1. Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants.
- Author
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Zhao X, Qiao D, Yang C, Kasela S, Kim W, Ma Y, Shrine N, Batini C, Sofer T, Taliun SAG, Sakornsakolpat P, Balte PP, Prokopenko D, Yu B, Lange LA, Dupuis J, Cade BE, Lee J, Gharib SA, Daya M, Laurie CA, Ruczinski I, Cupples LA, Loehr LR, Bartz TM, Morrison AC, Psaty BM, Vasan RS, Wilson JG, Taylor KD, Durda P, Johnson WC, Cornell E, Guo X, Liu Y, Tracy RP, Ardlie KG, Aguet F, VanDenBerg DJ, Papanicolaou GJ, Rotter JI, Barnes KC, Jain D, Nickerson DA, Muzny DM, Metcalf GA, Doddapaneni H, Dugan-Perez S, Gupta N, Gabriel S, Rich SS, O'Connor GT, Redline S, Reed RM, Laurie CC, Daviglus ML, Preudhomme LK, Burkart KM, Kaplan RC, Wain LV, Tobin MD, London SJ, Lappalainen T, Oelsner EC, Abecasis GR, Silverman EK, Barr RG, Cho MH, and Manichaikul A
- Subjects
- Adult, Aged, Aged, 80 and over, Alpha-Ketoglutarate-Dependent Dioxygenase FTO genetics, Calcium-Binding Proteins genetics, Feasibility Studies, Female, Follow-Up Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Intracellular Signaling Peptides and Proteins genetics, Lung physiopathology, Male, Middle Aged, Polymorphism, Single Nucleotide, Protein Inhibitors of Activated STAT genetics, Pulmonary Disease, Chronic Obstructive ethnology, Pulmonary Disease, Chronic Obstructive physiopathology, Small Ubiquitin-Related Modifier Proteins genetics, Black or African American genetics, Genetic Loci, Pulmonary Disease, Chronic Obstructive genetics, Respiratory Physiological Phenomena genetics, Whole Genome Sequencing
- Abstract
Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.
- Published
- 2020
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