PMID- 29313708

OWN - NLM
STAT- MEDLINE
DCOM- 20190819
LR - 20190819
IS - 1535-4970 (Electronic)
IS - 1073-449X (Print)
IS - 1073-449X (Linking)
VI - 197
IP - 10
DP - 2018 May 15
TI - Human Lung DNA Methylation Quantitative Trait Loci Colocalize with Chronic
Obstructive Pulmonary Disease Genome-Wide Association Loci.
PG - 1275-1284
LID - 10.1164/rccm.201707-1434OC [doi]
AB - RATIONALE: As the third leading cause of death in the United States, the
impact
of chronic obstructive pulmonary disease (COPD) makes identification of its
molecular mechanisms of great importance. Genome-wide association studies
(GWASs)
have identified multiple genomic regions associated with COPD. However,
genetic
variation only explains a small fraction of the susceptibility to COPD, and
sub-genome-wide significant loci may play a role in pathogenesis. OBJECTIVES:
Regulatory annotation with epigenetic evidence may give priority for further
investigation, particularly for GWAS associations in noncoding regions. We
performed integrative genomics analyses using DNA methylation profiling and
genome-wide SNP genotyping from lung tissue samples from 90 subjects with
COPD
and 36 control subjects. METHODS: We performed methylation quantitative trait
loci (mQTL) analyses, testing for SNPs associated with percent DNA
methylation
and assessed the colocalization of these results with previous COPD GWAS
findings
using Bayesian methods in the R package coloc to highlight potential
regulatory
features of the loci. MEASUREMENTS AND MAIN RESULTS: We identified 942,068
unique
SNPs and 33,996 unique CpG sites among the significant (5% false discovery
rate)
cis-mQTL results. The genome-wide significant and subthreshold (P < 10(-4))
GWAS
SNPs were enriched in the significant mQTL SNPs (hypergeometric test
P < 0.00001). We observed enrichment for sites located in CpG shores and
shelves,
but not CpG islands. Using Bayesian colocalization, we identified loci in
regions
near KCNK3, EEFSEC, PIK3CD, DCDC2C, TCERG1L, FRMD4B, and IL27. CONCLUSIONS:
Colocalization of mQTL and GWAS loci provides regulatory characterization of
significant and subthreshold GWAS findings, supporting a role for genetic
control
of methylation in COPD pathogenesis.
FAU - Morrow, Jarrett D
AU - Morrow JD
AUID- ORCID: 0000-0002-5670-5865
AD - 1 Channing Division of Network Medicine.
FAU - Glass, Kimberly
AU - Glass K
AD - 1 Channing Division of Network Medicine.
FAU - Cho, Michael H
AU - Cho MH
AD - 1 Channing Division of Network Medicine.
AD - 2 Division of Pulmonary and Critical Care Medicine, and.
FAU - Hersh, Craig P
AU - Hersh CP
AD - 1 Channing Division of Network Medicine.
AD - 2 Division of Pulmonary and Critical Care Medicine, and.
FAU - Pinto-Plata, Victor
AU - Pinto-Plata V
AD - 3 Baystate Health, Springfield, Massachusetts.
FAU - Celli, Bartolome
AU - Celli B
AD - 2 Division of Pulmonary and Critical Care Medicine, and.
FAU - Marchetti, Nathaniel
AU - Marchetti N
AD - 4 Division of Pulmonary and Critical Care Medicine, Temple University,
Philadelphia, Pennsylvania.
FAU - Criner, Gerard
AU - Criner G
AD - 4 Division of Pulmonary and Critical Care Medicine, Temple University,
Philadelphia, Pennsylvania.
FAU - Bueno, Raphael
AU - Bueno R
AD - 5 Division of Thoracic Surgery, Brigham and Women's Hospital, Boston,
Massachusetts.
FAU - Washko, George
AU - Washko G
AD - 2 Division of Pulmonary and Critical Care Medicine, and.
FAU - Choi, Augustine M K
AU - Choi AMK
AD - 6 Department of Medicine, New York Presbyterian/Weill Cornell Medical Center,
New
York, New York; and.
FAU - Quackenbush, John
AU - Quackenbush J
AD - 7 Department of Biostatistics and Computational Biology, Dana-Farber Cancer
Institute, Boston, Massachusetts.
FAU - Silverman, Edwin K
AU - Silverman EK
AD - 1 Channing Division of Network Medicine.
AD - 2 Division of Pulmonary and Critical Care Medicine, and.
FAU - DeMeo, Dawn L
AU - DeMeo DL
AUID- ORCID: 0000-0001-9653-0636
AD - 1 Channing Division of Network Medicine.
AD - 2 Division of Pulmonary and Critical Care Medicine, and.
LA - eng
GR - R01 HL089897/HL/NHLBI NIH HHS/United States
GR - N01HR76106/HL/NHLBI NIH HHS/United States
GR - N01HR76101/HL/NHLBI NIH HHS/United States
GR - N01HR76112/HL/NHLBI NIH HHS/United States
GR - R25 ES011080/ES/NIEHS NIH HHS/United States
GR - N01HR76108/HL/NHLBI NIH HHS/United States
GR - N01HR76109/HL/NHLBI NIH HHS/United States
GR - R01 HL130512/HL/NHLBI NIH HHS/United States
GR - U01 HL089897/HL/NHLBI NIH HHS/United States
GR - N01HR76103/HL/NHLBI NIH HHS/United States
GR - N01HR76113/HL/NHLBI NIH HHS/United States
GR - N01HR76102/HL/NHLBI NIH HHS/United States
GR - N01HR76107/HL/NHLBI NIH HHS/United States
GR - K25 HL133599/HL/NHLBI NIH HHS/United States
GR - R01 HL089856/HL/NHLBI NIH HHS/United States
GR - N01HR76114/HL/NHLBI NIH HHS/United States
GR - U01 HL089856/HL/NHLBI NIH HHS/United States
GR - N01HR76110/HL/NHLBI NIH HHS/United States
GR - P01 HL105339/HL/NHLBI NIH HHS/United States
GR - N01HR76119/HL/NHLBI NIH HHS/United States
GR - K25 HL136846/HL/NHLBI NIH HHS/United States
GR - N01HR76105/HL/NHLBI NIH HHS/United States
GR - N01 HR076115/HR/NHLBI NIH HHS/United States
GR - N01HR76111/HL/NHLBI NIH HHS/United States
GR - R01 HL125583/HL/NHLBI NIH HHS/United States
GR - P01 HL132825/HL/NHLBI NIH HHS/United States
GR - N01HR76116/HL/NHLBI NIH HHS/United States
GR - P01 HL114501/HL/NHLBI NIH HHS/United States
GR - N01HR76118/HL/NHLBI NIH HHS/United States
GR - R01 HL111759/HL/NHLBI NIH HHS/United States
GR - N01HR76104/HL/NHLBI NIH HHS/United States
PT - Journal Article
PT - Research Support, N.I.H., Extramural
TA - Am J Respir Crit Care Med
JT - American journal of respiratory and critical care medicine
JID - 9421642
CIN - Am J Respir Crit Care Med. 2018 May 15;197(10):1237-1239. PMID: 29425467
MH - Adult
MH - Aged
MH - Aged, 80 and over
MH - DNA Methylation/*genetics
MH - Epigenomics
MH - Female
MH - Gene Expression Regulation
MH - *Genetic Predisposition to Disease
MH - *Genome-Wide Association Study
MH - Humans
MH - Lung/*physiopathology
MH - Male
MH - Middle Aged
MH - Pulmonary Disease, Chronic Obstructive/epidemiology/*genetics
MH - Quantitative Trait Loci
MH - United States/epidemiology
PMC - PMC5955059
OTO - NOTNLM
OT - *chronic obstructive pulmonary disease
OT - *epigenetics
OT - *mQTL
OT - *methylation QTL
EDAT- 2018/01/10 06:00
MHDA- 2019/08/20 06:00
CRDT- 2018/01/10 06:00
PHST- 2018/01/10 06:00 [pubmed]
PHST- 2019/08/20 06:00 [medline]
PHST- 2018/01/10 06:00 [entrez]
AID - 10.1164/rccm.201707-1434OC [doi]
PST - ppublish
SO - Am J Respir Crit Care Med. 2018 May 15;197(10):1275-1284. doi:
10.1164/rccm.201707-1434OC.