Genome-wide Analysis Identifies Novel Gallstone-susceptibility Loci Including Genes Regulating Gastrointestinal Motility

Cameron Fairfield; Thomas Drake; Riinu Pius; Andrew D Bretherick; Archie Campbell; David Clark; Jonathan A Fallowfield; Caroline Hayward; Neil C Henderson; Andrii Iakovliev; Peter K Joshi; Nicholas L Mills; David John Porteous; Prakash Ramachandran; Robert K Semple; Katie Shaw; Cathie L M Sudlow; Paul Timmers; James F Wilson; Stephen J Wigmore; Athina Spiliopoulou; Ewen M Harrison

doi:10.1002/hep.32199

Genome-wide Analysis Identifies Novel Gallstone-susceptibility Loci Including Genes Regulating Gastrointestinal Motility

Cameron Fairfield, Thomas Drake, Riinu Pius, Andrew D Bretherick, Archie Campbell, David Clark, Jonathan A Fallowfield, Caroline Hayward, Neil C Henderson, Andrii Iakovliev, Peter K Joshi, Nicholas L Mills, David John Porteous, Prakash Ramachandran, Robert K Semple, Katie Shaw, Cathie L M Sudlow, Paul Timmers, James F Wilson, Stephen J WigmoreAthina Spiliopoulou, Ewen M Harrison

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

Abstract

Background & Aims
Genome-wide association studies (GWAS) have identified several risk loci for gallstone disease. As with most polygenic traits, it is likely many genetic determinants are undiscovered. The aim of this study was to identify novel genetic variants, representing new targets for gallstone research and treatment.

Approach & Results
We performed a GWAS of 28,627 gallstone cases and 348,373 controls in the UK Biobank, replicated findings in a Scottish cohort (1,089 cases, 5,228 controls) and conducted a GWA meta-analysis (43,639 cases, 506,798 controls) with the FinnGen cohort. We assessed pathway enrichment using gene-based then gene-set analysis and tissue expression of identified genes in Genotype-Tissue Expression project data. We constructed a polygenic risk score (PRS) and evaluated phenotypic traits associated with the score. Seventy-five risk loci were identified (P<5*10^-8), of which forty-six were novel. Pathway enrichment revealed associations with lipid homeostasis, glucuronidation, phospholipid metabolism and gastrointestinal motility. ANO1 and TMEM147, both in novel, replicated loci, are expressed in the gallbladder and gastrointestinal tract. Both regulate gastrointestinal motility. The gallstone risk allele rs7599-A leads to suppression of hepatic TMEM147 expression suggesting the protein protects against gallstone formation. The highest decile of the PRS demonstrated a 6-fold increased odds of gallstones compared to the lowest decile. The PRS was strongly associated with increased body mass index, serum liver enzymes and C-reactive protein concentrations and decreased lipoprotein cholesterol concentrations.

Conclusions
This GWAS demonstrates the polygenic nature of gallstone risk and identifies 46 novel susceptibility loci. For the first time, we implicate genes influencing gastrointestinal motility in the pathogenesis of gallstones.

Original language	English
Pages (from-to)	1-33
Number of pages	33
Journal	Hepatology
Early online date	15 Oct 2021
DOIs	https://doi.org/10.1002/hep.32199
Publication status	E-pub ahead of print - 15 Oct 2021

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10.1002/hep.32199Licence: Creative Commons: Attribution (CC-BY)

ManuscriptAccepted author manuscript, 53 KBLicence: Creative Commons: Attribution (CC-BY)

Causes and Consequences of Pathological Adipose Remodelling
Semple, R. (Principal Investigator)
UK-based charities
1/06/18 → 31/05/23
Project: Research
Generation Scotland
Porteous, D. (Principal Investigator)
UK central government bodies/local authorities, health and hospital authorities
1/04/11 → 31/03/14
Project: Research

Cite this

Fairfield, C., Drake, T., Pius, R., Bretherick, A. D., Campbell, A., Clark, D., Fallowfield, J. A., Hayward, C., Henderson, N. C., Iakovliev, A., Joshi, P. K., Mills, N. L., Porteous, D. J., Ramachandran, P., Semple, R. K., Shaw, K., Sudlow, C. L. M., Timmers, P., Wilson, J. F., ... Harrison, E. M. (2021). Genome-wide Analysis Identifies Novel Gallstone-susceptibility Loci Including Genes Regulating Gastrointestinal Motility. Hepatology, 1-33. Advance online publication. https://doi.org/10.1002/hep.32199

@article{1e9aff0efc414cb58dc585523449b45d,

title = "Genome-wide Analysis Identifies Novel Gallstone-susceptibility Loci Including Genes Regulating Gastrointestinal Motility",

abstract = "Background & AimsGenome-wide association studies (GWAS) have identified several risk loci for gallstone disease. As with most polygenic traits, it is likely many genetic determinants are undiscovered. The aim of this study was to identify novel genetic variants, representing new targets for gallstone research and treatment.Approach & ResultsWe performed a GWAS of 28,627 gallstone cases and 348,373 controls in the UK Biobank, replicated findings in a Scottish cohort (1,089 cases, 5,228 controls) and conducted a GWA meta-analysis (43,639 cases, 506,798 controls) with the FinnGen cohort. We assessed pathway enrichment using gene-based then gene-set analysis and tissue expression of identified genes in Genotype-Tissue Expression project data. We constructed a polygenic risk score (PRS) and evaluated phenotypic traits associated with the score. Seventy-five risk loci were identified (P<5*10-8), of which forty-six were novel. Pathway enrichment revealed associations with lipid homeostasis, glucuronidation, phospholipid metabolism and gastrointestinal motility. ANO1 and TMEM147, both in novel, replicated loci, are expressed in the gallbladder and gastrointestinal tract. Both regulate gastrointestinal motility. The gallstone risk allele rs7599-A leads to suppression of hepatic TMEM147 expression suggesting the protein protects against gallstone formation. The highest decile of the PRS demonstrated a 6-fold increased odds of gallstones compared to the lowest decile. The PRS was strongly associated with increased body mass index, serum liver enzymes and C-reactive protein concentrations and decreased lipoprotein cholesterol concentrations.ConclusionsThis GWAS demonstrates the polygenic nature of gallstone risk and identifies 46 novel susceptibility loci. For the first time, we implicate genes influencing gastrointestinal motility in the pathogenesis of gallstones.",

author = "Cameron Fairfield and Thomas Drake and Riinu Pius and Bretherick, {Andrew D} and Archie Campbell and David Clark and Fallowfield, {Jonathan A} and Caroline Hayward and Henderson, {Neil C} and Andrii Iakovliev and Joshi, {Peter K} and Mills, {Nicholas L} and Porteous, {David John} and Prakash Ramachandran and Semple, {Robert K} and Katie Shaw and Sudlow, {Cathie L M} and Paul Timmers and Wilson, {James F} and Wigmore, {Stephen J} and Athina Spiliopoulou and Harrison, {Ewen M}",

year = "2021",

month = oct,

day = "15",

doi = "10.1002/hep.32199",

language = "English",

pages = "1--33",

journal = "Hepatology",

issn = "1527-3350",

publisher = "Wiley",

}

Fairfield, C, Drake, T, Pius, R , Bretherick, AD , Campbell, A, Clark, D, Fallowfield, JA , Hayward, C , Henderson, NC , Iakovliev, A, Joshi, PK, Mills, NL, Porteous, DJ, Ramachandran, P , Semple, RK , Shaw, K , Sudlow, CLM, Timmers, P, Wilson, JF , Wigmore, SJ , Spiliopoulou, A & Harrison, EM 2021, 'Genome-wide Analysis Identifies Novel Gallstone-susceptibility Loci Including Genes Regulating Gastrointestinal Motility', Hepatology, pp. 1-33. https://doi.org/10.1002/hep.32199

TY - JOUR

T1 - Genome-wide Analysis Identifies Novel Gallstone-susceptibility Loci Including Genes Regulating Gastrointestinal Motility

AU - Fairfield, Cameron

AU - Drake, Thomas

AU - Pius, Riinu

AU - Bretherick, Andrew D

AU - Campbell, Archie

AU - Clark, David

AU - Fallowfield, Jonathan A

AU - Hayward, Caroline

AU - Henderson, Neil C

AU - Iakovliev, Andrii

AU - Joshi, Peter K

AU - Mills, Nicholas L

AU - Porteous, David John

AU - Ramachandran, Prakash

AU - Semple, Robert K

AU - Shaw, Katie

AU - Sudlow, Cathie L M

AU - Timmers, Paul

AU - Wilson, James F

AU - Wigmore, Stephen J

AU - Spiliopoulou, Athina

AU - Harrison, Ewen M

PY - 2021/10/15

Y1 - 2021/10/15

N2 - Background & AimsGenome-wide association studies (GWAS) have identified several risk loci for gallstone disease. As with most polygenic traits, it is likely many genetic determinants are undiscovered. The aim of this study was to identify novel genetic variants, representing new targets for gallstone research and treatment.Approach & ResultsWe performed a GWAS of 28,627 gallstone cases and 348,373 controls in the UK Biobank, replicated findings in a Scottish cohort (1,089 cases, 5,228 controls) and conducted a GWA meta-analysis (43,639 cases, 506,798 controls) with the FinnGen cohort. We assessed pathway enrichment using gene-based then gene-set analysis and tissue expression of identified genes in Genotype-Tissue Expression project data. We constructed a polygenic risk score (PRS) and evaluated phenotypic traits associated with the score. Seventy-five risk loci were identified (P<5*10-8), of which forty-six were novel. Pathway enrichment revealed associations with lipid homeostasis, glucuronidation, phospholipid metabolism and gastrointestinal motility. ANO1 and TMEM147, both in novel, replicated loci, are expressed in the gallbladder and gastrointestinal tract. Both regulate gastrointestinal motility. The gallstone risk allele rs7599-A leads to suppression of hepatic TMEM147 expression suggesting the protein protects against gallstone formation. The highest decile of the PRS demonstrated a 6-fold increased odds of gallstones compared to the lowest decile. The PRS was strongly associated with increased body mass index, serum liver enzymes and C-reactive protein concentrations and decreased lipoprotein cholesterol concentrations.ConclusionsThis GWAS demonstrates the polygenic nature of gallstone risk and identifies 46 novel susceptibility loci. For the first time, we implicate genes influencing gastrointestinal motility in the pathogenesis of gallstones.

AB - Background & AimsGenome-wide association studies (GWAS) have identified several risk loci for gallstone disease. As with most polygenic traits, it is likely many genetic determinants are undiscovered. The aim of this study was to identify novel genetic variants, representing new targets for gallstone research and treatment.Approach & ResultsWe performed a GWAS of 28,627 gallstone cases and 348,373 controls in the UK Biobank, replicated findings in a Scottish cohort (1,089 cases, 5,228 controls) and conducted a GWA meta-analysis (43,639 cases, 506,798 controls) with the FinnGen cohort. We assessed pathway enrichment using gene-based then gene-set analysis and tissue expression of identified genes in Genotype-Tissue Expression project data. We constructed a polygenic risk score (PRS) and evaluated phenotypic traits associated with the score. Seventy-five risk loci were identified (P<5*10-8), of which forty-six were novel. Pathway enrichment revealed associations with lipid homeostasis, glucuronidation, phospholipid metabolism and gastrointestinal motility. ANO1 and TMEM147, both in novel, replicated loci, are expressed in the gallbladder and gastrointestinal tract. Both regulate gastrointestinal motility. The gallstone risk allele rs7599-A leads to suppression of hepatic TMEM147 expression suggesting the protein protects against gallstone formation. The highest decile of the PRS demonstrated a 6-fold increased odds of gallstones compared to the lowest decile. The PRS was strongly associated with increased body mass index, serum liver enzymes and C-reactive protein concentrations and decreased lipoprotein cholesterol concentrations.ConclusionsThis GWAS demonstrates the polygenic nature of gallstone risk and identifies 46 novel susceptibility loci. For the first time, we implicate genes influencing gastrointestinal motility in the pathogenesis of gallstones.

U2 - 10.1002/hep.32199

DO - 10.1002/hep.32199

M3 - Article

SN - 1527-3350

SP - 1

EP - 33

JO - Hepatology

JF - Hepatology

ER -

Genome-wide Analysis Identifies Novel Gallstone-susceptibility Loci Including Genes Regulating Gastrointestinal Motility

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Causes and Consequences of Pathological Adipose Remodelling

Generation Scotland

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