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

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

Reply to: New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process?

This work was supported by National Institute of Biomedical Imaging and Bioengineering Grant No. U54EB020403 (to the ENIGMA consortium)

Cortical brain abnormalities in 4474 individuals with schizophrenia and 5098 control subjects via the enhancing neuro Imaging genetics through meta analysis (ENIGMA) Consortium

BACKGROUND: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group. METHODS: The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide. RESULTS: Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset. CONCLUSIONS: The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia

The Association Between Familial Risk and Brain Abnormalities Is Disease Specific: An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder

Background: Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects. Methods: We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects. Results: FDRs-BD had significantly larger ICV (d = +0.16, q <.05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = −0.12, q <.05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d < −0.09, q <.05 corrected); and third ventricle was larger (d = +0.15, q <.05 corrected). The findings were not explained by psychopathology in the relatives or control subjects. Conclusions: Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct

Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3–90 years

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta‐Analysis (ENIGMA) Consortium to examine age‐related trajectories inferred from cross‐sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3–90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter‐individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age‐related morphometric patterns

Cortical thickness across the lifespan: Data from 17,075 healthy individuals aged 3-90 years

Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large‐scale studies. In response, we used cross‐sectional data from 17,075 individuals aged 3–90 years from the Enhancing Neuroimaging Genetics through Meta‐Analysis (ENIGMA) Consortium to infer age‐related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta‐analysis and one‐way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes

Emotions in Times of Pandemic Crisis among Italian Children: A Systematic Review

: Several studies underlined the negative effects of forced social isolation on emotional processes in younger population. The current study aimed to review existing evidence of the pandemic's impact on the emotional regulation of Italian children aged 0-12 years in order to identify personal and contextual factors that may adversely impact their developmental process. Different electronic databases (Web of Science, APA PsycInfo, APA PsycArticles, MEDLINE, Psychology and Behavioral Sciences Collection, and Scopus) were used to identify peer-reviewed studies published in English and Italian. Thirteen studies were included in the review, covering a total of 18.843 children. All studies reported negative effects of the lockdown on a child's emotional processes. The most affected were children aged 3-5 years, those living in Northern Italy, and those with low socioeconomic status (SES) families. Alterations in emotional processes were associated with sleep disturbances, quality of family relationships, personality structures, the coping strategies used, and time spent with technological devices. Finally, two- (time × parenting) and three-way (time × parenting × environmental sensitivity) interactions resulted significantly in predicting a child's emotional regulation, respectively, in terms of externalizing and internalizing behaviors. This review remarks that children's emotional processes were negatively impacted during social lockdown, especially where acute social isolation interacted with a set of dispositional and situational risk factors

The interaction between cannabis use and a CB1-related polygenic co-expression index modulates dorsolateral prefrontal activity during working memory processing

Convergent findings indicate that cannabis use and variation in the cannabinoid CB1 receptor coding gene (CNR1) modulate prefrontal function during working memory (WM). Other results also suggest that cannabis modifies the physiological relationship between genetically induced expression of CNR1 and prefrontal WM processing. However, it is possible that cannabis exerts its modifying effect on prefrontal physiology by interacting with complex molecular ensembles co-regulated with CB1. Since co-regulated genes are likely co-expressed, we investigated how genetically predicted co-expression of a molecular network including CNR1 interacts with cannabis use in modulating WM processing in humans. Using post-mortem human prefrontal data, we first computed a polygenic score (CNR1-PCI), combining the effects of single nucleotide polymorphisms (SNPs) on co-expression of a cohesive gene set including CNR1, and positively correlated with such co-expression. Then, in an in vivo study, we computed CNR1-PCI in 88 cannabis users and 147 non-users and investigated its interaction with cannabis use on brain activity during WM. Results revealed an interaction between cannabis use and CNR1-PCI in the dorsolateral prefrontal cortex (DLPFC), with a positive relationship between CNR1-PCI and DLPFC activity in cannabis users and a negative relationship in non-users. Furthermore, DLPFC activity in cannabis users was positively correlated with the frequency of cannabis use. Taken together, our results suggest that co-expression of a CNR1-related network predicts WM-related prefrontal activation as a function of cannabis use. Furthermore, they offer novel insights into the biological mechanisms associated with the use of cannabis