The endocannabinoid system plays a key role in eating behavior regulating appetite and reward mechanisms, but the impact of its genetic variability has been scarcely studied in Anorexia Nervosa (AN). We aimed to analyze the association of genetic variants in cannabinoid receptors with the risk for AN and with psychiatric comorbidities that are commonplace in these patients.
We screened 221 AN patients and 396 controls for 14 tag-SNPs in the CNR1 and CNR2 genes, coding for cannabinoids receptors CB1 and CB2, respectively. Patients were diagnosed according to DSM-5 criteria and interviewed with the SCL-90R and the EDI-2 inventories to identify AN-coupled and general psychopathology.
None of the tag-SNPs was significantly related to AN risk. However, the rs806369-TT genotype and haplotype rs806368/rs1049353/rs806369 of CNR1 were respectively associated with lower weight (mean difference = − 4.92 kg, FDR-q = 0.044) and BMI (FDR-q = 0.042) in AN patients. CNR1 rs806374-TT and CNR2 rs3003335-AA and rs6658703-GG genotypes correlated with higher scores in the Positive Symptom Distress Index (PSDI, FDR-q = 0.011 and 0.009, respectively). These three genotypes were also linked to increased Hostility in the patients (FDR-q < 0.05). Remarkably, a proximal area of the CNR1 gene locus (positions 88,143,916–88,149,832) correlated with PSDI, Hostility, Asceticism and EDI-2 total scores after correcting by multiple testing (FDR-q < 0.05 in all instances). Finally, significant CNR1/CNR2 epistasis was observed in relation to Hostility (p < 0.01) and Maturity Fears (p < 0.001).
The CNR1 and CNR2 genes, coding for cannabinoid receptors, may constitute important loci regarding psychiatric comorbidities in AN patients.
Evidence obtained from well-designed cohort or case–control analytic studies.
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Availability of data and material
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Body mas index
Cannabinoid receptors 1 and 2
- CNR1-2 :
Cannabinoid receptor genes 1 and 2
Diagnostic and statistical manual of mental disorders
Eating disorders inventory test-2
Benjamini–Hochberg false discovery rate
Global symptom index
Positive symptom distress index
Positive symptom total
Symptom checklist 90 revised
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This work has been supported in part by grant GR18007 from Junta de Extremadura, Mérida (Spain) and Fondo Europeo de Desarrollo Regional (FEDER) “Una manera de hacer Europa” and a grant from the Alicia Koplowitz Foundation.
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The authors have no conflicts of interest to declare that are relevant to the content of this article.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the Bioethics Committee of the University of Extremadura and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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González, L.M., García-Herráiz, A., Mota-Zamorano, S. et al. Variability in cannabinoid receptor genes is associated with psychiatric comorbidities in anorexia nervosa. Eat Weight Disord (2021). https://doi.org/10.1007/s40519-021-01106-7
- Cannabinoid receptors
- Anorexia nervosa