Margarita C. T. Slof-Op’t Landt

Eating disorders: from twin studies to candidate genes and beyond.

Substantial effort has been put into the exploration of the biological background of eating disorders, through family, twin and molecular genetic studies. Family studies have shown that anorexia (AN) and bulimia nervosa (BN) are strongly familial, and that familial etiologic factors appear to be shared by both disorders. Twin studies often focus on broader phenotypes or subthreshold eating disorders. These studies consistently yielded moderate to substantial heritabilities. In addition, there has been a proliferation of molecular genetic studies that focused on Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994) AN and BN. Seven linkage regions have been identified in genome-wide screens. Many genetic association studies have been performed, but no consistent association between a candidate gene and AN or BN has been reported. Larger genetic association studies and collaborations are needed to examine the involvement of several candidate genes and biological pathways in eating disorders. In addition, twin studies should be designed to assist the molecular work by further exploring genetic determinants of endophenotypes, evaluating the magnitude of contribution to liability of measured genotypes as well as environmental risk factors related to eating disorders. In this manner twin and molecular studies can move the field forward in a mutually informative way.

The Val66Met polymorphism of the BDNF gene in anorexia nervosa: New data and a meta-analysis

Abstract Objectives. The Val66Met polymorphism (rs6265) of the BDNF gene is a non-synonymous polymorphism, previously associated with anorexia nervosa (AN). Methods. We genotyped rs6265 in 235 patients with AN and 643 controls. Furthermore, we performed a systematic review of all case–control and family-based studies testing this SNP in AN, and combined the results in a meta-analysis. Results. The results of the case–control study were non-significant. For the meta-analysis, nine studies were identified (ncases = 2,767; ncontrols = 3,322, ntrios = 53) and included. Primarily, the analyses indicated an association with OR of 1.11 (P = 0.024) in the allelic contrast, and OR of 1.14 (P = 0.025) for the dominant effect of the Met allele. However, additional analyses revealed that the first published study (from those included in the meta-analysis) overly influenced the pooled effect size (possibly due to a phenomenon known as a winners curse). When this case–control study was replaced by a trio study (ntrios = 293) performed on a largely overlapping sample, the effect size became smaller and non-significant, both for the allelic contrast (OR = 1.07, P = 0.156) and the dominant effect (OR = 1.07, P = 0.319). The quality of included studies was good and there was no significant heterogeneity across the effect sizes. Conclusions. Our analyses indicate that the BDNF Val66Met variant is not associated with AN at detectable levels.

Anorexia nervosa and the Val158Met polymorphism of the COMT gene: meta-analysis and new data

Objectives This study aimed to test the association between the Val158Met polymorphism (rs4680) of the catechol-O-methyl transferase gene and anorexia nervosa (AN). Methods First, an association study on two cohorts (306 cases and 1009 controls from Utrecht, and 174 cases and 466 controls from Leiden/NTR) was performed. Subsequently, the results were integrated into a meta-analysis, together with all the case–control and family-based studies, which were testing the same hypothesis and were available in the literature. Altogether, eight studies (11 datasets) were included in this meta-analysis, with a total of 2021 cases, 2848 controls, and 89 informative (heterozygous) trios. Results The present association studies found no association between AN and rs4680 when testing the allelic contrast [Utrecht odds ratio (OR)=1.14, P=0.14; Leiden OR=1.02, P=0.85]. There was an indication of an association under the dominant model of genetic effect in the Utrecht cohort (for the Met allele, OR=1.42, P=0.03). Nevertheless, the meta-analyses of both the allelic contrast and the dominant effect were nonsignificant (the allelic pooled OR=1.03, P=0.42 and the dominant pooled OR=1.1, P=0.18). The meta-analyses were performed under the fixed-effect model and there was no significant heterogeneity among the effect sizes. Conclusion Meta-analytically combined evidence from the present genotypings and the literature search shows that the effect sizes are homogeneous across studies and that rs4680 is not associated with AN.

Association study of the estrogen receptor I gene (ESR1) in anorexia nervosa and eating disorders: No replication found

OBJECTIVE The female preponderance and onset around puberty in the majority of eating disorders (EDs) suggest that sex hormones, like estrogens, may be involved in the onset of these disorders. An eight-SNP haplotype at the estrogen receptor I (ESR1) gene was found to be associated with anorexia nervosa (AN) (Versini et al., Neuropsychopharmacology, 35, 1818-1825, 2010) and three SNPs from this haplotype (rs726281, rs2295193, and rs3798577) were associated with AN and/or EDs. Our objective was to replicate these findings in an independent cohort of 520 patients with an eating disorder, of whom 244 had AN (142 restricting type) from the GenED study and 2,810 random women from the Netherlands Twin Registry. METHOD The frequencies of the eight-SNP haplotype and three ESR1 SNPs were compared between patients with an eating disorder, with AN (restricting type), with bulimia nervosa (BN), and the control women. RESULTS Neither the haplotype nor the three ESR1 SNPs were associated with EDs, BN, AN, or restricting type AN. DISCUSSION Despite sufficient statistical power, the associations reported by Versini et al. (Neuropsychopharmacology, 35, 1818-1825, 2010) were not replicated.

Predictors of psychological outcome in patients with eating disorders: A routine outcome monitoring study

BACKGROUND Identifying predictors of psychological outcome for patients with eating disorders may improve the effectiveness of treatment. Patients with different pre-treatment characteristics and symptoms may benefit from different therapies. This study aimed to identify potential predictors of treatment outcome in a large naturalistic cohort of patients with an eating disorder. METHOD The study sample included patients (N = 1153) with all types of eating disorders who were receiving residential, day, or outpatient treatment. Remission was defined by means of four different indicators based on the Eating Disorder Examination-Questionnaire global score: 1. achieving reliable change; 2. showing a 50% reduction in baseline symptom severity; 3. reaching the clinical significance cut-off point; and 4. a combination of indicators 2 and 3. Potential predictor variables were investigated in univariate and multivariate Cox regression models. RESULTS Different predictors were found for the four outcome criteria. Patients with high levels of interpersonal distrust at baseline were less likely to have achieved reliable change in eating disorder psychopathology. Higher self-esteem and less body dissatisfaction at baseline was independently associated with a symptom reduction of more than 50% and/or reaching the clinical significance cut-off point. Contrary to our expectations, no differences in outcome were found between the eating disorder subtypes. DISCUSSION Clinically, it is important to reduce the risk of poor outcome and to achieve a rapid response in treatment using an intervention designed for this purpose, such as shared decision making or an intervention directed at self-esteem or body image, which may act as a catalyst for change.

A Common Mineralocorticoid Receptor Polymorphism (I180V) Interacts with Life Events in Relation to Perfectionism in Eating Disorders: A Pilot Study

The stress response is regulated by the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). When the balance between GR and MR signalling is disturbed, ones capacity to cope with a stressful event is diminished. In this pilot study, we tested the hypothesis that an interaction between common variants in the MR (rs5522) or GR gene (rs41423247) and stressful life events influences perfectionism levels in a group of patients with an eating disorder (ED; n = 113). Patients carrying the minor G allele of rs5522 had a higher perfectionism score if more stressful life events were experienced [β = 0.95, t(109) = 3.75, p < 0.01]. This effect was not found for patients carrying the AA genotype. These results suggest that rs5522 G allele carriers might be vulnerable to stressful life events. When patients with an ED are carriers and experience multiple life events, this might fuel their insecurity, which in turn may engender higher levels of perfectionism. Further studies are necessary to replicate and expand our findings.

Prevalence of dieting and fear of weight gain across ages: a community sample from adolescents to the elderly

ObjectivesThe current study aimed to define the prevalence of dieting and fear of weight gain among men and women across the entire lifespan and identify factors associated with them.MethodsData were available for 31,636 participants (60.2% women; age 13–98 years) from the Netherlands Twin Register. Dieting and fear of weight gain were described by age and sex. Associations with BMI, exercise behavior, urbanization and educational attainment were examined by regression analyses in 19,294 participants.ResultsDieting was most frequently reported by 35- to 65-year-old women (56.6–63%), and 45- to 65-year-old men (31.7–31.9%). Fear of weight gain was most prevalent in women between 16 and 25 (73.2–74.3%), and in 25- to 55-year-old men (43.2–46.1%). In addition to sex and BMI, dieting and fear of weight gain were associated with each other. Furthermore, fear was associated with the age × sex interaction and educational attainment.ConclusionsDieting and fear of weight gain is common during the entire lifespan for women, but is also endorsed by a substantial number of men. Given the low rate of overweight in young women, the high levels of fear of weight gain are striking.