TY - JOUR
T1 - A GWAS study on liver function test using eMERGE network participants
AU - Namjou, Bahram
AU - Marsolo, Keith
AU - Lingren, Todd
AU - Ritchie, Marylyn D.
AU - Verma, Shefali S.
AU - Cobb, Beth L.
AU - Perry, Cassandra
AU - Kitchner, Terrie E.
AU - Brilliant, Murray H.
AU - Peissig, Peggy L.
AU - Borthwick, Kenneth M.
AU - Williams, Marc S.
AU - Grafton, Jane
AU - Jarvik, Gail P.
AU - Holm, Ingrid A.
AU - Harley, John B.
N1 - Funding Information:
We are grateful to the individuals who participated in this study. This work was supported by collaborative sites in the eMERGE Network and funded by NHGRI through the following grants: U01HG006828 (Cincinnati Children’s Hospital Medical Center/Boston Children’s Hospital); U01HG006389 (Essentia Institute of Rural Health, Marshfield Clinic Research Foundation and Pennsylvania State University); U01HG006382 (Geisinger Clinic); U01HG006375 (Group Health Cooperative/University of Washington); U01HG006385 (Vanderbilt University Medical Center serving as the Coordinating Center) and the PGRNSeq dataset (eMERGE PGx); U01HG004438 (CIDR) serving as a Sequencing Center. We would also like to thank other members of the eMERGE consortium for their support and feedback.
PY - 2015/9/28
Y1 - 2015/9/28
N2 - Introduction 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 = 1.30×10-118) 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 = 8.26×10-47, beta = 0.17). Further imputation using sequencing data as a reference panel revealed association of other markers including known TA7 repeat indels (rs8175347) (p = 9.78×10-117) and rs111741722 (p = 5.41×10-119) 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 = 9.44×10-15). 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.
AB - Introduction 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 = 1.30×10-118) 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 = 8.26×10-47, beta = 0.17). Further imputation using sequencing data as a reference panel revealed association of other markers including known TA7 repeat indels (rs8175347) (p = 9.78×10-117) and rs111741722 (p = 5.41×10-119) 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 = 9.44×10-15). 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.
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U2 - 10.1371/journal.pone.0138677
DO - 10.1371/journal.pone.0138677
M3 - Article
C2 - 26413716
AN - SCOPUS:84946934930
SN - 1932-6203
VL - 10
JO - PloS one
JF - PloS one
IS - 9
M1 - e0138677
ER -