Genetics variants in the NEGR1 gene, strongly expressed in the brain, have been reported to affect the neuronal control of food intake therefore inducing obesity. With the same rationale, we hypothesized that this genetic variability may be associated with psychological traits commonly displayed by eating disorder (ED) patients and/or with the risk for the disorder. We analyzed 21 tag-single-nucleotide polymorphisms (SNPs) in the coding sequence and adjacent regions of the NEGR1 gene. A total of 169 ED patients (106 with anorexia nervosa (AN) and 63 with bulimia nervosa (BN)) and 312 healthy subjects were genotyped. Personality traits and general psychopathological symptoms were assessed by the Eating Disorders Inventory Test-2 (EDI-2) and Symptom Checklist 90 Revised inventories. None of the SNPs or haplotypes analyzed were associated with a greater risk of ED or correlated with anthropometric parameters. However, in patients with BN, four SNPs (rs12740031, rs10789322, rs6659202 and rs591540) correlated with the scores in Drive for Thinness (DT), Ineffectiveness (I) and Interoceptive Awareness (IA) (Bonferroni-P<0.05 in all instances). The first two SNPs along with rs954299 and rs2422021 formed a haplotype block, which showed a consistent association with the EDI-2 score in BN patients (Bonferroni-P=0.01). A subsequent three-SNP sliding-window approach identified a central area, encompassing both the haplotype block and the individually relevant SNPs that strongly correlated with the scores of BN patients in DT, I, IA and Bulimia. No associations were identified in the AN group. These preliminary results indicate that NEGR1 could be an important locus influencing certain personality dimensions in BN patients.
Anorexia nervosa (AN) and bulimia nervosa (BN) are complex psychiatric disorders with an important genetic influence and disturbances of neurotransmitter, neuropeptide and neuroendocrine systems.1 A number of central genes present in the central nervous system and involved in the regulation of eating behavior and body weight have been pointed out as good, however untested, candidates in studies with eating disorder (ED) patients.2,3 One of such genes is the neuronal growth regulator 1 (NEGR1), which codes for a cell adhesion molecule of the immunoglobulin superfamily that belongs to the IgLON subgroup. NEGR1 is strongly expressed in various brain regions including the cerebral cortex and hypothalamus,4 where it seems to be involved in neurite outgrowth.5 The specific function of the gene is presently unknown, although experiments in mice with abolished NEGR1 function indicate a possible role in the neuronal control of body weight and food intake.4
In this regard, several human genome-wide association studies indicate that the NEGR1 gene may be an important obesity locus.6, 7, 8, 9, 10 Subsequent studies have replicated this observation in different cohorts.11, 12, 13 On the other hand, there also are indications that NEGR1 could also be involved in psychiatric disorders. For instance, Maccarrone et al.14 have recently identified differences in the cerebrospinal fluid levels of the NEGR1 protein between healthy subjects and depressed and bipolar patients.
It has been reported that genetic variability in brain-expressed genes associated with obesity such as FTO or MC4R can also be related to ED.15,16 Accordingly, we hypothesize that polymorphisms in or close to the NEGR1 gene locus could be involved in ED-related behaviors through similar neuronal mechanisms.
In order to test this hypothesis, we have analyzed 21 tag-single-nucleotide polymorphisms (SNPs) in the coding sequence and adjacent 3′- and 5′-untranslated regions of the NEGR1 gene in a population of ED patients and healthy subjects and identified associations with the susceptibility for the disorder, anthropometric parameters and psychopathological traits.
Materials and methods
The study group consisted of 169 unrelated consecutive female patients with AN (n=106) or BN (n=63), some of whom had also participated in previous studies by our group.17, 18, 19 The patients attended the collaborating Eating Disorders Unit at the Mental Health Outpatient Clinic in Badajoz (Spain), and were diagnosed by one psychiatrist and one psychologist using the ED section of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4th edn.20 Anthropometric (weight, height and body mass index) and psychological parameters (see below) were collected. Diagnosis was blind to genotype. Exclusion criteria, determined upon screening, included dementia, mental retardation, schizophrenia, Turner’s syndrome, other neurological disorders and underlying endocrine pathologies.
A total of 312 healthy women from the same geographical area as the patients (Health District of Badajoz, Spain) were recruited among University students and staff. Interviews were carried out to guarantee that they had never been diagnosed as having any psychiatric disorder or received any psychiatric treatment. None of the participating control subjects showed anthropometric parameters indicative of present ED.
All the participants were white Spanish individuals who gave written informed consent. The study protocol was approved by the Ethics Committee of the University of Extremadura and was conducted in accordance with the Declaration of Helsinki and its subsequent revisions.
European population (CEU) SNP data were downloaded from the International Haplotype Mapping Project website (http://hapmap.ncbi.nlm.nih.gov/cgi-perl/gbrowse/hapmap27_B36). We analyzed the coding sequence and adjacent 3′- and 5′-untranslated regions of the NEGR1 gene (ref. NC_000001.10) and tag SNPs were assigned by using Haploview v4.2 software (Daly Lab at the Broad Institute, Cambridge, MA, USA) (Table 1). The minor allele frequency considered was 10%, and pair-wise tagging with a minimum r2 of 0.80 was applied to capture common variations. A set of 24 tag SNPs was thus selected of which three (rs2630391, rs6696052 and rs11209817) did not survive quality-control with the genotyping methods. All the SNPs were intronic and located within an 824.4-kb region (chromosome positions 71910991 to 72735458) encompassing the NEGR1 gene
Blood samples from all participants were collected and stored at −80 °C until analysis. Genomic DNA was isolated from peripheral blood leukocytes in 2-ml aliquots of whole-blood samples with a Qiagen blood midi kit (Qiagen, Chatsworth, CA, USA). The purified DNA samples were then stored at 4 °C in sterile plastic vials.
Genotype analyses for SNPs determination were performed with the single-base extension polymerase chain reaction Sequenom iPLEX-Gold and the mass spectrometry-based platform MassARRAY MALDI-TOF (Sequenom, San Diego, CA, USA) at the Spanish Genotyping National Centre (CEGEN-ISCIII). In brief, the analyses consisted of an initial locus-specific PCR, followed by single-base extension using mass-modified dideoxynucleotide terminators of an oligonucleotide primer, which anneals immediately upstream of the polymorphic site of interest. Using matrix-assisted laser desorption ionization time-of-flight mass spectrometry, the distinct mass of the extended primer identifies the allele.21
Study of psychological traits
ED patients were evaluated on the first visit to the collaborating Eating Disorders Unit by experienced clinicians. The patients completed the Eating Disorders Inventory Test-2 (EDI-2) and the Symptom Checklist 90 Revised self-reported questionnaires. EDI-2 was designed to assess ED-related cognitive and behavioral characteristics by initially measuring eight main subscales (Drive for Thinness (DT), Bulimia, Body Dissatisfaction, Ineffectiveness, Perfectionism, Interpersonal Distrust, Interoceptive Awareness (IA) and Maturity Fears), to which other three (Asceticism, Impulse Regulation and Social Insecurity) were added in a second version of the inventory.22 The EDI-2 test has been validated in the Spanish population showing high internal consistency between the different subscales.23 The Symptom Checklist 90 Revised inventory, which has also been validated in Spaniards,24 assesses a broad range of psychopathological symptoms. Three indexes (Global Severity Index; Positive Symptom Distress Index; and Positive Symptom Total) and scores in nine primary symptom dimensions (somatization, depression, anxiety, hostility, phobic anxiety, paranoid ideation and psychoticism) are obtained upon completion of the questionnaire.25
Single-marker association analyses were carried out using logistic regression models adjusted for age using the SNPassoc R package.26 The statistical power of the sample size was evaluated with a log-additive genetic model, analyzing the frequency for carriers of the variant alleles with an arbitrarily established effect size set at 2.0 (type I error=0.05). With the available sample size, the statistical power for detecting associations with categorical variables ranged from 0.80 to 0.87 in BN and 0.93 to 0.97 in AN, depending on the minor allele frequency (Quanto software v. 1.2.4, University of Southern California). The study was, however, underpowered in the case of rs1413368, which displayed a very low frequency of 0.005.
Haplotype blocks were identified with Haploview v4.2 and associations with disease were assessed using PLINK v1.07 (ref. 27) with a haplotype frequency cutoff of 0.1. To refine the haplotype construction and to identify core regions with the potential to affect either the susceptibility for ED or the anthropometric/psychopathological parameters in the patients, we used a sliding-window approach to construct successive and adjacent three-SNP haplotypes. The P-value for the statistical significance of all observed associations was set at 0.0023 after Bonferroni correction for multiple testing.
Clinical and descriptive characteristics of ED patients and healthy subjects are summarized in Table 2. Control subjects displayed significantly higher weight and body mass index than AN patients (P<0.05). In addition, BN patients scored significantly higher than AN patients in the different scales measured in the psychometric evaluation (Table 2).
Minor allelic frequencies for the 21 polymorphisms assayed in the study population ranged from 0.005 to 0.486 (Table 1). None of the SNPs analyzed were individually associated with a greater risk of ED or altered anthropometric parameters after Bonferroni correction of the data (data not shown).
However, we observed a consistent association between four NEGR1 genetic variants and the scores of the EDI-2 test in the psychometric evaluation of the BN patients. First, two SNPs that were in complete linkage disequilibrium in this group, rs10789322 and rs12740031, were associated with the scores of the IA scale, with statistically significant differences between wild-type, heterozygous and mutant homozygous subjects (Table 3). In the same manner, the rs6659202 and rs591540 SNPs were associated with Ineffectiveness and DT, respectively (Table 3). Three other SNPs (rs1983121, rs12137231 and rs3851882) were related to at least one of the scales, but statistical significance was lost after correction for multiple testing (data not shown).
The linkage disequilibrium plot for NEGR1 in the whole population of the study is depicted in Supplementary Figure 1. Mirroring the results from the single-SNP study, there were no relevant differences in the distribution of the different haplotypes between AN or BN patients and control subjects (data not shown).
Interestingly, the results of the psychometric evaluation in the BN group were again subjected to influence by NEGR1 haplotypes. The haplotype analysis summarized in Figure 1 revealed two relevant regions, a two-SNP block encompassing 17 kb and a larger block encompassing 100 kb and including four SNPs (rs954299, rs2422021, rs10789322 and rs12740031). Haplotype GCAA in this second block displayed a strong association with higher total scores in the EDI-2 inventory (Figure 1). In order to investigate which specific EDI-2 scale(s) was/were behind this observation, we applied a sliding-window approach and analyzed the associations of the resulting 19 loci of interest with the scores obtained in the questionnaires. Figure 2 shows P-values for the correlation of these three-SNP combinations with several personality dimensions measured by the EDI-2 test. A central area spanning 210 kb can be easily discerned that was associated with the scores of DT, Bulimia, IA and Ineffectiveness. It is noteworthy that this central area encompassed the four SNPs included in the formerly described haplotype block 2 (Figure 2). Only one more marker combination, upstream of the NEGR1-coding region (rs12091740–rs7517923–rs10493494), was associated with the results of IA (Figure 2).
Genetic alterations in the complex neural system aimed to keep energy balance by food intake are known to trigger and maintain obesity. However, it has also been hypothesized that the genes involved in the neuronal control of weight regulation may also be relevant for ED.17,28, 29, 30 In this regard, the putative impact of the NEGR1 genetic variants, whose loci have repeatedly been shown to be associated with the risk for obesity6, 7, 8, 9, 10, 11, 12, 13 remained to be tested in the field of ED.
The main finding of this study was that genetic variability in a region within the NEGR1 gene locus showed a profound impact in the scores obtained by BN patients in various personality dimensions. The mechanisms underlying the different behaviors displayed by patients with psychiatric disorders are extremely complex, but it is known that some of these mechanisms may be mediated by the contribution of genes to psychological traits.31,32 In this regard, the trait most profoundly affected by NEGR1 genetic variability in the BN patients was IA, which measures the ability of an individual to discriminate between sensations and feelings, and, most interestingly, between the sensations of hunger and satiety.22 Interoceptive deficits have been suggested to be one factor that bridges the gap between abnormal functioning in interoceptive neural networks and symptom presentation in BN, as binging and purging may reflect a difficulty in internally regulating misinterpreted hunger and satiety cues.33 Indeed, several studies have reported that those with BN struggle to detect various body cues.34, 35, 36 This hypothesis is supported by imaging studies that identified irregular patterns of activation in the brain, when women with BN are given interoceptive taste stimuli.37 Being NEGR1 a gene expressed predominantly in brain with an important, although semi-unknown, role in neuronal growth, we propose that genetic variability in its locus might contribute to this altered interoceptive sensitivity.
It is also noteworthy that the interoceptive deficit seems to be higher in BN than in AN or obese patients.38 This is consistent with the lack of association observed between NEGR1 variants and this trait in our AN group, and with the fact that BN patients in our series displayed far worse IA than did women with AN (EDI-2 scores: 14.18±6.64 vs 9.38±7.23; P<0.0001).
Interestingly, Klabunde et al.33 found that the interoceptive-processing deficit is also present in women that recovered from BN, and the authors rightfully raised the question whether this deficit could be a consequence of having suffered from BN or a biological trait that is present prior to the development of bulimic symptoms. Our results describing a genetic alteration as a putative source of failure to correctly process hunger/satiety sensations would support their latter theory. Moreover, the connection between genetic variability in brain-expressed genes, eating disorders and IA is not unprecedented in the literature. We and others have suggested that BDNF, a gene also involved in neuronal growth and stability, may influence the severity of symptoms in ED by modulating the associated psychopathology,17,39 in particular through the impairment of IA.39
Ineffectiveness, which assesses feelings of inadequacy, insecurity, worthlessness and having no control over one’s life, was the other EDI-2 scale most deeply affected by NEGR1 genetic variability in the BN patients. The concept of Ineffectiveness, or poor self-esteem, as a risk factor for ED is still controversial,40,41 but it has been suggested that this trait could actually be the mediator of other risk factors in BN such as childhood abuse,42,43 an information that unfortunately was not available in our study. Goethals et al.44 have demonstrated that pathological scores in Ineffectiveness are supported by biological processes in the brain, as the scores correlate with cerebral blood flow in brain regions with a known role in foregoing functions, such as cortical areas. Given the lack of knowledge on the specific function of NEGR1 and the mechanisms by which this gene can affect behavior, it is difficult to establish a hypothesis for a link between variability in its locus and Ineffectiveness. Interestingly enough, however, this trait and DT, which was also affected by NEGR1 variability in our sample, have been reported to correlate with genetic variants of other brain genes.45, 46, 47 Moreover, and in line with our results, it has been shown that the connections among genotypes and these character scales were more expressed in BN patients than in women with AN.47
On the other hand, the results showed no significant increased risk for BN (or AN) associated with any SNP or haplotype, which suggests that the affected traits would be more important in terms of severity or duration of the disorder than in terms of increased susceptibility, where environmental and social factors must have an important role. In the same manner, we did not observe an effect of NEGR1 variants on either the weight or body mass index of our BN group. It would be very difficult to demonstrate an association of these SNPs with a tendency to obesity in bulimic patients, as their impact would likely be counteracted by compensatory mechanisms, for example, purging or extreme physical activity.
Several limitations have to be considered in this study. First, the relatively small size of the population studied, particularly of the BN group, might affect the generalizability of these results and therefore the findings presented herein should be considered as preliminary. On the other hand, this limited sample also allowed for all the patients to be diagnosed and treated by the same clinicians in the same facilities over a short period of time, which reduced the chance that the findings may be due to population structure. Second, we could not determine three of the tag SNPs initially established and therefore the relevance of the regions tagged by these variants could not be assessed. Finally, we did not consider the different psychopathological scales to correct for multiple testing, as we did with the 21 SNPs assayed, as this procedure has been suggested to be too stringent to detect a moderate correlation with different endophenotypes in similar studies.48
It should also be mentioned that, although the NEGR1 gene locus has been repeatedly associated with changes leading to obesity, which constitutes the backbone of our hypothesis, some studies have failed to reproduce this association.49,50 In the same manner, it must not be ruled out that the NEGR1 variants were in fact reflecting long-range associations with other genes. It has recently been reported that the increased risk of obesity conferred by a deletion in the NEGR1 gene was in fact driven by a neighboring 8-kb deletion (rs1993709)10 comprising the conserved transcription factor-binding site for NKX6.1, which is also involved in neuronal development.51
However, even acknowledging these limitations, there are some facts that highlight the significance of the findings described herein. First, both the single-SNP study and the two different multiple-SNP approaches pointed to the same region as an influential locus for ED-related psychological traits. Second, the P-values obtained for these associations survived multiple testing correction for 21 SNPs, and third, there is recent evidence relating NEGR1 protein levels to depression and other psychiatric disorders that could also be present in ED patients.14
These results taken together, preliminary as they are given the described limitations, indicate that the NEGR1 gene could be an important locus influencing certain personality dimensions in BN patients, particularly IA, DT and Ineffectiveness. Further studies with larger and homogeneous populations of patients evaluated with the same inventories are nevertheless warranted to confirm the reported associations.
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We are thankful to the Spanish Genotyping National Centre (CEGEN-ISCIII) in Santiago de Compostela (Spain), headed by Dr Angel Carracedo, for its valuable technical assistance. This work has been supported in part by the Alicia Koplowitz Foundation, Madrid, Spain, and grant GR10022 from Junta de Extremadura, Consejeria de Economia, Comercio e Innovacion, Merida (Spain).
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website
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Gamero-Villarroel, C., González, L., Gordillo, I. et al. Impact of NEGR1 genetic variability on psychological traits of patients with eating disorders. Pharmacogenomics J 15, 278–283 (2015). https://doi.org/10.1038/tpj.2014.53
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