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Background Accumulating evidence suggests that altered dopamine transmission may increase the risk of mental disorders such as ADHD, schizophrenia or depression, possibly mediated by reward system dysfunction. This study aimed to clarify the impact of the COMT Val 158 Met polymorphism in interaction with environmental variation (G × E) on neuronal activity during reward processing. Methods 168 healthy young adults from a prospective study conducted over 25 years participated in a monetary incentive delay task measured with simultaneous EEG-fMRI. DNA was genotyped for COMT , and childhood family adversity (CFA) up to age 11 was assessed by a standardized parent interview. Results At reward delivery, a G × E revealed that fMRI activation for win vs. no-win trials in reward-related regions increased with the level of CFA in Met homozygotes as compared to Val/Met heterozygotes and Val homozygotes, who showed no significant effect. During the anticipation of monetary vs. verbal rewards, activation decreased with the level of CFA, which was also observed for EEG, in which the CNV declined with the level of CFA. Conclusions These results identify convergent genetic and environmental effects on reward processing in a prospective study. Moreover, G × E effects during reward delivery suggest that stress during childhood is associated with higher reward sensitivity and reduced efficiency in processing rewarding stimuli in genetically at-risk individuals. Together with previous evidence, these results begin to define a specific system mediating interacting effects of early environmental and genetic risk factors, which may be targeted by early intervention and prevention. [ABSTRACT FROM AUTHOR]

Abstract: Variation in the CACNA1C gene has consistently been associated with psychosis in genome wide association studies. We have previously shown in a sample of n=110 healthy subjects that carriers of the CACNA1C rs1006737 risk variant exhibit hippocampal and perigenual anterior cingulate dysfunction (pgACC) during episodic memory recall. Here, we aimed to replicate our results, by testing for the effects of the rs1006737 risk variant in a new large cohort of healthy controls. We furthermore sought to refine these results by identifying the impact of a CACNA1C specific, gene-wide risk score in the absence of clinical pathology. An independent sample of 179 healthy subjects genotyped for rs1006737 underwent functional magnetic resonance imaging (fMRI) while performing an associative episodic memory task and underwent psychological testing similar to the discovery sample. The effect of gene-wide risk scores was analyzed in the combined sample of 289 subjects. We replicated our discovery findings of hippocampal and pgACC dysfunction in carriers of the rs1006737 risk variant. Additionally, we observed diminished activation of the dorsolateral prefrontal cortex, in the replication sample. Our replicated results as well as this new effect were also observable in the combined sample. Moreover, the same system-level phenotypes were significantly associated with the individual gene-based genetic risk score. Our findings suggest that altered hippocampal and frontolimbic function is associated with variants in the CACNA1C gene. Since CACNA1C variants have been associated repeatedly with psychosis at a genome-wide level, and preclinical data provide convergent evidence for the relevance of the CACNA1C gene for hippocampal and frontolimbic plasticity and adaptive regulation of stress, our data suggest a potential pathophysiological mechanism conferred by CACNA1C variants that may mediate risk for symptom dimensions shared among bipolar disorder, major depression, and schizophrenia. [Copyright &y& Elsevier]

Abstract: Background: Genome-wide association studies have identified the CACNA1C single nucleotide polymorphism (SNP) rs1006737 as one of the most consistent genetic findings as susceptibility locus for major psychiatric disorders. Furthermore, animal and genetic imaging studies have reported strong functional evidence for the association of CACNA1C with learning, memory, neural plasticity, and its association with the hippocampal formation. In the present study we investigated the impact of the CACNA1C SNP rs1006737 on the fractional anisotropy (FA) in the hippocampal formation as well as on verbal learning and memory in healthy individuals. Methods: 118 healthy individuals (72 males, 46 females, age 18–56years) initially underwent diffusion tensor imaging (DTI), 100 of them were included in the final analysis. We used Tract-Based Spatial Statistics (TBSS) to examine the impact of the CACNA1C SNP rs1006737 on the hippocampal formation as predefined region of interest (ROI). Furthermore, all participants completed the Verbal Learning and Memory Test (VLMT). Results: In the VLMT genotype was significantly associated with learning performance. Bonferroni corrected post-hoc tests indicated a diminished performance at the beginning of the learning curve in risk allele carriers compared to non-risk allele carriers. The TBSS ROI analysis revealed one cluster of reduced FA in risk allele carriers compared to non-risk allele carriers located in the right hippocampal formation. Moreover, an association between the initial learning performance and FA values was found. Discussion: These findings demonstrate that genetic variation in the CACNA1C SNP rs1006737 is associated with FA reduction in the hippocampal formation as well as with differences in learning performance in healthy individuals. [Copyright &y& Elsevier]

Abstract: Neuroimaging group analyses are used to relate inter-subject signal differences observed in brain imaging with behavioral or genetic variables and to assess risks factors of brain diseases. The lack of stability and of sensitivity of current voxel-based analysis schemes may however lead to non-reproducible results. We introduce a new approach to overcome the limitations of standard methods, in which active voxels are detected according to a consensus on several random parcellations of the brain images, while a permutation test controls the false positive risk. Both on synthetic and real data, this approach shows higher sensitivity, better accuracy and higher reproducibility than state-of-the-art methods. In a neuroimaging–genetic application, we find that it succeeds in detecting a significant association between a genetic variant next to the COMT gene and the BOLD signal in the left thalamus for a functional Magnetic Resonance Imaging contrast associated with incorrect responses of the subjects from a Stop Signal Task protocol. [Copyright &y& Elsevier]

Abstract: Schizophrenia is a severe neuropsychiatric disorder with high heritability, though its exact etiopathogenesis is yet unknown. An increasing number of studies point to the importance of white matter anomalies in the pathophysiology of schizophrenia. While several studies have identified the impact of schizophrenia susceptibility gene variants on gray matter anatomy in both schizophrenia patients and healthy risk variant carriers, studies dealing with the impact of these gene variants on white matter integrity are still scarce. We here present a study on the effects of a Dysbindin schizophrenia susceptibility gene variant on fiber tract integrity in healthy young subjects. 101 subjects genotyped for Dysbindin-gene variant rs1018381, though without personal or first degree relative history of psychiatric disorders underwent diffusion tensor imaging (DTI), 83 of them were included in the final analysis. We used Tract-Based Spatial Statistics (TBSS) analysis to delineate the major fiber tracts. Carriers of the minor allele T of the rs1018381 in the Dysbindin gene showed two clusters of reduced fractional anisotropy (FA) values in the perihippocampal region of the right temporal lobe compared to homozygote carriers of the major allele C. Clusters of increased FA values in T-allele carriers were found in the left prefrontal white matter, the right fornix, the right midbrain area, the left callosal body, the left cerebellum and in proximity of the right superior medial gyrus. Dysbindin has been implicated in neurite outgrowth and morphology. Impairments in anatomic connectivity as found associated with the minor Dysbindin allele in our study may result in increased risk for schizophrenia due to altered fiber tracts. [Copyright &y& Elsevier]

Abstract: Bipolar disorder is a devastating, highly heritable mental disorder related to disturbed connectivity between limbic and frontal brain areas. A meta-analysis of genome-wide association studies as well as independent replications showed ankyrin 3 (ANK3) to be one of the best-supported risk genes for bipolar disorder. Using an imaging genetics approach employing diffusion tensor imaging in 88 healthy volunteers, we show decreased white matter integrity, indicated by lower fractional anisotropy and longitudinal diffusivity, in healthy carriers of the ANK3 rs10994336 risk genotype in the anterior limb of the internal capsule. We are also able to show that the resulting alterations of cortical–striatal–thalamic circuits are related to impaired set-shifting and increased risk-taking. For risk-allele carriers of ANK3 rs9804190 no white matter alterations or neuropsychological impairments were observed. In sum, our findings show that ANK3 rs10994336 or a variant in linkage-disequilibrium is functional in the human brain and also influences behavioral phenotypes related to bipolar disorder. [Copyright &y& Elsevier]

Abstract: The drug metabolizing cytochrome P450 2D6 enzyme (CYP2D6) is highly expressed in brain and potentially involved in neurotransmitter biotransformation. Here, we report the effect of the CYP2D6 genotype on brain activation during a working memory and an emotional face matching task measured with fMRI. Subjects were taken from an ongoing large scale multicenter imaging genetic study. CYP2D6 genotyping of the alleles *2, *3, *4, *5, *6, *9, *10, *17, *35, *41 and the duplication was performed in N =114 healthy drug free individuals. All individuals had completed two tasks in functional brain imaging: an n-back working memory task and an implicit emotional face matching task. Contrast images were analyzed in second-level random effects models with CYP2D6 enzyme activity levels as regressor of interest and age, sex and scanning site as covariates. In the working memory task, a significant effect of CYP2D6 genotype was found in the fusiform gyrus and the precuneus. In the emotional face matching task, an effect was detected in the cuneus. No significant activation results were found in the thalamus. A conjunction analysis confirmed a significant joint effect of the CYP2D6 association in both regions. In both tasks activation increased with increasing CYP2D6 activity. In conclusion, we confirmed a central nervous system effect of CYP2D6 activity in a large independent sample using a different imaging modality, and provide evidence that basic cognitive processes related to such as alertness may be impacted. [Copyright &y& Elsevier]

Abstract: Alterations of connectivity are central to the systems-level pathophysiology of schizophrenia. One of the best-established genome-wide significant risk variants for this highly heritable disorder, the rs1344706 single nucleotide polymorphism in ZNF804A, was recently shown to modulate connectivity in healthy carriers during working memory (WM) in a pattern mirroring that which was found in overt disease. However, it was unclear whether this finding is specific to WM or if it is present regardless of cognitive state. Therefore, we examined genotype effects on connectivity in healthy carriers during rest and an emotion processing task without WM component. 111 healthy German subjects performed a battery of functional imaging tasks. Functional connectivity with the right dorsolateral prefrontal cortex during rest and an implicit emotion recognition task was determined using the seed voxel method and compared to results during WM. During rest and during the emotional task, a pattern of reduced interhemispheric prefrontal connectivity with increasing number of rs1344706 risk alleles could be seen that was close to identical to that during WM, suggesting a state-independent influence of the genetic variant on interhemispheric processing, possibly through structural effects. By contrast, the abnormal prefronto-hippocampal connectivity was only seen during the WM task, indicating a degree of task specificity in agreement with prior results in patients with schizophrenia. Our findings confirm a key role for disturbed functional connectivity in the genetic risk architecture of schizophrenia and identify cognitive state-dependent and independent components with regard to WM function. [Copyright &y& Elsevier]

Abstract: Polymorphisms in the G72 (also named d-amino acid oxidase activator, DAOA) gene increase the vulnerability for schizophrenia and affective psychosis. Three recent genetic neuroimaging studies showed that variation in G72 influences the brain activity in the medial temporal lobe (MTL), supporting the hypothesis that G72 might play a modulatory role on brain activity in MTL structures. In the present study we therefore investigated the effect of G72 on the neural correlates of long-term memory encoding and retrieval in a large sample of healthy subjects (n =83) using functional magnetic resonance imaging. A face encoding and a face retrieval memory task were chosen because on the one hand they specifically activate MTL structures and on the other hand they tap into memory processes that are compromised in patients with schizophrenia and affective disorder. Despite a strong a-priori hypothesis of genotype group activation differences in the MTL along with a large sample size we did neither find an effect of G72 genotype status on brain activity in the MTL nor in any other brain regions. The present data therefore do not support the view of a general modulatory role of G72 on MTL brain activity, at least not in the domain of long-term memory encoding and retrieval. Our results highlight the importance of replication studies in genetic neuroimaging. [Copyright &y& Elsevier]

Abstract: Neuregulin 1 (NRG1) has been found to be associated with schizophrenia. Impaired performance in episodic memory tasks is an often replicated finding in this disorder. In functional neuroimaging studies, this dysfunction has been linked to signal changes in prefrontal and medial temporal areas. Therefore, it is of interest whether genes associated with the disorder, such as NRG1, modulate episodic memory performance and its neural correlates. Ninety-four healthy individuals performed an episodic memory encoding and a retrieval task while brain activation was measured with functional MRI. All subjects were genotyped for the single nucleotide polymorphism (SNP) rs35753505 in the NRG1 gene. The effect of genotype on brain activation was assessed with fMRI during the two tasks. While there were no differences in performance, brain activation in the cingulate gyrus (BA 24), the left middle frontal gyrus (BA 9), the bilateral fusiform gyrus and the left middle occipital gyrus (BA 19) was positively correlated with the number of risk alleles in NRG1 during encoding. During retrieval brain activation was positively correlated with the number of risk alleles in the left middle occipital gyrus (BA 19). NRG1 genotype does modulate brain activation during episodic memory processing in key areas for memory encoding and retrieval. The results suggest that subjects with risk alleles show hyperactivations in areas associated with elaborate encoding strategies. [Copyright &y& Elsevier]

Abstract: Individuals carrying the short allele of a common polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) exhibit heightened amygdala responses to passive stimulation with aversive emotional material. In turn, the level of amygdala activation in response to emotion can be decreased by will, for example by using cognitive emotion regulation strategies. In the present study, 37 female subjects (s-carriers: n =21; l/l-homozygotes: n =16) performed an emotion regulation task during functional magnetic resonance imaging to determine whether cognitive emotion regulation can modulate the genetically determined amygdala hyperreactivity in 5-HTTLPR short allele carriers. Our results demonstrate that cognitive emotion regulation diminishes the difference in amygdala reactivity to threat-related stimuli between 5-HTTLPR genotype groups. Furthermore, we also provide evidence that the effect of cognitive regulation is mediated through altered coupling between the amygdala and prefrontal regulatory regions. Our findings demonstrate that while the presence of the 5-HTTLPR short allele leads to heightened responses in the amygdala, cognitive regulation can modify genetically mediated effects upon brain function by volitionally altering prefrontal-amygdala connectivity. [Copyright &y& Elsevier]

Abstract: G72 is a vulnerability gene for schizophrenia and affective psychosis, disorders that are characterized by deficits in working memory. In the present study we investigated whether the G72 genotype influences verbal and spatial working memory functions in healthy individuals. Working memory was assessed at the behavioural level in 423 subjects using the spatial span of the Wechsler Memory Scale (spatial working memory) and the letter–number-span test (verbal working memory). In a sub-sample of 83 subjects, we assessed working memory functions also at the neural level using functional magnetic resonance imaging during a classical letter variant of the n-back task. Unexpectedly the high risk allele carriers performed better in the verbal working memory task than the other subjects. These behavioural differences were accompanied by brain activation differences in the right parahippocampus, a brain region that plays a major role in schizophrenia and affective disorders. The high risk variant of a vulnerability gene therefore does not necessarily have to negatively affect cognitive abilities per se, but may even have beneficial effects on cognitive functions in the non-affected population. [Copyright &y& Elsevier]

Abstract: Working memory dysfunctions are a prominent feature in schizophrenia. These impairments have been linked to alterations in prefrontal brain activation with studies reporting hypo- and hyperactivations. Since schizophrenia has a high heritability, it is of interest whether susceptibility genes modulate working memory and its neural correlates. The aim of the present study was to test the influence of the NRG1 schizophrenia susceptibility gene on working memory and its neural correlates in healthy subjects. 429 healthy individuals performed a verbal and a spatial working memory task. A subsample of 85 subjects performed a 2-back version of the Continuous Performance Test (CPT) in a functional MRI study. The NRG1 SNP8NRG221533 (rs35753505) carrier status was determined and correlated with working memory performance and brain activation. There were no effects of genetic status on behavioural performance in the working memory tasks in the 429 subjects and in the fMRI task (n =85). A linear effect of NRG1 SNP8NRG221533 carrier status on neuronal activation emerged in the fMRI experiment. Hyperactivation of the superior frontal gyrus (BA 10) was correlated with the number of risk alleles. The fMRI data suggest that performance measures between groups did not differ due to a compensational activation of BA 10 in risk-allele carriers. Our results are in line with functional imaging studies in patients with schizophrenia, which also showed a differential activation in lateral prefrontal areas. [Copyright &y& Elsevier]

• Structural brain networks can be modeled as a trade-off between wiring cost and topological features. • Schizophrenia patients show lower spatial constraints and topological facilitation. • Individual model parameters are associated with genetic risk for schizophrenia and cognition. Alterations in the structural connectome of schizophrenia patients have been widely characterized, but the mechanisms remain largely unknown. Generative network models have recently been introduced as a tool to test the biological underpinnings of altered brain network formation. We evaluated different generative network models in healthy controls (n =152), schizophrenia patients (n =66), and their unaffected first-degree relatives (n =32), and we identified spatial and topological factors contributing to network formation. We further investigated how these factors relate to cognition and to polygenic risk for schizophrenia. Our data show that among the four tested classes of generative network models, structural brain networks were optimally accounted for by a two-factor model combining spatial constraints and topological neighborhood structure. The same wiring model explained brain network formation across study groups. However, relatives and schizophrenia patients exhibited significantly lower spatial constraints and lower topological facilitation compared to healthy controls. Further exploratory analyses point to potential associations of the model parameter reflecting spatial constraints with the polygenic risk for schizophrenia and cognitive performance. Our results identify spatial constraints and local topological structure as two interrelated mechanisms contributing to regular brain network formation as well as altered connectomes in schizophrenia and healthy individuals at familial risk for schizophrenia. On an exploratory level, our data further point to the potential relevance of spatial constraints for the genetic risk for schizophrenia and general cognitive functioning, thereby encouraging future studies in following up on these observations to gain further insights into the biological basis and behavioral relevance of model parameters. [ABSTRACT FROM AUTHOR]