Direct and indirect genetic effects on triglycerides through omics and correlated phenotypes 06 Biological Sciences 0604 Genetics

Anne E. Justice, Annie Green Howard, Lindsay Fernandez-Rhodes, Misa Graff, Ran Tao, Kari E. North

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Even though there has been great success in identifying lipid-associated single-nucleotide polymorphisms (SNPs), the mechanisms through which the SNPs act on each trait are poorly understood. The emergence of large, complex biological data sets in well-characterized cohort studies offers an opportunity to investigate the genetic effects on trait variability as a way of informing the causal genes and biochemical pathways that are involved in lipoprotein metabolism. However, methods for simultaneously analyzing multiple omics, environmental exposures, and longitudinally measured, correlated phenotypes are lacking. The purpose of our study was to demonstrate the utility of the structural equation modeling (SEM) approach to inform our understanding of the pathways by which genetic variants lead to disease risk. With the SEM method, we examine multiple pathways directly and indirectly through previously identified triglyceride (TG)-associated SNPs, methylation, and high-density lipoprotein (HDL), including sex, age, and smoking behavior, while adding in biologically plausible direct and indirect pathways. We observed significant SNP effects (P < 0.05 and directionally consistent) on TGs at visit 4 (TG4) for five loci, including rs645040 (DOCK7), rs964184 (ZPR1/ZNF259), rs4765127 (ZNF664), rs1121980 (FTO), and rs10401969 (SUGP1). Across these loci, we identify three with strong evidence of an indirect genetic effect on TG4 through HDL, one with evidence of pleiotropic effect on HDL and TG4, and one variant that acts on TG4 indirectly through a nearby methylation site. Such information can be used to prioritize candidate genes in regions of interest, inform mechanisms of action of methylation effects, and highlight possible genes with pleiotropic effects.

Original languageEnglish (US)
Article number22
JournalBMC Proceedings
Volume12
DOIs
StatePublished - Sep 17 2018

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Biological Science Disciplines
Polymorphism
Methylation
Single Nucleotide Polymorphism
Triglycerides
HDL Lipoproteins
Nucleotides
Phenotype
Genes
Genetic Pleiotropy
Environmental Exposure
Metabolism
Lipoproteins
Cohort Studies
Smoking
Lipids
Genetics

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

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title = "Direct and indirect genetic effects on triglycerides through omics and correlated phenotypes 06 Biological Sciences 0604 Genetics",
abstract = "Even though there has been great success in identifying lipid-associated single-nucleotide polymorphisms (SNPs), the mechanisms through which the SNPs act on each trait are poorly understood. The emergence of large, complex biological data sets in well-characterized cohort studies offers an opportunity to investigate the genetic effects on trait variability as a way of informing the causal genes and biochemical pathways that are involved in lipoprotein metabolism. However, methods for simultaneously analyzing multiple omics, environmental exposures, and longitudinally measured, correlated phenotypes are lacking. The purpose of our study was to demonstrate the utility of the structural equation modeling (SEM) approach to inform our understanding of the pathways by which genetic variants lead to disease risk. With the SEM method, we examine multiple pathways directly and indirectly through previously identified triglyceride (TG)-associated SNPs, methylation, and high-density lipoprotein (HDL), including sex, age, and smoking behavior, while adding in biologically plausible direct and indirect pathways. We observed significant SNP effects (P < 0.05 and directionally consistent) on TGs at visit 4 (TG4) for five loci, including rs645040 (DOCK7), rs964184 (ZPR1/ZNF259), rs4765127 (ZNF664), rs1121980 (FTO), and rs10401969 (SUGP1). Across these loci, we identify three with strong evidence of an indirect genetic effect on TG4 through HDL, one with evidence of pleiotropic effect on HDL and TG4, and one variant that acts on TG4 indirectly through a nearby methylation site. Such information can be used to prioritize candidate genes in regions of interest, inform mechanisms of action of methylation effects, and highlight possible genes with pleiotropic effects.",
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Direct and indirect genetic effects on triglycerides through omics and correlated phenotypes 06 Biological Sciences 0604 Genetics. / Justice, Anne E.; Howard, Annie Green; Fernandez-Rhodes, Lindsay; Graff, Misa; Tao, Ran; North, Kari E.

In: BMC Proceedings, Vol. 12, 22, 17.09.2018.

Research output: Contribution to journalArticle

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T1 - Direct and indirect genetic effects on triglycerides through omics and correlated phenotypes 06 Biological Sciences 0604 Genetics

AU - Justice, Anne E.

AU - Howard, Annie Green

AU - Fernandez-Rhodes, Lindsay

AU - Graff, Misa

AU - Tao, Ran

AU - North, Kari E.

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