Genomic underpinnings of human health and disease in the context of health disparities

National Institute Of Allergy And Infectious Diseases

Investigators

Abstract

Post the sequencing of the human genome, majority of our attention in genetics has been focused on inherited genetic causes of complex disease, i.e., germline genetic variation. In today’s era of massive amounts of whole genome sequencing (WGS) we have a tremendous opportunity to look beyond germline variation and consider acquired somatic changes to the human genome and their connection to complex disease. Collaborative efforts in large consortia such as TOPMed have led to some major advances in this area working on whole genome sequences on now ~200,000 genomes representing >80 studies using WGS to dissect genetic underpinnings of heart, lung, blood and sleep disease. We have either led or been a key contributor for a whole variety of somatic variation including telomere length, clonal hematopoiesis, clonal mosaicism, and mitochondrial DNA variation. Collectively referred to as the dynamic genome, these measures from the genome can themselves be thought of as phenotypes - measures of biological aging that can be correlates of aging-related diseases and outcomes, but more importantly offer a contrast to chronological age as a risk factor. There is now a growing body of evidence on the intersection of aging and complex disease burden, and the expansion of the study of genomic underpinnings of complex disease to include measures of the dynamic genome is critical. In FY2025, we have continued to participate in several consortia level efforts in the space of aging. We extended our prior work on late-life proteomic correlates of frailty to mid-life proteomic correlates of late life prefrailty and frailty identifying 12 and 221 proteins were associated with prefrailty and frailty in later life, respectively (FDR p < 0.05). Pathway analyses suggest midlife dysregulation of inflammation, metabolism, extracellular matrix, angiogenesis, and lysosomal autophagy among those at risk for late-life frailty. We have also found that long-term adherence to recommended moderate-to-vigorous physical activity (PA) improved the population levels of many frailty-associated proteins suggesting that long-term engagement in adequate habitual PA may reduce frailty risk through specific nervous systems and inflammatory proteins. In FY2025, we have helped with numerous methods-related projects in this area of complex disease. We have demonstrated that incorporating endophenotype information can improve polygenic risk scores, contributed to the extension of statistical frameworks for variant analysis across multiple traits, participated in efforts on inferring pedigrees from genetic data and importantly, actively contributed to recommendations for data models for population descriptors in genomic research. Our activity in methods-related aspects is an important contribution to complex disease genomics. In FY2025 we have identified additional areas of variant calling that will be of high value for the CSP including quantification of telomere length and clonal hematopoiesis of indeterminate potential (CHIP) from genomes/exomes. We have initiated the data calling of CHIP in all of CSP with the goal of evaluating accelerated aging in patients with underlying immunological disorders and have most recently helped design a proposal to generate genomewide methylation data on ~1000 study subjects from CSP to evaluate biological aging using methylation age clocks in the same.