1. ¹Department of Psychological Medicine, The Children's Hospital at Westmead, Westmead, NSW, Australia
2. ²Department of Molecular Genetics, The Children's Hospital at Westmead, Westmead, NSW, Australia
3. ³Department of Biochemical Genetics and Newborn Screening, The Children's Hospital at Westmead, Westmead, NSW, Australia
4. ⁴Department of Psychiatry, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
5. ⁵Discipline of Psychological Medicine, University of Sydney, NSW, Australia
6. ⁶Discipline of Paediatrics and Child Health, University of Sydney, NSW, Australia

Correspondence: RE Urwin, Department of Psychological Medicine, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia. Tel: +61 2 9845 2005; Fax: +61 2 9845 2009; E-mail: RuthU@chw.edu.au

Received 28 November 2002; Revised 18 February 2003; Accepted 11 March 2003; Published online 14 May 2003.

Abstract

Weight-restored patients with anorexia nervosa (AN) respond favorably to the selective serotonin reuptake inhibitor fluoxetine, which justifies association studies of the serotonin transporter gene (SLC6A4, alias SERT) and AN. Case–control studies suggest that the least transcriptionally active allele of the SERT gene promoter polymorphism (5-HTTLPR) has an increased frequency in AN patients. However, this finding was not replicated with 55 trios (AN child+parents) and the transmission disequilibrium test (TDT). To clarify the role of the 5-HTTLPR in susceptibility to AN, we used the TDT and 106 Australian trios to provide 93% power to detect a genotypic relative risk (GRR) of 2.0. Our results were negative for this GRR (McNemar's ²=0.01, df=1, p=0.921, odds ratio 1.0, 95% CI 0.7-1.5). Additionally, we found no association with AN females, AN subtype, age at onset, or minimum BMI. We then performed the first reported investigation of epistasis between the SERT gene and norepinephrine transporter gene (SLC6A2, alias NET) in AN, as an earlier study suggested that atypical AN responds to the dual serotonin–norepinephrine reuptake inhibitor venlafaxine. We observed no epistasis between the 5-HTTLPR and a polymorphism within the NET gene promoter polymorphic region (NETpPR) (²=0.48, df=1, p=0.490). Although 5-HTTLPR modulates serotonin reuptake by the serotonin transporter, our analyses provide no evidence that susceptibility to AN is modified by 5-HTTLPR alone, nor in concert with as yet undetermined functional effects of the NETpPR polymorphism.