A GWAS Study on Liver Function Test Using eMERGE Network Participants

被引：16

作者：

Namjou, Bahram ^{[1
,2
]}

Marsolo, Keith ^{[2
,3
]}

Lingren, Todd ^{[2
,3
]}

Ritchie, Marylyn D. ^{[4
]}

Verma, Shefali S. ^{[4
]}

Cobb, Beth L. ^{[1
]}

Perry, Cassandra ^{[5
]}

Kitchner, Terrie E. ^{[6
]}

Brilliant, Murray H. ^{[6
]}

Peissig, Peggy L. ^{[6
]}

Borthwick, Kenneth M. ^{[7
]}

Williams, Marc S. ^{[7
]}

Grafton, Jane ^{[8
]}

Jarvik, Gail P. ^{[9
,10
]}

Holm, Ingrid A. ^{[11
,12
,13
]}

Harley, John B. ^{[1
,2
,14
]}

机构：

[1] Cincinnati Childrens Hosp Med Ctr CCHMC, Ctr Autoimmune Genom & Etiol, Cincinnati, OH 45229 USA

[2] Univ Cincinnati, Coll Med, Cincinnati, OH USA

[3] Cincinnati Childrens Hosp Med Ctr, Div Biomed Informat, Cincinnati, OH 45229 USA

[4] Penn State Univ, Ctr Syst Genom, University Pk, PA 16802 USA

[5] Boston Childrens Hosp BCH, Div Genet & Genom, Boston, MA USA

[6] Marshfield Clin Fdn Med Res & Educ, Ctr Human Genet, Marshfield, WI USA

[7] Geisinger Hlth Syst, Genom Med Inst, Danville, PA USA

[8] Grp Hlth Res Inst, Seattle, WA USA

[9] Univ Washington, Dept Med, Seattle, WA USA

[10] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[11] Boston Childrens Hosp, Div Genet & Genom, Boston, MA USA

[12] Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA USA

[13] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA

[14] US Dept Vet Affairs, Med Ctr, Cincinnati, OH USA

来源：

PLOS ONE | 2015年 / 10卷 / 09期

基金：

美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; SERUM BILIRUBIN LEVELS; ALKALINE-PHOSPHATASE; ACTIVE METABOLITE; UGT1A1; GENE; POLYMORPHISMS; VARIANTS; LOCI; ABO; UGT1A1-ASTERISK-28;

D O I：

10.1371/journal.pone.0138677

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 = 1.30x10(-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.

引用

页数：14

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