NGI is one of the largest technical platforms at SciLifeLab. We provide access to technology for sequencing, genotyping and associated bioinformatics support to researchers based in Sweden.
We're thrilled to announce that we have now transitioned to exclusively using the data delivery system Data Delivery System (DDS) for all our data deliveries. DDS will now be our default system, streamlining our processes and enhancing our service.
An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans
RA Scott, LJ Scott, R Mägi, L Marullo, KJ Gaulton, M Kaakinen, N Pervjakova, TH Pers, AD Johnson, JD Eicher, AU Jackson, T Ferreira, Y Lee, C Ma, V Steinthorsdottir, G Thorleifsson, L Qi, NR Van Zuydam, A Mahajan, H Chen, P Almgren, BF Voight, H Grallert, M Müller-Nurasyid, JS Ried, NW Rayner, N Robertson, LC Karssen, EM van Leeuwen, SM Willems, C Fuchsberger, P Kwan, TM Teslovich, P Chanda, M Li, Y Lu, C Dina, D Thuillier, L Yengo, L Jiang, T Sparso, HA Kestler, H Chheda, L Eisele, S Gustafsson, M Frånberg, RJ Strawbridge, R Benediktsson, AB Hreidarsson, A Kong, G Sigurðsson, ND Kerrison, J Luan, L Liang, T Meitinger, M Roden, B Thorand, T Esko, E Mihailov, C Fox, CT Liu, D Rybin, B Isomaa, V Lyssenko, T Tuomi, DJ Couper, JS Pankow, N Grarup, CT Have, ME Jørgensen, T Jørgensen, A Linneberg, MC Cornelis, RM van Dam, DJ Hunter, P Kraft, Q Sun, S Edkins, KR Owen, JRB Perry, AR Wood, E Zeggini, J Tajes-Fernandes, GR Abecasis, LL Bonnycastle, PS Chines, HM Stringham, HA Koistinen, L Kinnunen, B Sennblad, TW Mühleisen, MM Nöthen, S Pechlivanis, D Baldassarre, K Gertow, SE Humphries, E Tremoli, N Klopp, J Meyer, G Steinbach, R Wennauer, JG Eriksson, S Mӓnnistö, L Peltonen, E Tikkanen, G Charpentier, E Eury, S Lobbens, B Gigante, K Leander, O McLeod, EP Bottinger, O Gottesman, D Ruderfer, M Blüher, P Kovacs, A Tonjes, NM Maruthur, C Scapoli, R Erbel, KH Jöckel, S Moebus, U de Faire, A Hamsten, M Stumvoll, P Deloukas, PJ Donnelly, TM Frayling, AT Hattersley, S Ripatti, V Salomaa, NL Pedersen, BO Boehm, RN Bergman, FS Collins, KL Mohlke, J Tuomilehto, T Hansen, O Pedersen, I Barroso, L Lannfelt, E Ingelsson, L Lind, CM Lindgren, S Cauchi, P Froguel, RJF Loos, B Balkau, H Boeing, PW Franks, A Barricarte Gurrea, D Palli, YT van der Schouw, D Altshuler, LC Groop, C Langenberg, NJ Wareham, E Sijbrands, CM van Duijn, JC Florez, JB Meigs, E Boerwinkle, C Gieger, K Strauch, A Metspalu, AD Morris, CNA Palmer, FB Hu, U Thorsteinsdottir, K Stefansson, J Dupuis, AP Morris, M Boehnke, MI McCarthy, I Prokopenko
Diabetes, 66 (11) 1939-327X (2017)
The human bone marrow plasma cell compartment in rheumatoid arthritis - Clonal relationships and anti-citrulline autoantibody producing cells.
A Hensvold, B Horuluoglu, P Sahlström, R Thyagarajan, JS Diaz Boada, M Hansson, L Mathsson-Alm, C Gerstner, N Sippl, L Israelsson, R Wedin, J Steen, L Klareskog, B Réthi, AI Catrina, L Diaz-Gallo, V Malmström, C Grönwall
J. Autoimmun., 136 1095-9157 (2023)
A majority of circulating IgG is produced by plasma cells residing in the bone marrow (BM). Long-lived BM plasma cells constitute our humoral immune memory and are essential for infection-specific immunity. They may also provide a reservoir of potentially pathogenic autoantibodies, including rheumatoid arthritis (RA)-associated anti-citrullinated protein autoantibodies (ACPA). Here we investigated paired human BM plasma cell and peripheral blood (PB) B-cell repertoires in seropositive RA, four ACPA+ RA patients and one ACPA- using two different single-cell approaches, flow cytometry sorting, and transcriptomics, followed by recombinant antibody generation. Immunoglobulin (Ig) analysis of >900 paired heavy-light chains from BM plasma cells identified by either surface CD138 expression or transcriptome profiles (including gene expression of MZB1, JCHAIN and XBP1) demonstrated differences in IgG/A repertoires and N-linked glycosylation between patients. For three patients, we identified clonotypes shared between BM plasma cells and PB memory B cells. Notably, four individuals displayed plasma cells with identical heavy chains but different light chains, which may indicate receptor revision or clonal convergence. ACPA-producing BM plasma cells were identified in two ACPA+ patients. Three of 44 recombinantly expressed monoclonal antibodies from ACPA+ RA BM plasma cells were CCP2+, specifically binding to citrullinated peptides. Out of these, two clones reacted with citrullinated histone-4 and activated neutrophils. In conclusion, single-cell investigation of B-cell repertoires in RA bone marrow provided new understanding of human plasma cells clonal relationships and demonstrated pathogenically relevant disease-associated autoantibody expression in long-lived plasma cells.
Asthma and affective traits in adults: a genetically informative study.
K Lehto, NL Pedersen, C Almqvist, Y Lu, BK Brew
Eur. Respir. J., 53 (5) 1399-3003 (2019)
Depression, anxiety and high neuroticism (affective traits) are often comorbid with asthma. A causal direction between the affective traits and asthma is difficult to determine; however, there may be a common underlying pathway attributable to shared genetic factors. Our aim was to determine whether a common genetic susceptibility exists for asthma and each of the affective traits.An adult cohort from the Swedish Twin Registry underwent questionnaire-based health assessments (n=23 693) and genotyping (n=15 908). Firstly, questionnaire-based associations between asthma and affective traits were explored. This was followed by genetic analyses: 1) polygenic risk scores (PRS) for affective traits were used as predictors of asthma in the cohort, and 2) genome-wide association results from UK Biobank were used in linkage-disequilibrium score regression (LDSC) to quantify genetic correlations between asthma and affective traits. Analyses found associations between questionnaire-based asthma and affective traits (OR 1.67, 95% CI 1.50-1.86 major depression; OR 1.45, 95% CI 1.30-1.61 anxiety; and OR 1.60, 95% CI 1.40-1.82 high neuroticism). Genetic susceptibility for neuroticism explained the variance in asthma with a dose-response effect; that is, study participants in the highest neuroticism PRS quartile were more likely to have asthma than those in the lowest quartile (OR 1.37, 95% CI 1.17-1.61). Genetic correlations were found between depression and asthma (r g=0.17), but not for anxiety or neuroticism.We conclude that the observed comorbidity between asthma and the affective traits may in part be due to shared genetic influences between asthma and depression (LDSC) and neuroticism (PRS), but not anxiety.
Integrated single cell and spatial transcriptomics reveal autoreactive differentiated B cells in joints of early rheumatoid arthritis.
U Hardt, K Carlberg, E Af Klint, P Sahlström, L Larsson, A van Vollenhoven, S Hernandez Machado, L Israelsson, K Amara, K Chemin, M Korotkova, GB Karlsson Hedestam, AI Catrina, SA Teichmann, PL Ståhl, V Malmström
Sci Rep, 12 (1) 2045-2322 (2022)
B cells play a significant role in established Rheumatoid Arthritis (RA). However, it is unclear to what extent differentiated B cells are present in joint tissue already at the onset of disease. Here, we studied synovial biopsies (n = 8) captured from untreated patients at time of diagnosis. 3414 index-sorted B cells underwent RNA sequencing and paired tissue pieces were subjected to spatial transcriptomics (n = 4). We performed extensive bioinformatics analyses to dissect the local B cell composition. Select plasma cell immunoglobulin sequences were expressed as monoclonal antibodies and tested by ELISA. Memory and plasma cells were found irrespective of autoantibody status of the patients. Double negative memory B cells were prominent, but did not display a distinct transcriptional profile. The tissue architecture implicate both local B cell maturation via T cell help and plasma cell survival niches with a strong CXCL12-CXCR4 axis. The immunoglobulin sequence analyses revealed clonality between the memory B and plasma cell pools further supporting local maturation. One of the plasma cell-derived antibodies displayed citrulline autoreactivity, demonstrating local autoreactive plasma cell differentiation in joint biopsies captured from untreated early RA. Hence, plasma cell niches are not a consequence of chronic inflammation, but are already present at the time of diagnosis.
Divergence in Coding Sequence and Expression of Different Functional Categories of Immune Genes between Two Wild Rodent Species.
X Zhong, M Lundberg, L Råberg
Genome Biol Evol, 13 (3) 1759-6653 (2021)
Differences in immune function between species could be a result of interspecific divergence in coding sequence and/or expression of immune genes. Here, we investigate how the degree of divergence in coding sequence and expression differs between functional categories of immune genes, and if differences between categories occur independently of other factors (expression level, pleiotropy). To this end, we compared spleen transcriptomes of wild-caught yellow-necked mice and bank voles. Immune genes expressed in the spleen were divided into four categories depending on the function of the encoded protein: pattern recognition receptors (PRR); signal transduction proteins; transcription factors; and cyto- and chemokines and their receptors. Genes encoding PRR and cyto-/chemokines had higher sequence divergence than genes encoding signal transduction proteins and transcription factors, even when controlling for potentially confounding factors. Genes encoding PRR also had higher expression divergence than genes encoding signal transduction proteins and transcription factors. There was a positive correlation between expression divergence and coding sequence divergence, in particular for PRR genes. We propose that this is a result of that divergence in PRR coding sequence leads to divergence in PRR expression through positive feedback of PRR ligand binding on PRR expression. When controlling for sequence divergence, expression divergence of PRR genes did not differ from other categories. Taken together, the results indicate that coding sequence divergence of PRR genes is a major cause of differences in immune function between species.
Novel PNKP mutations associated with reduced DNA single-strand break repair and severe microcephaly, seizures, and developmental delay.
A Thuresson, J Brazina, T Akram, J Albrecht, N Dahl, C Soussi Zander, KW Caldecott
Mol Genet Genomic Med, 2324-9269 (2023)
Microcephaly with early-onset seizures (MCSZ) is a neurodevelopmental disorder caused by pathogenic variants in the DNA strand break repair protein, polynucleotide kinase 3'-phosphatase (PNKP).
We have used whole genome sequencing and Sanger sequencing to identify disease-causing variants, followed by a minigene assay, Western blotting, alkaline comet assay, γH2AX, and ADP-ribose immunofluorescence.
Here, we describe a patient with compound heterozygous variants in PNKP, including a missense variant in the DNA phosphatase domain (T323M) and a novel splice acceptor site variant within the DNA kinase domain that we show leads to exon skipping. We show that primary fibroblasts derived from the patient exhibit greatly reduced levels of PNKP protein and reduced rates of DNA single-strand break repair, confirming that the mutated PNKP alleles are dysfunctional.
The data presented show that the detected compound heterozygous variants result in reduced levels of PNKP protein, which affect the repair of both oxidative and TOP1-induced single-strand breaks, and most likely causes MCSZ in this patient.
The Swedish childhood tumor biobank: systematic collection and molecular characterization of all pediatric CNS and other solid tumors in Sweden.
T Díaz de Ståhl, A Shamikh, M Mayrhofer, S Juhos, E Basmaci, G Prochazka, M Garcia, PR Somarajan, K Zielinska-Chomej, C Illies, I Øra, P Siesjö, P Sandström, J Stenman, M Sabel, B Gustavsson, P Kogner, S Pfeifer, G Ljungman, J Sandgren, M Nistér
The Swedish Childhood Tumor Biobank (BTB) is a nonprofit national infrastructure for collecting tissue samples and genomic data from pediatric patients diagnosed with central nervous system (CNS) and other solid tumors. The BTB is built on a multidisciplinary network established to provide the scientific community with standardized biospecimens and genomic data, thereby improving knowledge of the biology, treatment and outcome of childhood tumors. As of 2022, over 1100 fresh-frozen tumor samples are available for researchers. We present the workflow of the BTB from sample collection and processing to the generation of genomic data and services offered. To determine the research and clinical utility of the data, we performed bioinformatics analyses on next-generation sequencing (NGS) data obtained from a subset of 82 brain tumors and patient blood-derived DNA combined with methylation profiling to enhance the diagnostic accuracy and identified germline and somatic alterations with potential biological or clinical significance. The BTB procedures for collection, processing, sequencing, and bioinformatics deliver high-quality data. We observed that the findings could impact patient management by confirming or clarifying the diagnosis in 79 of the 82 tumors and detecting known or likely driver mutations in 68 of 79 patients. In addition to revealing known mutations in a broad spectrum of genes implicated in pediatric cancer, we discovered numerous alterations that may represent novel driver events and specific tumor entities. In summary, these examples reveal the power of NGS to identify a wide number of actionable gene alterations. Making the power of NGS available in healthcare is a challenging task requiring the integration of the work of clinical specialists and cancer biologists; this approach requires a dedicated infrastructure, as exemplified here by the BTB.
Last Updated: 25th February 2024
This website uses cookies to improve your experience. AcceptRead More
Privacy & Cookies Policy
Privacy Overview
This website uses cookies to improve your experience while you navigate through the website. Out of these, the cookies that are categorized as necessary are stored on your browser as they are essential for the working of basic functionalities of the website. We also use third-party cookies that help us analyze and understand how you use this website. These cookies will be stored in your browser only with your consent. You also have the option to opt-out of these cookies. But opting out of some of these cookies may affect your browsing experience.
Necessary cookies are absolutely essential for the website to function properly. This category only includes cookies that ensures basic functionalities and security features of the website. These cookies do not store any personal information.
Any cookies that may not be particularly necessary for the website to function and is used specifically to collect user personal data via analytics, ads, other embedded contents are termed as non-necessary cookies. It is mandatory to procure user consent prior to running these cookies on your website.