Network Approaches to Integrate Analyses of Genetics and Metabolomics Data with Applications to Fetal Programming Studies

Abstract

The integration of genetics and metabolomics data demands careful accounting of complex dependencies, particularly when modelling familial omics data, e.g., to study fetal programming of related maternal–offspring phenotypes. Efforts to identify genetically determined metabotypes using classic genome wide association approaches have proven useful for characterizing complex disease, but conclusions are often limited to a series of variant–metabolite associations. We adapt Bayesian network models to integrate metabotypes with maternal–offspring genetic dependencies and metabolic profile correlations in order to investigate mechanisms underlying maternal–offspring phenotypic associations. Using data from the multiethnic Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, we demonstrate that the strategic specification of ordered dependencies, pre-filtering of candidate metabotypes, incorporation of metabolite dependencies, and penalized network estimation methods clarify potential mechanisms for fetal programming of newborn adiposity and metabolic outcomes. The exploration of Bayesian network growth over a range of penalty parameters, coupled with interactive plotting, facilitate the interpretation of network edges. These methods are broadly applicable to integration of diverse omics data for related individuals.