Cross-definition GWAS of IBS in 2.8 million individuals reveals cardiometabolic and triglyceride-linked mechanisms, 2026, Di Lorenzo

Dolphin

Dolphin

Senior Member (Voting Rights)
PDF

Neurogastroenterology

Original research

Cross-definition GWAS of IBS in 2.8 million individuals reveals cardiometabolic and triglyceride-linked mechanisms


  1. Biagio Di Lorenzo1,
  2. Leticia Camargo Tavares2,3,4,5,
  3. http://orcid.org/0000-0002-1593-2885Cristian Díaz-Muñoz6,
  4. Francisco Heredia-Fernández6,
  5. Isotta Bozzarelli1,
  6. Cristina Esteban Blanco6,
  7. Zhe Wang7,8,
  8. Roelof A J Smit8,9,
  9. Ruth J F Loos8,9,
  10. Jibril Hirbo10,11,
  11. Nancy J Cox10,11,
  12. Peter Straub10,11,
  13. Marie-Julie Favé12,13,
  14. Philip Awadalla14,15,
  15. Nikita Pozdeyev16,17,18,19,
  16. Christopher R Gignoux16,18,19,20,
  17. Colorado Center for Personalized Medicine,
  18. Daniel F Gudbjartsson21,22,
  19. Gudmar Thorleifsson21,
  20. Ingileif Jonsdottir21,23,
  21. Kari Stefansson21,23,
  22. http://orcid.org/0000-0002-6529-3161Erik Abner24,
  23. Priit Palta24,
  24. Estonian Biobank Research Team,
  25. Alexander T Williams25,
  26. Kayesha Coley25,26,
  27. Gerald Sze25,26,
  28. Catherine John25,26,
  29. Anne Richmond27,
  30. Daniel McCartney27,
  31. Caroline Hayward27,
  32. Ashley J Mulford28,
  33. Alan R Sanders28,29,
  34. Raitis Peculis30,
  35. Vita Rovite30,
  36. Marija Simona Dombrovska30,
  37. Mario Capasso31,32,
  38. Valeria Lo Faro33,34,
  39. Trishla Sinha35,
  40. Esteban Alexander Lopera Maya35,
  41. Alexandra Zhernakova35,
  42. Lifelines Cohort,
  43. Ying Wang36,37,38,
  44. Alicia Martin36,37,38,
  45. Brett Vanderwerff39,
  46. Sebastian Zöllner39,40,
  47. Brian R Ferolito41,42,43,
  48. Alexander C Pereira41,42,43,
  49. John Michael Gaziano41,42,43,
  50. Kelly Cho41,42,43,
  51. Lanna Caruth44,
  52. Lindsay Guare44,
  53. Colleen M Kripke45,
  54. Daniel J Rader46,
  55. Shefali S Verma47,
  56. Anurag Verma45,
  57. Penn Medicine BioBank,
  58. Chadi Saad48,
  59. Hamdi Mbarek48,
  60. Pei-Yu Chao49,
  61. Tzu-Ting Chen50,
  62. Yen-Feng Lin50,
  63. Yen-Chen Anne Feng49,51,
  64. http://orcid.org/0009-0007-4043-3387Prasanna K Challa4,5,
  65. http://orcid.org/0000-0002-7956-6941Hamed Khalili4,5,43,52,
  66. Aristomo Andries53,
  67. http://orcid.org/0000-0001-6005-0729Eivind Ness-Jensen54,55,56,
  68. Ben Michael Brumpton53,54,57,
  69. http://orcid.org/0000-0001-5092-0831Madhusudan Grover58,
  70. FinnGen,
  71. Susanna Lemmelä59,60,
  72. Serena Sanna33,35,
  73. Ferdinando Bonfiglio31,32,
  74. http://orcid.org/0000-0003-2743-5197Mauro D’Amato1,6,61
  75. Correspondence to Professor Mauro D’Amato; damato@lum.it

Abstract​

Background Irritable bowel syndrome (IBS) is a complex disorder of gut-brain interaction, with heterogeneous symptoms, no available biomarkers and limited pathogenetic insight.
Objective To identify genetic risk factors and actionable mechanisms for future clinical translation in IBS.
Design We conducted a genome-wide association study (GWAS) meta-analysis of IBS in 2 775 539 individuals from 22 biobanks. IBS genetics was studied across multiple ancestries, different case definitions and symptom-related subtypes. Heritability and genetic correlations with other traits were estimated, and Mendelian randomisation was used to test causal relationships. GWAS data were functionally annotated and fine-mapped to prioritise tissues, cell types, pathways, candidate genes, specific mechanisms and druggable targets.
Results Significant heritability was only detected in individuals of European ancestry, with near-identical genetic architecture across case definitions. Genetic correlations with GI, psychiatric and cardiometabolic traits were observed, including causal relationships with triglyceride (TG) levels. Functional annotation of IBS risk loci highlighted cell types and pathways relevant to brain, enteric neuro-glial and cardiometabolic domains, as well as actionable targets like GCKR, a regulator of TG metabolism. Druggability analyses converged on cardiometabolic mechanisms, including TG modulation. IBS polygenic risk scores were derived and showed a significant association with case status in an independent case-control dataset, supporting further evaluation in external population-based and clinically ascertained cohorts.
Conclusions This study provides the most comprehensive assessment of IBS genetics to date, demonstrating reproducible polygenic inheritance. We link IBS risk to convergent neurogastrointestinal and novel cardiometabolic mechanisms, highlight specific biological pathways and actionable mechanisms and outline translational opportunities emerging from integrated computational analyses.
 
www.eurekalert.org

Genetic study links irritable bowel syndrome to lipid metabolism and triglyceride regulation

In the largest genetic study of irritable bowel syndrome (IBS) to date, researchers analysed DNA and health-related data from nearly 2.8 million people. The results point to new biological mechanisms connecting IBS with lipid metabolism and broader cardiometabolic health.
www.eurekalert.org

NEWS RELEASE 9-JUL-2026

Genetic study links irritable bowel syndrome to lipid metabolism and triglyceride regulation​

Peer-Reviewed Publication
CIC BIOGUNE


FacebookXLinkedInWeChatBlueskyMessageWhatsAppEmail

Irritable bowel syndrome (IBS) is a common condition that affects more than 10% of the general population, causing recurrent abdominal pain, bloating, constipation and diarrhoea. IBS is considered a disorder of gut-brain interaction, and previous research, including genetic research, has established links to nerve signalling, the nervous system and other conditions including anxiety and mood disorders. The exact biological mechanisms have however, remained frustratingly difficult to pin down, leaving many patients without effective, targeted treatments.

Now, a major new study published in Gut suggests that metabolism, specifically the regulation of blood fats known as triglycerides, may be a missing piece of the puzzle.

An international team led by Mauro D’Amato, Professor of Medical Genetics at LUM University and IkerbasqueResearch Professor at CIC bioGUNE, member of BRTA, conducted the most comprehensive assessment of IBS genetics to date. They analysed genetic and health data from 2,775,539 individuals across 22 biobanks worldwide, comparing people with and without IBS to find DNA differences associated with the condition.

The analysis identified 35 regions of the human genome linked to IBS risk. While several of these genetic signals pointed to the brain and enteric nervous system (the network of nerves controlling the gut), researchers also found a strong, unexpected overlap with cardiometabolic traits.

Using advanced computational methods, the team demonstrated a likely causal link between genetic liability for IBS and elevated levels of triglycerides, a type of fat found in the blood. The strongest evidence pointed to a specific variation in the GCKR gene, which acts as a master regulator of glucose and lipid metabolism in the liver. This variant, already known to promote fat accumulation in the liver and increase triglyceride production, was identified as a key mechanism connecting liver metabolism to IBS risk.

“We have long known that IBS involves a complex dialogue between the gut and the brain, but these results show that the conversation includes the body's metabolic system too,” said Prof. D’Amato. “The genetic link to triglyceride regulation and liver function gives us a completely new framework for understanding the condition.”

Importantly, the study also pointed to potential translational applications. By analysing gene-expression patterns associated with IBS risk, the team identified several compounds capable of reversing disease-related molecular signatures; among these were cardiovascular and lipid-modifying drugs, thus opening the door to possible drug repurposing strategies and mechanism-based therapies.

“Our findings support a more integrated view of IBS that extends beyond the traditional gut-brain axis,” added Prof D'Amato. “The specific pathways we highlighted may contribute to mechanism-based patient stratifications and the identification of new or existing drugs to be tested in patients who do not respond to current therapies.”

The study was conducted under the auspices of the “bellygenes initiative” coordinated by Prof. D’Amato, a large international collaboration involving academic and clinical, partners across Europe, North America and other regions, and drawing on data from several cohorts and major population-based biobanks including UK Biobank, FinnGen, the Million Veteran Program, All of Us and many others.

The research was supported by multiple individual grants including, among many others, MCIU/AEI/10.13039/501100011033 and ERDF/EU (PID2023-148957OB-I00); PRIN2022/NextGenerationEU (2022PMZKEC); The All of Us Research Program and the National Institutes of Health; the National Heart, Lung, and Blood Institute; the Estonian Research Council; the Wellcome; the Medical Research Council; the British Heart Foundation; the Scottish Government Health Directorates and the Scottish Funding Council; the Wellcome Trust; Endeavor Health; the Research Council of Norway; the Stiftelsen Kristian Gerhard Jebsen; the NWO Gravitation grant ExposomeNL; Mayo Clinic Biobank; European Union’s Horizon 2020 program; the Million Veteran Program.

Reference: Di Lorenzo B, Camargo Tavares L, Díaz-Muñoz C, et al. Cross-definition GWAS of irritable bowel syndrome in 2.8 million individuals reveals cardiometabolic and triglyceride-linked mechanisms. Gut. DOI: 10.1136/gutjnl-2026-338800

About CIC bioGUNE

The Centre for Cooperative Research in Biosciences (CIC bioGUNE), member of the Basque Research & Technology Alliance (BRTA), located in the Bizkaia Technology Park, is a biomedical research organisation conducting cutting-edge research at the interface between structural, molecular and cell biology, with a particular focus on generating knowledge on the molecular bases of disease, for use in the development of new diagnostic methods and advanced therapies.

About Ikerbasque

Ikerbasque -Basque Foundation for Science- is the result of an initiative of the Department of Education of the Basque Government that aims to reinforce the commitment to scientific research by attracting, recovering and consolidating excellent researchers from all over the world. Currently, it is a consolidated organization that has 290 researchers/s, who develop their work in all fields of knowledge.

About BRTA

BRTA is an alliance of 4 collaborative research centres (CIC bioGUNE, CIC nanoGUNE, CIC biomaGUNE y CIC energiGUNE) and 13 technology centres (Azterlan, Azti, Ceit, Cidetec, Gaiker, Ideko, Ikerlan, Leartiker, Lortek, Neiker, Tecnalia, Tekniker y Vicomtech) with the main objective of developing advanced technological solutions for the Basque corporate fabric.

With the support of the Basque Government, the SPRI Group and the Provincial Councils of the three territories, the alliance seeks to promote collaboration between the research centres, strengthen the conditions to generate and transfer knowledge to companies, contributing to their competitiveness and outspreading the Basque scientific-technological capacity abroad.

BRTA has a workforce of 3,500 professionals, executes 22 % of the Basque Country's R&D investment, registers an annual turnover of more than 300 million euros and generates 100 European and international patents per year.

JOURNAL​

Gut

DOI​

10.1136/gutjnl-2026-338800

ARTICLE TITLE​

Cross-definition GWAS of irritable bowel syndrome in 2.8 million individuals reveals cardiometabolic and triglyceride-linked mechanisms

ARTICLE PUBLICATION DATE​

9-Jul-
 
It is a pity that what is written is so embroidered with interpretation rather than just giving us data.

I find IBS a hard category to pin down. I suspect that biobank data may be heavily biased by common morbidities like obesity and insulin resistance. It would be useful to know if there were any overlaps with DecodeME genes of course.
 
You must log in or register to reply here.
Back
Top Bottom