1. Associations with metabolites in Chinese suggest new metabolic roles in Alzheimer's and Parkinson's diseases
- Author
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Suryaprakash Raichur, Jean-Paul Kovalik, Wee Siong Chew, Ing Wei Khor, Jianhong Ching, Federico Torta, Deron R. Herr, Xueling Sim, E. Shyong Tai, Jin-Fang Chai, Chin Meng Khoo, and Markus R. Wenk
- Subjects
Male ,China ,Metabolite ,Serine C-Palmitoyltransferase ,Disease ,Genome ,Glycosphingolipids ,ABCA7 ,03 medical and health sciences ,chemistry.chemical_compound ,Asian People ,Alzheimer Disease ,Sphingosine ,Tandem Mass Spectrometry ,Carnitine ,Genetics ,Serine ,Humans ,Genetic Predisposition to Disease ,Molecular Biology ,Genetics (clinical) ,Glutathione Transferase ,0303 health sciences ,Sphingolipids ,biology ,Liver-Specific Organic Anion Transporter 1 ,030305 genetics & heredity ,Membrane Proteins ,Parkinson Disease ,General Medicine ,Middle Aged ,Galactosyltransferases ,Sphingolipid ,Phosphoric Monoester Hydrolases ,DNA-Binding Proteins ,Metabolic pathway ,chemistry ,Genetic marker ,Genetic Loci ,biology.protein ,ATP-Binding Cassette Transporters ,Female ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Lysophospholipids ,Genome-Wide Association Study ,Transcription Factors - 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 1,954 Chinese from Singapore. At a conservative genome-wide threshold (3.7 x 10-10), we detected 1,899 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.
- Published
- 2019