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...
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doaj-64343507210b4057a1c34af2e81a13882020-11-24T21:36:54ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042014-03-01103e100421210.1371/journal.pgen.1004212Genetic determinants influencing human serum metabolome among African Americans.Bing YuYan ZhengDanny AlexanderAlanna C MorrisonJosef CoreshEric BoerwinklePhenotypes 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.http://europepmc.org/articles/PMC3952826?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Bing Yu Yan Zheng Danny Alexander Alanna C Morrison Josef Coresh Eric Boerwinkle |
spellingShingle |
Bing Yu Yan Zheng Danny Alexander Alanna C Morrison Josef Coresh Eric Boerwinkle Genetic determinants influencing human serum metabolome among African Americans. PLoS Genetics |
author_facet |
Bing Yu Yan Zheng Danny Alexander Alanna C Morrison Josef Coresh Eric Boerwinkle |
author_sort |
Bing Yu |
title |
Genetic determinants influencing human serum metabolome among African Americans. |
title_short |
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_sort |
genetic determinants influencing human serum metabolome among african americans. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Genetics |
issn |
1553-7390 1553-7404 |
publishDate |
2014-03-01 |
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. |
url |
http://europepmc.org/articles/PMC3952826?pdf=render |
work_keys_str_mv |
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