PT - JOURNAL ARTICLE AU - Marianna Parlato AU - Julia Pazmandi AU - Qing Nian AU - Fabienne Charbit-Henrion AU - Bernadette Bègue AU - Emmanuel Martin AU - Marini Thian AU - Felix Müller AU - Marco Maggioni AU - Rémi Duclaux-Loras AU - Frederic Rieux-Laucat AU - Thierry-Jo Molina AU - Sylvain Latour AU - Frank Ruemmele AU - Jörg Menche AU - Fernando Rodrigues-Lima AU - Kaan Boztug AU - Nadine Cerf-Bensussan TI - Network Analysis of Inflammatory Bowel Disease Reveals PTPN2 As New Monogenic Cause of Intestinal Inflammation AID - 10.1101/768028 DP - 2019 Jan 01 TA - bioRxiv PG - 768028 4099 - http://biorxiv.org/content/early/2019/09/16/768028.short 4100 - http://biorxiv.org/content/early/2019/09/16/768028.full AB - BACKGROUND & AIMS Genome-wide association studies (GWAS) have uncovered multiple loci associated with inflammatory bowel disease (IBD), yet delineating functional consequences is complex. We used a network-based approach to uncover traits common to monogenic and polygenic forms of IBD in order to reconstruct disease relevant pathways and prioritize causal genes.METHODS We have used an iterative random walk with restart to explore network neighborhood around the core monogenic IBD cluster and disease-module cohesion to identify functionally relevant GWAS genes. Whole exome sequencing was used to screen a cohort of monogenic IBD for germline mutations in top GWAS genes. One mutation was identified and validated by a combination of biochemical approaches.RESULTS Monogenic IBD genes clustered siginificantly on the molecular networks and had central roles in network topology. Iterative random walk from these genes allowed to rank the GWAS genes, among which 14 had high disease-module cohesion and were selected as putative causal genes. As a proof of concept, a germline loss of function mutation was identified in PTPN2, one of the top candidates, as a novel genetic etiology of early-onset intestinal autoimmunity. The mutation abolished the catalytic activity of the enzyme, resulting in haploinsufficiency and hyper-activation of the JAK/STAT pathway in lymphocytes.CONCLUSIONS Our network-based approach bridges the gap between large-scale network medicine prediction and single-gene defects and underscores the crucial need of fine tuning the JAK/STAT pathway to preserve intestinal immune homeostasis. Our data provide genetic-based rationale for using drugs targeting the JAK/STAT pathway in IBD.