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Searching for the genetic underpinnings of schizophrenia and bipolar disorder: Functional neuroimaging markers as potential endophenotypes

Martin, Jessica

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According to the Research Domain Criteria (RDoC) framework, mental diseases are conceptualized as disorders of brain circuits, which are measurable, and are based on genetic mechanisms. In the search for genetic underpinnings of psychopathology, the use of endophenotypes constitutes a promising approach.

This thesis aimed to contribute to the identification of biosignatures for schizophrenia and bipolar disorder on a neuroimaging and molecular genetic level by using functional neuroimaging endophenotypes and an imaging genetics approach. It comprises two parts: In study 1, neurofunctional correlates of reward processing in unaffected first-degree relatives of patients with schizophrenia and bipolar disorder was examined using the ‘desire-reason dilemma’ paradigm. Study 2 investigated the genetic underpinnings of resting-state functional connectivity between the left fronto-parietal network and Heschl’s gyrus, which constitutes a potential endophenotype for schizophrenia, using a genome-wide association approach in a homogeneous sample of healthy subjects.

Study 1 shows disruptions in mesocorticolimbic reward processing in first-degree relatives of patients with schizophrenia and bipolar disorder. Specifically, the study gives evidence for an enhanced bottom-up activation of the ventral striatum in first-degree relatives of patients with schizophrenia, which is in line with the hypothesis of a general hyperdopaminergic state in schizophrenia. In contrast, in first-degree relatives of patients with bipolar disorder, there was no difference in ventral striatal activation compared with controls, indicating intact bottom-up activation of the ventral striatum. More importantly, study results show a disturbed top-down control of mesolimbic reward signals by prefrontal brain regions in first-degree relatives of patients with schizophrenia and bipolar disorder. These results suggest that disrupted reward processing, possibly relying on dopamine malfunction, may be linked with the genetic vulnerability to develop schizophrenia or bipolar disorder, and thus constitutes a potential endophenotype for schizophrenia and bipolar disorder. Although these data suggests a genetic basis for mesocorticolimbic reward processing, an influence by environmental factors cannot be ruled out. Future studies in monozygotic and dizygotic twin pairs discordant for schizophrenia will be necessary to further investigate the genetic determinants of disturbed reward processing.

Study 2 was able to identify one genome-wide significant variant, as well as four intronic loci with suggestive evidence for association. Among the top hits was an intronic locus (rs4958456) within calcium/calmodulin dependent protein kinase II alpha (CAMK2a) gene, which is high-specifically expressed in brain cortical tissue. Its gene product CaM-kinase II may function in neurotransmitter release, long-term potentiation and synaptic plasticity in glutamatergic synapses. This finding is in line with earlier studies supporting the role of calcium signaling in schizophrenia. However, replication will be necessary to evaluate these preliminary findings.

Taken together, in line with the framework of RDoC, these findings contribute to the understanding of schizophrenia and bipolar disorder on a genomic and brain functional level.

Document type: Dissertation
Supervisor: Gruber, Prof. Dr. med. Oliver
Place of Publication: Heidelberg
Date of thesis defense: 26 April 2023
Date Deposited: 06 Jun 2023 07:10
Date: 2023
Faculties / Institutes: Medizinische Fakultät Heidelberg > Psychiatrische Universitätsklinik
DDC-classification: 150 Psychology
570 Life sciences
610 Medical sciences Medicine
Controlled Keywords: Psychiatrie, Neurowissenschaften, Funktionelle Kernspintomografie, Genetik, Schizophrenie, Bipolare affektive Störung
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