Genetic correlates of vitamin D-binding protein and 25-hydroxyvitamin D in neonatal dried blood spots

The vitamin D binding protein (DBP), encoded by the group-specific component (GC) gene, is a component of the vitamin D system. In a genome-wide association study of DBP concentration in 65,589 neonates we identify 26 independent loci, 17 of which are in or close to the GC gene, with fine-mapping identifying 2 missense variants on chromosomes 12 and 17 (within SH2B3 and GSDMA, respectively). When adjusted for GC haplotypes, we find 15 independent loci distributed over 10 chromosomes. Mendelian randomization analyses identify a unidirectional effect of higher DBP concentration and (a) higher 25-hydroxyvitamin D concentration, and (b) a reduced risk of multiple sclerosis and rheumatoid arthritis. A phenome-wide association study confirms that higher DBP concentration is associated with a reduced risk of vitamin D deficiency. Our findings provide valuable insights into the influence of DBP on vitamin D status and a range of health outcomes

Publisher Correction: Genetic correlates of vitamin D-binding protein and 25-hydroxyvitamin D in neonatal dried blood spots

Correction to "Genetic correlates of vitamin D-binding protein and 25-hydroxyvitamin D in neonatal dried blood spots

Genetic, clinical and socio-demographic factors associated with stimulant-treatment outcomes in ADHD

Objective: Stimulant medications are effective for treating attention deficit hyperactivity disorder (ADHD), yet discontinuation and switch to nonstimulant ADHD medications are common. This study aimed to identify genetic, clinical, and sociodemographic factors influencing stimulant treatment initiation, discontinuation, and switch to nonstimulants in individuals with ADHD. Methods: The authors obtained genetic and national register data for 9,133 individuals with ADHD from the Danish iPSYCH2012 sample and defined stimulant treatment initiation, discontinuation, and switch from prescriptions. For each stimulant treatment outcome, they examined associations with polygenic risk scores (PRSs) for psychiatric disorders and clinical and sociodemographic factors using survival analyses, and conducted genome-wide association studies (GWASs) and estimated single-nucleotide polymorphism heritability (h2SNP). Results: Eighty-one percent of the sample initiated stimulant treatment. Within 2 years, 45% discontinued stimulants and 15% switched to nonstimulants. Bipolar disorder PRS (hazard ratio=1.05, 95% CI=1.02, 1.09) and schizophrenia PRS (hazard ratio=1.07, 95% CI=1.03, 1.11) were associated with discontinuation. Depression, bipolar disorder, and schizophrenia PRSs were marginally but not significantly associated with switch (hazard ratio range, 1.05–1.07). No associations were observed for ADHD and autism PRSs. Individuals diagnosed with ADHD at age 13 or older had higher rates of stimulant initiation, discontinuation, and switch (hazard ratio range, 1.27–2.01). Psychiatric comorbidities generally reduced rates of initiation (hazard ratio range, 0.84–0.88) and increased rates of discontinuation (hazard ratio range, 1.19–1.45) and switch (hazard ratio range, 1.40–2.08). h2SNP estimates were not significantly different from zero. No GWAS hits were identified for stimulant initiation or discontinuation. A locus on chromosome 16q23.3 reached genome-wide significance for switch. Conclusions: The study findings suggest that individuals with ADHD with higher polygenic liability for mood and/or psychotic disorders, delayed ADHD diagnosis, and psychiatric comorbidities have a higher risk for stimulant treatment discontinuation and switch to nonstimulants. Despite the study’s limited sample size, one putative GWAS hit for switch was identified, illustrating the potential of utilizing genomics linked to prescription databases to advance ADHD pharmacogenomics

Postpartum and non-postpartum depression: a population-based matched case-control study comparing polygenic risk scores for severe mental disorders

It remains inconclusive whether postpartum depression (PPD) and depression with onset outside the postpartum period (MDD) are genetically distinct disorders. We aimed to investigate whether polygenic risk scores (PGSs) for major mental disorders differ between PPD cases and MDD cases in a nested case-control study of 50,057 women born from 1981 to 1997 in the iPSYCH2015 sample in Demark. We identified 333 women with first-onset postpartum depression (PPD group), who were matched with 993 women with first-onset depression diagnosed outside of postpartum (MDD group), and 999 female population controls. Data on genetics and depressive disorders were retrieved from neonatal biobanks and the Psychiatric Central Research Register. PGSs were calculated from both individual-level genetic data and meta-analysis summary statistics from the Psychiatric Genomics Consortium. Conditional logistic regression was used to calculate the odds ratio (OR), accounting for the selection-related reproductive behavior. After adjustment for covariates, higher PGSs for severe mental disorders were associated with increased ORs of both PPD and MDD. Compared with MDD cases, MDD PGS and attention-deficit/hyperactivity disorder PGS were marginally but not statistically higher for PPD cases, with the OR of PPD versus MDD being 1.12 (95% CI: 0 .97–1.29) and 1.11 (0.97–1.27) per-standard deviation increase, respectively. The ORs of PPD versus MDD did not statistically differ by PGSs of bipolar disorder, schizophrenia, or autism spectrum disorder. Our findings suggest that relying on PGS data, there was no clear evidence of distinct genetic make-up of women with depression occurring during or outside postpartum, after taking the selection-related reproductive behavior into account

Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth

A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n = 65,405), maternal (n = 61,228) and paternal (n = 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth

Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth

A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n = 65,405), maternal (n = 61,228) and paternal (n = 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth

CIBERER: Spanish national network for research on rare diseases: A highly productive collaborative initiative

13 páginas,1 figura, 3 tablas, 1 apéndice. Se extraen los autores pertenecientes a The CIBERER network que trabajan en Centros del CSIC del Appendix ACIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research.This study has been funded by Instituto de Salud Carlos III (ISCIII) and Spanish Ministry of Science and InnovationPeer reviewe

Functional effects of the genetic manipulation of the phosphorylation state of the Target of Rapamycin effector Npr1

[EN] The plasma membrane of eukaryotic cells is under constant remodelation of its receptor and transport proteins due to the changing needs of the cell to maintain its viability and for adapting to its environment. The flux of amino acids and other nutritional compounds transported into the cell depends on membrane protein transporters known as permeases. Opposing and parallel mechanisms of endocytosis of existing permeases and delivery of new ones determine the amount and collection of permeases present in the cell at any given time. The endocytosis and subsequent degradation of these permeases is regulated by post-translational modifications in which ubiquitination plays a fundamental role. The TORC1 kinase complex (Target Of Rapamycin) acts as a signal transducer for ubiquitin-mediated endocytosis, among other functions. Rsp5 is a HECT family E3 ubiquitin-ligase in S. cerevisiae which is responsible for the ubiquitination of the majority of nutrient and amino acid permeases. The interaction is done via adaptor proteins, many of which belong to the ART family (arrestin related trafficking adaptors). These adaptors determine the Rsp5 specificity for the membrane permeases. Npr1 kinase is one of the targets of phosphorylation of TORC1 and has been identified as the effector kinase responsible for the signal transduction to the ARTs. Npr1 phosphorylation of Art1 directly results in the inhibition of Rsp5-mediated endocytosis of permeases. Art3 has also been described as a substrate for Npr1. Our recent preliminary data shows that Npr1 binds physically to Art3. However, the role of Npr1 in Art3 regulation is still unclear. This project aims to observe the functional effects of the state of phosphorylation of Npr1. For that purpose, the Npr1 hypophosphorylation and hyperphosphorylation states have been artificially recreated by chemical treatments (rapamycin) or by genetic manipulation, using mutants of different phosphatases and kinases implied. Employing this experimental set-up, we will determine whether a correlation exists between the Npr1 phospho-state and three different outputs: 1) Npr1 binding to the Art3 alpha-arrestin, 2) the subcellular localization of Npr1 itself and 3) the subcellular localization of membrane permeases.[CA] El comportament dels microorganismes està basat en optimitzar el seu creixement i maximitzar la seua supervivència. Estes cèl•lules tenen la capacitat d’avaluar la quantitat i qualitat de nutrients disponibles i d’ajustar consegüentment els seus perfils transcripcionals, metabòlics i de desenvolupament per proporcionar el conjunt apropiat de les proteïnes responsables del consum, transport i processament dels nutrients. La ruta de senyalització TORC1 (Target Of Rapamycin Complex 1), o complex diana de la rapamicina, és un controlador central del creixement cel•lular i és en gran part responsable de la coordinació de la resposta cel•lular als canvis en la font i la disponibilitat del nitrogen. El flux d’aminoàcids i altres compostos nitrogenats transportats cap a l’interior cel•lular depèn d’uns transportadors de membrana anomenats permeases. Els mecanismes oposats i en paral•lel d’endocitosis de permeases existents i el lliurament de noves determinen la quantitat i diversitat d’estes proteïnes a la membrana plasmàtica en cada moment. L’endocitosi i subsegüent degradació d’estes permeases és regulat per modificacions post-traduccionals, on la ubiquitinació juga un paper fonamental. Rsp5 és una E3 ubiquitina ligasa de S. cerevisiae de la família HECT responsable de la ubiquitinació de la majoria de les permeases dels nutrients i aminoàcids. La interacció es dóna via proteïnes adaptadores, on moltes de les quals pertanyen a la família ART (arrestin-related trafficking) o proteïnes adaptadores de tràfic relacionades amb arrestina. Estos adaptadors determinen l’especificitat de Rsp5 per les permeases de membrana. Npr1 és una de les dianes de fosforilació de TORC1 i promou l’activitat de diversos sistemes de transport de nutrients nitrogenats. S’ha identificat com la quinasa efectora de TORC1 és responsable de la transducció del senyal a les ARTs. Específicament, s’ha demostrat que Npr1 fosfoinhibeix directament a Art1, el qual resulta en la inhibició de l’endocitosi de permeases mediada per Rsp5. A més, Npr1 també és capaç d’unir-se i fosforilar Art3, encara que les conseqüències d’aquesta regulació encara no s’han establert. L’activitat de Npr1 es regula a través del seu estat de fosforilació, estant actiu quan es troba desfosforilat i inactiu quan es troba fosforilat. En aquest projecte s’ha intentat arribar més lluny en l’exploració d’este particular mecanisme depenent de TORC1 d’ubiquitinació mediada per les ARTs i de la subsegüent endocitosi de transportadors de nutrients fent la hipòtesi on l’estat de fosforilació de Npr1 es correlaciona amb la seua funcionalitat en el context d’aquest procés. La hipòtesi va ser explorada utilitzant diferents plantejaments experimentals per a analitzar un conjunt de cepes mutants en les quals s’havia descrit un efecte permanent en l’estat de fosforilació de Npr1.Albiñana Climent, C. (2016). Functional effects of the genetic manipulation of the phosphorylation state of the Target of Rapamycin effector Npr1. http://hdl.handle.net/10251/68618.TFG

Inferring disease architecture and predictive ability with LDpred2-auto.

LDpred2 is a widely used Bayesian method for building polygenic scores (PGSs). LDpred2-auto can infer the two parameters from the LDpred model, the SNP heritability h2 and polygenicity p, so that it does not require an additional validation dataset to choose best-performing parameters. The main aim of this paper is to properly validate the use of LDpred2-auto for inferring multiple genetic parameters. Here, we present a new version of LDpred2-auto that adds an optional third parameter α to its model, for modeling negative selection. We then validate the inference of these three parameters (or two, when using the previous model). We also show that LDpred2-auto provides per-variant probabilities of being causal that are well calibrated and can therefore be used for fine-mapping purposes. We also introduce a formula to infer the out-of-sample predictive performance r2 of the resulting PGS directly from the Gibbs sampler of LDpred2-auto. Finally, we extend the set of HapMap3 variants recommended to use with LDpred2 with 37% more variants to improve the coverage of this set, and we show that this new set of variants captures 12% more heritability and provides 6% more predictive performance, on average, in UK Biobank analyses