title: A genome-wide assessment of variability in human serum metabolism.
abstract: The study of the genetic regulation of metabolism in human serum samples can contribute to a better understanding of the intermediate biological steps that lead from polymorphism to disease. Here, we conducted a genome-wide association study (GWAS) to discover metabolic quantitative trait loci (mQTLs) utilizing samples from a study of prostate cancer in Swedish men, consisting of 402 individuals (214 cases and 188 controls) in a discovery set and 489 case-only samples in a replication set. A global nontargeted metabolite profiling approach was utilized resulting in the detection of 6,138 molecular features followed by targeted identification of associated metabolites. Seven replicating loci were identified (PYROXD2, FADS1, PON1, CYP4F2, UGT1A8, ACADL, and LIPC) with associated sequence variants contributing significantly to trait variance for one or more metabolites (P = 10(-13) -10(-91)). Regional mQTL enrichment analyses implicated two loci that included FADS1 and a novel locus near PDGFC. Biological pathway analysis implicated ACADM, ACADS, ACAD8, ACAD10, ACAD11, and ACOXL, reflecting significant enrichment of genes with acyl-CoA dehydrogenase activity. mQTL SNPs and mQTL-harboring genes were over-represented across GWASs conducted to date, suggesting that these data may have utility in tracing the molecular basis of some complex disease associations.
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
authors.forename: Mun-Gwan
authors.initials: MG
authors.lastname: Hong
authors.forename: Robert
authors.initials: R
authors.lastname: Karlsson
authors.forename: Patrik K E
authors.initials: PK
authors.lastname: Magnusson
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Lewis
authors.forename: William
authors.initials: W
authors.lastname: Isaacs
authors.forename: Lilly S
authors.initials: LS
authors.lastname: Zheng
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
authors.forename: Henrik
authors.initials: H
authors.lastname: Grönberg
authors.forename: Erik
authors.initials: E
authors.lastname: Ingelsson
authors.forename: Yudi
authors.initials: Y
authors.lastname: Pawitan
authors.forename: Corey
authors.initials: C
authors.lastname: Broeckling
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Prenni
authors.forename: Fredrik
authors.initials: F
authors.lastname: Wiklund
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Prince
mesh_terms: D042964:Acyl-CoA Dehydrogenase / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D000090943:Delta-5 Fatty Acid Desaturase; D044943:Fatty Acid Desaturases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism; D008297:Male; D055442:Metabolome; D055432:Metabolomics; D009154:Mutation; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics*; D040901:Proteomics; D040641:Quantitative Trait Loci; D013548:Sweden
chemical_list: D000090943:Delta-5 Fatty Acid Desaturase; D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; C411423:platelet-derived growth factor C; D044943:Fatty Acid Desaturases; C000716847:FADS1 protein, human; D042964:Acyl-CoA Dehydrogenase