Multi-ethnic Genetic Association Study of Percent Emphysema and CT Emphysema Subtypes with Whole Genome Sequencing in the Trans-Omics for Precision Medicine (TOPMed) Program

Columbia University Health Sciences, New York NY

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Abstract

Chronic obstructive pulmonary disease (COPD) and emphysema are, jointly, the fourth leading cause of death in the United States and third leading cause globally. COPD prevalence and mortality have doubled in the US in the last several decades, particularly among women and minorities, despite large reductions in smoking and in part due to population aging. The Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study found that emphysema measured quantitatively on computed tomography (CT) is common and morbid among older adults in the general population; however, standard measures underestimate the complexity of the disease. We hypothesize that machine-learned CT emphysema subtypes are distinct, have different causes and prognoses, and that distinguishing pathological emphysema from that resulting from normal aging with help the prevention and treatment of COPD and emphysema. The main objective of the proposed research is to identify the genetic and epigenetic landscape of CT emphysema phenotypes in racially/ethnically diverse populations. The proposed research will: (1) Identify the common variant genetic landscape of CT emphysema phenotypes utilizing whole genome sequencing data (2) Identify the rare variant genetic landscape of CT emphysema phenotypes utilizing whole genome sequencing data, and (3) Identify the functional landscape of sub- phenotypes of emphysema utilizing publicly available tissue specific databases. These study aims are nested within the parent study, Precision Phenotyping of Emphysema in the Elderly: the MESA Lung Study, 2R01HL077612-13A1, a collaborative effort between Columbia University, the University of Virginia, The New York Genome Center, the University of Iowa, and the University of Washington, using high-quality harmonized, and centrally available data from the Trans-Omics for Precision Medicine (TOPMed) Consortium and the ancillary Collaborative Cohort of Cohorts for COVID-19 Research (C4R) Study. Through the proposed Investigator Supplement, Dr. Pottinger will gain training in developing, and validating the genetic and epigenetic determinants of emphysema in multiethnic populations, and professional development. The expertise obtained from the completion of training and research aims of this proposal will result in scientific presentations and publications, pilot data for future successful grant funding, and uniquely position Dr. Pottinger for the study of genetic and epigenetic determinants of lung disease.