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; Tarun Veer Singh Ahluwalia; Jonas Bacelis; Jonathan P Bradfield; Carla M T Tiesler; Fernando Rivadeneira; Susan M Ring; Nadja Hawwa Vissing; Nadia R Fink; Astanand Jugessur; Frank D Mentch; Ferran Ballester; Jennifer Kriebel; Jessica C Kiefte-de Jong; Helene M Wolsk; 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 Estivill; Jordi Sunyer

doi:10.1093/hmg/ddw264

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, Tarun Veer Singh Ahluwalia, Jonas Bacelis, Jonathan P Bradfield, Carla M T Tiesler, Fernando Rivadeneira, Susan M Ring, Nadja Hawwa Vissing, Nadia R Fink, Astanand Jugessur, Frank D Mentch, Ferran Ballester, Jennifer Kriebel, Jessica C Kiefte-de Jong, Helene M WolskSabrina 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 Estivill, Jordi Sunyer

Department of Clinical Medicine

20 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 language	English
Journal	Human Molecular Genetics
Volume	25
Issue number	18
Pages (from-to)	4127-4142
ISSN	0964-6906
DOIs	https://doi.org/10.1093/hmg/ddw264
Publication status	Published - 15 Sept 2016

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Bustamante, M., Standl, M., Bassat, Q., Vilor-Tejedor, N., Medina-Gomez, C., Bonilla, C., Ahluwalia, T. V. S., Bacelis, J., Bradfield, J. P., Tiesler, C. M. T., Rivadeneira, F., Ring, S. M., Vissing, N. H., Fink, N. R., Jugessur, A., Mentch, F. D., Ballester, F., Kriebel, J., Kiefte-de Jong, J. 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

Bustamante, M, Standl, M, Bassat, Q, Vilor-Tejedor, N, Medina-Gomez, C, Bonilla, C, Ahluwalia, TVS, Bacelis, J, Bradfield, JP, Tiesler, CMT, Rivadeneira, F, Ring, SM, 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, Davey-Smith, G, Moll, HA, Heinrich, J, Estivill, X & 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

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

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.",

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

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T1 - A genome-wide association meta-analysis of diarrhoeal disease in young children identifies FUT2 locus and provides plausible biological pathways

AU - Bustamante, Mariona

AU - Standl, Marie

AU - Bassat, Quique

AU - Vilor-Tejedor, Natalia

AU - Medina-Gomez, Carolina

AU - Bonilla, Carolina

AU - Ahluwalia, Tarun Veer Singh

AU - Bacelis, Jonas

AU - Bradfield, Jonathan P

AU - Tiesler, Carla M T

AU - Rivadeneira, Fernando

AU - Ring, Susan M

AU - Vissing, Nadja Hawwa

AU - Fink, Nadia R

AU - Jugessur, Astanand

AU - Mentch, Frank D

AU - Ballester, Ferran

AU - Kriebel, Jennifer

AU - Kiefte-de Jong, Jessica C

AU - Wolsk, Helene M

AU - Llop, Sabrina

AU - Thiering, Elisabeth

AU - Beth, Systke A.

AU - Timpson, Nicholas J

AU - Andersen, Josefine

AU - Schulz, Holger

AU - Jaddoe, Vincent W V

AU - Evans, David M

AU - Waage, Johannes

AU - Hakonarson, Hakon

AU - Grant, Struan F A

AU - Jacobsson, Bo

AU - Bønnelykke, Klaus

AU - Bisgaard, Hans

AU - Davey-Smith, George

AU - Moll, Henriette A

AU - Heinrich, Joachim

AU - Estivill, Xavier

AU - Sunyer, Jordi

PY - 2016/9/15

Y1 - 2016/9/15

N2 - 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.

AB - 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.

U2 - 10.1093/hmg/ddw264

DO - 10.1093/hmg/ddw264

M3 - Journal article

C2 - 27559109

SN - 0964-6906

VL - 25

SP - 4127

EP - 4142

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 18

ER -

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

Abstract

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