Über den Einfluss von Risikofaktoren und deren Interaktion auf die weiße Substanz im Kontext der Schizophrenie
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Abstract
Schizophrenia is a serious mental disorder that is associated with significant morbidity
and mortality among those affected and, due to its high prevalence, results in major
social costs. Even though a high heritability of around 80% is known, the etiopathogenesis
is ultimately not yet fully understood. For example, an association with schizophrenia
has been controversially discussed for various genes, particularly Neuregulin 1 (NRG1),
but these genes only show small effect sizes. In addition to genetic risk variants, it is
known that environmental factors also contribute to an increased risk of schizophrenia -
for example, traumatic childhood experiences. However, since environmental factors alone
cannot explain the development of schizophrenia either, an interaction between genetic
and environmental risk factors is discussed in the literature.
In this study, an interaction of the possible risk factors NRG1 rs35753505 and traumatic
childhood experiences was investigated in the sense of a gene-environment interaction.
Both factors are known to have effects on neuronal development and in particular on white
matter. In order to better understand the connections, this study therefore examined
changes in white matter, attention and (subclinical) paranoid thinking. These changes were
considered so-called „endophenotypes“ for schizophrenia and could therefore be examined
in healthy subjects - however, fewer confounds due to, for example, disease or medication
effects and lower genetic complexity are expected than in patients with schizophrenia.
The study presented here was conducted as part of the Marburg Münster Affective Cohort
Study on 550 healthy, well-characterized subjects. For this purpose, the subjects’ fractional
anisotropy (FA) was determined to assess the white matter using diffusion tensor imaging
and tract-based spatial statistics (TBSS), and NRG1 rs35753505 was genotyped. Traumatic
childhood experiences were recorded using the Childhood Trauma Questionnaire, attention
using the d2 test, and paranoid thinking using the symptom checklist by Derogatis
(SCL-90-R). The analysis with TBSS showed an interaction effect of genotype and traumatic childhood
experiences with regard to fractional anisotropy for several white matter clusters. For
example, in homozygous risk allele carriers (CC), there is a significantly stronger negative
association between traumatic childhood experiences and fractional anisotropy than
in homozygous and heterozygous non-risk allele carriers (TT/CT), accompanied by a
resilience of non-risk allele carriers to traumatic childhood experiences. Furthermore,
the analysis of the relationship between genotype and FA shows an increased FA in
heterozygous compared to homozygous non-risk allele carriers. Together, these findings
provide a possible explanation for a selective advantage of heterozygous allele carriers and
may thus help explain the relatively constant prevalence of schizophrenia worldwide.
Subsequent conditional process analyses were also used to investigate a model of moderated
mediation. A multivariate model was proposed that took into account risk factors, fractional
anisotropy and clinical parameters, whereby the connection between traumatic childhood
experiences and attention processes or paranoid thinking in homozygous risk allele carriers
is mediated via clusters of fractional anisotropy. This supports the clinical relevance of
the interaction found. In addition, the results of the mediation show the mediation of
cognitive processes via the white matter, including in the corpus callosum.
The study also offers a possible explanation for the heterogeneous epidemiological study
situation on the association between NRG1 and schizophrenia, since the ability to show
the effects of traumatic childhood experiences depends on the genetic composition of
the study population, but the effect of the gene can also depend on the occurrence of
traumatic childhood experiences. Both would be biologically plausible. Conversely, this
would mean that in studies that do not take genotype into account, the effect of traumatic
childhood experiences on white matter is underestimated or overestimated depending on
the genotype. These - as well as other interactions - may help to clarify the problem of
the missing heritability of schizophrenia.
Following the study, further research questions arise, such as the specificity of traumatic
childhood experiences, temporal periods of vulnerability, the specificity of the location
of the interaction in the etiopathogenesis of schizophrenia (or a translational context) or
the definition of subgroups in schizophrenia - which in turn could enable earlier and more
targeted initiation of therapy.
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Issued: 2026-02-25
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FB20:Medizin
Language
de
Keywords
Schizophrenieweiße SubstanzDTIFraktionale AnisotropieGen-Umwelt Interaktionentraumatische KindheitserfahrungenCTQNRG1Neuregulin 1TBSS
Funding
Funding Organisations:
DFG
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Fischer, Elena Katharina: Über den Einfluss von Risikofaktoren und deren Interaktion auf die weiße Substanz im Kontext der Schizophrenie. : 2026-02-25. DOI: https://doi.org/10.17192/openumr/937.
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Except where otherwised noted, this item's license is described as Attribution 4.0 International