Electron Spectroscopy with the SLICES setup

The subject of this thesis is the setup of a new spectrometer for internal conversion elec- tron measurements, SLICES (Spes Low energy Internal Conversion Electron Spectrom- eter), and its first use in an experiment aimed to study the structure of the low-lying states in 106Pd. Electron spectroscopy is a powerful tool in the investigation of fundamental properties of the atomic nucleus, essential in the study of nuclear structure, where empirical nuclear models provide a framework to understand many nuclear phenomena. For instance shape coexistence, that is, following the Poves [55] states, “ a very peculiar nuclear phenomenon consisting in the presence in the same nuclei, at low excitation energy, and within a very narrow energy range, of two or more states (or bands of states) which: (a) have well defined and distinct properties, and, (b) which can be interpreted in terms of different intrinsic shapes.”. Shape coexistence is a widespread feature that is thought to occur in nearly all nuclei [32]. It is associated with the fundamental tendency of nuclei to deform, if not in their ground states, in their excited states. The distinctive character of shape coexistence lies in the interplay between two opposing trends: shell and subshell closures have a stabilizing effect leading to sphericity while residual interactions between protons and neutrons outside closed shells drive the nucleus to deformation. The study of electric monopole transitions between nuclear states having the same spin and parity, the main topic of this thesis, can give an important contribution to clarify the configuration of the nuclear states. Electric monopole (E0) transitions are determined by a change in the radial distribution of the electric charge inside the nucleus, and high E0 transition strengths are expected whenever configurations with different mean-square charge radii mix. In this regard, an enhancement of the monopole strength in transitions between ∆J = 0 states may be considered as a ”signature” for shape coexistence [34]. This conclusion involves also states with J>0, in fact, as recently pointed out in Ref. [67], J π → J π (J 6= 0) transitions in both even and odd nuclei with shape-coexisting configurations can have large E0 components accompanying their M1+E2 allowed multipolarities. E0 transitions play a crucial role in determining nuclear structure properties and provide sensitive tests for nuclear models, developed since the second half of the 20th century, from the formulation of the Shell Model [48] and the Bohr-Mottelson Hamil- tonian [11] to the Interacting Boson Model [33]. The measurement of the monopole strength is complicated by the fact that E0 tran- sitions can proceed solely via internal conversion or pair production ( if the transition energy is larger than 2m0c 2 ). Simultaneous emission of two photons is a higher order process (relative probability ∼ 10−3 ÷ 10−4 ) and is usually neglected. The measurement of conversion electrons is typically achieved using silicon detectors, drifted with lithium (Si(Li)), coupled with a magnetic transport system. The latter allows a high efficiency for electron collection on the detector together with the powerful rejection of background γ-rays. The design of the different components of the magnetic transport system, studied in detail in this thesis, depends also on the electron energies of interest. In each case, before proposing an experiment, Monte Carlo simulations for different configurations have to be performed. For this reason, a GEANT4 simulation has been implemented to provide useful tools to plan future experiments with SLICES, paving the way to experimental campaigns with radioactive beams. Advances in accelerator and ion-source technologies have made it possible to produce Radioactive Ion Beams (RIBs) and have thus opened many horizons to investigate the structure of exotic nuclei. The Selective Production of Exotic Species (SPES) facility [61], currently under construction at INFN Laboratori Nazionali di Legnaro (LNL), aims to produce RIBs using the Isotope Separation OnLine (ISOL) technique with a particular focus on neutron-rich beams in the vicinity of 78Ni and 132Sn, where detailed nuclear structure information is scarce. The development of an experimental setup to perform electron spectroscopy of radioactive beam represents a crucial requirement for the SPES project. To this end, SLICES has been developed to be used in conjunction with the β-decay station that is envisaged at the SPES low energy beam line. Waiting for the future radioactive SPES beams, the commissioning of SLICES has been successfully performed at LNL using the proton beams provided by the Van de Graaf CN accelerator at LNL. The levels of interest have been populated via EC/β + decays of 106Ag produced in the 106Pd(p,n)106Ag reaction. Following the decay of the 106Ag isotope, the 106Pd isotope was populated in its excited states. In the nu- clear de-excitation process, γ-rays and internal conversion electrons are emitted. In our spectroscopic study, these were detected by an HPGe detector and the SLICES spectrometer, respectively. The measurement was performed alternating irradiation and measurement periods using a movable target remotely controlled with a dedicated control system developed in this thesis. Measurements of E0 strengths for transitions between the first excited states 0+ and 2 + in this nucleus have been achieved. The isotope was carefully chosen: some nuclear observables were known with high accuracy, offering the possibility to have a stringent test for the new setup. However, some observables necessary to the 106Pd structure description had never been measured, and, for others, conflicting results were available in the literature. The theoretical interpretation of Palladium isotopes is still controversial: on one hand, their level schemes have been organized into rotational bands, while on the other hand they have been interpreted as vibrational-like nuclei in the framework of Inter- acting Boson Model (IBM). The predictions of this model have been compared to the experimental values for many nuclear observables e.g. excitation energies, static mo- ment and E2/M1 transition strengths but a systematic study of the E0 strengths is still missing. For this reason, in the present work, IBM calculations of E0 transitions have been performed in order to further clarify the level scheme interpretation of 104,106Pd isotopes. A re-analysis of old ICE data on 104Pd has been performed with the intent to extend our study in the Palladium isotopic chain. The thesis is organized as follows: Chapter 1 introduces the general framework of this work, describing the nuclear observables relevant in the considered experiment, the theoretical models used in the description of the nuclei of interest, and the definition of nuclear shape coexistence phenomenon. The spectroscopic information obtained from the measurements of internal conversion electrons are presented in chapter 2, focusing on the experimental techniques involved in this thesis. Finally, a review of the current experimental and theoretical knowledge on the structure of even-even Pd isotopes is provided. Chapter 3 describes the experimental setup, starting from an overview of the SPES facility and its β-decay station, followed by a detailed description of the SLICES spectrometer components, with particular attention to the tests performed for the Si(Li) detector and the design of the magnetic transport system components. The commissioning experiment of SLICES is presented in chapter 4. Since this was the first experiment using SLICES, a detailed description of the setup implemented for the CN accelerator and of the controls developed in this work is provided. The data reduction and the comparison between the obtained results and previous measurements are presented. In chapter 5 the experimental results are interpreted by performing IBM calculations, followed by a description of the ground state and first excited 0+ state in the context of the two-level mixing model. Finally, the outcome of this work is summarized in Chapter 6

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Genome-wide interaction study of a proxy for stress-sensitivity and its prediction of major depressive disorder

Individual response to stress is correlated with neuroticism and is an important predictor of both neuroticism and the onset of major depressive disorder (MDD). Identification of the genetics underpinning individual differences in response to negative events (stress-sensitivity) may improve our understanding of the molecular pathways involved, and its association with stress-related illnesses. We sought to generate a proxy for stress-sensitivity through modelling the interaction between SNP allele and MDD status on neuroticism score in order to identify genetic variants that contribute to the higher neuroticism seen in individuals with a lifetime diagnosis of depression compared to unaffected individuals. Meta-analysis of genome-wide interaction studies (GWIS) in UK Biobank (N = 23,092) and Generation Scotland: Scottish Family Health Study (N = 7,155) identified no genome-wide significance SNP interactions. However, gene-based tests identified a genome-wide significant gene, ZNF366, a negative regulator of glucocorticoid receptor function implicated in alcohol dependence (p = 1.48x10-7; Bonferroni-corrected significance threshold p < 2.79x10-6). Using summary statistics from the stress-sensitivity term of the GWIS, SNP heritability for stress-sensitivity was estimated at 5.0%. In models fitting polygenic risk scores of both MDD and neuroticism derived from independent GWAS, we show that polygenic risk scores derived from the UK Biobank stress-sensitivity GWIS significantly improved the prediction of MDD in Generation Scotland. This study may improve interpretation of larger genome-wide association studies of MDD and other stress-related illnesses, and the understanding of the etiological mechanisms underpinning stress-sensitivity

Identification of common genetic risk variants for autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Evidence for Increased Genetic Risk Load for Major Depression in Patients Assigned to Electroconvulsive Therapy

Electroconvulsive therapy (ECT) is the treatment of choice for severe and treatment-resistant depression; disorder severity and unfavorable treatment outcomes are shown to be influenced by an increased genetic burden for major depression (MD). Here, we tested whether ECT assignment and response/nonresponse are associated with an increased genetic burden for major depression (MD) using polygenic risk score (PRS), which summarize the contribution of diseaserelated common risk variants. Fifty-one psychiatric inpatients suffering from a major depressive episode underwent ECT. MD-PRS were calculated for these inpatients and a separate population-based sample (n = 3,547 healthy; n = 426 self-reported depression) based on summary statistics from the Psychiatric Genomics Consortium MDD-working group (Cases: n = 59,851; Controls: n = 113,154). MD-PRS explained a significant proportion of disease status between ECT patients and healthy controls (p = .022, R2 = 1.173%); patients showed higher MD-PRS. MD-PRS in population-based depression self-reporters were intermediate between ECT patients and controls (n.s.). Significant associations between MD-PRS and ECT response (50% reduction in Hamilton depression rating scale scores) were not observed. Our findings indicate that ECT cohorts show an increased genetic burden for MD and are consistent with the hypothesis that treatment-resistant MD patients represent a subgroup with an increased genetic risk for MD. Larger samples are needed to better substantiate these findings

A phenome-wide association and Mendelian Randomisation study of polygenic risk for depression in UK Biobank.

Depression is a leading cause of worldwide disability but there remains considerable uncertainty regarding its neural and behavioural associations. Here, using non-overlapping Psychiatric Genomics Consortium (PGC) datasets as a reference, we estimate polygenic risk scores for depression (depression-PRS) in a discovery (N = 10,674) and replication (N = 11,214) imaging sample from UK Biobank. We report 77 traits that are significantly associated with depression-PRS, in both discovery and replication analyses. Mendelian Randomisation analysis supports a potential causal effect of liability to depression on brain white matter microstructure (β: 0.125 to 0.868, pFDR < 0.043). Several behavioural traits are also associated with depression-PRS (β: 0.014 to 0.180, pFDR: 0.049 to 1.28 × 10-14) and we find a significant and positive interaction between depression-PRS and adverse environmental exposures on mental health outcomes. This study reveals replicable associations between depression-PRS and white matter microstructure. Our results indicate that white matter microstructure differences may be a causal consequence of liability to depression

Association of whole-genome and NETRIN1 signaling pathway-derived polygenic risk scores for Major Depressive Disorder and white matter microstructure in UK Biobank

Background: Major depressive disorder is a clinically heterogeneous psychiatric disorder with a polygenic architecture. Genome-wide association studies have identified a number of risk-associated variants across the genome and have reported growing evidence of NETRIN1 pathway involvement. Stratifying disease risk by genetic variation within the NETRIN1 pathway may provide important routes for identification of disease mechanisms by focusing on a specific process, excluding heterogeneous risk-associated variation in other pathways. Here, we sought to investigate whether major depressive disorder polygenic risk scores derived from the NETRIN1 signaling pathway (NETRIN1-PRSs) and the whole genome, excluding NETRIN1 pathway genes (genomic-PRSs), were associated with white matter microstructure. Methods: We used two diffusion tensor imaging measures, fractional anisotropy (FA) and mean diffusivity (MD), in the most up-to-date UK Biobank neuroimaging data release (FA: n = 6401; MD: n = 6390). Results: We found significantly lower FA in the superior longitudinal fasciculus (β = −.035, p =.029) and significantly higher MD in a global measure of thalamic radiations (β =.029, p =.021), as well as higher MD in the superior (β =.034, p =.039) and inferior (β =.029, p =.043) longitudinal fasciculus and in the anterior (β =.025, p =.046) and superior (β =.027, p =.043) thalamic radiation associated with NETRIN1-PRS. Genomic-PRS was also associated with lower FA and higher MD in several tracts. Conclusions: Our findings indicate that variation in the NETRIN1 signaling pathway may confer risk for major depressive disorder through effects on a number of white matter tracts

Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns

Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike's information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk.Peer reviewe

Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression

Background The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a plausible explanation for the overlap, and in this study we tested whether genetic variation in the major histocompatibility complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression. Methods We fine-mapped the classical MHC (chr6: 29.6–33.1 Mb), imputing 216 human leukocyte antigen (HLA) alleles and 4 complement component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium Major Depressive Disorder Working Group and the UK Biobank. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants, applying both a region-wide significance threshold (3.9 × 10−6) and a candidate threshold (1.6 × 10−4). Results No HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold for testing in HLA genes in the meta-analysis (odds ratio = 0.98, 95 confidence interval = 0.97–0.99). Conclusions We found no evidence that an increased risk for depression was conferred by HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia. These results suggest that any HLA or C4 variants associated with depression either are rare or have very modest effect sizes