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

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

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

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

Stress-related psychiatric disorders across the life spa

Experimental access to Transition Distribution Amplitudes with the P̄ANDA experiment at FAIR

Baryon-to-meson Transition Distribution Amplitudes (TDAs) encoding valuable new information on hadron structure appear as building blocks in the collinear factorized description for several types of hard exclusive reactions. In this paper, we address the possibility of accessing nucleon-to-pion (\u3c0N) TDAs from \uafpp \u2192 e+e 12\u3c00 reaction with the future PANDA detector at the FAIR facility. At high center- of-mass energy and high invariant mass squared of the lepton pair q2, the amplitude of the signal channel pp\uaf \u2192 e+e 12\u3c00 admits a QCD factorized description in terms of \u3c0N TDAs and nucleon Distribution Amplitudes (DAs) in the forward and backward kinematic regimes. Assuming the validity of this factorized description, we perform feasibility studies for measuring \uafpp \u2192 e+e 12\u3c00 with the PANDA detector. Detailed simulations on signal reconstruction efficiency as well as on rejection of the most severe background channel, i.e. pp\uaf \u2192 \u3c0+\u3c0 12\u3c00 were performed for the center-of-mass energy squared s = 5 GeV2 and s = 10 GeV2, in the kinematic regions 3.0 0.5 in the proton-antiproton center-of-mass frame. Results of the simulation show that the particle identification capabilities of the PANDA detector will allow to achieve a background rejection factor of 5 \ub7 107 (1 \ub7 107) at low (high) q2 for s = 5 GeV2, and of 1 \ub7 108 (6 \ub7 106) at low (high) q2 for s = 10 GeV2, while keeping the signal reconstruction efficiency at around 40%. At both energies, a clean lepton signal can be reconstructed with the expected statistics corresponding to 2 fb 121 of integrated luminosity. The cross sections obtained from the simulations are used to show that a test of QCD collinear factorization can be done at the lowest order by measuring scaling laws and angular distributions. The future measurement of the signal channel cross section with PANDA will provide a new test of the perturbative QCD description of a novel class of hard exclusive reactions and will open the possibility of experimentally accessing \u3c0N TDAs

Eperimental access to Transition Distribution Amplitudes with the PANDA experiment at FAIR

We address the possibility of accessing nucleon-to-pion (πN) Transition Distribution Amplitudes (TDAs) from p¯p→e+e−π0 reaction with the future \={P}ANDA detector at the FAIR facility. At high center of mass energy and high invariant mass of the lepton pair q2, the amplitude of the signal channel p¯p→e+e−π0 admits a QCD factorized description in terms of πN TDAs and nucleon Distribution Amplitudes (DAs) in the forward and backward kinematic regimes. Assuming the validity of this factorized description, we perform feasibility studies for measuring p¯p→e+e−π0 with the \={P}ANDA detector. Detailed simulations on signal reconstruction efficiency as well as on rejection of the most severe background channel, {\it i.e.} p¯p→π+π−π0 were performed for the center of mass energy squared s=5 GeV2 and s=10 GeV2, in the kinematic regions 3.00.5 in the proton-antiproton center of mass frame. Results of the simulation show that the particle identification capabilities of the \={P}ANDA detector will allow to achieve a background rejection factor at the level of 108 (2⋅107) at low (high) q2 while keeping the signal reconstruction efficiency at around 40% and that a clean lepton signal can be reconstructed with the expected statistics corresponding to 2 fb−1 of integrated luminosity. The future measurement of the signal channel cross section with \={P}ANDA will provide a new test of perturbative QCD description of a novel class of hard exclusive reactions and will open the possibility of experimentally accessing πN TDAs