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A genome-wide metabolic QTL analysis in europeans implicates two Loci shaped by recent positive selection
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نویسنده
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nicholson g. ,rantalainen m. ,li j.v. ,maher a.d. ,malmodin d. ,ahmadi k.r. ,faber j.h. ,barrett a. ,min j.l. ,rayner n.w. ,toft h. ,krestyaninova m. ,viksna j. ,neogi s.g. ,dumas m.-e. ,sarkans u. ,donnelly p. ,illig t. ,adamski j. ,suhre k. ,allen m. ,zondervan k.t. ,spector t.d. ,nicholson j.k. ,lindon j.c. ,baunsgaard d. ,holmes e. ,mccarthy m.i. ,holmes c.c.
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منبع
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plos genetics - 2011 - دوره : 7 - شماره : 9
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چکیده
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We have performed a metabolite quantitative trait locus (mqtl) study of the 1h nuclear magnetic resonance spectroscopy ( 1h 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 1h 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. © 2011 nicholson et al.
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آدرس
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department of statistics,university of oxford,oxford, United Kingdom, department of statistics,university of oxford,oxford, United Kingdom, biomolecular medicine,department of surgery and cancer,imperial college london,london, United Kingdom, biomolecular medicine,department of surgery and cancer,imperial college london,london,united kingdom,biosciences research division,department of primary industries,bundoora, Australia, novo nordisk a/s,måløv, Denmark, department of twin research and genetic epidemiology,king's college london,london, United Kingdom, novo nordisk a/s,måløv, Denmark, oxford centre for diabetes,endocrinology,and metabolism,university of oxford,oxford, United Kingdom, wellcome trust centre for human genetics,university of oxford,oxford, United Kingdom, oxford centre for diabetes,endocrinology,and metabolism,university of oxford,oxford,united kingdom,wellcome trust centre for human genetics,university of oxford,oxford, United Kingdom, novo nordisk a/s,måløv, Denmark, european bioinformatics institute,wellcome trust genome campus,hinxton,cambridge, United Kingdom, institute of mathematics and computer science,riga, Latvia, nihr cambridge biomedical research centre,institute of metabolic science,addenbrooke's hospital,cambridge, United Kingdom, biomolecular medicine,department of surgery and cancer,imperial college london,london, United Kingdom, european bioinformatics institute,wellcome trust genome campus,hinxton,cambridge, United Kingdom, department of statistics,university of oxford,oxford,united kingdom,wellcome trust centre for human genetics,university of oxford,oxford, United Kingdom, institute of epidemiology,helmholtz zentrum münchen,neuherberg, Germany, institute of experimental genetics,genome analysis center,helmholtz zentrum münchen,neuherberg,germany,institute of experimental genetics,life and food science center weihenstephan,technische universität münchen,freising-weihenstephan, Germany, institute of bioinformatics and systems biology,helmholtz zentrum münchen,neuherberg,germany,faculty of biology,ludwig-maximilians-universität,planegg-martinsried,germany,department of physiology and biophysics,weill cornell medical college in qatar,education city,qatar foundation,doha, Qatar, oxford centre for diabetes,endocrinology,and metabolism,university of oxford,oxford, United Kingdom, wellcome trust centre for human genetics,university of oxford,oxford, United Kingdom, department of twin research and genetic epidemiology,king's college london,london, United Kingdom, biomolecular medicine,department of surgery and cancer,imperial college london,london, United Kingdom, biomolecular medicine,department of surgery and cancer,imperial college london,london, United Kingdom, novo nordisk a/s,måløv, Denmark, biomolecular medicine,department of surgery and cancer,imperial college london,london, United Kingdom, oxford centre for diabetes,endocrinology,and metabolism,university of oxford,oxford,united kingdom,wellcome trust centre for human genetics,university of oxford,oxford,united kingdom,oxford nihr biomedical research centre,churchill hospital,oxford, United Kingdom, department of statistics,university of oxford,oxford, United Kingdom
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Authors
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