Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants

Nat Commun. 2020 Oct 14;11(1):5182. doi: 10.1038/s41467-020-18334-7.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • African Americans / genetics*
  • Aged
  • Aged, 80 and over
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO / genetics
  • Calcium-Binding Proteins / genetics
  • Feasibility Studies
  • Female
  • Follow-Up Studies
  • Genetic Loci*
  • 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 / genetics*
  • Pulmonary Disease, Chronic Obstructive / physiopathology
  • Respiratory Physiological Phenomena / genetics*
  • Small Ubiquitin-Related Modifier Proteins / genetics
  • Whole Genome Sequencing*

Substances

  • Calcium-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • PIAS1 protein, human
  • Protein Inhibitors of Activated STAT
  • RGN protein, human
  • Small Ubiquitin-Related Modifier Proteins
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • FTO protein, human