Interaction Between Functional Genetic Variation of DRD2 and Cannabis Use on Risk of Psychosis

Both cannabis use and the dopamine receptor (DRD2) gene have been associated with schizophrenia, psychosis-like experiences, and cognition. However, there are no published data investigating whether genetically determined variation in DRD2 dopaminergic signaling might play a role in individual susceptibility to cannabis-associated psychosis. We genotyped (1) a case-control study of 272 patients with their first episode of psychosis and 234 controls, and also from (2) a sample of 252 healthy subjects, for functional variation in DRD2, rs1076560. Data on history of cannabis use were collected on all the studied subjects by administering the Cannabis Experience Questionnaire. In the healthy subjects' sample, we also collected data on schizotypy and cognitive performance using the Schizotypal Personality Questionnaire and the N-back working memory task. In the case-control study, we found a significant interaction between the rs1076560 DRD2 genotype and cannabis use in influencing the likelihood of a psychotic disorder. Among cannabis users, carriers of the DRD2, rs1076560, T allele showed a 3-fold increased probability to suffer a psychotic disorder compared with GG carriers (OR = 3.07; 95% confidence interval [CI]: 1.22-7.63). Among daily users, T carrying subjects showed a 5-fold increase in the odds of psychosis compared to GG carriers (OR = 4.82; 95% CI: 1.39-16.71). Among the healthy subjects, T carrying cannabis users had increased schizotypy compared with T carrying cannabis-naïve subjects, GG cannabis users, and GG cannabis-naïve subjects (all P ≤ .025). T carrying cannabis users had reduced working memory accuracy compared with the other groups (all P ≤ .008). Thus, variation of the DRD2, rs1076560, genotype may modulate the psychosis-inducing effect of cannabis us

Genetically Determined Measures of Striatal D2 Signaling Predict Prefrontal Activity during Working Memory Performance

Background: Variation of the gene coding for D2 receptors (DRD2) has been associated with risk for schizophrenia and with working memory deficits. A functional intronic SNP (rs1076560) predicts relative expression of the two D2 receptors isoforms, D2S (mainly pre-synaptic) and D2L (mainly post-synaptic). However, the effect of functional genetic variation of DRD2 on striatal dopamine D2 signaling and on its correlation with prefrontal activity during working memory in humans is not known. Methods: Thirty-seven healthy subjects were genotyped for rs1076560 (G>T) and underwent SPECT with [123I]IBZM (which binds primarily to post-synaptic D2 receptors) and with [123I]FP-CIT (which binds to pre-synaptic dopamine transporters, whose activity and density is also regulated by pre-synaptic D2 receptors), as well as BOLD fMRI during N-Back working memory. Results: Subjects carrying the T allele (previously associated with reduced D2S expression) had striatal reductions of [ 123I]IBZM and of [123I]FP-CIT binding. DRD2 genotype also differentially predicted the correlation between striatal dopamine D2 signaling (as identified with factor analysis of the two radiotracers) and activity of the prefrontal cortex during working memory as measured with BOLD fMRI, which was positive in GG subjects and negative in GT. Conclusions: Our results demonstrate that this functional SNP within DRD2 predicts striatal binding of the two radiotracers to dopamine transporters and D2 receptors as well as the correlation between striatal D2 signaling with prefrontal cortex activity during performance of a working memory task. These data are consistent with the possibility that the balance of excitatory/inhibitory modulation of striatal neurons may also affect striatal outputs in relationship with prefrontal activity during working memory performance within the cortico-striatal-thalamic- cortical pathwa

Interaction Between Functional Genetic Variation of DRD2 and Cannabis Use on Risk of Psychosis

Both cannabis use and the dopamine receptor (DRD2) gene have been associated with schizophrenia, psychosis-like experiences, and cognition. However, there are no published data investigating whether genetically determined variation in DRD2 dopaminergic signaling might play a role in individual susceptibility to cannabis-associated psychosis. We genotyped (1) a case-control study of 272 patients with their first episode of psychosis and 234 controls, and also from (2) a sample of 252 healthy subjects, for functional variation in DRD2, rs1076560. Data on history of cannabis use were collected on all the studied subjects by administering the Cannabis Experience Questionnaire. In the healthy subjects’ sample, we also collected data on schizotypy and cognitive performance using the Schizotypal Personality Questionnaire and the N-back working memory task. In the case-control study, we found a significant interaction between the rs1076560 DRD2 genotype and cannabis use in influencing the likelihood of a psychotic disorder. Among cannabis users, carriers of the DRD2, rs1076560, T allele showed a 3-fold increased probability to suffer a psychotic disorder compared with GG carriers (OR = 3.07; 95% confidence interval [CI]: 1.22–7.63). Among daily users, T carrying subjects showed a 5-fold increase in the odds of psychosis compared to GG carriers (OR = 4.82; 95% CI: 1.39–16.71). Among the healthy subjects, T carrying cannabis users had increased schizotypy compared with T carrying cannabis-naïve subjects, GG cannabis users, and GG cannabis-naïve subjects (all P ≤ .025). T carrying cannabis users had reduced working memory accuracy compared with the other groups (all P ≤ .008). Thus, variation of the DRD2, rs1076560, genotype may modulate the psychosisinducing effect of cannabis use

Prefronto-striatal physiology is associated with schizotypy and is modulated by a functional variant of DRD2

Peer reviewe

DRD2 genotype predicts prefrontal activity during working memory after stimulation of D2 receptors with bromocriptine

Rationale: Pharmacological stimulation of D2 receptors modulates prefrontal neural activity associated with working memory (WM) processing. The T allele of a functional single-nucleotide polymorphism (SNP) within DRD2 (rs1076560 G > T) predicts reduced relative expression of the D2S receptor isoform and less efficient neural cortical responses during WM tasks. Objective: We used functional MRI to test the hypothesis that DRD2 rs1076560 genotype interacts with pharmacological stimulation of D2 receptors with bromocriptine on prefrontal responses during different loads of a spatial WM task (N-Back). Methods: Fifty-three healthy subjects (38 GG and 15 GT) underwent two 3-T functional MRI scans while performing the 1-, 2- and 3-Back versions of the N-Back WM task. Before the imaging sessions, either bromocriptine or placebo was administered to all subjects in a counterbalanced order. A factorial repeated-measures ANOVA within SPM8 (p < 0.05, family-wise error corrected) was used. Results: On bromocriptine, GG subjects had reduced prefrontal activity at 3-Back together with a significant decrement in performance, compared with placebo. On the other hand, GT subjects had lower activity for the same level of performance at 1-Back but a trend for reduced behavioral performance in the face of unchanged activity at 2-Back. Conclusions: These results indicate that bromocriptine stimulation modulates prefrontal activity in terms of disengagement or of efficiency depending on DRD2 genotype and working memory load

Expression of DISC1-Interactome Members Correlates with Cognitive Phenotypes Related to Schizophrenia

Cognitive dysfunction is central to the schizophrenia phenotype. Genetic and functional studies have implicated Disrupted-in-Schizophrenia 1 (DISC1), a leading candidate gene for schizophrenia and related psychiatric conditions, in cognitive function. Altered expression of DISC1 and DISC1-interactors has been identified in schizophrenia. Dysregulated expression of DISC1-interactome genes might, therefore, contribute to schizophrenia susceptibility via disruption of molecular systems required for normal cognitive function. Here, the blood RNA expression levels of DISC1 and DISC1-interacting proteins were measured in 63 control subjects. Cognitive function was assessed using neuropsychiatric tests and functional magnetic resonance imaging was used to assess the activity of prefrontal cortical regions during the N-back working memory task, which is abnormal in schizophrenia. Pairwise correlations between gene expression levels and the relationship between gene expression levels and cognitive function and N-back-elicited brain activity were assessed. Finally, the expression levels of DISC1, AKAP9, FEZ1, NDEL1 and PCM1 were compared between 63 controls and 69 schizophrenic subjects. We found that DISC1-interactome genes showed correlated expression in the blood of healthy individuals. The expression levels of several interactome members were correlated with cognitive performance and N-back-elicited activity in the prefrontal cortex. In addition, DISC1 and NDEL1 showed decreased expression in schizophrenic subjects compared to healthy controls. Our findings highlight the importance of the coordinated expression of DISC1-interactome genes for normal cognitive function and suggest that dysregulated DISC1 and NDEL1 expression might, in part, contribute to susceptibility for schizophrenia via disruption of prefrontal cortex-dependent cognitive functions

Genetic determinants in a critical domain of ns5a correlate with hepatocellular carcinoma in cirrhotic patients infected with hcv genotype 1b

HCV is an important cause of hepatocellular carcinoma (HCC). HCV NS5A domain‐1 interacts with cellular proteins inducing pro‐oncogenic pathways. Thus, we explore genetic variations in NS5A domain‐1 and their association with HCC, by analyzing 188 NS5A sequences from HCV genotype‐1b infected DAA‐naïve cirrhotic patients: 34 with HCC and 154 without HCC. Specific NS5A mutations significantly correlate with HCC: S3T (8.8% vs. 1.3%, p = 0.01), T122M (8.8% vs. 0.0%, p &lt; 0.001), M133I (20.6% vs. 3.9%, p &lt; 0.001), and Q181E (11.8% vs. 0.6%, p &lt; 0.001). By multivariable analysis, the presence of &gt;1 of them independently correlates with HCC (OR (95%CI): 21.8 (5.7–82.3); p &lt; 0.001). Focusing on HCC‐group, the presence of these mutations correlates with higher viremia (median (IQR): 5.7 (5.4–6.2) log IU/mL vs. 5.3 (4.4–5.6) log IU/mL, p = 0.02) and lower ALT (35 (30–71) vs. 83 (48–108) U/L, p = 0.004), suggesting a role in enhancing viral fitness without affecting necroinflammation. Notably, these mutations reside in NS5A regions known to interact with cellular proteins crucial for cell‐cycle regulation (p53, p85‐PIK3, and β‐ catenin), and introduce additional phosphorylation sites, a phenomenon known to ameliorate NS5A interaction with cellular proteins. Overall, these results provide a focus for further investigations on molecular bases of HCV‐mediated oncogenesis. The role of these NS5A domain‐1 mutations in triggering pro‐oncogenic stimuli that can persist also despite achievement of sustained virological response deserves further investigation

Site response characteristics at Amatrice from ambient noise analysis

The 6.0 Mw earthquake that hit central Italy on 24 August 2016 caused at Amatrice damage of unprecedented severity for an earthquake of such a magnitude. The Amatrice’s old town centre was literally razed to the ground, accounting for more than 3/4 of the 300 victims of the earthquake. Different factors could have contributed to such a large amount of fatalities, including building vulnerability and local amplification of ground motion. Therefore, in view of the planning of the post-earthquake rebuilding of the town, it is of the utmost importance to clarify the reasons of this disaster. One of the questions that need to be investigated is the role of site response in aggravating the earthquake damage. A first contribution to shed some light on this aspect can derive from the study of ambient noise, since the employment of single station measurements using a lightweight, compact sensor allows a quick acquisition of data even within the context of an area that has to cope with the problems of emergency management. Hence, a series of campaigns of ambient noise acquisition were arranged, using a set of 3 tromographs “Tromino”. The data were acquired keeping one of the sensor at a “reference” station, where ambient noise was recorded continuously, while the other two tromographs were used for measurement sessions of 30-46 minutes at different sites. In this way, it is possible to check if differences in ambient noise properties acquired by different stations at different times reflect spatial changes in site-specific characteristics of soil dynamic response rather than temporal changes of environmental conditions generating ground vibrations. Furthermore, this configuration of data acquisition offers the possibility of additional types of data processing (e.g. through the analysis of correlation between simultaneous recordings to derive constraints for subsoil velocity models). Noise recordings were acquired on three different dates (October and December 2016, April 2017) at sites located within the most damaged area (known as the “red zone”) and outside it. Ambient noise data acquired in this area were processed following the traditional Nakamura’s approach (Nakamura, 1989) and the one recently proposed by one of us (Del Gaudio, 2017). The traditional Nakamura’s approach calculates the average spectral ratios HVNR between horizontal and vertical component of noise recording. The new approach, through instantaneous polarization analysis, identifies packets of Rayleigh waves within the noise recording and determines their ellipticity (ratio between horizontal H and vertical V component of elliptical particle motion), together with the azimuth of the vertical plane containing the elliptical motion. This method can provide thousands of estimates of H/V ratios from instantaneous polarization properties of ground motion (hereafter named HVIP), isolating the properties of portions of noise recordings where Rayleigh waves are dominant and then inferring curves of Rayleigh wave ellipticity HVIP as function of frequency. Such curves can be related to site response properties like frequency resonance, directivity of site response and impedance contrast between surface layer and bedrock. Our initial results show that, at different sites of Amatrice, both data processing methods consistently pointed out more or less pronounced maxima of H/V ratios at similar frequencies, comprised between 2 and 4 Hz. The frequency upper bound was observed at station Ama1, at the NW limit of the red zone, the lower bound at Ama8, at the SE limit of the same zone, and an intermediate value at the “reference” station Ama2 located about 300 m away from the red zone (Figs. 1-2). The measurements carried out at different dates provided similar results at Ama2, apart from a slight rotation of the H/V maximum direction, whereas evident differences were found in H/V peak amplitude and in directivity at stations within the red zone. Comparatively, the differences appear stronger for the HVNR measurements than for the HVIP ones. This confirms what we had observed in previous tests i.e., within noise recording, the superimposition of different types of waves (Love and body waves) over Rayleigh waves enhances the variability of the results from HVNR calculations, depending on the efficiency with which certain wave types are excited under different environmental conditions. However, the HVIP-derived results show that, even isolating the contribution of Rayleigh waves to the H/V ratios, a certain variability is observed. Our previous study (Del Gaudio et al., 2014) hypothesized that variations could derive from changes of the Poisson ratio of surface layers, related to seasonal changes of water content. The verification of such hypothesis, however, will require further measurement repetitions. At station Ama1, main differences from October 2016 to April 2017 measurements concern the enlargement of the most amplified frequency band and the passage from a more directional character of the H/V peak (oriented in NNW direction at October 2016) to an almost isotropy of the H/V maximum on April 2017. This suggests that the directivity observed in the first campaign at Ama1 might not reflect a property of the site response, being conditioned by changing environmental conditions (e.g., the presence and spatial distribution of sources of more or less polarized noise around the measurement station). More striking appears the variation at the station Ama11, located at the center of the old town, near the clock tower. The results obtained on April 2017 showed a strong generalized reduction of H/V ratios, so that on the basis of this measurement alone, one would totally exclude the presence of site amplification. However, it would appear that evidences of amplification are less pronounced at the sites in the central part of the red zone with respect to those near its limits. At present we do not have a straightforward explanation for these spatial differences in amplification. Nevertheless, in general, the amplification registered at Amatrice can be linked to the local geologic setting and in particular to the presence of the impedance contrast between few tens of meters thick surficial Quaternary alluvial deposits and the underlying flysch-like bedrock. We can speculate that the above-mentioned spatial variations in the amplification could result from local changes in the bedrock lithology, with more rocky (sandstones) flysch sites producing greater impedance contrast than more marly-argillaceous sites. Overall, the extension and repetition of noise measurements are necessary to achieve a better comprehension of the properties of site response in different part of the Amatrice town and to pin point possible correlations with the damage distribution. These additional measurements should help us to better distinguish noise characteristics controlled by site condition peculiarities from those depending on changes of noise sources

Poster #M195 THE INTERACTION BETWEEN CNR1 GENETIC VARIATION AND CANNABIS EXPOSURE PREDICTS PREFRONTAL FUNCTIONAL CONNECTIVITY AND BEHAVIOR DURING WORKING MEMORY

Background: Background: Previous evidence suggests an association between cognition and cannabis use in healthy subjects and in patients with schizophrenia. However, results on this association are not always consistent and they do not always indicate a deleterious effects of cannabis on cognition. Several different factors may be invoked to explain these differences, including the possibility that deleterious effects of cannabis use are best elicited on particular genetic backgrounds. A crucial determinant of cannabinoid signaling in the brain is the cannabinoid receptor 1 (CNR1), which has also been associated with schizophrenia in previous reports and is coded by the CNR1 gene. Here, our aim was to investigate in healthy subjects the association between CNR1 variation and prefrontal expression of CNR1. Once this association was established, we also studied if functional variation in CNR1 and cannabis exposure interact in modulating prefrontal functional connectivity during working memory processing, as well as related behavior. Methods: Methods: CNR1 mRNA expression as a function of genetic variation was investigated in post-mortem prefrontal human tissue using Braincloud (http://braincloud.jhmi.edu/). Based on this investigation, a single nucleotide polymorphism, rs1406977, was selected. Thus, 232 healthy subjects(125males)weregenotypedforthisSNPbyDNAdirectsequencing. Assessment of cannabis use was performed with the Cannabis Experience Questionnaire. Furthermore, all individuals performed the 2-back working memory task during functional Magnetic Resonance Imaging (fMRI). A General Linear Model and the Independent Component Analysis approach were used within SPM8 to study functional connectivity as a function of CNR1 genotype, of cannabis use and of their interaction. Results: Results: A single nucleotide polymorphism (SNP) within CNR1 (rs1406977) was associated with CNR1 prefrontal mRNA expression in prefrontal cortex. In particular, G carrier individuals had signi\ufb01cantly lower mRNA levels than AA subjects. Moreover, rs1406977 G carrier cannabis users had greater functional connectivity in the left ventrolateral prefrontal cortex (VLPFC) compared with G carrier cannabis na\uefve and AA cannabis users. Furthermore, G carrier cannabis users also had lower behavioral accuracy and slower reaction time than the other groups. Discussion: Discussion: genetically mediated low levels of prefrontal CNR1 levels may modulate the association between cannabis use and working memory processing in healthy subjects. Relevance of these \ufb01ndings for the pathophysiology of schizophrenia should be further investigated

Metformin and Autoimmunity: A “New Deal” of an Old Drug

Metformin (dimethyl biguanide) is a synthetic derivative of guanidine, isolated from the extracts of Galega officinalis, a plant with a prominent antidiabetic effect. Since its discovery more than 50 years ago, metformin represents a worldwide milestone in treatment of patients with type 2 diabetes (T2D). Recent evidence in humans indicates novel pleiotropic actions of metformin which span from its consolidated role in T2D management up to various regulatory properties, including cardio- and nephro-protection, as well as antiproliferative, antifibrotic, and antioxidant effects. These findings, together with ground-breaking studies demonstrating its ability to prolong healthspan and lifespan in mice, provided the basis for defining metformin as a potential antiaging molecule. Moreover, emerging in vivo and in vitro evidence support the novel hypothesis that metformin can exhibit immune-modulatory features. Studies suggest that metformin interferes with key immunopathological mechanisms involved in systemic autoimmune diseases, such as the T helper 17/regulatory T cell balance, germinal centers formation, autoantibodies production, macrophage polarization, cytokine synthesis, neutrophil extracellular traps release, and bone or extracellular matrix remodeling. These effects may represent a powerful contributor to antiaging and anticancer properties exerted by metformin and, from another standpoint, may open the way to assess whether metformin can be a candidate molecule for clinical trials involving patients with immune-mediated diseases. In this article, we will review the available preclinical and clinical evidence regarding the effect of metformin on individual cells of the immune system, with emphasis on immunological mechanisms related to the development and maintenance of autoimmunity and its potential relevance in treatment of autoimmune diseases