Case-control studies of gene-environment interactions. When a case might not be the case.

TitleCase-control studies of gene-environment interactions. When a case might not be the case.
Publication TypeJournal Article
Year of Publication2018
AuthorsLobach I, Sampson J, Alekseyenko A, Lobach S, Zhang L
JournalPLoS One
Volume13
Issue8
Paginatione0201140
Date Published2018
ISSN1932-6203
Abstract

Case-control Genome-Wide Association Studies (GWAS) provide a rich resource for studying the genetic architecture of complex diseases. A key is to elucidate how the genetic effects vary by the environment, what is traditionally defined by Gene-Environment interactions (GxE). The overlooked complication is that multiple, distinct pathophysiologic mechanisms may lead to the same clinical diagnosis and often these mechanisms have distinct genetic bases. In this paper, we first show that using the clinically diagnosed status can lead to severely biased estimates of GxE interactions in situations when the frequency of the pathologic diagnosis of interest, as compared to other diagnoses, depends on the environment. We then propose a pseudo-likelihood solution to correct the bias. Finally, we demonstrate our method in extensive simulations and in a GWAS of Alzheimer's disease.

DOI10.1371/journal.pone.0201140
Alternate JournalPLoS ONE
PubMed ID30133451
PubMed Central IDPMC6104951
Grant ListRC2 AG036528 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States
R21 AG043710 / AG / NIA NIH HHS / United States
U24 AG041689 / AG / NIA NIH HHS / United States