Objectives
Genome‐wide association studies (GWAS) have become increasingly popular to identify associations between single nucleotide polymorphisms (SNPs) and phenotypic traits. The GWAS method is ...commonly applied within the social sciences. However, statistical analyses will need to be carefully conducted and the use of dedicated genetics software will be required. This tutorial aims to provide a guideline for conducting genetic analyses.
Methods
We discuss and explain key concepts and illustrate how to conduct GWAS using example scripts provided through GitHub (https://github.com/MareesAT/GWA_tutorial/).
In addition to the illustration of standard GWAS, we will also show how to apply polygenic risk score (PRS) analysis. PRS does not aim to identify individual SNPs but aggregates information from SNPs across the genome in order to provide individual‐level scores of genetic risk.
Results
The simulated data and scripts that will be illustrated in the current tutorial provide hands‐on practice with genetic analyses. The scripts are based on PLINK, PRSice, and R, which are commonly used, freely available software tools that are accessible for novice users.
Conclusions
By providing theoretical background and hands‐on experience, we aim to make GWAS more accessible to researchers without formal training in the field.
The co-occurrence of substance use disorders (SUDs) and anxiety disorders has been now well established. This association is frequent and can be explained by three models: the shared vulnerability ...factors model, the self-medication model, and the substance-induced model. General population epidemiological studies provide strong evidence of the frequency of the association for the most used substances: tobacco, alcohol, cannabis, and to a lesser extent sedatives, opiates, and cocaine. For substances that are less commonly used in the general population, the frequency of the co-occurrence can more precisely be studied in clinical samples. We provide the most recent literature results on the association of SUDs and anxiety, and evidence for one explicative model or the other when available. For substances with sedative properties (alcohol, benzodiazepines, cannabis, opioids), both evidence for a self-medication and for a toxic effect exist. For substances with psychostimulant properties (tobacco, cocaine, and amphetamines), the literature favors the toxic hypothesis to explain the association with anxiety disorders. We give practical steps for the recognition of these dual diagnoses and present therapeutic issues, although the strategies are rarely evidence based.
Background:
Cocaine addiction is a global health issue with limited therapeutic options and a high relapse rate. Attentional bias towards substance-related cues may be an important factor for ...relapse. However, it has never been compared in former and current cocaine-dependent patients.
Methods:
Attentional bias towards cocaine-related words was assessed using an emotional Stroop task in cocaine-dependent patients (N = 40), long-term abstinent former cocaine-dependent patients (N = 24; mean abstinence: 2 years) and control subjects (N = 28). Participants had to name the colour of cocaine-related words, neutral words and colour names. We assessed response times using an automatic voice-onset detection method we developed and we measured attentional bias as the difference in response times between cocaine-related and neutral conditions.
Results:
There was an overall group effect on attentional bias towards cocaine, but no group effect on the colour Stroop effect. Two-by-two comparison showed a difference in attentional bias between cocaine-dependent patients and controls, whereas long-term abstinent former cocaine-dependent patients were not different from either. Although cocaine-dependent patients showed a significant attentional bias, consistent with the literature, neither long-term abstinent former cocaine-dependent patients nor controls showed a significant attentional bias towards cocaine-related words. We found no link between attentional bias size and either addiction severity or craving.
Conclusions:
Cocaine abstinence was associated with an absence of significant attentional bias towards cocaine-related words, which may be interpreted either as an absence of attentional bias predicting success in maintaining abstinence, or as attentional bias being able to disappear with long-term cocaine abstinence. Further research is needed to distinguish the role of attentional bias in maintaining abstinence.
The risk of developing drug addiction is strongly influenced by the epigenetic landscape and chromatin remodeling. While histone modifications such as methylation and acetylation have been studied in ...the ventral tegmental area and nucleus accumbens (NAc), the role of H2A monoubiquitination remains unknown. Our investigations, initially focused on the scaffold protein melanoma-associated antigen D1 (Maged1), reveal that H2A monoubiquitination in the paraventricular thalamus (PVT) significantly contributes to cocaine-adaptive behaviors and transcriptional repression induced by cocaine. Chronic cocaine use increases H2A monoubiquitination, regulated by Maged1 and its partner USP7. Accordingly, Maged1 specific inactivation in thalamic Vglut2 neurons, or USP7 inhibition, blocks cocaine-evoked H2A monoubiquitination and cocaine locomotor sensitization. Additionally, genetic variations in MAGED1 and USP7 are linked to altered susceptibility to cocaine addiction and cocaine-associated symptoms in humans. These findings unveil an epigenetic modification in a non-canonical reward pathway of the brain and a potent marker of epigenetic risk factors for drug addiction in humans.
Background
Major contributors to the global burden of bipolar disorders (BD) are the early age at onset (AAO) and the co-occurrence of non-mood disorders before and after the onset of BD. Using data ...from two independent cohorts from Europe and the USA, we investigated whether the trajectories of BD-I onset and patterns of psychiatric comorbidities differed in (a) individuals with or without a family history (FH) of BD, or (b) probands and parents who both had BD-I.
Methods
First, we estimated cumulative probabilities and AAO of comorbid mental disorders in familial and non-familial cases of BD-I (Europe, n = 573), and sex-matched proband-parent pairs of BD-I cases (USA, n = 194). Then we used time to onset analyses to compare overall AAO of BD-I and AAO according to onset polarity. Next, we examined associations between AAO and polarity of onset of BD-I according to individual experiences of comorbidities. This included analysis of the density of antecedent events (defined as the number of antecedent comorbidities per year of exposure to mental illness per individual) and time trend analysis of trajectory paths plotted for the subgroups included in each cohort (using R
2
goodness of fit analysis).
Results
Earlier AAO of BD-I was found in FH versus non-FH cases (log rank test = 7.63; p = 0.006) and in probands versus parents with BD-I (log rank test = 15.31; p = 0.001). In the European cohort, AAO of BD-I was significantly associated with factors such as: FH of BD (hazard ratio HR: 0.60), earlier AAO of first non-mood disorder (HR: 0.93) and greater number of comorbidities (HR: 0.74). In the USA cohort, probands with BD-I had an earlier AAO for depressive and manic episodes and AAO was also associated with e.g., number of comorbidities (HR: 0.65) and year of birth (HR: 2.44). Trajectory path analysis indicated significant differences in density of antecedents between subgroups within each cohort. However, the time trend R
2
analysis was significantly different for the European cohort only.
Conclusions
Estimating density of antecedent events and comparing trajectory plots for different BD subgroups are informative adjuncts to established statistical approaches and may offer additional insights that enhance understanding of the evolution of BD-I.
Suicide attempts (SA), especially recurrent SA or serious SA, are common in substance use disorders (SUD). However, the genetic component of SA in SUD samples remains unclear. Brain-derived ...neurotrophic factor (BDNF) alleles and levels have been repeatedly involved in stress-related psychopathology. This investigation uses a within-cases study of BDNF and associated factors in three suicidal phenotypes ('any', 'recurrent', and 'serious') of outpatients seeking treatment for opiate and/or cocaine use disorder. Phenotypic characterization was ascertained using a semi-structured interview. After thorough quality control, 98 SNPs of BDNF and associated factors (the BDNF pathway) were extracted from whole-genome data, leaving 411 patients of Caucasian ancestry, who had reliable data regarding their SA history. Binary and multinomial regression with the three suicidal phenotypes were further performed to adjust for possible confounders, along with hierarchical clustering and compared to controls (N = 2504). Bayesian analyses were conducted to detect pleiotropy across the suicidal phenotypes. Among 154 (37%) ever suicide attempters, 104 (68%) reported at least one serious SA and 96 (57%) two SA or more. The median number of non-tobacco SUDs was three. The BDNF gene remained associated with lifetime SA in SNP-based (rs7934165, rs10835210) and gene-based tests within the clinical sample. rs10835210 clustered with serious SA. Bayesian analysis identified genetic correlation between 'any' and 'serious' SA regarding rs7934165. Despite limitations, 'serious' SA was shown to share both clinical and genetic risk factors of SA-not otherwise specified, suggesting a shared BDNF-related pathophysiology of SA in this population with multiple SUDs.
Abstract Cholinergic striatal interneurons (ChIs) express the vesicular glutamate transporter 3 (VGLUT3) which allows them to regulate the striatal network with glutamate and acetylcholine (ACh). In ...addition, VGLUT3-dependent glutamate increases ACh vesicular stores through vesicular synergy. A missense polymorphism, VGLUT3-p.T8I, was identified in patients with substance use disorders (SUDs) and eating disorders (EDs). A mouse line was generated to understand the neurochemical and behavioral impact of the p.T8I variant. In VGLUT3 T8I/T8I male mice, glutamate signaling was unchanged but vesicular synergy and ACh release were blunted. Mutant male mice exhibited a reduced DA release in the dorsomedial striatum but not in the dorsolateral striatum, facilitating habit formation and exacerbating maladaptive use of drug or food. Increasing ACh tone with donepezil reversed the self-starvation phenotype observed in VGLUT3 T8I/T8I male mice. Our study suggests that unbalanced dopaminergic transmission in the dorsal striatum could be a common mechanism between SUDs and EDs.
Purpose
Brain positron emission tomography using 18F-fluorodeoxyglucose (18FDG-PET) provides a metabolic assessment of brain function that is useful for differential diagnosis among several ...neurodegenerative diseases manifested by cognitive impairment (CI). The purpose of the study is to describe the pattern of 18FDG-PET abnormalities in patients with CI related to alcohol use disorder.
Methods
Patients admitted to the addiction medicine department of a university hospital in Paris between January 2017 and October 2018 with a confirmed diagnosis of alcohol-related cognitive impairment (ARCI) or Wernicke encephalopathy (WE) were included. Brain 18FDG-PET uptake was measured after at least 1 month of monitored abstinence from alcohol. Standardized uptake values were obtained for 13 regions of interest (ROI) and normalized to the pons. Individual patients’ ROI
Z
-scores were calculated from healthy sex- and age-matched controls provided by Cortex ID software.
Results
Twenty-five patients were included in the analysis (20 males and 5 females; mean age 57.6 years (45–76 years old)). The group consisted of 19 ARCI and 6 WE cases. The mean hypometabolism was most severe in the prefrontal medial cortex (PFM) (− 2.80 (± 1.30)), the prefrontal lateral cortex (− 2.20 (± 1.35)), and the anterior cingulate cortex (− 2.24 (± 1.19)). Hypometabolism (
Z
-score < − 2) was most frequent in the PFM (72.0% of the sample,
N
= 18). Other regions were also affected (with 5.32/13 hypometabolic ROIs on average (SD = 4.16, range 0–13)). The
Z
-scores in the 13 ROIs did not differ significantly between the ARCI and WE patients (
p
≥ 0.05).
Conclusions
Predominant prefrontal and cingulate cortex hypometabolism was the most frequent brain 18FDG-PET pattern in our sample of patients with ARCI and WE.
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