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Variability in cannabinoid receptor genes is associated with psychiatric comorbidities in anorexia nervosa



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.

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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.



Anorexia nervosa


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


Linkage disequilibrium


Positive symptom distress index


Positive symptom total


Symptom checklist 90 revised


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We would like to thank the DNA repository of the Instituto de Salud Carlos III ( for providing with genetic material from healthy individuals and the members of the Centro Nacional de Genotipado-Instituto de Salud Carlos III (CeGen; for their technical assistance.


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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Author GG designed and carried out the study conception. Material preparation was performed by Isalud Flores, data collection was performed by SM-Z and AG-H, data analysis was performed by LMG and DA. The first draft of the manuscript was written by LMG. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Guillermo Gervasini.

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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 26, 2597–2606 (2021).

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  • Cannabinoid receptors
  • Anorexia nervosa
  • Comorbidities
  • CNR1
  • CNR2