title: The emerging role of the FKBP5 gene polymorphisms in vulnerability-stress model of schizophrenia: further evidence from a Serbian population.
abstract: Increased reactivity to stress is observed in patients with schizophrenia spectrum disorders and their healthy siblings in comparison with the general population. Additionally, higher levels of neuroticism, as a proposed psychological measure of stress sensitivity, increase the risk of schizophrenia. HPA axis dysregulation is one of the possible mechanisms related to the vulnerability-stress model of schizophrenia, and recent studies revealed a possible role of the functional genetic variants of FK506-binding protein 51 (FKBP5) gene which modulate activity of HPA axis. The purpose of the present study was to investigate impact of FKBP5 on schizophrenia in Serbian patients and to explore relationship between genetic variants and neuroticism by using the case-sibling-control design. In 158 subjects, we measured psychotic experiences, childhood trauma and neuroticism. Nine single-nucleotide polymorphisms (rs9295158, rs3800373, rs9740080, rs737054, rs6926133, rs9380529, rs9394314, rs2766533 and rs12200498) were genotyped. The genetic influence was modeled using logistic regression, and the relationship between genetic variants and neuroticism was assessed by linear mixed model. Our results revealed genetic main effect of FKBP5 risk alleles (A allele of rs9296158 and T allele of rs3800373) and AGTC "risk" haplotype combination (rs9296158, rs3800373, rs9470080 and rs737054, respectively) on schizophrenia, particularly when childhood trauma was set as a confounding factor. We confirmed strong relationship between neuroticism and psychotic experiences in patients and siblings and further showed relationship between higher levels of neuroticism and FKBP5 risk variants suggesting potential link between biological and psychosocial risk factors. Our data support previous findings that trauma exposure shapes FKBP5 impact on schizophrenia.
authors.affiliation: Clinic for Psychiatry, Clinical Centre of Serbia, Pasterova 2, Belgrade, 11000, Serbia. mihaljevicm@yahoo.com.
authors.forename: Marina
authors.identifier: http://orcid.org/0000-0003-3415-8706
authors.initials: M
authors.lastname: Mihaljevic
authors.affiliation: Genetics and Evolution Department, Faculty of Biology, University of Belgarde, Studentski trg 3, Belgrade, 11000, Serbia.
authors.forename: Katarina
authors.initials: K
authors.lastname: Zeljic
authors.affiliation: Faculty of Medicine, Institute for Biostatistics, Medical Informatics and Researches in Medicine, University of Belgrade, Dr Subotica 15, Belgrade, 11000, Serbia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Soldatovic
authors.affiliation: Clinic for Psychiatry, Clinical Centre of Serbia, Pasterova 2, Belgrade, 11000, Serbia.
authors.forename: Sanja
authors.initials: S
authors.lastname: Andric
authors.affiliation: Special Hospital for Psychiatric Disorders Kovin, Cara Lazara 253, Kovin, 26220, Serbia.
authors.forename: Tijana
authors.initials: T
authors.lastname: Mirjanic
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, CF24 4HQ, Wales, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Richards
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, CF24 4HQ, Wales, UK.
authors.forename: Kiran
authors.initials: K
authors.lastname: Mantripragada
authors.affiliation: Faculty of Medicine, Institute of Epidemiology, University of Belgrade, Visegradska 26, Belgrade, 11000, Serbia.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Pekmezovic
authors.affiliation: Faculty of Medicine, Institute of Human Genetics, University of Belgrade, Visegradska 26, Belgrade, 11000, Serbia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Novakovic
authors.affiliation: Clinic for Psychiatry, Clinical Centre of Serbia, Pasterova 2, Belgrade, 11000, Serbia.|Faculty of Medicine, University of Belgrade, Dr Subotica 8, Belgrade, 11000, Serbia.
authors.forename: Nadja P
authors.initials: NP
authors.lastname: Maric
mesh_terms: D000328:Adult; D000069586:Adult Survivors of Child Adverse Events; D016022:Case-Control Studies; D004198:Disease Susceptibility; D005260:Female; D059647:Gene-Environment Interaction; D006801:Humans; D008297:Male; D008962:Models, Theoretical; D000075384:Neuroticism; D020641:Polymorphism, Single Nucleotide; D011618:Psychotic Disorders / Q000209:etiology* / Q000235:genetics*; D012307:Risk Factors; D012559:Schizophrenia / Q000209:etiology* / Q000235:genetics*; D055771:Serbia; D035781:Siblings; D013315:Stress, Psychological / Q000150:complications*; D022021:Tacrolimus Binding Proteins / Q000235:genetics*; D055815:Young Adult; D000099159:Tacrolimus Binding Protein 5
chemical_list: D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5
keywords: FKBP5 genetic variants; Haplotypes; Healthy siblings; Neuroticism; Schizophrenia