View Abstract

A4185 - Whole Genome Sequencing in Moderate and Severe Chronic Obstructive Pulmonary Disease
Author Block: D. Prokopenko1, P. Sakornsakolpat1, H. Loehlein Fier2, D. Qiao1, C. Lange3, T. H. Beaty4, J. D. Crapo5, E. K. Silverman6, M. H. Cho6; 1Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, United States, 2Working Group of Genomic Mathematics, University of Bonn, Bonn, Germany, 3Biostatistics, Harvard School of Public Health, Boston, MA, United States, 4Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States, 5National Jewish Health, Denver, CO, United States, 6Channing Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, United States.
Rationale: Genome-wide association studies have identified multiple common variants associated with chronic obstructive pulmonary disease (COPD). Whole-genome sequencing (WGS) offers comprehensive coverage of the genome, which gives several advantages over exome sequencing and imputation, including improvements in calling of coding regions and interrogation of impactful variants in non-coding regions. We hypothesize that novel variants in non-coding regions, identified through WGS, play an additional role in determining COPD susceptibility.
Methods: As part of the NHLBI Trans‐Omics for Precision Medicine (TOPMed) freeze 5 release, we submitted DNA samples from the COPDGene and Boston Early-Onset COPD studies for sequencing from 2517 non-Hispanic white (NHW) and 723 African American (AA) cases with moderate to very severe COPD (mean forced expiratory volume in 1 second % predicted (FEV1pp) of 49±18 and 52±18 respectively). 2189 NHW and 1472 AA current and ex-smoking controls with normal lung function had a mean FEV1pp of 97±11 and 98±12 respectively. We used hybrid Firth logistic regression to perform single-variant genome-wide analysis and controlled for effects of population stratification using the rare variant Jaccard method.
Results: We performed separate analyses on more than 90,000,000 variants in non-Hispanic White and African American individuals for 2 phenotypes: moderate-to-severe COPD and severe COPD. Top signals included a known association region near FAM13A in NHW (p=3x10-9) and a rare non-coding variant in AA (9p24.2, p=2x10-7) for moderate COPD. For severe COPD we identified known association regions near CHRNA3 and HHIP in NHW (p=4x10-9); the top novel region in AA was in 20q11.22 (p=6x10-8).
Conclusions: Whole-genome sequencing provides an important source for identifying causal variants at known and novel loci for COPD. It allows to evaluate the role of variants in non-coding regulatory regions in COPD and related phenotypes. Currently we are performing region-based and gene-based analysis. Future plans include testing COPD-related phenotypes, fine-mapping of known signals and evaluating the quality of imputed data.
Funding: This work was supported by NHLBI R01 HL084323, P01 HL114501, P01 HL105339 and R01 HL089856 (E.K.S.); R01 HL113264 (M.H.C. and E.K.S.), and R01 HL089897 (J.D.C.). The COPDGene study (NCT00608764) is also supported by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer, GlaxoSmithKline, Siemens and Sunovion.