title: Whole genome sequence analysis of serum amino acid levels.
abstract: Blood levels of amino acids are important biomarkers of disease and are influenced by synthesis, protein degradation, and gene-environment interactions. Whole genome sequence analysis of amino acid levels may establish a paradigm for analyzing quantitative risk factors.
  
  
  
  In a discovery cohort of 1872 African Americans and a replication cohort of 1552 European Americans we sequenced exons and whole genomes and measured serum levels of 70 amino acids. Rare and low-frequency variants (minor allele frequency ≤5%) were analyzed by three types of aggregating motifs defined by gene exons, regulatory regions, or genome-wide sliding windows. Common variants (minor allele frequency >5%) were analyzed individually. Over all four analysis strategies, 14 gene-amino acid associations were identified and replicated. The 14 loci accounted for an average of 1.8% of the variance in amino acid levels, which ranged from 0.4 to 9.7%. Among the identified locus-amino acid pairs, four are novel and six have been reported to underlie known Mendelian conditions. These results suggest that there may be substantial genetic effects on amino acid levels in the general population that may underlie inborn errors of metabolism. We also identify a predicted promoter variant in AGA (the gene that encodes aspartylglucosaminidase) that is significantly associated with asparagine levels, with an effect that is independent of any observed coding variants.
  
  
  
  These data provide insights into genetic influences on circulating amino acid levels by integrating -omic technologies in a multi-ethnic population. The results also help establish a paradigm for whole genome sequence analysis of quantitative traits.
authors.affiliation: Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Yu
authors.affiliation: Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Paul S
authors.initials: PS
authors.lastname: de Vries
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Ginger A
authors.initials: GA
authors.lastname: Metcalf
authors.affiliation: Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Feofanova
authors.affiliation: Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Liu
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Donna Marie
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Lynne E
authors.initials: LE
authors.lastname: Wagenknecht
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Alanna C
authors.initials: AC
authors.lastname: Morrison
authors.affiliation: Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA. Eric.Boerwinkle@uth.tmc.edu.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA. Eric.Boerwinkle@uth.tmc.edu.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
mesh_terms: D000328:Adult; D000368:Aged; D000596:Amino Acids / Q000097:blood*; D015415:Biomarkers; D005091:Exons; D005260:Female; D015894:Genome, Human; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D059372:Nucleotide Motifs; D020641:Polymorphism, Single Nucleotide; D011159:Population Surveillance; D012045:Regulatory Sequences, Nucleic Acid
chemical_list: D000596:Amino Acids; D015415:Biomarkers
keywords: Amino acids; Metabolomics; Multi-ethnic; Rare variants; Whole genome sequence