We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

Discussing the putative role of obesity-associated genes in the etiopathogenesis of eating disorders

    Guillermo Gervasini

    *Author for correspondence:

    E-mail Address: ggervasi@unex.es

    Department of Medical & Surgical Therapeutics, Division of Pharmacology, Medical School, University of Extremadura, Av. Elvas s/n, E-06005, Badajoz, Spain

    &
    Carmen Gamero-Villarroel

    Department of Medical & Surgical Therapeutics, Division of Pharmacology, Medical School, University of Extremadura, Av. Elvas s/n, E-06005, Badajoz, Spain

    Published Online:https://doi.org/10.2217/pgs.15.77

    In addition to the identification of mutations clearly related to Mendelian forms of obesity; genome-wide association studies and follow-up studies have in the last years pinpointed several loci associated with BMI. These genetic alterations are located in or near genes expressed in the hypothalamus that are involved in the regulation of eating behavior. Accordingly, it seems plausible that these SNPs, or others located in related genes, could also help develop aberrant conduct patterns that favor the establishment of eating disorders should other susceptibility factors or personality dimensions be present. However, and somewhat surprisingly, with few exceptions such as BDNF, the great majority of the genes governing these pathways remain untested in patients with anorexia nervosa, bulimia nervosa or binge-eating disorder. In the present work, we review the few existing studies, but also indications and biological concepts that point to these genes in the CNS as good candidates for association studies with eating disorder patients.

    References

    • 1 Herpertz-Dahlmann B. Adolescent eating disorders: definitions, symptomatology, epidemiology and comorbidity. Child Adolesc. Psychiatr. Clin. N. Am. 18(1), 31–47 (2009).
    • 2 Bergh C, Sodersten P. Anorexia nervosa: rediscovery of a disorder. Lancet 351(9113), 1427–1429 (1998).
    • 3 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. American Psychiatric Press, Washington, DC, USA (2013).
    • 4 Hoek HW. Incidence, prevalence and mortality of anorexia nervosa and other eating disorders. Curr. Opin. Psychiatry 19(4), 389–394 (2006).
    • 5 Chandra PS, Abbas S, Palmer R. Are eating disorders a significant clinical issue in urban india? A survey among psychiatrists in Bangalore. Int. J. Eat. Disord. 45(3), 443–446 (2012).
    • 6 Eddy KT, Hennessey M, Thompson-Brenner H. Eating pathology in east african women: the role of media exposure and globalization. J. Nerv. Ment. Dis. 195(3), 196–202 (2007).
    • 7 Hudson JI, Hiripi E, Pope HG Jr, Kessler RC. The prevalence and correlates of eating disorders in the national comorbidity survey replication. Biol. Psychiatry 61(3), 348–358 (2007).
    • 8 Mendolicchio L, Maggio G, Fortunato F, Ragione LD. Update on eating disorders: epidemiology, mortality and comorbidity. Psychiatr. Danub. 26(Suppl. 1), 85–88 (2014).
    • 9 Tozzi F, Thornton LM, Klump KL et al. Symptom fluctuation in eating disorders: correlates of diagnostic crossover. Am. J. Psychiatry 162(4), 732–740 (2005).
    • 10 Bulik CM, Thornton LM, Root TL, Pisetsky EM, Lichtenstein P, Pedersen NL. Understanding the relation between anorexia nervosa and bulimia nervosa in a swedish national twin sample. Biol. Psychiatry 67(1), 71–77 (2010).
    • 11 Gillberg C, Rastam M. The etiology of anorexia nervosa. In: Neurobiology in the Treatment of Eating Disorders. Hoek HW, Treasure JL, Katzman MA (Eds). John Wiley & Sons Ltd, Chichester, UK, 127–141 (1998).
    • 12 Palmer RL. The aetiology of bulimia nervosa. In: Neurobiology in the Treatment of Eating Disorders. Hoek HW, Treasure JL, Katzman MA (Eds). John Wiley & Sons Ltd, Chichester, UK, 143–159 (1998).
    • 13 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 157(3), 393–401 (2000).
    • 14 Bulik CM, Sullivan PF, Kendler KS. Heritability of binge-eating and broadly defined bulimia nervosa. Biol. Psychiatry 44(12), 1210–1218 (1998).
    • 15 Bulik CM, Sullivan PF, Wade TD, Kendler KS. Twin studies of eating disorders: a review. Int. J. Eat. Disord. 27(1), 1–20 (2000).
    • 16 Gorwood P, Kipman A, Foulon C. The human genetics of anorexia nervosa. Eur. J. Pharmacol. 480(1–3), 163–170 (2003).
    • 17 Kipman A, Gorwood P, Mouren-Simeoni MC, Ades J. Genetic factors in anorexia nervosa. Eur. Psychiatry 14(4), 189–198 (1999).
    • 18 Klump KL, Miller KB, Keel PK, McGue M, Iacono WG. Genetic and environmental influences on anorexia nervosa syndromes in a population-based twin sample. Psychol. Med. 31(4), 737–740 (2001).
    • 19 Thornton LM, Mazzeo SE, Bulik CM. The heritability of eating disorders: methods and current findings. Curr. Top. Behav. Neurosci. 6, 141–156 (2011).
    • 20 Klump KL, Burt SA, McGue M, Iacono WG. Changes in genetic and environmental influences on disordered eating across adolescence: a longitudinal twin study. Arch. Gen. Psychiatry 64(12), 1409–1415 (2007).
    • 21 Keski-Rahkonen A, Neale BM, Bulik CM et al. Intentional weight loss in young adults: sex-specific genetic and environmental effects. Obes. Res. 13(4), 745–753 (2005).
    • 22 Wade TD, Treloar SA, Heath AC, Martin NG. An examination of the overlap between genetic and environmental risk factors for intentional weight loss and overeating. Int. J. Eat. Disord. 42(6), 492–497 (2009).
    • 23 Schur E, Noonan C, Polivy J, Goldberg J, Buchwald D. Genetic and environmental influences on restrained eating behavior. Int. J. Eat. Disord. 42(8), 765–772 (2009).
    • 24 Neale BM, Mazzeo SE, Bulik CM. A twin study of dietary restraint, disinhibition and hunger: an examination of the eating inventory (three factor eating questionnaire). Twin Res. 6(6), 471–478 (2003).
    • 25 Garner DM, Olmsted MP, Polivy J. Development and validation of a multidimensional eating disorder inventory for anorexia nervosa and bulimia. Int. J. Eat. Disord. 2(2), 15–34 (1983).
    • 26 Keski-Rahkonen A, Bulik CM, Neale BM, Rose RJ, Rissanen A, Kaprio J. Body dissatisfaction and drive for thinness in young adult twins. Int. J. Eat. Disord. 37(3), 188–199 (2005).
    • 27 Rutherford J, McGuffin P, Katz RJ, Murray RM. Genetic influences on eating attitudes in a normal female twin population. Psychol. Med. 23(2), 425–436 (1993).
    • 28 Kamakura T, Ando J, Ono Y, Maekawa H. A twin study of genetic and environmental influences on psychological traits of eating disorders in a Japanese female sample. Twin Res. 6(4), 292–296 (2003).
    • 29 Wade TD, Tiggemann M, Bulik CM, Fairburn CG, Wray NR, Martin NG. Shared temperament risk factors for anorexia nervosa: a twin study. Psychosom. Med. 70(2), 239–244 (2008).
    • 30 Root TL, Thornton LM, Lindroos AK et al. Shared and unique genetic and environmental influences on binge eating and night eating: a Swedish twin study. Eat. Behav. 11(2), 92–98 (2010).
    • 31 Sullivan PF, Bulik CM, Kendler KS. Genetic epidemiology of binging and vomiting. Br. J. Psychiatry 173, 75–79 (1998).
    • 32 Wade TD, Treloar S, Martin NG. Shared and unique risk factors between lifetime purging and objective binge eating: a twin study. Psychol. Med. 38(10), 1455–1464 (2008).
    • 33 Consortium C-DGOTPG. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 381(9875), 1371–1379 (2013).
    • 34 Hebebrand J, Scherag A, Schimmelmann BG, Hinney A. Child and adolescent psychiatric genetics. Eur. Child Adolesc. Psychiatry 19(3), 259–279 (2010).
    • 35 Nakabayashi K, Komaki G, Tajima A et al. Identification of novel candidate loci for anorexia nervosa at 1q41 and 11q22 in Japanese by a genome-wide association analysis with microsatellite markers. J. Hum. Genet. 54(9), 531–537 (2009).
    • 36 Wang K, Zhang H, Bloss CS et al. A genome-wide association study on common snps and rare cnvs in anorexia nervosa. Mol. Psychiatry 16(9), 949–959 (2011).
    • 37 Boraska V, Franklin CS, Floyd JA et al. A genome-wide association study of anorexia nervosa. Mol. Psychiatry 19(10), 1085–1094 (2014).
    • 38 Wade TD, Gordon S, Medland S et al. Genetic variants associated with disordered eating. Int. J. Eat. Disord. 46(6), 594–608 (2013).
    • 39 Trace SE, Baker JH, Penas-Lledo E, Bulik CM. The genetics of eating disorders. Annu. Rev. Clin. Psychol. 9, 589–620 (2013).
    • 40 Himmerich H, Schonknecht P, Heitmann S, Sheldrick AJ. Laboratory parameters and appetite regulators in patients with anorexia nervosa. J. Psychiatr. Pract. 16(2), 82–92 (2010).
    • 41 Ando T, Kodama N, Ishikawa T et al. Uncoupling protein-2/uncoupling protein-3 gene polymorphism is not associated with anorexia nervosa. Psychiatr. Genet. 14(4), 215–218 (2004).
    • 42 Campbell DA, Sundaramurthy D, Gordon D, Markham AF, Pieri LF. Association between a marker in the ucp-2/ucp-3 gene cluster and genetic susceptibility to anorexia nervosa. Mol. Psychiatry 4(1), 68–70 (1999).
    • 43 Ando T, Ishikawa T, Kawamura N et al. Analysis of tumor necrosis factor-alpha gene promoter polymorphisms in anorexia nervosa. Psychiatr. Genet. 11(3), 161–164 (2001).
    • 44 Kanbur N, Mesci L, Derman O et al. Tumor necrosis factor alpha-308 gene polymorphism in patients with anorexia nervosa. Turk. J. Pediatr. 50(3), 219–222 (2008).
    • 45 Zhang C, Chen J, Jia X et al. Estrogen receptor 1 gene rs2295193 polymorphism and anorexia nervosa: new data and meta-analysis. Asia Pac. Psychiatry 5(4), 331–335 (2013).
    • 46 Slof-Op ‘T Landt MC, Van Furth EF, Meulenbelt I et al. Association study of the estrogen receptor I gene (esr1) in anorexia nervosa and eating disorders: no replication found. Int. J. Eat. Disord. 47(2), 211–214 (2014).
    • 47 Koronyo-Hamaoui M, Frisch A, Stein D et al. Dual contribution of nr2b subunit of nmda receptor and sk3 ca(2+)-activated k+ channel to genetic predisposition to anorexia nervosa. J. Psychiatr. Res. 41(1–2), 160–167 (2007).
    • 48 Monteleone P, Tortorella A, Docimo L et al. Investigation of 3111t/c polymorphism of the clock gene in obese individuals with or without binge eating disorder: association with higher body mass index. Neurosci. Lett. 435(1), 30–33 (2008).
    • 49 Tortorella A, Monteleone P, Martiadis V, Perris F, Maj M. The 3111t/c polymorphism of the clock gene confers a predisposition to a lifetime lower body weight in patients with anorexia nervosa and bulimia nervosa: a preliminary study. Am. J. Med. Genet. B Neuropsychiatr. Genet. 144B(8), 992–995 (2007).
    • 50 Rask-Andersen M, Olszewski PK, Levine AS, Schioth HB. Molecular mechanisms underlying anorexia nervosa: focus on human gene association studies and systems controlling food intake. Brain Res. Rev. 62(2), 147–164 (2010).
    • 51 Monteleone P, Maj M. Genetic susceptibility to eating disorders: associated polymorphisms and pharmacogenetic suggestions. Pharmacogenomics 9(10), 1487–1520 (2008).
    • 52 Hinney A, Volckmar AL. Genetics of eating disorders. Curr. Psychiatry Rep. 15(12), 423 (2013).
    • 53 Scherag S, Hebebrand J, Hinney A. Eating disorders: the current status of molecular genetic research. Eur. Child Adolesc. Psychiatry 19(3), 211–226 (2010).
    • 54 Waalen J. The genetics of human obesity. Transl. Res. 164(4), 293–301 (2014).
    • 55 Olszewski PK, Cedernaes J, Olsson F, Levine AS, Schioth HB. Analysis of the network of feeding neuroregulators using the allen brain atlas. Neurosci. Biobehav. Rev. 32(5), 945–956 (2008).
    • 56 Day J, Ternouth A, Collier DA. Eating disorders and obesity: two sides of the same coin? Epidemiol. Psychiatr. Soc. 18(2), 96–100 (2009).
    • 57 Lee WW. An overview of pediatric obesity. Pediatr. Diabetes 8(Suppl. 9), 76–87 (2007).
    • 58 Speakman JR. Evolutionary perspectives on the obesity epidemic: adaptive, maladaptive, and neutral viewpoints. Annu. Rev. Nutr. 33, 289–317 (2013).
    • 59 Guisinger S. Adapted to flee famine: adding an evolutionary perspective on anorexia nervosa. Psychol. Rev. 110(4), 745–761 (2003).
    • 60 Bouchard L, Drapeau V, Provencher V et al. Neuromedin beta: a strong candidate gene linking eating behaviors and susceptibility to obesity. Am. J. Clin. Nutr. 80(6), 1478–1486 (2004).
    • 61 Kim HJ, Yoo YJ, Ju YS et al. Combined linkage and association analyses identify a novel locus for obesity near prox1 in asians. Obesity (Silver Spring) 21(11), 2405–2412 (2013).
    • 62 Bulik CM, Devlin B, Bacanu SA et al. Significant linkage on chromosome 10p in families with bulimia nervosa. Am. J. Hum. Genet. 72(1), 200–207 (2003).
    • 63 Blakemore AI, Froguel P. Investigation of mendelian forms of obesity holds out the prospect of personalized medicine. Ann. NY Acad. Sci. 1214, 180–189 (2010).
    • 64 Hennigan A, O'callaghan RM, Kelly AM. Neurotrophins and their receptors: roles in plasticity, neurodegeneration and neuroprotection. Biochem. Soc. Trans. 35(Pt 2), 424–427 (2007).
    • 65 Kernie SG, Liebl DJ, Parada LF. Bdnf regulates eating behavior and locomotor activity in mice. EMBO J. 19(6), 1290–1300 (2000).
    • 66 Rosas-Vargas H, Martinez-Ezquerro JD, Bienvenu T. Brain-derived neurotrophic factor, food intake regulation, and obesity. Arch. Med. Res. 42(6), 482–494 (2011).
    • 67 Fox EA, Byerly MS. A mechanism underlying mature-onset obesity: evidence from the hyperphagic phenotype of brain-derived neurotrophic factor mutants. Am. J. Physiol. Regul. Integr. Comp. Physiol. 286(6), R994–R1004 (2004).
    • 68 Rios M, Fan G, Fekete C et al. Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity. Mol. Endocrinol. 15(10), 1748–1757 (2001).
    • 69 Rodriguez-Lopez R, Perez JM, Balsera AM et al. The modifier effect of the BDNF gene in the phenotype of the wagro syndrome. Gene 516(2), 285–290 (2013).
    • 70 Cordeira J, Rios M. Weighing in the role of BDNF in the central control of eating behavior. Mol. Neurobiol. 44(3), 441–448 (2011).
    • 71 Rios M. New insights into the mechanisms underlying the effects of BDNF on eating behavior. Neuropsychopharmacology 36(1), 368–369 (2011).
    • 72 Gray J, Yeo GS, Cox JJ et al. Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene. Diabetes 55(12), 3366–3371 (2006).
    • 73 Burns B, Schmidt K, Williams SR, Kim S, Girirajan S, Elsea SH. Rai1 haploinsufficiency causes reduced BDNF expression resulting in hyperphagia, obesity and altered fat distribution in mice and humans with no evidence of metabolic syndrome. Hum. Mol. Genet. 19(20), 4026–4042 (2010).
    • 74 Monteleone P, Tortorella A, Martiadis V, Serritella C, Fuschino A, Maj M. Opposite changes in the serum brain-derived neurotrophic factor in anorexia nervosa and obesity. Psychosom. Med. 66(5), 744–748 (2004).
    • 75 Nakazato M, Hashimoto K, Shimizu E et al. Decreased levels of serum brain-derived neurotrophic factor in female patients with eating disorders. Biol. Psychiatry 54(4), 485–490 (2003).
    • 76 Phillips K, Keane K, Wolfe BE. Peripheral brain derived neurotrophic factor (BDNF) in bulimia nervosa: a systematic review. Arch. Psychiatr. Nurs. 28(2), 108–113 (2014).
    • 77 Brandys MK, Kas MJ, Van Elburg AA, Campbell IC, Adan RA. A meta-analysis of circulating BDNF concentrations in anorexia nervosa. World J. Biol. Psychiatry 12(6), 444–454 (2011).
    • 78 Dmitrzak-Weglarz M, Skibinska M, Slopien A et al. Serum neurotrophin concentrations in polish adolescent girls with anorexia nervosa. Neuropsychobiology 67(1), 25–32 (2013).
    • 79 Mercader JM, Fernandez-Aranda F, Gratacos M et al. Correlation of BDNF blood levels with interoceptive awareness and maturity fears in anorexia and bulimia nervosa patients. J. Neural Transm. 117(4), 505–512 (2010).
    • 80 Mercader JM, Fernandez-Aranda F, Gratacos M et al. Blood levels of brain-derived neurotrophic factor correlate with several psychopathological symptoms in anorexia nervosa patients. Neuropsychobiology 56(4), 185–190 (2007).
    • 81 Mercader JM, Ribases M, Gratacos M et al. Altered brain-derived neurotrophic factor blood levels and gene variability are associated with anorexia and bulimia. Genes Brain Behav. 6(8), 706–716 (2007).
    • 82 Egan MF, Kojima M, Callicott JH et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112(2), 257–269 (2003).
    • 83 Ventriglia M, Bocchio Chiavetto L, Benussi L et al. Association between the BDNF 196 a/g polymorphism and sporadic Alzheimer's disease. Mol. Psychiatry 7(2), 136–137 (2002).
    • 84 Momose Y, Murata M, Kobayashi K et al. Association studies of multiple candidate genes for parkinson's disease using single nucleotide polymorphisms. Ann. Neurol. 51(1), 133–136 (2002).
    • 85 Sen S, Nesse RM, Stoltenberg SF et al. A BDNF coding variant is associated with the neo personality inventory domain neuroticism, a risk factor for depression. Neuropsychopharmacology 28(2), 397–401 (2003).
    • 86 Neves-Pereira M, Mundo E, Muglia P, King N, Macciardi F, Kennedy JL. The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study. Am. J. Hum. Genet. 71(3), 651–655 (2002).
    • 87 Croteau-Chonka DC, Marvelle AF, Lange EM et al. Genome-wide association study of anthropometric traits and evidence of interactions with age and study year in filipino women. Obesity (Silver Spring) 19(5), 1019–1027 (2011).
    • 88 Beckers S, Peeters A, Zegers D, Mertens I, Van Gaal L, Van Hul W. Association of the BDNF val66met variation with obesity in women. Mol. Genet. Metab. 95(1–2), 110–112 (2008).
    • 89 Skledar M, Nikolac M, Dodig-Curkovic K, Curkovic M, Borovecki F, Pivac N. Association between brain-derived neurotrophic factor val66met and obesity in children and adolescents. Prog. Neuropsychopharmacol. Biol. Psychiatry 36(1), 136–140 (2012).
    • 90 Brandys MK, Kas MJ, Van Elburg AA et al. The val66met polymorphism of the BDNF gene in anorexia nervosa: new data and a meta-analysis. World J. Biol. Psychiatry 14(6), 441–451 (2013).
    • 91 Ribases M, Gratacos M, Armengol L et al. Met66 in the brain-derived neurotrophic factor (BDNF) precursor is associated with anorexia nervosa restrictive type. Mol. Psychiatry 8(8), 745–751 (2003).
    • 92 Kunugi H, Ueki A, Otsuka M et al. A novel polymorphism of the brain-derived neurotrophic factor (BDNF) gene associated with late-onset Alzheimer's disease. Mol. Psychiatry 6(1), 83–86 (2001).
    • 93 Watanabe Y, Muratake T, Kaneko N, Nunokawa A, Someya T. No association between the brain-derived neurotrophic factor gene and schizophrenia in a Japanese population. Schizophr. Res. 84(1), 29–35 (2006).
    • 94 Xu M, Li S, Xing Q et al. Genetic variants in the BDNF gene and therapeutic response to risperidone in schizophrenia patients: a pharmacogenetic study. Eur. J. Hum. Genet. 18(6), 707–712 (2010).
    • 95 Nishimura M, Kuno S, Kaji R, Kawakami H. Brain-derived neurotrophic factor gene polymorphisms in Japanese patients with sporadic Alzheimer's disease, parkinson's disease, and multiple system atrophy. Mov. Disord. 20(8), 1031–1033 (2005).
    • 96 Kishikawa S, Li JL, Gillis T et al. Brain-derived neurotrophic factor does not influence age at neurologic onset of Huntington's disease. Neurobiol. Dis. 24(2), 280–285 (2006).
    • 97 Ribases M, Gratacos M, Fernandez-Aranda F et al. Association of BDNF with anorexia, bulimia and age of onset of weight loss in six European populations. Hum. Mol. Genet. 13(12), 1205–1212 (2004).
    • 98 Martinowich K, Manji H, Lu B. New insights into BDNF function in depression and anxiety. Nat. Neurosci. 10(9), 1089–1093 (2007).
    • 99 Carvalho AL, Caldeira MV, Santos SD, Duarte CB. Role of the brain-derived neurotrophic factor at glutamatergic synapses. Br. J. Pharmacol. 153(Suppl. 1), S310–S324 (2008).
    • 100 Berton O, Mcclung CA, Dileone RJ et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311(5762), 864–868 (2006).
    • 101 Hyman C, Hofer M, Barde YA et al. Bdnf is a neurotrophic factor for dopaminergic neurons of the substantia nigra. Nature 350(6315), 230–232 (1991).
    • 102 Terracciano A, Tanaka T, Sutin AR et al. BDNF val66met is associated with introversion and interacts with 5-HTTLPR to influence neuroticism. Neuropsychopharmacology 35(5), 1083–1089 (2010).
    • 103 Lang UE, Hellweg R, Kalus P et al. Association of a functional BDNF polymorphism and anxiety-related personality traits. Psychopharmacology (Berl.) 180(1), 95–99 (2005).
    • 104 Terracciano A, Martin B, Ansari D et al. Plasma BDNF concentration, val66met genetic variant and depression-related personality traits. Genes Brain Behav. 9(5), 512–518 (2010).
    • 105 Lang UE, Hellweg R, Gallinat J. BDNF serum concentrations in healthy volunteers are associated with depression-related personality traits. Neuropsychopharmacology 29(4), 795–798 (2004).
    • 106 Rybakowski F, Dmitrzak-Weglarz M, Szczepankiewicz A et al. Brain derived neurotrophic factor gene val66met and -270c/t polymorphisms and personality traits predisposing to anorexia nervosa. Neuro. Endocrinol. Lett. 28(2), 153–158 (2007).
    • 107 Gamero-Villarroel C, Gordillo I, Carrillo JA et al. Bdnf genetic variability modulates psychopathological symptoms in patients with eating disorders. Eur. Child Adolesc. Psychiatry 23(8), 669–679 (2014).
    • 108 Ando T, Ishikawa T, Hotta M et al. No association of brain-derived neurotrophic factor val66met polymorphism with anorexia nervosa in Japanese. Am. J. Med. Genet. B Neuropsychiatr. Genet. 159B(1), 48–52 (2012).
    • 109 Tao YX. The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology. Endocr. Rev. 31(4), 506–543 (2010).
    • 110 Mountjoy KG, Mortrud MT, Low MJ, Simerly RB, Cone RD. Localization of the melanocortin-4 receptor (mc4-r) in neuroendocrine and autonomic control circuits in the brain. Mol. Endocrinol. 8(10), 1298–1308 (1994).
    • 111 Huszar D, Lynch CA, Fairchild-Huntress V et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88(1), 131–141 (1997).
    • 112 Yeo GS, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG, O'Rahilly S. A frameshift mutation in mc4r associated with dominantly inherited human obesity. Nat. Genet. 20(2), 111–112 (1998).
    • 113 Vaisse C, Clement K, Guy-Grand B, Froguel P. A frameshift mutation in human mc4r is associated with a dominant form of obesity. Nat. Genet. 20(2), 113–114 (1998).
    • 114 Farooqi S, O'rahilly S. Genetics of obesity in humans. Endocr. Rev. 27(7), 710–718 (2006).
    • 115 Vaisse C, Clement K, Durand E, Hercberg S, Guy-Grand B, Froguel P. Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J. Clin. Invest. 106(2), 253–262 (2000).
    • 116 Hebebrand J, Fichter M, Gerber G et al. Genetic predisposition to obesity in bulimia nervosa: a mutation screen of the melanocortin-4 receptor gene. Mol. Psychiatry 7(6), 647–651 (2002).
    • 117 Sina M, Hinney A, Ziegler A et al. Phenotypes in three pedigrees with autosomal dominant obesity caused by haploinsufficiency mutations in the melanocortin-4 receptor gene. Am. J. Hum. Genet. 65(6), 1501–1507 (1999).
    • 118 Branson R, Potoczna N, Kral JG, Lentes KU, Hoehe MR, Horber FF. Binge eating as a major phenotype of melanocortin 4 receptor gene mutations. N. Engl. J. Med. 348(12), 1096–1103 (2003).
    • 119 Potoczna N, Branson R, Kral JG et al. Gene variants and binge eating as predictors of comorbidity and outcome of treatment in severe obesity. J. Gastrointest. Surg. 8(8), 971–981; discussion 981–972 (2004).
    • 120 Tao YX, Segaloff DL. Functional analyses of melanocortin-4 receptor mutations identified from patients with binge eating disorder and nonobese or obese subjects. J. Clin. Endocrinol. Metab. 90(10), 5632–5638 (2005).
    • 121 Hebebrand J, Geller F, Dempfle A et al. Binge-eating episodes are not characteristic of carriers of melanocortin-4 receptor gene mutations. Mol. Psychiatry 9(8), 796–800 (2004).
    • 122 Lubrano-Berthelier C, Dubern B, Lacorte JM et al. Melanocortin 4 receptor mutations in a large cohort of severely obese adults: prevalence, functional classification, genotype-phenotype relationship, and lack of association with binge eating. J. Clin. Endocrinol. Metab. 91(5), 1811–1818 (2006).
    • 123 Valette M, Poitou C, Kesse-Guyot E et al. Association between melanocortin-4 receptor mutations and eating behaviors in obese patients: a case-control study. Int. J. Obes. (Lond.) 38(6), 883–885 (2013).
    • 124 Stutzmann F, Cauchi S, Durand E et al. Common genetic variation near mc4r is associated with eating behaviour patterns in european populations. Int. J. Obes. (Lond.) 33(3), 373–378 (2009).
    • 125 Gamero-Villarroel C, Rodriguez-Lopez R, Jimenez M et al. Melanocortin-4 receptor gene variants are not associated with binge-eating behavior in nonobese patients with eating disorders. Psychiatr. Genet. 25(1), 35–38 (2014).
    • 126 Yilmaz Z, Kaplan AS, Tiwari AK et al. The role of leptin, melanocortin, and neurotrophin system genes on body weight in anorexia nervosa and bulimia nervosa. J. Psychiatr. Res. 55, 77–86 (2014).
    • 127 Brandys MK, Van Elburg AA, Loos RJ et al. Are recently identified genetic variants regulating bmi in the general population associated with anorexia nervosa? Am. J. Med. Genet. B Neuropsychiatr. Genet. 153B(2), 695–699 (2010).
    • 128 Horstmann A, Kovacs P, Kabisch S et al. Common genetic variation near mc4r has a sex-specific impact on human brain structure and eating behavior. PLoS ONE 8(9), e74362 (2013).
    • 129 Han Z, Niu T, Chang J et al. Crystal structure of the fto protein reveals basis for its substrate specificity. Nature 464(7292), 1205–1209 (2010).
    • 130 Hess ME, Hess S, Meyer KD et al. The fat mass and obesity associated gene (fto) regulates activity of the dopaminergic midbrain circuitry. Nat. Neurosci. 16(8), 1042–1048 (2013).
    • 131 Frayling TM, Timpson NJ, Weedon MN et al. A common variant in the fto gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316(5826), 889–894 (2007).
    • 132 Scuteri A, Sanna S, Chen WM et al. Genome-wide association scan shows genetic variants in the fto gene are associated with obesity-related traits. PLoS Genet. 3(7), e115 (2007).
    • 133 Liu C, Mou S, Cai Y. Fto gene variant and risk of overweight and obesity among children and adolescents: a systematic review and meta-analysis. PLoS ONE 8(11), e82133 (2013).
    • 134 Peters U, North KE, Sethupathy P et al. A systematic mapping approach of 16q12.2/fto and bmi in more than 20,000 African Americans narrows in on the underlying functional variation: results from the population architecture using genomics and epidemiology (page) study. PLoS Genet. 9(1), e1003171 (2013).
    • 135 Fischer J, Koch L, Emmerling C et al. Inactivation of the fto gene protects from obesity. Nature 458(7240), 894–898 (2009).
    • 136 Church C, Moir L, Mcmurray F et al. Overexpression of fto leads to increased food intake and results in obesity. Nat. Genet. 42(12), 1086–1092 (2010).
    • 137 Peng S, Zhu Y, Xu F, Ren X, Li X, Lai M. Fto gene polymorphisms and obesity risk: a meta-analysis. BMC Med. 9, 71 (2011).
    • 138 Muller TD, Greene BH, Bellodi L et al. Fat mass and obesity-associated gene (fto) in eating disorders: evidence for association of the rs9939609 obesity risk allele with bulimia nervosa and anorexia nervosa. Obes. Facts 5(3), 408–419 (2012).
    • 139 Jonassaint CR, Szatkiewicz JP, Bulik CM et al. Absence of association between specific common variants of the obesity-related fto gene and psychological and behavioral eating disorder phenotypes. Am. J. Med. Genet. B Neuropsychiatr. Genet. 156B(4), 454–461 (2011).
    • 140 Fairburn CG, Welch SL, Doll HA, Davies BA, O'connor ME. Risk factors for bulimia nervosa. A community-based case-control study. Arch. Gen. Psychiatry 54(6), 509–517 (1997).
    • 141 Smemo S, Tena JJ, Kim KH et al. Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature 507(7492), 371–375 (2014).
    • 142 Stratigopoulos G, Martin Carli JF, O'day DR et al. Hypomorphism for rpgrip1l, a ciliary gene vicinal to the fto locus, causes increased adiposity in mice. Cell Metab. 19(5), 767–779 (2014).
    • 143 Bell CG, Finer S, Lindgren CM et al. Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus. PLoS ONE 5(11), e14040 (2010).
    • 144 Marg A, Sirim P, Spaltmann F et al. Neurotractin, a novel neurite outgrowth-promoting Ig-like protein that interacts with CEPU-1 and LAMP. J. Cell Biol. 145(4), 865–876 (1999).
    • 145 Lee AW, Hengstler H, Schwald K et al. Functional inactivation of the genome-wide association study obesity gene neuronal growth regulator 1 in mice causes a body mass phenotype. PLoS ONE 7(7), e41537 (2012).
    • 146 Speliotes EK, Willer CJ, Berndt SI et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat. Genet. 42(11), 937–948 (2010).
    • 147 Willer CJ, Speliotes EK, Loos RJ et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat. Genet. 41(1), 25–34 (2009).
    • 148 Gamero-Villarroel C, Gonzalez LM, Gordillo I et al. Impact of negr1 genetic variability on psychological traits of patients with eating disorders. Pharmacogenomics J. 15(3), 278–283 (2014).
    • 149 Dennis EL, Jahanshad N, Braskie MN et al. Obesity gene negr1 associated with white matter integrity in healthy young adults. Neuroimage 102(Pt 2), 548–557 (2014).
    • 150 Damberg M, Garpenstrand H, Hallman J, Oreland L. Genetic mechanisms of behavior – don't forget about the transcription factors. Mol. Psychiatry 6(5), 503–510 (2001).
    • 151 Moser M, Pscherer A, Roth C et al. Enhanced apoptotic cell death of renal epithelial cells in mice lacking transcription factor ap-2beta. Genes Dev. 11(15), 1938–1948 (1997).
    • 152 Damberg M, Berggard C, Mattila-Evenden M et al. Transcription factor ap-2beta genotype associated with anxiety-related personality traits in women. A replication study. Neuropsychobiology 48(4), 169–175 (2003).
    • 153 Damberg M, Garpenstrand H, Alfredsson J et al. A polymorphic region in the human transcription factor ap-2beta gene is associated with specific personality traits. Mol. Psychiatry 5(2), 220–224 (2000).
    • 154 Nilsson KW, Sjoberg RL, Leppert J, Oreland L, Damberg M. Transcription factor ap-2 beta genotype and psychosocial adversity in relation to adolescent depressive symptomatology. J. Neural Transm. 116(3), 363–370 (2009).
    • 155 Prichard ZM, Jorm AF, Mackinnon A, Easteal S. Association analysis of 15 polymorphisms within 10 candidate genes for antisocial behavioural traits. Psychiatr. Genet. 17(5), 299–303 (2007).
    • 156 Schabram I, Eggermann T, Siegel SJ, Grunder G, Zerres K, Vernaleken I. Neuropsychological correlates of transcription factor ap-2beta, and its interaction with comt and maoa in healthy females. Neuropsychobiology 68(2), 79–90 (2013).
    • 157 Oreland L, Hallman J. The correlation between platelet mao activity and personality: short review of findings and a discussion on possible mechanisms. Prog. Brain Res. 106, 77–84 (1995).
    • 158 Rui L. Sh2b1 regulation of energy balance, body weight, and glucose metabolism. World J. Diabetes 5(4), 511–526 (2014).
    • 159 Ren D, Zhou Y, Morris D, Li M, Li Z, Rui L. Neuronal sh2b1 is essential for controlling energy and glucose homeostasis. J. Clin. Invest. 117(2), 397–406 (2007).
    • 160 Doche ME, Bochukova EG, Su HW et al. Human sh2b1 mutations are associated with maladaptive behaviors and obesity. J. Clin. Invest. 122(12), 4732–4736 (2012).
    • 161 Speakman JR. Functional analysis of seven genes linked to body mass index and adiposity by genome-wide association studies: a review. Hum. Hered. 75(2–4), 57–79 (2013).
    • 162 Robiou-Du-Pont S, Yengo L, Vaillant E et al. Common variants near BDNF and sh2b1 show nominal evidence of association with snacking behavior in european populations. J. Mol. Med. (Berl.) 91(9), 1109–1115 (2013).
    • 163 Pei YF, Zhang L, Liu Y et al. Meta-analysis of genome-wide association data identifies novel susceptibility loci for obesity. Hum. Mol. Genet. 23(3), 820–830 (2014).
    • 164 Scherag A, Jarick I, Grothe J et al. Investigation of a genome wide association signal for obesity: synthetic association and haplotype analyses at the melanocortin 4 receptor gene locus. PLoS ONE 5(11), e13967 (2010).
    • 165 Li F, Zhao J, Yuan Z, Zhang X, Ji J, Xue F. A powerful latent variable method for detecting and characterizing gene-based gene-gene interaction on multiple quantitative traits. BMC Genet. 14, 89 (2013).
    • 166 Jurvansuu J, Zhao Y, Leung DS et al. Transmembrane protein 18 enhances the tropism of neural stem cells for glioma cells. Cancer Res. 68(12), 4614–4622 (2008).
    • 167 Almen MS, Jacobsson JA, Shaik JH et al. The obesity gene, tmem18, is of ancient origin, found in majority of neuronal cells in all major brain regions and associated with obesity in severely obese children. BMC Med. Genet. 11, 58 (2010).
    • 168 Jurvansuu JM, Goldman A. Obesity risk gene tmem18 encodes a sequence-specific DNA-binding protein. PLoS ONE 6(9), e25317 (2011).
    • 169 Graff M, North KE, Richardson AS et al. Screen time behaviours may interact with obesity genes, independent of physical activity, to influence adolescent bmi in an ethnically diverse cohort. Pediatr Obes. 8(6), e74–79 (2013).
    • 170 Albayrak O, Putter C, Volckmar AL et al. Common obesity risk alleles in childhood attention-deficit/hyperactivity disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 162B(4), 295–305 (2013).
    • 171 Richardson AS, North KE, Graff M et al. Moderate to vigorous physical activity interactions with genetic variants and body mass index in a large us ethnically diverse cohort. Pediatr Obes. 9(2), e35–46 (2014).
    • 172 Grinberg M, Schwarz M, Zaltsman Y et al. Mitochondrial carrier homolog 2 is a target of tbid in cells signaled to die by tumor necrosis factor alpha. Mol. Cell. Biol. 25(11), 4579–4590 (2005).
    • 173 Palmieri F. The mitochondrial transporter family (slc25): physiological and pathological implications. Pflugers Arch. 447(5), 689–709 (2004).
    • 174 Bauer F, Elbers CC, Adan RA et al. Obesity genes identified in genome-wide association studies are associated with adiposity measures and potentially with nutrient-specific food preference. Am. J. Clin. Nutr. 90(4), 951–959 (2009).
    • 175 Hofker M, Wijmenga C. A supersized list of obesity genes. Nat. Genet. 41(2), 139–140 (2009).
    • 176 Cornelis MC, Rimm EB, Curhan GC et al. Obesity susceptibility loci and uncontrolled eating, emotional eating and cognitive restraint behaviors in men and women. Obesity (Silver Spring) 22(5), E135–141 (2014).
    • 177 Llaurado M, Abal M, Castellvi J et al. Etv5 transcription factor is overexpressed in ovarian cancer and regulates cell adhesion in ovarian cancer cells. Int. J. Cancer 130(7), 1532–1543 (2012).
    • 178 Thorleifsson G, Walters GB, Gudbjartsson DF et al. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat. Genet. 41(1), 18–24 (2009).
    • 179 Schlesser HN, Simon L, Hofmann MC et al. Effects of etv5 (ets variant gene 5) on testis and body growth, time course of spermatogonial stem cell loss, and fertility in mice. Biol. Reprod. 78(3), 483–489 (2008).
    • 180 Boender AJ, Van Rozen AJ, Adan RA. Nutritional state affects the expression of the obesity-associated genes etv5, faim2, fto, and negr1. Obesity (Silver Spring) 20(12), 2420–2425 (2012).
    • 181 Boender AJ, Koning NA, Van Den Heuvel JK et al. Aav-mediated gene transfer of the obesity-associated gene etv5 in rat midbrain does not affect energy balance or motivated behavior. PLoS ONE 9(4), e94159 (2014).
    • 182 Alonso-Alconada L, Eritja N, Muinelo-Romay L et al. Etv5 transcription program links BDNF and promotion of EMT at invasive front of endometrial carcinomas. Carcinogenesis 35(12), 2679–2686 (2014).
    • 183 Zarelli VE, Dawid IB. Inhibition of neural crest formation by kctd15 involves regulation of transcription factor ap-2. Proc. Natl Acad. Sci. USA 110(8), 2870–2875 (2013).
    • 184 Paternoster L, Evans DM, Nohr EA et al. Genome-wide population-based association study of extremely overweight young adults – the Goya study. PLoS ONE 6(9), e24303 (2011).
    • 185 Clarke TK, Weiss AR, Berrettini WH. The genetics of anorexia nervosa. Clin. Pharmacol. Ther. 91(2), 181–188 (2012).
    • 186 Graham AL, Gluck ME, Votruba SB, Krakoff J, Thearle MS. Perseveration augments the effects of cognitive restraint on ad libitum food intake in adults seeking weight loss. Appetite 82, 78–84 (2014).
    • 187 Tung YC, Yeo GS, O'Rahilly S, Coll AP. Obesity and fto: changing focus at a complex locus. Cell Metab. 20(5), 710–718 (2014).
    • 188 Koizumi H, Hashimoto K, Itoh K et al. Association between the brain-derived neurotrophic factor 196g/a polymorphism and eating disorders. Am. J. Med. Genet. B Neuropsychiatr. Genet. 127B(1), 125–127 (2004).
    • 189 Friedel S, Horro FF, Wermter AK et al. Mutation screen of the brain derived neurotrophic factor gene (BDNF): identification of several genetic variants and association studies in patients with obesity, eating disorders, and attention-deficit/hyperactivity disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 132B(1), 96–99 (2005).
    • 190 De Krom M, Bakker SC, Hendriks J et al. Polymorphisms in the brain-derived neurotrophic factor gene are not associated with either anorexia nervosa or schizophrenia in dutch patients. Psychiatr. Genet. 15(2), 81 (2005).