Community Based Genomic Medicine and Polygenic Scoring

Mayo Clinic Rochester, Rochester MN

Investigators

Abstract

PROJECT SUMMARY The study of genomes and genomic medicine is an urgent and critical need and using population genetics data to inform construction of polygenic scores for biologically relevant quantitative traits is a scientific imperative. The Southeast Minnesota region represents a population offering access to a blend of urban and rural communities. Using a well-established research framework to guide efforts, we will engage with the regional population across age ranges.. Our prior research interactions have identified significant enthusiasm to engage in genomic medicine and other research. Therefore we see no difficulty in establishing a genomic medicine research program in this region. We propose the following specific aims: Specific Aim 1. (a) Establish a genomic medicine research program in the Southeast Minnesota region. We will seek input from an Advisory Board with broad representation including old, middle-aged and young subjects. We will conduct a series of engagement efforts and seek feedback regarding research priorities and expectations related to genomic medicine, informed consent for genomic research, data sharing, and return of actionable results; (b) Create a biobank of 1000 individuals that includes plasma, DNA, and RNA. Clinical variables, health drivers (including occupation, activity levels, sleep and diet) and non-clinical factors will be obtained from the electronic health record (EHR) and from surveys and measures that ascertain risk factors for cardiometabolic diseases, family history, and lifestyle factors. Specific Aim 2. (a) Perform population genetic analyses of WGS (30x) data, to investigate the demographic history of the Southeast Minnesota population. We will use a graph genome reference for more accurate variant calling, and will assess demographic history including ancient/recent admixture, population structure, and signals of polygenic adaptation, using state-of-the art methods; (b) Use population genetics analyses to inform the construction of polygenic scores (PGS) for biologically relevant quantitative traits, starting with lipid levels, height, and body mass index (BMI). Specific Aim 3. (a) Identify actionable variants in medically relevant genes (including the American College of Medical Genetics and Genomics Secondary Findings v3.0 list) as well as select pharmacogenomic variants; we will leverage ClinGen resources for variant curation; (b) Return actionable results based on participant choice and assess near term outcomes using a previously described framework. Long term impact. This grant application will enable a research partnership with the Southeast Minnesota population, create a biobank for ‘omic’ studies, generate insights into human evolutionary history, and catalog actionable genetic information. By conducting comprehensive integrated genotype-phenotype research in a regional sample, the proposed work will extend our knowledge of genomic medicine and provide novel insights that are relevant to using population genetics data to inform construction of polygenic scores for biologically relevant quantitative traits.