Genome-wide association study implicatesCHRNA2in cannabis use disorder

Abstract

2 Introductory paragraphCannabis is among the most frequently used illicit psychoactive substance worldwide 1 . Life time use was reported among 35-40% of adults in Denmark 2 and the United States 3 . Cannabis use is increasing in the population 4-6 and among users around 9% become dependent 7 . The genetic risk component is high with heritability estimates of 51 8 -70% 9 . Here we report the first genome-wide significant risk locus for cannabis use disorder (CUD, ) that replicates in an independent population (P replication =3.27x10 -3 , P metaanalysis =9.09x10 -12 ) based on genome-wide association study (GWAS) of 2,387 cases and 48,985 controls followed by replication in 5,501 cases and 301,041 controls. The index SNP (rs56372821) is a strong eQTL for CHRNA2 and analyses of the genetic regulated gene expressions identified significant association of CHRNA2 expression in cerebellum with CUD, indicating potential therapeutic use in CUD of compounds with agonistic effect on CHRNA2.At the polygenic level analyses revealed a significant decrease in the risk of CUD with increased load of variants associated with cognitive performance. MainOverall the prevalence of diagnosed CUD in the population has been estimated to 1-1.5% among Europeans 10,11 and Americans 5 . CUD is associated with a range of adverse health problems 12,13 including risk of psychosis 14,15 , bipolar disorder 16 , anxiety disorder 17 and cognitive impairment with more persistent use associated with greater decline 18 . Estimates of the heritability for cannabis use initiation and life-time cannabis use, with respect to the amount of variance explained by common variants (i.e. the SNP heritability), has been estimated to 0.06 19 -0.2 20 . Four GWASs related to cannabis use have been conducted without genome-wide significant findings: one study of cannabis dependence 21 and three studies of lifetime cannabis use 19,20,22 . In addition, two recent GWASs have reported genome-wide significant associations, albeit with negative or ambiguous replication 3 results: a study of DSM-IV cannabis dependence criterion counts in a combined sample of 14,754 European Americans and African Americans 23 , which reported three genome-wide significant loci associated with cannabis use severity; and a GWAS of cannabis dependence of 2,080 European cases and 6,435 controls which identified one genome-wide significant locus 24 .Here we present results from a GWAS and subsequent replication based on analyses of the largest cohorts of diagnosed CUD reported so far. Individuals included in the discovery GWAS come from the Danish nation-wide population based cohort collected by the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) 25 . The iPSYCH cohort was ascertained to study six major psychiatric disorders (schizophrenia, bipolar disorder, major depressive disorder, attentiondeficit hyperactivity disorder (ADHD), anorexia nervosa and autism spectrum disorder) and consists of 79,492 genotyped individuals. The present GWAS was based on 2,387 ind...

Prenatal cannabis exposure and childhood outcomes: Results from the ABCD study

“…45 Third, sustained use during pregnancy may reflect a genetic predisposition to the observed negative outcomes, and the resulting associations may simply reflect pleiotropy. 46,47 However, controlling for maternal behavior and genetic susceptibility did not eliminate associations (Supplemental eTables 2-3, 15). Fourth, associations may be attributable to an unmeasured common variable (e.g., paternal germline exposure to cannabis) 48 or an alternate derivation of an included confounder.…”

Exploring Phenotypic and Genetic Overlap Between Cannabis Use and Schizotypy

“…Genomewide association analyses were conducted on six psychosis and two cannabis phenotypes within the UKB. The remaining phenotypes were operationalized using GWAS summary statistics from Demontis et al (2019), Ortega-Alonso et al 2017, and Pasman et al (2018). An overview of all phenotypes analyzed is provided in Table 1.…”

“…Both phenotypes were measured on an ordinal scale. Additionally, we used GWAS summary statistics of CUD by Demontis et al (2019) with a sample size of 51,372 (2387 cases, 48,985 controls). Participants were all part of the iPSYCH database in Denmark, and cases were defined as having an International Classification of Diseases, Tenth Revision diagnosis of a CUD as confirmed by the Danish Psychiatric Central Research Register.…”

Genome-wide Association Study of Anxiety and Stress-related Disorders in the iPSYCH Cohort

“…We therefore aimed to adjust for mental comorbidity in a framework of sensitivity analyses. With regards to the study design we ran two additional models, one that randomly selected a subset of ASRD cases mimicking the comorbidity patterns observed in population-based samples (following the idea of a "weighted design") and a second that included psychiatric phenotypes as covariates 52 . We also removed individuals with comorbid depression in an attempt to identify the impact of this subgroup on the overall association.…”