title: Genetic determinants influencing human serum metabolome among African Americans.
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.
authors.affiliation: Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
authors.forename: Bing
authors.initials: B
authors.lastname: Yu
authors.affiliation: Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Metabolon, Inc., Durham, North Carolina, United States of America.
authors.forename: Danny
authors.initials: D
authors.lastname: Alexander
authors.affiliation: Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
authors.forename: Alanna C
authors.initials: AC
authors.lastname: Morrison
authors.affiliation: Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Josef
authors.initials: J
authors.lastname: Coresh
authors.affiliation: 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.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
mesh_terms: D000123:Acetyltransferases / Q000097:blood / Q000235:genetics; D001741:Black or African American / Q000235:genetics; D000483:Alleles; D050197:Atherosclerosis / Q000097:blood* / Q000235:genetics / Q000473:pathology; D003920:Diabetes Mellitus / Q000097:blood / Q000235:genetics / Q000378:metabolism; D055106:Genome-Wide Association Study; D006801:Humans; D055442:Metabolome / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D014199:Trehalose / Q000097:blood / Q000235:genetics
chemical_list: D014199:Trehalose; D000123:Acetyltransferases; C116373:NAT8 protein, human