Search

Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (40-48%). The International Cannabis Consortium was established with the aim to identify genetic risk variants of cannabis use. We conducted a meta-analysis of genome-wide association data of 13 cohorts (N=32 330) and four replication samples (N=5627). In addition, we performed a gene-based test of association, estimated single-nucleotide polymorphism (SNP)-based heritability and explored the genetic correlation between lifetime cannabis use and cigarette use using LD score regression. No individual SNPs reached genome-wide significance. Nonetheless, gene-based tests identified four genes significantly associated with lifetime cannabis use: NCAM1, CADM2, SCOC and KCNT2. Previous studies reported associations of NCAM1 with cigarette smoking and other substance use, and those of CADM2 with body mass index, processing speed and autism disorders, which are phenotypes previously reported to be associated with cannabis use. Furthermore, we showed that, combined across the genome, all common SNPs explained 13-20% (P

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGG overall ) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGG overall . The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E-06), PCDH7 (P = 2.0E-06), and IPO13 (P = 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (r g ) among rater-specific assessment of AGG ranged from r g  = 0.46 between self- and teacher-assessment to r g  = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong r g s with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range [Formula: see text]: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (r g  = ~-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range [Formula: see text]: 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG., (© 2021. The Author(s).)

Compelling evidence supports alterations in gut microbial diversity, bacterial composition, and/or relative abundance of several bacterial taxa in attention-deficit/hyperactivity disorder (ADHD). However, findings for ADHD are inconsistent among studies, and specific gut microbiome signatures for the disorder remain unknown. Given that previous studies have mainly focused on the pediatric form of the disorder and involved small sample sizes, we conducted the largest study to date to compare the gastrointestinal microbiome composition in 100 medication-naïve adults with ADHD and 100 sex-matched healthy controls. We found evidence that ADHD subjects have differences in the relative abundance of several microbial taxa. At the family level, our data support a lower relative abundance of Gracilibacteraceae and higher levels of Selenomonadaceae and Veillonellaceae in adults with ADHD. In addition, the ADHD group showed higher levels of Dialister and Megamonas and lower abundance of Anaerotaenia and Gracilibacter at the genus level. All four selected genera explained 15% of the variance of ADHD, and this microbial signature achieved an overall sensitivity of 74% and a specificity of 71% for distinguishing between ADHD patients and healthy controls. We also tested whether the selected genera correlate with age, body mass index (BMI), or scores of the ADHD rating scale but found no evidence of correlation between genera relative abundance and any of the selected traits. These results are in line with recent studies supporting gut microbiome alterations in neurodevelopment disorders, but further studies are needed to elucidate the role of the gut microbiota on the ADHD across the lifespan and its contribution to the persistence of the disorder from childhood to adulthood.

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder that often persists into adulthood. There is growing evidence that epigenetic dysregulation participates in ADHD. Given that only a limited number of epigenome-wide association studies (EWASs) of ADHD have been conducted so far and they have mainly focused on pediatric and population-based samples, we performed an EWAS in a clinical sample of adults with ADHD. We report one CpG site and four regions differentially methylated between patients and controls, which are located in or near genes previously involved in autoimmune diseases, cancer or neuroticism. Our sensitivity analyses indicate that smoking status is not responsible for these results and that polygenic risk burden for ADHD does not greatly impact the signatures identified. Additionally, we show an overlap of our EWAS findings with genetic signatures previously described for ADHD and with epigenetic signatures for smoking behavior and maternal smoking. These findings support a role of DNA methylation in ADHD and emphasize the need for additional efforts in larger samples to clarify the role of epigenetic mechanisms on ADHD across the lifespan.

Genetic factors are strongly implicated in the susceptibility to develop externalizing syndromes such as attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder, conduct disorder, and substance use disorder (SUD). Variants in the ADGRL3 (LPHN3) gene predispose to ADHD and predict ADHD severity, disruptive behaviors comorbidity, long-term outcome, and response to treatment. In this study, we investigated whether variants within ADGRL3 are associated with SUD, a disorder that is frequently co-morbid with ADHD. Using family-based, case-control, and longitudinal samples from disparate regions of the world (n = 2698), recruited either for clinical, genetic epidemiological or pharmacogenomic studies of ADHD, we assembled recursive-partitioning frameworks (classification tree analyses) with clinical, demographic, and ADGRL3 genetic information to predict SUD susceptibility. Our results indicate that SUD can be efficiently and robustly predicted in ADHD participants. The genetic models used remained highly efficient in predicting SUD in a large sample of individuals with severe SUD from a psychiatric institution that were not ascertained on the basis of ADHD diagnosis, thus identifying ADGRL3 as a risk gene for SUD. Recursive-partitioning analyses revealed that rs4860437 was the predominant predictive variant. This new methodological approach offers novel insights into higher order predictive interactions and offers a unique opportunity for translational application in the clinical assessment of patients at high risk for SUD.