Association of forced vital capacity with the developmental gene NCOR2

Minelli, Cosetta, Dean, Charlotte H., Hind, Matthew, Alves, Alexessander Couto, Amaral, Andre F. S., Siroux, Valerie, Huikari, Ville, Artigas, Maria Soler, Evans, David M., Loth, Daan W., Bosse, Yohan, Postma, Dirkje S., Sin, Don, Thompson, John, Demenais, Florence, Henderson, John, Bouzigon, Emmanuelle, Jarvis, Deborah, Jarvelin, Marjo-Riitta and Burney, Peter (2016) Association of forced vital capacity with the developmental gene NCOR2. Plos One, 11 2: . doi:10.1371/journal.pone.0147388


Author Minelli, Cosetta
Dean, Charlotte H.
Hind, Matthew
Alves, Alexessander Couto
Amaral, Andre F. S.
Siroux, Valerie
Huikari, Ville
Artigas, Maria Soler
Evans, David M.
Loth, Daan W.
Bosse, Yohan
Postma, Dirkje S.
Sin, Don
Thompson, John
Demenais, Florence
Henderson, John
Bouzigon, Emmanuelle
Jarvis, Deborah
Jarvelin, Marjo-Riitta
Burney, Peter
Title Association of forced vital capacity with the developmental gene NCOR2
Formatted title
Association of forced vital capacity with the developmental gene NCOR2
Journal name Plos One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2016-02
Sub-type Article (original research)
DOI 10.1371/journal.pone.0147388
Open Access Status DOI
Volume 11
Issue 2
Total pages 17
Place of publication San Francisco, United States
Publisher Public Library of Science
Collection year 2017
Language eng
Formatted 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.

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.
Keyword Genome-Wide Association
Adult Lung-Function
Disease
Heritability
Regeneration
Mechanisms
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
UQ Diamantina Institute Publications
 
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