A genome-wide metabolic QTL analysis in Europeans implicates two loci shaped by recent positive selection
We have performed a metabolite quantitative trait locus (mQTL) study of the (1)H nuclear magnetic resonance spectroscopy ((1)H NMR) metabolome in humans, building on recent targeted knowledge of genetic drivers of metabolic regulation. Urine and plasma samples were collected from two cohorts of indi...
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| creator | Nicholson, George Rantalainen, Mattias Li, Jia V Maher, Anthony D Malmodin, Daniel Ahmadi, Kourosh R Faber, Johan H Barrett, Amy Min, Josine L Rayner, N William Toft, Henrik Krestyaninova, Maria Viksna, Juris Neogi, Sudeshna Guha Dumas, Marc-Emmanuel Sarkans, Ugis Donnelly, Peter Illig, Thomas Adamski, Jerzy Suhre, Karsten Allen, Maxine Zondervan, Krina T Spector, Tim D Nicholson, Jeremy K Lindon, John C Baunsgaard, Dorrit Holmes, Elaine McCarthy, Mark I Holmes, Chris C |
| description | We have performed a metabolite quantitative trait locus (mQTL) study of the (1)H nuclear magnetic resonance spectroscopy ((1)H NMR) metabolome in humans, building on recent targeted knowledge of genetic drivers of metabolic regulation. Urine and plasma samples were collected from two cohorts of individuals of European descent, with one cohort comprised of female twins donating samples longitudinally. Sample metabolite concentrations were quantified by (1)H NMR and tested for association with genome-wide single-nucleotide polymorphisms (SNPs). Four metabolites' concentrations exhibited significant, replicable association with SNP variation (8.6×10(-11) |
| doi_str_mv | 10.1371/journal.pgen.1002270 |
| format | Article |
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Urine and plasma samples were collected from two cohorts of individuals of European descent, with one cohort comprised of female twins donating samples longitudinally. Sample metabolite concentrations were quantified by (1)H NMR and tested for association with genome-wide single-nucleotide polymorphisms (SNPs). Four metabolites' concentrations exhibited significant, replicable association with SNP variation (8.6×10(-11)<p<2.8×10(-23)). Three of these-trimethylamine, 3-amino-isobutyrate, and an N-acetylated compound-were measured in urine. The other-dimethylamine-was measured in plasma. Trimethylamine and dimethylamine mapped to a single genetic region (hence we report a total of three implicated genomic regions). Two of the three hit regions lie within haplotype blocks (at 2p13.1 and 10q24.2) that carry the genetic signature of strong, recent, positive selection in European populations. Genes NAT8 and PYROXD2, both with relatively uncharacterized functional roles, are good candidates for mediating the corresponding mQTL associations. The study's longitudinal twin design allowed detailed variance-components analysis of the sources of population variation in metabolite levels. The mQTLs explained 40%-64% of biological population variation in the corresponding metabolites' concentrations. These effect sizes are stronger than those reported in a recent, targeted mQTL study of metabolites in serum using the targeted-metabolomics Biocrates platform. By re-analysing our plasma samples using the Biocrates platform, we replicated the mQTL findings of the previous study and discovered a previously uncharacterized yet substantial familial component of variation in metabolite levels in addition to the heritability contribution from the corresponding mQTL effects.</description><identifier>ISSN: 1553-7404</identifier><identifier>ISSN: 1553-7390</identifier><identifier>EISSN: 1553-7404</identifier><identifier>DOI: 10.1371/journal.pgen.1002270</identifier><identifier>PMID: 21931564</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acetyltransferases - genetics ; Acetyltransferases - metabolism ; Biology ; Chemistry ; Dimethylamines - blood ; Dimethylamines - metabolism ; Female ; Gene loci ; Genetics ; Genome-Wide Association Study ; Genomics ; Haplotypes ; Humans ; Isobutyrates - metabolism ; Isobutyrates - urine ; Magnetic Resonance Spectroscopy ; Mathematics ; Medicine ; Metabolic Networks and Pathways - genetics ; Metabolites ; Metabolome - genetics ; Methylamines - metabolism ; Methylamines - urine ; NMR ; Nuclear magnetic resonance ; Nuclear magnetic resonance spectroscopy ; Pathology ; Patologi ; Polymorphism, Single Nucleotide ; Quantitative trait loci ; Quantitative Trait Loci - genetics ; Selection, Genetic ; Single nucleotide polymorphisms</subject><ispartof>PLoS genetics, 2011-09, Vol.7 (9), p.e1002270-e1002270</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>Nicholson et al. 2011</rights><rights>2011 Nicholson et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Nicholson G, Rantalainen M, Li JV, Maher AD, Malmodin D, et al. (2011) A Genome-Wide Metabolic QTL Analysis in Europeans Implicates Two Loci Shaped by Recent Positive Selection. 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Urine and plasma samples were collected from two cohorts of individuals of European descent, with one cohort comprised of female twins donating samples longitudinally. Sample metabolite concentrations were quantified by (1)H NMR and tested for association with genome-wide single-nucleotide polymorphisms (SNPs). Four metabolites' concentrations exhibited significant, replicable association with SNP variation (8.6×10(-11)<p<2.8×10(-23)). Three of these-trimethylamine, 3-amino-isobutyrate, and an N-acetylated compound-were measured in urine. The other-dimethylamine-was measured in plasma. Trimethylamine and dimethylamine mapped to a single genetic region (hence we report a total of three implicated genomic regions). Two of the three hit regions lie within haplotype blocks (at 2p13.1 and 10q24.2) that carry the genetic signature of strong, recent, positive selection in European populations. Genes NAT8 and PYROXD2, both with relatively uncharacterized functional roles, are good candidates for mediating the corresponding mQTL associations. The study's longitudinal twin design allowed detailed variance-components analysis of the sources of population variation in metabolite levels. The mQTLs explained 40%-64% of biological population variation in the corresponding metabolites' concentrations. These effect sizes are stronger than those reported in a recent, targeted mQTL study of metabolites in serum using the targeted-metabolomics Biocrates platform. By re-analysing our plasma samples using the Biocrates platform, we replicated the mQTL findings of the previous study and discovered a previously uncharacterized yet substantial familial component of variation in metabolite levels in addition to the heritability contribution from the corresponding mQTL effects.</description><subject>Acetyltransferases - genetics</subject><subject>Acetyltransferases - metabolism</subject><subject>Biology</subject><subject>Chemistry</subject><subject>Dimethylamines - blood</subject><subject>Dimethylamines - metabolism</subject><subject>Female</subject><subject>Gene loci</subject><subject>Genetics</subject><subject>Genome-Wide Association Study</subject><subject>Genomics</subject><subject>Haplotypes</subject><subject>Humans</subject><subject>Isobutyrates - metabolism</subject><subject>Isobutyrates - urine</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Mathematics</subject><subject>Medicine</subject><subject>Metabolic Networks and Pathways - genetics</subject><subject>Metabolites</subject><subject>Metabolome - genetics</subject><subject>Methylamines - metabolism</subject><subject>Methylamines - urine</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>Nuclear magnetic resonance spectroscopy</subject><subject>Pathology</subject><subject>Patologi</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Quantitative trait loci</subject><subject>Quantitative Trait Loci - genetics</subject><subject>Selection, Genetic</subject><subject>Single nucleotide polymorphisms</subject><issn>1553-7404</issn><issn>1553-7390</issn><issn>1553-7404</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>DOA</sourceid><recordid>eNqVk12LEzEUhgdR3HX1H4gGBEWwNR_zkbkRyrpqobio696GTOZMm5KZjElma_-96ba7dMALJZCcJM_7kpzkJMlzgqeEFeT92g6uk2baL6GbEowpLfCD5JRkGZsUKU4fHsUnyRPv1xizjJfF4-SEkpKRLE9PEz1DUW9bmGx0DaiFICtrtELfrhZIRv-t1x7pDl0MzvYguzhp-wjIAB6FjUXGKo38SvZQo2qLHCjoAuqt10HfAPJgQAVtu6fJo0YaD88O41ny89PF1fmXyeLy8_x8tpgojnGYsIrQQgIHTLmscbypyglhoDJaQlryvI4hBlpnKUiZ1znUtKK0zKuCyqoi7Cx5ufftjfXikCUvCCMsoznOykjM90Rt5Vr0TrfSbYWVWtwuWLcU0gWtDAiiSJplKea8in0BZdnwmjeUxpiknEWvd3svv4F-qEZuH_X17NZtGAQpCGM84h8OhxuqFupdqpw0I9V4p9MrsbQ3gpG8jBmIBm8OBs7-GsAH0WqvwBjZgR28KDEuCp7yIpKv9uRSxovorrHRUO1oMaN5mUeS4EhN_0LFVkOrle2g0XF9JHg7EkQmwO-wlIP3Yv7j-3-wX_-dvbwes6-P2BVIE1bemmH3zfwYTPegctZ7B819pgkWuyq6-x9iV0XiUEVR9uL4le5Fd2XD_gA32RbX</recordid><startdate>20110901</startdate><enddate>20110901</enddate><creator>Nicholson, George</creator><creator>Rantalainen, Mattias</creator><creator>Li, Jia V</creator><creator>Maher, Anthony D</creator><creator>Malmodin, Daniel</creator><creator>Ahmadi, Kourosh R</creator><creator>Faber, Johan H</creator><creator>Barrett, Amy</creator><creator>Min, Josine L</creator><creator>Rayner, N William</creator><creator>Toft, Henrik</creator><creator>Krestyaninova, Maria</creator><creator>Viksna, Juris</creator><creator>Neogi, Sudeshna Guha</creator><creator>Dumas, Marc-Emmanuel</creator><creator>Sarkans, Ugis</creator><creator>Donnelly, Peter</creator><creator>Illig, Thomas</creator><creator>Adamski, Jerzy</creator><creator>Suhre, Karsten</creator><creator>Allen, Maxine</creator><creator>Zondervan, Krina T</creator><creator>Spector, Tim D</creator><creator>Nicholson, Jeremy K</creator><creator>Lindon, John C</creator><creator>Baunsgaard, Dorrit</creator><creator>Holmes, Elaine</creator><creator>McCarthy, Mark I</creator><creator>Holmes, Chris C</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>ISN</scope><scope>ISR</scope><scope>7X8</scope><scope>5PM</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>DF2</scope><scope>DOA</scope></search><sort><creationdate>20110901</creationdate><title>A genome-wide metabolic QTL analysis in Europeans implicates two loci shaped by recent positive selection</title><author>Nicholson, George ; Rantalainen, Mattias ; Li, Jia V ; Maher, Anthony D ; Malmodin, Daniel ; Ahmadi, Kourosh R ; Faber, Johan H ; Barrett, Amy ; Min, Josine L ; Rayner, N William ; Toft, Henrik ; Krestyaninova, Maria ; Viksna, Juris ; Neogi, Sudeshna Guha ; Dumas, Marc-Emmanuel ; Sarkans, Ugis ; Donnelly, Peter ; Illig, Thomas ; Adamski, Jerzy ; Suhre, Karsten ; Allen, Maxine ; Zondervan, Krina T ; Spector, Tim D ; Nicholson, Jeremy K ; Lindon, John C ; Baunsgaard, Dorrit ; Holmes, Elaine ; McCarthy, Mark I ; Holmes, Chris C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c800t-3b127ae8e028ad0371c6113ec529e4986dec50e2d54eaa6d6ed2b2296b72abb13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Acetyltransferases - 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Urine and plasma samples were collected from two cohorts of individuals of European descent, with one cohort comprised of female twins donating samples longitudinally. Sample metabolite concentrations were quantified by (1)H NMR and tested for association with genome-wide single-nucleotide polymorphisms (SNPs). Four metabolites' concentrations exhibited significant, replicable association with SNP variation (8.6×10(-11)<p<2.8×10(-23)). Three of these-trimethylamine, 3-amino-isobutyrate, and an N-acetylated compound-were measured in urine. The other-dimethylamine-was measured in plasma. Trimethylamine and dimethylamine mapped to a single genetic region (hence we report a total of three implicated genomic regions). Two of the three hit regions lie within haplotype blocks (at 2p13.1 and 10q24.2) that carry the genetic signature of strong, recent, positive selection in European populations. Genes NAT8 and PYROXD2, both with relatively uncharacterized functional roles, are good candidates for mediating the corresponding mQTL associations. The study's longitudinal twin design allowed detailed variance-components analysis of the sources of population variation in metabolite levels. The mQTLs explained 40%-64% of biological population variation in the corresponding metabolites' concentrations. These effect sizes are stronger than those reported in a recent, targeted mQTL study of metabolites in serum using the targeted-metabolomics Biocrates platform. By re-analysing our plasma samples using the Biocrates platform, we replicated the mQTL findings of the previous study and discovered a previously uncharacterized yet substantial familial component of variation in metabolite levels in addition to the heritability contribution from the corresponding mQTL effects.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21931564</pmid><doi>10.1371/journal.pgen.1002270</doi><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1313526059 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Public Library of Science (PLoS) |
| subjects | Acetyltransferases - genetics Acetyltransferases - metabolism Biology Chemistry Dimethylamines - blood Dimethylamines - metabolism Female Gene loci Genetics Genome-Wide Association Study Genomics Haplotypes Humans Isobutyrates - metabolism Isobutyrates - urine Magnetic Resonance Spectroscopy Mathematics Medicine Metabolic Networks and Pathways - genetics Metabolites Metabolome - genetics Methylamines - metabolism Methylamines - urine NMR Nuclear magnetic resonance Nuclear magnetic resonance spectroscopy Pathology Patologi Polymorphism, Single Nucleotide Quantitative trait loci Quantitative Trait Loci - genetics Selection, Genetic Single nucleotide polymorphisms |
| title | A genome-wide metabolic QTL analysis in Europeans implicates two loci shaped by recent positive selection |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-27T06%3A02%3A46IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20genome-wide%20metabolic%20QTL%20analysis%20in%20Europeans%20implicates%20two%20loci%20shaped%20by%20recent%20positive%20selection&rft.jtitle=PLoS%20genetics&rft.au=Nicholson,%20George&rft.aucorp=MolPAGE%20Consortium&rft.date=2011-09-01&rft.volume=7&rft.issue=9&rft.spage=e1002270&rft.epage=e1002270&rft.pages=e1002270-e1002270&rft.issn=1553-7404&rft.eissn=1553-7404&rft_id=info:doi/10.1371/journal.pgen.1002270&rft_dat=%3Cgale_plos_%3EA269690010%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=900778487&rft_id=info:pmid/21931564&rft_galeid=A269690010&rft_doaj_id=oai_doaj_org_article_1c14554088b5407e99f8d8f2207e1483&rfr_iscdi=true |