Pathogen exposure misclassification can bias association signals in GWAS of infectious diseases when using population-based common control subjects.
GWAS
common controls
genetic epidemiology
infectious disease
misclassification bias
population-based controls
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
02 02 2023
02 02 2023
Historique:
received:
13
06
2022
accepted:
20
12
2022
pubmed:
18
1
2023
medline:
8
2
2023
entrez:
17
1
2023
Statut:
ppublish
Résumé
Genome-wide association studies (GWASs) have been performed to identify host genetic factors for a range of phenotypes, including for infectious diseases. The use of population-based common control subjects from biobanks and extensive consortia is a valuable resource to increase sample sizes in the identification of associated loci with minimal additional expense. Non-differential misclassification of the outcome has been reported when the control subjects are not well characterized, which often attenuates the true effect size. However, for infectious diseases the comparison of affected subjects to population-based common control subjects regardless of pathogen exposure can also result in selection bias. Through simulated comparisons of pathogen-exposed cases and population-based common control subjects, we demonstrate that not accounting for pathogen exposure can result in biased effect estimates and spurious genome-wide significant signals. Further, the observed association can be distorted depending upon strength of the association between a locus and pathogen exposure and the prevalence of pathogen exposure. We also used a real data example from the hepatitis C virus (HCV) genetic consortium comparing HCV spontaneous clearance to persistent infection with both well-characterized control subjects and population-based common control subjects from the UK Biobank. We find biased effect estimates for known HCV clearance-associated loci and potentially spurious HCV clearance associations. These findings suggest that the choice of control subjects is especially important for infectious diseases or outcomes that are conditional upon environmental exposures.
Identifiants
pubmed: 36649706
pii: S0002-9297(22)00547-X
doi: 10.1016/j.ajhg.2022.12.013
pmc: PMC9943744
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
336-348Subventions
Organisme : Medical Research Council
ID : MC_PC_17228
Pays : United Kingdom
Organisme : NIAID NIH HHS
ID : R01 AI148049
Pays : United States
Organisme : NHGRI NIH HHS
ID : R35 HG011944
Pays : United States
Informations de copyright
Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests All authors declare no competing interests.
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