Association of Forced Vital Capacity with the Developmental Gene NCOR2
File(s)
Published version
Author(s)
Minelli, C
Burney, P
Type
Journal Article
Abstract
Background
Forced Vital Capacity (FVC) is an important predictor of all-cause mortality in the absence
of chronic respiratory conditions. Epidemiological evidence highlights the role of early life
factors on adult FVC, pointing to environmental exposures and genes affecting lung development
as risk factors for low FVC later in life. Although highly heritable, a small number of
genes have been found associated with FVC, and we aimed at identifying further genetic
variants by focusing on lung development genes.
PLOS ONE | DOI:10.1371/journal.pone.0147388 February 2, 2016 1 / 17
OPEN ACCESS
Citation: Minelli C, Dean CH, Hind M, Alves AC,
Amaral AFS, Siroux V, et al. (2016) Association of
Forced Vital Capacity with the Developmental Gene
NCOR2. PLoS ONE 11(2): e0147388. doi:10.1371/
journal.pone.0147388
Editor: Philipp Latzin, University Children's Hospital
Basel, SWITZERLAND
Received: August 28, 2015
Accepted: January 4, 2016
Published: February 2, 2016
Copyright: © 2016 Minelli et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are
credited.
Data Availability Statement: All relevant data are
within the paper and its Supporting Information files.
Funding: The authors have no support or funding to
report.
Competing Interests: The authors have declared
that no competing interests exist.
Methods
Per-allele effects of 24,728 SNPs in 403 genes involved in lung development were tested in
7,749 adults from three studies (NFBC1966, ECRHS, EGEA). The most significant SNP for
the top 25 genes was followed-up in 46,103 adults (CHARGE and SpiroMeta consortia) and
5,062 children (ALSPAC). Associations were considered replicated if the replication p-value
survived Bonferroni correction (p<0.002; 0.05/25), with a nominal p-value considered as
suggestive evidence. For SNPs with evidence of replication, effects on the expression levels
of nearby genes in lung tissue were tested in 1,111 lung samples (Lung eQTL consortium),
with further functional investigation performed using public epigenomic profiling data
(ENCODE).
Results
NCOR2-rs12708369 showed strong replication in children (p = 0.0002), with replication
unavailable in adults due to low imputation quality. This intronic variant is in a strong transcriptional
enhancer element in lung fibroblasts, but its eQTL effects could not be tested
due to low imputation quality in the eQTL dataset. SERPINE2-rs6754561 replicated at nominal
level in both adults (p = 0.036) and children (p = 0.045), while WNT16-rs2707469 replicated
at nominal level only in adults (p = 0.026). The eQTL analyses showed association of
WNT16-rs2707469 with expression levels of the nearby gene CPED1. We found no statistically
significant eQTL effects for SERPINE2-rs6754561.
Conclusions
We have identified a new gene, NCOR2, in the retinoic acid signalling pathway pointing to a
role of vitamin A metabolism in the regulation of FVC. Our findings also support SERPINE2,
a COPD gene with weak previous evidence of association with FVC, and suggest WNT16
as a further promising candidate.
Forced Vital Capacity (FVC) is an important predictor of all-cause mortality in the absence
of chronic respiratory conditions. Epidemiological evidence highlights the role of early life
factors on adult FVC, pointing to environmental exposures and genes affecting lung development
as risk factors for low FVC later in life. Although highly heritable, a small number of
genes have been found associated with FVC, and we aimed at identifying further genetic
variants by focusing on lung development genes.
PLOS ONE | DOI:10.1371/journal.pone.0147388 February 2, 2016 1 / 17
OPEN ACCESS
Citation: Minelli C, Dean CH, Hind M, Alves AC,
Amaral AFS, Siroux V, et al. (2016) Association of
Forced Vital Capacity with the Developmental Gene
NCOR2. PLoS ONE 11(2): e0147388. doi:10.1371/
journal.pone.0147388
Editor: Philipp Latzin, University Children's Hospital
Basel, SWITZERLAND
Received: August 28, 2015
Accepted: January 4, 2016
Published: February 2, 2016
Copyright: © 2016 Minelli et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are
credited.
Data Availability Statement: All relevant data are
within the paper and its Supporting Information files.
Funding: The authors have no support or funding to
report.
Competing Interests: The authors have declared
that no competing interests exist.
Methods
Per-allele effects of 24,728 SNPs in 403 genes involved in lung development were tested in
7,749 adults from three studies (NFBC1966, ECRHS, EGEA). The most significant SNP for
the top 25 genes was followed-up in 46,103 adults (CHARGE and SpiroMeta consortia) and
5,062 children (ALSPAC). Associations were considered replicated if the replication p-value
survived Bonferroni correction (p<0.002; 0.05/25), with a nominal p-value considered as
suggestive evidence. For SNPs with evidence of replication, effects on the expression levels
of nearby genes in lung tissue were tested in 1,111 lung samples (Lung eQTL consortium),
with further functional investigation performed using public epigenomic profiling data
(ENCODE).
Results
NCOR2-rs12708369 showed strong replication in children (p = 0.0002), with replication
unavailable in adults due to low imputation quality. This intronic variant is in a strong transcriptional
enhancer element in lung fibroblasts, but its eQTL effects could not be tested
due to low imputation quality in the eQTL dataset. SERPINE2-rs6754561 replicated at nominal
level in both adults (p = 0.036) and children (p = 0.045), while WNT16-rs2707469 replicated
at nominal level only in adults (p = 0.026). The eQTL analyses showed association of
WNT16-rs2707469 with expression levels of the nearby gene CPED1. We found no statistically
significant eQTL effects for SERPINE2-rs6754561.
Conclusions
We have identified a new gene, NCOR2, in the retinoic acid signalling pathway pointing to a
role of vitamin A metabolism in the regulation of FVC. Our findings also support SERPINE2,
a COPD gene with weak previous evidence of association with FVC, and suggest WNT16
as a further promising candidate.
Date Issued
2016-02-02
Date Acceptance
2016-01-20
Citation
PLOS One
ISSN
1932-6203
Publisher
Public Library of Science
Journal / Book Title
PLOS One
Volume
11
Issue
2
Copyright Statement
© 2016 Minelli et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are
credited
access article distributed under the terms of the
Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are
credited
License URL
Sponsor
Medical Research Council (MRC)
Grant Number
G0901214
Subjects
General Science & Technology
MD Multidisciplinary
Publication Status
Published
Article Number
e0147388