Identification of Rare Variants in Metabolites of the Carnitine Pathway by Whole Genome Sequencing Analysis

Genet Epidemiol. 2016 Sep;40(6):486-91. doi: 10.1002/gepi.21980. Epub 2016 Jun 3.


We use whole genome sequence data and rare variant analysis methods to investigate a subset of the human serum metabolome, including 16 carnitine-related metabolites that are important components of mammalian energy metabolism. Medium pass sequence data consisting of 12,820,347 rare variants and serum metabolomics data were available on 1,456 individuals. By applying a penalization method, we identified two genes FGF8 and MDGA2 with significant effects on lysine and cis-4-decenoylcarnitine, respectively, using Δ-AIC and likelihood ratio test statistics. Single variant analyses in these regions did not identify a single low-frequency variant (minor allele count > 3) responsible for the underlying signal. The results demonstrate the utility of whole genome sequence and innovative analyses for identifying candidate regions influencing complex phenotypes.

Keywords: carnitine; linkage disequilibrium; metabolomics; penalization; rare variants.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Biomarkers / blood
  • Carnitine / metabolism*
  • Female
  • Fibroblast Growth Factor 8 / genetics
  • GPI-Linked Proteins / genetics
  • Genetic Variation
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Linkage Disequilibrium
  • Lysine / metabolism
  • Male
  • Metabolomics*
  • Middle Aged
  • Neural Cell Adhesion Molecules / genetics
  • Polymorphism, Single Nucleotide
  • Sequence Analysis, DNA


  • Biomarkers
  • GPI-Linked Proteins
  • MDGA2 protein, human
  • Neural Cell Adhesion Molecules
  • Fibroblast Growth Factor 8
  • Lysine
  • Carnitine