DSM-5 cannabis use disorder: A phenotypic and genomic perspective

Abstract

Background

We explore the factor structure of DSM-5 cannabis use disorders, examine its prevalence across European- and African-American respondents as well as its genetic underpinnings, utilizing data from a genome-wide study of single nucleotide polymorphisms (SNPs). We also estimate the heritability of DSM-5 cannabis use disorders explained by these common SNPs.

Methods

Data on 3053 subjects reporting a lifetime history of cannabis use were utilized. Exploratory and confirmatory factor analyses were conducted to create a factor score, which was used in a genome-wide association analysis. p-values from the single SNP analysis were examined for evidence of gene-based association. The aggregate effect of all SNPs was also estimated using Genome-Wide Complex Traits Analysis.

Results

The unidimensionality of DSM-5 cannabis use disorder criteria was demonstrated. Comparing DSM-IV to DSM-5, a decrease in prevalence of cannabis use disorders was only noted in European-American respondents and was exceedingly modest. For the DSM-5 cannabis use disorders factor score, no SNP surpassed the genome-wide significance testing threshold. However, in the European-American subsample, gene-based association testing resulted in significant associations in 3 genes (C17orf58, BPTF and PPM1D) on chromosome 17q24. In aggregate, 21% of the variance in DSM-5 cannabis use disorders was explained by the genome-wide SNPs; however, this estimate was not statistically significant.

Conclusions

DSM-5 cannabis use disorder represents a unidimensional construct, the prevalence of which is only modestly elevated above the DSM-IV version. Considerably larger sample sizes will be required to identify individual SNPs associated with cannabis use disorders and unequivocally establish its polygenic underpinnings.

Introduction

Cannabis is the most commonly used illicit psychoactive substance in developed nations (Degenhardt and Hall, 2012). While a majority of cannabis users do not report problems, 10–30% of those who ever use cannabis meet criteria for a lifetime history of cannabis abuse or dependence as defined by the fourth edition of the Diagnostic and Statistical Manual (DSM-IV; American Psychiatric Association, 1994). Recently, changes to the diagnostic criteria for substance use disorder have been made in DSM-5 (American Psychiatric Association, 2013), including several for the diagnosis of cannabis use disorders (Hasin et al., 2013). Across the broad range of substance use disorders, (i) the distinction between abuse and dependence has been replaced by a unidimensional symptom count, with endorsement of 2 or more symptoms resulting in a DSM-5 diagnosis of substance use disorder (endorsement of specific numbers of symptoms define a mild, moderate or severe diagnosis); (ii) the DSM-IV criterion of legal problems has been eliminated from the diagnostic repertoire; and (iii) a new criterion for the DSM-5, craving (a long held substance dependence criterion in the International Classification of Disease, ICD) has been added. More specifically for cannabis, withdrawal is now a criterion. A wealth of psychometric evaluations in epidemiological (Agrawal et al., 2008, Compton et al., 2009, Gillespie et al., 2005, Hartman et al., 2008, Hasin et al., 2012, Hasin et al., 2008, Langenbucher et al., 2004, Lynskey and Agrawal, 2007, Martin et al., 2006, Piontek et al., 2011, Wu et al., 2009, Wu et al., 2012) and clinical samples (Budney, 2006, Budney and Hughes, 2006) support these recommendations; however, the impact of these revisions on the prevalence of cannabis use disorders under the new DSM-5 classification remains largely unexplored. A recent study of Australian adults found a modest reduction in the rate of cannabis use disorder with the transition from DSM-IV to DSM-5 (Mewton et al., 2013), while another study of individuals with substance use disorders noted a modest increase of 4% (Peer et al., 2013).

Twin studies indicate that 50–60% of the variation in cannabis use disorders (abuse/dependence, variously defined using DSM-IIIR, DSM-IV and ICD) can be attributed to heritable influences (Verweij et al., 2010). Despite this robust heritability estimate, association studies for cannabis use disorders have largely failed to identify genetic variants of significant and replicable effect. A prior genome-wide association study (GWAS) of DSM-IV cannabis dependence, conducted in the sample used in this study, failed to identify genetic variants at a statistically significant level (Agrawal et al., 2011b). This has resulted in speculation regarding the biological underpinnings of cannabis use disorders; in particular, the question of whether common variation available in commercially available genome-wide arrays captures it (Sullivan et al., 2012).

Aggregating the effects of all single nucleotide polymorphisms (SNPs) on commercial arrays might quantify the overall role of common SNPs as well as causal variants in linkage disequilibrium (LD) with these SNPs on the trait of interest (Yang et al., 2010, Yang et al., 2011b). When significant, this would indicate that heritable variation in the trait is at least partially captured by these SNPs in a highly polygenic manner. Applying this methodology, investigators have successfully attributed 23–51% of the variation in current smoking, major depression, schizophrenia and human intelligence to genetic influences (Davies et al., 2011, Lee et al., 2012, Lubke et al., 2012).

The present study uses a multi-pronged phenotypic and genomic approach to evaluate, respectively, the architecture and genetic underpinnings of DSM-5 cannabis use disorders, defined as a quantitative phenotype. Instead of relying on a diagnostic measure, we first utilize item response models to construct a factor representing liability to DSM-5 cannabis use disorders, while accounting for sex and ethnic differences. Second, we use this psychometrically constructed factor score in a genome-wide association analysis. Finally, we evaluate whether genome-wide SNPs and putative causal variants in linkage disequilibrium with them explain a significant proportion of the heritable variation in DSM-5 cannabis use disorders.