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Sökning: WFRF:(Hammer Christian)

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  • Huckins, Laura M., et al. (författare)
  • Gene expression imputation across multiple brain regions provides insights into schizophrenia risk
  • 2019
  • Ingår i: Nature genetics. - 1546-1718. ; 51:4, s. 659-
  • Tidskriftsartikel (refereegranskat)abstract
    • Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression.
  • Ripke, Stephan, et al. (författare)
  • Biological insights from 108 schizophrenia-associated genetic loci
  • 2014
  • Ingår i: Nature. - 0028-0836. ; 511:7510, s. 421-427
  • Tidskriftsartikel (refereegranskat)abstract
    • Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.
  • Scepanovic, Petar, et al. (författare)
  • Human genetic variants and age are the strongest predictors of humoral immune responses to common pathogens and vaccines
  • 2018
  • Ingår i: Genome Medicine. - BioMed Central. - 1756-994X. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Humoral immune responses to infectious agents or vaccination vary substantially among individuals, and many of the factors responsible for this variability remain to be defined. Current evidence suggests that human genetic variation influences (i) serum immunoglobulin levels, (ii) seroconversion rates, and (iii) intensity of antigen-specific immune responses. Here, we evaluated the impact of intrinsic (age and sex), environmental, and genetic factors on the variability of humoral response to common pathogens and vaccines. Methods: We characterized the serological response to 15 antigens from common human pathogens or vaccines, in an age- and sex-stratified cohort of 1000 healthy individuals (Milieu Intérieur cohort). Using clinical-grade serological assays, we measured total IgA, IgE, IgG, and IgM levels, as well as qualitative (serostatus) and quantitative IgG responses to cytomegalovirus, Epstein-Barr virus, herpes simplex virus 1 and 2, varicella zoster virus, Helicobacter pylori, Toxoplasma gondii, influenza A virus, measles, mumps, rubella, and hepatitis B virus. Following genome-wide genotyping of single nucleotide polymorphisms and imputation, we examined associations between ~5 million genetic variants and antibody responses using single marker and gene burden tests. Results: We identified age and sex as important determinants of humoral immunity, with older individuals and women having higher rates of seropositivity for most antigens. Genome-wide association studies revealed significant associations between variants in the human leukocyte antigen (HLA) class II region on chromosome 6 and anti-EBV and anti-rubella IgG levels. We used HLA imputation to fine map these associations to amino acid variants in the peptide-binding groove of HLA-DRβ1 and HLA-DPβ1, respectively. We also observed significant associations for total IgA levels with two loci on chromosome 2 and with specific KIR-HLA combinations. Conclusions: Using extensive serological testing and genome-wide association analyses in a well-characterized cohort of healthy individuals, we demonstrated that age, sex, and specific human genetic variants contribute to inter-individual variability in humoral immunity. By highlighting genes and pathways implicated in the normal antibody response to frequently encountered antigens, these findings provide a basis to better understand disease pathogenesis.
  • Hansen, Madlen, et al. (författare)
  • Macrophage Phosphoproteome Analysis Reveals MINCLE-dependent and -independent Mycobacterial Cord Factor Signaling.
  • 2019
  • Ingår i: Molecular & cellular proteomics : MCP. - 1535-9484. ; 18:4, s. 669-685
  • Tidskriftsartikel (refereegranskat)abstract
    • Immune sensing of Mycobacterium tuberculosis relies on recognition by macrophages. Mycobacterial cord factor, trehalose-6,6'-dimycolate (TDM), is the most abundant cell wall glycolipid and binds to the C-type lectin receptor (CLR) MINCLE. To explore the kinase signaling linking the TDM-MINCLE interaction to gene expression, we employed quantitative phosphoproteome analysis. TDM caused upregulation of 6.7% and suppressed 3.8% of the 14,000 phospho-sites identified on 3727 proteins. MINCLE-dependent phosphorylation was observed for canonical players of CLR signaling (e.g. PLCγ, PKCδ), and was enriched for PKCδ and GSK3 kinase motifs. MINCLE-dependent activation of the PI3K-AKT-GSK3 pathway contributed to inflammatory gene expression and required the PI3K regulatory subunit p85α. Unexpectedly, a substantial fraction of TDM-induced phosphorylation was MINCLE-independent, a finding paralleled by transcriptome data. Bioinformatics analysis of both data sets concurred in the requirement for MINCLE for innate immune response pathways and processes. In contrast, MINCLE-independent phosphorylation and transcriptome responses were linked to cell cycle regulation. Collectively, our global analyses show substantial reprogramming of macrophages by TDM and reveal a dichotomy of MINCLE-dependent and -independent signaling linked to distinct biological responses.
  • Karmin, Monika, et al. (författare)
  • A recent bottleneck of Y chromosome diversity coincides with a global change in culture.
  • 2015
  • Ingår i: Genome Research. - 1088-9051 .- 1549-5469. ; 25:4
  • Tidskriftsartikel (refereegranskat)abstract
    • It is commonly thought that human genetic diversity in non-African populations was shaped primarily by an out-of-Africa dispersal 50-100 thousand yr ago (kya). Here, we present a study of 456 geographically diverse high-coverage Y chromosome sequences, including 299 newly reported samples. Applying ancient DNA calibration, we date the Y-chromosomal most recent common ancestor (MRCA) in Africa at 254 (95% CI 192-307) kya and detect a cluster of major non-African founder haplogroups in a narrow time interval at 47-52 kya, consistent with a rapid initial colonization model of Eurasia and Oceania after the out-of-Africa bottleneck. In contrast to demographic reconstructions based on mtDNA, we infer a second strong bottleneck in Y-chromosome lineages dating to the last 10 ky. We hypothesize that this bottleneck is caused by cultural changes affecting variance of reproductive success among males.
  • Patin, Etienne, et al. (författare)
  • Natural variation in the parameters of innate immune cells is preferentially driven by genetic factors
  • 2018
  • Ingår i: Nature Immunology. - Nature Publishing Group. - 1529-2908. ; 19, s. 302-314
  • Tidskriftsartikel (refereegranskat)abstract
    • The quantification and characterization of circulating immune cells provide key indicators of human health and disease. To identify the relative effects of environmental and genetic factors on variation in the parameters of innate and adaptive immune cells in homeostatic conditions, we combined standardized flow cytometry of blood leukocytes and genome-wide DNA genotyping of 1,000 healthy, unrelated people of Western European ancestry. We found that smoking, together with age, sex and latent infection with cytomegalovirus, were the main non-genetic factors that affected variation in parameters of human immune cells. Genome-wide association studies of 166 immunophenotypes identified 15 loci that showed enrichment for disease-associated variants. Finally, we demonstrated that the parameters of innate cells were more strongly controlled by genetic variation than were those of adaptive cells, which were driven by mainly environmental exposure. Our data establish a resource that will generate new hypotheses in immunology and highlight the role of innate immunity in susceptibility to common autoimmune diseases.
  • Pertold, Cino, et al. (författare)
  • Prevalence of skull pathologies in European harbor seals (Phoca vitulina) during 1981–2014
  • 2018
  • Ingår i: Mammal Research. - 2199-2401 .- 2199-241X. ; 63:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Harbor seals (Phoca vitulina) inhabit the seas surrounding Denmark and are an important top predator in the marine food chain. This trophic position exposes them to environmental contaminants with disease epi- demics and hunting being additional threats to this popu- lation. It is therefore important to study how environmen- tal pollution at the current order of magnitude affects the health of the population. Earlier studies have shown that occurrence of periodontitis could be linked to the amount of pollution the seals were subjected to. In order to inves- tigate this further, 380 skulls and 141 mandibles of harbor seals (Phoca vitulina) from the Wadden Sea, the Limfjord, and Kattegat collected during the period 1970–2014 were examined. The skulls were examined for pathological le- sions. The Hounsfield Units (HU) which are correlated to the bone mineral density (BMD) were measured in a sub- sample (n= 34) using CT scans. The macroscopic examination revealed (with the exception of the Swedish part of Kattegat) a significant increase of pathological lesions over the study period of 1981–2014. The exami- nation of HU showed that median HU measured at mul- tiple sites was highest in the healthy skulls compared to the skulls with one or more of the lesions. A discriminant analysis allowed high discriminatory capacity to separate healthy skulls from the skulls with pathologies, simply by the utilization of the HU data. Former studies of BMD in marine mammals have shown that exposure to environ- mental chemicals alter BMD and cause periodontitis. The present study, based on temporal and spatial trends in BMD, confirms the results of previous studies Prevalence of skull pathologies in European harbor seals (Phoca vitulina) during 1981–2014 (PDF Download Available). Available from: https://www.researchgate.net/publication/320586176_Prevalence_of_skull_pathologies_in_European_harbor_seals_Phoca_vitulina_during_1981-2014 [accessed Dec 15 2017].
  • RYBERG, EMIL, 1987-, et al. (författare)
  • Constraining low-energy proton capture on beryllium-7 through charge radius measurements
  • 2014
  • Ingår i: Ab initio approach to nuclear structure and reactions (++) (ANSR).
  • Tidskriftsartikel (refereegranskat)abstract
    • In this paper, we point out that a measurement of the charge radius of boron-8 provides indirect access to the S-factor for radiative proton capture on beryllium-7 at low energies. We use leading-order halo effective field theory to explore this correlation and we give a relation between the charge radius and the S-factor. Furthermore, we present important technical aspects relevant to the renormalization of point-like P -wave interactions in the presence of a repulsive Coulomb interaction.
  • RYBERG, EMIL, 1987-, et al. (författare)
  • Effective field theory for proton halo nuclei
  • 2014
  • Ingår i: Ab initio approach to nuclear structure and reactions (++) (ANSR).
  • Tidskriftsartikel (refereegranskat)abstract
    • We use halo effective field theory to analyze the universal features of proton halo nuclei bound due to a large S-wave scattering length. Our work provides a fully field-theoretical treatment of bound halo nuclei in the presence of a repulsive Coulomb interaction. With a Lagrangian built from effective core and valence-proton fields, we derive a leading-order expression for the charge form factor. Within the same framework we also calculate the radiative proton capture cross section. We present general results at leading order that can be applied to any one-proton halo system bound in a relative S wave. We illustrate the method by studying the excited 1/2(+) state of fluorine 17, for which we give results for the charge radius and the astrophysical S factor.
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