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

paper Primary Public

Authors: Cheng, Zhongshan; Phokaew, Chureerat; Chou, Yi-Ling; Lai, Dongbing; Meyers, Jacquelyn L; Agrawal, Arpana; Farrer, Lindsay A; Kranzler, Henry R; Gelernter, Joel
Year: 2019
Journal: Translational psychiatry
PMID: 31740666
DOI: 10.1038/s41398-019-0639-7
PMCID: PMC6861240

Fig. 1

Manhattan plots showing genome-wide association signals of cannabis-induced hallucinations in long-term cannabis-exposed European Americans (EAs) by meta-analysis.a Manhattan plot with three significant variants, rs115455482, rs74722579, and rs1938228, on chromosome 1, in a meta-analysis of two EA cohorts. The three variants are in high linkage disequilibrium (all r2 ≥ 0.95) in EAs. The line in the plot represents the genome-wide significance cutoff (5 × 10−8). b Regional Manhattan plot demonstrates rs115455482 is close to gene CHRM3 (and regulates CHRM3 expression; see Fig. 2 and text). According to a published schizophrenia genome-wide association study36, these top three SNPs associated with cannabis-induced hallucinations were not significantly associated with schizophrenia (all associations P ~ 0.25); one SNP rs12081830, associated with cannabis-induced hallucination (P = 8.5 × 10−5), was nominally associated with schizophrenia (P = 4.3 × 10−2). rs115455482 and rs12081830 are not highly linked with each other (r2 < 0.2 in EAs). The light blue line and right Y-axis show the observed recombination rate in the 1000 Genomes Project European samples (EUR, hg19). The SNPs are colored in accordance to r2 with rs115455482.

Fig. 2

rs115455482 is a regulatory variant of CHRM3.The correlation between rs115455482 genotype and CHRM3 expression across ten brain tissues in European samples. Line within each boxplot represents median and box region indicates the range from first quantile to third quantile. Up and down whiskers, as well as dots outside box region, represent maximum value, minimum value, and outliers, respectively. The boxplot was generated in Braineac (http://www.braineac.org/). The abbreviations for ten brain tissues are CRBL (cerebellar cortex), FCTX (frontal cortex), HIPP (hippocampus), MEDU (medulla specifically inferior olivary nucleus), OCTX (occipital cortex), PUTM (putamen), SNIG (substantia nigra), TCTX (temporal cortex), THAL (thalamus), and WHMT (intralobular white matter). Affymetrix ID t2387606 represents transcript IDs for CHRM3 at mRNA level.

#	Section	Preview
0	Introduction	Cannabis is the most widely used illicit drug. It has acute and chronic effects on physical and…
1	Introduction	Genome-wide association study (GWAS) is a useful strategy to study the genetics and ultimately the…
2	Materials and methods — Subjects, genotyping, and imputation	Subjects were selected from among previously described samples, Yale-Penn 1 (n = 5540) and 2 (n =…
3	Materials and methods — Subjects, genotyping, and imputation	in each cohort was carried out using PLINK1.97 based on the following criteria: (1) individual…
4	Materials and methods — Subjects, genotyping, and imputation	with the GWAS software, Genome-wide Efficient Mixed Model Association (GEMMA)12. After retaining…
5	Materials and methods — Subjects, genotyping, and imputation	Apart from the above Yale-Penn samples used in our discovery GWAS, an independent cohort, the…
6	Materials and methods — Definition of Ca-HL	Ca-HL was defined using similar questions in the Semi-Structured Assessment for Drug Dependence and…
7	Materials and methods — Ca-HL sample description	For Ca-HL samples in Yale-Penn cohorts, there were 1092 Yale-Penn 1 EAs (cases = 51 and controls =…
8	Materials and methods — GWAS analysis — GWAS software	GEMMA12 was used separately in each Yale-Penn subgroup of EAs and AAs, with adjustment for sex, age,…
9	Materials and methods — GWAS analysis — GWAS software	For the two GWS variants that emerged in the meta-analysis of Yale-Penn cohorts, we used logistic…
10	Materials and methods — Correlation between rs115455482 genotype and CHRM3 expression	To facilitate the biological interpretation of our top association signal, we explored the potential…
11	Materials and methods — CHRM3 co-expression analysis and disease gene-enrichment analysis	Gene co-expression information can be used to evaluate a gene’s function and identify related…
12	Materials and methods — CHRM3 co-expression analysis and disease gene-enrichment analysis	these 101 genes. Finally, CHRM3 co-expressed genes that emerged in the top ten enriched gene…
13	Materials and methods — CHRM3 co-expression analysis and disease gene-enrichment analysis	2015b, The MathWorks, Inc., Natick, Massachusetts, USA). The same correlation analysis was performed…
14	Results	In the discovery GWAS, we meta-analyzed Yale-Penn 1 and 2 EAs and AAs separately by population (Fig.…
15	Results	Fig. 3) and AAs (λ = 1.02; Supplementary Fig. 2).Table 1Meta-analysis of rs115455482 and rs74722579…
16	Results	Association (GEMMA)eCOGA: Collaborative Study on the Genetics of AlcoholismNote: The two variants…
17	Results	The independent COGA sample was used to attempt to replicate these top signals in the discovery…
18	Results	To evaluate a potential underlying mechanism for the association of rs115455482 genotype with Ca-HL,…
19	Results	To infer the potential biological function of CHRM3, we carried out co-expression analysis. We…

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

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