AUTHOR=Ajnakina Olesya , Borges Susana , Di Forti Marta , Patel Yogen , Xu Xiaohui , Green Priscilla , Stilo Simona A. , Kolliakou Anna , Sood Poonam , Marques Tiago Reis , David Anthony S. , Prata Diana , Dazzan Paola , Powell John , Pariante Carmine , Mondelli Valeria , Morgan Craig , Murray Robin M. , Fisher Helen L. , Iyegbe Conrad 

TITLE=Role of Environmental Confounding in the Association between FKBP5 and First-Episode Psychosis

JOURNAL=Frontiers in Psychiatry

VOLUME=5

YEAR=2014

URL=https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2014.00084

DOI=10.3389/fpsyt.2014.00084

ISSN=1664-0640

ABSTRACT=<p><bold>Background:</bold> 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.</p><p><bold>Methods:</bold> 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 <italic>FKBP5</italic>. The relationship between <italic>FKBP5</italic> 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.</p><p><bold>Results:</bold> 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, <italic>p</italic> = 0.02). A statistical interaction between rs1360780 and parental separation was confirmed by stratified tests (OR = 2.8, <italic>p</italic> = 0.02 vs. OR = 0.89, <italic>p</italic> = 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 (<italic>r</italic> = 0.95).</p><p><bold>Conclusion:</bold> Our results suggest that the extent to which genetic variants in <italic>FKBP5</italic> 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.</p>