Gene-gene interaction between the monoamine oxidase A gene and solute carrier family 6 (neurotransmitter transporter, noradrenalin) member 2 gene in anorexia nervosa (restrictive subtype).

We earlier found an association between anorexia nervosa (AN) restrictive subtype (AN-R) and an inserted sequence within the NETpPR, a polymorphic region located in the promoter of the solute carrier family 6 (neurotransmitter transporter, noradrenalin) member 2 (SLC6A2) gene. To further examine the noradrenergic system in AN-R we performed an association study with a functional polymorphism (MAOA-uVNTR) in the promoter of the monoamine oxidase A (MAOA) gene. Since monoamine oxidase A metabolises noradrenalin, a positive association with the MAOA gene would be biologically plausible. The transmission disequilibrium test and 95 trios/duos (AN-R females+biological parents) showed the main effect of the longer, more transcriptionally active form of the MAOA-uVNTR (MAOA-L) to be statistically non-significant (McNemar's chi(2)=1.4, df=1, P=0.238, odds ratio: 1.4, 95% CI 0.8-2.7). A case-control approach supported this finding. We then stratified the MAOA-uVNTR TDT data according to the (a) NETpPR genotype of the AN-R females, and (b) NETpPR allele transmitted from NETpPR-S4/L4 heterozygous mothers. In both cases, contingency table analysis revealed previously unreported gene-gene interaction between the MAOA and SLC6A2 genes (P=0.019 and 0.019, respectively). Receiving an MAOA-L allele more than doubles the risk for developing AN-R, conditional on an individual also being a NETpPR-L4 homozygote (stratum-specific odds ratio: 2.4, 95% CI 1.1-6.0). These results suggest important involvement of the noradrenergic system in the biological underpinnings of AN-R.

Investigation of epistasis between the serotonin transporter and norepinephrine transporter genes in anorexia nervosa.

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 chi(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) (chi(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.