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. 2019 Jul;22(7):1066-1074.
doi: 10.1038/s41593-019-0416-1. Epub 2019 Jun 17.

Genome-wide association study implicates CHRNA2 in cannabis use disorder

Ditte Demontis  1   2   3 , Veera Manikandan Rajagopal  4   5   6 , Thorgeir E Thorgeirsson  7 , Thomas D Als  4   5   6 , Jakob Grove  4   5   6   8 , Kalle Leppälä  4   5   6 , Daniel F Gudbjartsson  7 , Jonatan Pallesen  4   5   6 , Carsten Hjorthøj  5   9 , Gunnar W Reginsson  7 , Thorarinn Tyrfingsson  10 , Valgerdur Runarsdottir  10 , Per Qvist  4   5   6 , Jane Hvarregaard Christensen  4   5   6 , Jonas Bybjerg-Grauholm  5   11 , Marie Bækvad-Hansen  5   11 , Laura M Huckins  12   13 , Eli A Stahl  12   13 , Allan Timmermann  14 , Esben Agerbo  5   14   15 , David M Hougaard  5   11 , Thomas Werge  5   16   17 , Ole Mors  5   18 , Preben Bo Mortensen  5   14   15 , Merete Nordentoft  5   9   19 , Mark J Daly  20   21   22 , Hreinn Stefansson  7 , Kari Stefansson  7 , Mette Nyegaard  4   5 , Anders D Børglum  23   24   25
Affiliations

Genome-wide association study implicates CHRNA2 in cannabis use disorder

Ditte Demontis et al. Nat Neurosci. 2019 Jul.

Abstract

Cannabis is the most frequently used illicit psychoactive substance worldwide; around one in ten users become dependent. The risk for cannabis use disorder (CUD) has a strong genetic component, with twin heritability estimates ranging from 51 to 70%. Here we performed a genome-wide association study of CUD in 2,387 cases and 48,985 controls, followed by replication in 5,501 cases and 301,041 controls. We report a genome-wide significant risk locus for CUD (P = 9.31 × 10-12) that replicates in an independent population (Preplication = 3.27 × 10-3, Pmeta-analysis = 9.09 × 10-12). The index variant (rs56372821) is a strong expression quantitative trait locus for cholinergic receptor nicotinic α2 subunit (CHRNA2); analyses of the genetically regulated gene expression identified a significant association of CHRNA2 expression with CUD in brain tissue. At the polygenic level, analyses revealed a significant decrease in the risk of CUD with increased load of variants associated with cognitive performance. The results provide biological insights and inform on the genetic architecture of CUD.

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Figures

Figure 1.
Figure 1.. Genome-wide association results from the CUD GWAS results
A) Manhattan plot of the results from the GWAS of CUD (2,387 individuals with CUD and 48,985 controls). Results are from logistic regression and P-values are two-sided. The red horizontal line indicates the threshold for genome-wide significance (P=5x10−8). The index variant is highlighted as a green diamond and SNPs in high LD with the index SNP are marked in green. B) Quantile-quantile plot of the expected and observed P-values from GWAS of CUD (2,387 individuals with CUD and 48,985 controls). The blue line indicates the distribution under the null hypothesis and the shaded area indicates the 95% confidence band.
Figure 2.
Figure 2.. Association results for the geneomic region with the CUD risk locus
Regional association plot of the local association results for the risk locus at chromosome 8 based analysis of 2,387 individuals with CUD and 48,985 controls. Results are from logistic regression and P-values are two-sided. The index variant (rs56372821) and additional three correlated genome-wide significant variants (LD with index variant: 0.2 < r2 < 0.7) are marked with letters (a-d), the triangle represents the two-sided P-value from meta-analysis (inverse variance weighted fixed effects model) with the replication cohort from deCODE (5,501 individuals with CUD and 301,041 controls). The location and orientation of the genes in the region and the local estimates of recombination rate is shown. The association P-value (p), odds ratio (or), minor allele frequency (maf) and imputation info-score (info) is presented in upper right corner. The horizontal green line represents the threshold for genome-wide significant (P=5x10−8).
Figure 3.
Figure 3.. Association of CHRNA2 expression with CUD
Association of the imputed genetically regulated expression of CHRNA2 with CUD in three brain tissues with a valid model (cerebellar hemisphere, dorsolateret prefrontal contex and cerebellum). The two-side P-value from logistic regression for the association of gene expression with CUD (−log10(PrediXcan:P-value) and two-side P-value from logistic regression from the CUD GWAS (−log10(GWAS:P-value)) is given on the y-axis, with a red dotted line indicating statistical significance. Both analyses include 2,387 individuals with CUD and 48,985 controls. Chromosome position is given on the x-axis and the light grey lines indicate which SNPs that are included in the models used to predict gene expression. The thin red lines indicate genetic predictors that are genome-wide significantly associated with CUD.
Figure 4.
Figure 4.. Association of PRS with CUD
PRSs was generated for phenotypes related to cognition, personality, psychiatric disorders, reproduction and smoking behavior based on summary statistics from 22 published GWASs. The variance explained by the scores (Nagelkerke-R2) is given on the x-axis and the P-value from logistic regression for association of the PRS with CUD on the y-axis (based on analyses of 2,387 individuals with CUD and 48,985 controls). The vertical blue line indicate statistical significance (P=0.0023; correcting for 22 test). In PRS analyses of psychiatric disorders, individuals having a diagnosis of the respective psychiatric disorder being analysed (ADHD, schizophrenia, depressive symptoms and major depressive disorder) were excluded in the CUD target sample.
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