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Severity of eating disorder symptoms related to oxytocin receptor polymorphisms in anorexia nervosa
Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
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Severity of eating disorder symptoms related to oxytocin receptor polymorphisms in anorexia nervosa Summer F. Acevedo a, Celeste Valencia a, Michael Lutter b, Carrie J. McAdams a,n a b
University of Texas at Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas TX 75390-8828, USA Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, IA 52242, USA
art ic l e i nf o
a b s t r a c t
Article history: Received 23 January 2015 Received in revised form 21 April 2015 Accepted 5 May 2015
Oxytocin is a peptide hormone important for social behavior and differences in psychological traits have been associated with variants of the oxytocin receptor gene in healthy people. We examined whether single nucleotide polymorphisms (SNPs) of the oxytocin receptor gene (OXTR) correlated with clinical symptoms in women with anorexia nervosa, bulimia nervosa, and healthy comparison (HC) women. Subjects completed clinical assessments and provided DNA for analysis. Subjects were divided into four groups: HC, subjects currently with anorexia nervosa (AN-C), subjects with a history of anorexia nervosa but in long-term weight recovery (AN-WR), and subjects with bulimia nervosa (BN). Five SNPs of the oxytocin receptor were examined. Minor allele carriers showed greater severity in most of the psychiatric symptoms. Importantly, the combination of having had anorexia and carrying either of the A alleles for two SNPS in the OXTR gene (rs53576, rs2254298) was associated with increased severity specifically for ED symptoms including cognitions and behaviors associated both with eating and appearance. A review of psychosocial data related to the OXTR polymorphisms examined is included in the discussion. OXTR polymorphisms may be a useful intermediate endophenotype to consider in the treatment of patients with anorexia nervosa. & 2015 Published by Elsevier Ireland Ltd.
Keywords: Oxytocin Anorexia nervosa Bulimia nervosa Social behavior Eating disorders
1. Introduction Eating disorders (ED) are complex psychiatric illnesses with environmental, cognitive, and biological contributions to their etiology and manifestation (Becker, 2004; Bulik et al., 2007; HerpertzDahlmann et al., 2011; Kaye et al., 2011). Biological pathway differences that contribute to a mental illness, but are not necessarily describing all aspects of the illness, have been called intermediate phenotypes (Flint et al., 2014). Improving our understanding of intermediate phenotypes within EDs may allow for individualized treatments targeted to the specific mechanistic dysfunctions. Social cognitive differences have been proposed as a specific intermediate phenotype related to anorexia nervosa (Harrison et al., 2012; Zucker et al., 2007). Reduced social cognitive function has been observed using psychological assessments in both acutely ill and weight-recovered subjects with anorexia nervosa (Oldershaw et al., 2011; Tchanturia et al., 2011). Additionally, neural differences in the engagement of social cognitive regions during social tasks have been observed (McAdams and Krawczyk, 2011; Schulte-Ruther et al., 2012).
n
Corresponding author. Tel.: þ 1 214 648 4145; fax: þ1 214 648 5321. E-mail address: [email protected] (C.J. McAdams).
Oxytocin is a neurotransmitter important for many forms of both social behavior including pair-bonding, maternal attachment, and group identification, as well as appetite suppression (Leng et al., 2008a; Leng et al., 2008b). Oxytocin has been linked to many psychiatric illnesses, including autism, EDs, addiction, schizophrenia, and post-traumatic stress disorder (Maguire et al., 2013; Marazziti and Catena Dell’osso, 2008). Most recently, Kim et al. (2014b) reported increased methylation of CpG dinucleotides in the oxytocin receptor (OXTR) gene in a small sample of patients with anorexia nervosa, a modification that has previously been associated with reduced expression of oxytocin receptors in the brain (Gregory et al., 2009). Polymorphic and epigenetic changes in the OXTR gene have been related to psychological and neural differences in healthy individuals. One OXTR single nucleotide polymorphism (SNP), the A allele of rs2254298, has been associated with the volume of the amygdala, a structure associated with anxiety and fear (Inoue et al., 2010). This polymorphism has also been associated with a sexual dimorphism related to the expressed psychological phenotype, with male carriers expressing autistic traits and female carriers expressing anxiety traits (Chen and Johnson, 2012). Another OXTR SNP, the A allele of rs53576, has been associated with low levels of self-esteem, optimism, and mastery (SaphireBernstein et al., 2011). This SNP also prevents social support from
http://dx.doi.org/10.1016/j.psychres.2015.05.040 0165-1781/& 2015 Published by Elsevier Ireland Ltd.
Please cite this article as: Acevedo, S.F., et al., Severity of eating disorder symptoms related to oxytocin receptor polymorphisms in anorexia nervosa. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.05.040i
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reducing the cortisol response of healthy individuals in a laboratory stress-induction procedure (Chen et al., 2011a). We hypothesized that the minor alleles of OXTR would be more common in patients with EDs, because high anxiety, low-self esteem, and difficulty managing social stresses are also common amongst these patients (Grilo et al., 2012; Gual et al., 2002; Herpertz-Dahlmann et al., 2001).
2. Methods 2.1. Participants A total of 124 female participants over age 18 were included in this study. The study was approved by the institutional review board of the University of Texas at Southwestern Medical Center, and participants were recruited from the public and ED treatment programs in the Dallas-Fort Worth area. Subjects came to an initial appointment at which they provided written informed consent to participate in this study. All subjects were then interviewed using the Structured Clinical Interview for DSM-IV disorders (SCID-RV, (First et al., 2002)). A detailed history of all past and current ED symptoms was also obtained. Subjects were classified into four groups. Healthy comparison subjects (HC, n¼ 35) were those subjects without any ED symptoms that did not have any first-degree relatives with an ED. Subjects currently with anorexia (AN-C, n ¼36), were all subjects who had met full DSM-IV criteria for anorexia nervosa during the preceding 12 months. Subjects currently in weight-recovery from anorexia (ANWR, n¼ 26), were all subjects who had met DSM-IV criteria for anorexia nervosa in their lifetime but had maintained a BMI greater than or equal to 19.0 for 24 months or longer. Subjects in the BN group were all subjects that had met DSM-IV criteria for bulimia nervosa in their lifetime and had never met DSM-IV criteria for anorexia nervosa (BN, n¼ 27). 2.2. Measures The Wechsler Abbreviated Scale of Intelligence (WASI, (Pearson Corporation, 1999)) was administered to provide an estimate of intelligence quotient. Three clinician-based measures were used to assess current depression, anxiety, and ED symptoms. The Quick Inventory of Depressive Symptomalogy (QIDS-CR, (Rush et al., 2003)) is a 16 question clinician-administered inventory of depressive symptoms. The Structured Interview Guide for the Hamilton Anxiety Scale (SIGHA, (Shear et al., 2001)) is a clinician-administered assessment assessing anxiety symptoms in fourteen categories. The Yale Brown Cornell Eating Disorder Survey (YBC-EDS, (Mazure et al., 1994; Sunday et al., 1995)) is a self-report check list followed by a 22-statement clinician-administered ED inventory for current eating preoccupations and rituals. Each participant also completed a self-report packet. The Young-Brown Obsessive-Compulsive Symptoms (Y-BOCS, (Woody et al., 1995)) provided an overall estimate of obsessions and compulsions, including those unrelated to the ED. The 26-item Eating Attitudes Test (EAT-26, (Berland et al., 1986)) provided a second measure of ED behaviors with subscales for dieting behavior (EAT-D), bulimia behaviors (EAT-B), and oral control behaviors (EAT-O). The 34-item Body Shape Questionnaire (BSQ, (Rosen et al., 1996)) provided a measure of ED symptomatology related to shape and weight concerns.
3. Results 3.1. Demographic and clinical profile of study groups The groups consisted of females between the ages 18–67 years old and grouped based on clinical diagnosis at the time of enrollment (HC, AN-C, AN-WR, BN). The subject population was primarily Caucasian (77–100%) with less than eight individuals per group of other races and ethnicities (Asian, African Americans, or Native Americans) and primarily Non-Hispanic (92–100%). Oneway ANOVA's indicated that the subjects recruited did not differ across groups in age at enrollment, years of education or intelligence measured by the Wechsler's Assessment Scale for Intelligence (WASI). A one-way ANOVA (F¼ 18.69, p o0.001) followed by Tukey's post-hoc analysis indicated that the current body mass index (BMI) was similar in HC (22.9 þ 0.8), AN-WR (22.9 þ0.7) and BN (23.4 þ0.7) groups with only the AN-C group (17.9þ0.3) differing from all other groups (p o0.05). One-way ANOVA (F¼6.39, p o0.003) followed by Tukey's post-hoc analysis within the clinical population suggest age of onset of the ED was lower in the AN-WR (13.5 þ 0.7) group compared to either the AN-C (16.7 þ0.7) and BN (17.8þ 1.2) groups. 3.2. OXTR SNP frequency not predictive of development of ED Table 1 is the genotype frequency of all the OXTR SNPs (rs53576, rs2254298, rs2228485, rs2268493 and rs918316) analyzed. Table 2 shows the minor allele frequency for all the SNPs and Chi-square (χ2) analysis for all the clinical groups compared HC. The results indicated that none of the OXTR SNPs were predictive of development of anorexia nervosa or bulimia nervosa. Haplotype combinations were also examined for any combination that had at least five subjects per haplotype group with no significant findings (data not shown). 3.3. OXTR SNP associated with ED clinical assessments In order to examine if any of the OXTR SNPs or haplotype combinations of SNPs had an effect on any of the ED symptoms or psychological measures, two-way ANOVA's between group (HC, AN-C, AN-WR, BN) and SNP or haplotype were conducted for all individual SNPs or haplotype combinations. Two-way ANOVAs between group and rs53576 (GG vs. C carriers) indicated Table 1 Genotype frequency of OXTR SNPs.
2.3. DNA processing
Genotype
Blood samples were collected from patients and submitted to McDermott Center for Human Growth & Development Human Genetics Clinical Laboratory located at UT Southwestern Medical Center in Dallas, TX, for processing and isolation of DNA. Samples were quantified using nanodrop and diluted in 96 well plates. The plated samples were then sent for Single Nucleotide Polymorphism (SNP) analysis at McDermott Center for Human Growth & Development DNA Sanger Sequencing Core located at UT Southwestern Medical Center in Dallas, TX. All oxytocin receptor SNPs were premade and purchased from Applied Biosystems by life technology: rs53576/CG (G/A), rs2254298 (G/A), rs2228485/CG_15917821_20 (T/C), rs2268493/CG_3290331_1 (T/C), rs918316/CG_7622139_10 (T/C).
rs53576 GG GA AA rs2254298 GG GA AA rs2228485 TT TC CC rs2268493 TT TC CC rs918316 TT TC CC
2.4. Statistical analysis All data was collected using standard data forms and entered into a Microsoft Excel spreadsheet for analysis using The Statistical Package for the Social Sciences (SPSS) software (version 21). Genotypic/haplotype differences within each patient group (HC, AN-C, AN-WR, and BN) were examined using independent Student's Ttests. Analysis of Variances (ANOVA) were calculated to examine associations between genotype/haplotype and subject groups (HC, AN-C, and AN-WR). A p value of o0.05 was considered significant.
HC
AN-C
AN-WR
BN
48.6% (17) 45.7% (16) 5.7% (2)
58.3% (21) 27.8% (10) 13.9% (5)
38.5% (10) 50.0% (13) 11.5% (3)
55.6% (15) 37.9% (11) 3.7% (1)
80.0% (28) 20.0% (7)
63.9% (23) 36.1% (13)
76.9% (20) 19.2% (5) 3.8% (1)
81.5% (22) 18.5% (5)
54.3% (19) 28.6% (10) 17.1% (6)
44.4% (16) 41.7% (15) 13.9% (5)
42.3% (11) 42.3% (11) 15.4% (4)
51.9% (14) 48.1% (13)
57.1% (20) 37.1% (13) 5.7% (2)
50.0% (18) 41.7% (15) 8.3% (3)
46.2% (12) 46.2% (12) 7.7% (2)
44.4% (12) 44.4% (12) 11.1% (3)
85.7% (30) 14.3% (5)
77.8% (28) 19.4% (7) 2.8% (1)
88.5% (23) 11.5% (3)
77.8% (21) 22.2% (6)
Please cite this article as: Acevedo, S.F., et al., Severity of eating disorder symptoms related to oxytocin receptor polymorphisms in anorexia nervosa. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.05.040i
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the semi-structured interviews, and demonstrate that the AN-C group has the highest severity of clinical and psychological illness.
significant interactions between group and genotype for the EAT-O (F¼ 3.59, p o0.02) subscale and YBC-EDS (F¼ 2.71, po 0.05). Within group analysis for both EAT-O and YBC-EDS indicated that only in the AN-C group did GG carriers report less symptoms compared to C carriers (Student's T-test, p o0.05). There were also interactions between group and rs2254298 (GG vs. C carriers) on the EAT-O subscale (F¼2.88, p o0.04) with the AN-C subjects that were GG homozygotes having less symptoms compared to C carriers (Student's T-test, p o0.02). Similar interactions between group and rs2228485 (TT vs. C carriers) were found on the EAT-O subscale (F¼ 4.38, p o0.04) with only the AN-C subjects that were TT homozygotes having less symptoms compared to C carriers (Student's T-test, p o0.005). The only haplotype combination with significant interactions between group and haplotype was the combination of rs53576 and rs2228485 comparing those that were GG homozygotes at both loci to C carriers at either loci (Table 3); therefore, all further analysis was done with this haplotype combination (see below).
3.5. rs53576/rs2254298 haplotype differences on clinical assessments Mann-U Whitney post-hoc analysis showed differences based on the rs53576/rs2254298 haplotype. The GG/GG subjects in the entire sample had the lowest overall symptoms on the EAT, all the EAT subscales, YBC-EDS, SIGH-A, Y-BOCS, and BSQ (Table 3, Fig. 1) compared to those that were A carriers. This data suggest that the GG/GG haplotype is associated with less pre-occupation about food and body shape, lower anxiety, and lower obsessive/compulsive behaviors. 3.6. Group and OXTR haplotype interactions on clinical assessments The two-way ANOVA between group and rs53576/rs2254298 (GG/GG vs. A carriers of either) haplotype interactions were significant for EAT, EAT-D subscale, EAT-O subscale, YBC-EDS, and BSQ (Table 3). A carriers amongst the AN-C group had higher incidence of symptoms for the overall EAT, EAT-D subscale, and EAT-O subscale (po 0.01, Fig. 1A, B and D). AN-C women that are A carriers also had the highest scores on the YBC-EDS and BSQ (p o0.05, Fig. 2A and C). This suggests that the GG/GG haplotype may be protective leading to less pre-occupation with food and body shape compared to A carriers at either loci. Similarly, the AN-WR subjects that were A carriers had higher scores on the overall EAT, EAT-D subscale, and EAT-B subscales (p o0.05, Fig. 1A–C), and more reported symptoms on the YBCEDS (p o0.03), SIGH-A (p o0.004), and BSQ (po 0.05) (Fig. 2A–C), with levels similar to those of the other clinical groups. In contrast, the GG/GG AN-WR subjects appeared more similar to HC. These
3.4. Group differences on clinical assessments To examine group differences between our subjects, two-way ANOVA's between group and rs53576/rs2254298 (GG/GG vs A carriers) haplotype with Bonferroni post-hoc comparisons were conducted. Results indicate that the HC group reported the lowest number of symptoms and the AN-C groups had the highest number of symptoms on the EAT and its subscales as well as the semi-structured interview YBC-EDS (Table 3). All clinical groups had significantly higher scores than the HC group for depression (QID-CR), anxiety (SIGH-A), obsessive-compulsive behaviors (YBOCS), and body shape concerns (BSQ) (Table 3). Overall, these data suggest there is consistency in the self-report measures and
Table 2 Minor allelic frequency of subjects with each group (HC, AN-C, AN-R, and BN) for OXTR SNPs. Genotype
Minor/ Major
Location/ Modification
HC
ANC
rs53576 rs2254298 rs2228485 rs2268493 rs918316
A/G A/G C/T C/T C/T
intron 0.29 0.28 intron 0.10 0.18 synonymous Asn [N] 0.31 0.35 intron 0.24 0.27 intron 0.07 0.13
HC vs. AN-C χ2 (p) ANWR
HC vs. AN-WR χ2 (p) HC vs. AN χ2 (p) BN
HC vs. BN χ2 (p) Overall HWE p
0.01 1.90 0.17 0.43 1.15
0.87 0.35 0.35 0.64 0.09
0.32 0.02 0.81 1.23 0.59
(0.92) (0.17) (0.68) (0.51) (0.28)
0.37 0.13 0.37 0.31 0.06
(0.35) (0.55) (0.55) (0.43) (0.76)
0.08 1.05 0.61 0.38 0.30
(0.78) (0.31) (0.43) (0.54) (0.58)
0.24 0.09 0.24 0.36 0.11
(0.57) (0.89) (0.37) (0.27) (0.44)
0.29 0.13 0.32 0.29 0.09
0.81 0.40 0.32 0.84 0.94
MAF ¼ minor allele frequency (minor alleles/total alleles). Chi-square χ2 (p-value). Table 3 Two-way ANOVA's group X rs53576/rs2254298 haplotype interactions. Assessments
Groupa
F p Eating Attitudes Test (EAT) 22.87 o 0.001 Diet (EAT-D) 15.39 o 0.001 Bulimia (EAT-B) 23.24 o 0.001 Oral (EAT-O) 10.21 o 0.001 Yale Brown Cornell Eating Disorder Survey (YBC-EDS) 38.35 o 0.001 Quick Inventory of Depression (QID) 4.33 0.006 Structured Interview Guide for the Hamilton Anxiety Index (SIGH-A) 5.66 0.001 Young-Brown Obsessive-Compulsive Symptoms (Y-BOCS) 10.74 o 0.001 Body Shape Questionnaire (% BSQ) 12.39 o 0.001
Bonferroni
HCo BN/AN-WR o AN-C HCo BN/AN-WR o AN-C HCo BN/AN-WR o AN-C HCo BN/AN-WR o AN-C HCo BN/AN-WR o AN-C HC oBN/AN-WR/AN-C HC oBN/AN-WR/AN-C HC oBN/AN-WR/AN-C HC oBN/AN-WR/AN-C
Mann–U Whitney rs53576/ rs2254298aGG/GG vs. A carrier F 9.70 7.73 7.01 6.38 8.35 3.71 5.42 5.04 4.61
p 0.002 0.006 0.009 0.002 0.002 0.057 0.022 0.027 0.034
GG/GG o A GG/GG o A GG/GG o A GG/GG o A GG/GG o A GG/GG o A GG/GG o A GG/GG o A
Group X haplotypea
F 2.93 3.00 0.98 5.38 3.64 1.31 1.46 1.67 4.15
p 0.037 0.034 0.41 0.002 0.015 0.27 0.23 0.18 0.008
Bold indicates significant difference p o 0.05. a
Two-way ANOVA's group X haplotype.
Please cite this article as: Acevedo, S.F., et al., Severity of eating disorder symptoms related to oxytocin receptor polymorphisms in anorexia nervosa. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.05.040i
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Fig. 1. Lower overall Eating Attitudes Test (EAT) and EAT subscales raw scores for rs53576/rs2254298 GG/GG homozygotes compared to A carriers at either loci. (A) On the overall EAT and (B) EAT diet (EAT-D) subscale the AN-C, AN-WR and the combined Sample whom are GG/GG homozygotes had lower scores compared to A carriers at either loci. (C) Raw scores on the EAT-bulimia (EAT-B) subscale were higher for A carriers at either loci then GG/GG homozygotes for the AN-WR and combined Sample. (D) On the EAT-oral (EAT-O) subscale the AN-C group A carriers scores were twice as high as the GG/GG homozygotes and were higher in the overall Sample. (Student's T-test; p o 0.05).
data suggest that even when maintaining a healthy weight women that have had anorexia nervosa that are A carriers still have heightened pre-occupation with food and body shape, as well as higher anxiety, relative to their GG/GG counterparts.
4. Discussion This study provides evidence that polymorphisms of OXTR are relevant to clinical symptoms in anorexia nervosa. Regarding our initial hypothesis, we did not find increased representation of the OXTR minor alleles amongst the ED groups. This is consistent with the large, genome-wide association studies examining common genetic variants in people with EDs that have not found significance differences in these allelic frequencies (Boraska et al., 2014; Pinheiro et al., 2009). However, we did find differences in the clinical symptoms, with elevated severity specific for food behaviors and body-shape, in patients that have had anorexia and are A carriers for two common SNPs of the OXTR gene. This supports a theory that OXTR haplotype may be a treatment modulator in anorexia nervosa. In Table 4, we summarize a number of studies that have reported differences related to clinical symptoms and social measures related to OXTR polymorphisms in non-clinical populations. The presence of the most common minor allele of rs53576, has been linked to less social behavior and reduced reward
dependence (Saphire-Bernstein et al., 2011; Tost et al., 2010). Social anxiety and negative affect are associated with rs2254298 and rs53576 (Chen and Johnson, 2012; Lucht et al., 2009; Thompson et al., 2011). Increased reactivity to stressors has been found in A carriers (Rodrigues et al., 2009). Brain structure and function also differ based on OXTR polymorphisms (Furman et al., 2011; Inoue et al., 2010; Tost et al., 2010; Tost et al., 2011), with more gray matter observed in limbic structures including the amygdala, hypothalamus, and anterior cingulate for A carriers of both rs53576 and rs2254298 (see Table 4). In concert, OXTR genotype may provide a biomarker related to processing anxiety that is relevant as a treatment modulator in those with EDs. Furthermore, the specific psychological scales showing significant group-haplotype interactions: the EAT-D and EAT-O, the YBCEDS, and the BSQ suggest a personality profile of higher concern related to oral control, eating obsessions, and appearance concerns. If the differences we found in the A allele carriers of these two SNPs of OXTR were merely related to an amplification of preexisting traits related to those alleles, we would expect to see similar interactions based on ED symptom severity within the BN group. Instead, having anorexia itself appears to contribute to an environment-gene interaction that exacerbates symptoms of the illness in these minor allele carriers of OXTR. The most objective environmental difference in subjects with anorexia and those with bulimia is low weight, as the DSM IV criteria for diagnosis of anorexia required a period in which the subject is underweight.
Please cite this article as: Acevedo, S.F., et al., Severity of eating disorder symptoms related to oxytocin receptor polymorphisms in anorexia nervosa. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.05.040i
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One of the challenges in understanding common genotype variants in psychiatric illness is that there are seldom universally beneficial genes for mental health. Common variants may exist with each variant being optimal for a different environment. In considering OXTR alleles, the rs53576 G carriers have been described as more likely to develop depression when experiencing adversity or stress (Costa et al., 2009; McQuaid et al., 2013) yet other work has suggested A carriers are more at risk for impaired social behaviors and depressive symptoms (Kogan et al., 2011; Lucht et al., 2009). Analysis of the cohort from the Avon Longititudual Study of Parents and Children (ALSPCA) indicated pregnant women that are GG homozygotes display lower levels of emotional loneliness (Connelly et al., 2014). They also found that GG homozygotes reported higher incidence of laxative use, selfinduced vomiting and dieting characteristic behaviors of bulimia nervosa. This appears to differ from our overall results that demonstrate that A carriers have more ED symptoms than the GG homozygotes, however, we did not see differences related to the EAT-B subscale, our measure that is most specific for bulimia symptoms (Table 3). Mothers that are A carriers appear less responsive to their children (Bakermans-Kranenburg and van Ijzendoorn, 2008) and men that are A carriers do not benefit from social support during stressors (Chen et al., 2011b). One hypothesis consistent with the literature is that G carriers are more sensitive to social stressors, but also benefit more from social support, whereas A carriers may be less affected by both positive and negative social situations. Here, we see that A carriers may also have more severe ED symptoms if they develop anorexia nervosa. Recognition of a particular person's vulnerabilities in terms of both gene and environment may help in identification of specific treatment needs of individuals. Although the rs53576 and rs2254298 are both located in introns and are thus unlikely to affect the protein structure or function of the oxytocin receptor itself, there is substantial evidence that differences in these SNPs are associated with changes in brain structure and function (Table 4). Allelic differences that occur in introns may act by altering gene expression. Changes in gene expression may occur because the ability of transcriptional regulatory factors, such as promotors or enhancers, to bind to the gene may be altered, resulting in differential amounts of production of the protein (Wang et al., 2005; Hrdlickova et al., 2014). Alternatively, changes in the non-coding regions may also lead to differences related to epigenetic modifications, including methylation (De Sario, 2009). For the OXTR, methylation differences have been associated with functional changes in the brain (Jack et al., 2012), and are a likely candidate for the differences in brain structure and function that are related to differences in these SNPs. 4.1. Strengths and limitations
Fig. 2. Lower overall raw scores for rs53576/rs2254298 GG/GG homozygotes compared to A carriers at either loci for ED symptoms, anxiety, body-shape, and negative problem orientation. (A) On the Yale Brown Cornell Eating Disorder Survey (YBC-EDS) A carriers had higher scores compared to GG/GG homozygotes in the AN-C, AN-WR and overall sample. (B) In the AN-WR group and overall sample A carriers had higher anxiety [Structured Interview Guide for the Hamilton Anxiety Index (SIGH-A)]. (C) In both of the AN groups (AN-C, AN-WR) and in the overall sample A carriers reported higher pre-occupation with body shape [Body Shape Questionnaire (% BSQ)]. (Student's T-test; p o0.05).
Oxytocin plays a central role in feeding behaviors, essentially shifting one's motivation away from food, particularly carbohydrates, towards prosocial activities (Leng et al., 2008b).
There are a number of strengths and limitations of this work. First, each group contained 25–30 subjects, with each genetic subgroup containing a minimum of five participants. Larger sample sizes will be useful to confirm these findings and identify any differences of smaller magnitude that may be missed due to Type II error. For example, this sample size could not be further subdivided to examine whether these OXTR SNPs are related to binge-purge or restricting subtypes of anorexia nervosa. A strength of this study is its ability to separate history of illness from current illness by dividing the anorexia group into currently-ill and long-term recovered subjects. Further, the subjects with bulimia nervosa provided a withinstudy control group with comparable psychiatric symptoms for depression, anxiety, and ED, but no history of weight loss. The lack of differentiation of clinical and psychiatric symptoms within both the BN and HC groups supports our theory that A carriers for either the rs53576 and rs2254298 polymorphisms of the OXTR gene may
Please cite this article as: Acevedo, S.F., et al., Severity of eating disorder symptoms related to oxytocin receptor polymorphisms in anorexia nervosa. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.05.040i
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Table 4 Summary of articles examining OXTR SNPs in non-clinical populations, presented alphabetically by first author and SNP. Reference
SNP
MAF
Population
Studies with differences related to OXTR SNP rs53576 Bakermans-Kranenburg and rs53576 0.30 Mothers van IJzendoorn, 2008 (F, Caucasian/ European) Chang et al., 2014 rs53576 0.59 Healthy volunteers (M/F, Han Chinese) Chen et al., 2011a, 2011b rs53576 0.37 Healthy volunteers (M, European/ Other) Connelly et al., 2014 rs53576 0.32 Pregnant women rs2254298 0.11 (F, Caucasian/ English) Lucht et al., 2009
rs53576
0.29
rs2254298 0.08 rs2228485 0.29 McQuaid et al., 2013
rs53576
0.37
Rodrigues et al., 2009
rs53576
0.49
Saphire-Bernstein et al., 2011
rs53576
0.43
Tost et al., 2010
rs53576
0.32
Healthy volunteers (M/F, European/ Caucasian) College undergraduates (M/F, White/ Black/Asian) College students (M/F, Asian/ Caucasian) College students/ employees (M/F, Asian/ Caucasian) Healthy volunteers (M/F, European)
Studies with differences related to OXTR SNP rs2254298 Chen and Johnson, 2012 rs2254298 0.16– Healthy college 0.30 students (M/F, Caucasian and Asian) Feldman et al., 2012 rs2254298 NR Pregnant women (F, Caucasian/ Isreal-Jewish) Furman et al., 2011 rs2254298 0.16 Healthy girls (F, Caucasian) Inoue et al., 2010
rs53576
0.40
Thompson et al., 2011
rs2254298 0.42 rs2268493 0.18 rs2254298 0.17
Tost et al., 2011
rs2254298 0.14
n
Results
159
Mothers that are A carriers displayed lower levels of sensitive responsiveness to their toddlers.
82
Lower striatal dopamine transporter (DAT) in GG/AG subjects compared to AA homozygotes. In those with GG/AG correlations were found between peripheral oxytocin levels and striatal DAT.
194
G carriers show reduced cortisol with social support during stressor task. No change in cortisol for AA.
8340 The rs53576 GG homozygotes differ in eating habits including higher reported incidence of self-induced vomiting, use of laxatives and dieting compared to the AG/AA group of pregnant women. rs53576 GG homozygotes also report lower incidence of emotional loneliness. No associations were found for rs225498 related to eating, mood, social or relationship characteristics. 289 Lower positive affect, more negative affect, and emotional loneliness in minor allele carriers. Sexual dimorphism with more effects in males.
288
G carriers show depressive symptoms with high childhood maltreatment. AA genotype resilient.
192
A carrier's had lower behavioral and dispositional empathy, higher physiological and dispositional stress reactivity.
326
A carrier's display lower optimism, mastery, self-esteem and depressive symptomatology.
345
Allele difference in prosocial temperament, hypothalamus volume and amygdala activation.
178
Females with A allele have higher attachment anxiety; Males with A allele have higher autistic traits.
272
Lower plasma levels of oxytocin in GG homozygotes compared to A carriers.
51
A carrier's lower gray matter volume and higher amygdala both sides compared to GG homozygotes. Additional genotype differences in posterior brain stem and dorsomedial anterior cingulated cortex. The rs2254298A carrier's larger bilateral amygdala volume increased with number of alleles.
Healthy volunteers (M/F, Asian)
208
Healthy girls (F, Caucasian) Healthy volunteers (M/F, European/ Caucasian)
92 343
Heterozygotes with early adversity reported higher levels of depression, physical anxiety and social anxiety. Higher gray matter volume in GG homozygotes in hypothalamus and anterior cingulate particularly in males.
MAF ¼minor allele frequency (minor alleles/total alleles); M¼ male; F¼ female; ADHD¼ Attention deficient disorder; OXTR¼ oxytocin receptor; OXT ¼oxytocin gene; NR¼ not reported
be more sensitive to effects of starvation. Finally, while these studies may identify SNPs of the OXTR gene associated with endophenotypes of ED patients, the functional consequence of these SNPs on oxytocin pathway function in the brain remains unknown.
4.2. Future directions In the context of the starvation, decreasing prosocial behavior in favor of feeding behaviors is appropriate and consistent with
Please cite this article as: Acevedo, S.F., et al., Severity of eating disorder symptoms related to oxytocin receptor polymorphisms in anorexia nervosa. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.05.040i
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animal studies (Barrett et al., 2014). Examination of the methylation status of risk genes in psychiatric illness may provide an additional indicator of gene expression (Hing et al., 2014). One study has reported that OXTR is more highly methylated in subjects with anorexia than healthy women (Kim et al., 2014b). Methylation of the OXTR gene has also been related to neural activity during social cognition in healthy individuals (Jack et al., 2012). One hypothesis is that an environment with limited food supply may promote methylation of OXTR gene, thereby driving behaviors towards feeding and away from socialization, whereas an environment with plentiful food may encourage demethylation of this gene. The ability to methylate or demethylate the OXTR gene in response to environmental availability of food could vary with the specific OXTR allele. Thus, carrying minor alleles of OXTR may result in increased methylation of OXTR gene in response to weight loss, potentially reducing social reward but increasing the importance of food. Examination of methylation of OXTR gene during the course of the illness in concert with genotype information may provide a more precise indicator of oxytocin function for future studies. Administration of oxytocin is now being explored as a potential adjunctive treatment for anorexia nervosa (Kim et al., 2014a, 2014c), but it is possible this treatment may only be beneficial to carriers of specific alleles. Improving our understanding of the interaction between gene and environment for oxytocin may be necessary to optimize treatment of anorexia.
Acknowledgments Funding for this research was provided by NIMH K23 MH093684 to Dr. McAdams, a Junior Investigator Award from the Children's Clinical Research Advisory Board at Children's Medical Center to Dr. McAdams, the UT Southwestern Medical Center Disease-Oriented Clinical Scholars Program to Dr. Lutter, and a UT Southwestern Medical Center High-Risk/High-Impact grant to Dr. Lutter. The Human Genetics Clinical Core is supported in part by the NIH National Center for Advancing Translational Sciences (UL1TR001105). References Bakermans-Kranenburg, M.J., van Ijzendoorn, M.H., 2008. Oxytocin receptor (OXTR) and serotonin transporter (5-HTT) genes associated with observed parenting. Social Cognitive and Affective Neuroscience 3, 128–134. Barrett, C.E., Modi, M.E., Zhang, B.C., Walum, H., Inoue, K., Young, L.J., 2014. Neonatal melanocortin receptor agonist treatment reduces play fighting and promotes adult attachment in prairie voles in a sex-dependent manner. Neuropharmacology 85, 357–366. Becker, A.E., 2004. New global perspectives on eating disorders. Culture, Medicine and Psychiatry 28, 433–437. Berland, N.W., Thompson, J.K., Linton, P.H., 1986. Correlation between the Eat-26 and the Eat-40, the eating disorders inventory, and the restrained eating inventory. International Journal of Eating Disorders 5, 569–574. Boraska, V., Franklin, C.S., Floyd, J.A., Thornton, L.M., Huckins, L.M., Southam, L., Rayner, N.W., Tachmazidou, I., Klump, K.L., Treasure, J., Lewis, C.M., Schmidt, U., Tozzi, F., Kiezebrink, K., Hebebrand, J., Gorwood, P., Adan, R.A., Kas, M.J., Favaro, A., Santonastaso, P., Fernandez-Aranda, F., Gratacos, M., Rybakowski, F., Dmitrzak-Weglarz, M., Kaprio, J., Keski-Rahkonen, A., Raevuori, A., Van Furth, E.F., Slof-Op ‘t Landt, M.C., Hudson, J.I., Reichborn-Kjennerud, T., Knudsen, G.P., Monteleone, P., Kaplan, A.S., Karwautz, A., Hakonarson, H., Berrettini, W.H., Guo, Y., Li, D., Schork, N.J., Komaki, G., Ando, T., Inoko, H., Esko, T., Fischer, K., Mannik, K., Metspalu, A., Baker, J.H., Cone, R.D., Dackor, J., Desocio, J.E., Hilliard, C.E., O'Toole, J.K., Pantel, J., Szatkiewicz, J.P., Taico, C., Zerwas, S., Trace, S.E., Davis, O. S., Helder, S., Buhren, K., Burghardt, R., de Zwaan, M., Egberts, K., Ehrlich, S., Herpertz-Dahlmann, B., Herzog, W., Imgart, H., Scherag, A., Scherag, S., Zipfel, S., Boni, C., Ramoz, N., Versini, A., Brandys, M.K., Danner, U.N., de Kovel, C., Hendriks, J., Koeleman, B.P., Ophoff, R.A., Strengman, E., van Elburg, A.A., Bruson, A., Clementi, M., Degortes, D., Forzan, M., Tenconi, E., Docampo, E., Escaramis, G., Jimenez-Murcia, S., Lissowska, J., Rajewski, A., SzeszeniaDabrowska, N., Slopien, A., Hauser, J., Karhunen, L., Meulenbelt, I., Slagboom, P.E., Tortorella, A., Maj, M., Dedoussis, G., Dikeos, D., Gonidakis, F., Tziouvas, K., Tsitsika, A., Papezova, H., Slachtova, L., Martaskova, D., Kennedy, J.L., Levitan, R. D., Yilmaz, Z., Huemer, J., Koubek, D., Merl, E., Wagner, G., Lichtenstein, P.,
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Please cite this article as: Acevedo, S.F., et al., Severity of eating disorder symptoms related to oxytocin receptor polymorphisms in anorexia nervosa. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.05.040i
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Severity of eating disorder symptoms related to oxytocin receptor polymorphisms in anorexia nervosa Summer F. Acevedo a, Celeste Valencia a, Michael Lutter b, Carrie J. McAdams a,n a b
University of Texas at Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas TX 75390-8828, USA Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, IA 52242, USA
art ic l e i nf o
a b s t r a c t
Article history: Received 23 January 2015 Received in revised form 21 April 2015 Accepted 5 May 2015
Oxytocin is a peptide hormone important for social behavior and differences in psychological traits have been associated with variants of the oxytocin receptor gene in healthy people. We examined whether single nucleotide polymorphisms (SNPs) of the oxytocin receptor gene (OXTR) correlated with clinical symptoms in women with anorexia nervosa, bulimia nervosa, and healthy comparison (HC) women. Subjects completed clinical assessments and provided DNA for analysis. Subjects were divided into four groups: HC, subjects currently with anorexia nervosa (AN-C), subjects with a history of anorexia nervosa but in long-term weight recovery (AN-WR), and subjects with bulimia nervosa (BN). Five SNPs of the oxytocin receptor were examined. Minor allele carriers showed greater severity in most of the psychiatric symptoms. Importantly, the combination of having had anorexia and carrying either of the A alleles for two SNPS in the OXTR gene (rs53576, rs2254298) was associated with increased severity specifically for ED symptoms including cognitions and behaviors associated both with eating and appearance. A review of psychosocial data related to the OXTR polymorphisms examined is included in the discussion. OXTR polymorphisms may be a useful intermediate endophenotype to consider in the treatment of patients with anorexia nervosa. & 2015 Published by Elsevier Ireland Ltd.
Keywords: Oxytocin Anorexia nervosa Bulimia nervosa Social behavior Eating disorders
1. Introduction Eating disorders (ED) are complex psychiatric illnesses with environmental, cognitive, and biological contributions to their etiology and manifestation (Becker, 2004; Bulik et al., 2007; HerpertzDahlmann et al., 2011; Kaye et al., 2011). Biological pathway differences that contribute to a mental illness, but are not necessarily describing all aspects of the illness, have been called intermediate phenotypes (Flint et al., 2014). Improving our understanding of intermediate phenotypes within EDs may allow for individualized treatments targeted to the specific mechanistic dysfunctions. Social cognitive differences have been proposed as a specific intermediate phenotype related to anorexia nervosa (Harrison et al., 2012; Zucker et al., 2007). Reduced social cognitive function has been observed using psychological assessments in both acutely ill and weight-recovered subjects with anorexia nervosa (Oldershaw et al., 2011; Tchanturia et al., 2011). Additionally, neural differences in the engagement of social cognitive regions during social tasks have been observed (McAdams and Krawczyk, 2011; Schulte-Ruther et al., 2012).
n
Corresponding author. Tel.: þ 1 214 648 4145; fax: þ1 214 648 5321. E-mail address: [email protected] (C.J. McAdams).
Oxytocin is a neurotransmitter important for many forms of both social behavior including pair-bonding, maternal attachment, and group identification, as well as appetite suppression (Leng et al., 2008a; Leng et al., 2008b). Oxytocin has been linked to many psychiatric illnesses, including autism, EDs, addiction, schizophrenia, and post-traumatic stress disorder (Maguire et al., 2013; Marazziti and Catena Dell’osso, 2008). Most recently, Kim et al. (2014b) reported increased methylation of CpG dinucleotides in the oxytocin receptor (OXTR) gene in a small sample of patients with anorexia nervosa, a modification that has previously been associated with reduced expression of oxytocin receptors in the brain (Gregory et al., 2009). Polymorphic and epigenetic changes in the OXTR gene have been related to psychological and neural differences in healthy individuals. One OXTR single nucleotide polymorphism (SNP), the A allele of rs2254298, has been associated with the volume of the amygdala, a structure associated with anxiety and fear (Inoue et al., 2010). This polymorphism has also been associated with a sexual dimorphism related to the expressed psychological phenotype, with male carriers expressing autistic traits and female carriers expressing anxiety traits (Chen and Johnson, 2012). Another OXTR SNP, the A allele of rs53576, has been associated with low levels of self-esteem, optimism, and mastery (SaphireBernstein et al., 2011). This SNP also prevents social support from
http://dx.doi.org/10.1016/j.psychres.2015.05.040 0165-1781/& 2015 Published by Elsevier Ireland Ltd.
Please cite this article as: Acevedo, S.F., et al., Severity of eating disorder symptoms related to oxytocin receptor polymorphisms in anorexia nervosa. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.05.040i
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reducing the cortisol response of healthy individuals in a laboratory stress-induction procedure (Chen et al., 2011a). We hypothesized that the minor alleles of OXTR would be more common in patients with EDs, because high anxiety, low-self esteem, and difficulty managing social stresses are also common amongst these patients (Grilo et al., 2012; Gual et al., 2002; Herpertz-Dahlmann et al., 2001).
2. Methods 2.1. Participants A total of 124 female participants over age 18 were included in this study. The study was approved by the institutional review board of the University of Texas at Southwestern Medical Center, and participants were recruited from the public and ED treatment programs in the Dallas-Fort Worth area. Subjects came to an initial appointment at which they provided written informed consent to participate in this study. All subjects were then interviewed using the Structured Clinical Interview for DSM-IV disorders (SCID-RV, (First et al., 2002)). A detailed history of all past and current ED symptoms was also obtained. Subjects were classified into four groups. Healthy comparison subjects (HC, n¼ 35) were those subjects without any ED symptoms that did not have any first-degree relatives with an ED. Subjects currently with anorexia (AN-C, n ¼36), were all subjects who had met full DSM-IV criteria for anorexia nervosa during the preceding 12 months. Subjects currently in weight-recovery from anorexia (ANWR, n¼ 26), were all subjects who had met DSM-IV criteria for anorexia nervosa in their lifetime but had maintained a BMI greater than or equal to 19.0 for 24 months or longer. Subjects in the BN group were all subjects that had met DSM-IV criteria for bulimia nervosa in their lifetime and had never met DSM-IV criteria for anorexia nervosa (BN, n¼ 27). 2.2. Measures The Wechsler Abbreviated Scale of Intelligence (WASI, (Pearson Corporation, 1999)) was administered to provide an estimate of intelligence quotient. Three clinician-based measures were used to assess current depression, anxiety, and ED symptoms. The Quick Inventory of Depressive Symptomalogy (QIDS-CR, (Rush et al., 2003)) is a 16 question clinician-administered inventory of depressive symptoms. The Structured Interview Guide for the Hamilton Anxiety Scale (SIGHA, (Shear et al., 2001)) is a clinician-administered assessment assessing anxiety symptoms in fourteen categories. The Yale Brown Cornell Eating Disorder Survey (YBC-EDS, (Mazure et al., 1994; Sunday et al., 1995)) is a self-report check list followed by a 22-statement clinician-administered ED inventory for current eating preoccupations and rituals. Each participant also completed a self-report packet. The Young-Brown Obsessive-Compulsive Symptoms (Y-BOCS, (Woody et al., 1995)) provided an overall estimate of obsessions and compulsions, including those unrelated to the ED. The 26-item Eating Attitudes Test (EAT-26, (Berland et al., 1986)) provided a second measure of ED behaviors with subscales for dieting behavior (EAT-D), bulimia behaviors (EAT-B), and oral control behaviors (EAT-O). The 34-item Body Shape Questionnaire (BSQ, (Rosen et al., 1996)) provided a measure of ED symptomatology related to shape and weight concerns.
3. Results 3.1. Demographic and clinical profile of study groups The groups consisted of females between the ages 18–67 years old and grouped based on clinical diagnosis at the time of enrollment (HC, AN-C, AN-WR, BN). The subject population was primarily Caucasian (77–100%) with less than eight individuals per group of other races and ethnicities (Asian, African Americans, or Native Americans) and primarily Non-Hispanic (92–100%). Oneway ANOVA's indicated that the subjects recruited did not differ across groups in age at enrollment, years of education or intelligence measured by the Wechsler's Assessment Scale for Intelligence (WASI). A one-way ANOVA (F¼ 18.69, p o0.001) followed by Tukey's post-hoc analysis indicated that the current body mass index (BMI) was similar in HC (22.9 þ 0.8), AN-WR (22.9 þ0.7) and BN (23.4 þ0.7) groups with only the AN-C group (17.9þ0.3) differing from all other groups (p o0.05). One-way ANOVA (F¼6.39, p o0.003) followed by Tukey's post-hoc analysis within the clinical population suggest age of onset of the ED was lower in the AN-WR (13.5 þ 0.7) group compared to either the AN-C (16.7 þ0.7) and BN (17.8þ 1.2) groups. 3.2. OXTR SNP frequency not predictive of development of ED Table 1 is the genotype frequency of all the OXTR SNPs (rs53576, rs2254298, rs2228485, rs2268493 and rs918316) analyzed. Table 2 shows the minor allele frequency for all the SNPs and Chi-square (χ2) analysis for all the clinical groups compared HC. The results indicated that none of the OXTR SNPs were predictive of development of anorexia nervosa or bulimia nervosa. Haplotype combinations were also examined for any combination that had at least five subjects per haplotype group with no significant findings (data not shown). 3.3. OXTR SNP associated with ED clinical assessments In order to examine if any of the OXTR SNPs or haplotype combinations of SNPs had an effect on any of the ED symptoms or psychological measures, two-way ANOVA's between group (HC, AN-C, AN-WR, BN) and SNP or haplotype were conducted for all individual SNPs or haplotype combinations. Two-way ANOVAs between group and rs53576 (GG vs. C carriers) indicated Table 1 Genotype frequency of OXTR SNPs.
2.3. DNA processing
Genotype
Blood samples were collected from patients and submitted to McDermott Center for Human Growth & Development Human Genetics Clinical Laboratory located at UT Southwestern Medical Center in Dallas, TX, for processing and isolation of DNA. Samples were quantified using nanodrop and diluted in 96 well plates. The plated samples were then sent for Single Nucleotide Polymorphism (SNP) analysis at McDermott Center for Human Growth & Development DNA Sanger Sequencing Core located at UT Southwestern Medical Center in Dallas, TX. All oxytocin receptor SNPs were premade and purchased from Applied Biosystems by life technology: rs53576/CG (G/A), rs2254298 (G/A), rs2228485/CG_15917821_20 (T/C), rs2268493/CG_3290331_1 (T/C), rs918316/CG_7622139_10 (T/C).
rs53576 GG GA AA rs2254298 GG GA AA rs2228485 TT TC CC rs2268493 TT TC CC rs918316 TT TC CC
2.4. Statistical analysis All data was collected using standard data forms and entered into a Microsoft Excel spreadsheet for analysis using The Statistical Package for the Social Sciences (SPSS) software (version 21). Genotypic/haplotype differences within each patient group (HC, AN-C, AN-WR, and BN) were examined using independent Student's Ttests. Analysis of Variances (ANOVA) were calculated to examine associations between genotype/haplotype and subject groups (HC, AN-C, and AN-WR). A p value of o0.05 was considered significant.
HC
AN-C
AN-WR
BN
48.6% (17) 45.7% (16) 5.7% (2)
58.3% (21) 27.8% (10) 13.9% (5)
38.5% (10) 50.0% (13) 11.5% (3)
55.6% (15) 37.9% (11) 3.7% (1)
80.0% (28) 20.0% (7)
63.9% (23) 36.1% (13)
76.9% (20) 19.2% (5) 3.8% (1)
81.5% (22) 18.5% (5)
54.3% (19) 28.6% (10) 17.1% (6)
44.4% (16) 41.7% (15) 13.9% (5)
42.3% (11) 42.3% (11) 15.4% (4)
51.9% (14) 48.1% (13)
57.1% (20) 37.1% (13) 5.7% (2)
50.0% (18) 41.7% (15) 8.3% (3)
46.2% (12) 46.2% (12) 7.7% (2)
44.4% (12) 44.4% (12) 11.1% (3)
85.7% (30) 14.3% (5)
77.8% (28) 19.4% (7) 2.8% (1)
88.5% (23) 11.5% (3)
77.8% (21) 22.2% (6)
Please cite this article as: Acevedo, S.F., et al., Severity of eating disorder symptoms related to oxytocin receptor polymorphisms in anorexia nervosa. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.05.040i
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the semi-structured interviews, and demonstrate that the AN-C group has the highest severity of clinical and psychological illness.
significant interactions between group and genotype for the EAT-O (F¼ 3.59, p o0.02) subscale and YBC-EDS (F¼ 2.71, po 0.05). Within group analysis for both EAT-O and YBC-EDS indicated that only in the AN-C group did GG carriers report less symptoms compared to C carriers (Student's T-test, p o0.05). There were also interactions between group and rs2254298 (GG vs. C carriers) on the EAT-O subscale (F¼2.88, p o0.04) with the AN-C subjects that were GG homozygotes having less symptoms compared to C carriers (Student's T-test, p o0.02). Similar interactions between group and rs2228485 (TT vs. C carriers) were found on the EAT-O subscale (F¼ 4.38, p o0.04) with only the AN-C subjects that were TT homozygotes having less symptoms compared to C carriers (Student's T-test, p o0.005). The only haplotype combination with significant interactions between group and haplotype was the combination of rs53576 and rs2228485 comparing those that were GG homozygotes at both loci to C carriers at either loci (Table 3); therefore, all further analysis was done with this haplotype combination (see below).
3.5. rs53576/rs2254298 haplotype differences on clinical assessments Mann-U Whitney post-hoc analysis showed differences based on the rs53576/rs2254298 haplotype. The GG/GG subjects in the entire sample had the lowest overall symptoms on the EAT, all the EAT subscales, YBC-EDS, SIGH-A, Y-BOCS, and BSQ (Table 3, Fig. 1) compared to those that were A carriers. This data suggest that the GG/GG haplotype is associated with less pre-occupation about food and body shape, lower anxiety, and lower obsessive/compulsive behaviors. 3.6. Group and OXTR haplotype interactions on clinical assessments The two-way ANOVA between group and rs53576/rs2254298 (GG/GG vs. A carriers of either) haplotype interactions were significant for EAT, EAT-D subscale, EAT-O subscale, YBC-EDS, and BSQ (Table 3). A carriers amongst the AN-C group had higher incidence of symptoms for the overall EAT, EAT-D subscale, and EAT-O subscale (po 0.01, Fig. 1A, B and D). AN-C women that are A carriers also had the highest scores on the YBC-EDS and BSQ (p o0.05, Fig. 2A and C). This suggests that the GG/GG haplotype may be protective leading to less pre-occupation with food and body shape compared to A carriers at either loci. Similarly, the AN-WR subjects that were A carriers had higher scores on the overall EAT, EAT-D subscale, and EAT-B subscales (p o0.05, Fig. 1A–C), and more reported symptoms on the YBCEDS (p o0.03), SIGH-A (p o0.004), and BSQ (po 0.05) (Fig. 2A–C), with levels similar to those of the other clinical groups. In contrast, the GG/GG AN-WR subjects appeared more similar to HC. These
3.4. Group differences on clinical assessments To examine group differences between our subjects, two-way ANOVA's between group and rs53576/rs2254298 (GG/GG vs A carriers) haplotype with Bonferroni post-hoc comparisons were conducted. Results indicate that the HC group reported the lowest number of symptoms and the AN-C groups had the highest number of symptoms on the EAT and its subscales as well as the semi-structured interview YBC-EDS (Table 3). All clinical groups had significantly higher scores than the HC group for depression (QID-CR), anxiety (SIGH-A), obsessive-compulsive behaviors (YBOCS), and body shape concerns (BSQ) (Table 3). Overall, these data suggest there is consistency in the self-report measures and
Table 2 Minor allelic frequency of subjects with each group (HC, AN-C, AN-R, and BN) for OXTR SNPs. Genotype
Minor/ Major
Location/ Modification
HC
ANC
rs53576 rs2254298 rs2228485 rs2268493 rs918316
A/G A/G C/T C/T C/T
intron 0.29 0.28 intron 0.10 0.18 synonymous Asn [N] 0.31 0.35 intron 0.24 0.27 intron 0.07 0.13
HC vs. AN-C χ2 (p) ANWR
HC vs. AN-WR χ2 (p) HC vs. AN χ2 (p) BN
HC vs. BN χ2 (p) Overall HWE p
0.01 1.90 0.17 0.43 1.15
0.87 0.35 0.35 0.64 0.09
0.32 0.02 0.81 1.23 0.59
(0.92) (0.17) (0.68) (0.51) (0.28)
0.37 0.13 0.37 0.31 0.06
(0.35) (0.55) (0.55) (0.43) (0.76)
0.08 1.05 0.61 0.38 0.30
(0.78) (0.31) (0.43) (0.54) (0.58)
0.24 0.09 0.24 0.36 0.11
(0.57) (0.89) (0.37) (0.27) (0.44)
0.29 0.13 0.32 0.29 0.09
0.81 0.40 0.32 0.84 0.94
MAF ¼ minor allele frequency (minor alleles/total alleles). Chi-square χ2 (p-value). Table 3 Two-way ANOVA's group X rs53576/rs2254298 haplotype interactions. Assessments
Groupa
F p Eating Attitudes Test (EAT) 22.87 o 0.001 Diet (EAT-D) 15.39 o 0.001 Bulimia (EAT-B) 23.24 o 0.001 Oral (EAT-O) 10.21 o 0.001 Yale Brown Cornell Eating Disorder Survey (YBC-EDS) 38.35 o 0.001 Quick Inventory of Depression (QID) 4.33 0.006 Structured Interview Guide for the Hamilton Anxiety Index (SIGH-A) 5.66 0.001 Young-Brown Obsessive-Compulsive Symptoms (Y-BOCS) 10.74 o 0.001 Body Shape Questionnaire (% BSQ) 12.39 o 0.001
Bonferroni
HCo BN/AN-WR o AN-C HCo BN/AN-WR o AN-C HCo BN/AN-WR o AN-C HCo BN/AN-WR o AN-C HCo BN/AN-WR o AN-C HC oBN/AN-WR/AN-C HC oBN/AN-WR/AN-C HC oBN/AN-WR/AN-C HC oBN/AN-WR/AN-C
Mann–U Whitney rs53576/ rs2254298aGG/GG vs. A carrier F 9.70 7.73 7.01 6.38 8.35 3.71 5.42 5.04 4.61
p 0.002 0.006 0.009 0.002 0.002 0.057 0.022 0.027 0.034
GG/GG o A GG/GG o A GG/GG o A GG/GG o A GG/GG o A GG/GG o A GG/GG o A GG/GG o A
Group X haplotypea
F 2.93 3.00 0.98 5.38 3.64 1.31 1.46 1.67 4.15
p 0.037 0.034 0.41 0.002 0.015 0.27 0.23 0.18 0.008
Bold indicates significant difference p o 0.05. a
Two-way ANOVA's group X haplotype.
Please cite this article as: Acevedo, S.F., et al., Severity of eating disorder symptoms related to oxytocin receptor polymorphisms in anorexia nervosa. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.05.040i
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Fig. 1. Lower overall Eating Attitudes Test (EAT) and EAT subscales raw scores for rs53576/rs2254298 GG/GG homozygotes compared to A carriers at either loci. (A) On the overall EAT and (B) EAT diet (EAT-D) subscale the AN-C, AN-WR and the combined Sample whom are GG/GG homozygotes had lower scores compared to A carriers at either loci. (C) Raw scores on the EAT-bulimia (EAT-B) subscale were higher for A carriers at either loci then GG/GG homozygotes for the AN-WR and combined Sample. (D) On the EAT-oral (EAT-O) subscale the AN-C group A carriers scores were twice as high as the GG/GG homozygotes and were higher in the overall Sample. (Student's T-test; p o 0.05).
data suggest that even when maintaining a healthy weight women that have had anorexia nervosa that are A carriers still have heightened pre-occupation with food and body shape, as well as higher anxiety, relative to their GG/GG counterparts.
4. Discussion This study provides evidence that polymorphisms of OXTR are relevant to clinical symptoms in anorexia nervosa. Regarding our initial hypothesis, we did not find increased representation of the OXTR minor alleles amongst the ED groups. This is consistent with the large, genome-wide association studies examining common genetic variants in people with EDs that have not found significance differences in these allelic frequencies (Boraska et al., 2014; Pinheiro et al., 2009). However, we did find differences in the clinical symptoms, with elevated severity specific for food behaviors and body-shape, in patients that have had anorexia and are A carriers for two common SNPs of the OXTR gene. This supports a theory that OXTR haplotype may be a treatment modulator in anorexia nervosa. In Table 4, we summarize a number of studies that have reported differences related to clinical symptoms and social measures related to OXTR polymorphisms in non-clinical populations. The presence of the most common minor allele of rs53576, has been linked to less social behavior and reduced reward
dependence (Saphire-Bernstein et al., 2011; Tost et al., 2010). Social anxiety and negative affect are associated with rs2254298 and rs53576 (Chen and Johnson, 2012; Lucht et al., 2009; Thompson et al., 2011). Increased reactivity to stressors has been found in A carriers (Rodrigues et al., 2009). Brain structure and function also differ based on OXTR polymorphisms (Furman et al., 2011; Inoue et al., 2010; Tost et al., 2010; Tost et al., 2011), with more gray matter observed in limbic structures including the amygdala, hypothalamus, and anterior cingulate for A carriers of both rs53576 and rs2254298 (see Table 4). In concert, OXTR genotype may provide a biomarker related to processing anxiety that is relevant as a treatment modulator in those with EDs. Furthermore, the specific psychological scales showing significant group-haplotype interactions: the EAT-D and EAT-O, the YBCEDS, and the BSQ suggest a personality profile of higher concern related to oral control, eating obsessions, and appearance concerns. If the differences we found in the A allele carriers of these two SNPs of OXTR were merely related to an amplification of preexisting traits related to those alleles, we would expect to see similar interactions based on ED symptom severity within the BN group. Instead, having anorexia itself appears to contribute to an environment-gene interaction that exacerbates symptoms of the illness in these minor allele carriers of OXTR. The most objective environmental difference in subjects with anorexia and those with bulimia is low weight, as the DSM IV criteria for diagnosis of anorexia required a period in which the subject is underweight.
Please cite this article as: Acevedo, S.F., et al., Severity of eating disorder symptoms related to oxytocin receptor polymorphisms in anorexia nervosa. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.05.040i
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One of the challenges in understanding common genotype variants in psychiatric illness is that there are seldom universally beneficial genes for mental health. Common variants may exist with each variant being optimal for a different environment. In considering OXTR alleles, the rs53576 G carriers have been described as more likely to develop depression when experiencing adversity or stress (Costa et al., 2009; McQuaid et al., 2013) yet other work has suggested A carriers are more at risk for impaired social behaviors and depressive symptoms (Kogan et al., 2011; Lucht et al., 2009). Analysis of the cohort from the Avon Longititudual Study of Parents and Children (ALSPCA) indicated pregnant women that are GG homozygotes display lower levels of emotional loneliness (Connelly et al., 2014). They also found that GG homozygotes reported higher incidence of laxative use, selfinduced vomiting and dieting characteristic behaviors of bulimia nervosa. This appears to differ from our overall results that demonstrate that A carriers have more ED symptoms than the GG homozygotes, however, we did not see differences related to the EAT-B subscale, our measure that is most specific for bulimia symptoms (Table 3). Mothers that are A carriers appear less responsive to their children (Bakermans-Kranenburg and van Ijzendoorn, 2008) and men that are A carriers do not benefit from social support during stressors (Chen et al., 2011b). One hypothesis consistent with the literature is that G carriers are more sensitive to social stressors, but also benefit more from social support, whereas A carriers may be less affected by both positive and negative social situations. Here, we see that A carriers may also have more severe ED symptoms if they develop anorexia nervosa. Recognition of a particular person's vulnerabilities in terms of both gene and environment may help in identification of specific treatment needs of individuals. Although the rs53576 and rs2254298 are both located in introns and are thus unlikely to affect the protein structure or function of the oxytocin receptor itself, there is substantial evidence that differences in these SNPs are associated with changes in brain structure and function (Table 4). Allelic differences that occur in introns may act by altering gene expression. Changes in gene expression may occur because the ability of transcriptional regulatory factors, such as promotors or enhancers, to bind to the gene may be altered, resulting in differential amounts of production of the protein (Wang et al., 2005; Hrdlickova et al., 2014). Alternatively, changes in the non-coding regions may also lead to differences related to epigenetic modifications, including methylation (De Sario, 2009). For the OXTR, methylation differences have been associated with functional changes in the brain (Jack et al., 2012), and are a likely candidate for the differences in brain structure and function that are related to differences in these SNPs. 4.1. Strengths and limitations
Fig. 2. Lower overall raw scores for rs53576/rs2254298 GG/GG homozygotes compared to A carriers at either loci for ED symptoms, anxiety, body-shape, and negative problem orientation. (A) On the Yale Brown Cornell Eating Disorder Survey (YBC-EDS) A carriers had higher scores compared to GG/GG homozygotes in the AN-C, AN-WR and overall sample. (B) In the AN-WR group and overall sample A carriers had higher anxiety [Structured Interview Guide for the Hamilton Anxiety Index (SIGH-A)]. (C) In both of the AN groups (AN-C, AN-WR) and in the overall sample A carriers reported higher pre-occupation with body shape [Body Shape Questionnaire (% BSQ)]. (Student's T-test; p o0.05).
Oxytocin plays a central role in feeding behaviors, essentially shifting one's motivation away from food, particularly carbohydrates, towards prosocial activities (Leng et al., 2008b).
There are a number of strengths and limitations of this work. First, each group contained 25–30 subjects, with each genetic subgroup containing a minimum of five participants. Larger sample sizes will be useful to confirm these findings and identify any differences of smaller magnitude that may be missed due to Type II error. For example, this sample size could not be further subdivided to examine whether these OXTR SNPs are related to binge-purge or restricting subtypes of anorexia nervosa. A strength of this study is its ability to separate history of illness from current illness by dividing the anorexia group into currently-ill and long-term recovered subjects. Further, the subjects with bulimia nervosa provided a withinstudy control group with comparable psychiatric symptoms for depression, anxiety, and ED, but no history of weight loss. The lack of differentiation of clinical and psychiatric symptoms within both the BN and HC groups supports our theory that A carriers for either the rs53576 and rs2254298 polymorphisms of the OXTR gene may
Please cite this article as: Acevedo, S.F., et al., Severity of eating disorder symptoms related to oxytocin receptor polymorphisms in anorexia nervosa. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.05.040i
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Table 4 Summary of articles examining OXTR SNPs in non-clinical populations, presented alphabetically by first author and SNP. Reference
SNP
MAF
Population
Studies with differences related to OXTR SNP rs53576 Bakermans-Kranenburg and rs53576 0.30 Mothers van IJzendoorn, 2008 (F, Caucasian/ European) Chang et al., 2014 rs53576 0.59 Healthy volunteers (M/F, Han Chinese) Chen et al., 2011a, 2011b rs53576 0.37 Healthy volunteers (M, European/ Other) Connelly et al., 2014 rs53576 0.32 Pregnant women rs2254298 0.11 (F, Caucasian/ English) Lucht et al., 2009
rs53576
0.29
rs2254298 0.08 rs2228485 0.29 McQuaid et al., 2013
rs53576
0.37
Rodrigues et al., 2009
rs53576
0.49
Saphire-Bernstein et al., 2011
rs53576
0.43
Tost et al., 2010
rs53576
0.32
Healthy volunteers (M/F, European/ Caucasian) College undergraduates (M/F, White/ Black/Asian) College students (M/F, Asian/ Caucasian) College students/ employees (M/F, Asian/ Caucasian) Healthy volunteers (M/F, European)
Studies with differences related to OXTR SNP rs2254298 Chen and Johnson, 2012 rs2254298 0.16– Healthy college 0.30 students (M/F, Caucasian and Asian) Feldman et al., 2012 rs2254298 NR Pregnant women (F, Caucasian/ Isreal-Jewish) Furman et al., 2011 rs2254298 0.16 Healthy girls (F, Caucasian) Inoue et al., 2010
rs53576
0.40
Thompson et al., 2011
rs2254298 0.42 rs2268493 0.18 rs2254298 0.17
Tost et al., 2011
rs2254298 0.14
n
Results
159
Mothers that are A carriers displayed lower levels of sensitive responsiveness to their toddlers.
82
Lower striatal dopamine transporter (DAT) in GG/AG subjects compared to AA homozygotes. In those with GG/AG correlations were found between peripheral oxytocin levels and striatal DAT.
194
G carriers show reduced cortisol with social support during stressor task. No change in cortisol for AA.
8340 The rs53576 GG homozygotes differ in eating habits including higher reported incidence of self-induced vomiting, use of laxatives and dieting compared to the AG/AA group of pregnant women. rs53576 GG homozygotes also report lower incidence of emotional loneliness. No associations were found for rs225498 related to eating, mood, social or relationship characteristics. 289 Lower positive affect, more negative affect, and emotional loneliness in minor allele carriers. Sexual dimorphism with more effects in males.
288
G carriers show depressive symptoms with high childhood maltreatment. AA genotype resilient.
192
A carrier's had lower behavioral and dispositional empathy, higher physiological and dispositional stress reactivity.
326
A carrier's display lower optimism, mastery, self-esteem and depressive symptomatology.
345
Allele difference in prosocial temperament, hypothalamus volume and amygdala activation.
178
Females with A allele have higher attachment anxiety; Males with A allele have higher autistic traits.
272
Lower plasma levels of oxytocin in GG homozygotes compared to A carriers.
51
A carrier's lower gray matter volume and higher amygdala both sides compared to GG homozygotes. Additional genotype differences in posterior brain stem and dorsomedial anterior cingulated cortex. The rs2254298A carrier's larger bilateral amygdala volume increased with number of alleles.
Healthy volunteers (M/F, Asian)
208
Healthy girls (F, Caucasian) Healthy volunteers (M/F, European/ Caucasian)
92 343
Heterozygotes with early adversity reported higher levels of depression, physical anxiety and social anxiety. Higher gray matter volume in GG homozygotes in hypothalamus and anterior cingulate particularly in males.
MAF ¼minor allele frequency (minor alleles/total alleles); M¼ male; F¼ female; ADHD¼ Attention deficient disorder; OXTR¼ oxytocin receptor; OXT ¼oxytocin gene; NR¼ not reported
be more sensitive to effects of starvation. Finally, while these studies may identify SNPs of the OXTR gene associated with endophenotypes of ED patients, the functional consequence of these SNPs on oxytocin pathway function in the brain remains unknown.
4.2. Future directions In the context of the starvation, decreasing prosocial behavior in favor of feeding behaviors is appropriate and consistent with
Please cite this article as: Acevedo, S.F., et al., Severity of eating disorder symptoms related to oxytocin receptor polymorphisms in anorexia nervosa. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.05.040i
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animal studies (Barrett et al., 2014). Examination of the methylation status of risk genes in psychiatric illness may provide an additional indicator of gene expression (Hing et al., 2014). One study has reported that OXTR is more highly methylated in subjects with anorexia than healthy women (Kim et al., 2014b). Methylation of the OXTR gene has also been related to neural activity during social cognition in healthy individuals (Jack et al., 2012). One hypothesis is that an environment with limited food supply may promote methylation of OXTR gene, thereby driving behaviors towards feeding and away from socialization, whereas an environment with plentiful food may encourage demethylation of this gene. The ability to methylate or demethylate the OXTR gene in response to environmental availability of food could vary with the specific OXTR allele. Thus, carrying minor alleles of OXTR may result in increased methylation of OXTR gene in response to weight loss, potentially reducing social reward but increasing the importance of food. Examination of methylation of OXTR gene during the course of the illness in concert with genotype information may provide a more precise indicator of oxytocin function for future studies. Administration of oxytocin is now being explored as a potential adjunctive treatment for anorexia nervosa (Kim et al., 2014a, 2014c), but it is possible this treatment may only be beneficial to carriers of specific alleles. Improving our understanding of the interaction between gene and environment for oxytocin may be necessary to optimize treatment of anorexia.
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Please cite this article as: Acevedo, S.F., et al., Severity of eating disorder symptoms related to oxytocin receptor polymorphisms in anorexia nervosa. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.05.040i