title: A GWAS Study on Liver Function Test Using eMERGE Network Participants.
abstract: BACKGROUND
  Liver enzyme levels and total serum bilirubin are under genetic control and in recent years genome-wide population-based association studies have identified different susceptibility loci for these traits. We conducted a genome-wide association study in European ancestry participants from the Electronic Medical Records and Genomics (eMERGE) Network dataset of patient medical records with available genotyping data in order to identify genetic contributors to variability in serum bilirubin levels and other liver function tests and to compare the effects between adult and pediatric populations.
  
  
  METHODS
  The process of whole genome imputation of eMERGE samples with standard quality control measures have been described previously. After removing missing data and outliers based on principal components (PC) analyses, 3294 samples from European ancestry were used for the GWAS study. The association between each single nucleotide polymorphism (SNP) and total serum bilirubin and other liver function tests was tested using linear regression, adjusting for age, gender, site, platform and ancestry principal components (PC).
  
  
  RESULTS
  Consistent with previous results, a strong association signal has been detected for UGT1A gene cluster (best SNP rs887829, beta = 0.15, p = 1.30x10-118) for total serum bilirubin level. Indeed, in this region more than 176 SNPs (or indels) had p<10-8 spanning 150Kb on the long arm of chromosome 2q37.1. In addition, we found a similar level of magnitude in a pediatric group (p = 8.26x10-47, beta = 0.17). Further imputation using sequencing data as a reference panel revealed association of other markers including known TA7 repeat indels (rs8175347) (p = 9.78x10-117) and rs111741722 (p = 5.41x10-119) which were in proxy (r2 = 0.99) with rs887829. Among rare variants, two Asian subjects homozygous for coding SNP rs4148323 (G71R) were identified. Additional known effects for total serum bilirubin were also confirmed including organic anion transporters SLCO1B1-SLCO1B3, TDRP and ZMYND8 at FDR<0.05 with no gene-gene interaction effects. Phenome-wide association studies (PheWAS) suggest a protective effect of TA7 repeat against cerebrovascular disease in an adult cohort (OR = 0.75, p = 0.0008). Among other liver function tests, we also confirmed the previous effect of the ABO blood group locus for variation in serum alkaline phosphatase (rs579459, p = 9.44x10-15).
  
  
  CONCLUSIONS
  Taken together, our data present interesting findings with strong confirmation of previous effects by simply using the eMERGE electronic health record phenotyping. In addition, our findings indicate that similar to the adult population, the UGT1A1 is the main locus responsible for normal variation of serum bilirubin in pediatric populations.
authors.affiliation: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, United States of America; University of Cincinnati, College of Medicine, Cincinnati, OH, United States of America.
authors.forename: Bahram
authors.initials: B
authors.lastname: Namjou
authors.affiliation: University of Cincinnati, College of Medicine, Cincinnati, OH, United States of America; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America.
authors.forename: Keith
authors.initials: K
authors.lastname: Marsolo
authors.affiliation: University of Cincinnati, College of Medicine, Cincinnati, OH, United States of America; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America.
authors.forename: Todd
authors.initials: T
authors.lastname: Lingren
authors.affiliation: Center for Systems Genomics, The Pennsylvania State University, University Park, PA, United States of America.
authors.forename: Marylyn D
authors.initials: MD
authors.lastname: Ritchie
authors.affiliation: Center for Systems Genomics, The Pennsylvania State University, University Park, PA, United States of America.
authors.forename: Shefali S
authors.initials: SS
authors.lastname: Verma
authors.affiliation: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, United States of America.
authors.forename: Beth L
authors.initials: BL
authors.lastname: Cobb
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital (BCH), Boston, MA, United States of America.
authors.forename: Cassandra
authors.initials: C
authors.lastname: Perry
authors.affiliation: Center for Human Genetics, Marshfield Clinic, Marshfield, Wisconsin, United States of America.
authors.forename: Terrie E
authors.initials: TE
authors.lastname: Kitchner
authors.affiliation: Center for Human Genetics, Marshfield Clinic, Marshfield, Wisconsin, United States of America.
authors.forename: Murray H
authors.initials: MH
authors.lastname: Brilliant
authors.affiliation: Center for Human Genetics, Marshfield Clinic, Marshfield, Wisconsin, United States of America.
authors.forename: Peggy L
authors.initials: PL
authors.lastname: Peissig
authors.affiliation: Genomic Medicine Institute, Geisinger Health System, Danville, PA, United States of America.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Borthwick
authors.affiliation: Genomic Medicine Institute, Geisinger Health System, Danville, PA, United States of America.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Williams
authors.affiliation: Group Health Research Institute, Seattle, WA, United States of America.
authors.forename: Jane
authors.initials: J
authors.lastname: Grafton
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA, United States of America; Department of Genome Sciences, University of Washington, Seattle, WA, United States of America.
authors.forename: Gail P
authors.initials: GP
authors.lastname: Jarvik
authors.affiliation: Division of Genetics and Genomics and The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, United States of America; Department of Pediatrics, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Ingrid A
authors.initials: IA
authors.lastname: Holm
authors.affiliation: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, United States of America; University of Cincinnati, College of Medicine, Cincinnati, OH, United States of America; U.S. Department of Veterans Affairs Medical Center, Cincinnati, OH, United States of America.
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
mesh_terms: D000328:Adult; D000469:Alkaline Phosphatase / Q000097:blood; D001663:Bilirubin / Q000097:blood; D016022:Case-Control Studies; D002648:Child; D015331:Cohort Studies; D003710:Demography; D057286:Electronic Health Records; D005260:Female; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D023281:Genomics; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008111:Liver Function Tests; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D044465:White People / Q000235:genetics; D000099148:UGT1A1 Enzyme
chemical_list: D000469:Alkaline Phosphatase; D001663:Bilirubin; D014453:Glucuronosyltransferase; D000099148:UGT1A1 Enzyme