Four Susceptibility Loci for Gallstone Disease Identified in a Meta-analysis of Genome-Wide Association Studies.
OBJECTIVE
A genome-wide association study (GWAS) of 280 cases identified the hepatic cholesterol transporter ABCG8 as a locus associated with risk for gallstone disease, but findings have not been reported from any other GWAS of this phenotype. We performed a large-scale, meta-analysis of GWASs of individuals of European ancestry with available prior genotype data, to identify additional genetic risk factors for gallstone disease.


METHODS
We obtained per-allele odds ratio (OR) and standard error estimates using age- and sex-adjusted logistic regression models within each of the 10 discovery studies (8720 cases and 55,152 controls). We performed an inverse variance weighted, fixed-effects meta-analysis of study-specific estimates to identify single-nucleotide polymorphisms that were associated independently with gallstone disease. Associations were replicated in 6489 cases and 62,797 controls.


RESULTS
We observed independent associations for 2 single-nucleotide polymorphisms at the ABCG8 locus: rs11887534 (OR, 1.69; 95% confidence interval [CI], 1.54-1.86; P = 2.44 × 10(-60)) and rs4245791 (OR, 1.27; P = 1.90 × 10(-34)). We also identified and/or replicated associations for rs9843304 in TM4SF4 (OR, 1.12; 95% CI, 1.08-1.16; P = 6.09 × 10(-11)), rs2547231 in SULT2A1 (encodes a sulfoconjugation enzyme that acts on hydroxysteroids and cholesterol-derived sterol bile acids) (OR, 1.17; 95% CI, 1.12-1.21; P = 2.24 × 10(-10)), rs1260326 in glucokinase regulatory protein (OR, 1.12; 95% CI, 1.07-1.17; P = 2.55 × 10(-10)), and rs6471717 near CYP7A1 (encodes an enzyme that catalyzes conversion of cholesterol to primary bile acids) (OR, 1.11; 95% CI, 1.08-1.15; P = 8.84 × 10(-9)). Among individuals of African American and Hispanic American ancestry, rs11887534 and rs4245791 were associated positively with gallstone disease risk, whereas the association for the rs1260326 variant was inverse.


CONCLUSIONS
In this large-scale GWAS of gallstone disease, we identified 4 loci in genes that have putative functions in cholesterol metabolism and transport, and sulfonylation of bile acids or hydroxysteroids.
Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Clinical and Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address: ajoshi@hsph.harvard.edu.
Amit D
AD
Joshi
The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts. Electronic address: ca@heart.dk.
Charlotte
C
Andersson
Medical Department 1, University Hospital Dresden, Technische Universität Dresden, Dresden, Germany.
Stephan
S
Buch
Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark.
Stefan
S
Stender
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
Raymond
R
Noordam
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minnesota.
Lu-Chen
LC
Weng
Department of Medicine, Vanderbilt University, Nashville, Tennessee; Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen, Denmark.
Peter E
PE
Weeke
Joseph J. Zilber School of Public Health, University of Wisconsin, Milwaukee, Wisconsin; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Paul L
PL
Auer
Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany.
Bernhard
B
Boehm
Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts.
Constance
C
Chen
Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, Massachusetts.
Hyon
H
Choi
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Gary
G
Curhan
Department of Medicine, Vanderbilt University, Nashville, Tennessee; Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee.
Joshua C
JC
Denny
Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
Immaculata
I
De Vivo
The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts; Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Framingham, Massachusetts.
John D
JD
Eicher
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
David
D
Ellinghaus
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minnesota.
Aaron R
AR
Folsom
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
Charles
C
Fuchs
Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
Manish
M
Gala
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Jeffrey
J
Haessler
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
Albert
A
Hofman
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts.
Frank
F
Hu
Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
David J
DJ
Hunter
Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands; Toronto Centre for Liver Disease, Toronto Western and General Hospital, University Health Network, Toronto, Canada.
Harry L A
HL
Janssen
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Jae H
JH
Kang
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Charles
C
Kooperberg
Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
Peter
P
Kraft
Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany.
Wolfgang
W
Kratzer
Institute of Epidemiology, Christian-Albrechts-University of Kiel, Kiel, Germany.
Wolfgang
W
Lieb
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minnesota.
Pamela L
PL
Lutsey
Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands.
Sarwa
S
Darwish Murad
The Copenhagen General Population Study, Herlev Hospital, Herlev, Denmark; Department of Clinical Biochemistry, Herlev Hospital, Herlev, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Børge G
BG
Nordestgaard
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts.
Louis R
LR
Pasquale
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Alex P
AP
Reiner
Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Paul M
PM
Ridker
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts.
Eric
E
Rimm
Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Lynda M
LM
Rose
Department of Medicine, Vanderbilt University, Nashville, Tennessee.
Christian M
CM
Shaffer
Department of General, Abdominal, Thoracic and Transplantation Surgery, University of Kiel, Kiel, Germany.
Clemens
C
Schafmayer
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
Rulla M
RM
Tamimi
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
André G
AG
Uitterlinden
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
Uwe
U
Völker
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany; German Center for Cardiovascular Research, Greifswald, Germany; German Center for Diabetes Research, Greifswald, Germany.
Henry
H
Völzke
National Heart, Lung, and Blood Institute, DNA Sequencing Core Laboratory, Bethesda, Maryland.
Yoshiyuki
Y
Wakabayashi
Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts.
Janey L
JL
Wiggs
National Heart, Lung, and Blood Institute, DNA Sequencing Core Laboratory, Bethesda, Maryland.
Jun
J
Zhu
Department of Medicine, Vanderbilt University, Nashville, Tennessee.
Dan M
DM
Roden
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
Bruno H
BH
Stricker
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minnesota.
Weihong
W
Tang
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
Alexander
A
Teumer
Medical Department 1, University Hospital Dresden, Technische Universität Dresden, Dresden, Germany.
Jochen
J
Hampe
Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark; Department of Clinical Biochemistry, Herlev Hospital, Herlev, Denmark.
Anne
A
Tybjærg-Hansen
Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Daniel I
DI
Chasman
Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Clinical and Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address: achan@mgh.harvard.edu.
Andrew T
AT
Chan
The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts; Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Framingham, Massachusetts. Electronic address: johnsonad2@nhlbi.nih.gov.
Andrew D
AD
Johnson
D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8 / Q000235:genetics*; D000328:Adult; D001741:Black or African American / Q000235:genetics; D000368:Aged; D016022:Case-Control Studies; D002784:Cholesterol / Q000378:metabolism; D005260:Female; D042882:Gallstones / Q000235:genetics*; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
C416946:ABCG8 protein, human; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D002784:Cholesterol
GWAS; Genetics; Risk Factors; SNP