Abstract
Eating disorders such as anorexia nervosa, bulimia nervosa and binge-eating disorder, have a deep social impact, concluding with death in cases of severe disease. Eating disorders affect up to 5% of the population in the industrialized countries, but probably the phenomenon is under-detection and under-diagnosis. Eating disorders are multifactorial disorders, resulting from the interaction between environmental triggers, psychological factors, but there is also a strong genetic component. In fact, genetic factors predispose for approximately 33-84% to anorexia nervosa, 28-83% to bulimia nervosa, and 41-57% to binge eating disorder. Twins and family studies have provided an unassailable proof on the heritability of these disorders. Other types of genetic studies, including genome-wide association studies, whole genome sequencing and linkage analysis, allowed to identify the genes and their variants associated with eating disorders and moreover global collaborative efforts have led to delineate the etiology of these disorders. Next Generation Sequencing technologies can be considered as an ideal diagnostic approach to identify not only the common variants, such as single nucleotide polymorphism, but also rare variants. Here we summarize the present knowledge on the molecular etiology and genetic determinants of eating disorders including serotonergic genes, dopaminergic genes, opioid genes, appetite regulation genes, endocannabinoid genes and vitamin D3.
References
[2] American Psychiatric Association. Diagnostic and statistical manual of mental disorders (5th ed.). Washington DC: American Psychiatric Publishing 2013
[3] Ceccarini MR, Precone V, Manara E, Paolacci S, Maltese PE, Benfatti V, Dhuli K, Donato K, Guerri G, Marceddu G, Chiurazzi P, Dalla Ragione L, Beccari T, Bertelli M. A next generation sequencing gene panel for use in the diagnosis of anorexia nervosa. Eat Weight Disord 2022;27:1869-80. https://doi.org/10.1007/s40519-021-01331-0
[4] Watson HJ, Palmos AB, Hunjan A, Baker JH, Yilmaz Z, Davies HL. Genetics of eating disorders in the genome-wide era. Psychol Med 2021;51:2287-97. https://doi.org/10.1017/S0033291720005474
[5] Himmerich H, Bentley J, Kan C, Treasure J. Genetic risk factors for eating disorders: an update and insights into pathophysiology. Ther Adv Psychopharmacol 2019;9:2045125318814734. https://doi.org/10.1177/2045125318814734
[6] Yao S, Larsson H, Norring C, Birgegård A, Lichtenstein P, DʼOnofrio BM, Almqvist C, Thornton LM, Bulik CM, Kuja-Halkola R. Genetic and environmental contributions to diagnostic fluctuation in anorexia nervosa and bulimia nervosa. Psychol Med 2021;51:62-9. https://doi.org/10.1017/S0033291719002976
[7] Wray NR, Lin T, Austin J, McGrath JJ, Hickie IB, Murray GK, Visscher PM. From Basic Science to Clinical Application of Polygenic Risk Scores: A Primer. JAMA Psychiatry 2021;78:101-9. https://doi.org/10.1001/jamapsychiatry.2020.3049
[8] Watson HJ, Yilmaz Z, Thornton LM, Hübel C, Coleman JRI, Gaspar HA, Bryois J, Hinney A, Leppä VM, Mattheisen M, Medland SE, Ripke S, Yao S, Giusti-Rodríguez P; Anorexia Nervosa Genetics Initiative, Hanscombe KB, Purves KL; Eating Disorders Working Group of the Psychiatric Genomics Consortium, Adan RAH, Alfredsson L, Ando T, Andreassen OA, Baker JH, Berrettini WH, Boehm I, Boni C, Perica VB, Buehren K, Burghardt R, Cassina M, Cichon S, Clementi M, Cone RD, Courtet P, Crow S, Crowley JJ, Danner UN, Davis OSP, de Zwaan M, Dedoussis G, Degortes D, DeSocio JE, Dick DM, Dikeos D, Dina C, Dmitrzak-Weglarz M, Docampo E, Duncan LE, Egberts K, Ehrlich S, Escaramís G, Esko T, Estivill X, Farmer A, Favaro A, Fernández-Aranda F, Fichter MM, Fischer K, Föcker M, Foretova L, Forstner AJ, Forzan M, Franklin CS, Gallinger S, Giegling I, Giuranna J, Gonidakis F, Gorwood P, Mayora MG, Guillaume S, Guo Y, Hakonarson H, Hatzikotoulas K, Hauser J, Hebebrand J, Helder SG, Herms S, Herpertz-Dahlmann B, Herzog W, Huckins LM, Hudson JI, Imgart H, Inoko H, Janout V, Jiménez-Murcia S, Julià A, Kalsi G, Kaminská D, Kaprio J, Karhunen L, Karwautz A, Kas MJH, Kennedy JL, Keski-Rahkonen A, Kiezebrink K, Kim YR, Klareskog L, Klump KL, Knudsen GPS, La Via MC, Le Hellard S, Levitan RD, Li D, Lilenfeld L, Lin BD, Lissowska J, Luykx J, Magistretti PJ, Maj M, Mannik K, Marsal S, Marshall CR, Mattingsdal M, McDevitt S, McGuffin P, Metspalu A, Meulenbelt I, Micali N, Mitchell K, Monteleone AM, Monteleone P, Munn-Chernoff MA, Nacmias B, Navratilova M, Ntalla I, O'Toole JK, Ophoff RA, Padyukov L, Palotie A, Pantel J, Papezova H, Pinto D, Rabionet R, Raevuori A, Ramoz N, Reichborn-Kjennerud T, Ricca V, Ripatti S, Ritschel F, Roberts M, Rotondo A, Rujescu D, Rybakowski F, Santonastaso P, Scherag A, Scherer SW, Schmidt U, Schork NJ, Schosser A, Seitz J, Slachtova L, Slagboom PE, Slof-Op 't Landt MCT, Slopien A, Sorbi S, Świątkowska B, Szatkiewicz JP, Tachmazidou I, Tenconi E, Tortorella A, Tozzi F, Treasure J, Tsitsika A, Tyszkiewicz-Nwafor M, Tziouvas K, van Elburg AA, van Furth EF, Wagner G, Walton E, Widen E, Zeggini E, Zerwas S, Zipfel S, Bergen AW, Boden JM, Brandt H, Crawford S, Halmi KA, Horwood LJ, Johnson C, Kaplan AS, Kaye WH, Mitchell JE, Olsen CM, Pearson JF, Pedersen NL, Strober M, Werge T, Whiteman DC, Woodside DB, Stuber GD, Gordon S, Grove J, Henders AK, Juréus A, Kirk KM, Larsen JT, Parker R, Petersen L, Jordan J, Kennedy M, Montgomery GW, Wade TD, Birgegård A, Lichtenstein P, Norring C, Landén M, Martin NG, Mortensen PB, Sullivan PF, Breen G, Bulik CM. Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa. Nat Genet 2019;51:1207-14. https://doi.org/10.1038/s41588-019-0439-2
[9] Cuesto G, Everaerts C, León LG, Acebes A. Molecular bases of anorexia nervosa, bulimia nervosa and binge eating disorder: shedding light on the darkness. J Neurogenet 2017;31:266-87. https://doi.org/10.1080/01677063.2017.1353092
[10] Galusca B, Prévost G, Germain N, Dubuc I, Ling Y, Anouar Y, Estour B, Chartrel N. Neuropeptide Y and a-MSH circadian levels in two populations with low body weight: Anorexia nervosa and constitutional thinness. PLoS One 2015;10:e0122040. https://doi.org/10.1371/journal.pone.0122040
[11] Park JH, Shim HM, Na AY, Bae JH, Im SS, Song DK. Orexin A regulates plasma insulin and leptin levels in a time-dependent manner following a glucose load in mice. Diabetol 2015;58:1542-
50. https://doi.org/10.1007/s00125-015-3573-0
[12] Zhou Y, Kreek MJ. Persistent increases in rat hypothalamic POMC gene expression following chronic withdrawal from chronic “binge” pattern escalating-dose, but not steady-dose, cocaine. Neuroscience 2015;289:63-70. https://doi.org/10.1038/npp.2011.97
[13] Burmester V, Nicholls D, Buckle A, Stanojevic B, Crous-Bou M. Review of eating disorders and oxytocin receptor polymorphisms. J Eat Disord 2021;9:85. https://doi.org/10.1186/s40337-021-00438-0
[14] Strober M, Freeman R, Lampert C, Diamond J, Kaye W. Controlled family study of anorexia nervosa and bulimia nervosa: evidence of shared liability and transmission of partial syndromes. Am J Psychiatry 2000;157:393-401. https://doi.org/10.1176/appi. ajp.157.3.393
[15] Munn-Chernoff MA, Baker JH. A primer on the genetics of comorbid eating disorders and substance use disorders. Eur Eat Disord Rev 2016;24:91-100. https://doi.org/10.1002/erv.2424
[16] Paolacci S, Kiani AK, Manara E, Beccari T, Ceccarini MR, Stuppia L, Chiurazzi P, Dalla Ragione L, Bertelli M. Genetic contributions to the etiology of anorexia nervosa: New perspectives in molecular diagnosis and treatment. Mol Genet Genomic Med 2020;8:e1244. https://doi.org/10.1002/mgg3.1244
[17] Yokokura M, Terada T, Bunai T, Nakaizumi K, Kato Y, Yoshikawa E, Futatsubashi M, Suzuki K, Yamasue H, Ouchi Y. Alterations in serotonin transporter and body image-related cognition in anorexia nervosa. Neuroimage Clin 2019;23:101928. https://doi.org/10.1002/mgg3.1244
[18] Boehm I, Walton E, Alexander N, Batury VL, Seidel M, Geisler D, King JA, Weidner K, Roessner V, Ehrlich S. Peripheral serotonin transporter DNA methylation is linked to increased salience network connectivity in females with anorexia nervosa. J Psychiatry Neurosci 2020;45:206-13. https://doi.org/10.1503/jpn.190016
[19] Trace SE, Baker JH, Peñas-Lledó E, Bulik CM. The genetics of eating disorders. Annu Rev Clin Psychol 2013;9:589-620. https://doi.org/10.1146/annurev-clinpsy-050212-185546
[20] Compan V. Serotonin 4 Receptors: A Cornerstone in anorexia nervosa? Autism Open Access 2017;7:207. https://doi.org/10.4172/2165-7890.1000207
[21] Brown KM, Bujac SR, Mann ET, Campbell DA, Stubbins MJ, Blundell JE. Further evidence of association of OPRD1 & HTR1D polymorphisms with susceptibility to anorexia nervosa. Biol Psychiatry 2007;61:367-73. https://doi.org/10.1016/j.biopsych.2006.04.007
[22] Boraska V, Franklin CS, Floyd JA. A genome-wide association study of anorexia nervosa. Mol Psychiatry 2014;19:1085-94. https://doi.org/10.1038/mp.2013.187
[23] Duncan L, Yilmaz Z, Gaspar H, Walters R, Goldstein J, Anttila V, Bulik-Sullivan B, Ripke S; Eating Disorders Working Group of the Psychiatric Genomics Consortium, Thornton L, Hinney A, Daly M, Sullivan PF, Zeggini E, Breen G, Bulik CM. Significant locus and metabolic genetic correlations revealed in genome-wide association study of anorexia nervosa. Am J Psychiatry 2017;174:850-8. https://doi.org/10.1176/appi.ajp.2017.16121402
[24] Perry B, Wang Y. Appetite regulation and weight control: The role of gut hormones. Nutr Diabetes 2012;2:e26. https://doi.org/10.1038/nutd.2011.21
[25] Blauwhoff-Buskermolen S, Langius JA, Heijboer AC, Becker A, de van der Schueren MA, Verheul HM. Plasma ghrelin levels are associated with anorexia but not cachexia in patients with NSCLC. Front Physiol 2017;8:119. https://doi.org/10.3389/fphys.2017.00119
[26] Steiner AA, Romanovsky AA. Leptin: At the cross- roads of energy balance and systemic inflammation. Prog Lipid Res 2007;46:89-107. https://doi.org/10.1016/j.plipres.2006.11.001
[27] Föcker M, Timmesfeld N, Scherag S, Bühren K, Langkamp M, Dempfle A, Sheridan EM, de Zwaan M, Fleischhaker C, Herzog W, Egberts K, Zipfel S, Herpertz-Dahlmann B, Hebebrand J. Screening for anorexia nervosa via measurement of serum leptin levels. J Neural Transm (Vienna) 2011;118:571-8. https://doi.org/10.1007/s00702-010-0551-z
[28] Monteleone P, Matias I, Martiadis V, De Petrocellis L, Maj M, Di Marzo V. Blood levels of the endocannabinoid anandamide are increased in anorexia nervosa and in binge-eating disorder, but not in bulimia nervosa. Neuropsychopharmacology 2005;30:1216-21. https://doi.org/10.1038/sj.npp.1300695
[29] Monteleone P, Fabrazzo M, Tortorella A, Fuschino A, Maj M. Opposite modifications in circulating leptin and soluble leptin receptor across the eating disorder spectrum. Mol Psychiatry 2002;7:641-6. https://doi.org/10.1038/sj.mp.4001043
[30] Karra E, Chandarana K, Batterham RL. The role of peptide YY in appetite regulation and obesity. J Physiol 2009;587:19-25. https://doi.org/10.1113/jphysiol.2008.164269
[31] De Silva A, Bloom SR. Gut hormones and appetite control: A focus on PYY and GLP-1 as therapeutic targets in obesity. Gut Liver 2012;6:10-20. https://doi.org/10.5009/gnl.2012.6.1.10
[32] Lenka A, Arumugham SS, Christopher R, Pal PK. Genetic substrates of psychosis in patients with Parkinson’s disease: A critical review. J Neurol Sci 2016;364:33-41. https://doi.org/10.1016/j.jns.2016.03.005
[33] Cuntz U, Enck P, Frühauf E, Lehnert P, Riepl RL, Fichter MM, Otto B. Cholecystokinin revisited: CCK and the hunger trap in anorexia nervosa. PloS One 2013;8:e54457. https://doi.org/10.1371/journal. pone.0054457
[34] Richard JE, Farkas I, Anesten F. GLP-1 receptor stimulation of the lateral parabrachial nucleus reduces food intake: Neuroanatomical, electrophysiological, and behavioral evidence. Endocrinology 2014;155:4356-67. https://doi.org/10.1210/en.2014-1248
[35] Tomasik PJ, Sztefko K, Starzyk J, Rogatko I, Szafran Z. Entero-insular axis in children with anorexia nervosa. Psychoneuroendocrinology 2005;30:364-72. https://doi.org/10.1016/j.psyneuen.2004.10.003
[36] González LM, García-Herráiz A, Mota-Zamorano S, Flores I, Albuquerque D, Gervasini G. Variability in cannabinoid receptor genes is associated with psychiatric comorbidities in anorexia nervosa. Eat Weight Disord 2021;26:2597-606. https://doi.org/10.1007/s40519-021-01106-7
[37] González LM, Mota-Zamorano S, García-Herráiz A, López-Nevado E, Gervasini G. Genetic variants in dopamine pathways affect personality dimensions displayed by patients with eating disorders. Eating and Weight Disorders. Eat Weight Disord 2021;26:93-101. https://doi.org/10.1007/s40519-019-00820-7
[38] Soria-Gómez E, Matias I, Rueda-Orozco PE, Cisneros M, Petrosino S, Navarro L, Di Marzo V, Prospéro-García O. Pharmacological enhancement of the endocannabinoid system in the nucleus ac- cumbens shell stimulates food intake and increases c-Fos expression in the hypothalamus. Br J Pharmacol 2007;151:1109-16. https://doi.org/10.1038/sj.bjp.0707313
[39] Scopinho AA, Guimarães FS, Corrêa FM, Resstel LB. Cannabidiol inhibits the hyperphagia induced by cannabinoid-1 or serotonin-1A receptor agonists. Pharmacol Biochem Behav 2011;98:268-72. https://doi.org/10.1016/j.pbb.2011.01.007
[40] Riedel G, Fadda P, McKillop-Smith S, Pertwee RG, Platt B, Robinson L. Synthetic and plant-derived cannabinoid receptor antagonists show hypophagic properties in fasted and non-fasted mice. Br J Pharmacol 2009;156:1154-66. https://doi.org/10.1111/j.1476-5381.2008.00107.x
[41] McLaughlin PJ, Winston K, Swezey L, Wisniecki A, Aberman J, Tardif DJ, Betz AJ, Ishiwari K, Makriyannis A, Salamone JD. The cannabinoid CB1 antagonists SR 141716A and AM 251 suppress food intake and food-reinforced behavior in a variety of tasks in rats. Behav Pharmacol 2003;14:583-8. https://doi.org/10.1097/00008877-200312000-00002
[42] Siegfried Z, Kanyas K, Latzer Y, Karni O, Bloch M, Lerer B, Berry EM. 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 2004;125:126-30. https://doi.org/10.1002/ajmg.b.20089
[43] Fuss J, Steinle J, Bindila L, Auer MK, Kirchherr H, Lutz B, Gass P. A runner’s high depends on cannabinoid receptors in mice. Proc Natl Acad Sci USA 2015;112:13105-8. https://doi.org/10.1073/pnas.1514996112
[44] Rueda D, Navarro B, Martinez-Serrano A, Guzman M, Galve-Roperh I. The endocannabinoid anandamide inhibits neuro- nal progenitor cell differentiation through attenuation of the Rap1/B. J Biol Chem 2002;277:46645-50. https://doi.org/10.1074/jbc. M206590200
[45] Hansen HS, Kleberg K,Hassing HA. Non- endocannabinoid N-acylethanolamines and monoacylglycerols: old molecules new targets. In: Di Marzo V, Wang J, eds. The Endocannabinoidome. Amsterdam: Academic Press 2015, pp. 1-13. https://doi.org/10.1016/B978-0-12-420126-2.00001-8
[46] Gaetani S, Kaye WH, Cuomo V, Piomelli D. Role of endocannabinoids and their analogues in obesity and eating disorders. Eat Weight Disord 2008;13:e42–e48.
[47] Clayton P, Hill M, Bogoda N, Subah S, Venkatesh R. Palmitoylethanolamide: A Natural Compound for Health Management. Int J Mol Sci 2021;22:5305. https://doi.org/10.3390/ijms22105305
[48] Monteleone AM, Di Marzo V, Aveta T, Piscitelli F, Dalle Grave R, Scognamiglio P, El Ghoch M, Calugi S, Monteleone P, Maj M. Deranged endocannabinoid responses to hedonic eating in underweight and recently weight-restored patients with anorexia nervosa. Am J Clin Nutr 2015;101:262-9. https://doi.org/10.3945/ajcn.114.096164
[49] Giollo A, Idolazzi L, Caimmi C, Fassio A, Bertoldo F, Dalle Grave R, El Ghoch M, Calugi S, Bazzani PV, Viapiana O, Rossini M, Gatti D. Vitamin D levels strongly influence bone mineral density and bone turnover markers during weight gain in female patients with anorexia nervosa. Int J Eat Disord 2017;50:1041-9. https://doi.org/10.1002/eat.22731
[50] Bella VL, Gizzi G, Albi E, Codini M, Marucci S, Ragione L, Beccari T, Ceccarini MR. Vitamin D3 as possible diagnostic marker of Eating Disorders. EuroBiotech J 2021;5:24-33. https://doi.org/10.2478/ebtj-2021-0005
[51] Tasegian A, Curcio F, Dalla Ragione L, Rossetti F, Cataldi S, Codini M, Ambesi-Impiombato FS, Beccari T, Albi E. Hypovitaminosis D3, leukopenia, and human serotonin transporter polymorphism in anorexia nervosa and bulimia nervosa. Mediators Inflamm 2016;8046479. https://doi.org/10.1155/2016/8046479
[52] Groves NJ, McGrath JJ, Burne THJ. Vitamin D as a neurosteroid affecting the developing and adult brain. Annu Rev Nutr 2014;34:117-41. https://doi.org/10.1146/annurev-nutr-071813-105557
[53] Hinney A, Kesselmeier M, Jall S, Volckmar AL, Föcker M, Antel J; GCAN; WTCCC3, Heid IM, Winkler TW; GIANT, Grant SF; EGG, Guo Y, Bergen AW, Kaye W, Berrettini W, Hakonarson H; Price Foundation Collaborative Group; Children’s Hospital of Philadelphia/Price Foundation, Herpertz-Dahlmann B, de Zwaan M, Herzog W, Ehrlich S, Zipfel S, Egberts KM, Adan R, Brandys M, van Elburg A, Boraska Perica V, Franklin CS, Tschöp MH, Zeggini E, Bulik CM, Collier D, Scherag A, Müller TD, Hebebrand J. Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index. Mol Psychiatry 2015;22:192-01. https://doi.org/10.1038/mp.2016.71
[54] Scott-Van Zeeland AA, Bloss CS, Tewhey R, Bansal V, Torkamani A, Libiger O, Duvvuri V, Wineinger N, Galvez L, Darst BF, Smith EN, Carson A, Pham P, Phillips T, Villarasa N, Tisch R, Zhang G, Levy S, Murray S, Chen W, Srinivasan S, Berenson G, Brandt H, Crawford S, Crow S, Fichter MM, Halmi KA, Johnson C, Kaplan AS, La Via M, Mitchell JE, Strober M, Rotondo A, Treasure J, Woodside DB, Bulik CM, Keel P, Klump KL, Lilenfeld L, Plotnicov K, Topol EJ, Shih PB, Magistretti P, Bergen AW, Berrettini W, Kaye W, Schork NJ. Evidence for the role of EPHX2 gene variants in anorexia nervosa. Mol Psychiatry 2014;19:724-32. https://doi.org/10.1038/mp.2013.91
[55] Cui H, Moore J, Ashimi SS, Mason BL, Drawbridge JN, Han S, Hing B, Matthews A, McAdams CJ, Darbro BW, Pieper AA, Waller DA, Xing C, Lutter M. Eating disorder predisposition is associated with ESRRA and HDAC4 mutations. J Clin Invest 2013;123:4706-13. https://doi.org/10.1172/JCI71400
[56] Sild M, Booij L. Histone deacetylase 4 (HDAC4): A new player in anorexia nervosa? Mol Psychiatry 2019;24:1425-34. https://doi.org/10.1038/s41380-019-0366-8
[57] Lombardi L, Blanchet C, Poirier K, Lebrun N, Ramoz N, Rose Moro M, Gorwood P, Bienvenu T. Anorexia nervosa is associated with Neuronatin variants. Psychiatr Genet 2019;29:103-10. https://doi.org/10.1097/YPG.0000000000000224
[58] Lutter M, Bahl E, Hannah C, Hofammann D, Acevedo S, Cui H, McAdams CJ, Michaelson JJ. Novel and ultra-rare damaging variants in neuropeptide signaling are associated with disordered eating behaviors. PLoS One 2017;12:e0181556. https://doi.org/10.1371/journal.pone.0181556
[59] Bienvenu T, Lebrun N, Clarke J, Duriez P, Gorwood P, Ramoz N. De novo deleterious variants that may alter the dopaminergic reward pathway are associated with anorexia nervosa. Eat Weight Disord 2019;1:1-8. https://doi.org/10.1007/s40519-019-00802-9
[60] Bienvenu T, Lebrun N, Clarke J, Duriez P, Gorwood P, Ramoz N. Exome sequencing in a familial form of anorexia ner- vosa supports multigenic etiology. J Neural Transm (Vienna) 2019;126:1505-11. https://doi.org/10.1007/s00702-019-02056-2
[61] Steiger H, Thaler L. Eating disorders, gene-environment interactions and the epigenome: Roles of stress exposures and nutritional status. Physiol Behav 2016;162:181-5. https://doi.org/10.1016/j.physbeh.2016.01.041
[62] Kaye WH, Bailer UF, Frank GK, Wagner A, Henry SE. Brain imaging of serotonin after recovery from anorexia and bulimia nervosa. Physiol Behav 2005;86:15-7. https://doi.org/10.1016/j. physbeh.2005.06.019
[63] Steiger H, Bruce KR, Groleau P. Neural circuits, neurotransmitters, and behavior: serotonin and temperament in bulimic syndromes. Curr Top Behav Neurosci 2011;6:125-38. https://doi.org/10.1007/7854_2010_88
[64] Polsinelli GN, Levitan RN, De Luca V. 5-HTTLPR polymorphism in bulimia nervosa: a multiple-model meta-analysis. Psychiatr Genet 2012;22:219-25. https://doi.org/10.1097/YPG.0b013e32835669b3
[65] Berner LA, Winter SR, Matheson BE, Benson L, Lowe MR. Behind binge eating: A review of food-specific adaptations of neurocognitive and neuroimaging tasks. Physiol Behav 2017;176:59-70. https://doi.org/10.1016/j.physbeh.2017.03.037
[66] Kalyanasundar B, Perez CI, Luna A. D1 and D2 antagonists reverse the effects of appetite suppressants on weight loss, food intake, locomotion, and rebalance spiking inhibition in the rat NAc shell. J Neurophysiol 2015;114:585-607. https://doi.org/10.1152/jn.00012.2015
[67] Avena NM, Rada P, Hoebel BG. Underweight rats have enhanced dopamine release and blunted acetylcholine response in the nucleus accumbens while bingeing on sucrose. Neuroscience 2008;156:865-71. https://doi.org/10.1016/j.neuroscience.2008.08.017
[68] Valbrun LP, Zvonarev V. The opioid system and food intake: use of opiate antagonists in treatment of binge eating disorder and abnormal eating behavior. J Clin Med Res 2020;12:41-63. https://doi.org/10.14740/jocmr4066
[69] Monteleone P, Tortorella A, Castaldo E. No association of the Arg51Gln and Leu72Met polymorphisms of the ghrelin gene with anorexia nervosa or bulimia nervosa. Neurosci Lett. 2006;398:325-
7. https://doi.org/10.1016/j.neulet.2006.01.023
[70] Homan P, Grob S, Milos G, Schnyder U, Eckert A, Lang U, Hasler G. The role of BDNF, leptin, and catecholamines in reward learning in bulimia nervosa. Int J Neuropsychopharmacol 2014;18:pyu092. https://doi.org/10.1093/ijnp/pyu092
[71] Eddy KT, Lawson EA, Meade C, Meenaghan E, Horton SE, Misra M, Klibanski A, Miller KK. Appetite regulatory hormones in women with anorexia nervosa: Binge-eating/purging versus restricting type. J Clin Psychiatry 2015;76:19-24. https://doi.org/10.4088/JCP.13m08753
[72] Smitka K, Papezova H, Vondra K, Hill M, Hainer V, Nedvidkova J. The role of “mixed” orexigenic and anorexigenic signals and autoantibodies reacting with appetite-regulating neuropeptides and peptides of the adipose tissue-gut-brain axis: relevance to food intake and nutritional status in patients with anorexia nervosa and bulimia nervosa. Int J Endocrinol 2013;2013:483145. https://doi.org/10.1155/2013/483145
[73] Dossat AM, Bodell LP, Williams DL, Eckel LA, Keel PK. Preliminary examination of glucagon-like peptide-1 levels in women with purging disorder and bulimia nervosa. Int J Eat Disord 2015;48:199-205. https://doi.org/10.1002/eat.22264
[74] Scherma M, Fattore L, Castelli MP, Fratta W, Fadda P. The role of the endocannabinoid system in eating disorders: neurochemical and behavioural preclinical evidence. Curr Pharm Des 2014;20:2089-99. https://doi.org/10.2174/13816128113199990429
[75] Mayhew AJ, Pigeyre M, Couturier J, Meyre D. An evolutionary genetic perspective of eating disorders. Neuroendocrinology 2018;106:292-306. https://doi.org/10.1159/000484525
[76] Koren R, Duncan AE, Munn-Chernoff MA, Bucholz KK, Lynskey MT, Heath AC, Agrawal A. Preliminary evidence for the role of HTR2A variants in binge eating in young women. Psychiatr Genet 2014;24:28-33. https://doi.org/10.1097/YPG.0000000000000014
[77] McCuen-Wurst C, Ruggieri M, Allison KC. Disordered eating and obesity: associations between binge-eating disorder, night-eating syndrome, and weight-related comorbidities. Ann N Y Acad Sci 2018;1411:96-105. https://doi.org/10.1111/nyas.13467
[78] Manfredi L, Accoto A, Couyoumdjian A, Conversi D. A systematic review of genetic polymorphisms associated with binge eating disorder. Nutrients 2021;13:848. https://doi.org/10.3390/nu13030848
[79] Davis C, Levitan RD, Kaplan AS, Carter J, Reid C, Curtis C, Patte K, Hwang R, Kennedy JL. Reward sensitivity and the D2 dopamine receptor gene: a case-control study of binge eating disorder. Prog Neuropsychopharmacol Biol Psychiatry 2008;32:620-8. https://doi.org/10.1016/j.pnpbp.2007.09.024
[80] Palacios A, Canto P, Tejeda ME, Stephano S, Luján H, García-García E, Rojano-Mejía D, Méndez JP. Complete sequence of the ANKK1 gene in Mexican-Mestizo individuals with obesity, with or without binge eating disorder. Eur Psychiatry 2018;54:59-64. https://doi.org/10.1016/j.eurpsy.2018.07.010
[81] Naleid AM, Grace MK, Chimukangara M, Billington CJ, Levine AS. Paraventricular opioids alter intake of high-fat but not high-sucrose diet depending on diet preference in a binge model of feeding. Am J Physiol Regul Integr Comp Physiol 2007;293:99.105. https://doi.org/10.1152/ajpregu.00675.2006
[82] Popik P, Kos T, Zhang Y, Bisaga A. Memantine reduces consumption of highly palatable food in a rat model of binge eating. Amino Acids 2011;40:477-85. https://doi.org/10.1007/s00726-010-0659-3
[83] Keski-Rahkonen A, Mustelin L. Epidemiology of eating disorders in Europe: Prevalence, incidence, comorbidity, course, consequences, and risk factors. Curr Opin Psychiatry 2016;29:340-5. https://doi.org/10.1097/YCO.0000000000000278
[84] Hübel C, Abdulkadir M, Herle M, Loos RJF, Breen G, Bulik CM, Micali N. One size does not fit all. Genomics differentiates among anorexia nervosa, bulimia nervosa, and binge-eating disorder. Int J Eat Disord 2021;54:785-793. https://doi.org/10.1002/eat.23481
[85] Bulik CM, Thornton LM, Parker R, Kennedy H, Baker JH, MacDermod C, Guintivano J, Cleland L, Miller AL, Harper L, Larsen JT, Yilmaz Z, Grove J, Sullivan PF, Petersen LV, Jordan J, Kennedy MA, Martin NG. The Eating Disorders Genetics Initiative (EDGI): study protocol. BMC Psychiatry 2021;21:234. https://doi.org/10.1186/s12888-021-03212-3