GWAS meta-analysis of ten studies identifies five novel loci associated with gallstone disease in European ancestry individuals. A. D. Joshi1, C. Andersson2, S. Buch3, M. Gala4, R. Noordam5, A. Teumer6, S. Stender7, B. G. Nordestgaard7, L. Weng8, A. R. Folsom8, P. L. Lutsey8, D. Ellinghaus9, W. Lieb10, C. Shafmayer11, B. Boehm12, A. TybjŠrg-Hansen7, U. V÷lker13, H. V÷lzke6, L. Rose14, P. E. Weeke15, D. M. Roden15, J. C. Denny15, W. Tang8, B. H. Stricker5, J. Hampe3, D. I. Chasman14, A. D. Johnson2, A. T. Chan4,16 1) Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, MA; 2) The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA; 3) Department of General Internal Medicine, University Hospital Schleswig-Holstein, Kiel, Germany; 4) Division of Gastroenterology and Hepatology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA; 5) Department of Internal Medicine and Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; 6) Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany; 7) Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark; 8) Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, MN; 9) nstitute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany; 10) Institute of Epidemiology, Christian Albrechts Universitńt Kiel, Niemannsweg 11, Kiel, Germany; 11) Department of General, Abdominal, Thoracic and Transplantation Surgery, University of Kiel, Kiel, Germany; 12) Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany; 13) Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Germany; 14) Division of Preventive Medicine, Department of Medicine, Brigham and Womens Hospital and Harvard Medical School, Boston, MA; 15) Department of Medicine, Vanderbilt University, Nashville, TN; 16) Channing Division of Network Medicine, Department of Medicine, Brigham and Womens Hospital and Harvard Medical School, Boston, MA.

   In 2007, a modestly sized genome wide association study (GWAS) consisting of 280 cases identified the hepatic cholesterol transporter ABCG8 locus as a susceptibility factor for human gallstone disease. To date, no other population-based GWAS has been reported for this phenotype. Therefore, we performed a large-scale GWAS meta-analysis of 9,298 gallstone cases and 62,007 controls of European ancestry pooled from 8 cohort and 2 case-control studies to discover additional genetic variants associated with gallstone disease. In the case-control sets nested within each discovery study described in Table 1, we used age and sex adjusted logistic regression models to obtain effect size estimates. Inverse variance weighted meta-analysis of study-specific estimates was performed and 91 SNPs were observed to be individually associated with gallstone disease at a genome-wide significance level (p < 5x10-8) from a total of 5 distinct genomic regions. Conditional analyses were performed in genomic regions (10 mega-base windows around SNPs) that showed nominal significance (p < 5x10-6) at the meta-analyses stage to identify SNPs that were independently associated with gallstones disease after adjusting for the top-hits in the region. After conditional analyses, two SNPs in ABCG8, rs11887534 (p=7.2x10-53) and rs4245791 (p=4.0x10-31), were independently associated with gallstone disease. Additionally, we identified novel independent associations for rs1025447 (p=4.7x10-11) in DYNC2LI1, which plays a structural role in cilia formation; rs9843304 (p=3.3x10-9) in TM4SF4; rs2547231 in SULT2A1, which is a sulfo-conjugation enzyme that act on hydroxysteroids and cholesterol-derived sterol bile acids (p=1.9x10-9); and rs1260326 (p=1.4x10-8) in GCKR, a glucokinase regulator. A borderline genome-wide significant association was observed for rs6471717 (p=1.09x10-7) near the CYP7A1 gene that codes for an enzyme to catalyze formation of bile salts from cholesterol. Replication was performed for six SNPs in five loci (except the DYNC2LI1 locus), and all of them were observed to be associated with gallstone disease in independent replication samples (p < 5x10-6 ; 6,489 cases and 66,366 controls) from three studies (Table 1). In this large-scale GWAS meta-analysis of gallstone disease, we identified five biologically plausible novel loci, which have putative functions in cholesterol transport and metabolism, cilia structure/bile flow, and sulfonylation of bile acids/ hyrdoxysteroids.
Table 1. Sample sizes of discovery and replication studies included in the meta-analysis
Discovery studiesStudy DesignCasesControls
Women's Genome Health Study (WGHS)Nested case control study2,85320,436
Nurses' Health Study (NHS-1/2) and Health Professionals Follow-Up Study (HPFS)Nested case control study2,47210,155
Study of Health in Pomerania (SHIP)Nested case control study8433,134
Atherosclerosis Risk In Communities (ARIC) prevalence studyCase-control study (prevalent cases)8328,032
Rotterdam StudyProspective cohort study7055,269
ARIC incidence studyLongitudinal cohort study6877,311
Framingham Heart Study (FHS)Nested case control study5153,783
BioVU - (Vanderbilt University)Hospital-based case-control study2022,542
SPC (PopGen cohort)Nested case control study122527
SHIP-TREND (Germany)Nested case control study67818
All discovery samples 9,29862,007
Replication studiesStudy DesignCasesControls
Copenhagen City Heart Study and Copenhagen General Population StudyNested case-control study3,59960,958
Kiel UniversityHospital-based case-control study2,1042,225
NHS1/HPFS-replication setNested case control study7863,183
All replication samples 6,48966,366
Combined discovery + replication 15,787128,373
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