Abstract Background Attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUDs) commonly co-occur and have overlapping genetic liabilities. Less is known regarding the phenomenology and genetics of ADHD in a cohort enriched for SUDs and the extent to which ADHD genetic liability contributes to SUD risk when controlling for substance specific genetic risk. Methods We used data from the Yale-Penn cohort, which comprises ~14,000 individuals ascertained for SUDs and/or as controls. Psychiatric and substance use phenotypes were ascertained from the semi-structured assessment for drug dependence and alcohol survey for all participants. Polygenic scores (PGSs) were developed for ADHD and multiple substance-related traits using summary statistics from large genome-wide association studies on participants with genetic data (N = 10,275). Results Participants who met DSM-IV Criteria for ADHD had significantly increased odds for every DSM-5 SUD analyzed, greater polysubstance use, and younger age of onset of substance use. Among participants of European-like ancestry, ADHD PGS was associated with multiple SUDs, even after controlling for substance-specific PGS. Of the substance-related PGS, only the smoking initiation PGS was associated with ADHD diagnosis and criterion count and only among individuals of European-like ancestry. Conclusions In this sample, ADHD was associated with increased risk for SUDs and earlier onset of substance use. Additionally, genetic liability to ADHD was independently associated with multiple SUDs and SUD criteria counts. PGS for substance-related traits tended to be less significantly associated with ADHD. Further studies in large, diverse populations are needed to enhance our understanding of these associations.
Michael R. Setzer, R. Kember, Emily E. Hartwell et al.· Psychological Medicine· 0 citations
Abstract Background Genetic and environmental factors, and psychiatric traits, contribute to risk for alcohol use disorder (AUD) and other substance use disorders (SUDs) and traits. Weighing the importance of the different kinds of contribution to risk is important in understanding risk prediction – which may be important clinically -- and in formulating prevention and treatment strategies. Aims & Objectives We worked to quantify the contribution of environmental, psychiatric, and genetic factors to AUD across different ancestries. Although polygenic risk prediction represents an important future application, its utility may be enhanced when considered in the context of environmental predictors. We used deeply phenotyped African- and European-ancestry (AFR and EUR) samples to examine how genetic, psychiatric, and environmental factors predict AUD criterion count. Method We analyzed data from 11,021 individuals in the Yale-Penn Study sample, 5,843 AFR and 5,178 EUR. Polygenic risk scores (PRSs) were generated from genome-wide association studies (GWAS) of problematic alcohol use (PAU). Generalized linear regression and relative importance analyses determined the independent and interactive effects of environmental and genetic factors on AUD, considering criterion count rather than binary diagnosis to maximize power. Results PRSs for PAU were positively associated with AUD criterion count in both ancestries and predicted 1.9% of variance in AUD criterion count in the EUR sample and 1.3% in the AFR sample. A combination of education, substance use in the household before age 13, annual household income, and male sex explained 73.1% of the variance in AUD criterion count in the AFR sample and 58.9% in EUR. Among examined psychiatric disorders, posttraumatic stress disorder explained the most variance (10.0% in AFR, 9.4% in EUR), followed by anxiety disorders (3.4% in AFR, 6.2% in EUR) and major depressive disorder (1.3% in AFR, 2.1% in EUR). In the EUR sample, education level moderated the relationship between PRS for PAU and AUD criterion count. We completed similar analyses for several other SUDs, including opioid use disorder (OUD), which will also be discussed. Discussion & Conclusions In both AFR and EUR, environmental factors explained most of the variance in AUD criterion count, but polygenic risk was also a statistically significant predictor. The pattern of results for OUD was similar. These findings may help inform clinical, research, and policy efforts to mitigate AUD and OUD risk.
P. Na, J. Deak, D. Levey et al.· International Journal of Neu...· 0 citations
Migraine is a leading cause of disability, yet preventive treatment remains largely empirical despite the availability of several mechanistically distinct therapies. Genetic data can clarify mechanisms and therapeutic hypotheses when association signals are integrated with molecular and clinical data. We meta-analyzed migraine GWAS data from 12 European ancestry cohorts (206,893 cases and 2,093,175 controls) and four African ancestry cohorts (22,115 cases and 178,626 controls). We identified 311 lead variants in European-ancestry analyses and 316 lead variants in trans-ancestry analysis. Fine-mapping and transcriptome-wide analyses prioritized variants and genes implicated in sensory neuronal signaling, vascular tone, and immune regulation, with convergent evidence at several established loci including TRPM8 and PHACTR1. Drug-repurposing analyses identified therapeutic targets and compounds, including established migraine treatments and candidates requiring experimental validation. Genetic correlations, Mendelian randomization, and a phenome-wide scan linked migraine liability to psychiatric, pain, and gastrointestinal phenotypes. Together, these findings expand the known genetic architecture of migraine across ancestries and provide a genetics-led map connecting association signals with biological pathways, multimorbidity and candidate therapeutic mechanisms, providing a foundation for future functional and translational studies.
C. Overstreet, M. Galimberti, K. Harsan et al.· medRxiv· 0 citations
OBJECTIVE
Suicidal ideation (SI) and suicide attempt (SA) are both influenced by genetic, behavioral, and environmental factors. Alcohol use disorder (AUD) and adverse childhood experiences (ACEs) may mediate or moderate the effects of genetic liability for suicidality.
METHODS
Using data from 10,275 participants (43.8% female; 47.2% African-like genetic ancestry [AFR], 52.8% European-like genetic ancestry [EUR]), we tested whether polygenic scores (PGS) for SI and SA predicted lifetime suicidality outcomes. We evaluated whether AUD partially accounted for these associations and ACEs moderated the direct and indirect associations.
RESULTS
The SA PGS was significantly associated with SA (AFR: b = 0.36, SE = 0.01; EUR: b = 0.17, SE = 0.01; both ps < 2e-16), but the SI PGS was not associated with SI (p > 0.55). AUD statistically mediated the association between the SA PGS and SA, accounting for approximately 2% of the total association in AFR individuals and 10% in EUR individuals (both ps < 2e-16). Notably, the proportion of the association that was accounted for by AUD decreased as ACEs exposure increased, from 4.30% to 0.54% in AFR individuals and from 13.31% to 3.44% in EUR individuals. In contrast, there was only very modest mediation and no moderated mediation for SI.
CONCLUSIONS
Particularly among individuals with lower ACEs exposure, AUD accounted for a meaningful proportion of the association between genetic liability to SA and lifetime SA. These findings highlight different correlates across suicidality phenotypes and suggest potential clinical relevance for AUD in the association between genetic liability and SA.
V. Wu, X. Qin, A. Ashley-Koch et al.· Journal of Affective Disorde...· 0 citations
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