Physical Sciences Division
Published January 13, 2023 | Version v1
Journal article Open

Multi-omic association study identifies DNA methylation-mediated genotype and smoking exposure effects on lung function in children living in urban settings

Creators

  • 1. University of Chicago
  • 2. Rho Inc.
  • 3. Harvard University
  • 4. Johns Hopkins University
  • 5. Lurie Children's Hospital
  • 6. University of Cincinnati
  • 7. University of Texas Southwestern Medical Center
  • 8. Washington University School of Medicine
  • 9. University of Colorado
  • 10. Henry Ford Health System
  • 11. Columbia University
  • 12. Vanderbilt University Medical Center
  • 13. Children's National Health System
  • 14. University of Washington

Description

Impaired lung function in early life is associated with the subsequent development of chronic respiratory disease. Most genetic associations with lung function have been identified in adults of European descent and therefore may not represent those most relevant to pediatric populations and populations of different ancestries. In this study, we performed genome-wide association analyses of lung function in a multiethnic cohort of children (n = 1,035) living in low-income urban neighborhoods. We identified one novel locus at the TDRD9 gene in chromosome 14q32.33 associated with percent predicted forced expiratory volume in one second (FEV1) (p = 2.4x10-9; βz = -0.31, 95% CI = -0.41- -0.21). Mendelian randomization and mediation analyses revealed that this genetic effect on FEV1 was partially mediated by DNA methylation levels at this locus in airway epithelial cells, which were also associated with environmental tobacco smoke exposure (p = 0.015). Promoter-enhancer interactions in airway epithelial cells revealed chromatin interaction loops between FEV1-associated variants in TDRD9 and the promoter region of the PPP1R13B gene, a stimulator of p53-mediated apoptosis. Expression of PPP1R13B in airway epithelial cells was significantly associated the FEV1 risk alleles (p = 1.3x10-5; β = 0.12, 95% CI = 0.06–0.17). These combined results highlight a potential novel mechanism for reduced lung function in urban youth resulting from both genetics and smoking exposure.

Data availability

Phenotype, genotype, GWAS summary statistics, and whole-genome sequencing files are available in dbGaP under accession phs002921.v1.p1. The URECA gene expression data are available on the Gene Expression Omnibus (GEO) under accession numbers GSE145505 (NECs) and GSE96783 (PBMCs). The URECA DNA methylation data are available in GEO under the reference series GSE217337. The pcHI-C data are available in GEO under the reference series GSE152550.

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Additional details

Identifiers

DOI
10.1371/journal.pgen.1010594
Other
oai:uchicago.tind.io:6335

Funding

National Institutes of Health
U19 AI62310
National Institutes of Health
HHSN272200900052C
National Institutes of Health
HHSN272201000052I
National Institutes of Health
UM1 AI114271
National Institutes of Health
UG3 OD023282
National Institutes of Health
UM1 AI160040
National Institutes of Health
RR00052
National Institutes of Health
UL1 TR001079
National Institutes of Health
M01 RR00533
National Institutes of Health
UL1 RR025771
National Institutes of Health
1 UL1 TR001430
National Institutes of Health
UL1 TR000150
National Institutes of Health
UL1 TR000451
National Institutes of Health
UL1 TR001105
National Institutes of Health
Ul1 RR025780
National Institutes of Health
UL1 TR000040
National Institutes of Health
M01 RR00071
National Institutes of Health
UL1 RR024156
National Institutes of Health
UL1 TR000075
National Institutes of Health
UL1 TR000077
National Institutes of Health
TL1 TR002388
National Institutes of Health
T32 HL007605

UChicago Information

Division(s)
Biological Sciences Division, Physical Sciences Division
Department(s)
Human Genetics, Statistics