Anorexia nervosa: From single SNP studies, through biomarkers, to genome-wide association

The research in this thesis focused on searching for: -the genetic variants which increase or decrease the risk of developing anorexia nervosa (AN) -the variants which play a role in the body-weight related parameters in the general population -the variants which might shed light on the hypothetical common genetic background of AN and obesity -the biochemical markers of the disease and the genetic variants related to them. Single-nucleotide polymorphisms (SNPs) associated with BMI in the general population were tested for association with AN, both on an individual basis and as a combined score (a so-called polygenic risk score). There was no evidence of association with AN in both scenarios. We also studied variants in the POMC gene locus and its association to several body-weight and food intake related phenotypes. Signals of association with waist:hip ratio, visceral fat and abdominal fat made POMC a strong candidate for further studies. We further focused on two SNPs located on the BDNF and COMT genes, which both have theoretical and empirical support for playing a role in the aetiology of psychiatric disorders. Each of those SNPs was tested several times in previous studies in AN, but the results were inconsistent. We applied the meta-analytic framework to evaluate and combine the evidence from those previous studies with our own, novel data. This work showed that SNPs rs6265 (BDNF) and rs4680 (COMT) were not associated with AN. Our results resolve the controversy stemming from prior inconsistent results and underlie the necessity for large sample sizes and stringent quality control and analysis of the data. Brain-derived neurotrophic factor (BDNF) belongs to a family of neurotrophins and has multiple functions which might theoretically play a role in the development and maintenance of AN. Here, we combined the data from several studies and performed a meta-analysis on the levels of BDNF protein in the blood serum of patients with AN. This study showed that the serum BDNF level in patients with AN is lower than in healthy controls. Several large and recurrent copy-number variants (CNVs) have been associated with psychiatric disorders. We tested preselected CNVs in cases with AN versus control. None of the tested CNVs appeared to be associated with AN, although there were important caveats which needed to be taken into account when interpreting these results. A genome-wide association study of SNPs in AN and controls was part of this thesis work. Even though it was the largest study of its kind in AN, no variants associated at a genome-wide significance level were found. The current accomplishments of the gene-association research in AN are more modest, compared to the research in some other psychiatric disorders, such as schizophrenia. The main reason for that are the smaller numbers of the available DNA samples from patients with AN. The genetic architecture of AN suggest that (similarly as in schizophrenia) when the sample sizes increase substantially, new loci harbouring variants associated with susceptibility to AN will be determined.