A Systems-Level Approach to Understand The Seasonal Factors Of Early Development With Clinical and Pharmacological Applications

Major developmental defects occur in 100,000 to 200,000 children born each year in the United States of America. 97% of these defects are from unidentified causes. Many fetal outcomes (e.g., developmental defects), result from interactions between genetic and environmental factors. The lifetime effects from prenatal exposures with low impact (e.g., air pollution) are often understudied. Even when these exposures are studied, the focus is often placed on immediate effects of the exposure (e.g., fetal anomalies, miscarriage rates) leaving lifetime effects largely unexplored. This makes prolonged (or lifetime) effects of low-impact exposures an understudied research area. Included in this set of low-impact exposures is seasonal variance at birth. This thesis measures the effects of seasonal variance at birth on lifetime disease risk at both the population-level and molecular-levels. Four aims, comprising this thesis study, were conducted that utilize data from pharmacology, clinical care (Electronic Health Records) and genetics. These aims included: 1.) Development of an Algorithm to Reveal Diseases with a Prenatal/Perinatal Seasonality Component (described in chapter 2); 2.) Investigation of Climate Variables that Affect Lifetime Disease Risk By Altering Environmental Drivers (described in chapters 3 and 4); 3.) Discovery of Genes Involved in Birth Season – Disease Effects (described in chapter 5) and 4.) Investigation of Pharmacological Inhibitors As Phenocopies of the Birth Season – Disease Effect (described in chapters 6 and 7). Knowledge gained from these four areas, through seven distinct studies, establishes that birth season is a causal risk factor in a number of common diseases including cardiovascular diseases.