Brain-derived neurotrophic factor/FK506-binding protein 5 genotype by childhood trauma interactions do not impact on hippocampal volume and cognitive performance

Dennis Hernaus; Ruud van Winkel; Ed Gronenschild; Petra Habets; Gunter Kenis; Machteld Marcelis; Jim van Os; Inez Myin-Germeys; Dina Collip; for Genetic Risk and Outcome in Psychosis (G.R.O.U.P.)

doi:10.1371/journal.pone.0092722

Brain-derived neurotrophic factor/FK506-binding protein 5 genotype by childhood trauma interactions do not impact on hippocampal volume and cognitive performance

PLoS One. 2014 Mar 21;9(3):e92722. doi: 10.1371/journal.pone.0092722. eCollection 2014.

Authors

Dennis Hernaus¹, Ruud van Winkel², Ed Gronenschild¹, Petra Habets¹, Gunter Kenis¹, Machteld Marcelis¹, Jim van Os³, Inez Myin-Germeys¹, Dina Collip¹; for Genetic Risk and Outcome in Psychosis (G.R.O.U.P.)

Affiliations

¹ Department of Psychiatry and Psychology, South Limburg Mental Health Research and Teaching Network, EURON, School for Mental Health and NeuroScience MHeNS Maastricht University, Maastricht, The Netherlands.
² Department of Psychiatry and Psychology, South Limburg Mental Health Research and Teaching Network, EURON, School for Mental Health and NeuroScience MHeNS Maastricht University, Maastricht, The Netherlands; University Psychiatric Centre Catholic University Leuven, Kortenberg, Belgium.
³ Department of Psychiatry and Psychology, South Limburg Mental Health Research and Teaching Network, EURON, School for Mental Health and NeuroScience MHeNS Maastricht University, Maastricht, The Netherlands; King's College London, King's Health Partners, Department of Psychosis Studies, Institute of Psychiatry, London, United Kingdom.

Abstract

In the development of psychotic symptoms, environmental and genetic factors may both play a role. The reported association between childhood trauma and psychotic symptoms could therefore be moderated by single nucleotide polymorphisms (SNPs) associated with the stress response, such as FK506-binding protein 5 (FKBP5) and brain-derived neurotrophic factor (BDNF). Recent studies investigating childhood trauma by SNP interactions have inconsistently found the hippocampus to be a potential target underlying these interactions. Therefore, more detailed modelling of these effects, using appropriate covariates, is required. We examined whether BDNF/FKBP5 and childhood trauma interactions affected two proxies of hippocampal integrity: (i) hippocampal volume and (ii) cognitive performance on a block design (BD) and delayed auditory verbal task (AVLT). We also investigated whether the putative interaction was different for patients with a psychotic disorder (n = 89) compared to their non-psychotic siblings (n = 95), in order to elicit possible group-specific protective/vulnerability effects. SNPs were rs9296158, rs4713916, rs992105, rs3800373 (FKBP5) and rs6265 (BDNF). In the combined sample, no BDNF/FKBP5 by childhood trauma interactions were apparent for either outcome, and BDNF/FKBP5 by childhood trauma interactions were not different for patients and siblings. The omission of drug use and alcohol consumption sometimes yielded false positives, greatly affected explained error and influenced p-values. The consistent absence of any significant BDNF/FKBP5 by childhood trauma interactions on assessments of hippocampal integrity suggests that the effect of these interactions on psychotic symptoms is not mediated by hippocampal integrity. The importance of appropriate statistical designs and inclusion of relevant covariates should be carefully considered.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Brain-Derived Neurotrophic Factor / genetics*
Cognition*
Female
Genotype*
Hippocampus / pathology*
Humans
Magnetic Resonance Imaging
Male
Neuropsychological Tests
Organ Size
Polymorphism, Single Nucleotide
Psychotic Disorders / diagnosis*
Psychotic Disorders / drug therapy
Psychotic Disorders / etiology*
Risk Factors
Tacrolimus Binding Proteins / genetics*
Tomography, X-Ray Computed
Young Adult

Substances

Brain-Derived Neurotrophic Factor
Tacrolimus Binding Proteins
tacrolimus binding protein 5

Grants and funding

This work was sponsored by the Geestkracht program of the Netherlands Organization for Scientific Research (NWO) (GROUP) and the European Community's Seventh Framework Programme under grant agreement HEALTH F2-2009-241909 (EU-GEI consortium). Furthermore, it was sponsored by a 2006 National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Award and by the Dutch Medical Research Council (VENI and VIDI grant), and a European Research Council consolidator grant (ERC-2012-StG – 309767) to I. Myin-Germeys. J. van Os is or has been an unrestricted research grant holder with, or his institution has received financial compensation as an independent symposium speaker from, Eli Lilly, BMS, Lundbeck, Organon, Janssen, GlaxoSmithKline, AstraZeneca, Pfizer, and Servier. M. Marcelis has received financial compensation as an independent symposium speaker from Eli Lilly and Janssen. G. Kenis has received financial compensation as an independent symposium speaker from Eli Lilly, Janssen and Servier. Ruud van Winkel is supported by the King Baudouin Foundation (Fund Dr. Gustave Delport). Dina Collip is supported by a Maastricht University post-doc Kootstra fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.