title: Role of Environmental Confounding in the Association between FKBP5 and First-Episode Psychosis.
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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, King's College London , London , UK.
authors.forename: Olesya
authors.initials: O
authors.lastname: Ajnakina
authors.affiliation: Department of Health Services and Population Research, Institute of Psychiatry, King's College London , London , UK.
authors.forename: Susana
authors.initials: S
authors.lastname: Borges
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, King's College London , London , UK.
authors.forename: Marta
authors.initials: M
authors.lastname: Di Forti
authors.affiliation: Department of Neuroscience, Institute of Psychiatry, King's College London , London , UK.
authors.forename: Yogen
authors.initials: Y
authors.lastname: Patel
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London , London , UK.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Neuroscience, Institute of Psychiatry, King's College London , London , UK.
authors.forename: Priscilla
authors.initials: P
authors.lastname: Green
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, King's College London , London , UK.
authors.forename: Simona A
authors.initials: SA
authors.lastname: Stilo
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, King's College London , London , UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Kolliakou
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, King's College London , London , UK.
authors.forename: Poonam
authors.initials: P
authors.lastname: Sood
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, King's College London , London , UK.
authors.forename: Tiago Reis
authors.initials: TR
authors.lastname: Marques
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, King's College London , London , UK.
authors.forename: Anthony S
authors.initials: AS
authors.lastname: David
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, King's College London , London , UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Prata
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, King's College London , London , UK.
authors.forename: Paola
authors.initials: P
authors.lastname: Dazzan
authors.affiliation: Department of Neuroscience, Institute of Psychiatry, King's College London , London , UK.
authors.forename: John
authors.initials: J
authors.lastname: Powell
authors.affiliation: Department of Psychological Medicine, Institute of Psychiatry, King's College London , London , UK.
authors.forename: Carmine
authors.initials: C
authors.lastname: Pariante
authors.affiliation: Department of Psychological Medicine, Institute of Psychiatry, King's College London , London , UK.
authors.forename: Valeria
authors.initials: V
authors.lastname: Mondelli
authors.affiliation: Department of Health Services and Population Research, Institute of Psychiatry, King's College London , London , UK.
authors.forename: Craig
authors.initials: C
authors.lastname: Morgan
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, King's College London , London , UK.
authors.forename: Robin M
authors.initials: RM
authors.lastname: Murray
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London , London , UK.
authors.forename: Helen L
authors.initials: HL
authors.lastname: Fisher
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, King's College London , London , UK ; MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London , London , UK.
authors.forename: Conrad
authors.initials: C
authors.lastname: Iyegbe
keywords: FKBP5; GWAS; cannabis; childhood adversity; confounding factors; gene–environment; missing heritability; psychosis
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