Genetic correlation, pleiotropy, and causal associations between substance use and psychiatric disorder

Abstract

Background Substance use occurs at a high rate in persons with a psychiatric disorder. Genetically informative studies have the potential to elucidate the etiology of these phenomena. Recent developments in genome-wide association studies (GWAS) allow new avenues of investigation. Method Using results of GWAS meta-analyses, we performed a factor analysis of the genetic correlation structure, a genome-wide search of shared loci, and causally informative tests for six substance use phenotypes (four smoking, one alcohol, and one cannabis use) and five psychiatric disorders (ADHD, anorexia, depression, bipolar disorder, and schizophrenia). Results Two correlated externalizing and internalizing/psychosis factor were found, although model fit was beneath conventional standards. Of 458 loci reported in previous univariate GWAS of substance use and psychiatric disorders, about 50% (230 loci) were pleiotropic with additional 111 pleiotropic loci not reported from past GWAS. Of the 341 pleiotropic loci, 152 were associated with both substance use and psychiatric disorders, implicating neurodevelopment, cell morphogenesis, biological adhesion pathways, and enrichment in 13 different brain tissues. Seventy-five and 114 pleiotropic loci were specific to either psychiatric disorders or substance use phenotypes, implicating neuronal signaling pathway and clathrin-binding functions/structures, respectively. No consistent evidence for phenotypic causation was found across different Mendelian randomization methods. Conclusions Genetic etiology of substance use and psychiatric disorders is highly pleiotropic and involves shared neurodevelopmental path, neurotransmission, and intracellular trafficking. In aggregate, the patterns are not consistent with vertical pleiotropy, more likely reflecting horizontal pleiotropy or more complex forms of phenotypic causation.

Genetic overlap and causality between substance use disorder and attention‐deficit and hyperactivity disorder

“…For the first time, we provide evidence of a common genetic background between lifetime cannabis use, alcohol dependence and smoking initiation in the general population and in subjects with ADHD and support previous findings of a causal relationship for the liability to ADHD on the risk for lifetime cannabis use, smoking initiation, age of smoking initiation and cigarettes per day. These results are in agreement with epidemiological evidence showing increased risk and higher severity of substance use, abuse and dependence in ADHD subjects (Groenman et al, 2013;Groenman et al, 2017;van de Glind et al, 2014;van Emmerik-van Oortmerssen et al, 2012;Wilens & Morrison, 2012) and support previous reports showing that the liability to ADHD is on the causal pathway to smoking and SUD (Artigas Soler et al, 2019;Treur et al, 2019;Jang et al, 2020).…”

“…MR results should be interpreted taking into consideration the evidence of horizontal pleiotropy for some smoking-related phenotypes. These findings, however, add additional evidence to the growing literature showing that individuals with ADHD are at higher risk of initiating smoking at younger ages and of being heavier smokers, as well as the existence of a causal effect of smoking initiation on ADHD (Jang et al, 2020;Treur et al, 2019).…”

Comorbid Bipolar and Alcohol Use Disorder—A Therapeutic Challenge

“…Candidate genes include a shared polymorphism of the aldehyde hydrogenase and alcohol dehydrogenase (44), a Ser23Cys (rs6318) polymorphism of the 5HT2C gene (in female bipolar patients) (45) and a VAL-158-MET polymorphism of the cathechol-o-methyltransferase (COMT) (46) impacting on the monoamine metabolism. However, recent GWAS finding pointed out that the correlation between genetic alterations and psychiatric disorders is not simple; the genetic connection of substance use and psychiatric disorders is rather highly pleiotropic and involves shared neurodevelopmental path, neurotransmission, and intracellular trafficking (47).…”

PIP5K2A (rs10828317) polymorphism in patients with alcohol dependence and affective disorders

“…Существует гипотеза о том, что оба расстройства имеют общую нейробиологическую основу [4]. Анализ данных полногеномного поиска ассоциаций (genome-wide association studies, GWAS) демонстрирует большой вклад общих вариантов генов в риск развития как зависимости от психоактивных веществ, так и психических расстройств [5].…”

“…Кроме того, дисбаланс ряда компонентов PI3K/AKT1-сигнального пути (PIK3C3, PIP5K2A, PLCG1, SYNJ1, IMPA2, AKT1, GSK3B, TCF4), которые активируются как нейротрофическими факторами, так и через глутаматные рецепторы, выявляется при депрессивных расстройствах и алкогольной зависимости [5].…”