Progress in Neuro-Psychopharmacology and Biological Psychiatry
Epistatic interactions implicating dopaminergic genes in bulimia nervosa (BN): Relationships to eating- and personality-related psychopathology
Highlights
► Interactions of polymorphisms of dopamine system were examined in women with BN. ► Impact of polymorphisms on eating and personality measures was explored. ► DRD2 and DAT interacted on BMI; DRD4 and COMT interacted on self‐harming behaviors. ► Findings show lowered dopamine transmission corresponded to greater pathology.
Introduction
Bulimia nervosa (BN) is a severe eating disorder characterized by recurrent binge-eating and compensatory behaviors (such as vomiting, fasting or laxative abuse), and an overevaluation of shape, weight and their control. The disorder affects between 1% and 3% of young women (American Psychiatric Association, 2000). BN co-aggregates with various psychopathological traits, including impulsivity, novelty seeking, compulsivity, and self-harming behaviors (Steiger et al., 2007).
Although BN is almost certain to be multiply determined, recent evidence focuses attention on the etiological role of genetic factors — not surprising, given that heritability estimates for BN from twin studies range from 28% to 83% (Bulik and Tozzi, 2004). Although findings have been such as to imply that no single candidate gene accounts for risk of BN development (see Pinheiro et al., 2009, Scherag et al., 2010), accumulating evidence suggests that genes influencing monoamine activity contribute to sub-diagnostic expressions of BN, defined by variations as to concurrent psychopathology. For instance, bulimic carriers of low-function serotonin (5-HT) transporter promoter (5HTTLPR) alleles display elevated affective instability, impulsivity (Steiger et al., 2005, Steiger et al., 2009), sensation seeking (Steiger et al., 2007), dissocial-impulsive tendencies (Steiger et al., 2008, Steiger et al., 2009), anxiety (Ribases et al., 2008), and harm avoidance (Monteleone et al., 2006). Similarly, in BN, polymorphisms coding for 5HT2A, 5HT2C, Tryptophan hydroxylase-2 (TPH2) and Monoamine oxidase A (MAOA) reportedly shape expressions of impulsivity (Bruce et al., 2005, Nishiguchi et al., 2001), suicidality, self-injuriousness (Steiger et al., 2011) and harm avoidance (Monteleone et al., 2007).
Recently, the dopaminergic system has garnered attention as a system of interest in BN, due to demonstrated links between dopamine (DA) activity and food intake, emotion (Le Foll et al., 2009), novelty seeking (Cloninger et al., 1993), and impulsivity (Eisenberg et al., 2007b, White et al., 2008). Consistent with implication of DA in BN, people with BN are reported to display decreased DA metabolites (Jimerson et al., 1992), DA transporter (DAT) availability (Tauscher et al., 2001), and striatal activity during tasks involving reward (Wagner et al., 2010) and self-regulatory control (Marsh et al., 2009, Marsh et al., 2011). In addition, BN has been linked to variants of DAT and Dopamine D2 receptor (DRD2) polymorphisms (Scherag et al., 2010). In keeping with the preceding, recent research has focused on the identification of candidate genes of the DA system that may be involved in bulimic pathophysiology. Studies on eating disorders (EDs) have focused on polymorphisms of two genes coding for dopamine receptors — DRD2 and DRD4 (dopamine D4 receptor) — as well as DAT and catechol-O-methyltransferase (COMT) genes.
The Taq1 A polymorphism is a commonly studied variant of DRD2. Its two alleles are denoted A1 (T allele) and A2 (C allele) (Davis et al., 2008). Across populations, carriers of the low-function, T allele (T/T or T/C genotypes) show reduced brain dopamine function when compared to C/C homozygotes (Ritchie and Noble, 2003). Furthermore, the T allele has been associated greater food craving and motivation for food (Comings et al., 1993, Epstein et al., 2007), and greater weight gain and risk for obesity (Stice et al., 2010). The low-function T allele has also been linked to measures of impulsivity (Eisenberg et al., 2007b, White et al., 2008), sensation seeking (Berman et al., 2002, Ratsma et al., 2001), and substance use (Le Foll et al., 2009). A few studies have examined this polymorphism's association with eating disorders. One study found a significant interaction between the T allele and reward sensitivity in people with Binge Eating Disorder (Davis et al., 2008), an eating disorder characterized by recurrent episodes of binge eating in the absence of compensatory behaviors. Nisoli et al. (2007) failed to find an association between the T allele and either anorexia nervosa (AN) or BN. However, another study found that the T allele was linked with purging-type AN (Bergen et al., 2005), an eating disorder characterized by extreme low body weight, fear of weight gain, and engaging in purging behaviors. Interestingly, women with purging-type AN have higher levels of impulsivity as compared to controls (see Waxman, 2009 for review), inviting the conjecture that the DRD2 T allele may be more related to the trait of impulsivity in women with eating disorders characterized by binge eating or purging more than with Bulimic vs. non-bulimic status per se.
DRD4 has a functional polymorphism in the third exon which codes for part of the third intracellular loop of the receptor, i.e., the Exon-3 seven-repeat (7R) allele. This hypofunctional allele codes for decreased receptor affinity for dopamine (Asghari et al., 1995), and is associated with novelty-seeking (Benjamin et al., 1996, Ebstein et al., 1996) and impulsivity (Eisenberg et al., 2007b). The 7-repeat allele of DRD4 seems to be relevant to BN: Levitan et al. (2004) found higher rates of binge eating in women carrying the 7-repeat allele. Furthermore, the same group has reported the allele to be associated with higher maximal Body Mass Indexes (BMIs) in women with BN, both directly and in interaction with BDNF and season of birth (Kaplan et al., 2008, Levitan et al., 2010).
The catechol-O-methyltransferase (COMT) gene catabolizes brain catecholamine neurotransmitters such as dopamine and norepinephrine (Scherag et al., 2010). A substitution (472 G → A) in the mRNA creates an amino acid change (158Val → Met) leading to two alleles with different levels of enzymatic activity: the 158Val allele (G), which is about four times more active than the 158Met allele (A) (Lachman et al., 1996). COMT has been linked to suicidal behavior (Kia-Keating et al., 2007), and impulsivity in some reports (e.g., Paloyelis et al., 2010), but not others (Forbes et al., 2007). In heterogeneous groups of individuals with an ED (consisting of both AN and BN), carriers of at least one Met allele of the COMT gene had significantly higher scores on the Eating Disorder Inventory-2 (EDI-2) (Frieling et al., 2006), and carriers of two copies of the Val allele (Val/Val) were at increased risk for BN (Mikolajczyk et al., 2010).
The dopamine transporter (DAT) has a variable number tandem repeat (VNTR) polymorphism that produces various allelic variations. In non-eating disordered populations, DAT has been linked to poor inhibitory control (Congdon et al., 2008) and alcoholism (Köhnke et al., 2005). Shinohara et al. (2004) found that people with bulimic eating disorder variants (BN and AN binge/purge type) had higher frequencies of 7- and 9-repeat alleles than did controls. Hersrud and Stoltenberg (2009) examined the epistatic interaction between COMT and DAT on eating behavior in a non-clinical sample of women, and found that the combination of Met/10 and Val/9 genotypes was associated with elevated binge eating and eating psychopathology. Of note, findings inconsistently associate greatest DAT expression (and correspondingly heightened DA reuptake) with either the 9- (Miller and Madras, 2002) or 10-repeat allele (Heinz et al., 2000), or homozygosity for the 10 allele (i.e. a 10/10 genotype) (Davis et al., 2007, Heinz et al., 2000, Prata et al., 2009, VanNess et al., 2005). Due to the generally low frequency of homozygosity for the 9 tandem repeat of the DAT 1 gene (Bello and Hajnal, 2010), some investigators have argued that studies for this gene should compare individuals who are homozygous for the 10 and heterozygous for the 9 tandem repeat allele (Davis et al., 2007).
Although evidence supports the idea that polymorphisms acting within the DA system play a role in the pathophysiology of BN and of such associated traits as impulsivity, novelty-seeking, and self-harming behaviors, to our knowledge, no study to date has explored the extent to which epistatic interactions among genes acting in the dopamine system might account for heterogeneous clinical presentations seen in individuals suffering BN-spectrum disorders. The preceding is of particular interest given that BN is characterized by striking individual differences as to comorbid characteristics: about 30% of those affected being frankly “dysregulated” (emotionally labile and impulsive), a third “over-regulated” (emotionally constricted and inhibited), and another third quite free of psychopathology (Cassin and von Ranson, 2005, Lilenfeld et al., 2006, Steiger and Bruce, 2007). The present study investigated the possible role of Gene × Gene (G × G) interactions within the DA system in accounting for variations in the comorbid profiles presented by individuals with BN-spectrum disorders. To do so, we explored two-way interactions involving postsynaptic receptors (DRD2 TaqA1 rs1800497 and DRD4 7R), on the one hand, and dopamine regulators (DAT1 and COMT rs4680), on the other, assuming that combinations of these polymorphisms might influence eating and generalized psychopathology in women with BN. We chose to pair receptor genes with genes responsible for the breakdown and transport of dopamine, given presumed functional significance of such pairings—and hypothesized that carriers of alleles coding for relatively reduced post-synaptic receptor sensitivity (i.e., low-function alleles of DRD2 or DRD4), when also carrying variants of genes coding for relatively high DA breakdown (i.e., COMT Val/Val or DAT 10/10), would be prone to more pronounced eating and generalized psychopathology than would individuals carrying other combinations of genetic factors. Assuming additive effects of different polymorphisms in combination, we speculated that psychopathological manifestations might become progressively less pronounced across individuals carrying two “risk-disposing” polymorphisms, those carrying only one such polymorphism, and then those carrying no “risk” disposition.
Section snippets
Participants
This study received institutional ethics board approval, and all study participants gave informed consent. Participants were compensated monetarily for participation in the study. Previous research suggests that women with full-blown BN do not differ substantially from those with sub-threshold forms on key clinical dimensions such as severity of symptoms and course of the disorder (Fairburn and Harrison, 2003). In addition, we believe that the diagnostic variations described below allow for
Results
Table 1 displays frequencies and percentages of DRD2, DRD4, COMT and DAT genotypes. Hardy–Weinberg tests were conducted on observed genotypes and indicated genotype rates to be in equilibrium for DRD2 [χ(1)2 = 2.2, n.s.], COMT [χ(1)2 = 0.73, n.s.], and DAT [χ(1)2 = 1.5, n.s.]. For DRD4, Hardy–Weinberg tests indicated genotype rates to be in disequilibrium [χ(1)2 = 8.51, p < 0.01], when treating all alleles 7 or higher as low function and 6 or lower as high function (as per Eisenberg et al., 2007b).
Discussion
In women with bulimia-spectrum disorders, we explored possible pairwise (epistatic) interaction effects influencing personality and eating psychopathology, implicating DRD2 TaqA1 rs1800497 and DRD4 7R, on the one hand, and COMT rs4680 and DAT1, on the other. In keeping with previous findings associating DA polymorphisms coding for reduced dopamine activity with heightened expression of traits such as novelty or sensation seeking (Benjamin et al., 1996, Berman et al., 2002, Ebstein et al., 1996,
Acknowledgments
This research was supported by grants awarded to Dr. Steiger and colleagues (nos. MOP-79490 and MOP-57929) from the Canadian Institutes for Health Research. The funding agencies had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report, or in the decision to submit the paper for publication.
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2018, GeneCitation Excerpt :The conclusions of this report are consistent with those of our study, as the authors suggest that genes acting in the dopamine system may influence personality-related psychopathology in BN patients. It should be noted however, that Thaler et al. only determined the DRD4 exon 3 VNTR non7R/7R polymorphism and analyzed interactions with variants in other dopaminergic genes such as COMT (Thaler et al., 2012). The authors claimed that the combination of these polymorphisms would lead to lower levels of dopaminergic neurotransmission, which would in turn result in increased psychopathology.
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2016, Journal of Psychiatric ResearchCitation Excerpt :Given the preceding, we applied dichotomous classifications for each of COMT, DRD2, and DRD4 in all subsequent analyses, examining differences between individuals in whom there was presence or absence of a Met allele for COMT (Val/Val vs. Met carriers), a T allele for DRD2, or the low function 7-repeat (7R) allele for DRD4. Such dichotomous classifications for COMT, DRD2 and DRD4 genotypes have been applied in previous studies (e.g., Davis et al., 2008; Mikołajczyk et al., 2010; Benjamin et al., 1996; Eisenberg et al., 2007; Thaler et al., 2012). Our principle analyses involved a series of separate logistic multiple regressions, structured to explore main and interaction effects of genetic factors (either DRD2 x COMT or DRD4 x COMT), on dependent variables (presence or absence of alcohol, cannabis, stimulant, cocaine, or any substance abuse), while controlling for extraneous effects of depression and impulsivity.
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2015, Psychiatry ResearchCitation Excerpt :It has been reported in rodents that D2S- and D2L-receptor subsensitivity, higher levels of DA synthesis, and higher extracellular DA are related to novelty-seeking, addictive behaviors, aggression, behavioral sensitization, incentive motivation, response perseveration, and lower levels of anxiety (Mällo et al., 2007; de Miguel et al., 2011; Beiderbeck et al., 2013; Tournier et al., 2013; Lehner et al., 2014; de Jong et al., in press; Holroyd et al., 2015), suggesting that the A1-allele of the TaqIA-ANKK1 SNP may relate to analogous traits in humans. In agreement, A1-allele carriers display higher levels of childhood antisocial behavior, bipolar disorder with low anxiety, impulsivity, novelty/stimulus seeking, aggression, antisocial/borderline traits, faster habituation to positive feedback (decoupling behavior from experience), and substance abuse/dependence but also adaptive traits such as extraversion, behavioral activation, low depression or harm avoidance, and improved cognitive performance (Noble et al., 1998; Bartrés-Faz et al., 2002; Eisenberg et al., 2007; Hoenicka et al., 2007; Ponce et al., 2008; Althaus et al., 2009; Esposito-Smythers et al., 2009; Ponce et al., 2009; Barskiĭ et al., 2010; Nemoda et al., 2010; Smillie et al., 2010; Stelzel et al., 2010; Thaler et al., 2012; Kazantseva et al., 2011; Lu et al., 2012; Zai et al., 2012; Wang et al., 2013a, 2014). A1-carriers also showed significantly lower levels of risk for depression and higher engagement bias towards positive social stimuli, thus evincing a more stable and higher DA functioning (Elovainio et al., 2007; Gong et al., 2013).