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
Mendolicchio L, Maggio G, Fortunato F, Ragione LD (2014) Update on eating disorders: epidemiology, mortality and comorbidity. Psychiatr Danub 26(Suppl 1):85–88
Atiye M, Miettunen J, Raevuori-Helkamaa A (2015) A meta-analysis of temperament in eating disorders. Eur Eat Disord Rev 23:89–99. https://doi.org/10.1002/erv.2342
Lilenfeld LR (2011) Personality and temperament. Curr Top Behav Neurosci 6:3–16. https://doi.org/10.1007/7854_2010_86
Monteleone P, Maj M (2008) Genetic susceptibility to eating disorders: associated polymorphisms and pharmacogenetic suggestions. Pharmacogenomics 9:1487–1520
Gorwood P, Kipman A, Foulon C (2003) The human genetics of anorexia nervosa. Eur J Pharmacol 480:163–170
Rybakowski F, Slopien A, Dmitrzak-Weglarz M, Czerski P, Rajewski A, Hauser J (2006) The 5-HT2A -1438 A/G and 5-HTTLPR polymorphisms and personality dimensions in adolescent anorexia nervosa: association study. Neuropsychobiology 53:33–39
Gervasini G, Gamero-Villarroel C (2015) Discussing the putative role of obesity-associated genes in the etiopathogenesis of eating disorders. Pharmacogenomics 16:1287–1305. https://doi.org/10.2217/pgs.15.77
Rybakowski F, Dmitrzak-Weglarz M, Szczepankiewicz A, Skibinska M, Slopien A, Rajewski A et al (2007) Brain derived neurotrophic factor gene Val66Met and -270C/T polymorphisms and personality traits predisposing to anorexia nervosa. Neuro Endocrinol Lett 28:153–158
Boraska V, Davis OS, Cherkas LF, Helder SG, Harris J, Krug I et al (2012) Genome-wide association analysis of eating disorder-related symptoms, behaviors, and personality traits. Am J Med Genet B Neuropsychiatr Genet 159B:803–811. https://doi.org/10.1002/ajmg.b.32087
Bachner-Melman R, Lerer E, Zohar AH, Kremer I, Elizur Y, Nemanov L et al (2007) Anorexia nervosa, perfectionism, and dopamine D4 receptor (DRD4). Am J Med Genet B Neuropsychiatr Genet 144B:748–756
Parsons LH, Hurd YL (2015) Endocannabinoid signalling in reward and addiction. Nat Rev Neurosci 16:579–594. https://doi.org/10.1038/nrn4004
Jager G, Witkamp RF (2014) The endocannabinoid system and appetite: relevance for food reward. Nutr Res Rev 27:172–185. https://doi.org/10.1017/S0954422414000080
Zarate J, Churruca I, Pascual J, Casis L, Salles J, Echevarria E (2008) Brain endocannabinoid system is involved in fluoxetine-induced anorexia. Nutr Neurosci 11:111–118. https://doi.org/10.1179/147683008X301496
Casteels C, Gerard N, van Kuyck K, Pottel L, Nuttin B, Bormans G et al (2014) Small animal PET imaging of the type 1 cannabinoid receptor in a rodent model for anorexia nervosa. Eur J Nucl Med Mol Imaging 41:308–321. https://doi.org/10.1007/s00259-013-2522-8
Mendez-Diaz M, Amancio-Belmont O, Hernandez-Vazquez E, Ruiz-Contreras AE, Hernandez-Luis F, Prospero-Garcia O (2015) ENP11, a potential CB1R antagonist, induces anorexia in rats. Pharmacol Biochem Behav 135:177–181. https://doi.org/10.1016/j.pbb.2015.06.007
de Luis DA, Izaola O, Primo D, de la Fuente B, Aller R (2017) Polymorphism rs3123554 in the cannabinoid receptor gene type 2 (CNR2) reveals effects on body weight and insulin resistance in obese subjects. Endocrinol Diabetes Nutr 64:440–445. https://doi.org/10.1016/j.endinu.2017.06.001
Ketterer C, Heni M, Stingl K, Tschritter O, Linder K, Wagner R et al (2014) Polymorphism rs3123554 in CNR2 reveals gender-specific effects on body weight and affects loss of body weight and cerebral insulin action. Obesity (Silver Spring) 22:925–931. https://doi.org/10.1002/oby.20573
Sadeghian M, Rahmani S, Mansoori A (2018) G1359A Variant of the Cannabinoid Receptor Gene (rs1049353) and Obesity-Related Traits and Related Endophenotypes: A Meta-Analysis. Ann Nutr Metab 73:76–85. https://doi.org/10.1159/000490668
D’Addario C, Zaplatic E, Giunti E, Pucci M, Micioni Di Bonaventura MV, Scherma M et al (2020) Epigenetic regulation of the cannabinoid receptor CB1 in an activity-based rat model of anorexia nervosa. Int J Eat Disord 53:432–446. https://doi.org/10.1002/eat.23271
Rask-Andersen M, Olszewski PK, Levine AS, Schioth HB (2010) Molecular mechanisms underlying anorexia nervosa: focus on human gene association studies and systems controlling food intake. Brain Res Rev 62:147–164. https://doi.org/10.1016/j.brainresrev.2009.10.007
Monteleone P, Bifulco M, Di Filippo C, Gazzerro P, Canestrelli B, Monteleone F et al (2009) Association of CNR1 and FAAH endocannabinoid gene polymorphisms with anorexia nervosa and bulimia nervosa: evidence for synergistic effects. Genes Brain Behav 8:728–732. https://doi.org/10.1111/j.1601-183X.2009.00518.x
Muller TD, Reichwald K, Bronner G, Kirschner J, Nguyen TT, Scherag A et al (2008) Lack of association of genetic variants in genes of the endocannabinoid system with anorexia nervosa. Child Adolesc Psychiatry Ment Health 2:33. https://doi.org/10.1186/1753-2000-2-33
Siegfried Z, Kanyas K, Latzer Y, Karni O, Bloch M, Lerer B et al (2004) Association study of cannabinoid receptor gene (CNR1) alleles and anorexia nervosa: differences between restricting and binging/purging subtypes. Am J Med Genet B Neuropsychiatr Genet 125B:126–130. https://doi.org/10.1002/ajmg.b.20089
Bae JS, Kim JY, Park BL, Kim JH, Kim B, Park CS et al (2014) Genetic association analysis of CNR1 and CNR2 polymorphisms with schizophrenia in a Korean population. Psychiatr Genet 24:225–229. https://doi.org/10.1097/YPG.0000000000000047
Kong X, Miao Q, Lu X, Zhang Z, Chen M, Zhang J et al (2019) The association of endocannabinoid receptor genes (CNR1 and CNR2) polymorphisms with depression: A meta-analysis. Medicine (Baltimore) 98:e17403. https://doi.org/10.1097/MD.0000000000017403
Matsunaga M, Masuda T, Ishii K, Ohtsubo Y, Noguchi Y, Ochi M et al (2018) Culture and cannabinoid receptor gene polymorphism interact to influence the perception of happiness. PLoS ONE 13:e0209552. https://doi.org/10.1371/journal.pone.0209552
Minocci D, Massei J, Martino A, Milianti M, Piz L, Di Bello D et al (2011) Genetic association between bipolar disorder and 524A>C (Leu133Ile) polymorphism of CNR2 gene, encoding for CB2 cannabinoid receptor. J Affect Disord 134:427–430. https://doi.org/10.1016/j.jad.2011.05.023
Smith DR, Stanley CM, Foss T, Boles RG, McKernan K (2017) Rare genetic variants in the endocannabinoid system genes CNR1 and DAGLA are associated with neurological phenotypes in humans. PLoS ONE 12:e0187926. https://doi.org/10.1371/journal.pone.0187926
Wirz L, Reuter M, Felten A, Schwabe L (2018) An endocannabinoid receptor polymorphism modulates affective processing under stress. Soc Cogn Affect Neurosci 13:1177–1189. https://doi.org/10.1093/scan/nsy083
Lester KJ, Coleman JR, Roberts S, Keers R, Breen G, Bogels S et al (2017) Genetic variation in the endocannabinoid system and response to Cognitive Behavior Therapy for child anxiety disorders. Am J Med Genet B Neuropsychiatr Genet 174:144–155. https://doi.org/10.1002/ajmg.b.32467
Derogaitis LR (2002) SCL-90R: Cuestionario de 90 síntomas. TEA, Madrid
Guimera E, Torrubia R (1987) Adaptación española del Eating Disorder Inventory Inventory (EDI) en una muestra de pacientes anoréxicas. Anal Psiquiat 3:185–190
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575. https://doi.org/10.1086/519795
Benzinou M, Chevre JC, Ward KJ, Lecoeur C, Dina C, Lobbens S et al (2008) Endocannabinoid receptor 1 gene variations increase risk for obesity and modulate body mass index in European populations. Hum Mol Genet 17:1916–1921. https://doi.org/10.1093/hmg/ddn089
Ceccarini J, Weltens N, Ly HG, Tack J, Van Oudenhove L, Van Laere K (2016) Association between cerebral cannabinoid 1 receptor availability and body mass index in patients with food intake disorders and healthy subjects: a [(18)F]MK-9470 PET study. Transl Psychiatry 6:e853. https://doi.org/10.1038/tp.2016.118
Gamero-Villarroel C, Gonzalez LM, Gordillo I, Carrillo JA, Garcia-Herraiz A, Flores I et al (2015) Impact of NEGR1 genetic variability on psychological traits of patients with eating disorders. Pharmacogenomics J 15:278–283. https://doi.org/10.1038/tpj.2014.53
Gamero-Villarroel C, Gonzalez LM, Rodriguez-Lopez R, Albuquerque D, Carrillo JA, Garcia-Herraiz A et al (2017) Influence of TFAP2B and KCTD15 genetic variability on personality dimensions in anorexia and bulimia nervosa. Brain Behav 7:e00784. https://doi.org/10.1002/brb3.784
Gamero-Villarroel C, Gordillo I, Carrillo JA, Garcia-Herraiz A, Flores I, Jimenez M et al (2014) BDNF genetic variability modulates psychopathological symptoms in patients with eating disorders. Eur Child Adolesc Psychiatry 23:669–679. https://doi.org/10.1007/s00787-013-0495-6
Gervasini G, Gonzalez LM, Gamero-Villarroel C, Mota-Zamorano S, Carrillo JA, Flores I et al (2018) Effect of dopamine receptor D4 (DRD4) haplotypes on general psychopathology in patients with eating disorders. Gene 654:43–48. https://doi.org/10.1016/j.gene.2018.02.035
Palmer RHC, McGeary JE, Knopik VS, Bidwell LC, Metrik JM (2019) CNR1 and FAAH variation and affective states induced by marijuana smoking. Am J Drug Alcohol Abuse 45:514–526. https://doi.org/10.1080/00952990.2019.1614596
Mercader JM, Fernandez-Aranda F, Gratacos M, Aguera Z, Forcano L, Ribases M et al (2010) Correlation of BDNF blood levels with interoceptive awareness and maturity fears in anorexia and bulimia nervosa patients. J Neural Transm 117:505–512
Gonzalez LM, Mota-Zamorano S, Garcia-Herraiz A, Lopez-Nevado E, Gervasini G (2019) Genetic variants in dopamine pathways affect personality dimensions displayed by patients with eating disorders. Eat Weight Disord. https://doi.org/10.1007/s40519-019-00820-7
Monteleone P, Bifulco M, Maina G, Tortorella A, Gazzerro P, Proto MC et al (2010) Investigation of CNR1 and FAAH endocannabinoid gene polymorphisms in bipolar disorder and major depression. Pharmacol Res 61:400–404. https://doi.org/10.1016/j.phrs.2010.01.002
Agrawal A, Nelson EC, Littlefield AK, Bucholz KK, Degenhardt L, Henders AK et al (2012) Cannabinoid receptor genotype moderation of the effects of childhood physical abuse on anhedonia and depression. Arch Gen Psychiatry 69:732–740. https://doi.org/10.1001/archgenpsychiatry.2011.2273
Isir AB, Baransel C, Nacak M (2016) An information theoretical study of the epistasis between the CNR1 1359 G/A polymorphism and the Taq1A and Taq1B DRD2 polymorphisms: assessing the susceptibility to cannabis addiction in a turkish population. J Mol Neurosci 58:456–460. https://doi.org/10.1007/s12031-016-0721-z
Ehlers CL, Slutske WS, Lind PA, Wilhelmsen KC (2007) Association between single nucleotide polymorphisms in the cannabinoid receptor gene (CNR1) and impulsivity in southwest California Indians. Twin Res Hum Genet 10:805–811. https://doi.org/10.1375/twin.10.6.805
Qin H, Zeng J, Chen H, Deng L, Su L (2018) Can your DNA influence your bet-placing? The impact of cannabinoid receptor 1 gene on gambling tasks. Front Hum Neurosci 12:458. https://doi.org/10.3389/fnhum.2018.00458
Buchmann AF, Hohm E, Witt SH, Blomeyer D, Jennen-Steinmetz C, Schmidt MH et al (2015) Role of CNR1 polymorphisms in moderating the effects of psychosocial adversity on impulsivity in adolescents. J Neural Transm (Vienna) 122:455–463. https://doi.org/10.1007/s00702-014-1266-3
Onwuameze OE, Nam KW, Epping EA, Wassink TH, Ziebell S, Andreasen NC et al (2013) MAPK14 and CNR1 gene variant interactions: effects on brain volume deficits in schizophrenia patients with marijuana misuse. Psychol Med 43:619–631. https://doi.org/10.1017/S0033291712001559
Stoving RK, Andries A, Brixen K, Flyvbjerg A, Horder K, Frystyk J (2009) Leptin, ghrelin, and endocannabinoids: potential therapeutic targets in anorexia nervosa. J Psychiatr Res 43:671–679. https://doi.org/10.1016/j.jpsychires.2008.09.007
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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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). https://doi.org/10.1007/s40519-021-01106-7
- Cannabinoid receptors
- Anorexia nervosa