A Genome-Wide Assessment of Variability in Human Serum Metabolism

被引：36

作者：

Hong, Mun-Gwan ^{[1
]}

Karlsson, Robert ^{[1
]}

Magnusson, Patrik K. E. ^{[1
]}

Lewis, Matthew R. ^{[2
,3
]}

Isaacs, William ^{[4
]}

Zheng, Lilly S. ^{[5
]}

Xu, Jianfeng ^{[5
]}

Gronberg, Henrik ^{[1
]}

Ingelsson, Erik ^{[1
]}

Pawitan, Yudi ^{[1
]}

Broeckling, Corey ^{[3
]}

Prenni, Jessica E. ^{[6
]}

Wiklund, Fredrik ^{[1
]}

Prince, Jonathan A. ^{[1
]}

机构：

[1] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden

[2] Univ London Imperial Coll Sci Technol & Med, Dept Mol Biol, London, England

[3] Colorado State Univ, Prote & Metabol Facil, Ft Collins, CO 80523 USA

[4] Johns Hopkins Med Inst, Dept Urol, Baltimore, MD 21205 USA

[5] Wake Forest Univ, Bowman Gray Sch Med, Ctr Canc Genom, Winston Salem, NC USA

[6] Colorado State Univ, Dept Biochem & Mol Biol, Ft Collins, CO 80523 USA

来源：

HUMAN MUTATION | 2013年 / 34卷 / 03期

关键词：

serum; metabolome; genome-wide; association; variation; pleiotropy; ASSOCIATION;

D O I：

10.1002/humu.22267

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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=10131091). 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.

引用

页码：515 / 524

页数：10

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