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J Abnorm Psychol. Author manuscript; available in PMC Aug 1, 2012.
Published in final edited form as:
PMCID: PMC3169010
NIHMSID: NIHMS319468
Consideration of the BDNF Gene in relation to two phenotypes: Hoarding and Obesity
Kiara R. Timpano,1 Norman B. Schmidt,2 Michael G. Wheaton,3 Jens R. Wendland,3 and Dennis L. Murphy3*
1University of Miami, Miami, FL 33146
2Florida State University, Tallahassee, FL 32306-1270
3Laboratory of Clinical Science, NIMH Intramural Research Program, Bethesda, MD 20892
Corresponding author: Kiara R. Timpano, Ph.D., Department of Psychology, University of Miami, 5665 Ponce de Leon Blvd., Coral Gables, FL 33146, Tel: 202-441-2597, kiaratimpano/at/gmail.com
The gene coding for the brain derived neurotrophic factor (BDNF) has emerged as an interesting candidate for multiple brain and brain disorder-related phenomena. The primary aim of the present investigation was to consider the relationship between the BDNF Val66Met variant and two phenotypes: compulsive hoarding as a symptom dimension of obsessive compulsive disorder (OCD), and body mass index (BMI). We examined the BDNF gene in a large (N=301) clinical sample of probands with OCD. Participants were classified as hoarding or non-hoarding using a strict, multi-measure grouping approach. Results revealed that the Val/Val genotype was linked with hoarding classification and more severe hoarding behaviors, as well as greater BMI levels. Hoarding status was also associated with greater BMI scores, with individuals in the hoarding group being far more likely to be classified as obese compared to the non-hoarding group. Our findings may provide a distinct avenue through which hoarding and BMI could be linked. These findings are suggestive of a complex gene, body weight, and psychopathology relationship wherein a primitive, survival “thrifty gene” strategy may be conserved and represented in a subgroup of humans manifesting severe hoarding symptoms.
Keywords: brain derived neurotrophic factor gene, Val66Met SNP, hoarding, OCD, body mass index
Across recent animal and human genetic investigations, the brain derived neurotrophic factor (BDNF) has emerged as an interesting candidate for multiple pathologies (Bath & Lee, 2006; Duman & Monteggia, 2006). BDNF is a member of the neurotrophin family that influences neuronal transmission and plasticity, and plays an important role in the synaptic development and survival of several neuronal systems, including glutamatergic (Falkenberg, Lindefors, Camilli, Metsis, & Ungerstedt, 1996), dopaminergic (Guillin et al., 2001) and serotonergic systems (Djalali et al., 2005). Given the influence of BDNF on neuronal functioning, variants in the BDNF gene have been evaluated in relation to a number of disease-associated phenotypes. In particular, a non-synonymous single nucleotide polymorphism (SNP; rs6265), which results in a valine (Val) to methionine (Met) substitution at codon 66 in the 5’ pro-region of the human BDNF protein (Val66Met), has been investigated as the only known functional variant.
The Val66Met variant leads to changes in BDNF protein distribution in the central nervous system, along with alterations in hippocampal size and function (Govindarajan et al., 2006; Monteggia et al., 2004). Studies with gene-targeted murine models have demonstrated that Bdnf variation is linked with memory impairment, greater avoidance, greater anxiety, aggression, and obesity (Chen et al., 2006; Kernie, Liebl, & Parada, 2000; Lyons et al., 1999; Monteggia, et al., 2004; Ren-Patterson et al., 2006; Rios et al., 2001). Parallel findings have emerged from human investigations. For example, the Val66Met SNP has been associated with hippocampal volume variations, altered memory performance (Egan et al., 2003), and weight regulation (Gray et al., 2006; Gunstad et al., 2006; Shugart et al., 2009). Additional investigations have found that the Val allele is associated with the Neuroticism personality variable, and thus may be relevant to the broad construct of anxiety (Lang et al., 2005; Sen et al., 2003). Considering specific psychiatric conditions, the Val66Met BDNF SNP has been associated with multiple neuropsychiatric disorders, including eating disorders (Ribases et al., 2003; Ribases et al., 2004) and obsessive compulsive disorder (OCD) (Hall, Dhilla, Charalambous, Gogos, & Karayiorgou, 2003).
The primary aim of the present investigation was to examine the BDNF Val66Met variant in relationship to two phenotypes: compulsive hoarding within the context of a larger OCD sample, and body mass index (BMI). OCD has been identified as a global, public health concern (Lopez & Murray, 1998), with a lifetime prevalence of approximately 2–3% (Angst et al., 2004). The symptoms of OCD are broadly conceptualized as distressing and recurrent intrusive thoughts and compulsive behaviors, though recent reports have highlighted the high degree of heterogeneity in the presentation (Mataix-Cols, Rosario-Campos, & Leckman, 2005). One symptom type that has emerged as a related, yet potentially separate phenomenon from OCD, is hoarding. Hoarding is defined as the acquisition of and failure to discard possessions, which results in debilitating clutter and impairment (Frost & Hartl, 1996). Research on this syndrome has identified hoarding as the most familial symptom type among OCD sibling pairs (Hasler et al., 2007), and has also highlighted certain phenomenological elements that set it apart from other OCD symptoms (Pertusa et al., 2008). Efforts are under-way to clarify the diagnostic status of hoarding, including its relationship to OCD (Mataix-Cols et al., 2010; Pertusa et al., 2010). Until this question is resolved, there is a growing consensus that etiological and phenomenological investigations should take hoarding and other possible OCD sub-phenotypes into account to reduce sample heterogeneity and clarify research findings.
There are several lines of support for jointly considering hoarding, BMI, and BDNF. The regulation of energy expenditures and eating behaviors has been linked with BDNF in animal research (Lebrun, Bariohay, Moyse, & Jean, 2006b; Xu et al., 2003), as well as human investigations that found associations with obesity and eating disorders (Monteleone et al., 2005; Ribases et al., 2005). Energy expenditures/eating behaviors might also be dysregulated in relation to hoarding, as suggested by a recent investigation that found individuals with hoarding had significantly greater BMI levels (obese range) than non-hoarding family-members (Tolin, Frost, Steketee, Gray, & Fitch, 2008). From an evolutionary perspective, animals have developed two main strategies for managing energy demands prior to and during times of diminished food availability and other stresses: (1) gaining weight by increasing internal fat storage and (2) hoarding actual food stores (de Kort & Clayton, 2006; Francis, 2005; Healy, de Kort, & Clayton, 2005; Prentice, 2005). In addition, research in mice and other rodents has found a correlation between hoarding and body weight in the context of stressful environments (Brodin, 2007). If we consider clinical hoarding as an exaggerated or dysregulated form of an adaptive evolutionary behavior (Leckman & Mayes, 1998), then it may be hypothesized that individuals with hoarding could be at risk for enhanced internal fat production and storage mechanisms that contribute to elevations in BMI. In addition, it may also be hypothesized that a common genetic basis links these two phenotypes.
In addition to this evolutionary-based hypothesis, a second line of evidence focused on the role of emotion regulation supports our aim of considering hoarding, BMI, and BDNF together. Both hoarding and dysregulated eating have been linked with difficulties in emotion regulation. Research in children has found that loss of control eating is associated with dysfunctional emotion regulation strategies (Czaja, Rief, & Hilbert, 2009), and emotion regulation difficulties in toddlers is a significant predictor of pediatric obesity (Graziano, Calkins, & Keane, 2010). In addition to the large literature on emotional eating in adults and the relationship between self-regulation and obesity/binge eating disorder (Davis, Patte, Curtis, & Reid, 2010; Newman, O'Connor, & Conner, 2007; Polivy & Herman, 2002), a series of three experimental studies by Evers and colleagues (Evers, Marijn Stok, & de Ridder, 2010) found that emotional self-regulatory difficulties were linked with greater food consumption, particularly of comfort-foods. Although less extensively researched, there is also support for emotion regulation difficulties and greater emotional reactivity associated with hoarding behaviors, as evidenced by lower levels of distress tolerance and greater avoidance behaviors (Steketee & Frost, 2003; Timpano, Buckner, Richey, Murphy, & Schmidt, 2009). Turning to the BDNF literature, the Val/Val genotype has been associated with greater HPA-axis reactivity (Alexander et al., 2010) and interacts with the serotonin transporter polymorphism (5-HTTLPR) to influence cognitive reactivity and dysfunctional thinking (Wells, Beevers, & McGeary, 2010).
Although there have been investigations to examine the association between BMI and the Vall66Met BDNF polymorphism (Gunstad, et al., 2006; Shugart, et al., 2009), as well one study on the BMI-hoarding relationship (Tolin, et al., 2008), the link between hoarding and BNDF has not been adequately considered. Following an initial report of a strong association between BDNF and OCD (Hall, et al., 2003), a handful of studies have considered the symptom dimensions of OCD (Katerberg et al., 2009; Wendland, Kruse, Cromer, & Murphy, 2007). Unfortunately, none of these investigations adequately assessed hoarding, relying instead on measures (e.g., YBOCS) that have been found to be insufficient in fully capturing the hoarding phenomenon (Cromer, Schmidt, & Murphy, 2007).
The primary aim of this investigation was to examine the relationships between the BDNF Val66Met variant, compulsive hoarding, and BMI. In contrast to past investigations (Alonso et al., 2008; Wendland, et al., 2007), we sought to carefully capture the hoarding construct by relying on two complementary, multi-method assessments: a dichotomous classification and a continuous measure of severity. Based on the extant literature, we hypothesized that the homozygote Val/Val genotype would be associated with both hoarding and greater BMI levels, and that hoarding would be associated with greater BMI. In addition to examining the primary relationships between BDNF and the two phenotypes, we also set out to consider the relationship between genotype and a combination phenotype of hoarding and obesity, within a more exploratory vein. We hypothesized that those individuals with the combination phenotype would have the greatest proportion of the Val/Val genotype.
Participants
This study recruited 301 OCD probands from an ongoing outpatient OCD program at the National Institute of Mental Health. Participants were recruited in the general context of an OCD study through referrals, websites, conferences and newspaper advertisements, and the NIMH website. Advertisements specifically mentioned interest in hoarding behaviors. Study data were collected from consecutive intakes across a 10 year time-span. Inclusion criteria for participation consisted of being at least 18 years of age and having a primary OCD diagnosis based on the Structured Clinical Interview for DSM-IV (SCID; First, 2001). Exclusion criteria included active schizophrenia or psychosis, or severe mental retardation that did not permit an evaluation. All procedures were in accordance with American Psychological Association standard ethical guidelines, and this study was approved by the Institutional Review Board prior to data collection.
The sample consisted of 122 (40.5%) men and 179 (59.5%) women. Participants were generally well educated, with 64.0% reporting a college degree and 20.7% achieving a graduate degree. The sample was primarily Caucasian (88.4%), but included small groups of Hispanic (2.4%), Asian (2.2%), African American (2.4%), and other (4.6%) participants. The mean age of the sample was 39.1 (SD=13.4); please see Table 1 for further sample characteristics.
Table 1
Table 1
Association between BDNF, compulsive hoarding, and BMI.
Measures
Structured Clinical Interview for DSM-IV-TR Axis I Disorders Patient Edition (SCID-P)
The SCID-P (First, 2001) was used to diagnose major DSM-IV Axis I disorders, including OCD. Interviews were conducted by trained and clinically experienced interviewers (RN and masters-level psychologist). To ensure reliability, a blind diagnostic procedure was used in which two independent reviewers evaluated each SCID. Any diagnostic discrepancies were discussed with the PI (D. Murphy). SCID diagnoses demonstrated excellent reliability with kappas ranging from .86–.93 for the various comorbid disorders (eg., major depression, eating disorders); primary OCD diagnoses were highly reliable with a kappa value of .96 and 98% agreement.
Hoarding Classification
This study used a strict definition of hoarding that combined both the Yale-Brown Obsessive Compulsive Scale (YBOCS) symptom checklist and an interview-based clinical assessment of hoarding. The YBOCS (Goodman et al., 1989a; Goodman et al., 1989b) is a reliable assessment of OCD symptom severity, and includes a symptom checklist for a range of OCD symptoms, including two items on saving and difficulty discarding. In the current investigation the YBOCS-SC was administered as a self-report measure (Steketee, Frost, & Bogart). Patients who endorsed both of the YBOCS-SC hoarding questions and confirmed hoarding symptoms during the clinical interview were classified as hoarders. Patients who did not report hoarding on the YBOCS-SC or who did not describe hoarding symptoms during the interview were placed in the non-hoarding group. This method is described in detail in a previous report by our group (Wheaton, Timpano, Lasalle-Ricci, & Murphy, 2008), and represents a conservative approach to identifying those individuals with definite hoarding symptoms.
Saving Inventory-Revised (SIR)
The SIR is a well-validated 23-item questionnaire designed to measure hoarding-related behaviors and symptom severity. Participants are required to answer items using a 5-point scale ranging from 0 (not at all) to 4 (almost all/complete).The measure includes three factor analytically derived subscales, including acquisition (e.g., “How distressed or uncomfortable would you feel if you could not acquire something you wanted?”), clutter (e.g., “How much of your home does clutter prevent you from using?”), and difficulty discarding (e.g., “To what extent do you have difficulty throwing things away?). The SIR has been found to have strong internal consistency (Coles, Frost, Heimberg, & Steketee, 2003), good test-retest reliability, and satisfactory convergent validity (Frost, Steketee, & Grisham, 2004).
Body Mass Index
The BMI, defined as body weight (kg)/height (m2), is the established standard for measuring body composition, and is highly correlated with body fat composition (Khosla & Lowe, 1967). Standard guidelines were used to define underweight (BMI<19), normal (BMI 19–24), overweight (BMI 25–29.9) and obese (BMI >30) groups (NIH, 1998). BMI was calculated from self-reported weight and height, in-line with other recent investigations (e.g., Keel & Heatherton). Although small biases have been reported in self-reported height and weight, studies have uniformly concluded that self-reports are reliable and valid (Bowman & Delucia, 1992; Imrhan, Imrhan, & Hart, 1996; Spencer, Appleby, Davey, & Key, 2002; Stunkard & Albaum, 1981).
Genotyping
The BDNF Val66Met polymorphism (dbSNP rs6265) was genotyped by a 5’-exonuclease assay (TaqMan SNP genotyping assay-on-demand; Applied Biosystems, Foster City, CA, USA) using oligonucleotide primers GCC CAA GGC AGG TTC AAG AG and AAC TTT CTG GTC CTC ATC CAA CAG as well as fluorescent probes VIC-ACT TTC GAA CAC gTG ATA G-MGB and FAM-CTT TCG AAC ACa TGA TAG-MGB for Val66 and Met66, respectively, as reported previously (Wendland, et al., 2007). In a total reaction volume of 8 µL, 5–20 ng of genomic DNA were mixed with TaqMan Universal PCR master mix (Applied Biosystems) and genotyping assay to 1× final concentrations. Thermocycling and fluorescence acquisition conditions were as recommended using an MJ Chromo4 continuous fluorescence detector (Bio-Rad, Hercules, CA, USA) connected to a PC running Opticon Monitor software version 3.1. Genotypes were scored by endpoint fluorescence analysis using global minimum baseline subtraction. The overall genotype completion exceeded 98%; no-template-controls and a randomly chosen subgroup of 15% samples run in duplicate consistently yielded expected results.
Using the Genetic Power Calculator (Purcell, Cherny, & Sham, 2003), we determined that our sample had 17% power at p=.05 (risk allele frequency=0.8; disease prevalence=0.25; genotypic relative risk Aa=2 and AA=2; marker allele frequency=0.2 at D΄=1 with risk variant).
Statistical analyses
Genotype data were analyzed for Hardy-Weinberg equilibrium (HWE) using the Pearson and log likelihood ratio χ2 as well as exact test with the de Finetti program (Cannings & Edwards, 1968). All other statistical analyses were carried out using the Software Package for Social Sciences (SPSS) version 14.0 for Windows. To examine possible population stratification, we conducted an ANOVA with phenotype/genotype as the dependent variable and strata (self-reported ethnicity) as the independent variable. Both logistic regression for dichotomous dependent variables and linear regression for continuous dependent variables were used for the remaining analyses, as appropriate. Primary analyses examined hoarding/obesity status, whereas secondary analyses considered the continuous variables. All tests were performed with a two-sided p < 0.05. Given missing data, the N varies somewhat for the secondary analyses with the two continuous variables (SIR n=198; BMI n =254).
The BDNF genotype frequency was 4% for Met/Met (n=12), 31.9% for Val/Met (n=96), and 64.1% for Val/Val (n=193). The frequency of alleles was 0.80 for Val and 0.20 for Met, in line with previous reports (Hall, et al., 2003; Lang, et al., 2005). The observed genotype distribution did not significantly deviate from Hardy-Weinberg equilibrium with any of the statistical tests utilized. We compared the Val/Val group to Met allele carriers in our analyses, in line with other reports (Lang, et al., 2005; Oroszi et al., 2006), and given the evidence that the Met allele may be functionally dominant (Chen, et al., 2006; Sen, et al., 2003). There was no effect of population strata on either phenotype or the genotype/allele distribution, and all ethnicity sub-samples were therefore considered jointly.
Sample descriptions are provided in Table 1. The hoarding group scored markedly higher on the SIR than the non-hoarding group (t = −13.78, p < .001). Of the sample, 4.3% (n=11) were in the underweight category, 43.3% (n=110) were in the normal category, 25.2% (n=64) were in the overweight category, and 27.2% (n=69) fell into the obesity category. Given that age is often correlated with weight/BMI levels, we examined age at BMI assessment and found no differences based on hoarding (t = .44, p < .67) or genotype (t = .42, p < .68) status. Age was therefore not included as a covariate in the following analyses.
BDNF and compulsive hoarding1
Results demonstrated that those individuals with the Val/Val genotype were at a significantly greater risk than Met carriers (risk ratio: 1.8) of being classified in the hoarding group (Wald = 6.84, p < .01, OR = 2.2, 95% CI = 1.22 – 3.97). Allele-wise comparison revealed a significant difference (Wald = 4.07, p< .04 OR = 1.68, 95% CI = 1.02–2.78) in that the frequency for the Val allele was significantly higher among the hoarding group than in the non-hoarding group. Considering hoarding symptom severity, we found that the Val/Val genotype (mean SIR = 31.1, SD = 22.3) was significantly associated with greater hoarding symptom severity (β = .15, t(198) = 2.12, p < .03), compared to Met carriers (mean SIR = 24.3, SD = 19.5).
BDNF and BMI1
With regard to a possible association between BDNF and BMI we found individuals with the Val/Val genotype were more likely to be classified as obese relative to Met carriers with a risk ratio of 1.8 (Wald = 6.91, p < .01, OR = 2.18, 95% CI = 1.24 – 4.40). Allele-wise comparison also revealed a significant difference (Wald = 6.53, p< .01 OR=2.05, 95% CI = 1.18–3.55), in that the Val allele was associated with obesity to a greater degree than the Met allele. Secondary analyses found that the Val/Val genotype (mean BMI=27.5, SD = 7.10) was associated with greater BMI levels (β = .15, t(254) = 2.34, p < .02), compared to Met carriers (mean BMI = 25.6, SD = 5.6)
Compulsive hoarding & BMI1
We found that hoarding group status was significantly associated with higher BMI (Wald = 8.44, p < .01, OR = 1.1, 95% CI = 1.02 – 1.11). Similarly, greater SIR hoarding severity scores were linked with greater BMI levels (β = .32, t(190) = 4.45, p < .001), explaining 9.7% of the variance. We next considered the weight categories, by comparing the SIR hoarding symptom severity scores for each weight group. The overall ANOVA was significant (F = 11.42, p<.001), though post-hoc comparisons revealed that the underweight, normal and overweight groups did not significantly differ from one another. Those individuals in the obesity category evidenced markedly greater hoarding severity, and we therefore compared the non-hoarding and hoarding groups on dichotomous obesity classification (obese versus non-obese groups). Results revealed that individuals in the hoarding group were over two times more likely to be classified as obese compared to non-hoarders (Wald = 14.22, p <.001, OR = 3.29, 95% CI = 1.77 – 6.12).
Relationship between BDNF and a combination phenotype
The sample was divided into four groups based on each participant’s hoarding and obesity status: hoarding-obese; hoarding-only; obese-only; neither. Frequencies of the BDNF variants for each of these groups are presented in Table 2. Chi-square analysis revealed an overall significant difference (χ2 = 7.83 (df=3), p < .05). More fine-grained comparisons demonstrated that the hoarding-obese group was significantly different from the neither group (χ2 = 5.71 (df=1), p < .05) in the proportion of Val/Val variants, but not significantly different from either the hoarding-only or the obese-only groups. The hoarding-only, obese-only, and neither groups did not significantly differ from one another.
Table 2
Table 2
Association between BDNF and a combination phenotype of hoarding and obesity.
The present report is the first to examine associations between BDNF, hoarding, and BMI in a large sample of individuals with OCD. Results revealed that the Val/Val genotype was associated with the hoarding group and the highest levels of hoarding symptom severity, as well as higher BMI levels and obesity classification. Our results regarding the relationship between BDNF and BMI levels fit within a growing literature examining the association between the BDNF Val66Met variants, body mass index, and eating disorders (Ribases, et al., 2004; Shugart, et al., 2009). BDNF and its receptor, TrkB, have known roles in body weight regulation, via effects on food intake and metabolic rate, with BDNF alterations in rodents leading to hyperphagia and obesity (Ren-Patterson et al., 2005; Wang, Bomberg, Billington, Levine, & Kotz, 2007).
We found that within this OCD sample BDNF was associated with hoarding symptoms, which sheds additional light on the literature examining the OCD-BDNF link. Following the seminal report by Hall and colleagues (2003)—which considered several BDNF SNPs with both single locus and multi-SNP haplotype tests and found a strong role of Val66Met in OCD—a series of investigations have examined the role of BDNF in OCD. Additional support for the role of BDNF has emerged from findings related to the BDNF receptor gene and BDNF secretion in OCD samples (e.g., Alonso, et al., 2008). Despite growing evidence that the marked heterogeneity associated with OCD might impact etiological investigations (Mataix-Cols, et al., 2005), not all of these investigations considered potentially more homogeneous sub-groups. More recent studies have analyzed factors that may separate OCD into more meaningful and uniform sub-phenotypes, including age of onset and the symptom dimensions (Katerberg, et al., 2009); however, the characterizations of these sub-groups might not always lead to the identification of differences. This is particularly poignant in consideration of hoarding. The largest study to date of sibling pairs with OCD found that individuals with marked hoarding showed linkage to a different chromosomal region than individuals without definite hoarding symptoms (Samuels et al., 2007). This finding, in conjunction with our results, brain imaging evidence, and symptomatic and gender differences in hoarding compared to other forms of OCD, provide further credence to the growing notion of hoarding as a separable and distinct phenomenon (Pertusa, et al., 2008; Saxena, 2008)
The association between hoarding and BMI reported in this sample supports an earlier report of a hoarding-obesity association (Tolin, et al., 2008). Within the animal literature, hoarding behaviors have been associated with food intake dysregulation (Deacon, 2006). Long-term selection [45 generations] for body weight in chickens led to “compulsive feeding” and a nine-fold difference in weight accompanied by Bdnf expression differences identified by array analysis (Ka et al., 2009). The set-point for hoarding food in response to food deprivation is closely regulated by elements of the HPA axis, and multiple studies have demonstrated high correlations between body weight, different stresses, and hoarding (Brodin, 2007; Manosevitz, 1965). Once again, there are only limited studies to date that have examined these relationships in humans, but it should be noted that greater levels of traumatic life stress have been linked with hoarding, compared to non-hoarding OCD (Cromer, et al., 2007).
Our findings should be considered in light of several limitations. While our investigation represents the second largest BDNF-OCD association study, a primary limitation is our sample size. This, arguably, had the greatest impact on our combination phenotype analyses, where cell-sizes among the four groups varied dramatically and most likely contributed to the lack of significant differences between the hoarding-obese group and the hoarding-only/obese-only groups. Conclusions emerging from these analyses should therefore be tempered accordingly. A second limitation is that we only focused on a single polymorphism, rather than multiple variants within the BDNF gene. Our reliance on self-reported weight and height constitutes another limitation of the present study. Previous investigations have demonstrated reporting bias in height and weight; however, such errors are typically small (Spencer, et al., 2002) and no association has been found between misreporting height/weight and psychological variables (Yannakoulia, Panagiotakos, Pitsavos, & Stefanadis, 2006). A similar limitation was our assessment of ethnicity by self-report. Although we did not find any difference in the phenotype and genotype/allele distribution by population strata, we cannot rule-out the possibility that population stratification could influence the results. Future research should consider Ancestral Information Markers as an alternative to self-report on ethnicity. A final limitation is that we considered hoarding solely within a larger OCD sample, which may not capture the full range of the hoarding phenomenon (Pertusa, et al., 2008). We have tried to address this concern with our recruitment methods, which focused on hoarding, and the use of two measures to characterize hoarding symptoms; however, replication in hoarding samples not recruited within the context of OCD will be necessary.
Our findings point to a number of avenues for future research. Considering the three-fold association we identified (i.e., BDNF-hoarding, BDNF-BMI, and hoarding-BMI) and our exploratory analyses with the combination phenotype, it may be of interest to examine mechanisms through which hoarding, BMI, and BDNF are related. Emotion regulation difficulties, which have been associated with both phenotypes and the BDNF SNP (Evers, et al., 2010; Timpano, et al., 2009; Wells, et al., 2010), may be one such mechanism, or endophenotype, that accounts for the associations noted. This is particularly interesting in consideration of the animal literature, where Sert-deficient mice and those interbred with Bdnf-deficient mice display greater stress responses, anxiety, and obesity (Ren-Patterson, et al., 2005). Studies have further revealed that BDNF administration reduces feeding behaviors and blood glucose in obese and diabetic rodents, apparently via a central, probably hypothalamic mechanism (Lebrun, Bariohay, Moyse, & Jean, 2006a). This same mechanism may play a role in humans, perhaps via alterations in activity-dependent secretion of BDNF (Egan, et al., 2003).
Future investigations on complex phenomenon, such as hoarding, BMI, and a potential combination phenotype, may want to consider the intricacies of gene × gene × environment interactions (Lander & Schork, 1994; Murphy et al., 2003). Given that BDNF has been found to interact with other genes or gene systems, such as the serotonergic system (Kaufman et al., 2006; Wells, et al., 2010), which in turn have been associated with OCD and obesity (Fuemmeler et al., 2008; Wendland et al., 2008), examining polygenetic relationships may be a fruitful avenue for further clarifying the relationships between BDNF, hoarding, and BMI. Future investigations of these epistatic interactions may also warrant consideration of factors such as environmental modifiers and sex.
Footnotes
The following manuscript is the final accepted manuscript. It has not been subjected to the final copyediting, fact-checking, and proofreading required for formal publication. It is not the definitive, publisher-authenticated version. The American Psychological Association and its Council of Editors disclaim any responsibility or liabilities for errors or omissions of this manuscript version, any version derived from this manuscript by NIH, or other third parties. The published version is available at www.apa.org/pubs/journals/ABN
1We conducted a series of supplemental analyses using an alternative grouping strategy. Specifically, we categorized the sample using an established clinical cut-off for the SIR (Frost and colleagues have identified a score of 40 or above as being typical in clinical hoarding samples). We found that this approach also provided the same pattern of findings.
  • Alexander N, Osinsky R, Schmitz A, Mueller E, Kuepper Y, Hennig J. The BDNF Val66Met polymorphism affects HPA-axis reactivity to acute stress. Psychoneuroendocrinology. 2010;35(6):949–953. [PubMed]
  • Alonso P, Gratacos M, Menchon JM, Saiz-Ruiz J, Segalas C, Baca-Garcia E, et al. Extensive genotyping of the BDNF and NTRK2 genes define protective haplotypes against obsessive-compulsive disorder. Biol Psychiatry. 2008;63(6):619–628. [PubMed]
  • Angst J, Gamma A, Endrass J, Goodwin R, Ajdacic V, Eich D, et al. Obsessive-compulsive severity spectrum in the community: prevalence, comorbidity, and course. Eur Arch Psychiatry Clin Neurosci. 2004;254(3):156–164. [PubMed]
  • Bath KG, Lee FS. Variant BDNF (Val66Met) impact on brain structure and function. Cognitive, Affective, & Behavioral Neuroscience. 2006;6(1):79–85. [PubMed]
  • Bowman RL, Delucia JL. Accuracy of self-reported weight: a meta-analysis. Behavior Therapy. 1992;23:637–655.
  • Brodin A. Theoretical models of adaptive energy management in small wintering birds. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 2007;362(1486):1857–1871. [PMC free article] [PubMed]
  • Cannings C, Edwards AW. Natural selection and the de Finetti diagram. Ann Hum Genet. 1968;31(4):421–428. [PubMed]
  • Chen ZY, Jing D, Bath KG, Ieraci A, Khan T, Siao CJ, et al. Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science. 2006;314(5796):140–143. [PMC free article] [PubMed]
  • Coles ME, Frost RO, Heimberg RG, Steketee G. Hoarding behaviors in a large college sample. Behaviour Research and Therapy. 2003;41(2):179–194. [PubMed]
  • Cromer KR, Schmidt NB, Murphy DL. Do traumatic events influence the clinical expression of compulsive hoarding? Behaviour Research and Therapy. 2007;45(11):2581–2592. [PubMed]
  • Czaja J, Rief W, Hilbert A. Emotion regulation and binge eating in children. International Journal of Eating Disorders. 2009;42(4):356–362. [PubMed]
  • Davis C, Patte K, Curtis C, Reid C. Immediate pleasures and future consequences. A neuropsychological study of binge eating and obesity. Appetite. 2010;54(1):208–213. [PubMed]
  • de Kort SR, Clayton NS. An evolutionary perspective on caching by corvids. Proceedings. Biological sciences. 2006;273(1585):417–423. [PMC free article] [PubMed]
  • Deacon RM. Assessing hoarding in mice. Nature Protocols. 2006;1(6):2828–2830. [PubMed]
  • Djalali S, Holtje M, Grosse G, Rothe T, Stroh T, Grosse J, et al. Effects of brain-derived neurotrophic factor (BDNF) on glial cells and serotonergic neurones during development. Journal of Neurochemistry. 2005;92(3):616–627. [PubMed]
  • Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biological Psychiatry. 2006;59(12):1116–1127. [PubMed]
  • Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell. 2003;112(2):257–269. [PubMed]
  • Evers C, Marijn Stok F, de Ridder DT. Feeding your feelings: Emotion regulation strategies and emotional eating. Personality and Social Psychology Bulletin. 2010;36(6):792–804. [PubMed]
  • Falkenberg T, Lindefors N, Camilli F, Metsis M, Ungerstedt U. Glutamate release correlates with brain-derived neurotrophic factor and trkB mRNA expression in the CA1 region of rat hippocampus. Brain Res Mol Brain Res. 1996;42(2):317–327. [PubMed]
  • First MB, Spitzer RL, Gibbon M, Williams JBW. Sturctured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition (SCID-I/P) New York: Biometrics Research, New York State Psychiatric Institute; 2001.
  • Francis RC. It's a puzzle all right: the hippocampus and food hoarding. Trends in Ecology & Evolution. 2005;20(9):476–477. author reply 477. [PubMed]
  • Frost RO, Hartl TL. A cognitive-behavioral model of compulsive hoarding. Behaviour Research and Therapy. 1996;34(4):341–350. [PubMed]
  • Frost RO, Steketee G, Grisham JR. Measurement of compulsive hoarding: saving inventory-revised. Behaviour Research and Therapy. 2004;42(10):1163–1182. [PubMed]
  • Fuemmeler BF, Agurs-Collins TD, McClernon FJ, Kollins SH, Kail ME, Bergen AW, et al. Genes implicated in serotonergic and dopaminergic functioning predict BMI categories. Obesity (Silver Spring) 2008;16(2):348–355. [PMC free article] [PubMed]
  • Goodman WK, Price LH, Rasmussen SA, Mazure C, Delgado P, Heninger GR, et al. The Yale-Brown Obsessive Compulsive Scale. II. Validity. Archives of General Psychiatry. 1989a;46(11):1012–1016. [PubMed]
  • Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL, et al. The Yale-Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Archives of General Psychiatry. 1989b;46(11):1006–1011. [PubMed]
  • Govindarajan A, Rao BS, Nair D, Trinh M, Mawjee N, Tonegawa S, et al. Transgenic brain-derived neurotrophic factor expression causes both anxiogenic and antidepressant effects. Proceedings of the National Academy of Science. 2006;103(35):13208–13213. [PubMed]
  • Gray J, Yeo GS, Cox JJ, Morton J, Adlam AL, Keogh JM, et al. Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene. Diabetes. 2006;55(12):3366–3371. [PMC free article] [PubMed]
  • Graziano PA, Calkins SD, Keane SP. Toddler self-regulation skills predict risk for pediatric obesity. International journal of obesity : Journal of the International Association for the Study of Obesity. 2010;34(4):633–641. [PMC free article] [PubMed]
  • Guillin O, Diaz J, Carroll P, Griffon N, Schwartz JC, Sokoloff P. BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization. Nature. 2001;411(6833):86–89. [PubMed]
  • Gunstad J, Schofield P, Paul RH, Spitznagel MB, Cohen RA, Williams LM, et al. BDNF Val66Met polymorphism is associated with body mass index in healthy adults. Neuropsychobiology. 2006;53(3):153–156. [PubMed]
  • Hall D, Dhilla A, Charalambous A, Gogos JA, Karayiorgou M. Sequence variants of the brain-derived neurotrophic factor (BDNF) gene are strongly associated with obsessive-compulsive disorder. American Journal of Human Genetics. 2003;73(2):370–376. [PubMed]
  • Hasler G, Pinto A, Greenberg BD, Samuels J, Fyer AJ, Pauls D, et al. Familiality of factor analysis-derived YBOCS dimensions in OCD-affected sibling pairs from the OCD Collaborative Genetics Study. Biological Psychiatry. 2007;61(5):617–625. [PubMed]
  • Healy SD, de Kort SR, Clayton NS. The hippocampus, spatial memory and food hoarding: a puzzle revisited. Trends in Ecology & Evolution. 2005;20(1):17–22. [PubMed]
  • Imrhan SN, Imrhan V, Hart C. Can self-estimates of body weight and height be used in place of measurements for college students? Ergonomics. 1996;39:1445–1453.
  • Ka S, Lindberg J, Stromstedt L, Fitzsimmons C, Lindqvist N, Lundeberg J, et al. Extremely different behaviours in high and low body weight lines of chicken are associated with differential expression of genes involved in neuronal plasticity. Journal of Neuroendocrinology. 2009;21(3):208–216. [PubMed]
  • Katerberg H, Lochner C, Cath DC, de Jonge P, Bochdanovits Z, Moolman-Smook JC, et al. The role of the brain-derived neurotrophic factor (BDNF) val66met variant in the phenotypic expression of obsessive-compulsive disorder (OCD) American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. 2009 [PubMed]
  • Kaufman J, Yang BZ, Douglas-Palumberi H, Grasso D, Lipschitz D, Houshyar S, et al. Brain-derived neurotrophic factor-5-HTTLPR gene interactions and environmental modifiers of depression in children. Biological Psychiatry. 2006;59(8):673–680. [PubMed]
  • Keel PK, Heatherton TF. Weight suppression predicts maintenance and onset of bulimic syndromes at 10-year follow-up. Journal of Abnormal Psychology. 119(2):268–275. [PMC free article] [PubMed]
  • Kernie SG, Liebl DJ, Parada LF. BDNF regulates eating behavior and locomotor activity in mice. The EMBO Journal. 2000;19(6):1290–1300. [PubMed]
  • Khosla T, Lowe CR. Indices of obesity derived from body weight and height. British Journal of Preventive & Social Medicine. 1967;21(3):122–128. [PMC free article] [PubMed]
  • Lander ES, Schork NJ. Genetic dissection of complex traits. Science. 1994;265(5181):2037–2048. [PubMed]
  • Lang UE, Hellweg R, Kalus P, Bajbouj M, Lenzen KP, Sander T, et al. Association of a functional BDNF polymorphism and anxiety-related personality traits. Psychopharmacology (Berl) 2005;180(1):95–99. [PubMed]
  • Lebrun B, Bariohay B, Moyse E, Jean A. Brain-derived neurotrophic factor (BDNF) and food intake regulation: a minireview. Auton Neurosci. 2006a;126–127:30–38. [PubMed]
  • Lebrun B, Bariohay B, Moyse E, Jean A. Brain-derived neurotrophic factor (BDNF) and food intake regulation: a minireview. Autonomic Neuroscience. 2006b;126–127:30–38. [PubMed]
  • Leckman JF, Mayes LC. Understanding developmental psychopathology: how useful are evolutionary accounts? Journal of the American Academy of Child and Adolescent Psychiatry. 1998;37(10):1011–1021. [PubMed]
  • Lopez AD, Murray CC. The global burden of disease, 1990–2020. Nat Med. 1998;4(11):1241–1243. [PubMed]
  • Lyons WE, Mamounas LA, Ricaurte GA, Coppola V, Reid SW, Bora SH, et al. Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities. Proceedings of the National Academy of Sciences of the United States of America. 1999;96(26):15239–15244. [PubMed]
  • Manosevitz M. Genotype, fear, and hoarding. Journal of Comparative and Physiological Psychology. 1965;60(3):412–416. [PubMed]
  • Mataix-Cols D, Frost RO, Pertusa A, Clark LA, Saxena S, Leckman JF, et al. Hoarding disorder: a new diagnosis for DSM-V? Depression and Anxiety. 2010;27(6):556–572. [PubMed]
  • Mataix-Cols D, Rosario-Campos MC, Leckman JF. A multidimensional model of obsessive-compulsive disorder. American Journal of Psychiatry. 2005;162(2):228–238. [PubMed]
  • Monteggia LM, Barrot M, Powell CM, Berton O, Galanis V, Gemelli T, et al. Essential role of brain-derived neurotrophic factor in adult hippocampal function. Proc Natl Acad Sci U S A. 2004;101(29):10827–10832. [PubMed]
  • Monteleone P, Fabrazzo M, Martiadis V, Serritella C, Pannuto M, Maj M. Circulating brain-derived neurotrophic factor is decreased in women with anorexia and bulimia nervosa but not in women with binge-eating disorder: relationships to co-morbid depression, psychopathology and hormonal variables. Psychol Med. 2005;35(6):897–905. [PubMed]
  • Murphy DL, Uhl GR, Holmes A, Ren-Patterson R, Hall FS, Sora I, et al. Experimental gene interaction studies with SERT mutant mice as models for human polygenic and epistatic traits and disorders. Genes, Brain and Behavior. 2003;2(6):350–364. [PubMed]
  • Newman E, O'Connor DB, Conner M. Daily hassles and eating behaviour: The role of cortisol reactivity status. Psychoneuroendocrinology. 2007;32(2):125–132. [PubMed]
  • NIH. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. 1998 [PubMed]
  • Oroszi G, Lapteva L, Davis E, Yarboro CH, Weickert T, Roebuck-Spencer T, et al. The Met66 allele of the functional Val66Met polymorphism in the brain-derived neurotrophic factor gene confers protection against neurocognitive dysfunction in systemic lupus erythematosus. Annals of the Rheumatic Diseases. 2006;65(10):1330–1335. [PMC free article] [PubMed]
  • Pertusa A, Frost RO, Fullana MA, Samuels JF, Steketee G, Tolin DF, et al. Refining the diagnostic boundaries of compulsive hoarding: A critical review. Clinical Psychology Review. 2010;30(4):371–386. [PubMed]
  • Pertusa A, Fullana MA, Singh S, Alonso P, Menchon JM, Mataix-Cols D. Compulsive Hoarding: OCD Symptom, Distinct Clinical Syndrome, or Both? American Journal of Psychiatry. 2008;165(10):1289–1298. [PubMed]
  • Polivy J, Herman CP. Causes of eating disorders. Annual Review of Psychology. 2002;53:187–213. [PubMed]
  • Prentice AM. Early influences on human energy regulation: thrifty genotypes and thrifty phenotypes. Physiology & Behavior. 2005;86(5):640–645. [PubMed]
  • Purcell S, Cherny SS, Sham PC. Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics. 2003;19:149–150. [PubMed]
  • Ren-Patterson RF, Cochran LW, Holmes A, Lesch K-P, Lu B, Murphy DL. Gender-Dependent Modulation of Brain Monoamines and Anxiety-like Behaviors in Mice with Genetic Serotonin Transporter and BDNF Deficiencies. Cellular and Molecular Neurobiology. 2006;26:775–780. [PubMed]
  • Ren-Patterson RF, Cochran LW, Holmes A, Sherrill S, Huang SJ, Tolliver T, et al. Loss of brain-derived neurotrophic factor gene allele exacerbates brain monoamine deficiencies and increases stress abnormalities of serotonin transporter knockout mice. Journal of Neuroscience Research. 2005;79(6):756–771. [PubMed]
  • Ribases M, Gratacos M, Armengol L, de Cid R, Badia A, Jimenez L, et al. Met66 in the brain-derived neurotrophic factor (BDNF) precursor is associated with anorexia nervosa restrictive type. Molecular Psychiatry. 2003;8(8):745–751. [PubMed]
  • Ribases M, Gratacos M, Fernandez-Aranda F, Bellodi L, Boni C, Anderluh M, et al. Association of BDNF with anorexia, bulimia and age of onset of weight loss in six European populations. Human Molecular Genetics. 2004;13(12):1205–1212. [PubMed]
  • Ribases M, Gratacos M, Fernandez-Aranda F, Bellodi L, Boni C, Anderluh M, et al. Association of BDNF with restricting anorexia nervosa and minimum body mass index: a family-based association study of eight European populations. European Journal of Human Genetics. 2005;13(4):428–434. [PubMed]
  • Rios M, Fan G, Fekete C, Kelly J, Bates B, Kuehn R, et al. Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity. Molecular Endocrinology. 2001;15(10):1748–1757. [PubMed]
  • Samuels J, Shugart YY, Grados MA, Willour VL, Bienvenu OJ, Greenberg BD, et al. Significant linkage to compulsive hoarding on chromosome 14 in families with obsessive-compulsive disorder: results from the OCD Collaborative Genetics Study. American Journal of Psychiatry. 2007;164(3):493–499. [PubMed]
  • Saxena S. Neurobiology and treatment of compulsive hoarding. CNS Spectrum. 2008;13(9) Suppl 14:29–36. [PubMed]
  • Sen S, Nesse RM, Stoltenberg SF, Li S, Gleiberman L, Chakravarti A, et al. A BDNF coding variant is associated with the NEO personality inventory domain neuroticism, a risk factor for depression. Neuropsychopharmacology. 2003;28(2):397–401. [PubMed]
  • Shugart YY, Chen L, Day INM, Lewis SJ, Timpson NJ, Yuan W, et al. Two British women studies replicated the association between the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) and BMI. European Journal of Human Genetics. 2009;17(8):1050–1055. [PMC free article] [PubMed]
  • Spencer EA, Appleby PN, Davey GK, Key TJ. Validity of self-reported height and weight in 4808 EPIC-Oxford participants. Public Health and Nutrition. 2002;5(4):561–565. [PubMed]
  • Steketee G, Frost R, Bogart K. The Yale-Brown Obsessive Compulsive Scale: interview versus self-report. Behaviour Research and Therapy. 1996;34(8):675–684. [PubMed]
  • Steketee G, Frost RO. Compulsive hoarding: current status of the research. Clinical Psychology Review. 2003;23(7):905–927. [PubMed]
  • Stunkard AJ, Albaum JM. The accuracy of self-reported weights. American Journal of Clinical Nutrition. 1981;34(8):1593–1599. [PubMed]
  • Timpano KR, Buckner JD, Richey JA, Murphy DL, Schmidt NB. Exploration of anxiety sensitivity and distress tolerance as vulnerability factors for hoarding behaviors. Depression and Anxiety. 2009;26(4):343–353. [PMC free article] [PubMed]
  • Tolin DF, Frost RO, Steketee G, Gray KD, Fitch KE. The economic and social burden of compulsive hoarding. Psychiatry Research. 2008;160(2):200–211. [PMC free article] [PubMed]
  • Wang C, Bomberg E, Billington C, Levine A, Kotz CM. Brain-derived neurotrophic factor in the hypothalamic paraventricular nucleus increases energy expenditure by elevating metabolic rate. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 2007;293(3):R992–R1002. [PubMed]
  • Wells TT, Beevers CG, McGeary JE. Serotonin transporter and BDNF genetic variants interact to predict cognitive reactivity in healthy adults. Journal of Affective Disorders. 2010;126(1–2):223–229. [PMC free article] [PubMed]
  • Wendland JR, Kruse MR, Cromer KR, Murphy DL. A large case-control study of common functional SLC6A4 and BDNF variants in obsessive-compulsive disorder. Neuropsychopharmacology. 2007;32(12):2543–2551. [PubMed]
  • Wendland JR, Moya PR, Kruse MR, Ren-Patterson RF, Jensen CL, Timpano KR, et al. A novel, putative gain-of-function haplotype at SLC6A4 associates with obsessive-compulsive disorder. Human Molecular Genetics. 2008;17(5):717–723. [PubMed]
  • Wheaton M, Timpano KR, Lasalle-Ricci VH, Murphy D. Characterizing the hoarding phenotype in individuals with OCD: associations with comorbidity, severity and gender. Journal of Anxiety Disorders. 2008;22(2):243–252. [PMC free article] [PubMed]
  • Xu B, Goulding EH, Zang K, Cepoi D, Cone RD, Jones KR, et al. Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nature Neuroscience. 2003;6(7):736–742. [PMC free article] [PubMed]
  • Yannakoulia M, Panagiotakos DB, Pitsavos C, Stefanadis C. Correlates of BMI misreporting among apparently healthy individuals: the ATTICA study. Obesity. 2006;14(5):894–901. [PubMed]