Overview of genetic research in anorexia nervosa: The past, the present and the future.

BACKGROUND: Even though the evidence supporting the presence of a heritable component in the aetiology of anorexia nervosa (AN) is strong, the underlying genetic mechanisms remain poorly understood. The recent publication of a genome-wide association study (GWAS) of AN (Boraska, Mol Psychiatry, 2014) was an important step in genetic research in AN. OBJECTIVE: To briefly sum up strengths and weaknesses of candidate-gene and genome-wide approaches, to discuss the genome-wide association studies of AN and to make predictions about the genetic architecture of AN by comparing it to that of schizophrenia (since the diseases share some similarities and genetic research in schizophrenia is more advanced). METHOD: Descriptive literature review. RESULTS: Despite remarkable efforts, the gene-association studies in AN did not advance our knowledge as much as had been hoped, although some results still await replication. DISCUSSION: Continuous effort of participants, clinicians and researchers remains necessary to ensure that genetic research in AN follows a similarly successful path as in schizophrenia. Identification of genetic susceptibility loci provides a basis for follow-up studies.

Are recently identified genetic variants regulating BMI in the general population associated with anorexia nervosa?

The influence of body mass index (BMI) on susceptibility to anorexia nervosa (AN) is not clear. Recently published genome-wide association (GWA) studies of the general population identified several variants influencing BMI. We genotyped these variants in an AN sample to test for association and to investigate a combined effect of BMI-increasing alleles (as determined in the original GWA studies) on the risk of developing the disease. Individual single nucleotide polymorphisms (SNPs) were tested for association with AN in a sample of 267 AN patients and 1,636 population controls. A logistic regression for the combined effect of BMI-increasing alleles included 225 cases and 1,351 controls. We found no significant association between individual SNPs and AN. The analysis of a combined effect of BMI-increasing alleles showed absence of association with the investigated condition. The percentages of BMI-increasing alleles were equal between cases and controls. This study found no evidence that genetic variants regulating BMI in the general population are significantly associated with susceptibility to AN.

Exploration of large, rare copy number variants associated with psychiatric and neurodevelopmental disorders in individuals with anorexia nervosa.

Anorexia nervosa (AN) is a serious and heritable psychiatric disorder. To date, studies of copy number variants (CNVs) have been limited and inconclusive because of small sample sizes. We conducted a case-only genome-wide CNV survey in 1983 female AN cases included in the Genetic Consortium for Anorexia Nervosa. Following stringent quality control procedures, we investigated whether pathogenic CNVs in regions previously implicated in psychiatric and neurodevelopmental disorders were present in AN cases. We observed two instances of the well-established pathogenic CNVs in AN cases. In addition, one case had a deletion in the 13q12 region, overlapping with a deletion reported previously in two AN cases. As a secondary aim, we also examined our sample for CNVs over 1 Mbp in size. Out of the 40 instances of such large CNVs that were not implicated previously for AN or neuropsychiatric phenotypes, two of them contained genes with previous neuropsychiatric associations, and only five of them had no associated reports in public CNV databases. Although ours is the largest study of its kind in AN, larger datasets are needed to comprehensively assess the role of CNVs in the etiology of AN.

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

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 winner's 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 POMC variants with body composition measures and nutrient choice.

Genome linkage scans and candidate gene studies have implicated the pro-opiomelanocortin (POMC) locus in traits related to food intake, metabolic function, and body mass index. Here we investigate single nucleotide polymorphisms at the POMC locus in order to evaluate the influence of its genetic variance on body fat distribution and diet in a sample of middle-aged men from The Netherlands. 366 Dutch males from the Hamlet cohort were asked detailed questions about food choice, nutrient intake and exercise. Furthermore, their weight and body fat composition were measured. Each cohort member was genotyped for a set of single nucleotide polymorphisms (SNPs) at the POMC locus. Regression analysis, adjusted for several covariates, was used to test for the association between genetic variants and the phenotypes measured. POMC variation was associated with waist:hip ratio, visceral fat and abdominal fat (rs6713532, P=0.020, 0.019, and 0.021, respectively), and nutrient choice (rs1042571, P=0.034), but in light of limited power and multiple testing these results should be taken with caution. POMC is a strong candidate for involvement in appetite regulation as supported by animal, physiological, and genetic studies and variation at the POMC locus may affect an individual's energy intake which in turn leads to variation in body composition and body fat.

A meta-analysis of circulating BDNF concentrations in anorexia nervosa.

OBJECTIVES: Brain derived neurotrophic factor (BDNF) is involved in neuroplasticity, and in the homeostatic regulation of food intake and energy expenditure. It also has a role in stress responsivity and reward processing. On the basis of its involvement in these various processes, BDNF can be hypothesized to be an important factor in the development and maintenance of anorexia nervosa (AN). This study meta-analytically summarizes investigations of serum BDNF concentrations in people currently ill with AN, in comparison to healthy controls. METHODS: Seven studies measuring BDNF in serum of individuals with AN (n=155) and healthy controls (n=174) were identified and included in the meta-analysis of the mean differences between case and control groups. RESULTS: This study confirms that AN is associated with decreased serum BDNF concentrations, in comparison to healthy controls. The combined effect size (standardized mean difference, SMD) was large (SMD=-0.96; 95% CI -1.33 to -0.59; P<0.001). Significant heterogeneity of effect sizes was identified (I(2)=58.3%; P<0.001), which emerged as being primarily attributable to the first published study on the investigated association. CONCLUSIONS: The present meta-analytical summary of studies measuring circulating BDNF concentrations in women with AN and healthy controls confirms that it is significantly reduced in this patient group. Difficulties associated with the measurement of BDNF have been identified and potential confounding factors have been discussed. Current data do not allow inferences to be made about causal links between levels of circulating BDNF and AN. However, possible explanations for the relationship between BDNF and AN have been presented.