Associations with metabolites in Chinese suggest new metabolic roles in Alzheimer's and Parkinson's diseases

Hum Mol Genet. 2020 Jan 15;29(2):189-201. doi: 10.1093/hmg/ddz246.

Abstract

Metabolites are small intermediate products of cellular metabolism perturbed in a variety of complex disorders. Identifying genetic markers associated with metabolite concentrations could delineate disease-related metabolic pathways in humans. We tested genetic variants for associations with 136 metabolites in 1954 Chinese from Singapore. At a conservative genome-wide threshold (3.7 × 10-10), we detected 1899 variant-metabolite associations at 16 genetic loci. Three loci (ABCA7, A4GALT, GSTM2) represented novel associations with metabolites, with the strongest association observed between ABCA7 and d18:1/24:1 dihexosylceramide. Among 13 replicated loci, we identified six new variants independent of previously reported metabolite or lipid signals. We observed variant-metabolite associations at two loci (ABCA7, CHCHD2) that have been linked to neurodegenerative diseases. At SGPP1 and SPTLC3 loci, genetic variants showed preferential selectivity for sphingolipids with d16 (rather than d18) sphingosine backbone, including sphingosine-1-phosphate (S1P). Our results provide new genetic associations for metabolites and highlight the role of metabolites as intermediate modulators in disease metabolic pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism
  • Asian Continental Ancestry Group / genetics*
  • Carnitine / analogs & derivatives
  • Carnitine / metabolism
  • China
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Female
  • Galactosyltransferases / genetics
  • Galactosyltransferases / metabolism
  • Genetic Loci
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Glutathione Transferase / genetics
  • Glutathione Transferase / metabolism
  • Glycosphingolipids / genetics
  • Glycosphingolipids / metabolism*
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / metabolism
  • Liver-Specific Organic Anion Transporter 1 / genetics
  • Liver-Specific Organic Anion Transporter 1 / metabolism
  • Lysophospholipids / metabolism
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Middle Aged
  • Parkinson Disease / genetics*
  • Parkinson Disease / metabolism
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / metabolism
  • Serine / metabolism
  • Serine C-Palmitoyltransferase / genetics
  • Serine C-Palmitoyltransferase / metabolism
  • Sphingolipids / chemistry
  • Sphingolipids / metabolism*
  • Sphingosine / analogs & derivatives
  • Sphingosine / metabolism
  • Tandem Mass Spectrometry
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • ABCA7 protein, human
  • ATP-Binding Cassette Transporters
  • CHCHD2 protein, human
  • DNA-Binding Proteins
  • Glycosphingolipids
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Liver-Specific Organic Anion Transporter 1
  • Lysophospholipids
  • Membrane Proteins
  • SLCO1B1 protein, human
  • Sphingolipids
  • Transcription Factors
  • acylcarnitine
  • dihexosylceramide
  • sphingosine 1-phosphate
  • Serine
  • SPTLC3 protein, human
  • Serine C-Palmitoyltransferase
  • Galactosyltransferases
  • UDP-galactose-lactosylceramide alpha 1-4-galactosyltransferase
  • Glutathione Transferase
  • glutathione S-transferase Mu 2
  • SGPP1 protein, human
  • Phosphoric Monoester Hydrolases
  • Sphingosine
  • Carnitine