A genome-wide association meta-analysis of diarrhoeal disease in young children identifies FUT2 locus and provides plausible biological pathways

Mariona Bustamante, Marie Standl, Quique Bassat, Natalia Vilor-Tejedor, Carolina Medina-Gomez, Carolina Bonilla, Tarunveer S. Ahluwalia, Jonas Bacelis, Jonathan P. Bradfield, Carla M.T. Tiesler, Fernando Rivadeneira, Susan Ring, Nadja H. Vissing, Nadia R. Fink, Astanand Jugessur, Frank D. Mentch, Ferran Ballester, Jennifer Kriebel, Jessica C. Kiefte-de Jong, Helene M. Wolsk & 19 others Sabrina Llop, Elisabeth Thiering, Systke A. Beth, Nicholas J. Timpson, Josefine Andersen, Holger Schulz, Vincent W.V. Jaddoe, David M. Evans, Johannes Waage, Hakon Hakonarson, Struan F.A. Grant, Bo Jacobsson, Klaus Bønnelykke, Hans Bisgaard, George Davey Smith, Henriette A. Moll, Joachim Heinrich, Xavier P. Estivill, Jordi Sunyer

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

More than a million childhood diarrhoeal episodes occur worldwide each year, and in developed countries a considerable part of them are caused by viral infections. In this study, we aimed to search for genetic variants associated with diarrhoeal disease in young children by meta-analyzing genome-wide association studies, and to elucidate plausible biological mechanisms. The study was conducted in the context of the Early Genetics and Lifecourse Epidemiology (EAGLE) consortium. Data about diarrhoeal disease in two time windows (around 1 year of age and around 2 years of age) was obtained via parental questionnaires, doctor interviews or medical records. Standard quality control and statistical tests were applied to the 1000 Genomes imputed genotypic data. The meta-analysis (N=5758) followed by replication (N=3784) identified a genome-wide significant association between rs8111874 and diarrhoea at age 1 year. Conditional analysis suggested that the causal variant could be rs601338 (W154X) in the FUT2 gene. Children with the A allele, which results in a truncated FUT2 protein, had lower risk of diarrhoea. FUT2 participates in the production of histo-blood group antigens and has previously been implicated in the susceptibility to infections, including Rotavirus and Norovirus. Gene-set enrichment analysis suggested pathways related to the histo-blood group antigen production, and the regulation of ion transport and blood pressure. Among others, the gastrointestinal tract, and the immune and neuro-secretory systems were detected as relevant organs. In summary, this genome-wide association meta-analysis suggests the implication of the FUT2 gene in diarrhoeal disease in young children from the general population.

Original languageEnglish
Pages (from-to)4127-4142
Number of pages16
JournalHuman Molecular Genetics
Volume25
Issue number18
DOIs
Publication statusPublished - 2016

Fingerprint

Genome-Wide Association Study
Meta-Analysis
Blood Group Antigens
Diarrhea
Genome
Genes
Rotavirus Infections
Norovirus
Molecular Epidemiology
Ion Transport
Virus Diseases
Developed Countries
Quality Control
Medical Records
Gastrointestinal Tract
Alleles
Interviews
Blood Pressure
Population
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Bustamante, M., Standl, M., Bassat, Q., Vilor-Tejedor, N., Medina-Gomez, C., Bonilla, C., ... Sunyer, J. (2016). A genome-wide association meta-analysis of diarrhoeal disease in young children identifies FUT2 locus and provides plausible biological pathways. Human Molecular Genetics, 25(18), 4127-4142. https://doi.org/10.1093/hmg/ddw264

A genome-wide association meta-analysis of diarrhoeal disease in young children identifies FUT2 locus and provides plausible biological pathways. / Bustamante, Mariona; Standl, Marie; Bassat, Quique; Vilor-Tejedor, Natalia; Medina-Gomez, Carolina; Bonilla, Carolina; Ahluwalia, Tarunveer S.; Bacelis, Jonas; Bradfield, Jonathan P.; Tiesler, Carla M.T.; Rivadeneira, Fernando; Ring, Susan; Vissing, Nadja H.; Fink, Nadia R.; Jugessur, Astanand; Mentch, Frank D.; Ballester, Ferran; Kriebel, Jennifer; Kiefte-de Jong, Jessica C.; Wolsk, Helene M.; Llop, Sabrina; Thiering, Elisabeth; Beth, Systke A.; Timpson, Nicholas J.; Andersen, Josefine; Schulz, Holger; Jaddoe, Vincent W.V.; Evans, David M.; Waage, Johannes; Hakonarson, Hakon; Grant, Struan F.A.; Jacobsson, Bo; Bønnelykke, Klaus; Bisgaard, Hans; Smith, George Davey; Moll, Henriette A.; Heinrich, Joachim; Estivill, Xavier P.; Sunyer, Jordi.

In: Human Molecular Genetics, Vol. 25, No. 18, 2016, p. 4127-4142.

Research output: Contribution to journalArticle

Bustamante, M, Standl, M, Bassat, Q, Vilor-Tejedor, N, Medina-Gomez, C, Bonilla, C, Ahluwalia, TS, Bacelis, J, Bradfield, JP, Tiesler, CMT, Rivadeneira, F, Ring, S, Vissing, NH, Fink, NR, Jugessur, A, Mentch, FD, Ballester, F, Kriebel, J, Kiefte-de Jong, JC, Wolsk, HM, Llop, S, Thiering, E, Beth, SA, Timpson, NJ, Andersen, J, Schulz, H, Jaddoe, VWV, Evans, DM, Waage, J, Hakonarson, H, Grant, SFA, Jacobsson, B, Bønnelykke, K, Bisgaard, H, Smith, GD, Moll, HA, Heinrich, J, Estivill, XP & Sunyer, J 2016, 'A genome-wide association meta-analysis of diarrhoeal disease in young children identifies FUT2 locus and provides plausible biological pathways', Human Molecular Genetics, vol. 25, no. 18, pp. 4127-4142. https://doi.org/10.1093/hmg/ddw264
Bustamante, Mariona ; Standl, Marie ; Bassat, Quique ; Vilor-Tejedor, Natalia ; Medina-Gomez, Carolina ; Bonilla, Carolina ; Ahluwalia, Tarunveer S. ; Bacelis, Jonas ; Bradfield, Jonathan P. ; Tiesler, Carla M.T. ; Rivadeneira, Fernando ; Ring, Susan ; Vissing, Nadja H. ; Fink, Nadia R. ; Jugessur, Astanand ; Mentch, Frank D. ; Ballester, Ferran ; Kriebel, Jennifer ; Kiefte-de Jong, Jessica C. ; Wolsk, Helene M. ; Llop, Sabrina ; Thiering, Elisabeth ; Beth, Systke A. ; Timpson, Nicholas J. ; Andersen, Josefine ; Schulz, Holger ; Jaddoe, Vincent W.V. ; Evans, David M. ; Waage, Johannes ; Hakonarson, Hakon ; Grant, Struan F.A. ; Jacobsson, Bo ; Bønnelykke, Klaus ; Bisgaard, Hans ; Smith, George Davey ; Moll, Henriette A. ; Heinrich, Joachim ; Estivill, Xavier P. ; Sunyer, Jordi. / A genome-wide association meta-analysis of diarrhoeal disease in young children identifies FUT2 locus and provides plausible biological pathways. In: Human Molecular Genetics. 2016 ; Vol. 25, No. 18. pp. 4127-4142.
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abstract = "More than a million childhood diarrhoeal episodes occur worldwide each year, and in developed countries a considerable part of them are caused by viral infections. In this study, we aimed to search for genetic variants associated with diarrhoeal disease in young children by meta-analyzing genome-wide association studies, and to elucidate plausible biological mechanisms. The study was conducted in the context of the Early Genetics and Lifecourse Epidemiology (EAGLE) consortium. Data about diarrhoeal disease in two time windows (around 1 year of age and around 2 years of age) was obtained via parental questionnaires, doctor interviews or medical records. Standard quality control and statistical tests were applied to the 1000 Genomes imputed genotypic data. The meta-analysis (N=5758) followed by replication (N=3784) identified a genome-wide significant association between rs8111874 and diarrhoea at age 1 year. Conditional analysis suggested that the causal variant could be rs601338 (W154X) in the FUT2 gene. Children with the A allele, which results in a truncated FUT2 protein, had lower risk of diarrhoea. FUT2 participates in the production of histo-blood group antigens and has previously been implicated in the susceptibility to infections, including Rotavirus and Norovirus. Gene-set enrichment analysis suggested pathways related to the histo-blood group antigen production, and the regulation of ion transport and blood pressure. Among others, the gastrointestinal tract, and the immune and neuro-secretory systems were detected as relevant organs. In summary, this genome-wide association meta-analysis suggests the implication of the FUT2 gene in diarrhoeal disease in young children from the general population.",
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AU - Vilor-Tejedor, Natalia

AU - Medina-Gomez, Carolina

AU - Bonilla, Carolina

AU - Ahluwalia, Tarunveer S.

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AU - Bradfield, Jonathan P.

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AU - Rivadeneira, Fernando

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AU - Fink, Nadia R.

AU - Jugessur, Astanand

AU - Mentch, Frank D.

AU - Ballester, Ferran

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AU - Kiefte-de Jong, Jessica C.

AU - Wolsk, Helene M.

AU - Llop, Sabrina

AU - Thiering, Elisabeth

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AU - Timpson, Nicholas J.

AU - Andersen, Josefine

AU - Schulz, Holger

AU - Jaddoe, Vincent W.V.

AU - Evans, David M.

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AU - Hakonarson, Hakon

AU - Grant, Struan F.A.

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AU - Sunyer, Jordi

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