Systems Genetics Analysis of Gene-by-Environment Interactions in Human Cells

Casey E. Romanoski, Sangderk Lee, Michelle J. Kim, Leslie Ingram-Drake, Christopher L. Plaisier, Roumyana Yordanova, Charles Tilford, Bo Guan, Aiqing He, Peter S. Gargalovic, Todd G. Kirchgessner, Judith A. Berliner, Aldons J. Lusis

Research output: Contribution to journalArticlepeer-review

91 Scopus citations


Gene by environment (GxE) interactions are clearly important in many human diseases, but they have proven to be difficult to study on a molecular level. We report genetic analysis of thousands of transcript abundance traits in human primary endothelial cell (EC) lines in response to proinflammatory oxidized phospholipids implicated in cardiovascular disease. Of the 59 most regulated transcripts, approximately one-third showed evidence of GxE interactions. The interactions resulted primarily from effects of distal-, trans-acting loci, but a striking example of a local-GxE interaction was also observed for FGD6. Some of the distal interactions were validated by siRNA knockdown experiments, including a locus involved in the regulation of multiple transcripts involved in the ER stress pathway. Our findings add to the understanding of the overall architecture of complex human traits and are consistent with the possibility that GxE interactions are responsible, in part, for the failure of association studies to more fully explain common disease variation.

Original languageEnglish (US)
Pages (from-to)399-410
Number of pages12
JournalAmerican Journal of Human Genetics
Issue number3
StatePublished - 2010
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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