Elsevier

Drug and Alcohol Dependence

Volume 190, 1 September 2018, Pages 143-150
Drug and Alcohol Dependence

Genetic vulnerability to schizophrenia is associated with cannabis use patterns during adolescence

https://doi.org/10.1016/j.drugalcdep.2018.05.024Get rights and content

Highlights

  • Evidence of a genetic overlap between schizophrenia (SCZ) and cannabis use pattern over time.

  • Lenient PRS thresholds for schizophrenia were associated with delayed cannabis use.

  • Stringent PRS thresholds were associated with a stronger increase in cannabis use.

  • No evidence for a genetic overlap between SCZ, alcohol, and smoking pattern over time.

Abstract

Background

Previously reported comorbidity between schizophrenia and substance use may be explained by shared underlying risk factors, such as genetic background. The aim of the present longitudinal study was to investigate how a genetic predisposition to schizophrenia was associated with patterns of substance use (cannabis use, smoking, alcohol use) during adolescence (comparing ages 13–16 with 16–20 years).

Method

Using piecewise latent growth curve modelling in a longitudinal adolescent cohort (RADAR-Y study, N = 372), we analyzed the association of polygenic risk scores for schizophrenia (PRS; p-value thresholds (pt) < 5e-8 to pt< 0.5) with increase in substance use over the years, including stratified analyses for gender. Significance thresholds were set to adjust for multiple testing using Bonferroni at p ≤ 0.001.

Results

High schizophrenia vulnerability was associated with a stronger increase in cannabis use at age 16–20 (PRS thresholds pt < 5e-5 and pt< 5e-4; pt < 5e-6 was marginally significant), whereas more lenient PRS thresholds (PRS thresholds pt< 5e-3 to pt< 0.5) showed the reverse association. For smoking and alcohol, no clear relations were found.

Conclusions

In conclusion, our findings support a relation between genetic risk to schizophrenia and prospective cannabis use patterns during adolescence. In contrast, no relation between alcohol and smoking was established.

Introduction

During early adolescence, many youths start using alcohol, tobacco, and cannabis after which substance use increases rapidly (e.g., Hibell et al., 2012; Van Laar et al., 2013). At the age of 12 years, 17% of Dutch adolescents reported lifetime alcohol use (de Looze et al., 2014), 6% had smoked at least once (Verdurmen et al., 2014) and 0.3% reported ever using cannabis (Van Laar et al., 2013). By the age of 16, these percentages of substance use had increased to 79.3%, 43%, and 26.9% for lifetime alcohol use, smoking, and cannabis use respectively. In addition to the use of specific substances, the frequency and intensity of use also increase during adolescence. For example, binge drinking in the past month (i.e., drinking five or more glasses on one occasion) increased from 47.2% at age 12 to 79.9% at age 16 among adolescents who drink alcohol (de Looze et al., 2014).

Earlier studies of adolescents and young adults have shown an association of mental health problems including schizophrenia, depression, and anxiety disorders, with substance use (e.g., Kendler et al., 2015; Moore et al., 2007; Schubart et al., 2011). More specifically, studies have shown that cannabis use (e.g., Arseneault et al., 2002; Kendler et al., 2015; Moore et al., 2007; Schubart et al., 2011) and cigarette smoking (de Leon and Diaz, 2005; McGrath et al., 2015; van Gastel et al., 2012, van Gastel et al., 2013) are associated with psychosis proneness. Also, high comorbidity between alcohol dependence and psychiatric disorders, in general, has been reported (e.g., Kessler et al., 1994).

Several possible mechanisms may explain the comorbidity between schizophrenia and substance use (e.g., Gage and Munafo, 2015; Hartz et al., 2018). 1) Substance use may lead to the onset of schizophrenia. 2) Schizophrenia may cause the development of substance addiction (the self-medication hypothesis), and 3) shared underlying risk factors, both environmental and genetic may predispose to schizophrenia and substance use such as is suggested for cannabis (Verweij et al., 2017). In the present study, we focus on the genetic background as the shared underlying risk factor. Genetic risk factors are relevant as both schizophrenia and substance use are heritable. The heritability estimates of schizophrenia are around 80% for (Sullivan et al., 2003) and 11–84% for substance use (Verweij et al., 2010; Ho and Tyndale, 2007; Goldman et al., 2005). Moreover, a large number of common variants of small genetic effects are involved in both traits (e.g., Ripke et al., 2013; Tobacco and Genetics Consortium, 2010; Stringer et al., 2016).

To investigate the genetic overlap between schizophrenia and substance use, polygenic risk scores (PRS) based on genome-wide association studies (GWAS) are used (Ripke et al., 2013). PRS is the weighted sum of all the alleles that either confer risk for or are protective against a specific disease (Purcell et al., 2007). PRS can be used to predict individual genetic risk for schizophrenia in a nonpatient sample. More specifically, PRS can be constructed by multiple-testing different sets of single nucleotide polymorphisms (SNPs) selected at various thresholds of significance (i.e., in the present study: p-value thresholds 5e-8 to 0.5 were used to investigate the full range of genetic background).

Recent studies have shown a genetic overlap between schizophrenia PRS and substance use, particularly cannabis use. More specifically, an association between schizophrenia genetic risk alleles and cannabis use was found among 2082 adults (mean age 41.3 years for users and 53.0 years for non-users) (Power et al., 2014). Recently, Carey et al. (2016) and Verweij et al. (2017) replicated these findings. Carey et al. (2016) found an association between PRS scores of schizophrenia and cannabis use in a sample of 2573 adults (mean age 38.7 years). Verweij et al. (2017) found an association with initiation of cannabis, more regular use of cannabis, and more cannabis use over their lifetime in a sample of 6931 adults (mean age 43 years). In contrast, Sherva et al. (2016) did not find an association between schizophrenia genetic risk alleles and cannabis dependency among 6000 African-American and 8754 European participants (mean age was 39.2 years).

For smoking, a recent study showed an association between schizophrenia polygenic risk threshold (pt < 0.005; pt < 0.05; pt < 0.5) and nicotine dependence and cigarettes smoked per day (Chen et al., 2016). However, the genetic variants most strongly associated with schizophrenia (i.e., threshold pt < 5e-4 and pt < 5e-5) were not associated with smoking. Carey et al. (2016) also found that schizophrenia PRS was associated with tobacco use compared to non-use. Also for other smoking phenotypes (e.g., age of onset, cigarettes per day) a genetic correlation with schizophrenia was reported (e.g., Bulik-Sullivan et al., 2015; Hartz et al., 2018). Only one study examined the association between PRS and alcohol use and the results showed that elevated schizophrenia PRS were associated with severe alcohol dependence (Carey et al., 2016).

An explanation for contrasting findings could be sample ascertainment and phenotypic definitions (Walters and Owen, 2016). In addition, previous studies measured substance use retrospectively and the cross-sectional designs do not inform when such genetic risk is expressed and what the role of the potential onset of symptoms is (Power et al., 2014). Therefore, longitudinal studies on the relation between genetic risk for schizophrenia and patterns of increasing substance use during adolescence are needed. The focus on adolescence is important because the onset of substance use often starts during this age period and is often associated with substance use addiction (e.g., Chassin et al., 2000) and future health problems.

The present longitudinal study aimed to investigate whether genetic predisposition to schizophrenia, as reflected in schizophrenia PRS (at a chosen p-value threshold of 5e-8 to 0.5), was associated with a pattern of increasing substance use (i.e., cannabis use, smoking, alcohol use) during adolescence (from ages 13–20 years) in a general population sample. Based on previous research, we expected that adolescents with a genetic loading for schizophrenia would use substances more frequently and would have a stronger increase over time. A difference in substance use between age 13–16 and 16–20 was hypothesized since it was legal to smoke and drink at age 16 in the Netherlands until 2013. Moreover, cannabis use before the age of 16 is rare (van Dorsselaer et al., 2016). Considering the differences in schizophrenia risk between men and women (Aleman et al., 2003) as well as the different relation between substance use and psychotic symptoms in men and women (van Gastel et al., 2013) the relation between schizophrenia genes and substance use may be gender specific. To investigate this relation, we analyzed the interaction of PRS and gender in predicting patterns of increasing substance use. We expected that genetic predisposition to schizophrenia would be stronger associated with substance use in girls considering the stronger relationship between cannabis and psychotic-like experiences in women (van Gastel et al., 2013). Overall, the present longitudinal study can provide more insight into the shared genetic risk between schizophrenia and substance use.

Section snippets

Procedure

Data of the RADAR-Y (Research on Adolescent Development and Relationships Young cohort) study were used, which is an ongoing longitudinal Dutch community study in which adolescents have been followed from mean age 13 onwards. Adolescents were recruited from randomly selected secondary schools in the western and central parts of the Netherlands. In total, 230 (69%) of the invited schools were willing to participate. Before the start of the study, adolescents and their parents received a complete

Descriptive statistics

During adolescence, substance use substantially increased (see Table 1). For cannabis use, most of the 372 adolescents were non-users at baseline (T1; 99.2%). This decreased to 51.1% at T7. For smoking, 77.2% of the adolescents were non-smoker at T1. However, daily smoking increased from 0.8% at T1 to 26.9% at T7. For frequency of alcohol use, at T1 82.5% of the adolescents indicated that they did not use alcohol in the last 4 weeks, which decreased to 12.8% at T6. For binge drinking, at T1

Discussion

In the present study, we examined whether increased genetic risk for schizophrenia was associated with patterns of substance use (i.e., cannabis use, smoking, and alcohol use) from early to late adolescence in a general population sample. The results showed that schizophrenia PRS is associated with diverging patterns of cannabis use across adolescence. High schizophrenia vulnerability was related to a stronger increase in cannabis use after age 16, whereas more lenient PRS thresholds after age

Role of funding source

This work was supported by a Dynamics of Youth grant from the University Utrecht, the Netherlands. Data from the Research on Adolescent Development and Relationships (RADAR) study were used. RADAR has been financially supported by main grants from the Netherlands Organisation for Scientific Research (GB-MAGW 480-03-005, GB-MAGW 480-08-006), the Stichting Achmea Slachtoffer en Samenleving (SASS), a grant from the Netherlands Organisation for Scientific Research to the Consortium Individual

Contributors

SB, CV, PvL, WM, and MB contributed to study conception and design. SB, PvL, WM, and SN were responsible for acquisition of data. MH, SN, KvE, and JJH performed analysis and interpretation of data. MH and MPB drafted the manuscript. SB, CV, PvL, WM, and MB aided in critical revision of the manuscript. All authors have read and approved the final manuscript.

Conflict of interest

No conflict declared.

Compliance with ethical standards

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study. Additional informed consent was obtained from all individual participants for whom identifying information is included in this article.

References (51)

  • F.Z. Basurto et al.

    Validity of the self-report on drug use by university students: correspondence between self-reported use and use detected in urine

    Psicothema

    (2009)
  • B.J. Buchan et al.

    Cannabis use: consistency and validity of self-report, on-site urine testing and laboratory testing

    Addiction

    (2002)
  • B. Bulik-Sullivan et al.

    An atlas of genetic correlations across human diseases and traits

    Nat. Genet.

    (2015)
  • C.E. Carey et al.

    Associations between polygenic risk for psychiatric disorders and substance involvement

    Front. Genet.

    (2016)
  • L. Chassin et al.

    The natural history of cigarette smoking from adolescence to adulthood in a midwestern community sample: multiple trajectories and their psychosocial correlates

    Health Psychol.

    (2000)
  • J. Chen et al.

    Genetic relationship between schizophrenia and nicotine dependence

    Sci. Rep.

    (2016)
  • R. de Leeuw et al.

    The relation between smoking-specific parenting and smoking trajectories of adolescents: how are changes in parenting related to changes in smoking?

    Psychol. Health

    (2010)
  • M. de Looze et al.

    Gezondheid, Welzijn En Opvoeding Van Jongeren in Nederland [Health, Well-Being, and Parenting of Youth in the Netherlands]

    (2014)
  • F.K. Del Boca et al.

    Truth or consequences: the validity of self-report data in health services research on addictions

    Addiction

    (2000)
  • E.M. Derks et al.

    Kraepelin was right: a latent class analysis of symptom dimensions in patients and controls

    Schizophr. Bull.

    (2012)
  • M.M. Dolcini et al.

    An assessment of the validity of adolescent self-reported smoking using three biological indicators

    Nicotine Tob. Res.

    (2003)
  • F. Dudbridge

    Power and predictive accuracy of polygenic risk scores

    PLoS Genet.

    (2013)
  • R.C. Engels et al.

    Predictability of smoking in adolescence: between optimism and pessimism

    Addiction

    (1999)
  • D. Goldman et al.

    The genetics of addictions: uncovering the genes

    Nat. Rev. Genet.

    (2005)
  • S.M. Hartz et al.

    Genetic correlation between smoking behaviors and schizophrenia

    Schizophr. Res.

    (2018)
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