in-silico and in-vitro analysis of IL36RN mutations reveals critical residues for the function of the interleukin-36 receptor complex

Generalized pustular psoriasis (GPP) is a potentially life-threatening skin disease, associated with IL36RN mutations. IL36RN encodes the interleukin (IL)-36 receptor antagonist (IL-36Ra), a protein that downregulates the activity of IL-36 cytokines by blocking their receptor (IL-36R). While GPP can be treated with IL-36R inhibitors, the structural underpinnings of the IL-36Ra/IL-36R interaction remain poorly understood. Here, we sought to address this question by systematically investigating the effects of IL36RN mutations. We experimentally characterized the effects of 30 IL36RN variants on protein stability. In parallel, we used a machine-learning tool (Rhapsody) to analyse the IL-36Ra three-dimensional structure and predict the impact of all possible amino acid substitutions. This integrated approach identified 21 amino acids that are essential to IL-36Ra stability. We next investigated the effects of IL36RN changes on IL-36Ra/IL-36R binding and IL-36R signalling. By combining in-vitro assays and machine-learning with a second programme (mCSM), we identified 13 amino acids that are critical to IL-36Ra/IL36R engagement. Finally, we experimentally validated three representative predictions, further confirming the reliability of Rhapsody and mCSM. These findings shed light on the structural determinants of IL-36Ra activity, with potential to facilitate the design of new IL-36 inhibitors and aid the interpretation of IL36RN variants in diagnostic settings

Genome-wide multi-trait analysis of irritable bowel syndrome and related mental conditions identifies 38 new independent variants

Irritable bowel syndrome (IBS) is a chronic disorder of gut-brain interaction frequently accompanied by mental conditions, including depression and anxiety. Despite showing substantial heritability and being partly determined by a genetic component, the genetic underpinnings explaining the high rates of comorbidity remain largely unclear and there are no conclusive data on the temporal relationship between them. Exploring the overlapping genetic architecture between IBS and mental conditions may help to identify novel genetic loci and biological mechanisms underlying IBS and causal relationships between them. We quantified the genetic overlap between IBS, neuroticism, depression and anxiety, conducted a multi-trait genome-wide association study (GWAS) considering these traits and investigated causal relationships between them by using the largest GWAS to date. IBS showed to be a highly polygenic disorder with extensive genetic sharing with mental conditions. Multi-trait analysis of IBS and neuroticism, depression and anxiety identified 42 genome-wide significant variants for IBS, of which 38 are novel. Fine-mapping risk loci highlighted 289 genes enriched in genes upregulated during early embryonic brain development and gene-sets related with psychiatric, digestive and autoimmune disorders. IBS-associated genes were enriched for target genes of anti-inflammatory and antirheumatic drugs, anesthetics and opioid dependence pharmacological treatment. Mendelian-randomization analysis accounting for correlated pleiotropy identified bidirectional causal effects between IBS and neuroticism and depression and causal effects of the genetic liability of IBS on anxiety. These findings provide evidence of the polygenic architecture of IBS, identify novel genome-wide significant variants for IBS and extend previous knowledge on the genetic overlap and relationship between gastrointestinal and mental disorders. The online version contains supplementary material available at 10.1186/s12967-023-04107-5

Investigating the Genetic Basis of the Co-occurrence of Irritable Bowel Syndrome and Anxiety

Curs 2020-2021Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder representing a serious burden to the healthcare system. IBS research is extremely challenging due to the multifactorial etiology of the disease and the heterogeneity of patients that present high comorbidity rates with mental disorders including anxiety and depression. Such highly comorbid disorders show substantial heritability and are partly determined by a genetic component. In the present study, we used data available from large pre-existing genome-wide association studies on IBS (n=455,321) and anxiety (n=117,751) to assess the genetic overlap and causal relationship between these comorbid disorders and found strong and positive genetic correlation between them (rg=0.713, se= 0.076, P= 3.6e-20). The multi-trait analysis of GWAS (MTAG) highlighted three new genome-wide significant loci for IBS located in, or nearby, genes related to synaptic transmission, nervous system development, neuroticism, and epigenetic modification of chromatin. We also used Mendelian randomization with a range of sensitivity analyses to clarify the causal relationship between these disorders and found consistent evidence for a causal effect of the genetic liability of IBS on anxiety (P=7.6e-05) but no evidence of causal effect was detected in the opposite direction. Our results are consistent with a shared common genetic background between IBS and anxiety, highlight the importance of common genetic factors in the risk of these comorbid disorders, and add insight into the relationship between gastrointestinal and mental illnesses.Director/a: Mireia OlivellaSupervisor/a: Silvia Alemany i Marta Ribasé