Lifetime cannabis use and childhood trauma increase risk of psychosis in carriers of <i>CNR1</i> genetic variants: findings from the STREAM study

Loureiro, Camila Marcelino; Corsi-Zuelli, Fabiana; Fachim, Helene Aparecida; Shuhama, Rosana; de Oliveira, Adrielle Martins; Menezes, Paulo Rossi; Dalton, Caroline F.; Louzada-Junior, Paulo; Belangero, Sintia Iole; Coeli-Lacchini, Fernanda; Reynolds, Gavin P.; Lacchini, Riccardo; Del-Ben, Cristina Marta

doi:10.47626/1516-4446-2022-2882

Camila Marcelino Loureiro Correspondence: Camila Marcelino Loureiro, Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Av. Bandeirantes, 3900, Bairro Monte Alegre, CEP 14040-900, Ribeirão Preto, SP, Brasil. E-mail: camila.loureiro@usp.br

Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil

Centro de Pesquisas em Saúde Mental da População, São Paulo, SP, Brazil

http://orcid.org/0000-0002-0239-5064

Fabiana Corsi-Zuelli

Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil

http://orcid.org/0000-0001-9202-3987

Helene Aparecida Fachim

University of Manchester, Manchester, United Kingdom

http://orcid.org/0000-0003-3818-3167

Rosana Shuhama

Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil

Centro de Pesquisas em Saúde Mental da População, São Paulo, SP, Brazil

http://orcid.org/0000-0001-7626-7543

Adrielle Martins de Oliveira

Universidade Federal São Paulo, São Paulo, SP, Brazil

http://orcid.org/0000-0003-0173-6872

Paulo Rossi Menezes

Centro de Pesquisas em Saúde Mental da População, São Paulo, SP, Brazil

Faculdade de Medicina, USP, São Paulo, SP, Brazil

http://orcid.org/0000-0001-6330-3314

Caroline F. Dalton

Sheffield Hallam University, South Yorkshire, United Kingdom

http://orcid.org/0000-0002-1404-873X

Paulo Louzada-Junior

Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil

http://orcid.org/0000-0003-2585-3870

Sintia Iole Belangero

Universidade Federal São Paulo, São Paulo, SP, Brazil

http://orcid.org/0000-0002-2419-4351

Fernanda Coeli-Lacchini

Faculdade de Ciências Farmacêuticas, USP, São Paulo, SP, Brazil

http://orcid.org/0000-0001-6568-7497

Gavin P. Reynolds

Sheffield Hallam University, South Yorkshire, United Kingdom

http://orcid.org/0000-0001-9026-7726

Riccardo Lacchini

Escola de Enfermagem de Ribeirão Preto, USP, Ribeirão Preto, SP, Brazil

http://orcid.org/0000-0002-3738-2036

Cristina Marta Del-Ben

Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil

Centro de Pesquisas em Saúde Mental da População, São Paulo, SP, Brazil

http://orcid.org/0000-0003-0145-9975

Correspondence: Camila Marcelino Loureiro, Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Av. Bandeirantes, 3900, Bairro Monte Alegre, CEP 14040-900, Ribeirão Preto, SP, Brasil. E-mail: camila.loureiro@usp.br

Disclosure GPR has received honoraria for lectures and/or advisory panel membership from Janssen, Lundbeck, Otsuka, and Sunovion, and a research grant from Sunovion. The other authors report no conflicts of interest.

How to cite this article: Loureiro CM, Corsi-Zuelli F, Fachim HA, Shuhama R, de Oliveira AM, Menezes PR, et al. Lifetime cannabis use and childhood trauma increase risk of psychosis in carriers of CNR1 genetic variants: findings from the STREAM study. Braz J Psychiatry. 2023;45:226-235. http://doi.org/10.47626/1516-4446-2022-2882

Figures (3)
Tables (1)

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Figure 1
Principal components (PC) analysis plot of the studied Ribeirão Preto catchment area individuals in comparison to 1000 Genomes Project populations. The first two PCs (PC1 and PC2, corresponding to dimensions 1 and 2) are shown, and the colors illustrate the stream sample (143 cases, light blue; 286 controls, neon green) with the 1000 Genome Project sample Phase 3.⁴¹41. 1000 Genomes Project Consortium; Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, et al. A global reference for human genetic variation. Nature. 2015;526:68-74. ASW = Americans of African ancestry from Southwest United States; CEU = Utah residents with Northern and Western European ancestry from Utah, United States; CHB = Han Chinese from Beijing, China; CHD = Chinese from metropolitan Denver, Colorado, United States; GIH = Gujarati Indians from Houston, Texas, United States; JPT = Japanese from Tokyo, Japan; LWK = Luhya in Webuye, Kenya; MEX = Americans of Mexican ancestry from Los Angeles, California, United States; MKK = Maasai in Kinyawa, Kenya; TSI = Italians from Tuscany, Italy; YRI = Yoruba in Ibadan, Nigeria.

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Figure 2
Models assessing gene-environment and gene-gene associations considering: A) Lifetime cannabis use: individuals with lifetime cannabis use who were CNR1 rs12720071 T-allele carriers had a greater risk of psychosis (cross-validation consistency [CVC] = 10/10, testing accuracy = 66.4%, p < 0.001). The bars show the frequency distribution of genotypes for the first-episode psychosis patients (FEPp) and controls (left and right columns, respectively) in relation to lifetime cannabis use; B) Childhood trauma: risk association between individuals with childhood trauma and CNR1 rs12720071-T-allele carriers (CVC = 6/10, testing accuracy = 62.1%, p = 0.005). The bars show the frequency distribution of genotypes for the FEPp and controls (left and right columns, respectively) in relation to childhood trauma; and C) Lifetime cannabis use and childhood trauma: increased risk for developing psychosis in individuals with lifetime cannabis use, childhood trauma, and CNR1 rs7766029 T-allele carrier status (CVC = 8/10, testing accuracy = 69.3%, p < 0.001). The bars show the frequency distribution of genotypes for the FEPp and controls (left and right columns, respectively) in relation to both environmental risk factors.

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Figure 3
Schematic representation of our main findings. In the presence of CNR1 gene variants, lifetime cannabis use and childhood trauma may modulate the N-methyl-D-aspartate receptor (NMDAR) and dopamine-2 receptor (D2R) genes, increasing the risk of psychosis. CB1R = cannabinoid receptor type 1; SNVs = single nucleotide variants.

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Table 1
Sociodemographic and clinical variables of participants (n=429)

Characteristics	Community-based controls (n=286)	FEPp (n=143)	p-value
Sociodemographic variables
Sex^† † Fisher’s exact test.			< 0.001
Female	148 (51.7)^a a,b Different superscript letters denote statistically significant differences between means.	57 (39.9)^a a,b Different superscript letters denote statistically significant differences between means.
Male	138 (48.3)^a a,b Different superscript letters denote statistically significant differences between means.	86 (60.1)^a a,b Different superscript letters denote statistically significant differences between means.
Education in years^† † Fisher’s exact test.			< 0.001
≤ 9	64 (22.4)^a a,b Different superscript letters denote statistically significant differences between means.	58 (40.6)^b a,b Different superscript letters denote statistically significant differences between means.
> 9	222 (77.6)^a a,b Different superscript letters denote statistically significant differences between means.	85 (59.4)^b a,b Different superscript letters denote statistically significant differences between means.
Skin color^† † Fisher’s exact test.			0.004
White	196 (68.5)^a a,b Different superscript letters denote statistically significant differences between means.	76 (53.1)^b a,b Different superscript letters denote statistically significant differences between means.
Non-white	90 (31.5)^a a,b Different superscript letters denote statistically significant differences between means.	67 (46.9)^b a,b Different superscript letters denote statistically significant differences between means.
Clinical variables
Age,^‡ ‡ Student’s t test. years: mean (SD)	33.7 (12.6)	32.8 (12.1)	0.648
BMI,^‡ ‡ Student’s t test. kg/m²: mean (SD)	26.4 (6.4)	25.1 (6.5)	0.062
BPRS,^‡ ‡ Student’s t test. total score: mean (SD)	0.8 (1.9)^a a,b Different superscript letters denote statistically significant differences between means.	9.0 (7.1)^b a,b Different superscript letters denote statistically significant differences between means.	< 0.001
Age of onset,^‡ ‡ Student’s t test. years: mean (SD)		31.3 (11.9)
DUP, weeks: median (Min-Max)		10.0 (0.0-1.056.0)
Duration of disease, weeks: median (Min-Max)		39.6 (1.6-1.094.4)
Duration of treatment, weeks: median (Min-Max)		21.0 (0.0-155.4)
Tobacco smoking^† † Fisher’s exact test.			< 0.001
Yes	44 (15.4)^a a,b Different superscript letters denote statistically significant differences between means.	46 (32.2)^b a,b Different superscript letters denote statistically significant differences between means.
Lifetime cannabis use^† † Fisher’s exact test.			< 0.001
Yes	55 (19.2)^a a,b Different superscript letters denote statistically significant differences between means.	71 (49.7)^b a,b Different superscript letters denote statistically significant differences between means.
Childhood trauma^† † Fisher’s exact test.			< 0.001
Yes	68 (23.8)^a a,b Different superscript letters denote statistically significant differences between means.	74 (51.7)^b a,b Different superscript letters denote statistically significant differences between means.

[1] Correspondence: Camila Marcelino Loureiro, Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Av. Bandeirantes, 3900, Bairro Monte Alegre, CEP 14040-900, Ribeirão Preto, SP, Brasil. E-mail: camila.loureiro@usp.br

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Lifetime cannabis use and childhood trauma increase risk of psychosis in carriers of CNR1 genetic variants: findings from the STREAM study

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