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PLoS Genet. 2014 Mar 13;10(3):e1004212. doi: 10.1371/journal.pgen.1004212. eCollection 2014 Mar.

Genetic determinants influencing human serum metabolome among African Americans.

Author information

1
Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
2
Metabolon, Inc., Durham, North Carolina, United States of America.
3
Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland, United States of America.
4
Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, United States of America; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America.

Abstract

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.

PMID:
24625756
PMCID:
PMC3952826
DOI:
10.1371/journal.pgen.1004212
[Indexed for MEDLINE]
Free PMC Article

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