MR-pheWAS with stratification and interaction: Searching for the causal effects of smoking heaviness identified an effect on facial aging.
Biological Specimen Banks
Cigarette Smoking
/ adverse effects
Computational Biology
/ methods
Gene-Environment Interaction
Genetic Pleiotropy
Humans
Male
Mendelian Randomization Analysis
/ methods
Middle Aged
Polymorphism, Single Nucleotide
Proof of Concept Study
Skin Aging
/ drug effects
United Kingdom
/ epidemiology
Journal
PLoS genetics
ISSN: 1553-7404
Titre abrégé: PLoS Genet
Pays: United States
ID NLM: 101239074
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
29
10
2018
accepted:
07
08
2019
entrez:
1
11
2019
pubmed:
2
11
2019
medline:
30
1
2020
Statut:
epublish
Résumé
Mendelian randomization (MR) is an established approach to evaluate the effect of an exposure on an outcome. The gene-by-environment (GxE) study design can be used to determine whether the genetic instrument affects the outcome through pathways other than via the exposure of interest (horizontal pleiotropy). MR phenome-wide association studies (MR-pheWAS) search for the effects of an exposure, and can be conducted in UK Biobank using the PHESANT package. In this proof-of-principle study, we introduce the novel GxE MR-pheWAS approach, that combines MR-pheWAS with the use of GxE interactions. This method aims to identify the presence of effects of an exposure while simultaneously investigating horizontal pleiotropy. We systematically test for the presence of causal effects of smoking heaviness-stratifying on smoking status (ever versus never)-as an exemplar. If a genetic variant is associated with smoking heaviness (but not smoking initiation), and this variant affects an outcome (at least partially) via tobacco intake, we would expect the effect of the variant on the outcome to differ in ever versus never smokers. We used PHESANT to test for the presence of effects of smoking heaviness, instrumented by genetic variant rs16969968, among never and ever smokers respectively, in UK Biobank. We ranked results by the strength of interaction between ever and never smokers. We replicated previously established effects of smoking heaviness, including detrimental effects on lung function. Novel results included a detrimental effect of heavier smoking on facial aging. We have demonstrated how GxE MR-pheWAS can be used to identify potential effects of an exposure, while simultaneously assessing whether results may be biased by horizontal pleiotropy.
Identifiants
pubmed: 31671092
doi: 10.1371/journal.pgen.1008353
pii: PGENETICS-D-18-02014
pmc: PMC6822717
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1008353Subventions
Organisme : Medical Research Council
ID : MC_UU_00011/7
Pays : United Kingdom
Organisme : British Heart Foundation
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_QA137853
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_17228
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00011/3
Pays : United Kingdom
Organisme : Cancer Research UK
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00011/1
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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