show disease implicated networks retrieve known Alzheimer's disease drugs and novel drug repurposing candidates for follow-up functional studies. Our results improve the biological interpretation of recent genetic data for Alzheimer's disease and provide a list of potential anti-dementia drug repositioning candidates of which the efficacy should be investigated in functional validation studies.

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“…A previous GWAS study has incorporated PPI with 98 annotated RA risk genes to predict new drug targets, and highlighted CDK6 and CDK4 as promising candidates [47]. The incorporation of functional genomic and immune-related annotations as well as PPI has been demonstrated successfully in prioritizing potential drug target on immune-related traits [48]. Consistently, our study integrated both genetic association and PPI, and prioritized 25 candidate drug target genes on 7 autoimmune diseases, including many genes (16/25) with known indications on autoimmune diseases or other diseases.…”

Section: Discussionmentioning

confidence: 99%

Dissecting molecular regulatory mechanisms underlying noncoding susceptibility SNPs associated with 19 autoimmune diseases using multi-omics integrative analysis

Chen

Guo

Duan

et al. 2019

Preprint

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14The genome-wide association studies (GWAS) have identified hundreds of 15 susceptibility loci associated with autoimmune diseases. However, over 90% of risk 16 variants are located in the noncoding regions, leading to great challenges in 17 deciphering the underlying causal functional variants/genes and biological 18 mechanisms. Previous studies focused on developing new scoring method to 19 prioritize functional/disease-relevant variants. However, they principally 20 incorporated annotation data across all cells/tissues while omitted the cell-specific or 21 context-specific regulation. Moreover, limited analyses were performed to dissect the 22 detailed molecular regulatory circuits linking functional GWAS variants to disease 23 etiology. Here we devised a new analysis frame that incorporate hundreds of immune 24 cell-specific multi-omics data to prioritize functional noncoding susceptibility SNPs 25 with gene targets and further dissect their downstream molecular mechanisms and 26 clinical applications for 19 autoimmune diseases. Most prioritized SNPs have genetic 27 associations with transcription factors (TFs) binding, histone modification or 28 chromatin accessibility, indicating their allelic regulatory roles on target genes. Their 29 target genes were significantly enriched in immunologically related pathways and 30other immunologically related functions. We also detected long-range regulation on 31 90.7% of target genes including 132 ones exclusively regulated by distal SNPs (eg, 32 CD28, IL2RA), which involves several potential key TFs (eg, CTCF), suggesting the 33 important roles of long-range chromatin interaction in autoimmune diseases. 34Moreover, we identified hundreds of known or predicted druggable genes, and 35 predicted some new potential drug targets for several autoimmune diseases, including 36 two genes (NFKB1, SH2B3) with known drug indications on other diseases, 37 highlighting their potential drug repurposing opportunities. In summary, our analyses 38 may provide unique resource for future functional follow-up and drug application on 39 autoimmune diseases, which are freely available at http://fngwas.online/. 40 41 42 3 Author Summary 43Autoimmune diseases are groups of complex immune system disorders with high 44 prevalence rates and high heritabilities. Previous studies have unraveled thousands 45 of SNPs associated with different autoimmune diseases. However, it remains largely 46 unknown on the molecular mechanisms underlying these genetic associations. 47Striking, over 90% of risk SNPs are located in the noncoding region. By leveraging 48 multiple immune cell-specific multi-omics data across genomic, epigenetic, 49 transcriptomic and 3D chromatin interaction information, we systematically analyzed 50 the functional variants/genes and biological mechanisms underlying genetic 51 association on 19 autoimmune diseases. We found that most functional SNPs may 52 affect target gene expression through altering transcription factors (TFs) binding, 53 histone modification or chromatin acce...

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A genetics-led approach defines the drug target landscape of 30 immune-related traits

Cited by 182 publications

References 68 publications

An active chromatin interactome in relevant cell lines elucidates biological mechanisms at genetic risk loci for dermatological traits

An active chromatin interactome in relevant cell lines elucidates biological mechanisms at genetic risk loci for dermatological traits

An Integrative Network-based Analysis Reveals Gene Networks, Biological Mechanisms, and Novel Drug Targets in Alzheimer’s Disease

Dissecting molecular regulatory mechanisms underlying noncoding susceptibility SNPs associated with 19 autoimmune diseases using multi-omics integrative analysis

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