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. 2023 Apr 21;21(1):272.
doi: 10.1186/s12967-023-04107-5.

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

Silvia Alemany  1   2   3 , María Soler-Artigas  4   5   6   7 , Judit Cabana-Domínguez  4   5   6 , Dana Fakhreddine  4 , Natalia Llonga  4   5 , Laura Vilar-Ribó  4   5   6 , Amanda Rodríguez-Urrutia  4   5   6   8 , Judit Palacio  5 , Ana María González-Castro  9 , Beatriz Lobo  9   10   11 , Carmen Alonso-Cotoner  9   10   11   12 , Magnus Simrén  13   14 , Javier Santos  9   10   11   12 , Josep Antoni Ramos-Quiroga  4   5   6   8 , Marta Ribasés  15   16   17   18
Affiliations

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

Silvia Alemany et al. J Transl Med. .

Abstract

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 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.

Conclusions: 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.

Keywords: Anxiety; Depression; Irritable bowel syndrome (IBS); Multi-trait genome-wide association study (MTAG); Neuroticism.

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Conflict of 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, Rubió and Raffo in the last 3 years. He also received travel awards (air tickets + hotel) for taking part in psychiatric meetings from Janssen-Cilag, Rubió, 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 Rubió. 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 and 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.

Figures

Fig. 1
Fig. 1
MTAG results of IBS and overlap with previous GWAS on IBS, neuroticism, depression and anxiety. a Z-scores of MTAG-IBS and original GWAS on IBS, neuroticism, depression and anxiety for each of the independent lead SNPs (n = 42) found in MTAG-IBS results. Dotted grey line indicates 0 Z-score and solid grey lines indicate statistical significance at P < 5-E08. b Manhattan plot of the MTAG-IBS results. Dotted grey line indicates statistical significance at P < 5-E08. c QQ plot of the MTAG-IBS results. d Venn diagram depicting overlap among MTAG-IBS independent lead SNPs and genome-wide significant SNPs in the original GWAS
Fig. 2
Fig. 2
Follow-up analysis of MTAG-IBS results and causal analysis. a Functional annotation of the credible variants associated with MTAG-IBS. b RegulomeDB scores of the credible variants associated with MTAG-IBS. Low scores indicate increasing likelihood of having regulatory function. c Distribution of the credible variants associated with MTAG-IBS across 15 categories of minimum chromatin state. Lower state indicating higher accessibility and states from 1 to 7 refer to open chromatin states. d Genetic correlations (rg) between MTAG-IBS results and 17 phenotypes involving digestive, immunological and psychiatric disorders. Only significant correlations after Bonferroni correction are displayed. e Bar graphs depicting the size of the genomic locus (left), number of candidate SNPs in the locus (center) and number of mapped genes in the genomic locus (right). Genomic loci are displayed by “chromosome: start position-end position”. f Partitioning of the SNP heritability of the MTAG-IBS results using LD Score regression. Enrichment was calculated by dividing the partial heritability of a category by the proportion of SNPs in that category (proportion indicated by color). Only significant enrichments are displayed. g Causal relationships between IBS and neuroticism, depression and anxiety assessed using Causal Analysis Using Summary Effect estimates (CAUSE). Only associations with evidence of causal relationship are displayed
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