Short communication: Genetic association between schizophrenia and cannabis use

doi:10.1016/j.drugalcdep.2016.09.022

Drug and Alcohol Dependence

Volume 171, 1 February 2017, Pages 117-121

https://doi.org/10.1016/j.drugalcdep.2016.09.022 Get rights and content

Highlights

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Polygenic risk scores for schizophrenia are associated with cannabis use.
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There is a significant genetic correlation between schizophrenia and cannabis use.
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Common genetic variants underlying schizophrenia and cannabis use partly overlap.

Abstract

Background and aim

Previous studies have shown a relationship between schizophrenia and cannabis use. As both traits are substantially heritable, a shared genetic liability could explain the association. We use two recently developed genomics methods to investigate the genetic overlap between schizophrenia and cannabis use.

Methods

Firstly, polygenic risk scores for schizophrenia were created based on summary statistics from the largest schizophrenia genome-wide association (GWA) meta-analysis to date. We analysed the association between these schizophrenia polygenic scores and multiple cannabis use phenotypes (lifetime use, regular use, age at initiation, and quantity and frequency of use) in a sample of 6,931 individuals. Secondly, we applied LD-score regression to the GWA summary statistics of schizophrenia and lifetime cannabis use to calculate the genome-wide genetic correlation.

Results

Polygenic risk scores for schizophrenia were significantly (α < 0.05) associated with five of the eight cannabis use phenotypes, including lifetime use, regular use, and quantity of use, with risk scores explaining up to 0.5% of the variance. Associations were not significant for age at initiation of use and two measures of frequency of use analyzed in lifetime users only, potentially because of reduced power due to a smaller sample size. The LD-score regression revealed a significant genetic correlation of r_g = 0.22 (SE = 0.07, p = 0.003) between schizophrenia and lifetime cannabis use.

Conclusions

Common genetic variants underlying schizophrenia and lifetime cannabis use are partly overlapping. Individuals with a stronger genetic predisposition to schizophrenia are more likely to initiate cannabis use, use cannabis more regularly, and consume more cannabis over their lifetime.

Introduction

Numerous studies have observed an association between schizophrenia and cannabis use (McGrath et al., 2010, Moore et al., 2007, Morrison et al., 2009, van Os et al., 2002), although the direction of causation is still under debate. As both traits are substantially heritable, with heritability estimates of around 45% for lifetime cannabis use (Verweij et al., 2010) and 80% for schizophrenia (Sullivan et al., 2003), a shared genetic liability could explain the relationship. With methodological advances in molecular genetics and increased sample sizes in genome-wide association (GWA) studies it has become viable to use measured genetic variation among individuals to examine this relationship. Power et al. (2014) used results from the 2013 schizophrenia GWA study that included 13,833 schizophrenia cases and 18,310 controls (Ripke et al., 2013) to predict cannabis use in a target sample of 2082 Australian individuals. They found that the genetic variants underlying schizophrenia significantly predicted lifetime cannabis use, and quantity of use within users (maximum variance explained of R² = 0.47% and 0.85%, respectively), but not age at initiation of cannabis use.

Here, we used two recently developed methods to further investigate the genetic covariation between both traits. Firstly we performed a polygenic risk analysis to determine the extent to which common genetic variants that affect the risk of schizophrenia predict various measures of cannabis use. Based on the results from the latest and largest schizophrenia GWA study (with up to 36,989 schizophrenia cases and 113,075 controls; Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014) we generated genetic risk scores for schizophrenia in a large independent target sample from the Netherlands. We used LDpred to create the risk score, a method shown to have greater prediction accuracy than the conventional risk prediction approach involving linkage disequilibrium (LD) pruning followed by P-value thresholding (Vilhjalmsson et al., 2015). We then determined the association of the genetic risk score for schizophrenia with various cannabis use phenotypes, including lifetime (ever versus never) use, regular use, age at initiation of use, and quantity and frequency of use.

Secondly, we applied LD-score regression to the summary statistics of the largest GWA meta-analyses of schizophrenia (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014) and lifetime cannabis use (Stringer et al., 2016) to estimate the genome-wide genetic correlation. To our knowledge, this is the first study to determine the strength of the genetic correlation between schizophrenia and cannabis use; the information can provide useful etiological insights into the relationships between the two traits.

Section snippets

Polygenic risk prediction analysis

The target sample comprised 6,931 participants (64.1% females) from 3,244 twin families registered at the Netherlands Twin Registry (Boomsma et al., 2006). Participants were between 18 and 94 years old (M = 43.0, SD = 15.7). Data on cannabis use were obtained from five waves of self-report questionnaires sent out between 1993 and 2013 (see Willemsen et al., 2013). For subjects who participated in more than one wave we used data from their last questionnaire.

We analysed various cannabis use

Results

Individuals from more urbanised residential areas were more likely to have used cannabis (Nagelkerke R² = 3.3%, p < 0.001), whereas socio-economic status was not associated with lifetime cannabis use (p = 0.35). Polygenic risk scores for schizophrenia were significantly (α < 0.05) associated with five of the eight tested cannabis use phenotypes in the target sample, including lifetime use, regular use, and quantity of use, with risk scores explaining up to 0.5% of the variance (see Table 1). This

Discussion

Overall, results from our two analyses support the hypothesis that the association between schizophrenia and cannabis use is partly due to a shared genetic etiology. Polygenic risk scores based on the SNP effect sizes from a schizophrenia GWA meta-analysis significantly predicted most of the cannabis use variables in our target sample. Individuals with an increased genetic predisposition to schizophrenia were more likely to have initiated cannabis use, to have used cannabis regularly, and to

Contributors

KJHV was responsible for the study concept and the design of the study. GW, DIB and JMV contributed to the data acquisition. KJHV performed the data analyses with assistance from AA, MGN, ASC, LL and JJH. KJHV drafted the manuscript. AA, MGN, ASC, LL, HHMD, CCM, NAG, GW, JJH, DIB and JMV provided critical revision of the manuscript for important intellectual content. All authors approved the final version for publication.

Conflict of interest

No conflict declared.

Role of funding source

Nothing declare.

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¹: Details of the International Cannabis Consortium can be found in Appendix A.

View full text

Short communication: Genetic association between schizophrenia and cannabis use

Highlights

Abstract

Background and aim

Methods

Results

Conclusions

Introduction

Section snippets

Polygenic risk prediction analysis

Results

Discussion

Contributors

Conflict of interest

Role of funding source

Lancet (London England)

Am. J. Hum. Genet.

Population structure, migration, and diversifying selection in The Netherlands

Eur. J. Hum. Genet.

Netherlands twin register: from twins to twin families

Twin Res. Hum. Genet.

An atlas of genetic correlations across human diseases and traits

Nat. Genet.

LD score regression distinguishes confounding from polygenicity in genome-wide association studies

Nat. Genet.

Is socioeconomic status in early life associated with drug use? A systematic review of the evidence

Drug Alcohol Rev.

Do cannabis and urbanicity co-participate in causing psychosis? Evidence from a 10-year follow-up cohort study

Psychol. Med.

Developmental trajectories of substance use from early to late adolescence: a comparison of rural and urban youth

J. Stud. Alcohol Drugs

Association between cannabis use and psychosis-related outcomes using sibling pair analysis in a cohort of young adults

Arch. Gen. Psychiatry

MZ twin pairs or MZ singletons in population family-based GWAS? More power in pairs

Mol. Psychiatry