Clusters of Epigenetic Networks at Birth and Asthma Incidence in Children - This is an epidemiological study on the epigenetic origins of asthma in children and young adulthood. It has been increasingly recognized that asthma is a consequence of joint activities among genes rather than of individual genes’ independent contributions. Examining individual contributions of CpGs on asthma development is biologically ungrounded and we take a high risk of concluding incomplete and/or misleading findings. Such limitations have been widely agreed upon, and methods to address joint activities among genes have been proposed, including approaches to identify differentially methylated regions (DMRs) and those for detection of gene networks. However, the DMR approach is potentially flawed, since almost all DMRs are inferred based on effects of each individual CpG rather than joint effects of CpGs. Defining networks amongst genes or CpGs allow better understanding of their concerted effects. Current network constructions, however, either focus on a population as a whole or on a specific group. Constructing one network for a general population lacks purity, since it overlooks underlying heterogeneity among subjects (e.g., heterogeneity in asthma risk). Whilst building a network for a group of disease patients will substantially limit the ability to predict and prevent disease, due to potential reverse-causation on gene activities. Currently, no methods are available that address heterogeneity while building networks. We propose an approach to detect distinct epigenetic networks (DENs) with each unique to a group of subjects via network clustering using DNA methylation (DNAm) data before disease manifestation, e.g., at-birth DNAm and childhood asthma. The constructed network in each cluster will represent unique epigenetic features of a homogeneous group of subjects. Differentiation between networks constructed under different conditions support the feasibility of network clustering in a general population. In addition, in asthma studies, we will study the longitudinal association of DENs at birth with asthma incidence in children, post-adolescence, and young adulthood, assess the role of age, sex, and race in this association, and examine the benefit of evaluating joint rather than individual activities of CpGs on asthma incidence. The findings of this study will inform to what extent CpGs work jointly and contribute to the development of asthma, and will benefit future studies on early prediction of asthma acquisition for each sex and different races. Furthermore, the method to be developed will be readily applied to other health conditions with other omics data different from DNAm. We will carry out this important study in three birth cohorts, two cohorts with whites (the IOWBC and ALSPAC birth cohorts focusing on asthma history) and one cohort with both white and black participants (the NEST birth cohort). These three birth cohorts will allow us to discover, replicate, and assess region and race specificity of DENs and their epidemiological association with asthma incidence. For CpGs in modules of a network or networks showing association with asthma incidence at one or more stages of life, we will evaluate the potential causality of the CpGs via Mendelian randomization (MR) tests using the MR-base webtool. For the statistical methods to detect DENs, we will build the method into a publicly available R package accompanied by a detailed manual with concrete examples.
