BDNF genetic variability modulates psychopathological symptoms in patients with eating disorders

European Child & Adolescent Psychiatry volume 23, pages669–679(2014)Cite this article

Abstract

The brain-derived neurotrophic factor (BDNF) gene may influence eating behavior, body weight and cognitive impairments. We aimed to investigate whether BDNF genetic variability may affect anthropometric and psychological parameters in patients with anorexia or bulimia nervosa (AN, BN) and/or modulate the risk for the disorder. A total of 169 unrelated female patients and 312 healthy controls were genotyped for two common BDNF single-nucleotide polymorphisms (SNPs), Val66Met and C-270T, and several selected tag-SNPs. Associated personality characteristics and psychopathological symptoms were assessed by the EDI-2 and SCL-90R inventories, respectively. No single SNP or haplotype played a relevant role in the risk for AN or BN. The rs16917237 TT genotype was significantly associated with increased weight (74.63 ± 16.58 vs. 57.93 ± 13.02) and body mass index (28.94 ± 6.22 vs. 22.23 ± 4.77) in the BN group after correcting for multiple testing. Haplotype analyses using a sliding window approach with three adjacent SNPs produced four loci of interest. Locus 3 (rs10835210/rs16917237/C-270T) showed a broad impact on the measured psychopathological symptoms. Haplotypes CGC and CGT in this locus correlated with scores in all three scales of the SCL-90R inventory, both in AN and BN patients. In contrast, the results of the EDI-2 inventory were largely unaffected. These preliminary results suggest that variability in the BDNF gene locus may contribute to anthropometric characteristics and also psychopathological symptoms that are common but not exclusive of ED patients.

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References

  1. 1.

    Monteleone P, Maj M (2008) Genetic susceptibility to eating disorders: associated polymorphisms and pharmacogenetic suggestions. Pharmacogenomics 9(10):1487–1520

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Clarke TK, Weiss AR, Berrettini WH (2012) The genetics of anorexia nervosa. Clin Pharmacol Ther 91(2):181–188. doi:10.1038/clpt.2011.253

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    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(2):147–164

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Kernie SG, Liebl DJ, Parada LF (2000) BDNF regulates eating behavior and locomotor activity in mice. EMBO J 19(6):1290–1300. doi:10.1093/emboj/19.6.1290

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  5. 5.

    Cordeira J, Rios M (2011) Weighing in the role of BDNF in the central control of eating behavior. Mol Neurobiol 44(3):441–448. doi:10.1007/s12035-011-8212-2

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  6. 6.

    Rios M (2011) New insights into the mechanisms underlying the effects of BDNF on eating behavior. Neuropsychopharmacology 36(1):368–369. doi:10.1038/npp.2010.139

    PubMed  Article  PubMed Central  Google Scholar 

  7. 7.

    Rosas-Vargas H, Martinez-Ezquerro JD, Bienvenu T (2011) Brain-derived neurotrophic factor, food intake regulation, and obesity. Arch Med Res 42(6):482–494. doi:10.1016/j.arcmed.2011.09.005

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Ribases M, Gratacos M, Armengol L, de Cid R, Badia A, Jimenez L, Solano R et al (2003) Met66 in the brain-derived neurotrophic factor (BDNF) precursor is associated with anorexia nervosa restrictive type. Mol Psychiatry 8(8):745–751

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Ribases M, Gratacos M, Fernandez-Aranda F, Bellodi L, Boni C, Anderluh M, Cavallini MC et al (2004) Association of BDNF with anorexia, bulimia and age of onset of weight loss in six European populations. Hum Mol Genet 13(12):1205–1212

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Ando T, Ishikawa T, Hotta M, Naruo T, Okabe K, Nakahara T, Takii M et al (2012) 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. doi:10.1002/ajmg.b.32000

    PubMed  Google Scholar 

  11. 11.

    Brandys MK, Kas MJ, van Elburg AA, Ophoff R, Slof-Op’t Landt MC, Middeldorp CM, Boomsma DI et al (2011) The Val66Met polymorphism of the BDNF gene in anorexia nervosa: new data and a meta-analysis. World J Biol Psychiatry. doi:10.3109/15622975.2011.605470

  12. 12.

    Sen S, Nesse RM, Stoltenberg SF, Li S, Gleiberman L, Chakravarti A, Weder AB et al (2003) A BDNF coding variant is associated with the NEO personality inventory domain neuroticism, a risk factor for depression. Neuropsychopharmacology 28(2):397–401. doi:10.1038/sj.npp.1300053

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Terracciano A, Tanaka T, Sutin AR, Deiana B, Balaci L, Sanna S, Olla N et al (2010) BDNF Val66Met is associated with introversion and interacts with 5-HTTLPR to influence neuroticism. Neuropsychopharmacology 35(5):1083–1089. doi:10.1038/npp.2009.213

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  14. 14.

    Lang UE, Hellweg R, Kalus P, Bajbouj M, Lenzen KP, Sander T, Kunz D et al (2005) Association of a functional BDNF polymorphism and anxiety-related personality traits. Psychopharmacology 180(1):95–99. doi:10.1007/s00213-004-2137-7

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Kaye WH, Bulik CM, Plotnicov K, Thornton L, Devlin B, Fichter MM, Treasure J et al (2008) The genetics of anorexia nervosa collaborative study: methods and sample description. Int J Eat Disord 41(4):289–300. doi:10.1002/eat.20509

    PubMed  Article  PubMed Central  Google Scholar 

  16. 16.

    Klump KL, Bulik CM, Pollice C, Halmi KA, Fichter MM, Berrettini WH, Devlin B et al (2000) Temperament and character in women with anorexia nervosa. J Nerv Ment Dis 188(9):559–567

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Amianto F, Abbate-Daga G, Morando S, Sobrero C, Fassino S (2011) Personality development characteristics of women with anorexia nervosa, their healthy siblings and healthy controls: what prevents and what relates to psychopathology? Psychiatry Res 187(3):401–408. doi:10.1016/j.psychres.2010.10.028

    PubMed  Article  Google Scholar 

  18. 18.

    McDermott B, Forbes D, Harris C, McCormack J, Gibbon P (2006) Non-eating disorders psychopathology in children and adolescents with eating disorders: implications for malnutrition and symptom severity. J Psychosom Res 60(3):257–261. doi:10.1016/j.jpsychores.2005.08.004

    PubMed  Article  Google Scholar 

  19. 19.

    Ro O, Martinsen EW, Hoffart A, Rosenvinge JH (2004) Short-term follow-up of adults with long standing anorexia nervosa or non-specified eating disorder after inpatient treatment. Eat Weight Disord: EWD 9(1):62–68

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    de Cid R, Fonseca F, Gratacos M, Gutierrez F, Martin-Santos R, Estivill X, Torrens M (2008) BDNF variability in opioid addicts and response to methadone treatment: preliminary findings. Genes Brain Behav 7(5):515–522. doi:10.1111/j.1601-183X.2007.00386.x

    PubMed  Article  Google Scholar 

  21. 21.

    Pae CU, Chiesa A, Porcelli S, Han C, Patkar AA, Lee SJ, Park MH et al (2012) Influence of BDNF variants on diagnosis and response to treatment in patients with major depression, bipolar disorder and schizophrenia. Neuropsychobiology 65(1):1–11. doi:10.1159/000327605

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Terracciano A, Piras MG, Lobina M, Mulas A, Meirelles O, Sutin AR, Chan W et al (2011) Genetics of serum BDNF: meta-analysis of the Val66Met and genome-wide association study. World J Biol Psychiatry. doi:10.3109/15622975.2011.616533

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    Xie B, Wang B, Suo P, Kou C, Wang J, Meng X, Cheng L et al (2011) Genetic association between BDNF gene polymorphisms and phobic disorders: a case-control study among mainland Han Chinese. J Affect Disord 132(1–2):239–242. doi:10.1016/j.jad.2010.12.017

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Gervasini G, Gordillo I, Garcia-Herraiz A, Flores I, Jimenez M, Monge M, Carrillo JA (2012) Polymorphisms in serotonergic genes and psychopathological traits in eating disorders. J Clin Psychopharmacol 32(3):426–428. doi:10.1097/JCP.0b013e3182539f2b

    PubMed  Article  Google Scholar 

  25. 25.

    Gervasini G, Gordillo I, Garcia-Herraiz A, Flores I, Jimenez M, Monge M, Carrillo JA (2013) Influence of dopamine polymorphisms on the risk for anorexia nervosa and associated psychopathological features. J Clin Psychopharmacol. doi:10.1097/JCP.0b013e3182970469

    PubMed  Google Scholar 

  26. 26.

    First M, Spitzer R, Gibbon M, Williams J (1996) Structured clinical interview for DSM-IV axis I disorders (SCID), clinical version: administration booklet. American Psychiatric Press, Washington DC

    Google Scholar 

  27. 27.

    Gabriel S, Ziaugra L, Tabbaa D (2009) SNP genotyping using the Sequenom MassARRAY iPLEX platform. Current protocols in human genetics/editorial board. Haines JL [et al] Chapter 2:Unit 2 12. doi:10.1002/0471142905.hg0212s60

  28. 28.

    Garner D (1991) Eating disorder inventory-2: professional manual. Odessa

  29. 29.

    Guimera E, Torrubia R (1987) Adaptación española del “Eating Disorder Inventory Inventory” (EDI) en una muestra de pacientes anoréxicas. Anal Psiquiatr 3:185–190

    Google Scholar 

  30. 30.

    Derogaitis L (1977) SCL-90-R: administration, scoring and procedures manual. Clinical Psychometrics Research, Baltimore

    Google Scholar 

  31. 31.

    Derogaitis L (2002) SCL-90R: Cuestionario de 90 síntomas. TEA Ed, Madrid

    Google Scholar 

  32. 32.

    Sole X, Guino E, Valls J, Iniesta R, Moreno V (2006) SNPStats: a web tool for the analysis of association studies. Bioinformatics (Oxford, England) 22 (15):1928–1929

  33. 33.

    Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J et al (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81(3):559–575. doi:10.1086/519795

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. 34.

    Pinheiro AP, Bulik CM, Thornton LM, Sullivan PF, Root TL, Bloss CS, Berrettini WH et al (2010) Association study of 182 candidate genes in anorexia nervosa. Am J Med Genet B Neuropsychiatr Genet 153B(5):1070–1080. doi:10.1002/ajmg.b.31082

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Dmitrzak-Weglarz M, Skibinska M, Slopien A, Szczepankiewicz A, Rybakowski F, Kramer L, Hauser J et al (2007) BDNF Met66 allele is associated with anorexia nervosa in the Polish population. Psychiatr Genet 17(4):245–246. doi:10.1097/YPG.0b013e3280991229

    PubMed  Article  Google Scholar 

  36. 36.

    Monteleone P, Zanardini R, Tortorella A, Gennarelli M, Castaldo E, Canestrelli B, Maj M (2006) The 196G/A (val66met) polymorphism of the BDNF gene is significantly associated with binge eating behavior in women with bulimia nervosa or binge eating disorder. Neurosci Lett 406(1–2):133–137

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Gratacos M, Gonzalez JR, Mercader JM, de Cid R, Urretavizcaya M, Estivill X (2007) Brain-derived neurotrophic factor Val66Met and psychiatric disorders: meta-analysis of case-control studies confirm association to substance-related disorders, eating disorders, and schizophrenia. Biol Psychiatry 61(7):911–922

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Dardennes RM, Zizzari P, Tolle V, Foulon C, Kipman A, Romo L, Iancu-Gontard D et al (2007) Family trios analysis of common polymorphisms in the obestatin/ghrelin, BDNF and AGRP genes in patients with Anorexia nervosa: association with subtype, body-mass index, severity and age of onset. Psychoneuroendocrinology 32(2):106–113

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    de Krom M, Bakker SC, Hendriks J, van Elburg A, Hoogendoorn M, Verduijn W, Sinke R et al (2005) 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

    PubMed  Article  Google Scholar 

  40. 40.

    Friedel S, Horro FF, Wermter AK, Geller F, Dempfle A, Reichwald K, Smidt J et al (2005) 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

    CAS  PubMed  Google Scholar 

  41. 41.

    Rybakowski F, Dmitrzak-Weglarz M, Szczepankiewicz A, Skibinska M, Slopien A, Rajewski A, Hauser J (2007) Brain derived neurotrophic factor gene Val66Met and -270C/T polymorphisms and personality traits predisposing to anorexia nervosa. Neuro Endocrinol Lett 28(2):153–158

    PubMed  Google Scholar 

  42. 42.

    Hong CJ, Liou YJ, Tsai SJ (2011) Effects of BDNF polymorphisms on brain function and behavior in health and disease. Brain Res Bull 86(5–6):287–297. doi:10.1016/j.brainresbull.2011.08.019

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Mercader JM, Ribases M, Gratacos M, Gonzalez JR, Bayes M, de Cid R, Badia A et al (2007) Altered brain-derived neurotrophic factor blood levels and gene variability are associated with anorexia and bulimia. Genes Brain Behav 6(8):706–716

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Fairburn CG, Welch SL, Doll HA, Davies BA, O’Connor ME (1997) Risk factors for bulimia nervosa. A community-based case-control study. Arch Gen Psychiatry 54(6):509–517

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Fairburn CG, Stice E, Cooper Z, Doll HA, Norman PA, O’Connor ME (2003) Understanding persistence in bulimia nervosa: a 5-year naturalistic study. J Consult Clin Psychol 71(1):103–109

    PubMed  Article  Google Scholar 

  46. 46.

    Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, Jackson AU, Lango Allen H et al (2010) Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 42(11):937–948. doi:10.1038/ng.686

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  47. 47.

    Ribases M, Gratacos M, Fernandez-Aranda F, Bellodi L, Boni C, Anderluh M, Cristina Cavallini M et al (2005) Association of BDNF with restricting anorexia nervosa and minimum body mass index: a family-based association study of eight European populations. Eur J Hum Genet 13 (4):428–434

    Google Scholar 

  48. 48.

    Tozzi F, Thornton LM, Klump KL, Fichter MM, Halmi KA, Kaplan AS, Strober M et al (2005) Symptom fluctuation in eating disorders: correlates of diagnostic crossover. Am J Psychiatry 162(4):732–740

    PubMed  Article  Google Scholar 

  49. 49.

    Kaplan AS, Levitan RD, Yilmaz Z, Davis C, Tharmalingam S, Kennedy JL (2008) A DRD4/BDNF gene–gene interaction associated with maximum BMI in women with bulimia nervosa. Int J Eat Disord 41(1):22–28

    PubMed  Article  Google Scholar 

  50. 50.

    Saito S, Watanabe K, Hashimoto E, Saito T (2009) Low serum BDNF and food intake regulation: a possible new explanation of the pathophysiology of eating disorders. Prog Neuropsychopharmacol Biol Psychiatry 33(2):312–316. doi:10.1016/j.pnpbp.2008.12.009

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Duman RS, Monteggia LM (2006) A neurotrophic model for stress-related mood disorders. Biol Psychiatry 59(12):1116–1127. doi:10.1016/j.biopsych.2006.02.013

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Lang UE, Hellweg R, Gallinat J (2004) BDNF serum concentrations in healthy volunteers are associated with depression-related personality traits. Neuropsychopharmacology 29(4):795–798. doi:10.1038/sj.npp.1300382

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Sen S, Duman R, Sanacora G (2008) Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications. Biol Psychiatry 64(6):527–532. doi:10.1016/j.biopsych.2008.05.005

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  54. 54.

    Mercader JM, Fernandez-Aranda F, Gratacos M, Aguera Z, Forcano L, Ribases M, Villarejo C et al (2010) Correlation of BDNF blood levels with interoceptive awareness and maturity fears in anorexia and bulimia nervosa patients. J Neural Transm 117(4):505–512

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Mercader JM, Fernandez-Aranda F, Gratacos M, Ribases M, Badia A, Villarejo C, Solano R et al (2007) Blood levels of brain-derived neurotrophic factor correlate with several psychopathological symptoms in anorexia nervosa patients. Neuropsychobiology 56(4):185–190. doi:10.1159/000120623

    CAS  PubMed  Article  Google Scholar 

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Acknowledgments

This work was supported in part by the Alicia Koplowitz Foundation, Madrid (Spain) and by grant GR10022 from Junta de Extremadura, Consejeria de Economia, Comercio e Innovacion, Merida (Spain).

We are thankful to the Spanish Genotyping National Centre (CEGEN-ISCIII) in Santiago de Compostela (Spain), headed by Dr. Angel Carracedo, for its technical assistance.

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

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Affiliations

  1. Division of Clinical Pharmacology, Department of Medical and Surgical Therapeutics, Medical School, University of Extremadura, Avda. de Elvas s/n, 06005, Badajoz, Spain

    Carmen Gamero-Villarroel, Inmaculada Gordillo, Juan Antonio Carrillo, Mercedes Jiménez & Guillermo Gervasini

  2. Eating Disorders Unit, Institute of Mental Disorders, Health Service of Extremadura, Badajoz, Spain

    Angustias García-Herráiz, Isalud Flores & Melchora Monge

  3. Genetics Unit, Infanta Cristina Hospital, Badajoz, Spain

    Raquel Rodríguez-López

Authors
  1. Carmen Gamero-Villarroel
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  2. Inmaculada Gordillo
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  3. Juan Antonio Carrillo
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  4. Angustias García-Herráiz
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  5. Isalud Flores
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  9. Guillermo Gervasini
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Correspondence to Guillermo Gervasini.

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Gamero-Villarroel, C., Gordillo, I., Carrillo, J.A. et al. BDNF genetic variability modulates psychopathological symptoms in patients with eating disorders. Eur Child Adolesc Psychiatry 23, 669–679 (2014). https://doi.org/10.1007/s00787-013-0495-6

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Keywords

  • BDNF
  • Genetic polymorphism
  • Anorexia nervosa
  • Bulimia nervosa
  • Eating disorder