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Impact of NEGR1 genetic variability on psychological traits of patients with eating disorders

The Pharmacogenomics Journal volume 15, pages 278–283 (2015)Cite this article

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Abstract

Genetics variants in the NEGR1 gene, strongly expressed in the brain, have been reported to affect the neuronal control of food intake therefore inducing obesity. With the same rationale, we hypothesized that this genetic variability may be associated with psychological traits commonly displayed by eating disorder (ED) patients and/or with the risk for the disorder. We analyzed 21 tag-single-nucleotide polymorphisms (SNPs) in the coding sequence and adjacent regions of the NEGR1 gene. A total of 169 ED patients (106 with anorexia nervosa (AN) and 63 with bulimia nervosa (BN)) and 312 healthy subjects were genotyped. Personality traits and general psychopathological symptoms were assessed by the Eating Disorders Inventory Test-2 (EDI-2) and Symptom Checklist 90 Revised inventories. None of the SNPs or haplotypes analyzed were associated with a greater risk of ED or correlated with anthropometric parameters. However, in patients with BN, four SNPs (rs12740031, rs10789322, rs6659202 and rs591540) correlated with the scores in Drive for Thinness (DT), Ineffectiveness (I) and Interoceptive Awareness (IA) (Bonferroni-P<0.05 in all instances). The first two SNPs along with rs954299 and rs2422021 formed a haplotype block, which showed a consistent association with the EDI-2 score in BN patients (Bonferroni-P=0.01). A subsequent three-SNP sliding-window approach identified a central area, encompassing both the haplotype block and the individually relevant SNPs that strongly correlated with the scores of BN patients in DT, I, IA and Bulimia. No associations were identified in the AN group. These preliminary results indicate that NEGR1 could be an important locus influencing certain personality dimensions in BN patients.

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References

  1. Scherag A, Jarick I, Grothe J, Biebermann H, Scherag S, Volckmar AL 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 2010; 5: e13967.

    Article  Google Scholar 

  2. 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 2010; 62: 147–164.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Lee AW, Hengstler H, Schwald K, Berriel-Diaz M, Loreth D, Kirsch M 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 2012; 7: e41537.

    Article  CAS  Google Scholar 

  5. Marg A, Sirim P, Spaltmann F, Plagge A, Kauselmann G, Buck F et al. Neurotractin, a novel neurite outgrowth-promoting Ig-like protein that interacts with CEPU-1 and LAMP. J Cell Biol 1999; 145: 865–876.

    Article  CAS  Google Scholar 

  6. Thorleifsson G, Walters GB, Gudbjartsson DF, Steinthorsdottir V, Sulem P, Helgadottir A et al. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet 2009; 41: 18–24.

    Article  CAS  Google Scholar 

  7. Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, Jackson AU et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 2010; 42: 937–948.

    Article  CAS  Google Scholar 

  8. Willer CJ, Speliotes EK, Loos RJ, Li S, Lindgren CM, Heid IM et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet 2009; 41: 25–34.

    Article  CAS  Google Scholar 

  9. Magi R, Manning S, Yousseif A, Pucci A, Santini F, Karra E et al. Contribution of 32 GWAS-identified common variants to severe obesity in European adults referred for bariatric surgery. PloS One 2013; 8: e70735.

    Article  CAS  Google Scholar 

  10. Wheeler E, Huang N, Bochukova EG, Keogh JM, Lindsay S, Garg S et al. Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity. Nat Genet 2013; 45: 513–517.

    Article  CAS  Google Scholar 

  11. Mejia-Benitez A, Klunder-Klunder M, Yengo L, Meyre D, Aradillas C, Cruz E et al. Analysis of the contribution of FTO, NPC1, ENPP1, NEGR1, GNPDA2 and MC4R genes to obesity in Mexican children. BMC Med Genet 2013; 14: 21.

    Article  CAS  Google Scholar 

  12. Renstrom F, Payne F, Nordstrom A, Brito EC, Rolandsson O, Hallmans G et al. Replication and extension of genome-wide association study results for obesity in 4923 adults from northern Sweden. Hum Mol Genet 2009; 18: 1489–1496.

    Article  Google Scholar 

  13. Zhao J, Bradfield JP, Li M, Wang K, Zhang H, Kim CE et al. The role of obesity-associated loci identified in genome-wide association studies in the determination of pediatric BMI. Obesity (Silver Spring) 2009; 17: 2254–2257.

    Article  Google Scholar 

  14. Maccarrone G, Ditzen C, Yassouridis A, Rewerts C, Uhr M, Uhlen M et al. Psychiatric patient stratification using biosignatures based on cerebrospinal fluid protein expression clusters. J Psychiatr Res 2013; 47: 1572–1580.

    Article  Google Scholar 

  15. Hebebrand J, Fichter M, Gerber G, Gorg T, Hermann H, Geller F et al. Genetic predisposition to obesity in bulimia nervosa: a mutation screen of the melanocortin-4 receptor gene. Mol Psychiatry 2002; 7: 647–651.

    Article  CAS  Google Scholar 

  16. Muller TD, Greene BH, Bellodi L, Cavallini MC, Cellini E, Di Bella D 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 2012; 5: 408–419.

    Article  Google Scholar 

  17. Gamero-Villarroel C, Gordillo I, Carrillo JA, Garcia-Herraiz A, Flores I, Jimenez M et al. BDNF genetic variability modulates psychopathological symptoms in patients with eating disorders. Eur Child Adolesc Psychiatry 2013; 23: 669–679.

    Article  Google Scholar 

  18. Gervasini G, Gordillo I, Garcia-Herraiz A, Flores I, Jimenez M, Monge M et al. Polymorphisms in serotonergic genes and psychopathological traits in eating disorders. J Clin Psychopharmacol 2012; 32: 426–428.

    Article  Google Scholar 

  19. Gervasini G, Gordillo I, Garcia-Herraiz A, Flores I, Jimenez M, Monge M et al. Influence of dopamine polymorphisms on the risk for anorexia nervosa and associated psychopathological features. J Clin Psychopharmacol 2013; 33: 551–555.

    Article  CAS  Google Scholar 

  20. First M, Spitzer R, Gibbon M, Williams J . Structured Clinical Interview for DSM-IV Axis I Disorders (SCID), Clinical Version: Administration Booklet. American Psychiatric Press: Washington DC, USA, 1996.

    Google Scholar 

  21. Gabriel S, Ziaugra L, Tabbaa D . SNP genotyping using the Sequenom MassARRAY iPLEX platform. Curr Protoc Hum Genet 2009; Ch. 2. Unit 2.12.

  22. Garner D . Eating Disorder Inventory-2: Professional Manual. PAR Inc.: Odessa, FL, USA, 1991.

    Google Scholar 

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

    Google Scholar 

  24. Derogaitis L . SCL-90R: Cuestionario de 90 Síntomas. TEA Ediciones, Madrid, Spain, 2002.

  25. Derogaitis L . SCL-90-R: Administration, Scoring and Procedures Manual. Clinical Psychometrics Research: Baltimore, MD, USA, 1977.

    Google Scholar 

  26. Gonzalez JR, Armengol L, Sole X, Guino E, Mercader JM, Estivill X et al. SNPassoc: an R package to perform whole genome association studies. Bioinformatics 2007; 23: 644–645.

    PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  28. Day J, Ternouth A, Collier DA . Eating disorders and obesity: two sides of the same coin?. Epidemiol Psichiatr Soc 2009; 18: 96–100.

    PubMed  Google Scholar 

  29. Hinney A, Bettecken T, Tarnow P, Brumm H, Reichwald K, Lichtner P et al. Prevalence, spectrum, and functional characterization of melanocortin-4 receptor gene mutations in a representative population-based sample and obese adults from Germany. J Clin Endocrinol Metab 2006; 91: 1761–1769.

    Article  CAS  Google Scholar 

  30. Pinheiro AP, Bulik CM, Thornton LM, Sullivan PF, Root TL, Bloss CS et al. Association study of 182 candidate genes in anorexia nervosa. Am J Med Genet B Neuropsychiatr Genet 2010; 153B: 1070–1080.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Ebstein RP, Benjamin J, Belmaker RH . Genetics of personality dimensions. Curr Opin Psichiatry 2000; 13: 617–622.

    Article  Google Scholar 

  32. Cloninger CR . A new conceptual paradigm from genetics and psychobiology for the science of mental health. Aust N Z J Psychiatry 1999; 33: 174–186.

    Article  CAS  Google Scholar 

  33. Klabunde M, Acheson DT, Boutelle KN, Matthews SC, Kaye WH . Interoceptive sensitivity deficits in women recovered from bulimia nervosa. Eat Behav 2013; 14: 488–492.

    Article  Google Scholar 

  34. Zimmerli EJ, Walsh BT, Guss JL, Devlin MJ, Kissileff HR . Gastric compliance in bulimia nervosa. Physiol Behav 2006; 87: 441–446.

    Article  CAS  Google Scholar 

  35. Stein D, Kaye WH, Matsunaga H, Myers D, Orbach I, Har-Even D et al. Pain perception in recovered bulimia nervosa patients. Int J Eat Disord 2003; 34: 331–336.

    Article  Google Scholar 

  36. Garfinkel PE, Moldofsky H, Garner DM, Stancer HC, Coscina DV . Body awareness in anorexia nervosa: disturbances in ‘body image’ and ‘satiety’. Psychosom Med 1978; 40: 487–498.

    Article  CAS  Google Scholar 

  37. Bohon C, Stice E . Reward abnormalities among women with full and subthreshold bulimia nervosa: a functional magnetic resonance imaging study. Int J Eat Disord 2011; 44: 585–595.

    Article  Google Scholar 

  38. Fassino S, Daga GA, Boggio S, Garzaro L, Piero A . Use of reboxetine in bulimia nervosa: a pilot study. J Psychopharmacol 2004; 18: 423–428.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  40. Dobmeyer AC, Stein DM . A prospective analysis of eating disorder risk factors: drive for thinness, depressed mood, maladaptive cognitions, and ineffectiveness. Eat Behav 2003; 4: 135–147.

    Article  Google Scholar 

  41. Combs JL, Smith GT, Flory K, Simmons JR, Hill KK . The acquired preparedness model of risk for bulimic symptom development. Psychol Addict Behav 2010; 24: 475–486.

    Article  Google Scholar 

  42. Akkermann K, Kaasik K, Kiive E, Nordquist N, Oreland L, Harro J . The impact of adverse life events and the serotonin transporter gene promoter polymorphism on the development of eating disorder symptoms. J Psychiatr Res 2012; 46: 38–43.

    Article  Google Scholar 

  43. Groleau P, Steiger H, Bruce K, Israel M, Sycz L, Ouellette AS et al. Childhood emotional abuse and eating symptoms in bulimic disorders: an examination of possible mediating variables. Int J Eat Disord 2012; 45: 326–332.

    Article  Google Scholar 

  44. Goethals I, Vervaet M, Audenaert K, Jacobs F, Ham H, Van Heeringen C . Does regional brain perfusion correlate with eating disorder symptoms in anorexia and bulimia nervosa patients?. J Psychiatr Res 2007; 41: 1005–1011.

    Article  Google Scholar 

  45. Frieling H, Romer KD, Wilhelm J, Hillemacher T, Kornhuber J, de Zwaan M et al. Association of catecholamine-O-methyltransferase and 5-HTTLPR genotype with eating disorder-related behavior and attitudes in females with eating disorders. Psychiatr Genet 2006; 16: 205–208.

    Article  Google Scholar 

  46. Nisoli E, Brunani A, Borgomainerio E, Tonello C, Dioni L, Briscini L et al. D2 dopamine receptor (DRD2) gene Taq1A polymorphism and the eating-related psychological traits in eating disorders (anorexia nervosa and bulimia) and obesity. Eat Weight Disord 2007; 12: 91–96.

    Article  CAS  Google Scholar 

  47. Mikolajczyk E, Grzywacz A, Samochowiec J . The association of catechol-O-methyltransferase genotype with the phenotype of women with eating disorders. Brain Res 2010; 1307: 142–148.

    Article  CAS  Google Scholar 

  48. Mercader JM, Fernandez-Aranda F, Gratacos M, Ribases M, Badia A, Villarejo C et al. Blood levels of brain-derived neurotrophic factor correlate with several psychopathological symptoms in anorexia nervosa patients. Neuropsychobiology 2007; 56: 185–190.

    Article  CAS  Google Scholar 

  49. Leon-Mimila P, Villamil-Ramirez H, Villalobos-Comparan M, Villarreal-Molina T, Romero-Hidalgo S, Lopez-Contreras B et al. Contribution of common genetic variants to obesity and obesity-related traits in mexican children and adults. PloS One 2013; 8: e70640.

    Article  CAS  Google Scholar 

  50. Ng MC, Tam CH, So WY, Ho JS, Chan AW, Lee HM et al. Implication of genetic variants near NEGR1, SEC16B, TMEM18, ETV5/DGKG, GNPDA2, LIN7C/BDNF, MTCH2, BCDIN3D/FAIM2, SH2B1, FTO, MC4R, and KCTD15 with obesity and type 2 diabetes in 7705 Chinese. J Clin Endocrinol Metab 2010; 95: 2418–2425.

    Article  CAS  Google Scholar 

  51. Hafler BP, Choi MY, Shivdasani RA, Rowitch DH . Expression and function of Nkx6.3 in vertebrate hindbrain. Brain Res 2008; 1222: 42–50.

    Article  CAS  Google Scholar 

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Acknowledgements

We are thankful to the Spanish Genotyping National Centre (CEGEN-ISCIII) in Santiago de Compostela (Spain), headed by Dr Angel Carracedo, for its valuable technical assistance. This work has been supported in part by the Alicia Koplowitz Foundation, Madrid, Spain, and grant GR10022 from Junta de Extremadura, Consejeria de Economia, Comercio e Innovacion, Merida (Spain).

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Authors and Affiliations

  1. Department of Medical & Surgical Therapeutics, Division of Pharmacology, Medical School, University of Extremadura, Badajoz, Spain

    C Gamero-Villarroel, L María González, I Gordillo, J Antonio Carrillo & G Gervasini

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

    A García-Herráiz & I Flores

  3. Service of Clinical Analyses, General University Hospital, Valencia, Spain

    R Rodríguez-López

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  1. C Gamero-Villarroel
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Gamero-Villarroel, C., González, L., Gordillo, I. et al. Impact of NEGR1 genetic variability on psychological traits of patients with eating disorders. Pharmacogenomics J 15, 278–283 (2015). https://doi.org/10.1038/tpj.2014.53

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