A regulatory variant of CHRM3 is associated with cannabis-induced hallucinations in European Americans

A genome-wide association study of long-term cannabis users identified a significant signal at the CHRM3 gene linked to cannabis-induced hallucinations. The strongest association was found in European Americans, with the lead SNP rs115455482 reaching genome-wide significance. The risk allele was associated with lower CHRM3 expression in the thalamus, and CHRM3 was co-expressed with three psychosis risk genes in brain tissues. Findings did not replicate in an independent sample, though meta-analysis strengthened the association. No significant signals were found in African Americans. The results suggest CHRM3 may contribute to cannabis-induced hallucinations and point to the thalamus's potential role.

Study at a glance

Abstract

Abstract Cannabis, the most widely used illicit drug, can induce hallucinations. Our understanding of the biology of cannabis-induced hallucinations (Ca-HL) is limited. We used the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA) to identify cannabis-induced hallucinations (Ca-HL) among long-term cannabis users (used cannabis ≥1 year and ≥100 times). A genome-wide association study (GWAS) was conducted by analyzing European Americans (EAs) and African Americans (AAs) in Yale-Penn 1 and 2 cohorts individually, then meta-analyzing the two cohorts within population. In the meta-analysis of Yale-Penn EAs ( n = 1917), one genome-wide significant (GWS) signal emerged at the CHRM3 locus, represented by rs115455482 ( P = 1.66 × 10 −10 ), rs74722579 ( P = 2.81 × 10 −9 ), and rs1938228 ( P = 1.57 × 10 −8 ); signals were GWS in Yale-Penn 1 EAs ( n = 1092) and nominally significant in Yale-Penn 2 EAs ( n = 825). Two SNPs, rs115455482 and rs74722579, were available from the Collaborative Study on the Genetics of Alcoholism data (COGA; 3630 long-term cannabis users). The signals did not replicate, but when meta-analyzing Yale-Penn and COGA EAs, the two SNPs’ association signals were increased (meta- P -values 1.32 × 10 −10 and 2.60 × 10 −9 , respectively; n = 4291). There were no significant findings in AAs, but in the AA meta-analysis ( n = 3624), nominal significance was seen for rs74722579. The rs115455482*T risk allele was associated with lower CHRM3 expression in the thalamus. CHRM3 was co-expressed with three psychosis risk genes ( GABAG2 , CHRNA4 , and HRH3 ) in the thalamus and other human brain tissues and mouse GABAergic neurons. This work provides strong evidence for the association of CHRM3 with Ca-HL and provides insight into the potential involvement of thalamus for this trait.