Epistatic interaction between the monoamine oxidase A and serotonin transporter genes in anorexia nervosa

Article metrics


The serotonin (5-HT) and norepinephrine (NE) systems are likely involved in the aetiology of anorexia nervosa (AN) as sufferers are premorbidly anxious. Specifically, we hypothesize that genes encoding proteins, which clear 5-HT and NE from the synapse, are prime candidates for affecting susceptibility to AN. Supporting our hypothesis, we earlier showed that the NE transporter (NET) and monoamine oxidase A (MAOA) genes appear to contribute additively to increased risk of developing restricting AN (AN-R). With regard to the MAOA gene, a sequence variant that increases MAOA activity and has suggested association with the anxiety condition, panic disorder was preferentially transmitted from parents to affected children. Here we provide evidence in support of interaction between the MAOA and serotonin transporter (SERT) genes in 114 AN nuclear families (patient with AN plus biological parents). A SERT gene genotype with no apparent individual effect on risk and known to be associated with anxiety is preferentially transmitted to children with AN (χ2 trend=9.457, 1 df, P=0.0021) and AN-R alone (χ2 trend=7.477, 1 df, P=0.0063) when the ‘more active’ MAOA gene variant is also transmitted. The increased risk of developing the disorder is up to eight times greater than the risk imposed by the MAOA gene variant alone – an example of synergistic epistatic interaction. If independently replicated, our findings to date suggest that we may have identified three genes affecting susceptibility to AN, particularly AN-R: the MAOA, SERT, and NET genes.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1

    Bulik CM, Sullivan PF, Fear JL, Joyce PR : Eating disorders and antecedent anxiety disorders: a controlled study. Acta Psychiatr Scand 1997; 96: 101–107.

  2. 2

    Fairburn CG, Harrison PJ : Eating disorders. Lancet 2003; 361: 407–416.

  3. 3

    Zahniser NR, Doolen S : Chronic and acute regulation of Na+/Cl -dependent neurotransmitter transporters: drugs, substrates, presynaptic receptors, and signaling systems. Pharmacol Ther 2001; 92: 21–55.

  4. 4

    Sabol SZ, Hu S, Hamer D : A functional polymorphism in the monoamine oxidase A gene promoter. Hum Genet 1998; 103: 273–279.

  5. 5

    Deckert J, Catalano M, Syagailo YV et al: Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder. Hum Mol Genet 1999; 8: 621–624.

  6. 6

    Denney RM, Koch H, Craig IW : Association between monoamine oxidase A activity in human male skin fibroblasts and genotype of the MAOA promoter-associated variable number tandem repeat. Hum Genet 1999; 105: 542–551.

  7. 7

    Lesch KP, Bengel D, Heils A et al: Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996; 274: 1527–1531.

  8. 8

    Urwin RE, Bennetts B, Wilcken B et al: Anorexia nervosa (restrictive subtype) is associated with a polymorphism in the novel norepinephrine transporter gene promoter polymorphic region. Mol Psychiatry 2002; 7: 652–657.

  9. 9

    Urwin RE, Bennetts BH, Wilcken B et al: Gene–gene interaction between the monoamine oxidase A gene and solute carrier family 6 (neurotransmitter transporter, noradrenaline) member 2 gene in anorexia nervosa (restrictive subtype). Eur J Hum Genet 2003; 11: 945–950, doi:10.1038/sj.ejhg.5201077 advance online publication 24 September 2003.

  10. 10

    Urwin RE, Bennetts BH, Wilcken B, Beumont PJV, Russell JD, Nunn KP : Investigation of epistasis between the serotonin transporter and norepinephrine transporter genes in anorexia nervosa. Neuropsychopharmacology 2003; 28: 1351–1355, doi:10.1038/sj.npp.1300204 advance online publication 14 May 2003.

  11. 11

    Hinney A, Barth N, Ziegler A et al: Serotonin transporter gene-linked polymorphic region: allele distributions in relationship to body weight and in anorexia nervosa. Life Sci 1997; 61: PL295–PL303.

  12. 12

    Sundaramurthy D, Pieri LF, Gape H, Markham AF, Campbell DA : Analysis of the serotonin transporter gene linked polymorphism (5-HTTLPR) in anorexia nervosa. Am J Med Genet 2000; 96: 53–55.

  13. 13

    Fumeron F, Betoulle D, Aubert R, Herbeth B, Siest G, Rigaud D : Association of a functional 5-HT transporter gene polymorphism with anorexia nervosa and food intake. Mol Psychiatry 2001; 6: 9–10, (letter).

  14. 14

    Di Bella D, Catalano M, Cavallini MC, Riboldi C, Bellodi L : Serotonin transporter linked polymorphic region in anorexia nervosa and bulimia nervosa. Mol Psychiatry 2000; 5: 233–234, (letter).

  15. 15

    American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. Washington, DC: American Psychiatric Association, 1994, 4th edn.

  16. 16

    Lan NC, Heinzmann C, Gal A et al: Human monoamine oxidase A and B genes map to Xp 11.23 and are deleted in a patient with Norrie disease. Genomics 1989; 4: 552–559.

  17. 17

    Cordell HJ : Epistasis: what it means, what it doesn't mean, and statistical methods to detect it in humans. Hum Mol Genet 2002; 11: 2463–2468.

  18. 18

    Moore JH : The ubiquitous nature of epistasis in determining susceptibility to common human diseases. Hum Hered 2003; 56: 73–82.

  19. 19

    Spielman RS, McGinnis RE, Ewens WJ : Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 1993; 52: 506–516.

  20. 20

    Ramamoorthy S, Bauman AL, Moore KR et al: Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization. Proc Natl Acad Sci USA 1993; 90: 2542–2546.

  21. 21

    Nakamura M, Ueno S, Sano A, Tanabe H : The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants. Mol Psychiatry 2000; 5: 32–38.

  22. 22

    Lovejoy EA, Scott AC, Fiskerstrand CE, Bubb VJ, Quinn JP : The serotonin transporter intronic VNTR enhancer correlated with a predisposition to affective disorders has distinct regulatory elements within the domain based on the primary DNA sequence of the repeat unit. Eur J Neurosci 2003; 17: 417–420.

  23. 23

    Kaye WH, Gwirtsman HE, George DT, Ebert MH : Altered serotonin activity in anorexia nervosa after long-term weight restoration. Does elevated cerebrospinal fluid 5-hydroxyindoleacetic acid level correlate with rigid and obsessive behavior? Arch Gen Psychiatry 1991; 48: 556–562.

  24. 24

    Frank GK, Kaye WH, Meltzer CC et al: Reduced 5-HT2A receptor binding after recovery from anorexia nervosa. Biol Psychiatry 2002; 52: 896–906.

  25. 25

    Kaye WH, Barbarich NC, Putnam K et al: Anxiolytic effects of acute tryptophan depletion in anorexia nervosa. Int J Eat Disord 2003; 33: 257–267.

  26. 26

    Kaye WH, Jimerson DC, Lake CR, Ebert MH : Altered norepinephrine metabolism following long-term weight recovery in patients with anorexia nervosa. Psychiatry Res 1985; 14: 333–342.

  27. 27

    Frisch A, Laufer N, Danziger Y et al: Association of anorexia nervosa with the high activity allele of the COMT gene: a family-based study in Israeli patients. Mol Psychiatry 2001; 6: 243–245.

  28. 28

    Gabrovsek M, Brecelj-Anderluh M, Bellodi L et al: Combined family trio and case–control analysis of the COMT Val158Met polymorphism in European patients with anorexia nervosa. Am J Med Genet 2004; 124B: 68–72.

Download references


We specially thank the young people and their families for participating. We are grateful to B Bennetts for a helpful discussion on linkage disequilibrium, and to B Bennetts, V Wiley and K Carpenter for the use of their laboratories, and to those who helped recruit the study participants. This work was funded by the Children's Hospital Fund.

Author information

Correspondence to Ruth Elizabeth Urwin.

Rights and permissions

Reprints and Permissions

About this article


  • eating disorders
  • genetic epistasis
  • amino-acid oxidoreductases
  • biogenic amine neurotransmitters
  • tryptophan
  • tyrosine

Further reading