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

Background 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. Methods 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. Results 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 hits for IBS, of which 38 are novel. Fine-mapping risk loci highlighted 289 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. Conclusions These findings provide evidence of the polygenic architecture of IBS, identify novel hits for IBS and extend previous knowledge on the genetic overlap and relationship between gastrointestinal and mental disorders. ### Competing Interest Statement JARQ was on the speakers bureau and/or acted as consultant for Janssen-Cilag, Novartis, Shire, Takeda, Bial, Shionogi, Sincrolab, Novartis, BMS, Medice, Technofarma, Rubio and Raffo in the last 3 years. He also received travel awards (air tickets + hotel) for taking part in psychiatric meetings from Janssen-Cilag, Rubio, Shire, Takeda, Shionogi, Bial and Medice. The Department of Mental Health chaired by him received unrestricted educational and research support from the following companies in the last 3 years: Janssen- Cilag, Shire, Oryzon, Roche, Psious, and Rubio. ARU was on the speakers bureau and/or acted as consultant for Janssen-Cilag and Organon in tha last two years. All other authors declare no biomedical financial interests or conflicts of interest. JS has served as consultant for Noventure SL, Devintecpharma, Aboca, Reckitt, Ipsen & Pileje and discloses present and past recent scientific collaborations with Salvat, Norgine, Alfa-Sigma, Cosmo, Adare, Ordesa and Danone that do not constitute a conflict of interest in developing the content of the present manuscript. MS was on the speakers bureau and/or acted as consultant/advisory Board member for Tillotts, Menarini, Kyowa Kirin, Takeda, Biocodex, AlfaSigma, Sanofi, Janssen Immunology, Pfizer, Ferrer, BioGaia, Falk Foundation, Danone Nutricia Research, Ironwood, Genetic Analysis AS, DSM, Arena, Adnovate and Pharmanovia. He also was funded by Glycom/DSM research grants. ### Funding Statement This work was supported by the Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR, 2017SGR-00444 and 2017SGR-1461); the Ministry of Science, Innovation and Universities (RYC2021-031324-I to J.C.D), the Instituto de Salud Carlos III (CP22/00128 to M.S.A and CP22/00026 to S.A) and the European Regional Development Fund (ERDF), the European Union H2020 Programme (H2020/2014-2020) under grant agreements no. 848228 (DISCOvERIE). This document is also an output of a project grant (Grant Agreement number 848228, DISCOvERIE) funded under H2020 Research Programme of the European Commission. The content of this document represents the views of the author(s) only and is his/her/their sole responsibility; it cannot be considered to reflect the views of the European Commission or any other body of the European Union. The European Commission do not accept any responsibility for use that may be made of the information it contains. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All data used in the current study is publicly available. Summary statistics for IBS can be download from European Bioinformatics Institute GWAS Catalog (https://www.ebi.ac.uk/gwas/). Summary statistics for neuroticism can be downloaded from and . Summary statistics for depression can be downloaded from . Summary statistics for anxiety can be downloaded from [http://www.nealelab.is/uk-biobank][1]. Genotype tissue expression (GTEx v8) portal: . BRAINEAC: [http://www.braineac.org][2]. eQTL catalogue: https://www.ebi.ac.uk/eqtl/Methods/. PsychENCODE: [http://resource.psychencode.org][3]. CommonMind Consortium (CMC/CMC): https://www.synapse.org//#!Synapse:syn5585484. WEB-based GEne SeT AnaLysis Toolkit (WebGestAlt): [http://www.webgestalt.org][4]. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data used in the current study is publicly available. Summary statistics for IBS can be download from European Bioinformatics Institute GWAS Catalog (). Summary statistics for neuroticism can be downloaded from and . Summary statistics for depression can be downloaded from . Summary statistics for anxiety can be downloaded from [http://www.nealelab.is/uk-biobank][1]. Genotype tissue expression (GTEx v8) portal: . BRAINEAC: [http://www.braineac.org][2]. eQTL catalogue: . PsychENCODE: [http://resource.psychencode.org][3]. CommonMind Consortium (CMC/CMC): . WEB-based GEne SeT AnaLysis Toolkit (WebGestAlt): [http://www.webgestalt.org][4]. SNP heritability and genetic correlations: . MiXeR: . Conditional analysis: . Multi-Trait Analysis of GWAS (MTAG): ). Fine-mapping: . Functional Mapping and Annotation of Genome-Wide Association Studies (FUMA): . Partitioned heritability: . MR-Base database: . Causal Analysis Using Summary Effect estimates (CAUSE): . The use of each software tools has been described in the Methods section. Analysis code and scripts used in the current study are available upon request from the corresponding * ADHD : attention-deficit/hyperactivity disorder AIC : Akaike Information Criterion ASD : autism spectrum disorders ATC : Anatomical Therapeutic Chemical CAUSE : Causal Analysis Using Summary Effect estimates IBS : irritable bowel syndrome FDR : false discovery rate ELPD : expected log pointwise posterior density FUMA : Functional Mapping and Annotation of GWAS GCTA : Genome-wide Complex Trait Analysis GWAS : Genome-wide association study h 2 SNP : SNP heritability LDSC : Linkage disequilibrium score regression MAGMA : Generalized gene-set analysis of GWAS data MTAG : Multi-Trait Analysis of GWAS [1]: https://www.nealelab.is/uk-biobank [2]: https://www.braineac.org [3]: https://resource.psychencode.org [4]: https://www.webgestalt.org