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Integrating Mendelian randomization and multiple-trait colocalization to uncover cell-specific inflammatory drivers of autoimmune and atopic disease

Research output: Contribution to journalArticle

Original languageEnglish
Number of pages8
JournalHuman Molecular Genetics
Early online date5 Jul 2019
DOIs
DateAccepted/In press - 26 Jun 2019
DateE-pub ahead of print (current) - 5 Jul 2019

Abstract

Immune mediated diseases (IMDs) arise when tolerance is lost and chronic inflammation is targeted towards healthy tissues. Despite their growing prevalence, therapies to treat IMDs are lacking. Cytokines and their receptors orchestrate inflammatory responses by regulating elaborate and complex signaling networks across multiple cell-types; making it challenging to pinpoint therapeutically relevant drivers of IMDs. We developed an analytical framework which integrates Mendelian randomization (MR) and multiple-trait colocalization (moloc) analyses to highlight putative cell-specific drivers of IMDs. MR evaluated causal associations between the levels of 10 circulating cytokines and 9 IMDs within human populations. Subsequently, we undertook moloc analyses to assess whether IMD trait, cytokine protein and corresponding gene expression are driven by a shared causal variant. Moreover, we leveraged gene expression data from 3 separate cell-types (monocytes, neutrophils and T cells) to discern whether associations may be attributed to cell-type specific drivers of disease. MR analyses supported a causal role for IL-18 in inflammatory bowel disease (IBD) (P = 1.17 x 10-4) and eczema/dermatitis (P = 2.81 x 10-3), as well as associations between IL-2rα and IL-6R with several other IMDs. Multiple-trait colocalization strengthened evidence of a causal association for these results, as well as providing evidence of a monocyte and neutrophil-driven role for IL-18 in IBD pathogenesis. In contrast, IL-2rα and IL-6R associations were found to be T cell specific. Our analytical pipeline can help to elucidate putative molecular pathways in the pathogeneses of IMDs, which could be applied to other inflammatory disease contexts.

    Research areas

  • mendelian randomisation, multiple-trait colocalization, autoimmunity, atopy, cytokines, epidemiology

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