Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome

Ferdinando Bonfiglio; Tenghao Zheng; Koldo Garcia-Etxebarria; Fatemeh Hadizadeh; Luis Bujanda; Francesca Bresso; Lars Agreus; Anna Andreasson; Aldona Dlugosz; Greger Lindberg; Peter T. Schmidt; Pontus Karling; Bodil Ohlsson; Magnus Simren; Susanna Walter; Gerardo Nardone; Rosario Cuomo; Paolo Usai-Satta; Francesca Galeazzi; Matteo Neri; Piero Portincasa; Massimo Bellini; Giovanni Barbara; Anna Latiano; Matthias Huebenthal; Vincent Thijs; Mihai G. Netea; Daisy Jonkers; Lin Chang; Emeran A. Mayer; Mira M. Wouters; Guy Boeckxstaens; Michael Camilleri; Andre Franke; Alexandra Zhernakova; Mauro D'Amato

doi:10.1053/j.gastro.2018.03.064

Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome

Ferdinando Bonfiglio, Tenghao Zheng, Koldo Garcia-Etxebarria, Fatemeh Hadizadeh, Luis Bujanda, Francesca Bresso, Lars Agreus, Anna Andreasson, Aldona Dlugosz, Greger Lindberg, Peter T. Schmidt, Pontus Karling, Bodil Ohlsson, Magnus Simren, Susanna Walter, Gerardo Nardone, Rosario Cuomo, Paolo Usai-Satta, Francesca Galeazzi, Matteo NeriPiero Portincasa, Massimo Bellini, Giovanni Barbara, Anna Latiano, Matthias Huebenthal, Vincent Thijs, Mihai G. Netea, Daisy Jonkers, Lin Chang, Emeran A. Mayer, Mira M. Wouters, Guy Boeckxstaens, Michael Camilleri, Andre Franke, Alexandra Zhernakova, Mauro D'Amato^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

BACKGROUND & AIMS: Genetic factors are believed to affect risk for irritable bowel syndrome (IBS), but there have been no sufficiently powered and adequately sized studies. To identify DNA variants associated with IBS risk, we performed a genome-wide association study (GWAS) of the large UK Biobank population-based cohort, which includes genotype and health data from 500,000 participants. METHODS: We studied 7,287,191 high-quality single nucleotide polymorphisms in individuals who self-reported a doctor's diagnosis of IBS (cases; n = 9576) compared to the remainder of the cohort (controls; n = 336,499) (mean age of study subjects, 40-69 years). Genome-wide significant findings were further investigated in 2045 patients with IBS from tertiary centers and 7955 population controls from Europe and the United States, and a small general population sample from Sweden (n = 249). Functional annotation of GWAS results was carried out by integrating data from multiple biorepositories to obtain biological insights from the observed associations. RESULTS: We identified a genome-wide significant association on chromosome 9q31.2 (single nucleotide polymorphism rs10512344; P = 3.57 x 10(-8)) in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P <5.0 x 10(-6)). Sex-stratified analyses revealed that the variants at 9q31.2 affect risk of IBS in women only (P = 4.29 x 10(-10) in UK Biobank) and also

[GRAPHICS]

associate with constipation-predominant IBS in women (P = .015 in the tertiary cohort) and harder stools in women (P = .0012 in the population-based sample). Functional annotation of the 9q31.2 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKB-KAP), which is mutated in patients with familial dysautonomia. CONCLUSIONS: In a sufficiently powered GWAS of IBS, we associated variants at the locus 9q31.2 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS.

Original language	English
Pages (from-to)	168-179
Number of pages	12
Journal	Gastroenterology
Volume	155
Issue number	1
DOIs	https://doi.org/10.1053/j.gastro.2018.03.064
Publication status	Published - Jul 2018

Keywords

SNP
Biobank Research
Genetics
Bowel Symptoms
FUNCTIONAL GI DISORDERS
GENDER-RELATED DIFFERENCES
GENOME-WIDE ASSOCIATION
COLONIC TRANSIT
METAANALYSIS
RISK
AGE
POPULATION
GENETICS
CHANNELOPATHIES

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Bonfiglio, F., Zheng, T., Garcia-Etxebarria, K., Hadizadeh, F., Bujanda, L., Bresso, F., Agreus, L., Andreasson, A., Dlugosz, A., Lindberg, G., Schmidt, P. T., Karling, P., Ohlsson, B., Simren, M., Walter, S., Nardone, G., Cuomo, R., Usai-Satta, P., Galeazzi, F., ... D'Amato, M. (2018). Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome. Gastroenterology, 155(1), 168-179. https://doi.org/10.1053/j.gastro.2018.03.064

@article{19972c39f0dd48589639aa349f27df71,

title = "Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome",

abstract = "BACKGROUND & AIMS: Genetic factors are believed to affect risk for irritable bowel syndrome (IBS), but there have been no sufficiently powered and adequately sized studies. To identify DNA variants associated with IBS risk, we performed a genome-wide association study (GWAS) of the large UK Biobank population-based cohort, which includes genotype and health data from 500,000 participants. METHODS: We studied 7,287,191 high-quality single nucleotide polymorphisms in individuals who self-reported a doctor's diagnosis of IBS (cases; n = 9576) compared to the remainder of the cohort (controls; n = 336,499) (mean age of study subjects, 40-69 years). Genome-wide significant findings were further investigated in 2045 patients with IBS from tertiary centers and 7955 population controls from Europe and the United States, and a small general population sample from Sweden (n = 249). Functional annotation of GWAS results was carried out by integrating data from multiple biorepositories to obtain biological insights from the observed associations. RESULTS: We identified a genome-wide significant association on chromosome 9q31.2 (single nucleotide polymorphism rs10512344; P = 3.57 x 10(-8)) in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P <5.0 x 10(-6)). Sex-stratified analyses revealed that the variants at 9q31.2 affect risk of IBS in women only (P = 4.29 x 10(-10) in UK Biobank) and also[GRAPHICS]associate with constipation-predominant IBS in women (P = .015 in the tertiary cohort) and harder stools in women (P = .0012 in the population-based sample). Functional annotation of the 9q31.2 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKB-KAP), which is mutated in patients with familial dysautonomia. CONCLUSIONS: In a sufficiently powered GWAS of IBS, we associated variants at the locus 9q31.2 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS.",

keywords = "SNP, Biobank Research, Genetics, Bowel Symptoms, FUNCTIONAL GI DISORDERS, GENDER-RELATED DIFFERENCES, GENOME-WIDE ASSOCIATION, COLONIC TRANSIT, METAANALYSIS, RISK, AGE, POPULATION, GENETICS, CHANNELOPATHIES",

author = "Ferdinando Bonfiglio and Tenghao Zheng and Koldo Garcia-Etxebarria and Fatemeh Hadizadeh and Luis Bujanda and Francesca Bresso and Lars Agreus and Anna Andreasson and Aldona Dlugosz and Greger Lindberg and Schmidt, {Peter T.} and Pontus Karling and Bodil Ohlsson and Magnus Simren and Susanna Walter and Gerardo Nardone and Rosario Cuomo and Paolo Usai-Satta and Francesca Galeazzi and Matteo Neri and Piero Portincasa and Massimo Bellini and Giovanni Barbara and Anna Latiano and Matthias Huebenthal and Vincent Thijs and Netea, {Mihai G.} and Daisy Jonkers and Lin Chang and Mayer, {Emeran A.} and Wouters, {Mira M.} and Guy Boeckxstaens and Michael Camilleri and Andre Franke and Alexandra Zhernakova and Mauro D'Amato",

year = "2018",

month = jul,

doi = "10.1053/j.gastro.2018.03.064",

language = "English",

volume = "155",

pages = "168--179",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "Elsevier Saunders",

number = "1",

}

Bonfiglio, F, Zheng, T, Garcia-Etxebarria, K, Hadizadeh, F, Bujanda, L, Bresso, F, Agreus, L, Andreasson, A, Dlugosz, A, Lindberg, G, Schmidt, PT, Karling, P, Ohlsson, B, Simren, M, Walter, S, Nardone, G, Cuomo, R, Usai-Satta, P, Galeazzi, F, Neri, M, Portincasa, P, Bellini, M, Barbara, G, Latiano, A, Huebenthal, M, Thijs, V, Netea, MG, Jonkers, D, Chang, L, Mayer, EA, Wouters, MM, Boeckxstaens, G, Camilleri, M, Franke, A, Zhernakova, A & D'Amato, M 2018, 'Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome', Gastroenterology, vol. 155, no. 1, pp. 168-179. https://doi.org/10.1053/j.gastro.2018.03.064

TY - JOUR

T1 - Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome

AU - Bonfiglio, Ferdinando

AU - Zheng, Tenghao

AU - Garcia-Etxebarria, Koldo

AU - Hadizadeh, Fatemeh

AU - Bujanda, Luis

AU - Bresso, Francesca

AU - Agreus, Lars

AU - Andreasson, Anna

AU - Dlugosz, Aldona

AU - Lindberg, Greger

AU - Schmidt, Peter T.

AU - Karling, Pontus

AU - Ohlsson, Bodil

AU - Simren, Magnus

AU - Walter, Susanna

AU - Nardone, Gerardo

AU - Cuomo, Rosario

AU - Usai-Satta, Paolo

AU - Galeazzi, Francesca

AU - Neri, Matteo

AU - Portincasa, Piero

AU - Bellini, Massimo

AU - Barbara, Giovanni

AU - Latiano, Anna

AU - Huebenthal, Matthias

AU - Thijs, Vincent

AU - Netea, Mihai G.

AU - Jonkers, Daisy

AU - Chang, Lin

AU - Mayer, Emeran A.

AU - Wouters, Mira M.

AU - Boeckxstaens, Guy

AU - Camilleri, Michael

AU - Franke, Andre

AU - Zhernakova, Alexandra

AU - D'Amato, Mauro

PY - 2018/7

Y1 - 2018/7

N2 - BACKGROUND & AIMS: Genetic factors are believed to affect risk for irritable bowel syndrome (IBS), but there have been no sufficiently powered and adequately sized studies. To identify DNA variants associated with IBS risk, we performed a genome-wide association study (GWAS) of the large UK Biobank population-based cohort, which includes genotype and health data from 500,000 participants. METHODS: We studied 7,287,191 high-quality single nucleotide polymorphisms in individuals who self-reported a doctor's diagnosis of IBS (cases; n = 9576) compared to the remainder of the cohort (controls; n = 336,499) (mean age of study subjects, 40-69 years). Genome-wide significant findings were further investigated in 2045 patients with IBS from tertiary centers and 7955 population controls from Europe and the United States, and a small general population sample from Sweden (n = 249). Functional annotation of GWAS results was carried out by integrating data from multiple biorepositories to obtain biological insights from the observed associations. RESULTS: We identified a genome-wide significant association on chromosome 9q31.2 (single nucleotide polymorphism rs10512344; P = 3.57 x 10(-8)) in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P <5.0 x 10(-6)). Sex-stratified analyses revealed that the variants at 9q31.2 affect risk of IBS in women only (P = 4.29 x 10(-10) in UK Biobank) and also[GRAPHICS]associate with constipation-predominant IBS in women (P = .015 in the tertiary cohort) and harder stools in women (P = .0012 in the population-based sample). Functional annotation of the 9q31.2 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKB-KAP), which is mutated in patients with familial dysautonomia. CONCLUSIONS: In a sufficiently powered GWAS of IBS, we associated variants at the locus 9q31.2 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS.

AB - BACKGROUND & AIMS: Genetic factors are believed to affect risk for irritable bowel syndrome (IBS), but there have been no sufficiently powered and adequately sized studies. To identify DNA variants associated with IBS risk, we performed a genome-wide association study (GWAS) of the large UK Biobank population-based cohort, which includes genotype and health data from 500,000 participants. METHODS: We studied 7,287,191 high-quality single nucleotide polymorphisms in individuals who self-reported a doctor's diagnosis of IBS (cases; n = 9576) compared to the remainder of the cohort (controls; n = 336,499) (mean age of study subjects, 40-69 years). Genome-wide significant findings were further investigated in 2045 patients with IBS from tertiary centers and 7955 population controls from Europe and the United States, and a small general population sample from Sweden (n = 249). Functional annotation of GWAS results was carried out by integrating data from multiple biorepositories to obtain biological insights from the observed associations. RESULTS: We identified a genome-wide significant association on chromosome 9q31.2 (single nucleotide polymorphism rs10512344; P = 3.57 x 10(-8)) in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P <5.0 x 10(-6)). Sex-stratified analyses revealed that the variants at 9q31.2 affect risk of IBS in women only (P = 4.29 x 10(-10) in UK Biobank) and also[GRAPHICS]associate with constipation-predominant IBS in women (P = .015 in the tertiary cohort) and harder stools in women (P = .0012 in the population-based sample). Functional annotation of the 9q31.2 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKB-KAP), which is mutated in patients with familial dysautonomia. CONCLUSIONS: In a sufficiently powered GWAS of IBS, we associated variants at the locus 9q31.2 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS.

KW - SNP

KW - Biobank Research

KW - Genetics

KW - Bowel Symptoms

KW - FUNCTIONAL GI DISORDERS

KW - GENDER-RELATED DIFFERENCES

KW - GENOME-WIDE ASSOCIATION

KW - COLONIC TRANSIT

KW - METAANALYSIS

KW - RISK

KW - AGE

KW - POPULATION

KW - GENETICS

KW - CHANNELOPATHIES

U2 - 10.1053/j.gastro.2018.03.064

DO - 10.1053/j.gastro.2018.03.064

M3 - Article

C2 - 29626450

SN - 0016-5085

VL - 155

SP - 168

EP - 179

JO - Gastroenterology

JF - Gastroenterology

IS - 1

ER -