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  • 1. Acevedo, Nathalie
    et al.
    Benfeitas, Rui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Katayama, Shintaro
    Bruhn, Sören
    Andersson, Anna
    Wikberg, Gustav
    Lundeberg, Lena
    Lindvall, Jessica M.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Greco, Dario
    Kere, Juha
    Söderhäll, Cilla
    Scheynius, Annika
    Epigenetic alterations in skin homing CD4(+)CLA(+) T cells of atopic dermatitis patients2020In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 18020Article in journal (Refereed)
    Abstract [en]

    T cells expressing the cutaneous lymphocyte antigen (CLA) mediate pathogenic inflammation in atopic dermatitis (AD). The molecular alterations contributing to their dysregulation remain unclear. With the aim to elucidate putative altered pathways in AD we profiled DNA methylation levels and miRNA expression in sorted T cell populations -(CD4(+), -CD4(+)CD45RA(+) naive, -CD4(+)CLA(+), and -CD8(+)) from adult AD patients and healthy controls (HC). Skin homing -CD4(+)CLA(+) T cells from AD patients showed significant differences in DNA methylation in 40 genes compared to HC (p < 0.05). Reduced DNA methylation levels in the upstream region of the interleukin-13 gene (IL13) in -CD4(+)CLA(+) T cells from AD patients correlated with increased IL13 mRNA expression in these cells. Sixteen miRNAs showed differential expression in -CD4(+)CLA(+) T cells from AD patients targeting genes in 202 biological processes (p < 0.05). An integrated network analysis of miRNAs and CpG sites identified two communities of strongly interconnected regulatory elements with strong antagonistic behaviours that recapitulated the differences between AD patients and HC. Functional analysis of the genes linked to these communities revealed their association with key cytokine signaling pathways, MAP kinase signaling and protein ubiquitination. Our findings support that epigenetic mechanisms play a role in the pathogenesis of AD by affecting inflammatory signaling molecules in skin homing -CD4(+)CLA(+) T cells and uncover putative molecules participating in AD pathways.

  • 2. Acevedo, Nathalie
    et al.
    Bornacelly, Adriana
    Mercado, Dilia
    Unneberg, Per
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Mittermann, Irene
    Valenta, Rudolf
    Kennedy, Malcolm
    Scheynius, Annika
    Caraballo, Luis
    Genetic Variants in CHIA and CHI3L1 Are Associated with the IgE Response to the Ascaris Resistance Marker ABA-1 and the Birch Pollen Allergen Bet v 12016In: plos one, ISSN 1932-6203, Vol. 11, no 12, article id e0167453Article in journal (Refereed)
    Abstract [en]

    Helminth infections and allergic diseases are associated with IgE hyperresponsiveness but the genetics of this phenotype remain to be defined. Susceptibility to Ascaris lumbricoides infection and antibody levels to this helminth are associated with polymorphisms in locus 13q33-34. We aimed to explore this and other genomic regions to identify genetic variants associated with the IgE responsiveness in humans. Forty-eight subjects from Cartagena, Colombia, with extreme values of specific IgE to Ascaris and ABA-1, a resistance marker of this nematode, were selected for targeted resequencing. Burden analyses were done comparing extreme groups for IgE values. One-hundred one SNPs were genotyped in 1258 individuals of two well-characterized populations from Colombia and Sweden. Two low-frequency coding variants in the gene encoding the Acidic Mammalian Chitinase (CHIA rs79500525, rs139812869, tagged by rs10494133) were found enriched in high IgE responders to ABA-1 and confirmed by genetic association analyses. The SNP rs4950928 in the Chitinase 3 Like 1 gene (CHI3L1) was associated with high IgE to ABA-1 in Colombians and with high IgE to Bet v 1 in the Swedish population. CHIA rs10494133 and ABDH13 rs3783118 were associated with IgE responses to Ascaris. SNPs in the Tumor Necrosis Factor Superfamily Member 13b gene (TNFSF13B) encoding the cytokine B cell activating Factor were associated with high levels of total IgE in both populations. This is the first report on the association between low-frequency and common variants in the chitinases- related genes CHIA and CHI3L1 with the intensity of specific IgE to ABA-1 in a population naturally exposed to Ascaris and with Bet v 1 in a Swedish population. Our results add new information about the genetic influences of human IgE responsiveness; since the genes encode for enzymes involved in the immune response to parasitic infections, they could be helpful for understanding helminth immunity and allergic responses. We also confirmed that TNFSF13B has an important and conserved role in the regulation of total IgE levels, which supports potential evolutionary links between helminth immunity and allergic response.

  • 3. Aho, Vilma
    et al.
    Ollila, Hanna M.
    Rantanen, Ville
    Kronholm, Erkki
    Surakka, Ida
    van Leeuwen, Wessel M. A.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. University of Helsinki, Finland; Finnish Institute of Occupational Health, Finland.
    Lehto, Maili
    Matikainen, Sampsa
    Ripatti, Samuli
    Härmä, Mikko
    Sallinen, Mikael
    Salomaa, Veikko
    Jauhiainen, Matti
    Alenius, Harri
    Paunio, Tiina
    Porkka-Heiskanen, Tarja
    Partial Sleep Restriction Activates Immune Response-Related Gene Expression Pathways: Experimental and Epidemiological Studies in Humans2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 10, article id e77184Article in journal (Refereed)
    Abstract [en]

    Epidemiological studies have shown that short or insufficient sleep is associated with increased risk for metabolic diseases and mortality. To elucidate mechanisms behind this connection, we aimed to identify genes and pathways affected by experimentally induced, partial sleep restriction and to verify their connection to insufficient sleep at population level. The experimental design simulated sleep restriction during a working week: sleep of healthy men (N = 9) was restricted to 4 h/night for five nights. The control subjects (N = 4) spent 8 h/night in bed. Leukocyte RNA expression was analyzed at baseline, after sleep restriction, and after recovery using whole genome microarrays complemented with pathway and transcription factor analysis. Expression levels of the ten most up-regulated and ten most down-regulated transcripts were correlated with subjective assessment of insufficient sleep in a population cohort (N = 472). Experimental sleep restriction altered the expression of 117 genes. Eight of the 25 most up-regulated transcripts were related to immune function. Accordingly, fifteen of the 25 most up-regulated Gene Ontology pathways were also related to immune function, including those for B cell activation, interleukin 8 production, and NF-kappa B signaling (P<0.005). Of the ten most up-regulated genes, expression of STX16 correlated negatively with self-reported insufficient sleep in a population sample, while three other genes showed tendency for positive correlation. Of the ten most down-regulated genes, TBX21 and LGR6 correlated negatively and TGFBR3 positively with insufficient sleep. Partial sleep restriction affects the regulation of signaling pathways related to the immune system. Some of these changes appear to be long-lasting and may at least partly explain how prolonged sleep restriction can contribute to inflammation-associated pathological states, such as cardiometabolic diseases.

  • 4. Andersson, Evelyn
    et al.
    Rück, Christian
    Lavebratt, Catharina
    Hedman, Erik
    Schalling, Martin
    Lindefors, Nils
    Eriksson, Elias
    Carlbring, Per
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Andersson, Gerhard
    Furmark, Tomas
    Genetic Polymorphisms in Monoamine Systems and Outcome of Cognitive Behavior Therapy for Social Anxiety Disorder2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 11, article id e79015Article in journal (Refereed)
    Abstract [en]


    The role of genetics for predicting the response to cognitive behavior therapy (CBT) for social anxiety disorder (SAD) has only been studied in one previous investigation. The serotonin transporter (5-HTTLPR), the catechol-o-methyltransferase (COMT) val158met, and the tryptophan hydroxylase-2 (TPH2) G-703Tpolymorphisms are implicated in the regulation of amygdala reactivity and fear extinction and therefore might be of relevance for CBT outcome. The aim of the present study was to investigate if these three gene variants predicted response to CBT in a large sample of SAD patients.


    Participants were recruited from two separate randomized controlled CBT trials (trial 1: n = 112, trial 2: n = 202). Genotyping were performed on DNA extracted from blood or saliva samples. Effects were analyzed at follow-up (6 or 12 months after treatment) for both groups and for each group separately at post-treatment. The main outcome measure was the Liebowitz Social Anxiety Scale Self-Report.


    At long-term follow-up, there was no effect of any genotype, or gene × gene interactions, on treatment response. In the subsamples, there was time by genotype interaction effects indicating an influence of the TPH2 G-703T-polymorphism on CBT short-term response, however the direction of the effect was not consistent across trials.


    None of the three gene variants, 5-HTTLPR, COMTval158met and TPH2 G-703T, was associated with long-term response to CBT for SAD.

  • 5. Anh, Nhi
    et al.
    Taylan, Fulya
    Zachariadis, Vasilios
    Ivanov Öfverholm, Ingegerd
    Lindstrand, Anna
    Vezzi, Francesco
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Lötstedt, Britta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Nordenskjöld, Magnus
    Nordgren, Ann
    Nilsson, Daniel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Karolinska Institutet, Sweden.
    Barbany, Gisela
    High-resolution detection of chromosomal rearrangements in leukemias through mate pair whole genome sequencing2018In: PLOS ONE, E-ISSN 1932-6203, Vol. 13, no 3, article id e0193928Article in journal (Refereed)
    Abstract [en]

    The detection of recurrent somatic chromosomal rearrangements is standard of care for most leukemia types. Even though karyotype analysis-a low-resolution genome-wide chromosome analysis-is still the gold standard, it often needs to be complemented with other methods to increase resolution. To evaluate the feasibility and applicability of mate pair whole genome sequencing (MP-WGS) to detect structural chromosomal rearrangements in the diagnostic setting, we sequenced ten bone marrow samples from leukemia patients with recurrent rearrangements. Samples were selected based on cytogenetic and FISH results at leukemia diagnosis to include common rearrangements of prognostic relevance. Using MP-WGS and in-house bioinformatic analysis all sought rearrangements were successfully detected. In addition, unexpected complexity or additional, previously undetected rearrangements was unraveled in three samples. Finally, the MP-WGS analysis pinpointed the location of chromosome junctions at high resolution and we were able to identify the exact exons involved in the resulting fusion genes in all samples and the specific junction at the nucleotide level in half of the samples. The results show that our approach combines the screening character from karyotype analysis with the specificity and resolution of cytogenetic and molecular methods. As a result of the straightforward analysis and high-resolution detection of clinically relevant rearrangements, we conclude that MP-WGS is a feasible method for routine leukemia diagnostics of structural chromosomal rearrangements.

  • 6. Barnes, J. C.
    et al.
    Liu, Hexuan
    Motz, Ryan T.
    Tanksley, Peter T.
    Kail, Rachel
    Beckley, Amber L.
    Stockholm University, Faculty of Social Sciences, Department of Sociology. Duke University, USA.
    Belsky, Daniel W.
    Domingue, Benjamin W.
    Moffitt, Terrie E.
    Pratt, Travis C.
    Wertz, Jasmin
    The propensity for aggressive behavior and lifetime incarceration risk: A test for gene-environment interaction (G x E) using whole-genome data2019In: Aggression and Violent Behavior, ISSN 1359-1789, E-ISSN 1873-6335, Vol. 49, article id 101307Article in journal (Refereed)
    Abstract [en]

    Incarceration is a disruptive event that is experienced by a considerable proportion of the United States population. Research has identified social factors that predict incarceration risk, but scholars have called for a focus on the ways that individual differences combine with social factors to affect incarceration risk. Our study is an initial attempt to heed this call using whole-genome data. We use data from the Health and Retirement Study (HRS) (N = 6716) to construct a genome-wide measure of genetic propensity for aggressive behavior and use it to predict lifetime incarceration risk. We find that participants with a higher genetic propensity for aggression are more likely to experience incarceration, but the effect is stronger for males than females. Importantly, we identify a gene-environment interaction (G x E)-genetic propensity is reduced, substantively and statistically, to a non-significant predictor for males raised in homes where at least one parent graduated high school. We close by placing these findings in the broader context of concerns that have been raised about genetics research in criminology.

  • 7. Bellenguez, Céline
    et al.
    Grande, Giulia
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Laukka, Erika J.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm Gerontology Research Center, Sweden.
    Papenberg, Goran
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Lambert, Jean-Charles
    New insights into the genetic etiology of Alzheimer’s disease and related dementias2022In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 54, no 4, p. 412-436Article in journal (Refereed)
    Abstract [en]

    Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

  • 8. Ben Aissa, Alejandra
    et al.
    Madaboosi, Narayanan
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Indian Institute of Technology, India.
    Nilsson, Mats
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Pividori, Maria Isabel
    Electrochemical Genosensing of E. coli Based on Padlock Probes and Rolling Circle Amplification2021In: Sensors, E-ISSN 1424-8220, Vol. 21, no 5, article id 1749Article in journal (Refereed)
    Abstract [en]

    Isothermal amplification techniques are emerging nowadays for the rapid and accurate detection of pathogenic bacteria in low resource settings, where many infectious diseases are endemic, and the lack of reliable power supply, trained personnel and specialized facilities pose critical barriers for timely diagnosis. This work addresses the detection of E. coli based on DNA isothermal amplification performed on magnetic particles (MPs) followed by electrochemical genosensing on disposable electrodes by square-wave voltammetry. In this approach, the bacterial DNA is preconcentrated using a target-specific magnetic probe and then amplified on the MPs by rolling circle amplification (RCA). Two different electrochemical readout methods for the RCA amplicons are tested. The first one relied on the labelling of the magnetic RCA product with a digoxigenin probe followed by the incubation with antiDIG-HRP antibody as electrochemical reporter. In the second case, the direct detection with an HRP-probe was performed. This latter strategy showed an improved analytical performance, while simultaneously avoiding the use of thermocyclers or bulky bench top equipment.

  • 9. Bernal, Yanara A.
    et al.
    Blanco, Alejandro
    Sagredo, Eduardo A.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab). Karolinska Institutet, Sweden.
    Oróstica, Karen
    Alfaro, Ivan
    Marcelain, Katherine
    Armisén, Ricardo
    A Comprehensive Analysis of the Effect of A>I(G) RNA-Editing Sites on Genotoxic Drug Response and Progression in Breast Cancer2024In: Biomedicines, E-ISSN 2227-9059, Vol. 12, no 4, article id 728Article in journal (Refereed)
    Abstract [en]

    Dysregulated A>I(G) RNA editing, which is mainly catalyzed by ADAR1 and is a type of post-transcriptional modification, has been linked to cancer. A low response to therapy in breast cancer (BC) is a significant contributor to mortality. However, it remains unclear if there is an association between A>I(G) RNA-edited sites and sensitivity to genotoxic drugs. To address this issue, we employed a stringent bioinformatics approach to identify differentially RNA-edited sites (DESs) associated with low or high sensitivity (FDR 0.1, log2 fold change 2.5) according to the IC50 of PARP inhibitors, anthracyclines, and alkylating agents using WGS/RNA-seq data in BC cell lines. We then validated these findings in patients with basal subtype BC. These DESs are mainly located in non-coding regions, but a lesser proportion in coding regions showed predicted deleterious consequences. Notably, some of these DESs are previously reported as oncogenic variants, and in genes related to DNA damage repair, drug metabolism, gene regulation, the cell cycle, and immune response. In patients with BC, we uncovered DESs predominantly in immune response genes, and a subset with a significant association (log-rank test p < 0.05) between RNA editing level in LSR, SMPDL3B, HTRA4, and LL22NC03-80A10.6 genes, and progression-free survival. Our findings provide a landscape of RNA-edited sites that may be involved in drug response mechanisms, highlighting the value of A>I(G) RNA editing in clinical outcomes for BC.

  • 10. Blagodatskikh, Konstantin A.
    et al.
    Kramarov, Vladimir M.
    Barsova, Ekaterina V.
    Garkovenko, Alexey V.
    Shcherbo, Dmitriy S.
    Shelenkov, Andrew A.
    Ustinova, Vera V.
    Tokarenko, Maria R.
    Baker, Simon C.
    Kramarova, Tatiana V.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Ignatov, Konstantin B.
    Improved DOP-PCR (iDOP-PCR): A robust and simple WGA method for efficient amplification of low copy number genomic DNA2017In: PLOS ONE, E-ISSN 1932-6203, Vol. 12, no 9, article id e0184507Article in journal (Refereed)
    Abstract [en]

    Whole-genome amplification (WGA) techniques are used for non-specific amplification of low-copy number DNA, and especially for single-cell genome and transcriptome amplification. There are a number of WGA methods that have been developed over the years. One example is degenerate oligonucleotide-primed PCR (DOP-PCR), which is a very simple, fast and inexpensive WGA technique. Although DOP-PCR has been regarded as one of the pioneering methods for WGA, it only provides low genome coverage and a high allele dropout rate when compared to more modern techniques. Here we describe an improved DOP-PCR (iDOP-PCR). We have modified the classic DOP-PCR by using a new thermostable DNA polymerase (SD polymerase) with a strong strand-displacement activity and by adjustments in primers design. We compared iDOP-PCR, classic DOP-PCR and the well-established PicoPlex technique for whole genome amplification of both high-and low-copy number human genomic DNA. The amplified DNA libraries were evaluated by analysis of short tandem repeat genotypes and NGS data. In summary, iDOP-PCR provided a better quality of the amplified DNA libraries compared to the other WGA methods tested, especially when low amounts of genomic DNA were used as an input material.

  • 11.
    Bornscheuer, Lisa
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Public Health Sciences.
    Lundin, Andreas
    Forsell, Yvonne
    Lavebratt, Catharina
    Melas, Philippe A.
    Functional Variation in the FAAH Gene Is Directly Associated with Subjective Well-Being and Indirectly Associated with Problematic Alcohol Use2023In: Genes, E-ISSN 2073-4425, Vol. 14, no 9, article id 1826Article in journal (Refereed)
    Abstract [en]

    Fatty acid amide hydrolase (FAAH) is an enzyme that degrades anandamide, an endocannabinoid that modulates mesolimbic dopamine release and, consequently, influences states of well-being. Despite these known interactions, the specific role of FAAH in subjective well-being remains underexplored. Since well-being is a dynamic trait that can fluctuate over time, we hypothesized that we could provide deeper insights into the link between FAAH and well-being using longitudinal data. To this end, we analyzed well-being data collected three years apart using the WHO (Ten) Well-Being Index and genotyped a functional polymorphism in the FAAH gene (rs324420, Pro129Thr) in a sample of 2822 individuals. We found that the A-allele of rs324420, which results in reduced FAAH activity and elevated anandamide levels, was associated with lower well-being scores at both time points (Wave I, B: −0.52, p = 0.007; Wave II, B: −0.41, p = 0.03, adjusted for age and sex). A subsequent phenome-wide association study (PheWAS) affirmed our well-being findings in the UK Biobank (N = 126,132, alternative C-allele associated with elevated happiness, p = 0.008) and revealed an additional association with alcohol dependence. In our cohort, using lagged longitudinal mediation analyses, we uncovered evidence of an indirect association between rs324420 and problematic alcohol use (AUDIT-P) through the pathway of lower well-being (indirect effect Boot: 0.015, 95% CI [0.003, 0.030], adjusted for AUDIT in Wave I). We propose that chronically elevated anandamide levels might influence disruptions in the endocannabinoid system—a biological contributor to well-being—which could, in turn, contribute to increased alcohol intake, though multiple factors may be at play. Further genetic studies and mediation analyses are needed to validate and extend these findings.

  • 12.
    Bryant, Patrick
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    The relationship between ageing and changes in the human blood and brain methylomes 2022In: NAR Genomics and Bioinformatics, E-ISSN 2631-9268, Vol. 4, no 1, article id lqac001Article in journal (Refereed)
    Abstract [en]

    Changes in DNA methylation have been found to be strongly correlated with age, enabling the creation of ‘epigenetic clocks’. Previously, studies on the relationship between ageing and DNA methylation have assumed a linear relationship. Here, we show that several markers show a non-linear behaviour. In particular, we observe a tendency for saturation with age, especially in the cerebellum. Further, we show that the relationships between significant methylation changes and ageing are different in different tissues. We suggest a straightforward method of assessing all methylation-age relationships and cluster them according to their relative fold change. Our fold change selection outperforms the most common epigenetic clocks in predicting age for the cerebellum, but not for Blood or the Frontal Cortex. Further, we find that the saturation of methylation observed at older ages for the cerebellum explains why epigenetic clocks consistently underestimate the age there. The findings imply that assuming linear correlations might cause biologically important markers to be missed. 

  • 13. Burlacu, Elena
    et al.
    Lackmann, Fredrik
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Aguilar, Lisbeth-Carolina
    Belikov, Sergey
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    van Nues, Rob
    Trahan, Christian
    Hector, Ralph D.
    Dominelli-Whiteley, Nicholas
    Cockroft, Scott L.
    Wieslander, Lars
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Oeffinger, Marlene
    Granneman, Sander
    High-throughput RNA structure probing reveals critical folding events during early 60S ribosome assembly in yeast2017In: Nature Communications, E-ISSN 2041-1723, Vol. 8, article id 714Article in journal (Refereed)
    Abstract [en]

    While the protein composition of various yeast 60S ribosomal subunit assembly intermediates has been studied in detail, little is known about ribosomal RNA (rRNA) structural rearrangements that take place during early 60S assembly steps. Using a high-throughput RNA structure probing method, we provide nucleotide resolution insights into rRNA structural rearrangements during nucleolar 60S assembly. Our results suggest that many rRNA-folding steps, such as folding of 5.8S rRNA, occur at a very specific stage of assembly, and propose that downstream nuclear assembly events can only continue once 5.8S folding has been completed. Our maps of nucleotide flexibility enable making predictions about the establishment of protein-rRNA interactions, providing intriguing insights into the temporal order of protein-rRNA as well as long-range inter-domain rRNA interactions. These data argue that many distant domains in the rRNA can assemble simultaneously during early 60S assembly and underscore the enormous complexity of 60S synthesis.

  • 14. Bustamante, M.
    et al.
    Hernandez-Ferrer, C.
    Tewari, A.
    Sarria, Y.
    Harrison, G. I.
    Puigdecanet, E.
    Nonell, L.
    Kang, Wenjing
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Friedländer, Marc R.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Estivill, X.
    González, J. R.
    Nieuwenhuijsen, M.
    Young, A. R.
    Dose and time effects of solar-simulated ultraviolet radiation on the in vivo human skin transcriptome2020In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 182, no 6, p. 1458-1468Article in journal (Refereed)
    Abstract [en]

    Background Terrestrial ultraviolet (UV) radiation causes erythema, oxidative stress, DNA mutations and skin cancer. Skin can adapt to these adverse effects by DNA repair, apoptosis, keratinization and tanning.

    Objectives To investigate the transcriptional response to fluorescent solar-simulated radiation (FSSR) in sun-sensitive human skin in vivo.

    Methods Seven healthy male volunteers were exposed to 0, 3 and 6 standard erythemal doses (SED). Skin biopsies were taken at 6 h and 24 h after exposure. Gene and microRNA expression were quantified with next generation sequencing. A set of candidate genes was validated by quantitative polymerase chain reaction (qPCR); and wavelength dependence was examined in other volunteers through microarrays.

    Results The number of differentially expressed genes increased with FSSR dose and decreased between 6 and 24 h. Six hours after 6 SED, 4071 genes were differentially expressed, but only 16 genes were affected at 24 h after 3 SED. Genes for apoptosis and keratinization were prominent at 6 h, whereas inflammation and immunoregulation genes were predominant at 24 h. Validation by qPCR confirmed the altered expression of nine genes detected under all conditions; genes related to DNA repair and apoptosis; immunity and inflammation; pigmentation; and vitamin D synthesis. In general, candidate genes also responded to UVA1 (340-400 nm) and/or UVB (300 nm), but with variations in wavelength dependence and peak expression time. Only four microRNAs were differentially expressed by FSSR.

    Conclusions The UV radiation doses of this acute study are readily achieved daily during holidays in the sun, suggesting that the skin transcriptional profile of 'typical' holiday makers is markedly deregulated.

  • 15. Carfi, Angelo
    et al.
    Romano, Allegra
    Zaccaria, Giulia
    Villani, Emanuele Rocco
    Manes Gravina, Ester
    Vetrano, Davide Liborio
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Università Cattolica del Sacro Cuore, Italy.
    Bernabei, Roberto
    Onder, Graziano
    The burden of chronic disease, multimorbidity, and polypharmacy in adults with Down syndrome2020In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 182, no 7, p. 1735-1743Article in journal (Refereed)
    Abstract [en]

    Data on clinical characteristics of adults with Down syndrome (DS) are limited and the clinical phenotype of these persons is poorly described. This study aimed to describe the occurrence of chronic diseases and pattern of medication use in a population of adults with DS. Participants were 421 community dwelling adults with DS, aged 18 years or older. Individuals were assessed through a standardized clinical protocol. Multimorbidity was defined as the occurrence of two or more chronic conditions and polypharmacy as the concomitant use of five or more medications. The mean age of study participants was 38.3 +/- 12.8 years and 214 (51%) were women. Three hundred and seventy-four participants (88.8%) presented with multimorbidity. The most prevalent condition was visual impairment (72.9%), followed by thyroid disease (50.1%) and hearing impairment (26.8%). Chronic diseases were more prevalent among participants aged >40 years. The mean number of medications used was 2.09 and polypharmacy was observed in 10.5% of the study sample. Psychotropic medications were used by a mean of 0.7 individuals of the total sample. The high prevalence of multimorbidity and the common use of multiple medications contributes to a high level of clinical complexity, which appears to be similar to the degree of complexity of the older non-trisomic population. A comprehensive and holistic approach, commonly adopted in geriatric medicine, may provide the most appropriate care to persons with DS as they grow into adulthood.

  • 16. Corcoran, Martin M.
    et al.
    Phad, Ganesh E.
    Bernat, Nestor Vazquez
    Stahl-Hennig, Christiane
    Sumida, Noriyuki
    Persson, Mats A. A.
    Martin, Marcel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Hedestam, Gunilla B. Karlsson
    Production of individualized V gene databases reveals high levels of immunoglobulin genetic diversity2016In: nature communications, ISSN 2041-1723, Vol. 7, article id 13642Article in journal (Refereed)
    Abstract [en]

    Comprehensive knowledge of immunoglobulin genetics is required to advance our understanding of B cell biology. Validated immunoglobulin variable (V) gene databases are close to completion only for human and mouse. We present a novel computational approach, IgDiscover, that identifies germline V genes from expressed repertoires to a specificity of 100%. IgDiscover uses a cluster identification process to produce candidate sequences that, once filtered, results in individualized germline V gene databases. IgDiscover was tested in multiple species, validated by genomic cloning and cross library comparisons and produces comprehensive gene databases even where limited genomic sequence is available. IgDiscover analysis of the allelic content of the Indian and Chinese-origin rhesus macaques reveals high levels of immunoglobulin gene diversity in this species. Further, we describe a novel human IGHV3-21 allele and confirm significant gene differences between Balb/c and C57BL6 mouse strains, demonstrating the power of IgDiscover as a germline V gene discovery tool.

  • 17. Dalin, Martin G.
    et al.
    Engström, Pär G.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Ivarsson, Emil G.
    Unneberg, Per
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Light, Sara
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Schaufelberger, Maria
    Gilljama, Thomas
    Andersson, Bert
    Bergo, Martin O.
    Massive parallel sequencing questions the pathogenic role of missense variants in dilated cardiomyopathy2017In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 228, p. 742-748Article in journal (Refereed)
    Abstract [en]

    Background: Germline genetic variants are an important cause of dilated cardiomyopathy (DCM). However, recent sequencing studies have revealed rare variants in DCM-associated genes also in individuals without known heart disease. In this study, we investigate variant prevalence and genotype-phenotype correlations in Swedish DCM patients, and compare their genetic variants to those detected in reference cohorts. Methods and results: We sequenced the coding regions of 41 DCM-associated genes in 176 unrelated patients with idiopathic DCM and found 102 protein-altering variants with an allele frequency of <0.04% in reference cohorts; the majority were missense variants not previously described in DCM. Fifty-five (31%) patients had one variant, and 24 (14%) patients had two or more variants in the analysed genes. Detection of genetic variants in any gene, and in LMNA, MYII7 or TTN alone, was associated with early onset disease and reduced transplant-free survival. As expected, nonsense and frameshift variants were more common in DCM patients than in healthy individuals of the reference cohort 1000 Genomes Europeans. Surprisingly however, the prevalence, conservation and pathogenicity scores, and localization of missense variants were similar in DCM patients and healthy reference individuals. Conclusion: To our knowledge, this is the first study to identify correlations between genotype and prognosis when sequencing a large number of genes in unselected DCM patients. The similar distribution of missense variants in DCM patients and healthy reference individuals questions the pathogenic role of many variants, and suggests that results from genetic testing of DCM patients should be interpreted with caution.

  • 18. Endesfelder, David
    et al.
    Kulka, Ulrike
    Bucher, Martin
    Giesen, Ulrich
    Garty, Guy
    Beinke, Christina
    Port, Matthias
    Gruel, Gaëtan
    Gregoire, Eric
    Terzoudi, Georgia
    Triantopoulou, Sotiria
    Ainsbury, Elizabeth A.
    Moquet, Jayne
    Sun, Mingzhu
    Prieto, María Jesús
    Domene, Mercedes Moreno
    Barquinero, Joan-Francesc
    Pujol-Canadell, Monica
    Vral, Anne
    Baeyens, Ans
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Jan Kochanowski University, Poland.
    Oestreicher, Ursula
    International Comparison Exercise for Biological Dosimetry after Exposures with Neutrons Performed at Two Irradiation Facilities as Part of the BALANCE Project2024In: Cytogenetic and Genome Research, ISSN 1424-8581, E-ISSN 1424-859X, Vol. 163, no 3-4, p. 163-177Article in journal (Refereed)
    Abstract [en]

    In the case of a radiological or nuclear event, biological dosimetry can be an important tool to support clinical decision-making. During a nuclear event, individuals might be exposed to a mixed field of neutrons and photons. The composition of the field and the neutron energy spectrum influence the degree of damage to the chromosomes. During the transatlantic BALANCE project, an exposure similar to a Hiroshima-like device at a distance of 1.5 km from the epicenter was simulated and biological dosimetry based on dicentric chromosomes was performed to evaluate the participants ability to discover unknown doses and to test the influence of differences in neutron spectra. In a first step, calibration curves were established by irradiating blood samples with 5 doses in the range of 0 Gy to 4 Gy at two different facilities in Germany (PTB) and USA (CINF). The samples were sent to eight participating laboratories from the RENEB network and dicentric chromosomes were scored by each participant. Next, blood samples were irradiated with 4 blind doses in each of the two facilities and sent to the participants to provide dose estimates based on the established calibration curves. Manual and semi-automatic scoring of dicentric chromosomes were evaluated for their applicability to neutron exposures. Moreover, the biological effectiveness of the neutrons from the two irradiation facilities was compared. The calibration curves from samples irradiated at CINF showed a 1.4 times higher biological effectiveness compared to samples irradiated at PTB. For manual scoring of dicentric chromosomes, the doses of the test samples were mostly successfully resolved based on the calibration curves established during the project. For semi-automatic scoring, the dose estimation for the test samples was less successful. Doses >2 Gy in the calibration curves revealed non-linear associations between dose and dispersion index of the dicentric counts, especially for manual scoring. The differences in the biological effectiveness between the irradiation facilities suggested that the neutron energy spectrum can have a strong impact on the dicentric counts.

  • 19. Fardell, Camilla
    et al.
    Zettergren, Anna
    Ran, Caroline
    Carmine Belin, Andrea
    Ekman, Agneta
    Sydow, Olof
    Bäckman, Lars
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Holmberg, Björn
    Dizdar, Nil
    Söderkvist, Peter
    Nissbrandt, Hans
    S100B polymorphisms are associated with age of onset of Parkinson's disease2018In: BMC Medical Genetics, E-ISSN 1471-2350, Vol. 19, article id 42Article in journal (Refereed)
    Abstract [en]

    Background: In this study we investigated the association between SNPs in the S100B gene and Parkinson's disease (PD) in two independent Swedish cohorts. The SNP rs9722 has previously been shown to be associated with higher S100B concentrations in serum and frontal cortex in humans. S100B is widely expressed in the central nervous system and has many functions such as regulating calcium homeostasis, inflammatory processes, cytoskeleton assembly/disassembly, protein phosphorylation and degradation, and cell proliferation and differentiation. Several of these functions have been suggested to be of importance for the pathophysiology of PD. Methods: The SNPs rs9722, rs2239574, rs881827, rs9984765, and rs1051169 of the S100B gene were genotyped using the KASPar (R) PCR SNP genotyping system in a case-control study of two populations (431 PD patients and 465 controls, 195 PD patients and 378 controls, respectively). The association between the genotype and allelic distributions and PD risk was evaluated using Chi-Square and Cox proportional hazards test, as well as logistic regression. Linear regression and Cox proportional hazards tests were applied to assess the effect of the rs9722 genotypes on age of disease onset. Results: The S100B SNPs tested were not associated with the risk of PD. However, in both cohorts, the T allele of rs9722 was significantly more common in early onset PD patients compared to late onset PD patients. The SNP rs9722 was significantly related to age of onset, and each T allele lowered disease onset with 4.9 years. In addition, allelic variants of rs881827, rs9984765, and rs1051169, were significantly more common in early-onset PD compared to late-onset PD in the pooled population. Conclusions: rs9722, a functional SNP in the 3'-UTR of the S100B gene, was strongly associated with age of onset of PD.

  • 20. Fernell, Elisabeth
    et al.
    Bejerot, Susanne
    Westerlund, Joakim
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Miniscalco, Carmela
    Simila, Henry
    Eyles, Darryl
    Gillberg, Christopher
    Humble, Mats B.
    Autism spectrum disorder and low vitamin D at birth: a sibling control study2015In: Molecular Autism, ISSN 2040-2392, Vol. 6, article id 3Article in journal (Refereed)
    Abstract [en]

    Background: Insufficient vitamin D activity has attracted increasing interest as a possible underlying risk factor in disorders of the central nervous system, including autism. Methods: In this study, 25-hydroxyvitamin D (25(OH) D) was analysed in 58 Sweden-born sibling pairs, in which one child had autism spectrum disorder (ASD) and the other did not. The study group consisted of two representative samples; 47 Gothenburg sibling pairs with mixed ethnicities and 11 Stockholm sibling pairs with Somali background. 25(OH) D levels were analysed in the stored dried blood spots taken in the neonatal period for metabolic screening. Results: The collapsed group of children with ASD had significantly lower vitamin D levels (M = 24.0 nM, SD = 19.6) as compared with their siblings (M = 31.9 nM, SD = 27.7), according to a paired samples t-test (P = 0.013). The difference was-most likely-not only accounted for by a difference in season of birth between ASD and non-ASD siblings since the mean 25(OH)D levels differed with similar effect size between the sibling pairs born during winter and summer, respectively. All children with African/Middle East background, both the children with ASD and their non-ASD siblings, had vitamin D deficiency. Conclusions: The findings suggest that low prenatal vitamin D may act as a risk factor for ASD, however, there is a need for replication with larger samples. Future research should study whether or not adequate supplementation of vitamin D to pregnant women might lower the risk for ASD in the offspring.

  • 21. Franco, Irene
    et al.
    Helgadottir, Hafdis T.
    Moggio, Aldo
    Larsson, Malin
    Vrtacnik, Peter
    Johansson, Anna
    Norgren, Nina
    Lundin, Pär
    Stockholm University, Nordic Institute for Theoretical Physics (Nordita). Stockholm University, Science for Life Laboratory (SciLifeLab).
    Mas-Ponte, David
    Nordstrom, Johan
    Lundgren, Torbjorn
    Stenvinkel, Peter
    Wennberg, Lars
    Supek, Fran
    Eriksson, Maria
    Whole genome DNA sequencing provides an atlas of somatic mutagenesis in healthy human cells and identifies a tumor-prone cell type2019In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 20, no 1, article id 285Article in journal (Refereed)
    Abstract [en]

    Background: The lifelong accumulation of somatic mutations underlies age-related phenotypes and cancer. Mutagenic forces are thought to shape the genome of aging cells in a tissue-specific way. Whole genome analyses of somatic mutation patterns, based on both types and genomic distribution of variants, can shed light on specific processes active in different human tissues and their effect on the transition to cancer. Results: To analyze somatic mutation patterns, we compile a comprehensive genetic atlas of somatic mutations in healthy human cells. High-confidence variants are obtained from newly generated and publicly available whole genome DNA sequencing data from single non-cancer cells, clonally expanded in vitro. To enable a well-controlled comparison of different cell types, we obtain single genome data (92% mean coverage) from multi-organ biopsies from the same donors. These data show multiple cell types that are protected from mutagens and display a stereotyped mutation profile, despite their origin from different tissues. Conversely, the same tissue harbors cells with distinct mutation profiles associated to different differentiation states. Analyses of mutation rate in the coding and non-coding portions of the genome identify a cell type bearing a unique mutation pattern characterized by mutation enrichment in active chromatin, regulatory, and transcribed regions. Conclusions: Our analysis of normal cells from healthy donors identifies a somatic mutation landscape that enhances the risk of tumor transformation in a specific cell population from the kidney proximal tubule. This unique pattern is characterized by high rate of mutation accumulation during adult life and specific targeting of expressed genes and regulatory regions.

  • 22. Franco, Irene
    et al.
    Johansson, Anna
    Olsson, Karl
    Vrtačnik, Peter
    Lundin, Pär
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Karolinska Institutet, Sweden.
    Helgadottir, Hafdis T.
    Larsson, Malin
    Revêchon, Gwladys
    Bosia, Carla
    Pagnani, Andrea
    Provero, Paolo
    Gustafsson, Thomas
    Fischer, Helene
    Eriksson, Maria
    Somatic mutagenesis in satellite cells associates with human skeletal muscle aging2018In: Nature Communications, E-ISSN 2041-1723, Vol. 9, article id 800Article in journal (Refereed)
    Abstract [en]

    Human aging is associated with a decline in skeletal muscle (SkM) function and a reduction in the number and activity of satellite cells (SCs), the resident stem cells. To study the connection between SC aging and muscle impairment, we analyze the whole genome of single SC clones of the leg muscle vastus lateralis from healthy individuals of different ages (21-78 years). We find an accumulation rate of 13 somatic mutations per genome per year, consistent with proliferation of SCs in the healthy adult muscle. SkM-expressed genes are protected from mutations, but aging results in an increase in mutations in exons and promoters, targeting genes involved in SC activity and muscle function. In agreement with SC mutations affecting the whole tissue, we detect a missense mutation in a SC propagating to the muscle. Our results suggest somatic mutagenesis in SCs as a driving force in the age-related decline of SkM function.

  • 23.
    Fratiglioni, Laura
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Keller, Lina
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates A beta, tau, immunity and lipid processing2019In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 3, p. 414-430Article in journal (Refereed)
    Abstract [en]

    Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and A beta processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 x 10(-7)), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

  • 24.
    Frumerie, Clara
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Functional characterization of a phage integrase and its possible use in gene therapy2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Bacteriophage P2 infecting Escherichia coli can integrate into the bacterial chromosome by site-specific recombination, which is catalyzed by the P2 Int recombinase. The recombination event takes place between the phage attachment site, attP, and the bacterial attachment site, attB. Once integrated into the host chromosome the P2 prophage is very stable since an additional phage protein, Cox, is required for excision. For both integration and excision, the host-encoded protein IHF is also required.

    In this thesis, I have made a functional characterization of the P2 integrase and investigated its future potential as a tool for gene therapy. The P2 integrase was found to have cooperative interactions upon DNA binding with its accessory proteins, IHF and Cox. An N-terminal truncated Int protein retained these cooperative interactions, although it was disrupted in arm-binding. Moreover, the Int protein was found to form stable dimers in the absence of DNA, and the C-terminus and amino acid E197 was found to be important for dimerization. Dimerization was found to be essential for recombination, but dimerization deficient mutant proteins were able to bind as well as the wt protein to attP.

    The P2 Int was found to mediate recombination with a human sequence at a low frequency. It was also found that the insertion of HMG-recognition boxes can substitute for the requirement of IHF for recombination in an eukaryotic cell extract and that the integrase protein is localized in the cell nucleus. Taken together, these results indicate that the P2 integrase could be of potential use in gene therapy.

  • 25. Frykholm, Carina
    et al.
    Klar, Joakim
    Arnesson, Hanna
    Rehnman, Anna-Carin
    Stockholm University, Faculty of Social Sciences, Department of Special Education.
    Lodahl, Marianne
    Weden, Ulla
    Dahl, Niklas
    Tranebjaerg, Lisbeth
    Rendtorff, Nanna D.
    Phenotypic variability in a seven-generation Swedish family segregating autosomal dominant hearing impairment due to a novel EYA4 frameshift mutation2015In: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 563, no 1, p. 10-16Article in journal (Refereed)
    Abstract [en]

    Linkage to an interval overlapping the DFNA10 locus on chromosome 6q22-23 was found through genome wide linkage analysis in a seven-generation Swedish family segregating postlingual, autosomal dominant nonsyndromic sensorineural hearing impairment. A novel heterozygous frame-shift mutation (c.579_580insTACC, p.(Asp194Tyrfs*52)) in EYA4 was identified that truncates the so-called variable region of the protein. The mutation is predicted to result in haploinsufficiency of the EYA4 product. No evidence for dilated cardiomyopathy was found in the family, contrasting to a previous family with a deletion resulting in a similar truncation in the variable region. A highly variable age of onset was seen in the mutation carriers. For assessment of the aetiology of this variability, clinical and audiometric data analyses were performed. The affected family members all had similar cross-sectional and longitudinal deterioration of pure tone average (PTA) once the process of hearing deterioration had started, and no gender, parent-of-origin or family branch differences on PTA could be found. Age at onset varied between the family branches. In summary, this is the ninth published genetically verified DENA10 family. The results imply that unidentified factors, genetic or environmental, other than the EYA4 mutation, are of importance for the age at onset of DFNA10, and that mutation early in the variable region of the EYA4 protein can occur in the absence of dilated cardiomyopathy.

  • 26.
    Frånberg, Mattias
    Stockholm University, Faculty of Science, Numerical Analysis and Computer Science (NADA). Karolinska Institutet, Sweden.
    Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders2018In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 103, no 5, p. 691-706Article in journal (Refereed)
    Abstract [en]

    C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 x 10(-8)). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

  • 27.
    Frånberg, Mattias
    Stockholm University, Faculty of Science, Numerical Analysis and Computer Science (NADA). Karolinska Institutet, Sweden; Karolinska Universitetsjukhuset, Sweden.
    Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk2017In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 49, no 3, p. 403-415Article in journal (Refereed)
    Abstract [en]

    Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure-raising genetic variants on future cardiovascular disease risk.

  • 28. Gaulton, Kyle J.
    et al.
    Ferreira, Teresa
    Lee, Yeji
    Raimondo, Anne
    Maegi, Reedik
    Reschen, Michael E.
    Mahajan, Anubha
    Locke, Adam
    Rayner, N. William
    Robertson, Neil
    Scott, Robert A.
    Prokopenko, Inga
    Scott, Laura J.
    Green, Todd
    Sparso, Thomas
    Thuillier, Dorothee
    Yengo, Loic
    Grallert, Harald
    Wahl, Simone
    Frånberg, Mattias
    Stockholm University, Faculty of Science, Numerical Analysis and Computer Science (NADA). Stockholm University, Science for Life Laboratory (SciLifeLab). Karolinska Institutet, Sweden.
    Strawbridge, Rona J.
    Kestler, Hans
    Chheda, Himanshu
    Eisele, Lewin
    Gustafsson, Stefan
    Steinthorsdottir, Valgerdur
    Thorleifsson, Gudmar
    Qi, Lu
    Karssen, Lennart C.
    van Leeuwen, Elisabeth M.
    Willems, Sara M.
    Li, Man
    Chen, Han
    Fuchsberger, Christian
    Kwan, Phoenix
    Ma, Clement
    Linderman, Michael
    Lu, Yingchang
    Thomsen, Soren K.
    Rundle, Jana K.
    Beer, Nicola L.
    van de Bunt, Martijn
    Chalisey, Anil
    Kang, Hyun Min
    Voight, Benjamin F.
    Abecasis, Goncalo R.
    Almgren, Peter
    Baldassarre, Damiano
    Balkau, Beverley
    Benediktsson, Rafn
    Blueher, Matthias
    Boeing, Heiner
    Bonnycastle, Lori L.
    Bottinger, Erwin P.
    Burtt, Noel P.
    Carey, Jason
    Charpentier, Guillaume
    Chines, Peter S.
    Cornelis, Marilyn C.
    Couper, David J.
    Crenshaw, Andrew T.
    van Dam, Rob M.
    Doney, Alex S. F.
    Dorkhan, Mozhgan
    Edkins, Sarah
    Eriksson, Johan G.
    Esko, Tonu
    Eury, Elodie
    Fadista, Joao
    Flannick, Jason
    Fontanillas, Pierre
    Fox, Caroline
    Franks, Paul W.
    Gertow, Karl
    Gieger, Christian
    Gigante, Bruna
    Gottesman, Omri
    Grant, George B.
    Grarup, Niels
    Groves, Christopher J.
    Hassinen, Maija
    Have, Christian T.
    Herder, Christian
    Holmen, Oddgeir L.
    Hreidarsson, Astradur B.
    Humphries, Steve E.
    Hunter, David J.
    Jackson, Anne U.
    Jonsson, Anna
    Jorgensen, Marit E.
    Jorgensen, Torben
    Kao, Wen-Hong L.
    Kerrison, Nicola D.
    Kinnunen, Leena
    Klopp, Norman
    Kong, Augustine
    Kovacs, Peter
    Kraft, Peter
    Kravic, Jasmina
    Langford, Cordelia
    Leander, Karin
    Liang, Liming
    Lichtner, Peter
    Lindgren, Cecilia M.
    Lindholm, Eero
    Linneberg, Allan
    Liu, Ching-Ti
    Lobbens, Stephane
    Luan, Jian'an
    Lyssenko, Valeriya
    Mannisto, Satu
    McLeod, Olga
    Meyer, Julia
    Mihailov, Evelin
    Mirza, Ghazala
    Muehleisen, Thomas W.
    Mueller-Nurasyid, Martina
    Navarro, Carmen
    Noethen, Markus M.
    Oskolkov, Nikolay N.
    Owen, Katharine R.
    Palli, Domenico
    Pechlivanis, Sonali
    Peltonen, Leena
    Perry, John R. B.
    Platou, Carl G. P.
    Roden, Michael
    Ruderfer, Douglas
    Rybin, Denis
    van der Schouw, Yvonne T.
    Sennblad, Bengt
    Sigurdsson, Gunnar
    Stancakova, Alena
    Steinbach, Gerald
    Storm, Petter
    Strauch, Konstantin
    Stringham, Heather M.
    Sun, Qi
    Thorand, Barbara
    Tikkanen, Emmi
    Tonjes, Anke
    Trakalo, Joseph
    Tremoli, Elena
    Tuomi, Tiinamaija
    Wennauer, Roman
    Wiltshire, Steven
    Wood, Andrew R.
    Zeggini, Eleftheria
    Dunham, Ian
    Birney, Ewan
    Pasquali, Lorenzo
    Ferrer, Jorge
    Loos, Ruth J. F.
    Dupuis, Josee
    Florez, Jose C.
    Boerwinkle, Eric
    Pankow, James S.
    van Duijn, Cornelia
    Sijbrands, Eric
    Meigs, James B.
    Hu, Frank B.
    Thorsteinsdottir, Unnur
    Stefansson, Kari
    Lakka, Timo A.
    Rauramaa, Rainer
    Stumvoll, Michael
    Pedersen, Nancy L.
    Lind, Lars
    Keinanen-Kiukaanniemi, Sirkka M.
    Korpi-Hyovalti, Eeva
    Saaristo, Timo E.
    Saltevo, Juha
    Kuusisto, Johanna
    Laakso, Markku
    Metspalu, Andres
    Erbel, Raimund
    Joecke, Karl-Heinz
    Moebus, Susanne
    Ripatti, Samuli
    Salomaa, Veikko
    Ingelsson, Erik
    Boehm, Bernhard O.
    Bergman, Richard N.
    Collins, Francis S.
    Mohlke, Karen L.
    Koistinen, Heikki
    Tuomilehto, Jaakko
    Hveem, Kristian
    Njolstad, Inger
    Deloukas, Panagiotis
    Donnelly, Peter J.
    Frayling, Timothy M.
    Hattersley, Andrew T.
    de Faire, Ulf
    Hamsten, Anders
    Illig, Thomas
    Peters, Annette
    Cauchi, Stephane
    Sladek, Rob
    Froguel, Philippe
    Hansen, Torben
    Pedersen, Oluf
    Morris, Andrew D.
    Palmer, Collin N. A.
    Kathiresan, Sekar
    Melander, Olle
    Nilsson, Peter M.
    Groop, Leif C.
    Barroso, Ines
    Langenberg, Claudia
    Wareham, Nicholas J.
    O'Callaghan, Christopher A.
    Gloyn, Anna L.
    Altshuler, David
    Boehnke, Michael
    Teslovich, Tanya M.
    McCarthy, Mark I.
    Morris, Andrew P.
    Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci2015In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, no 12, p. 1415-+Article in journal (Refereed)
    Abstract [en]

    We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.

  • 29. Grapotte, Mathys
    et al.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Sachenkova, Oxana
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Bréhélin, Laurent
    Lecellier, Charles-Henri
    Discovery of widespread transcription initiation at microsatellites predictable by sequence-based deep neural network2022In: Nature Communications, E-ISSN 2041-1723, Vol. 13, no 1, article id 1200Article in journal (Refereed)
    Abstract [en]

    Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep learning models able to predict CAGE signal at STRs with high accuracy. These models unveil the importance of STR surrounding sequences not only to distinguish STR classes, but also to predict the level of transcription initiation. Importantly, genetic variants linked to human diseases are preferentially found at STRs with high transcription initiation level, supporting the biological and clinical relevance of transcription initiation at STRs. Together, our results extend the repertoire of non-coding transcription associated with DNA tandem repeats and complexify STR polymorphism.

  • 30. Habibi, Mahnaz
    et al.
    Taheri, Golnaz
    Stockholm University, Faculty of Social Sciences, Department of Computer and Systems Sciences.
    A new machine learning method for cancer mutation analysis2022In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 18, no 10, article id e1010332Article in journal (Refereed)
    Abstract [en]

    It is complicated to identify cancer-causing mutations. The recurrence of a mutation in patients remains one of the most reliable features of mutation driver status. However, some mutations are more likely to happen than others for various reasons. Different sequencing analysis has revealed that cancer driver genes operate across complex pathways and networks, with mutations often arising in a mutually exclusive pattern. Genes with low-frequency mutations are understudied as cancer-related genes, especially in the context of networks. Here we propose a machine learning method to study the functionality of mutually exclusive genes in the networks derived from mutation associations, gene-gene interactions, and graph clustering. These networks have indicated critical biological components in the essential pathways, especially those mutated at low frequency. Studying the network and not just the impact of a single gene significantly increases the statistical power of clinical analysis. The proposed method identified important driver genes with different frequencies. We studied the function and the associated pathways in which the candidate driver genes participate. By introducing lower-frequency genes, we recognized less studied cancer-related pathways. We also proposed a novel clustering method to specify driver modules. We evaluated each driver module with different criteria, including the terms of biological processes and the number of simultaneous mutations in each cancer. Materials and implementations are available at:

  • 31. Henström, Maria
    et al.
    Diekmann, Lena
    Bonfiglio, Ferdinando
    Hadizadeh, Fatemeh
    Kuech, Eva-Maria
    von Köckritz-Blickwede, Maren
    Thingholm, Louise B.
    Zheng, Tenghao
    Assadi, Ghazaleh
    Dierks, Claudia
    Heine, Martin
    Philipp, Ute
    Distl, Ottmar
    Money, Mary E.
    Belheouane, Meriem
    Heinsen, Femke-Anouska
    Rafter, Joseph
    Nardone, Gerardo
    Cuomo, Rosario
    Usai-Satta, Paolo
    Galeazzi, Francesca
    Neri, Matteo
    Walter, Susanna
    Simrén, Magnus
    Karling, Pontus
    Ohlsson, Bodil
    Schmidt, Peter T.
    Lindberg, Greger
    Dlugosz, Aldona
    Agreus, Lars
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Mayer, Emeran
    Baines, John F.
    Engstrand, Lars
    Portincasa, Piero
    Bellini, Massimo
    Stanghellini, Vincenzo
    Barbara, Giovanni
    Chang, Lin
    Camilleri, Michael
    Franke, Andre
    Naim, Hassan Y.
    D'Amato, Mauro
    Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome2018In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 67, no 2, p. 263-270Article in journal (Refereed)
    Abstract [en]

    Objective IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucraseisomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase-isomaltase (SI) gene variants for their potential relevance in IBS. Design We sequenced SI exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p. Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p.Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population. Results CSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case-control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (p<0.05). Conclusions SI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.

  • 32. Hofmeister, Wolfgang
    et al.
    Nilsson, Daniel
    Topa, Alexandra
    Anderlid, Britt-Marie
    Darki, Fahimeh
    Matsson, Hans
    Paez, Isabel Tapia
    Klingberg, Torkel
    Samuelsson, Lena
    Wirta, Valtteri
    Vezzi, Francesco
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Kere, Juha
    Nordenskjöld, Magnus
    Lundberg, Elisabeth Syk
    Lindstrand, Anna
    CTNND2-a candidate gene for reading problems and mild intellectual disability2015In: Journal of Medical Genetics, ISSN 0022-2593, Vol. 52, no 2, p. 111-122Article in journal (Refereed)
    Abstract [en]

    Background Cytogenetically visible chromosomal translocations are highly informative as they can pinpoint strong effect genes even in complex genetic disorders. Methods and results Here, we report a mother and daughter, both with borderline intelligence and learning problems within the dyslexia spectrum, and two apparently balanced reciprocal translocations: t(1;8)(p22; q24) and t(5; 18)(p15; q11). By low coverage mate-pair whole-genome sequencing, we were able to pinpoint the genomic breakpoints to 2 kb intervals. By direct sequencing, we then located the chromosome 5p breakpoint to intron 9 of CTNND2. An additional case with a 163 kb microdeletion exclusively involving CTNND2 was identified with genome-wide array comparative genomic hybridisation. This microdeletion at 5p15.2 is also present in mosaic state in the patient's mother but absent from the healthy siblings. We then investigated the effect of CTNND2 polymorphisms on normal variability and identified a polymorphism (rs2561622) with significant effect on phonological ability and white matter volume in the left frontal lobe, close to cortical regions previously associated with phonological processing. Finally, given the potential role of CTNND2 in neuron motility, we used morpholino knockdown in zebrafish embryos to assess its effects on neuronal migration in vivo. Analysis of the zebrafish forebrain revealed a subpopulation of neurons misplaced between the diencephalon and telencephalon. Conclusions Taken together, our human genetic and in vivo data suggest that defective migration of subpopulations of neuronal cells due to haploinsufficiency of CTNND2 contribute to the cognitive dysfunction in our patients.

  • 33. Huan, Ping-I
    et al.
    Shu, Huan
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. Karlstad University, Sweden.
    Mersha, Tesfaye B.
    Comparing DNA methylation profiles across different tissues associated with the diagnosis of pediatric asthma2020In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 151Article in journal (Refereed)
    Abstract [en]

    DNA methylation (DNAm) profiles in central airway epithelial cells (AECs) may play a key role in pathological processes in asthma. The goal of the current study is to compare the diagnostic performance of DNAm markers across three tissues: AECs, nasal epithelial cells (NECs), and peripheral blood mononuclear cells (PBMCs). Additionally, we focused on the results using the machine learning algorithm in the context of multi-locus effects to evaluate the diagnostic performance of the optimal subset of CpG sites. We obtained 74 subjects with asthma and 41 controls from AECs, 15 subjects with asthma and 14 controls from NECs, 697 subjects with asthma and 97 controls from PBMCs. Epigenome-wide DNA methylation levels in AECs, NECs and PBMCs were measured using the Infinium Human Methylation 450K BeadChip. Overlap analysis across the three different sample sources at the locus and pathway levels were studied to investigate shared or unique pathophysiological processes of asthma across tissues. Using the top 100 asthma-associated methylation markers as classifiers from each dataset, we found that both AEC- and NEC-based DNAm signatures exerted a lower classification error than the PBMC-based DNAm markers (p-value = 0.0002). The area-under-the-curve (AUC) analysis based on out-of-bag errors using the random forest classification algorithm revealed that PBMC-, NEC-, and AEC-based methylation data yielded 31 loci (AUC: 0.87), 8 loci (AUC: 0.99), and 4 loci (AUC: 0.97) from each optimal subset of tissue-specific markers, respectively. We also discovered the locus-locus interaction of DNAm levels of the CDH6 gene and RAPGEF3 gene might interact with each other to jointly predict the risk of asthma - which suggests the pivotal role of cell-cell junction in the pathological changes of asthma. Both AECs and NECs might provide better diagnostic accuracy and efficacy levels than PBMCs. Further research is warranted to evaluate how these tissue-specific DNAm markers classify and predict asthma risk.

  • 34. Johansson, Martin M.
    et al.
    Lundin, Elin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Qian, Xiaoyan
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Mirzazadeh, Mohammadreza
    Halvardson, Jonatan
    Darj, Elisabeth
    Feuk, Lars
    Nilsson, Mats
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Jazin, Elena
    Spatial sexual dimorphism of X and Y homolog gene expression in the human central nervous system during early male development2016In: Biology of Sex Differences, ISSN 2042-6410, Vol. 7Article in journal (Refereed)
    Abstract [en]

    Background: Renewed attention has been directed to the functions of the Y chromosome in the central nervous system during early human male development, due to the recent proposed involvement in neurodevelopmental diseases. PCDH11Y and NLGN4Y are of special interest because they belong to gene families involved in cell fate determination and formation of dendrites and axon. Methods: We used RNA sequencing, immunocytochemistry and a padlock probing and rolling circle amplification strategy, to distinguish the expression of X and Y homologs in situ in the human brain for the first time. To minimize influence of androgens on the sex differences in the brain, we focused our investigation to human embryos at 8-11 weeks post-gestation. Results: We found that the X- and Y-encoded genes are expressed in specific and heterogeneous cellular sub-populations of both glial and neuronal origins. More importantly, we found differential distribution patterns of X and Y homologs in the male developing central nervous system. Conclusions: This study has visualized the spatial distribution of PCDH11X/Y and NLGN4X/Y in human developing nervous tissue. The observed spatial distribution patterns suggest the existence of an additional layer of complexity in the development of the male CNS.

  • 35.
    Keller, Lina
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Welander, Hedvig
    Chiang, Huei-Hsin
    Tjernberg, Lars O
    Nennesmo, Inger
    Wallin, Asa K
    Graff, Caroline
    The PSEN1 I143T mutation in a Swedish family with Alzheimer's disease: clinical report and quantification of Aβ in different brain regions2010In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 18, no 11, p. 1202-1208Article in journal (Refereed)
    Abstract [en]

    Early-onset dominantly inherited forms of Alzheimer's disease (AD) are rare, but studies of such cases have revealed important information about the disease mechanisms. Importantly, mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1) and PSEN2, alter the APP processing and lead to an increased amyloid β-peptide (Aβ) 42/40 ratio. This, together with other studies on pathogenic mechanisms, show that Aβ42 is a major player in the etiology of AD. Here, we present a clinical and neuropathological description of a Swedish family with an I143T mutation in the PSEN1 gene, which gives rise to a severe form of AD. We also performed an extensive investigation on the concentration and distribution of Aβ species of different lengths in six brain regions from two mutation carriers. Our study showed that Aβ42 and a longer peptide, Aβ43, were present both in plaque cores and in total amyloid preparations, and were each clearly more frequent than Aβ40 in all examined regions, as shown by both mass spectrometry and immunohistochemistry.

  • 36. Kierczak, Marcin
    et al.
    Rafati, Nima
    Höglund, Julia
    Gourlé, Hadrien
    Lo Faro, Valeria
    Schmitz, Daniel
    Ek, Weronica E.
    Gyllensten, Ulf
    Enroth, Stefan
    Ekman, Diana
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Nystedt, Björn
    Karlsson, Torgny
    Johansson, Åsa
    Contribution of rare whole-genome sequencing variants to plasma protein levels and the missing heritability2022In: Nature Communications, E-ISSN 2041-1723, Vol. 13, no 1, article id 2532Article in journal (Refereed)
    Abstract [en]

    Despite the success of genome-wide association studies, much of the genetic contribution to complex traits remains unexplained. Here, we analyse high coverage whole-genome sequencing data, to evaluate the contribution of rare genetic variants to 414 plasma proteins. The frequency distribution of genetic variants is skewed towards the rare spectrum, and damaging variants are more often rare. We estimate that less than 4.3% of the narrow-sense heritability is expected to be explained by rare variants in our cohort. Using a gene-based approach, we identify Cis-associations for 237 of the proteins, which is slightly more compared to a GWAS (N = 213), and we identify 34 associated loci in Trans. Several associations are driven by rare variants, which have larger effects, on average. We therefore conclude that rare variants could be of importance for precision medicine applications, but have a more limited contribution to the missing heritability of complex diseases. 

  • 37. Langer, Yeshaya
    et al.
    Aran, Adi
    Gulsuner, Suleyman
    Abu Libdeh, Bassam
    Renbaum, Paul
    Brunetti, Dario
    Teixeira, Pedro-Filipe
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Walsh, Tom
    Zeligson, Sharon
    Ruotolo, Roberta
    Beeri, Rachel
    Dweikat, Imad
    Shahrour, Maher
    Weinberg-Shukron, Ariella
    Zandeh, Fouad
    Baruffini, Enrico
    Glaser, Elzbieta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    King, Mary-Claire
    Levy-Lahad, Ephrat
    Zeviani, Massimo
    Segel, Reeval
    Mitochondrial PITRM1 peptidase loss-of-function in childhood cerebellar atrophy2018In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 55, no 9, p. 599-606Article in journal (Refereed)
    Abstract [en]

    Objective To identify the genetic basis of a childhood-onset syndrome of variable severity characterised by progressive spinocerebellar ataxia, mental retardation, psychotic episodes and cerebellar atrophy. Methods Identification of the underlying mutations by whole exome and whole genome sequencing. Consequences were examined in patients' cells and in yeast. Results Two brothers from a consanguineous Palestinian family presented with progressive spinocerebellar ataxia, mental retardation and psychotic episodes. Serial brain imaging showed severe progressive cerebellar atrophy. Whole exome sequencing revealed a novel mutation: pitrilysin metallopeptidase 1 (PITRM1) c.2795C>T, p.T931M, homozygous in the affected children and resulting in 95% reduction in PITRM1 protein. Whole genome sequencing revealed a chromosome X structural rearrangement that also segregated with the disease. Independently, two siblings from a second Palestinian family presented with similar, somewhat milder symptoms and the same PITRM1 mutation on a shared haplotype. PITRM1T931M carrier frequency was 0.027 (3/110) in the village of the first family evaluated, and 0/300 among Palestinians from other locales. PITRM1 is a mitochondrial matrix enzyme that degrades 10-65 amino acid oligopeptides, including the mitochondrial fraction of amyloid-beta peptide. Analysis of peptide cleavage activity by the PITRM1T931M protein revealed a significant decrease in the degradation capacity specifically of peptides >= 40 amino acids. Conclusion PITRM1T931M results in childhood-onset recessive cerebellar pathology. Severity of PITRM1-related disease may be affected by the degree of impairment in cleavage of mitochondrial long peptides. Disruption and deletion of X linked regulatory segments may also contribute to severity.

  • 38. Le Guen, Yann
    et al.
    Papenberg, Goran
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Mignot, Emmanuel
    Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes2023In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 120, no 36, article id e2302720120Article in journal (Refereed)
    Abstract [en]

    Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues. 

  • 39. Lekman, Magnus
    et al.
    Hössjer, Ola
    Stockholm University, Faculty of Science, Department of Mathematics.
    Andrews, Peter
    Källberg, Henrik
    Uvehag, Daniel
    Charney, Dennis
    Manji, Husseini
    Rush, John A.
    McMahon, Francis J.
    Moore, Jason H.
    Kockum, Ingrid
    The genetic interacting landscape of 63 candidate genes in Major Depressive Disorder: an explorative study2014In: BioData Mining, E-ISSN 1756-0381, Vol. 7, p. 19-Article in journal (Refereed)
    Abstract [en]

    Background: Genetic contributions to major depressive disorder (MDD) are thought to result from multiple genes interacting with each other. Different procedures have been proposed to detect such interactions. Which approach is best for explaining the risk of developing disease is unclear. This study sought to elucidate the genetic interaction landscape in candidate genes for MDD by conducting a SNP-SNP interaction analysis using an exhaustive search through 3,704 SNP-markers in 1,732 cases and 1,783 controls provided from the GAIN MDD study. We used three different methods to detect interactions, two logistic regressions models (multiplicative and additive) and one data mining and machine learning (MDR) approach. Results: Although none of the interaction survived correction for multiple comparisons, the results provide important information for future genetic interaction studies in complex disorders. Among the 0.5% most significant observations, none had been reported previously for risk to MDD. Within this group of interactions, less than 0.03% would have been detectable based on main effect approach or an a priori algorithm. We evaluated correlations among the three different models and conclude that all three algorithms detected the same interactions to a low degree. Although the top interactions had a surprisingly large effect size for MDD (e. g. additive dominant model P-uncorrected = 9.10E-9 with attributable proportion (AP) value = 0.58 and multiplicative recessive model with P-uncorrected = 6.95E-5 with odds ratio (OR estimated from beta 3) value = 4.99) the area under the curve (AUC) estimates were low (< 0.54). Moreover, the population attributable fraction (PAF) estimates were also low (< 0.15). Conclusions: We conclude that the top interactions on their own did not explain much of the genetic variance of MDD. The different statistical interaction methods we used in the present study did not identify the same pairs of interacting markers. Genetic interaction studies may uncover previously unsuspected effects that could provide novel insights into MDD risk, but much larger sample sizes are needed before this strategy can be powerfully applied.

  • 40. Li, Yanni
    et al.
    Sundquist, Kristina
    Vats, Sakshi
    Hong, Mun-Gwan
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Wang, Xiao
    Chen, Yilun
    Hedelius, Anna
    Saal, Lao H.
    Sundquist, Jan
    Memon, Ashfaque A.
    Mitochondrial heteroplasmic shifts reveal a positive selection of breast cancer2023In: Journal of Translational Medicine, E-ISSN 1479-5876, Vol. 21, article id 696Article in journal (Refereed)
    Abstract [en]

    Background Breast cancer is, despite screening, not always detected early enough and is together with other tumor types known to shed genetic information in circulation. Unlike single-copy nuclear DNA, mitochondrial DNA (mtDNA) copies range from 100s to 10,000s per cell, thus providing a potentially alternative to identify potential missing cancer information in circulation at an early stage.

    Methods To characterize mitochondrial mutation landscapes in breast cancer, whole mtDNA sequencing and bioinformatics analyses were performed on 86 breast cancer biopsies and 50 available matched baseline cancer-free whole blood samples from the same individuals, selected from a cohort of middle-aged women in Sweden. To determine whether the mutations can be detected in blood plasma prior to cancer diagnosis, we further designed a nested case-control study (n = 663) and validated the shortlisted mutations using droplet digital PCR.

    Results We detected different mutation landscapes between biopsies and matched whole blood samples. Compared to whole blood samples, mtDNA from biopsies had higher heteroplasmic mutations in the D-loop region (P = 0.02), RNR2 (P = 0.005), COX1 (P = 0.037) and CYTB (P = 0.006). Furthermore, the germline mtDNA mutations had higher heteroplasmy level than the lost (P = 0.002) and de novo mutations (P = 0.04). The nonsynonymous to synonymous substitution ratio (dN/dS) was higher for the heteroplasmic mutations (P = 7.25 × 10−12) than that for the homoplasmic mutations, but the de novo (P = 0.06) and lost mutations (P = 0.03) had lower dN/dS than the germline mutations. Interestingly, we found that the critical regions for mitochondrial transcription: MT-HSP1 (odds ratio [OR]: 21.41), MT-TFH (OR: 7.70) and MT-TAS2 (OR: 3.62), had significantly higher heteroplasmic mutations than the rest of the D-loop sub-regions. Finally, we found that the presence of mt.16093T > C mutation increases 67% risk of developing breast cancer.

    Conclusions Our findings show that mitochondrial genetic landscape changes during cancer pathogenesis and positive selection of mtDNA heteroplasmic mutations in breast cancer. Most importantly, the mitochondrial mutations identified in biopsies can be traced back in matched plasma samples and could potentially be used as early breast cancer diagnostic biomarkers.

  • 41. Lill, Christina M.
    et al.
    Liu, Tian
    Schjeide, Brit-Maren M.
    Roehr, Johannes T.
    Akkad, Denis A.
    Damotte, Vincent
    Alcina, Antonio
    Ortiz, Miguel A.
    Arroyo, Rafa
    Lopez de Lapuente, Aitzkoa
    Blaschke, Paul
    Winkelmann, Alexander
    Gerdes, Lisa-Ann
    Luessi, Felix
    Fernadez, Oscar
    Izquierdo, Guillermo
    Antigüedad, Alfredo
    Hoffjan, Sabine
    Cournu-Rebeix, Isabelle
    Gromöller, Silvana
    Faber, Hans
    Liebsch, Maria
    Meissner, Esther
    Chanvillard, Coralie
    Touze, Emmanuel
    Pico, Fernando
    Corcia, Philippe
    Dörner, Thomas
    Steinhagen-Thiessen, Elisabeth
    Bäckman, Lars
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Heekeren, Hauke R.
    Li, Shu-Chen
    Lindenberger, Ulman
    Chan, Andrew
    Hartung, Hans-Peter
    Aktas, Orhan
    Lohse, Peter
    Kümpfel, Tania
    Kubisch, Christian
    Epplen, Joerg T.
    Zettl, Uwe K.
    Fontaine, Bertrand
    Vandenbroeck, Koen
    Matesanz, Fuencisla
    Urcelay, Elena
    Bertram, Lars
    Zipp, Frauke
    Closing the case of APOE in multiple sclerosis: no association with disease risk in over 29 000 subjects2012In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 49, no 9, p. 558-562Article in journal (Refereed)
    Abstract [en]

    Background Single nucleotide polymorphisms (SNPs) rs429358 (ε4) and rs7412 (ε2), both invoking changes in the amino-acid sequence of the apolipoprotein E (APOE) gene, have previously been tested for association with multiple sclerosis (MS) risk. However, none of these studies was sufficiently powered to detect modest effect sizes at acceptable type-I error rates. As both SNPs are only imperfectly captured on commonly used microarray genotyping platforms, their evaluation in the context of genome-wide association studies has been hindered until recently.

    Methods We genotyped 12 740 subjects hitherto not studied for their APOE status, imputed raw genotype data from 8739 subjects from five independent genome-wide association studies datasets using the most recent high-resolution reference panels, and extracted genotype data for 8265 subjects from previous candidate gene assessments.

    Results Despite sufficient power to detect associations at genome-wide significance thresholds across a range of ORs, our analyses did not support a role of rs429358 or rs7412 on MS susceptibility. This included meta-analyses of the combined data across 13 913 MS cases and 15 831 controls (OR=0.95, p=0.259, and OR 1.07, p=0.0569, for rs429358 and rs7412, respectively).

    Conclusion Given the large sample size of our analyses, it is unlikely that the two APOE missense SNPs studied here exert any relevant effects on MS susceptibility.

  • 42. Lindqvist, C. Mårten
    et al.
    Lundmark, Anders
    Nordlund, Jessica
    Freyhult, Eva
    Ekman, Diana
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Carlsson Almlöf, Jonas
    Raine, Amanda
    Övernäs, Elin
    Abrahamsson, Jonas
    Frost, Britt-Marie
    Grandér, Dan
    Heyman, Mats
    Palle, Josefine
    Forestier, Erik
    Lönnerholm, Gudmar
    Berglund, Eva C.
    Syvänen, Ann-Christine
    Deep targeted sequencing in pediatric acute lymphoblastic leukemia unveils distinct mutational patterns between genetic subtypes and novel relapse-associated genes2016In: Oncotarget, E-ISSN 1949-2553, Vol. 7, no 39, p. 64071-64088Article in journal (Refereed)
    Abstract [en]

    To characterize the mutational patterns of acute lymphoblastic leukemia (ALL) we performed deep next generation sequencing of 872 cancer genes in 172 diagnostic and 24 relapse samples from 172 pediatric ALL patients. We found an overall greater mutational burden and more driver mutations in T-cell ALL (T-ALL) patients compared to B-cell precursor ALL (BCP-ALL) patients. In addition, the majority of the mutations in T-ALL had occurred in the original leukemic clone, while most of the mutations in BCP-ALL were subclonal. BCP-ALL patients carrying any of the recurrent translocations ETV6-RUNX1, BCR-ABL or TCF3-PBX1 harbored few mutations in driver genes compared to other BCP-ALL patients. Specifically in BCP-ALL, we identified ATRX as a novel putative driver gene and uncovered an association between somatic mutations in the Notch signaling pathway at ALL diagnosis and increased risk of relapse. Furthermore, we identified EP300, ARID1A and SH2B3 as relapse-associated genes. The genes highlighted in our study were frequently involved in epigenetic regulation, associated with germline susceptibility to ALL, and present in minor subclones at diagnosis that became dominant at relapse. We observed a high degree of clonal heterogeneity and evolution between diagnosis and relapse in both BCP-ALL and T-ALL, which could have implications for the treatment efficiency.

  • 43. Lindqvist, Carl Mårten
    et al.
    Nordlund, Jessica
    Ekman, Diana
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Johansson, Anna
    Moghadam, Behrooz Torabi
    Raine, Amanda
    Övernäs, Elin
    Dahlberg, Johan
    Wahlberg, Per
    Henriksson, Niklas
    Abrahamsson, Jonas
    Frost, Britt-Marie
    Grander, Dan
    Heyman, Mats
    Larsson, Rolf
    Palle, Josefine
    Söderhall, Stefan
    Forestier, Erik
    Lönnerholm, Gudmar
    Syvänen, Ann-Christine
    Berglund, Eva C.
    The Mutational Landscape in Pediatric Acute Lymphoblastic Leukemia Deciphered by Whole Genome Sequencing2015In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, no 1, p. 118-128Article in journal (Refereed)
    Abstract [en]

    Genomic characterization of pediatric acute lymphoblastic leukemia (ALL) has identified distinct patterns of genes and pathways altered in patients with well-defined genetic aberrations. To extend the spectrum of known somatic variants in ALL, we performed whole genome and transcriptome sequencing of three B-cell precursor patients, of which one carried the t(12;21)ETV6-RUNX1 translocation and two lacked a known primary genetic aberration, and one T-ALL patient. We found that each patient had a unique genome, with a combination of well-known and previously undetected genomic aberrations. By targeted sequencing in 168 patients, we identified KMT2D and KIF1B as novel putative driver genes. We also identified a putative regulatory non-coding variant that coincided with overexpression of the growth factor MDK. Our results contribute to an increased understanding of the biological mechanisms that lead to ALL and suggest that regulatory variants may be more important for cancer development than recognized to date. The heterogeneity of the genetic aberrations in ALL renders whole genome sequencing particularly well suited for analysis of somatic variants in both research and diagnostic applications.

  • 44.
    Lundin Kleberg, Johan
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Personality, Social and Developmental Psychology.
    Key note: Reinforcement Learning and Social Attention in Rare Genetic Disorders: Results from the Swedish UNIKA Study2022Conference paper (Other academic)
  • 45. Mather, Lisa
    et al.
    Blom, Victoria
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Work and organizational psychology. The Swedish School of Sport and Health Sciences, Sweden; Karolinska Institutet, Sweden.
    Bergström, Gunnar
    Svedberg, Pia
    An Underlying Common Factor, Influenced by Genetics and Unique Environment, Explains the Covariation Between Major Depressive Disorder, Generalized Anxiety Disorder, and Burnout: A Swedish Twin Study2016In: Twin Research and Human Genetics, ISSN 1832-4274, E-ISSN 1839-2628, Vol. 19, no 6, p. 619-627Article in journal (Refereed)
    Abstract [en]

    Depression and anxiety are highly comorbid due to shared genetic risk factors, but less is known about whether burnout shares these risk factors. We aimed to examine whether the covariation between major depressive disorder (MDD), generalized anxiety disorder (GAD), and burnout is explained by common genetic and/or environmental factors. This cross-sectional study included 25,378 Swedish twins responding to a survey in 2005-2006. Structural equation models were used to analyze whether the trait variances and covariances were due to additive genetics, non-additive genetics, shared environment, and unique environment. Univariate analyses tested sex limitation models and multivariate analysis tested Cholesky, independent pathway, and common pathway models. The phenotypic correlations were 0.71 (0.69-0.74) between MDD and GAD, 0.58 (0.56-0.60) between MDD and burnout, and 0.53 (0.50-0.56) between GAD and burnout. Heritabilities were 45% for MDD, 49% for GAD, and 38% for burnout; no statistically significant sex differences were found. A common pathway model was chosen as the final model. The common factor was influenced by genetics (58%) and unique environment (42%), and explained 77% of the variation in MDD, 69% in GAD, and 44% in burnout. GAD and burnout had additive genetic factors unique to the phenotypes (11% each), while MDD did not. Unique environment explained 23% of the variability in MDD, 20% in GAD, and 45% in burnout. In conclusion, the covariation was explained by an underlying common factor, largely influenced by genetics. Burnout was to a large degree influenced by unique environmental factors not shared with MDD and GAD.

  • 46. Mathot, Lucy
    et al.
    Falk-Sörqvist, Elin
    Moens, Lotte
    Allen, Marie
    Sjöblom, Tobias
    Nilsson, Mats
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Uppsala University, Sweden.
    Automated Genotyping of Biobank Samples by Multiplex Amplification of Insertion/Deletion Polymorphisms2012In: PLOS ONE, E-ISSN 1932-6203, Vol. 7, no 12, article id e52750Article in journal (Refereed)
    Abstract [en]

    The genomic revolution in oncology will entail mutational analyses of vast numbers of patient-matched tumor and normal tissue samples. This has meant an increased risk of patient sample mix up due to manual handling. Therefore, scalable genotyping and sample identification procedures are essential to pathology biobanks. We have developed an efficient alternative to traditional genotyping methods suited for automated analysis. By targeting 53 prevalent deletions and insertions found in human populations with fluorescent multiplex ligation dependent genome amplification, followed by separation in a capillary sequencer, a peak spectrum is obtained that can be automatically analyzed. 24 tumor-normal patient samples were successfully matched using this method. The potential use of the developed assay for forensic applications is discussed.

  • 47. Matsson, Hans
    et al.
    Huss, Mikael
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Persson, Helena
    Einarsdottir, Elisabet
    Tiraboschi, Ettore
    Nopola-Hemmi, Jaana
    Schumacher, Johannes
    Neuhoff, Nina
    Warnke, Andreas
    Lyytinen, Heikki
    Schulte-Korne, Gert
    Nothen, Markus M.
    Leppanen, Paavo H. T.
    Peyrard-Janvid, Myriam
    Kere, Juha
    Polymorphisms in DCDC2 and S100B associate with developmental dyslexia2015In: Journal of Human Genetics, ISSN 1434-5161, E-ISSN 1435-232X, Vol. 60, no 7, p. 399-401Article in journal (Refereed)
    Abstract [en]

    Genetic studies of complex traits have become increasingly successful as progress is made in next-generation sequencing. We aimed at discovering single nucleotide variation present in known and new candidate genes for developmental dyslexia: CYP19A1, DCDC2, DIP2A, DYX1C1, GCFC2 (also known as C2orf3), KIAA0319, MRPL19, PCNT, PRMT2, ROBO1 and S100B. We used next-generation sequencing to identify single-nucleotide polymorphisms in the exons of these 11 genes in pools of 100 DNA samples of Finnish individuals with developmental dyslexia. Subsequent individual genotyping of those 100 individuals, and additional cases and controls from the Finnish and German populations, validated 92 out of 111 different single-nucleotide variants. A nonsynonymous polymorphism in DCDC2 (corrected P = 0.002) and a noncoding variant in S100B (corrected P = 0.016) showed a significant association with spelling performance in families of German origin. No significant association was found for the variants neither in the Finnish case-control sample set nor in the Finnish family sample set. Our findings further strengthen the role of DCDC2 and implicate S100B, in the biology of reading and spelling.

  • 48. Mesgari, Hassan
    et al.
    Esmaelian, Samar
    Nasiri, Kamyar
    Ghasemzadeh, Shabnam
    Doroudgar, Parisa
    Payandeh, Zahra
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Epigenetic Regulation in Oral Squamous Cell Carcinoma Microenvironment: A Comprehensive Review2023In: Cancers, ISSN 2072-6694, Vol. 15, no 23, article id 5600Article, review/survey (Refereed)
    Abstract [en]

    Oral squamous cell carcinoma (OSCC) is a prevalent and significant type of oral cancer that has far-reaching health implications worldwide. Epigenetics, a field focused on studying heritable changes in gene expression without modifying DNA sequence, plays a pivotal role in OSCC. Epigenetic changes, encompassing DNA methylation, histone modifications, and miRNAs, exert control over gene activity and cellular characteristics. In OSCC, aberrant DNA methylation of tumor suppressor genes (TSG) leads to their inactivation, subsequently facilitating tumor growth. As a result, distinct patterns of gene methylation hold promise as valuable biomarkers for the detection of OSCC. Oral cancer treatment typically involves surgery, radiation therapy, and chemotherapy, but even with these treatments, cancer cells cannot be effectively targeted and destroyed. Researchers are therefore exploring new methods to target and eliminate cancer cells. One promising approach is the use of epigenetic modifiers, such as DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors, which have been shown to modify abnormal epigenetic patterns in OSCC cells, leading to the reactivation of TSGs and the suppression of oncogenes. As a result, epigenetic-targeted therapies have the potential to directly alter gene expression and minimize side effects. Several studies have explored the efficacy of such therapies in the treatment of OSCC. Although studies have investigated the efficacy of epigenetic therapies, challenges in identifying reliable biomarkers and developing effective combination treatments are acknowledged. Of note, epigenetic mechanisms play a significant role in drug resistance in OSCC and other cancers. Aberrant DNA methylation can silence tumor suppressor genes, while alterations in histone modifications and chromatin remodeling affect gene expression related to drug metabolism and cell survival. Thus, understanding and targeting these epigenetic processes offer potential strategies to overcome drug resistance and improve the efficacy of cancer treatments in OSCC. This comprehensive review focuses on the complex interplay between epigenetic alterations and OSCC cells. This will involve a deep dive into the mechanisms underlying epigenetic modifications and their impact on OSCC, including its initiation, progression, and metastasis. Furthermore, this review will present the role of epigenetics in the treatment and diagnosis of OSCC.

  • 49. Moens, Lotte N.
    et al.
    Falk-Sorqvist, Elin
    Asplund, A. Charlotta
    Bernatowska, Ewa
    Smith, C. I. Edvard
    Nilsson, Mats
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Uppsala University, Sweden.
    Diagnostics of Primary Immunodeficiency Diseases: A Sequencing Capture Approach2014In: PLOS ONE, E-ISSN 1932-6203, Vol. 9, no 12, p. e114901-Article in journal (Refereed)
    Abstract [en]

    Primary Immunodeficiencies (PID) are genetically inherited disorders characterized by defects of the immune system, leading to increased susceptibility to infection. Due to the variety of clinical symptoms and the complexity of current diagnostic procedures, accurate diagnosis of PID is often difficult in daily clinical practice. Thanks to the advent of next generation'' sequencing technologies and target enrichment methods, the development of multiplex diagnostic assays is now possible. In this study, we applied a selector-based target enrichment assay to detect disease-causing mutations in 179 known PID genes. The usefulness of this assay for molecular diagnosis of PID was investigated by sequencing DNA from 33 patients, 18 of which had at least one known causal mutation at the onset of the experiment. We were able to identify the disease causing mutations in 60% of the investigated patients, indicating that the majority of PID cases could be resolved using a targeted sequencing approach. Causal mutations identified in the unknown patient samples were located in STAT3, IGLL1, RNF168 and PGM3. Based on our results, we propose a stepwise approach for PID diagnostics, involving targeted resequencing, followed by whole transcriptome and/or whole genome sequencing if causative variants are not found in the targeted exons.

  • 50. Moens, Lotte N. J.
    et al.
    Falk-Sörqvist, Elin
    Ljungström, Viktor
    Mattsson, Johanna
    Sundström, Magnus
    La Fleur, Linnéa
    Mathot, Lucy
    Micke, Patrick
    Nilsson, Mats
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Botling, Johan
    HaloPlex Targeted Resequencing for Mutation Detection in Clinical Formalin-Fixed, Paraffin-Embedded Tumor Samples2015In: Journal of Molecular Diagnostics, ISSN 1525-1578, E-ISSN 1943-7811, Vol. 17, no 6, p. 729-739Article in journal (Refereed)
    Abstract [en]

    In recent years, the advent of massively parallel next-generation sequencing technologies has enabled substantial advances in the study of human diseases. Combined with targeted DNA enrichment methods, high sequence coverage can be obtained for different genes simultaneously at a reduced cost per sample, creating unique opportunities for clinical cancer diagnostics. However, the formalin-fixed, paraffin-embedded (FFPE) process of tissue samples, routinely used in pathology departments, results in DNA fragmentation and nucleotide modifications that introduce a number of technical challenges for downstream biomotecular analyses. We evaluated the HaloPlex target enrichment system for somatic mutation detection in 80 tissue fractions derived from 20 clinical cancer cases with paired tumor and normal tissue available in both FFPE and fresh-frozen format. Several modifications to the standard method were introduced, including a reduced target fragment Length and two strand capturing. We found that FFPE material can be used for HaloPlex-based target enrichment and next-generation sequencing, even when starting from small amounts of DNA. By specifically capturing both strands for each target fragment, we were able to reduce the number of false-positive errors caused by FFPE-induced artifacts and Lower the detection limit for somatic mutations. We believe that the HaloPlex method presented here will be broadly applicable as a tool for somatic mutation detection in clinical cancer settings.

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