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A GWAS Study on Liver Function Test Using eMERGE Network Participants
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 Electro...
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| Published in: | PloS one 2015-09, Vol.10 (9), p.e0138677-e0138677 |
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| creator | Namjou, Bahram Marsolo, Keith Lingren, Todd Ritchie, Marylyn D Verma, Shefali S Cobb, Beth L Perry, Cassandra Kitchner, Terrie E Brilliant, Murray H Peissig, Peggy L Borthwick, Kenneth M Williams, Marc S Grafton, Jane Jarvik, Gail P Holm, Ingrid A Harley, John B |
| description | 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.
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).
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 |
| doi_str_mv | 10.1371/journal.pone.0138677 |
| format | article |
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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).
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).
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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0138677</identifier><identifier>PMID: 26413716</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>ABO system ; Adult ; Adults ; Alkaline phosphatase ; Alkaline Phosphatase - blood ; Bilirubin ; Bilirubin - blood ; Blood groups ; Cardiovascular disease ; Case-Control Studies ; Child ; Children & youth ; Chromosome 2 ; Cohort Studies ; Demography ; Disease prevention ; Electronic Health Records ; Electronic medical records ; Enzymes ; Etiology ; European Continental Ancestry Group - genetics ; Female ; Gene loci ; Gene Regulatory Networks ; Genetic control ; Genetics ; Genome-wide association studies ; Genome-Wide Association Study ; Genomes ; Genomics ; Genotyping ; Glucuronosyltransferase - genetics ; Hospitals ; Humans ; Informatics ; Linkage Disequilibrium - genetics ; Liver ; Liver Function Tests ; Male ; Medicine ; Missing data ; Mutation ; Outliers (statistics) ; Pediatrics ; Phenotyping ; Phosphatase ; Physiological aspects ; Polymorphism ; Polymorphism, Single Nucleotide - genetics ; Population ; Population studies ; Populations ; Quality control ; Regression analysis ; Single-nucleotide polymorphism</subject><ispartof>PloS one, 2015-09, Vol.10 (9), p.e0138677-e0138677</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication: https://creativecommons.org/publicdomain/zero/1.0/ (the “License”) Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-628c21ded2506c487ffc1799dcd8514d8c334b61d75c97714a5ba8d27fcf0c73</citedby><cites>FETCH-LOGICAL-c692t-628c21ded2506c487ffc1799dcd8514d8c334b61d75c97714a5ba8d27fcf0c73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1720074531/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1720074531?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,37013,44590,53791,53793,75126</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26413716$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Prokunina-Olsson, Ludmila</contributor><creatorcontrib>Namjou, Bahram</creatorcontrib><creatorcontrib>Marsolo, Keith</creatorcontrib><creatorcontrib>Lingren, Todd</creatorcontrib><creatorcontrib>Ritchie, Marylyn D</creatorcontrib><creatorcontrib>Verma, Shefali S</creatorcontrib><creatorcontrib>Cobb, Beth L</creatorcontrib><creatorcontrib>Perry, Cassandra</creatorcontrib><creatorcontrib>Kitchner, Terrie E</creatorcontrib><creatorcontrib>Brilliant, Murray H</creatorcontrib><creatorcontrib>Peissig, Peggy L</creatorcontrib><creatorcontrib>Borthwick, Kenneth M</creatorcontrib><creatorcontrib>Williams, Marc S</creatorcontrib><creatorcontrib>Grafton, Jane</creatorcontrib><creatorcontrib>Jarvik, Gail P</creatorcontrib><creatorcontrib>Holm, Ingrid A</creatorcontrib><creatorcontrib>Harley, John B</creatorcontrib><title>A GWAS Study on Liver Function Test Using eMERGE Network Participants</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.
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).
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).
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.</description><subject>ABO system</subject><subject>Adult</subject><subject>Adults</subject><subject>Alkaline phosphatase</subject><subject>Alkaline Phosphatase - blood</subject><subject>Bilirubin</subject><subject>Bilirubin - blood</subject><subject>Blood groups</subject><subject>Cardiovascular disease</subject><subject>Case-Control Studies</subject><subject>Child</subject><subject>Children & youth</subject><subject>Chromosome 2</subject><subject>Cohort Studies</subject><subject>Demography</subject><subject>Disease prevention</subject><subject>Electronic Health Records</subject><subject>Electronic medical records</subject><subject>Enzymes</subject><subject>Etiology</subject><subject>European Continental Ancestry Group - genetics</subject><subject>Female</subject><subject>Gene loci</subject><subject>Gene Regulatory Networks</subject><subject>Genetic control</subject><subject>Genetics</subject><subject>Genome-wide association studies</subject><subject>Genome-Wide Association Study</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Genotyping</subject><subject>Glucuronosyltransferase - genetics</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Informatics</subject><subject>Linkage Disequilibrium - genetics</subject><subject>Liver</subject><subject>Liver Function Tests</subject><subject>Male</subject><subject>Medicine</subject><subject>Missing data</subject><subject>Mutation</subject><subject>Outliers (statistics)</subject><subject>Pediatrics</subject><subject>Phenotyping</subject><subject>Phosphatase</subject><subject>Physiological aspects</subject><subject>Polymorphism</subject><subject>Polymorphism, Single Nucleotide - genetics</subject><subject>Population</subject><subject>Population studies</subject><subject>Populations</subject><subject>Quality control</subject><subject>Regression analysis</subject><subject>Single-nucleotide polymorphism</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNqNklFv0zAUhSMEYmPwDxBEQkLw0GI7ju28IFVTVyoVhtYCj5ZjO61LGhfbGezf46zZ1KA9oDw4tr97fH18kuQlBGOYUfhha1vXiHq8t40eA5gxQumj5BQWGRoRBLLHR_8nyTPvtwDkkSJPkxNEcKdBTpPpJJ39mCzTZWjVTWqbdGGutUsv2kYGE6cr7UP6zZtmnerP06vZNP2iw2_rfqZfhQtGmr1ogn-ePKlE7fWLfjxLVhfT1fmn0eJyNj-fLEaSFCjEVphEUGmFckAkZrSqJKRFoaRiOcSKySzDJYGK5rKgFGKRl4IpRCtZAUmzs-T1QXZfW897AzyHFAFAcZ7BSMwPhLJiy_fO7IS74VYYfrtg3Zrftl1rLpmUGmuRF7DElaRMkwxKjErEKlhIHbU-9qe15U4rqZvgRD0QHe40ZsPX9prjnJH4HlHgXS_g7K82Gsl3xktd16LRtu36hgxQAmge0Tf_oA_frqfWIl7ANJWN58pOlE9wBiBCBe5cGj9AxU_pnZExLZWJ64OC94OCyAT9J6xF6z2fL6_-n738PmTfHrEbLeqw8bZuu2D5IYgPoHTWe6ere5Mh4F1Q79zgXdh5H_ZY9ur4ge6L7tKd_QWFm_dy</recordid><startdate>20150928</startdate><enddate>20150928</enddate><creator>Namjou, Bahram</creator><creator>Marsolo, Keith</creator><creator>Lingren, Todd</creator><creator>Ritchie, Marylyn D</creator><creator>Verma, Shefali S</creator><creator>Cobb, Beth L</creator><creator>Perry, Cassandra</creator><creator>Kitchner, Terrie E</creator><creator>Brilliant, Murray H</creator><creator>Peissig, Peggy L</creator><creator>Borthwick, Kenneth M</creator><creator>Williams, Marc S</creator><creator>Grafton, Jane</creator><creator>Jarvik, Gail P</creator><creator>Holm, Ingrid A</creator><creator>Harley, John B</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150928</creationdate><title>A GWAS Study on Liver Function Test Using eMERGE Network Participants</title><author>Namjou, Bahram ; Marsolo, Keith ; Lingren, Todd ; Ritchie, Marylyn D ; Verma, Shefali S ; Cobb, Beth L ; Perry, Cassandra ; Kitchner, Terrie E ; Brilliant, Murray H ; Peissig, Peggy L ; Borthwick, Kenneth M ; Williams, Marc S ; Grafton, Jane ; Jarvik, Gail P ; Holm, Ingrid A ; Harley, John B</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-628c21ded2506c487ffc1799dcd8514d8c334b61d75c97714a5ba8d27fcf0c73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>ABO system</topic><topic>Adult</topic><topic>Adults</topic><topic>Alkaline phosphatase</topic><topic>Alkaline Phosphatase - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Namjou, Bahram</au><au>Marsolo, Keith</au><au>Lingren, Todd</au><au>Ritchie, Marylyn D</au><au>Verma, Shefali S</au><au>Cobb, Beth L</au><au>Perry, Cassandra</au><au>Kitchner, Terrie E</au><au>Brilliant, Murray H</au><au>Peissig, Peggy L</au><au>Borthwick, Kenneth M</au><au>Williams, Marc S</au><au>Grafton, Jane</au><au>Jarvik, Gail P</au><au>Holm, Ingrid A</au><au>Harley, John B</au><au>Prokunina-Olsson, Ludmila</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A GWAS Study on Liver Function Test Using eMERGE Network Participants</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-09-28</date><risdate>2015</risdate><volume>10</volume><issue>9</issue><spage>e0138677</spage><epage>e0138677</epage><pages>e0138677-e0138677</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>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.
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).
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).
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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26413716</pmid><doi>10.1371/journal.pone.0138677</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-09, Vol.10 (9), p.e0138677-e0138677 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1720074531 |
| source | Publicly Available Content (ProQuest); PubMed Central |
| subjects | ABO system Adult Adults Alkaline phosphatase Alkaline Phosphatase - blood Bilirubin Bilirubin - blood Blood groups Cardiovascular disease Case-Control Studies Child Children & youth Chromosome 2 Cohort Studies Demography Disease prevention Electronic Health Records Electronic medical records Enzymes Etiology European Continental Ancestry Group - genetics Female Gene loci Gene Regulatory Networks Genetic control Genetics Genome-wide association studies Genome-Wide Association Study Genomes Genomics Genotyping Glucuronosyltransferase - genetics Hospitals Humans Informatics Linkage Disequilibrium - genetics Liver Liver Function Tests Male Medicine Missing data Mutation Outliers (statistics) Pediatrics Phenotyping Phosphatase Physiological aspects Polymorphism Polymorphism, Single Nucleotide - genetics Population Population studies Populations Quality control Regression analysis Single-nucleotide polymorphism |
| title | A GWAS Study on Liver Function Test Using eMERGE Network Participants |
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