Investigation of Epistasis Between the Serotonin Transporter and Norepinephrine Transporter Genes in Anorexia Nervosa

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 w 2 ¼ 0.01, df ¼ 1, p ¼ 0.921, odds ratio 1.0, 95% CI 0.7À1.5). 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) (w 2 ¼ 0.48, df ¼ 1, p ¼ 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.

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

“…The independent contribution by MAOA-L to increased risk of panic disorder is also thought to be small. 5 To date no one has attempted a replication study to confirm or refute our findings regarding MAOA-L. 9 Recently, we found no evidence for an independent contribution by the 5-HTTLPR to AN susceptibility in our family-based sample of at least a genotypic relative risk of 2.0 with 93% statistical power (odds ratio 1.0, 95% CI 0.7 -1.5), 10 which confirmed independent findings by others in three earlier studies. 11 -13 Data from the only other independent study of AN and the 5-HTTLPR suggested association of AN-BP with the 5-HTTLPR-S allele and 5-HTTLPR-S/S genotype (both P ¼ 0.02).…”

“…14 Additionally, we found no suggestion of interaction between the NETpPR polymorphism and the 5-HTTLPR, that is, neither 5-HTTLPR allele appeared to increase risk of AN when 5-HTTLPR allele transmissions from 5-HTTLPR-S/L heterozygous parents were stratified based on the NETpPR genotypes of their children with AN. 10 To date no one has attempted a replication study to confirm or refute our negative interaction findings between the NETpPR polymorphism and the 5-HTTLPR. 10 In the current study, to further investigate our hypothesis that proteins which clear NE and 5-HT from the synaptic cleft modify susceptibility to develop AN, we assess potential interaction between the MAOA-uVNTR and 5-HTTLPR in 114 nuclear families.…”

“…10 To date no one has attempted a replication study to confirm or refute our negative interaction findings between the NETpPR polymorphism and the 5-HTTLPR. 10 In the current study, to further investigate our hypothesis that proteins which clear NE and 5-HT from the synaptic cleft modify susceptibility to develop AN, we assess potential interaction between the MAOA-uVNTR and 5-HTTLPR in 114 nuclear families. Findings from our analysis suggest that increased risk of AN due to the combined effects of these polymorphisms is greater than additive, meaning that these functional polymorphisms are interacting epistatically.…”

A review and primer of molecular genetic studies of anorexia nervosa

“…29,30 Findings for other serotonin-related genes (i.e., 5-HT7, 5-HT 1Db , 5-HTT, TPH) have largely been negative. 24,26,28,[31][32][33][34][35][36][37][38] Studies of other candidate genes have been broad in scope covering genes involved in neurotransmitter systems (e.g., dopamine, opioids) as well as the regulation of feeding and energy expenditure (e.g., neuropeptide Y, leptin, agouti-related protein). Only one or two studies have examined each candidate gene.…”

“…Bergen et al (41) Association Yes SERT, NET Urwin et al (37) TDT and Association No OPRD1 Bergen et al (41) Association Yes ER a Eastwood et al (48) Association No…”