Research

Overview

We apply molecular genetic techniques for collection of genotypic, DNA sequencing, and gene expression data. These data are analyzed within the lab and through collaborations within the Department of Genetics and with investigators from other institutions across the United States.

Our collaborations on population-based studies focus on family-based designs and look at molecular genetic variation and how it affects inter-individual variation in disease risk and treatment, particularly heart disease, hypertension, type 2 diabetes, kidney disease, obesity and their metabolic risk factors and consequences. We focus on American Indians (the Strong Heart Study [SHS] with representatives from 13 U.S. tribes, the Zuni Indians [GKDZI]), Alaskan Eskimos (GOCADAN), Mexican Americans (VIVA la Familia) and African Americans (PATH). These underserved minority populations with increased prevalence of metabolic and complex diseases are understudied relative to populations of European descent, especially when looking at how genetic risk factors affect disease and are modified according to ancestral backgrounds and environmental risk factors. We mainly use a family-based study design with multigenerational pedigrees, providing rich datasets for identification of rare and population-specific genetic variants. My previous research and current lab have generated molecular genetic data using samples from these population groups. In some cases it is the first generation of such data for a particular population group.

The Strong Heart Study of American Indians (SHS) is one of the largest (>7,600 participants) and longest-running (since 1988) epidemiological and genetic studies of American Indians in the US. SHS showed that American Indians have some of the highest rates of type 2 diabetes and cardiovascular disease (CVD) relative to other population groups in the US, helped determine type 2 diabetes as a major risk factor for CVD, and has been used by the Indian Health Service to develop treatment guidelines. I have been part of the SHS since 2000, currently as PI of the SHS Genetics Center (since 2008) and Chair of the SHS Steering Committee (since 2014) representing the five SHS centers.

Impact of common and rare genetic variants on disease. Our goal is to characterize molecular genetic variation and how it affects inter-individual variation in disease risk and treatment. In a collaboration on childhood obesity in the VIVA la Familia cohort, we identified a novel loss-of-function mutation (G55V) in MC4R and confirmed that it was responsible for the severe obesity seen in six related children. We also showed associations between MC4R variants and obesity measures in the entire childhood cohort, demonstrating that variants in MC4R have impacts on both rare, severe obesity as well as population-level obesity traits. We conducted a sequencing analysis of the FVIII gene in Black hemophilia patients as part of a study on inhibitor development to factor VIII (FVIII) replacement therapy in patients with hemophilia. It showed sequence variants present in Black patients that aren’t represented in the therapeutic replacement FVIII protein, which may affect inhibitor development and, if confirmed, indicates that therapies must consider the potential genetic differences present between population groups.

Main Technologies And Methods Used

• High- and medium-throughout molecular technologies
• Sequencing, genotyping, DNA methylation, gene expression
• Community-based approaches