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Genetic Determinants Influencing Human Serum Metabolome among African Americans
Phenotypes proximal to gene action generally reflect larger genetic effect sizes than those that are distant. The human metabolome, a result of multiple cellular and biological processes, are functional intermediate phenotypes proximal to gene action. Here, we present a genome-wide association study...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3952826/ https://www.ncbi.nlm.nih.gov/pubmed/24625756 http://dx.doi.org/10.1371/journal.pgen.1004212 |
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author | Yu, Bing Zheng, Yan Alexander, Danny Morrison, Alanna C. Coresh, Josef Boerwinkle, Eric |
author_facet | Yu, Bing Zheng, Yan Alexander, Danny Morrison, Alanna C. Coresh, Josef Boerwinkle, Eric |
author_sort | Yu, Bing |
collection | PubMed |
description | Phenotypes proximal to gene action generally reflect larger genetic effect sizes than those that are distant. The human metabolome, a result of multiple cellular and biological processes, are functional intermediate phenotypes proximal to gene action. Here, we present a genome-wide association study of 308 untargeted metabolite levels among African Americans from the Atherosclerosis Risk in Communities (ARIC) Study. Nineteen significant common variant-metabolite associations were identified, including 13 novel loci (p<1.6×10(−10)). These loci were associated with 7–50% of the difference in metabolite levels per allele, and the variance explained ranged from 4% to 20%. Fourteen genes were identified within the nineteen loci, and four of them contained non-synonymous substitutions in four enzyme-encoding genes (KLKB1, SIAE, CPS1, and NAT8); the other significant loci consist of eight other enzyme-encoding genes (ACE, GATM, ACY3, ACSM2B, THEM4, ADH4, UGT1A, TREH), a transporter gene (SLC6A13) and a polycystin protein gene (PKD2L1). In addition, four potential disease-associated paths were identified, including two direct longitudinal predictive relationships: NAT8 with N-acetylornithine, N-acetyl-1-methylhistidine and incident chronic kidney disease, and TREH with trehalose and incident diabetes. These results highlight the value of using endophenotypes proximal to gene function to discover new insights into biology and disease pathology. |
format | Online Article Text |
id | pubmed-3952826 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-39528262014-03-18 Genetic Determinants Influencing Human Serum Metabolome among African Americans Yu, Bing Zheng, Yan Alexander, Danny Morrison, Alanna C. Coresh, Josef Boerwinkle, Eric PLoS Genet Research Article Phenotypes proximal to gene action generally reflect larger genetic effect sizes than those that are distant. The human metabolome, a result of multiple cellular and biological processes, are functional intermediate phenotypes proximal to gene action. Here, we present a genome-wide association study of 308 untargeted metabolite levels among African Americans from the Atherosclerosis Risk in Communities (ARIC) Study. Nineteen significant common variant-metabolite associations were identified, including 13 novel loci (p<1.6×10(−10)). These loci were associated with 7–50% of the difference in metabolite levels per allele, and the variance explained ranged from 4% to 20%. Fourteen genes were identified within the nineteen loci, and four of them contained non-synonymous substitutions in four enzyme-encoding genes (KLKB1, SIAE, CPS1, and NAT8); the other significant loci consist of eight other enzyme-encoding genes (ACE, GATM, ACY3, ACSM2B, THEM4, ADH4, UGT1A, TREH), a transporter gene (SLC6A13) and a polycystin protein gene (PKD2L1). In addition, four potential disease-associated paths were identified, including two direct longitudinal predictive relationships: NAT8 with N-acetylornithine, N-acetyl-1-methylhistidine and incident chronic kidney disease, and TREH with trehalose and incident diabetes. These results highlight the value of using endophenotypes proximal to gene function to discover new insights into biology and disease pathology. Public Library of Science 2014-03-13 /pmc/articles/PMC3952826/ /pubmed/24625756 http://dx.doi.org/10.1371/journal.pgen.1004212 Text en © 2014 Yu et al http://creativecommons.org/licenses/by/4.0/ 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 properly credited. |
spellingShingle | Research Article Yu, Bing Zheng, Yan Alexander, Danny Morrison, Alanna C. Coresh, Josef Boerwinkle, Eric Genetic Determinants Influencing Human Serum Metabolome among African Americans |
title | Genetic Determinants Influencing Human Serum Metabolome among African Americans |
title_full | Genetic Determinants Influencing Human Serum Metabolome among African Americans |
title_fullStr | Genetic Determinants Influencing Human Serum Metabolome among African Americans |
title_full_unstemmed | Genetic Determinants Influencing Human Serum Metabolome among African Americans |
title_short | Genetic Determinants Influencing Human Serum Metabolome among African Americans |
title_sort | genetic determinants influencing human serum metabolome among african americans |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3952826/ https://www.ncbi.nlm.nih.gov/pubmed/24625756 http://dx.doi.org/10.1371/journal.pgen.1004212 |
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