The dopamine-4 receptor gene associated with binge eating and weight gain in women with seasonal affective disorder: An evolutionary perspective

The Dopamine-4 Receptor Gene Associated with Binge Eating and Weight Gain in Women with Seasonal Affective Disorder: An Evolutionary Perspective Robert D. Levitan, Mario Masellis, Vincenzo S. Basile, Raymond W. Lam, Allan S. Kaplan, Caroline Davis, Pierandrea Muglia, Bronwyn Mackenzie, Subi Tharmalingam, Sidney H. Kennedy, Fabio Macciardi, James L. Kennedy Background: We recently described a preliminary association between the hypofunctional seven-repeat allele of the dopamine-4 receptor gene (DRD4) and increased maximal lifetime body mass index in women with seasonal affective disorder (SAD). In this study, we examined whether binge eating behavior mediated this putative association. Methods: The study sample consisted of 131 women with winter SAD who reported increased intake of high-carbohydrate/high-fat foods during depressive episodes. We compared rates of binge eating behavior in the two genotypic groups defined by the presence or absence of the seven-repeat allele of DRD4. Results: Consistent with our working hypothesis, the proportion of binge eaters was significantly greater in probands with the seven-repeat allele (18 of 46, 39.1%) than in probands without this allele (14 of 85, 16.5%) [␹2(1)⫽ 8.32, p ⫽ .004; odds ratio ⫽ 3.25, 95% confidence interval 1.43, 7.41]. Conclusions: Pending replication in other samples, these results point to a genetic factor that could help in the early identification and treatment of women at higher risk for seasonal weight gain associated with binge eating behavior. At a theoretic level, the current results suggest a novel link between evolutionary models of seasonal weight gain on the one hand and the DRD4 gene on the other. Key Words: Seasonal affective disorder, genetics, weight gain, binge eating, dopamine-4 receptor gene, positive selection

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easonal affective disorder (SAD) is a mood disorder characterized by the predictable onset of depression in the fall/winter months with spontaneous remissions in the spring/summer period (Rosenthal et al 1984). The typical patient with SAD is a premenopausal woman with marked craving for high-carbohydrate/high-fat foods and significant weight gain during winter depressive episodes. As a result, SAD has been described as a naturally reversible form of obesity (Rosenthal et al 1987). Appetitive symptoms are particularly sensitive to bright light therapy in SAD patients (Kräuchi et al 1993), making this a potentially treatable form of weight gain as well. It has been suggested that fall/winter increases in eating behavior and weight might reflect the human expression of a basic evolutionary process, present across multiple species, ensuring maximum conservation of energy when food supplies are becoming scarce (Rosenthal et al 1987; Thomson 1950). In humans, although adaptive over the course of evolution, this same process might be maladaptive when highly palatable, high-caloric foods are readily available, as is the case in modern developed countries. Seasonal weight gain in the context of SAD might thus reflect a classic gene–

environment interaction, whereby a previously adaptive gene becomes a vulnerability gene when circumstances change. If so, this could have relatively broad public health implications in that 1) seasonal weight gain occurs in a large proportion of the North American population (Kasper et al 1989); and 2) gene– environment interactions acting at a behavioral as opposed to a metabolic level might best explain the very rapid increase in obesity in recent history (Blundell and Cooling 2000; Hewitt 1997). We recently reported an association between the sevenrepeat (7R) allele of the dopamine-4 receptor gene (DRD4) and obesity in a sample of women with SAD (Levitan et al 2004). In that initial report, we did not examine whether the increase in body mass associated with the 7R allele was attributable to a change in eating behavior per se. Other dopamine-based mechanisms, such as a decrease in physical activity, could also account for such a finding. The goal of the current analysis was to extend these findings and to more directly test the hypothesis that in overeating women with SAD, the putative association between DRD4 and increased body mass is mediated by increased eating behavior. The specific hypothesis was that the 7R allele would be associated with binge eating behavior and weight gain in overeating women with SAD.

Methods and Materials From the Mood and Anxiety Division (RDL, BM) and the Neurogenetics Section (MM, VSB, PM, ST, FM, JLK), Centre for Addiction and Mental Health; and the Eating Disorders Program (ASK, CD), Toronto General Hospital (SHK), University Health Network; University of Toronto, Department of Psychiatry, Toronto, Ontario; and Department of Psychiatry (RWL), University of British Columbia, Vancouver, British Columbia, Canada. Address reprint requests to Robert Levitan, M.D., Centre for Addiction and Mental Health, University of Toronto, Department of Psychiatry, 250 College Street, Room 1126, Toronto, Ontario M5T 1R8, Canada; E-mail: [email protected]. Received March 24, 2004; revised July 16, 2004; accepted August 25, 2004.

0006-3223/04/$30.00 doi:10.1016/j.biopsych.2004.08.013

Sample The current study group consisted of consecutive women 18 – 65 years of age who met DSM-IV criteria for major depression with a winter seasonal pattern. Some study subjects were presenting for a mood disorder consultation at the Centre for Addiction and Mental Health in Toronto, Canada, whereas others were recruited through advertisements in a local newspaper. The current sample included the same Toronto probands described in our prior report (n ⫽ 83; Levitan et al 2004), in addition to several new Toronto BIOL PSYCHIATRY 2004;56:665– 669 © 2004 Society of Biological Psychiatry

666 BIOL PSYCHIATRY 2004;56:665– 669

R.D. Levitan et al

Table 1. Mean Age and Maximal Body Mass Indices in Genotypic Groups Defined by the Presence or Absence of the Seven-Repeat Allele of the Dopamine-D4 Receptor Gene (DRD4) in 131 Women with Seasonal Affective Disorder DRD4 Genotypes

Age (y) Maximal Lifetime Body Mass Index

All Subjects

Seven-Repeat Allele Present

Seven-Repeat Allele Absent

n ⫽ 125 37.7 ⫾ 9.3 n ⫽ 128 27.0 ⫾ 7.6

n ⫽ 42 39.0 ⫾ 8.3 n ⫽ 45 29.3 ⫾ 7.6

n ⫽ 83 37.1 ⫾ 9.8 n ⫽ 83 25.8 ⫾ 7.3

t Statistic

df

p Value

1.07

123

.29

2.58

126

.011

Discrepancies in sample size are due to missing data.

probands recruited subsequently (n ⫽ 48). Probands from our British Columbia sample did not undergo an in-depth assessment of binge eating behavior and were thus excluded from the current analysis. Because our ongoing genetics project is limited to female subjects with increased eating behavior, only women who reported increased eating during their seasonal depressive episodes were included. Individuals had to report carbohydrate/fat craving and/or increased eating during winter depressive episodes, on the basis of their clinical consultation interview, done by one of us (RDL), and independent confirmation by a research assistant using structured interviewing with the Structured Clinical Interview for DSM-IV (SCID; First et al 2002) and the Structured Interview Guide for the Hamilton Depression Rating Scale-Seasonal Affective Disorder Version (Williams et al 1988). To limit the heterogeneity of the current sample, probands with a lifetime diagnosis of bulimia nervosa were excluded. Assessment of Maximal Body Mass Index and Binge Eating Behavior As part of the structured interviewing done by a research assistant, each subject was administered a brief questionnaire, which included a question about maximum weight achieved from age 16 onward, with corresponding height. A maximal lifetime body mass index (BMI) was calculated for each subject with the formula [maximum weight in kilograms/(corresponding height in meters)2]. Binge eating was assessed as part of the SCID interview, which included a section for binge eating disorder (BED). Although the proposed criteria for BED include four separate items, we were primarily interested in the first two items (“A” and “B”), which encompass the behavioral symptoms of binge eating disorder (see Appendix 1). Binge eating disorder rather than bulimia nervosa was chosen for diagnostic comparison because of the greater phenomenologic similarities between BED and SAD patients in terms of the tendency to overeat without compensation and sensitivity to the hedonic properties of foods. Each subject was given a spoken and written summary of the purposes, procedures, and potential risks of the project and gave written informed consent. The protocol was approved by the University of Toronto research ethics committee. Laboratory Methods Blood samples were sent to the Centre for Addiction and Mental Health Neurogenetics Laboratory. Genomic deoxyribonucleic acid (DNA) was extracted from white blood cells with the high-salt method. All genotyping of the DNA was performed blind to psychiatric diagnosis and vice versa. This was facilitated through a standard patient identification coding system used by www.elsevier.com/locate/biopsych

our laboratory. The 48-base-pair variable number of tandem repeats (VNTR) region in the third exon of DRD4 was amplified with polymerase chain reaction (PCR) techniques with primers and conditions as previously described (Lichter et al 1993). The PCR products were visualized by gel electrophoresis performed in 3.5% agarose prepared with ethidium bromide and 1⫻ TBE (Tris, boric acid, ethylenediaminetetraacetic acid). Statistical Methods Maximal lifetime BMI was compared across the two main genotypic groups (with and without the 7R allele) with unpaired t tests. Probands were designated as binge eaters if they met research criteria “A” and “B” for binge eating disorder, according to the SCID. Rates of binge eating in subjects with and without the 7R allele were compared with the Pearson ␹2 statistic. Odds ratios for binge eating in the two genotypic groups, with 95% confidence intervals (CIs), were also calculated.

Results Sample Characteristics The mean (⫾SD) age of the current sample was 37.7 ⫾ 9.3 years. Ancestral information was available for 124 probands, of whom 115 (92.7%) were Caucasian. The statistically significant results summarized below remained significant when only Caucasian probands were considered. Across the entire sample, the frequency of the common 4R, 7R, and 2R alleles was 68.3%, 19.5%, and 8.8%, respectively, consistent with results from prior studies. There was no deviation from Hardy-Weinberg equilibrium. There were 46 individuals (35.1%) with at least one version of the 7R allele. Table 1 indicates no significant difference in age between the two genotypic groups defined by the presence or absence of the 7R allele. As shown, maximal lifetime BMI was significantly greater in 7R allele carriers compared with noncarriers. As expected, there was a positive correlation between age and maximal BMI in the entire sample; this relationship was also significant in each of the two main genotypic groups considered separately. There was no significant difference in age in the two groups with and without binge eating. Table 2 indicates that the proportion of binge eaters was significantly higher in probands with the 7R allele (18 of 46, 39.1%) than in probands without this allele (14 of 85, 16.5%) [␹2(1) ⫽ 8.32, p ⫽ .004; odds ratio ⫽ 3.25, 95% CI 1.43, 7.41), consistent with our working hypothesis. Across all subjects, maximal lifetime BMI was significantly higher in probands with binge eating than in those without (30.7 ⫾ 7.8 vs. 25.8 ⫾ 7.2, respectively, df ⫽ 126, p ⫽ .001).

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R.D. Levitan et al Table 2. Frequency Analysis Comparing Rates of Binge Eating Behavior (Defined by Research Criteria A and B for Binge Eating Disorder) in Carriers and Noncarriers of the Seven-Repeat Allelea

Binge Eating Present Binge Eating Absent

Seven-Repeat Allele Present (Total n ⫽ 46)

Seven-Repeat Allele Absent (Total n ⫽ 85)

n ⫽ 18 (39.1%) n ⫽ 28 (60.9%)

n ⫽ 14 (16.5%) n ⫽ 71 (83.5%)

␹ (1) ⫽ 8.32, p ⫽ .004.

a 2

To further test the independent contribution of age, binge eating, and DRD4 on maximal BMI, a post hoc analysis of covariance (ANCOVA) was done, with maximum lifetime BMI as the dependent variable, DRD4 genotype (7R allele present/ absent) and binge eating grouping (present/absent, as defined above) as predictor variables, and age as a covariate. According to this model, binge eating continued to be a significant predictor of maximal BMI [F (1,122) ⫽ 7.98, p ⫽ .006], whereas the relationship between DRD4 and maximum BMI was no longer significant [F (1,122) ⫽ 1.05, p ⫽ .31]. The (DRD4 ⫻ BED grouping) interaction term was not a significant predictor of maximal BMI [F (1,122) ⫽ .437, p ⫽ .51]. These same results were found when age was not covaried. In sum, these ANCOVA results suggest that the association linking DRD4 and maximal BMI is attributable to the variance shared by DRD4 genotype and binge eating. DRD4 and Substance Abuse To explore whether 7R allele carriers in our sample binged on substances other than food, we examined post hoc whether 7R allele carriers were predisposed to alcoholism and/or other substance abuse. On the basis of a current and/or lifetime diagnosis, the rate of alcoholism was found to be nonsignificantly decreased in 7R allele carriers (2 of 43, 4.7%) compared with noncarriers (8 of 82, 9.8%; ␹2 ⫽ 1.00, p ⫽ .32). Similar results were found for other substances of abuse (2.3% in 7R allele carriers vs. 7.3% in noncarriers; ␹2 ⫽ 1.33, p ⫽ .25). This suggests that in overeating women with SAD, the association between the 7R allele and bingeing behavior might be limited to food.

Discussion An association between the 7R allele of the DRD4 exon-3 VNTR polymorphism and obesity has previously been reported in a group of overeating women with winter SAD (Levitan et al 2004). The goal of the current study was to extend our findings and to examine the role of increased eating behavior in mediating this putative association. Consistent with our working hypothesis, carriers of the 7R allele, a functional variant associated with decreased intracellular signaling (Asghari et al 1995) had a significantly greater risk of binge eating over their lifetime than did 7R allele noncarriers. A post hoc ANCOVA predicting maximal lifetime BMI with both genetic and clinical variables further supported the hypothesis that the 7R allele– high maximal BMI association was mediated by binge eating. Pending replication in other samples, these results point to a genetic vulnerability factor that could help in the early identification and treatment of women at higher risk for seasonal weight gain associated with binge eating behavior. How might altered activity of the D4 receptor be related to binge eating behavior and weight gain in women with SAD?

Although the specific behavioral effects of the D4 receptor in the human brain are unknown, SAD patients often consume palatable foods to reverse negative mood states (Kräuchi et al 1997), which suggests that food reward processes might be involved. Reward expectancy related to food presentation is mediated by the prefrontal cortex (PFC) (Watanabe 1996), a brain area both rich in D4 receptors (Meador-Woodruff et al 1996) and shown to mediate binge eating in animal (Inoue et al 1998) and human (Karhunen et al 2000) models. An inability to delay food reward, which could result from altered dopamine activity in the PFC, might be expected to contribute to binge-eating behavior in vulnerable individuals. A related hypothesis is that individuals with low intrinsic dopamine activity in brain reward pathways attempt to compensate by using various reinforcing behaviors, including increased food consumption (Comings and Blum 2000). This has been termed the reward deficiency syndrome and has been described previously in obese populations (Blum et al 1996). An Evolutionary Perspective It is interesting to consider the current results from the framework of previously established evolutionary models of SAD on the one hand and the DRD4 gene on the other. Regarding SAD, it has been suggested that fall/winter increases in eating behavior and weight might reflect the human expression of a basic evolutionary process, present across multiple species, ensuring maximum conservation of energy when food supplies are becoming scarce (Rosenthal et al 1987; Thomson 1950). Although adaptive over the course of evolution, particularly in northern latitudes, this same process might contribute to exaggerated increases in body mass and obesity when supplies of highly palatable, high-caloric foods are plentiful, as is the case in modern developed countries (Macdiarmid et al 1996). If so, seasonal weight gain might be a particularly interesting model for gene– environment interaction as it relates to obesity. Regarding the DRD4 gene, a recent analysis has found evidence that the 7R allele likely originated as a rare mutational event and that positive selection over the past 40,000 years might be maintaining it at a high frequency in certain populations (Ding et al 2002). On the basis of prior work linking the 7R allele to attentiondeficit/hyperactivity disorder primarily in men, Harpending and Cochran (2002) postulated that the basis for this positive selection might have been related to impulsive temperament in men and either increased migration and/or a reproductive advantage conferred to them in certain societies. The current results suggest a compatible hypothesis, which might also relate to trait impulsivity, that the ability of young women to conserve body mass in seasonal periods of dwindling food supply, mediated by an effect of the 7R allele on binge eating, might also have been a factor in this positive selection process. In this way, the current results suggest a link between evolutionary models of seasonal weight gain on the one hand and the DRD4 gene on the other. If our model linking seasonal weight gain and the 7R allele is correct, ethnic populations with high frequencies of this allele should have particularly high rates of seasonal weight gain secondarily to increased eating behavior, whereas populations with low frequencies of the 7R allele should not. Two populations of particular interest in this regard are American Indians (very high rates of 7R allele) and the Japanese (very low rates of 7R allele). Consistent with our model, seasonal changes in mood and behavior are less frequent in Japan than www.elsevier.com/locate/biopsych

668 BIOL PSYCHIATRY 2004;56:665– 669 in either the United States or in European countries at similar latitudes (Magnusson 2000; Ozaki et al 1995). Of particular interest for our hypothesis, when seasonal changes in mood and behavior are experienced in the Japanese population, they are much less likely to include “atypical” symptoms of overeating and weight gain (20%–30% of individuals) than in North American samples (⬎70% of individuals) (Rosenthal et al 1984; Sakamoto et al 1993). Japanese females with disordered eating also report less seasonality than their North American peers (Yamatsuji et al 2003). Although there is a dearth of data on seasonal affective disorder and seasonal weight gain in American Indians, overweight and obesity are growing at particularly high rates in various Indian populations in both North and South America. This might be attributable to increased exposure to highly palatable, high-caloric foods typical of North American diets. Although further research is needed to understand individual differences in susceptibility to weight gain in American Indians, their high rates of both the 7R allele and obesity suggest a possible role for the DRD4 gene and hedonic responsivity in these individuals. Limitations More work is needed to replicate and further extend our findings and to examine this association in other disorders characterized by increased eating behavior, such as BED, carbohydrate-craving obesity, and bulimia nervosa. Such studies would also clarify to what extent seasonality as opposed to weight regulation per se plays a role in the current results. To maximize the homogeneity of our SAD sample, to date we have recruited only female probands with increased eating behavior. Although this phenotype is the most common presentation of SAD, particularly in women, approximately 30% of SAD patients do not have increased eating. According to our model, one might expect a lower frequency of the 7R allele in these more “classically” depressed SAD probands. If so, addition of this subgroup would have strengthened the current results linking the 7R allele with bingeing behavior and weight gain. Although firm conclusions regarding this subgroup are not possible at the current time, this is an important consideration for future work in this area. Although D4 receptors are expressed on meso-corticolimbic structures that comprise the natural reward pathway (Meador-Woodruff et al 1996) and might in some way contribute to weight gain (Bromel et al 1998; Nothen et al 1994), relatively little is known about the physiologic role of D4 in the human brain. The 7R allele might promote the rapid consumption of highly palatable foods in many women with SAD, perhaps to compensate for a sluggish dopamine system (Wang et al 2001), but we cannot be sure that this is the mechanism involved. It is also possible that the VNTR polymorphism under consideration is in linkage disequilibrium with an entirely different gene in the same chromosomal region that itself affects the phenotype under investigation and/or alters the expression of this VNTR. The location of DRD4 on 11p15.5 is of interest in this regard because it is within 1.5 megabases of an insulin gene that has been associated with childhood obesity (Le Stunff et al 2000). In female probands with SAD and overeating, the 7R allele of DRD4 might contribute to binge eating behavior and thus higher maximal lifetime BMIs. Although replication in other samples is needed, these results point to a genetic vulnerability factor that could help in the early identification and treatment of girls and www.elsevier.com/locate/biopsych

R.D. Levitan et al women at higher risk for seasonal weight gain due to at least one manifestation of increased food intake.

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BIOL PSYCHIATRY 2004;56:665– 669 669 Appendix 1. “A” and “B” Research Criteria for Binge Eating Disorder Criterion A: Recurrent episodes of binge eating characterized by both of the following: 1. Eating, in a discrete period of time (e.g., within any 2-hour period), an amount of food that is definitely larger than most people would eat in a similar period of time under similar circumstances 2. A sense of lack of control over eating during the episode (i.e., feeling that one cannot stop eating or control what or how much one is eating) Criterion B: The binge-eating episodes are associated with three (or more) of the following: 1. Eating much more rapidly than normal 2. Eating until feeling uncomfortably full 3. Eating large amounts of food when not feeling physically hungry 4. Eating alone because of being embarrassed by how much one is eating 5. Feeling disgusted with oneself, depressed, or very guilty after overeating

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