Abstract
Stimulant dependence is heritable, but specific genetic factors underlying the trait have not been identified. A genome-wide association study for stimulant dependence was performed in a discovery cohort of African- (AA) and European-ancestry (EA) subjects ascertained for genetic studies of alcohol, opioid, and cocaine use disorders. The sample comprised individuals with DSM-IV stimulant dependence (393 EA cases, 5288 EA controls; 155 AA cases, 5603 AA controls). An independent cohort from the family-based Collaborative Study on the Genetics of Alcoholism (532 EA cases, 7635 EA controls; 53 AA cases, AA 3352 controls) was used for replication. One variant in SLC25A16 (rs2394476, p = 3.42 × 10−10, odds ratio [OR] = 3.70) was GWS in AAs. Four other loci showed suggestive evidence, including KCNA4 in AAs (rs11500237, p = 2.99 × 10−7, OR = 2.31) which encodes one of the potassium voltage-gated channel protein that has been linked to several other substance use disorders, and CPVL in the combined population groups (rs1176440, p = 3.05 × 10−7, OR = 1.35), whose expression was previously shown to be upregulated in the prefrontal cortex from users of cocaine, cannabis, and phencyclidine. Analysis of the top GWAS signals revealed a significant enrichment with nicotinic acetylcholine receptor genes (adjusted p = 0.04) and significant pleiotropy between stimulant dependence and alcohol dependence in EAs (padj = 3.6 × 10−3), an anxiety disorder in EAs (padj = 2.1 × 10−4), and ADHD in both AAs (padj = 3.0 × 10−33) and EAs (padj = 6.7 × 10−35). Our results implicate novel genes and pathways as having roles in the etiology of stimulant dependence.
Highlights
Amphetamines have been used to treat a variety of conditions including asthma, obesity, and attention-deficit/hyperactivity disorder (ADHD)[1]
All participants were interviewed using the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA)[12], which we have previously shown to be reliable with respect to both diagnoses and diagnostic criteria[13,14], to derive lifetime diagnoses for dependence on these and other substances and other major psychiatric disorders
Pleiotropy analyses Because > 70% of persons with stimulant use disorder have comorbid alcohol or cannabis use disorders and more than one-third have anxiety disorder[26], and amphetamine-related medications are used to treat attention deficit hyperactivity disorder (ADHD)[27], we investigated the possibility of pleiotropy using genome-wide association study (GWAS) summary statistics that were available in 2017 from the Psychiatric Genetics Consortium on LD Hub[28] for ADHD29, alcohol dependence[30], and anxiety disorder[31]
Summary
Amphetamines have been used to treat a variety of conditions including asthma, obesity, and attention-deficit/hyperactivity disorder (ADHD)[1]. Amphetamines and other stimulants increase alertness and physical and mental performance and reduce drowsiness. The mechanism by which stimulants exert these effects appears to involve the increase in the level of dopamine (DA) in the striatum that results from their competitive inhibition of DA uptake, which facilitates DA release from synaptic vesicles, and their promotion of reverse transport. Emergency room visits related to stimulant abuse increased from 2303 in 2004 to 17,272 in 20114. In 2015, there were ∼5.3 million non-medical users of prescription stimulants among individuals age 12 and older in the United States[5]. A meta-analysis of published neuroimaging data in individuals meeting DSM-IV criteria for stimulant dependence showed reduced gray matter in prefrontal cortical regions that are associated with selfregulation and self-awareness[6]
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