Dave Checknita's research while affiliated with McGill University and other places

High impulsive and aggressive traits associate with poor behavioural self-control. Despite their importance in predicting behavioural negative outcomes including suicide, the molecular mechanisms underlying the expression of impulsive and aggressive traits remain poorly understood. Here, we identified and characterized a novel long noncoding RNA (lncRNA), acting as a regulator of the monoamine oxidase A (MAOA) gene in the brain, and named it MAOA-associated lncRNA (MAALIN). Our results show that in the brain of suicide completers, MAALIN is regulated by a combination of epigenetic mechanisms including DNA methylation and chromatin modifications. Elevated MAALIN in the dentate gyrus of impulsive-aggressive suicides was associated with lower MAOA expression. Viral overexpression of MAALIN in neuroprogenitor cells decreased MAOA expression while CRISPR-mediated knock out resulted in elevated MAOA expression. Using viral-mediated gene transfer, we confirmed that MAALIN in the hippocampus significantly decreases MAOA expression and exacerbates the expression of impulsive-aggressive behavioural traits in CD1 aggressive mice. Overall, our findings suggest that variations in DNA methylation mediate the differential expression of a novel lncRNA that acts on MAOA expression to regulate impulsive-aggressive behaviours.

Background Childhood maltreatment interacts with a functional polymorphism in the monoamine oxidase A (MAOA) gene promoter region to modify the risk of aggressive behaviour. In females, the high-expressing variant (MAOA-L) interacts with maltreatment, whereas in males it is the low-expressing variant (MAOA-S) that interacts with maltreatment, highlighting a key sex-difference in the biology of aggression. It has been suggested that epigenetic processes, such as DNA methylation, may be one of the biological mechanisms underlying such gene-environment interactions. We investigated whether MAOA-uVNTR genotype, and methylation in a region spanning the MAOA first exon and part of the first intron, moderated associations between childhood physical and sexual abuse and aggressive behaviours in women and men. Methods A sample of 117 Swedish women and 77 men completed standardized diagnostic interviews, questionnaires to report maltreatment and aggressive behaviours, and provided saliva samples for DNA extraction. The MAOA-uVNTR polymorphism was genotyped, and methylation of a region of interest in MAOA (ChrX: 43,515,544 - 43,515,991) was analyzed. Results In women who experienced childhood maltreatment, MAOA-L and lower exonic methylation were associated with an increased number of aggressive behaviours. By contrast, among men who had experienced maltreatment, MAOA-S and higher exonic as well as lower intronic methylation were associated with an increased number of aggressive behaviors. Discussion Our study offers initial evidence that altered DNA methylation of MAOA may be one underlying biological mechanism accounting for gene-environment interactions of MAOA in aggressive behaviour. Further, our findings highlight the importance of considering sex-differences in the pathophysiology of aggression.

Background Epigenetic mechanisms are candidate moderators of the effect of maltreatment on brain and behavior. Interactions between maltreatment and the monoamine oxidase A upstream variable number tandem repeat genotype (MAOA‐uVNTR) are associated with alcohol‐related problems. However, presently it is not known whether DNA methylation moderates this association. The study focused on 53 young adult males and aimed to determine whether MAOA methylation moderated the association of alcohol‐related problems with the interaction of MAOA‐uVNTR and maltreatment, and whether alcohol consumption moderated the association of MAOA methylation with the interaction of MAOA‐uVNTR and maltreatment. Methods MAOA‐uVNTR genotypes with ≤ 3 and > 3 repeats were categorized as short (S) and long (L), respectively. Data on maltreatment were obtained retrospectively, using self‐reported questionnaires. DNA methylation of 16 candidate CpGs within part of the MAOA first exon and intron was assessed and grouped based on principal component analyses. Alcohol‐related problems were assessed using the Alcohol Use Disorders Identification Test (AUDIT). Alcohol consumption was measured using AUDIT‐C. Moderation effects were assessed and probed using the moderated moderation model and Johnson–Neyman's method, respectively. Results Carriers of the S allele, who experienced maltreatment and displayed lower Component 1 (mean of CpGs 13–16 in the first intron) MAOA methylation levels, reported higher AUDIT score in contrast to L‐allele carriers. Carriers of the S allele, who reported higher AUDIT‐C score and experienced maltreatment, displayed lower Component 3 (mean of CpGs 2–6 in the first exon) MAOA methylation levels than L‐allele carriers. Conclusions Intronic methylation moderated the association of alcohol‐related problems with the interaction of MAOA‐uVNTR and maltreatment. Alcohol consumption moderated the association of exonic methylation with the interaction of MAOA‐uVNTR and maltreatment. These results suggest that epigenetic factors as well as genotype and maltreatment play a role in the development of alcohol misuse among young adult males.

Background Some evidence suggests that the prevalence of Borderline Personality Disorder (BPD) is elevated among male criminal offenders. It is not presently known whether offending, and violent offending, are limited to those presenting comorbid Antisocial Personality Disorder (ASPD) who have a childhood history of conduct problems and whether offending is linked to psychopathic traits. Methods A community sample of 311 males followed from age 6 to 33 years, one third of whom had a criminal charge between ages 18 and 24, completed diagnostic interviews and the Psychopathy Checklist-Revised interview. Information on childhood included parent-reported family characteristics and teacher-rated of hurtful and uncaring behaviours, conduct problems, hyperactivity and inattention, and anxiety at age 6, 10, and 12 years. Health files were obtained as were records of criminal convictions from age 12 to 33. Results At age 33, 4% of the men presented BPD and not ASPD, 16% ASPD and not BPD, 8% BPD + ASPD, and 72% neither disorder (ND). Comorbid disorders were common: BPD were distinguished by high levels of anxiety disorders, BPD and BPD + ASPD by depression disorders, and BPD, BPD + ASPD, and ASPD by substance dependence. Official files indicated use of health services by all participants. One-third of participants with BPD and BPD + ASPD acquired a diagnosis of a personality disorder. More than one-third of participants with BPD + ASPD obtained scores indicative of the syndrome of psychopathy. Convictions for violent crimes varied across groups: In adolescence, BPD none, BPD + ASPD 16%, ASPD 16%, and ND 3.6%; from age 18 to 33, BPD 18%, ASPD 19%, BPD + ASPD 52%, and ND 4.4%. Offenders with BPD + ASPD were convicted, on average, for four times more violent crimes than offenders with ASPD and seven times more than ND offenders. In childhood, men with BPD + ASPD and with ASPD had obtained similarly elevated ratings for disruptive behaviours as compared to ND. Conclusion BPD comorbid with ASPD was associated with violent criminal offending in adolescence and most strongly in adulthood, elevated levels of psychopathic traits, and childhood disruptive behaviour. BPD showed similar characteristics but to a much less degree. Electronic supplementary material The online version of this article (10.1186/s40479-017-0076-2) contains supplementary material, which is available to authorized users.

Purpose Psychopathic traits are associated with multiple negative outcomes. The present prospective, longitudinal study identified associations of childhood factors with adult psychopathy scores. Methods 311 men, aged, on average, 33 years, were assessed using the Psychopathy Checklist-Revised (PCL-R). Predictors included neighbourhood deprivation, parents' characteristics, teacher ratings of behaviour at ages 6, 10 and 12, and academic performance at age 12. Hierarchical linear regression models were computed to identify predictors at different ages of PCL-R total and facet scores. Results Age 33 PCL-R total and facet scores were significantly, and independently, associated with father's and mother's criminality and mother's age at participant's birth when teacher ratings of childhood behaviours and mathematics marks were included in the models. Anxiety was negatively associated with facet 1 scores at age 6. At age 12, 22% of the variance in facet 2 scores was predicted by father's violent convictions, mother's age and criminal charges, and reactive aggression. Facet 3 scores were associated with mother's age (marginally), inattention, and reactive aggression. Facet 4 scores were associated with father's violent criminality, mother's age, conduct problems, inattention, and reactive aggression. Conclusion Etiological research and prevention programs should focus on antecedents of psychopathic traits present in early childhood.