We have been studying common diseases in the Hutterites since 1994. The >1,400 Hutterites in our studies are related to each other through multiple lines of descent in a ~3,000-person, 14-generation pedigree. Quantitative and disease phenotypes are assessed in all individuals 6 years old and older during field trips to Hutterite colonies in South Dakota. We recently imputed all genetic variation discovered by whole genome sequencing 98 Hutterites to the entire sample of Hutterites who have participated in our studies. These ~7M variants allow us to study the effects of rare vs. common variation on asthma risk, and on variation in quantitative phenotypes, including gene expression and methylation levels, and gene expression and methylation responses to known environmental risk factors. Our laboratory is particularly interested in the sex-specific responses, including parent-of-origin effects and the role of X chromosome variation.
We have initiated comparative studies between the Hutterites of South Dakota and the Amish of Indiana in collaboration with Drs. Erika von Mutius (Munich) and Donata Vercelli (University of Arizona) to elucidate the mechanisms underlying the opposite asthma risks in these two farming populations of nearly identical ancestry. While the prevalence of asthma in Hutterite children is relatively high (~15%), the Amish are nearly completely protected from asthma, with only 2% of children with symptoms consistent with a diagnosis of asthma. We have begun to characterize the environmental and host microbiomes in these children, and in collaboration with Dr. Anne Sperling at UChicago we are studying their immune cells and identifying specific cell populations that may be mediating the protective effect in Amish children.
Our studies of asthma and allergy in ethnically diverse populations began in 1992 as part of our participation in the NHLBI-funded Collaborative Study on the Genetics of Asthma and continue today as part of the NIAID-funded Asthma and Allergy Center at the UChicago. These studies have evolved from family-based linkage studies to genome-wide association studies (GWAS) to epigenetic and gene expression studies in freshly isolated and cultured airway cells. We are currently using cell culture models of gene-environment interactions to characterize transcriptional (mRNA and miRNA) and methylation responses to asthma-promoting cytokines (IL-13 and IL-17) in airway epithelial and airway smooth muscle cells. We are also part of the EVE Consortium, which is a collaboration between U.S. investigators who have conducted GWAS. As part of EVE, we have performed a meta-analyses of asthma GWAS, a sex-specific GWAS of asthma, and a study of rare and low frequency variants in asthma in >15,000 individuals representing European American, African American, U.S. Hispanic, and Mexican populations.
Using the extensive pedigree and life history data available on >500 married Hutterite couples and prospectively collected data in ~300 couples, we have studied the genetics of both male and female fertility traits in this population. We have recently integrated these studies with studies of expression quantitative trait loci (eQTLs) in mid-secretory phase endometrial cells to discover novel variants and genes that influence implantation success. Our GWAS of male fertility identified excellent candidates that are currently the focus of functional studies.
As part of a program project grant with Drs. Robert Lemanske, James Gern, and Daniel Jackson at the University of Wisconsin-Madison, we are investigating the genetics of immune responsiveness and asthma inception in children from high risk families. Our studies are currently focused on the effects of genetic variation at 17q12 asthma susceptibility locus on global transcriptional and epigenetic responses to rhinovirus infection, and the effects of puberty on immune response and gene regulatory mechanisms.
As part of a program project grant with Dr. Robert Schleimer (Northwestern University) and Dr. Brian Schwartz (Johns Hopkins University) and their colleagues, we are studying the epidemiology, immunology, and genetics of chronic rhinosinusitis (CRS) in adults. In collaboration with Dr. Jay Pinto (UChicago), our project is focused on transcriptional and methylation responses of cultured nasal epithelial cells to rhinovirus (viral) and to staph (bacterial) infection and on identifying genetic variants that regulate these responses as candidate for CRS susceptibility loci.
We are initiating a new program to understand mechanisms of gene regulation in cells relevant to pregnancy and parturition, and the impact of environmental ‘stressors’ on the regulatory architecture in those cells. These studies will be performed in freshly isolated cells collected during pregnancy, during labor, and after delivery, and in cell lines treated with relevant hormones. Genetic variants that influence gene expression, methylation, and chromatin architecture will be considered as candidate susceptibility loci for the occurrence of preterm birth and for the persistence of disparities across generations.