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Role of environmental confounding in the association between FKBP5 and first-episode psychosis

Title: Role of environmental confounding in the association between FKBP5 and first-episode psychosis
Author(s): Ajnakina, O
Borges, S
Di Forti, M
Patel, Y
Xu, X
Green, P
Stilo, SA
Kolliakou, A
Sood, P
Marques, TR
David, AS
Prata, D
Dazzan, P
Powell, J
Pariante, C
Mondelli, V
Morgan, C
Murray, RM
Fisher, HL
Iyegbe, C
Item Type: Journal Article
Abstract: BACKGROUND: Failure to account for the etiological diversity that typically occurs in psychiatric cohorts may increase the potential for confounding as a proportion of genetic variance will be specific to exposures that have varying distributions in cases. This study investigated whether minimizing the potential for such confounding strengthened the evidence for a genetic candidate currently unsupported at the genome-wide level. METHODS: Two hundred and ninety-one first-episode psychosis cases from South London, UK and 218 unaffected controls were evaluated for a functional polymorphism at the rs1360780 locus in FKBP5. The relationship between FKBP5 and psychosis was modeled using logistic regression. Cannabis use (Cannabis Experiences Questionnaire) and parental separation (Childhood Experience of Care and Abuse Questionnaire) were included as confounders in the analysis. RESULTS: Association at rs1360780 was not detected until the effects of the two environmental factors had been adjusted for in the model (OR = 2.81, 95% CI 1.23-6.43, p = 0.02). A statistical interaction between rs1360780 and parental separation was confirmed by stratified tests (OR = 2.8, p = 0.02 vs. OR = 0.89, p = 0.80). The genetic main effect was directionally consistent with findings in other (stress-related) clinical phenotypes. Moreover, the variation in effect magnitude was explained by the level of power associated with different cannabis constructs used in the model (r = 0.95). CONCLUSION: Our results suggest that the extent to which genetic variants in FKBP5 can influence susceptibility to psychosis may depend on other etiological factors. This finding requires further validation in large independent cohorts. Potentially this work could have translational implications; the ability to discriminate between genetic etiologies based on a case-by-case understanding of previous environmental exposures would confer an important clinical advantage that would benefit the delivery of personalizable treatment strategies.
Publication Date: 17-Jul-2014
Date of Acceptance: 3-Jul-2014
URI: http://hdl.handle.net/10044/1/40544
DOI: http://dx.doi.org/10.3389/fpsyt.2014.00084
ISSN: 1664-0640
Publisher: Frontiers Media
Journal / Book Title: Frontiers in Psychiatry
Volume: 5
Copyright Statement: © 2014 Ajnakina, Borges, Di Forti, Patel, Xu, Green, Stilo, Kolliakou, Sood, Marques, David, Prata, Dazzan, Powell, Pariante, Mondelli, Morgan, Murray, Fisher and Iyegbe. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Keywords: FKBP5
GWAS
cannabis
childhood adversity
confounding factors
gene–environment
missing heritability
psychosis
Publication Status: Published
Article Number: 84
Appears in Collections:Clinical Sciences
Imaging Sciences
Faculty of Medicine



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