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  • 1. 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.

  • 2. 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, ISSN 1932-6203, 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.

  • 3. 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, ISSN 1932-6203, 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.

  • 4. 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, ISSN 1932-6203, 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.

  • 5. 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.

  • 6. 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.

  • 7. Bustamante, M.
    et al.
    Hernandez-Ferrer, C.
    Tewari, A.
    Sarria, Y.
    Harrison, G. I.
    Puigdecanet, E.
    Nonell, L.
    Kang, Wenjing
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Friedländer, Marc R.
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    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 1365-2133Article 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.

  • 8. 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.

  • 9. 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.

  • 10. 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, ISSN 1471-2350, 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.

  • 11. 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.

  • 12. 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.

  • 13. 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, ISSN 2041-1723, 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.

  • 14.
    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.

  • 15.
    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.

  • 16. 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.

  • 17.
    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.

  • 18.
    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.

  • 19. 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.

  • 20. 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.

  • 21. 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.

  • 22. 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, ISSN 2045-2322, 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.

  • 23. 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.

  • 24.
    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.

  • 25. 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.

  • 26. 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, ISSN 1756-0381, 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.

  • 27. 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.

  • 28. 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, ISSN 1949-2553, 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.

  • 29. 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.

  • 30. 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.

  • 31. 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.

  • 32. 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, ISSN 1932-6203, 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.

  • 33. 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.

  • 34.
    Motwani, Hitesh
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Westberg, Emelie
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Lindh, Christian
    Abramsson-Zetterberg, Lilianne
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Serum albumin adducts, DNA adducts and micronuclei frequency measured in benzo[a]pyrene-exposed mice for estimation of genotoxic potency2020In: Mutation research. Genetic toxicology and environmental mutagenesis, ISSN 1383-5718, E-ISSN 1879-3592, Vol. 849, article id 503127Article in journal (Refereed)
    Abstract [en]

    The environmental and food contaminant, benzo[a]pyrene {B[a]P, a polycyclic aromatic hydrocarbon (PAH)}, is classified as a human carcinogen by the International Agency for Research on Cancer. The carcinogenicity of B[a]P is linked to the formation of electrophilic metabolites, namely B[a]P-diol epoxides (BPDEs) occurring as stereoisomers. In this work, we quantified the metabolic formation of BPDE isomers and the genotoxic effect in B[a]P-exposed mice, with an aim to estimate the genotoxic potency of B[a]P per in vivo dose of its most potent metabolite [i.e. ( + )-anti-BPDE]. The increase in frequency of micronuclei ((MN) in erythrocytes was measured as a biomarker for genotoxic effect. Covalent adducts to serum albumin (SA) and those to DNA from the BPDEs were analysed using liquid chromatography tandem mass spectrometry (LC-MS/MS), as adducts to histidine (BPDE-His-Pro) and deoxyguanosine (BPDE-dG), respectively. For the first time in animal experiments it was possible to resolve adducts to SA from ( + )-anti-, (-)-anti- and ( +/- )-syn-BPDE isomers by LC-MS/MS. The adduct levels in the protein were about 16 fmol/mg SA, which was orders of magnitude lower than that in the nucleic acid, 28 pmol/mg DNA, in mice exposed to 100 mg B[a]P per kg body weight (bw). Using SA adduct levels, the in vivo dose of ( + )-anti-BPDE was calculated to be approximately 50 nM.h per mg B[a]P per kg bw. This allowed to make a preliminary estimate of the genotoxic potency as 2 parts per thousand fMN per mu M.h of ( + )-anti-BPDE. This estimate was compared to that from another food toxicant, glycidol, studied with similar methods, which indicated that the BPDE has several orders of magnitude higher genotoxic potency. The demonstrated approach on integrating biomarkers of internal dose of a causative agent and that of genotoxic effect for assessing genotoxic potency, using B[a]P as a model, has a potential for improving cancer risk assessment procedures for PAHs.

  • 35. Mukwaya, Anthony
    et al.
    Lindvall, Jessica M.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Xeroudaki, Maria
    Peebo, Beatrice
    Ali, Zaheer
    Lennikov, Anton
    Dahl Ejby Jensen, Lasse
    Lagali, Neil
    A microarray whole-genome gene expression dataset in a rat model of inflammatory corneal angiogenesis2016In: Scientific Data, E-ISSN 2052-4463, Vol. 3, article id 160103Article in journal (Refereed)
    Abstract [en]

    In angiogenesis with concurrent inflammation, many pathways are activated, some linked to VEGF and others largely VEGF-independent. Pathways involving inflammatory mediators, chemokines, and micro-RNAs may play important roles in maintaining a pro-angiogenic environment or mediating angiogenic regression. Here, we describe a gene expression dataset to facilitate exploration of pro-angiogenic, pro-inflammatory, and remodelling/normalization-associated genes during both an active capillary sprouting phase, and in the restoration of an avascular phenotype. The dataset was generated by microarray analysis of the whole transcriptome in a rat model of suture-induced inflammatory corneal neovascularisation. Regions of active capillary sprout growth or regression in the cornea were harvested and total RNA extracted from four biological replicates per group. High quality RNA was obtained for gene expression analysis using microarrays. Fold change of selected genes was validated by qPCR, and protein expression was evaluated by immunohistochemistry. We provide a gene expression dataset that may be re-used to investigate corneal neovascularisation, and may also have implications in other contexts of inflammation-mediated angiogenesis.

  • 36. Myrum, Craig
    et al.
    Giddaluru, Sudheer
    Jacobsen, Kaya
    Espeseth, Thomas
    Nyberg, Lars
    Lundervold, Astri J.
    Haavik, Jan
    Nilsson, Lars-Göran
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Umeå University, Sweden.
    Reinvang, Ivar
    Steen, Vidar M.
    Johansson, Stefan
    Wibrand, Karin
    Le Hellard, Stephanie
    Bramham, Clive R.
    Common variants in the ARC gene are not associated withcognitive abilities2015In: Brain and Behavior, ISSN 2162-3279, E-ISSN 2162-3279, Vol. 5, no 10, article id e00376Article in journal (Refereed)
    Abstract [en]

    Introduction: The Activity-Regulated Cytoskeleton-associated (ARC) gene encodes a protein that is critical for the consolidation of synaptic plasticity and long-term memory formation. Given ARC's key role in synaptic plasticity, we hypothesized that genetic variations in ARC may contribute to interindividual variability in human cognitive abilities or to attention-deficit hyperactivity disorder (ADHD) susceptibility, where cognitive impairment often accompanies the disorder. Methods: We tested whether ARC variants are associated with six measures of cognitive functioning in 670 healthy subjects in the Norwegian Cognitive NeuroGenetics (NCNG) by extracting data from its Genome-Wide Association Study (GWAS). In addition, the Swedish Betula sample of 1800 healthy subjects who underwent similar cognitive testing was also tested for association with 19 tag SNPs. Results: No ARC variants show association at the study-wide level, but several markers show a trend toward association with human cognitive functions. We also tested for association between ARCSNPs and ADHD in a Norwegian sample of cases and controls, but found no significant associations. Conclusion: This study suggests that common genetic variants located in ARC do not account for variance in human cognitive abilities, though small effects cannot be ruled out.

  • 37.
    Papenberg, Göran
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Becker, Nina
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Max Planck Institute for Human Development, Germany.
    Ferencz, Beata
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Naveh-Benjamin, Moshe
    Laukka, Erika J.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Bäckman, Lars
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Brehmer, Yvonne
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Max Planck Institute for Human Development, Germany.
    Dopamine Receptor Genes Modulate Associative Memory in Old Age2017In: Journal of cognitive neuroscience, ISSN 0898-929X, E-ISSN 1530-8898, Vol. 29, no 2, p. 245-253Article in journal (Refereed)
    Abstract [en]

    Previous research shows that associative memory declines more than item memory in aging. Although the underlying mechanisms of this selective impairment remain poorly understood, animal and human data suggest that dopaminergic modulation may be particularly relevant for associative binding. We investigated the influence of dopamine (DA) receptor genes on item and associative memory in a population-based sample of older adults (n = 525, aged 60 years), assessed with a face-scene item associative memory task. The effects of single-nucleotide polymorphisms of DA D1 (DRD1; rs4532), D2 (DRD2/ANKK1/Taq1A; rs1800497), and D3 (DRD3/Ser9Gly; rs6280) receptor genes were examined and combined into a single genetic score. Individuals carrying more beneficial alleles, presumably associated with higher DA receptor efficacy (DRD1 C allele; DRD2 A2 allele; DRD3 T allele), performed better on associative memory than persons with less beneficial genotypes. There were no effects of these genes on item memory or other cognitive measures, such as working memory, executive functioning, fluency, and perceptual speed, indicating a selective association between DA genes and associative memory. By contrast, genetic risk for Alzheimer disease (AD) was associated with worse item and associative memory, indicating adverse effects of APOE epsilon 4 and a genetic risk score for AD (PICALM, BIN1, CLU) on episodic memory in general. Taken together, our results suggest that DA may be particularly important for associative memory, whereas AD-related genetic variations may influence overall episodic memory in older adults without dementia.

  • 38. Petaros, Anja
    et al.
    Garvi, Heather M.
    Sholts, Sabrina B.
    Schlager, Stefan
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. UCLA, USA; Linköping University, Sweden.
    Sexual dimorphism and regional variation in human frontal bone inclination measured via digital 3D models2017In: Legal Medicine, ISSN 1344-6223, E-ISSN 1873-4162, Vol. 29, p. 53-61Article in journal (Refereed)
    Abstract [en]

    The frontal bone is one of the most sexually dimorphic elements of the human skull, due to features such as the glabella, frontal eminences, and frontal inclination. While glabella is frequently evaluated in procedures to estimate sex in unknown human skeletal remains, frontal inclination has received less attention. In this study we present a straightforward, quick, and reproducible method for measuring frontal inclination angles from glabella and supraglabella. Using a sample of 413 human crania from four different populations (U.S. Whites, U.S. Blacks, Portuguese, and Chinese), we test the usefulness of the inclination angles for sex estimation and compare their performance to traditional methods of frontal inclination assessment. Accuracy rates in the range 75-81% were achieved for the U.S. White, U.S. Black, and Portuguese groups. For Chinese the overall accuracy was lower, i.e. 66%. Although some regional variation was observed, a cut-off value of 78.2 for glabellar inclination angles separates female and male crania from all studied populations with good accuracy. As inclination angles measured from glabella captures two sexually dimorphic features (i.e. glabellar prominence and frontal inclination) in a single measure, the observed clear male/female difference is not unexpected. Being continuous variables, inclination angles are suitable for use in statistical methods for sex estimations.

  • 39. Schafmayer, Clemens
    et al.
    Harrison, James William
    Buch, Stephan
    Lange, Christina
    Reichert, Matthias C.
    Hofer, Philipp
    Cossais, François
    Kupcinskas, Juozas
    von Schönfels, Witigo
    Schniewind, Bodo
    Kruis, Wolfgang
    Tepel, Jürgen
    Zobel, Myrko
    Rosendahl, Jonas
    Jacobi, Thorsten
    Walther-Berends, Andreas
    Schroeder, Michael
    Vogel, Ilka
    Sergeev, Petr
    Boedeker, Hans
    Hinrichsen, Holger
    Volk, Andreas
    Erk, Jens-Uwe
    Burmeister, Greta
    Hendricks, Alexander
    Hinz, Sebastian
    Wolff, Sebastian
    Böttner, Martina
    Wood, Andrew R.
    Tyrrell, Jessica
    Beaumont, Robin N.
    Langheinrich, Melanie
    Kucharzik, Torsten
    Brezina, Stefanie
    Huber-Schönauer, Ursula
    Pietsch, Leonora
    Noack, Laura Sophie
    Brosch, Mario
    Herrmann, Alexander
    Thangapandi, Raghavan Veera
    Schimming, Hans Wolfgang
    Zeissig, Sebastian
    Palm, Stefan
    Focke, Gerd
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Schmidt, Peter T.
    Weitz, Juergen
    Krawczak, Michael
    Völzke, Henry
    Leeb, Gernot
    Michl, Patrick
    Lieb, Wolfgang
    Grützmann, Robert
    Franke, Andre
    Lammert, Frank
    Becker, Thomas
    Kupcinskas, Limas
    D'Amato, Mauro
    Wedel, Thilo
    Datz, Christian
    Gsur, Andrea
    Weedon, Michael N.
    Hampe, Jochen
    Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms2019In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 68, no 5, p. 854-865Article in journal (Refereed)
    Abstract [en]

    Objective Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease. Design Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry. Results We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p< 0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3x10-10 and 0.002 (OR allelic = 1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33). Conclusion I n silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.

  • 40. Scholl, Michael
    et al.
    Carter, Stephen F.
    Westman, Eric
    Rodriguez-Vieitez, Elena
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology. Karolinska Institutet, Sweden; Karolinska University Hospital, Sweden.
    Thordardottir, Steinunn
    Wall, Anders
    Graff, Caroline
    Långström, Bengt
    Nordberg, Agneta
    Early astrocytosis in autosomal dominant Alzheimer's disease measured in vivo by multi-tracer positron emission tomography2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 16404Article in journal (Refereed)
    Abstract [en]

    Studying autosomal dominant Alzheimer's disease (ADAD), caused by gene mutations yielding nearly complete penetrance and a distinct age of symptom onset, allows investigation of presymptomatic pathological processes that can identify a therapeutic window for disease-modifying therapies. Astrocyte activation may occur in presymptomatic Alzheimer's disease (AD) because reactive astrocytes surround beta-amyloid (A beta) plaques in autopsy brain tissue. Positron emission tomography was performed to investigate fibrillar A beta, astrocytosis and cerebral glucose metabolism with the radiotracers C-11-Pittsburgh compound-B (PIB), C-11-deuterium-L-deprenyl (DED) and F-18-fluorodeoxyglucose (FDG) respectively in presymptomatic and symptomatic ADAD participants (n = 21), patients with mild cognitive impairment (n = 11) and sporadic AD (n = 7). Multivariate analysis using the combined data from all radiotracers clearly separated the different groups along the first and second principal components according to increased PIB retention/decreased FDG uptake (component 1) and increased DED binding (component 2). Presymptomatic ADAD mutation carriers showed significantly higher PIB retention than non-carriers in all brain regions except the hippocampus. DED binding was highest in presymptomatic ADAD mutation carriers. This suggests that non-fibrillar A beta or early stage plaque depostion might interact with inflammatory responses indicating astrocytosis as an early contributory driving force in AD pathology. The novelty of this finding will be investigated in longitudinal follow-up studies.

  • 41. Shen, Xia
    et al.
    Klarić, Lucija
    Sharapov, Sodbo
    Mangino, Massimo
    Ning, Zheng
    Wu, Di
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Trbojević-Akmačić, Irena
    Pučić-Baković, Maja
    Rudan, Igor
    Polašek, Ozren
    Hayward, Caroline
    Spector, Timothy D.
    Wilson, James F.
    Lauc, Gordan
    Aulchenko, Yurii S.
    Multivariate discovery and replication of five novel loci associated with Immunoglobulin G N-glycosylation2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 447Article in journal (Refereed)
    Abstract [en]

    Joint modeling of a number of phenotypes using multivariate methods has often been neglected in genome-wide association studies and if used, replication has not been sought. Modern omics technologies allow characterization of functional phenomena using a large number of related phenotype measures, which can benefit from such joint analysis. Here, we report a multivariate genome-wide association studies of 23 immunoglobulin G (IgG) N-glycosylation phenotypes. In the discovery cohort, our multi-phenotype method uncovers ten genome-wide significant loci, of which five are novel (IGH, ELL2, HLA-B-C, AZI1, FUT6-FUT3). We convincingly replicate all novel loci via multivariate tests. We show that IgG N-glycosylation loci are strongly enriched for genes expressed in the immune system, in particular antibody-producing cells and B lymphocytes. We empirically demonstrate the efficacy of multivariate methods to discover novel, reproducible pleiotropic effects.

  • 42.
    Skiöld, Sara
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Azimzadeh, Omid
    Merl-Pham, Juliane
    Naslund, Ingemar
    Wersall, Peter
    Lidbrink, Elisabet
    Tapio, Soile
    Harms-Ringdahl, Mats
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Unique proteomic signature for radiation sensitive patients; a comparative study between normo-sensitive and radiation sensitive breast cancer patients2015In: Mutation research, ISSN 0027-5107, E-ISSN 1873-135X, Vol. 776, p. 128-135Article in journal (Refereed)
    Abstract [en]

    Radiation therapy is a cornerstone of modern cancer treatment. Understanding the mechanisms behind normal tissue sensitivity is essential in order to minimize adverse side effects and yet to prevent local cancer reoccurrence. The aim of this study was to identify biomarkers of radiation sensitivity to enable personalized cancer treatment. To investigate the mechanisms behind radiation sensitivity a pilot study was made where eight radiation-sensitive and nine normo-sensitive patients were selected from a cohort of 2914 breast cancer patients, based on acute tissue reactions after radiation therapy. Whole blood was sampled and irradiated in vitro with 0, 1, or 150 mGy followed by 3 h incubation at 37 degrees C. The leukocytes of the two groups were isolated, pooled and protein expression profiles were investigated using isotope-coded protein labeling method (ICPL). First, leukocytes from the in vitro irradiated whole blood from normo-sensitive and extremely sensitive patients were compared to the non-irradiated controls. To validate this first study a second ICPL analysis comparing only the non-irradiated samples was conducted. Both approaches showed unique proteomic signatures separating the two groups at the basal level and after doses of 1 and 150 mGy. Pathway analyses of both proteomic approaches suggest that oxidative stress response, coagulation properties and acute phase response are hallmarks of radiation sensitivity supporting our previous study on oxidative stress response. This investigation provides unique characteristics of radiation sensitivity essential for individualized radiation therapy.

  • 43. Ståhl, Patrik L.
    et al.
    Salmen, Fredrik
    Vickovic, Sanja
    Lundmark, Anna
    Navarro, Jose Fernandez
    Magnusson, Jens
    Giacomello, Stefania
    Asp, Michaela
    Orzechowski Westholm, Jakub
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Huss, Mikael
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Mollbrink, Annelie
    Linnarsson, Sten
    Codeluppi, Simone
    Borg, Åke
    Ponten, Fredrik
    Costea, Paul Igor
    Sahlen, Pelin
    Mulder, Jan
    Bergmann, Olaf
    Lundeberg, Joakim
    Frisen, Jonas
    Visualization and analysis of gene expression in tissue sections by spatial transcriptomics2016In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 353, no 6294, p. 78-82Article in journal (Refereed)
    Abstract [en]

    Analysis of the pattern of proteins or messenger RNAs (mRNAs) in histological tissue sections is a cornerstone in biomedical research and diagnostics. This typically involves the visualization of a few proteins or expressed genes at a time. We have devised a strategy, which we call spatial transcriptomics, that allows visualization and quantitative analysis of the transcriptome with spatial resolution in individual tissue sections. By positioning histological sections on arrayed reverse transcription primers with unique positional barcodes, we demonstrate high-quality RNA-sequencing data with maintained two-dimensional positional information from the mouse brain and human breast cancer. Spatial transcriptomics provides quantitative gene expression data and visualization of the distribution of mRNAs within tissue sections and enables novel types of bioinformatics analyses, valuable in research and diagnostics.

  • 44. Suiter, Chase C.
    et al.
    Moriyama, Takaya
    Matreyek, Kenneth A.
    Yang, Wentao
    Scaletti, Emma Rose
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Lund University, Sweden.
    Nishii, Rina
    Yang, Wenjian
    Hoshitsuki, Keito
    Singh, Minu
    Trehan, Amita
    Parish, Chris
    Smith, Colton
    Li, Lie
    Bhojwani, Deepa
    Yuen, Liz Y. P.
    Li, Chi-kong
    Li, Chak-ho
    Yang, Yung-li
    Walker, Gareth J.
    Goodhand, James R.
    Kennedy, Nicholas A.
    Klussmann, Federico Antillon
    Bhatia, Smita
    Relling, Mary V.
    Kato, Motohiro
    Hori, Hiroki
    Bhatia, Prateek
    Ahmad, Tariq
    Yeoh, Allen E. J.
    Stenmark, Pål
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Lund University, Sweden.
    Fowler, Douglas M.
    Yang, Jun J.
    Massively parallel variant characterization identifies NUDT15 alleles associated with thiopurine toxicity2020In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 117, no 10, p. 5394-5401Article in journal (Refereed)
    Abstract [en]

    As a prototype of genomics-guided precision medicine, individualized thiopurine dosing based on pharmacogenetics is a highly effective way to mitigate hematopoietic toxicity of this class of drugs. Recently, NUDT15 deficiency was identified as a genetic cause of thiopurine toxicity, and NUDT15-informed preemptive dose reduction was quickly adopted in clinical settings. To exhaustively identify pharmacogenetic variants in this gene, we developed massively parallel NUDT15 function assays to determine the variants' effect on protein abundance and thiopurine cytotoxicity. Of the 3,097 possible missense variants, we characterized the abundance of 2,922 variants and found 54 hotspot residues at which variants resulted in complete loss of protein stability. Analyzing 2,935 variants in the thiopurine cytotoxicity-based assay, we identified 17 additional residues where variants altered NUDT15 activity without affecting protein stability. We identified structural elements key to NUDT15 stability and/or catalytical activity with single amino acid resolution. Functional effects for NUDT15 variants accurately predicted toxicity risk alleles in patients treated with thiopurines with far superior sensitivity and specificity compared to bioinformatic prediction algorithms. In conclusion, our massively parallel variant function assays identified 1,152 deleterious NUDT15 variants, providing a comprehensive reference of variant function and vastly improving the ability to implement pharmacogenetics-guided thiopurine treatment individualization.

  • 45. Tuominen, Rainer
    et al.
    Engstrom, Pär G.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Helgadottir, Hildur
    Eriksson, Hanna
    Unneberg, Per
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Kjellqvist, Sanela
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Yang, Muyi
    Linden, Diana
    Edsgard, Daniel
    Hansson, Johan
    Hoiom, Veronica
    The Role of Germline Alterations in the DNA Damage Response Genes BRIP1 and BRCA2 in Melanoma Susceptibility2016In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 55, no 7, p. 601-611Article in journal (Refereed)
    Abstract [en]

    We applied a targeted sequencing approach to identify germline mutations conferring a moderately to highly increased risk of cutaneous and uveal melanoma. Ninety-two high-risk melanoma patients were screened for inherited variation in 120 melanoma candidate genes. Observed gene variants were filtered based on frequency in reference populations, cosegregation with melanoma in families and predicted functional effect. Several novel or rare genetic variants in genes involved in DNA damage response, cell-cycle regulation and transcriptional control were identified in melanoma patients. Among identified genetic alterations was an extremely rare variant (minor allele frequency of 0.00008) in the BRIP1 gene that was found to cosegregate with the melanoma phenotype. We also found a rare nonsense variant in the BRCA2 gene (rs11571833), previously associated with cancer susceptibility but not with melanoma, which showed weak association with melanoma susceptibility in the Swedish population. Our results add to the growing knowledge about genetic factors associated with melanoma susceptibility and also emphasize the role of DNA damage response as an important factor in melanoma etiology. (C) 2016 Wiley Periodicals, Inc.

  • 46. Uhlén, Mathias
    et al.
    Fagerberg, Linn
    Hallström, Bjoern M.
    Lindskog, Cecilia
    Oksvold, Per
    Mardinoglu, Adil
    Sivertsson, Asa
    Kampf, Caroline
    Sjöstedt, Evelina
    Asplund, Anna
    Olsson, IngMarie
    Edlund, Karolina
    Lundberg, Emma
    Navani, Sanjay
    Szigyarto, Cristina Al-Khalili
    Odeberg, Jacob
    Djureinovic, Dijana
    Ottosson Takanen, Jenny
    Hober, Sophia
    Alm, Tove
    Edqvist, Per-Henrik
    Berling, Holger
    Tegel, Hanna
    Mulder, Jan
    Rockberg, Johan
    Nilsson, Peter
    Schwenk, Jochen M.
    Hamsten, Marica
    von Feilitzen, Kalle
    Forsberg, Mattias
    Persson, Lukas
    Johansson, Fredric
    Zwahlen, Martin
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nielsen, Jens
    Pontén, Fredrik
    Tissue-based map of the human proteome2015In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 347, no 6220, article id 1260419Article in journal (Refereed)
    Abstract [en]

    Resolving the molecular details of proteome variation in the different tissues and organs of the human body will greatly increase our knowledge of human biology and disease. Here, we present a map of the human tissue proteome based on an integrated omics approach that involves quantitative transcriptomics at the tissue and organ level, combined with tissue microarray-based immunohistochemistry, to achieve spatial localization of proteins down to the single-cell level. Our tissue-based analysis detected more than 90% of the putative protein-coding genes. We used this approach to explore the human secretome, the membrane proteome, the druggable proteome, the cancer proteome, and the metabolic functions in 32 different tissues and organs. All the data are integrated in an interactive Web-based database that allows exploration of individual proteins, as well as navigation of global expression patterns, in all major tissues and organs in the human body.

  • 47. Wanschers, Bas F. J.
    et al.
    Szklarczyk, Radek
    van den Brand, Mariel A. M.
    Jonckheere, An
    Suijskens, Janneke
    Smeets, Roel
    Rodenburg, Richard J.
    Stephan, Katharina
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Helland, Ingrid B.
    Elkamil, Areej
    Rootwelt, Terje
    Ott, Martin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    van den Heuvel, Lambert
    Nijtmans, Leo G.
    Huynen, Martijn A.
    A mutation in the human CBP4 ortholog UQCC3 impairs complex III assembly, activity and cytochrome b stability2014In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 23, no 23, p. 6356-6365Article in journal (Refereed)
    Abstract [en]

    Complex III (cytochrome bc(1)) is a protein complex of the mitochondrial inner membrane that transfers electrons from ubiquinol to cytochrome c. Its assembly requires the coordinated expression of mitochondrial-encoded cytochrome b and nuclear-encoded subunits and assembly factors. Complex III deficiency is a severe multisystem disorder caused by mutations in subunit genes or assembly factors. Sequence-profile-based orthology predicts C11orf83, hereafter named UQCC3, to be the ortholog of the fungal complex III assembly factor CBP4. We describe a homozygous c.59T > A missense mutation in UQCC3 from a consanguineous patient diagnosed with isolated complex III deficiency, displaying lactic acidosis, hypoglycemia, hypotonia and delayed development without dysmorphic features. Patient fibroblasts have reduced complex III activity and lower levels of the holocomplex and its subunits than controls. They have no detectable UQCC3 protein and have lower levels of cytochrome b protein. Furthermore, in patient cells, cytochrome b is absent from a high-molecular-weight complex III. UQCC3 is reduced in cells depleted for the complex III assembly factors UQCC1 and UQCC2. Conversely, absence of UQCC3 in patient cells does not affect UQCC1 and UQCC2. This suggests that UQCC3 functions in the complex III assembly pathway downstream of UQCC1 and UQCC2 and is consistent with what is known about the function of Cbp4 and of the fungal orthologs of UQCC1 and UQCC2, Cbp3 and Cbp6. We conclude that UQCC3 functions in complex III assembly and that the c.59T > A mutation has a causal role in complex III deficiency.

  • 48. Wright, Alison E.
    et al.
    Darolti, Iulia
    Bloch, Natasha I.
    Oostra, Vicencio
    Sandkam, Ben
    Buechel, Severine D.
    Stockholm University, Faculty of Science, Department of Zoology.
    Kolm, Niclas
    Stockholm University, Faculty of Science, Department of Zoology.
    Breden, Felix
    Vicoso, Beatriz
    Mank, Judith E.
    Convergent recombination suppression suggests role of sexual selection in guppy sex chromosome formation2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 14251Article in journal (Refereed)
    Abstract [en]

    Sex chromosomes evolve once recombination is halted between a homologous pair of chromosomes. The dominant model of sex chromosome evolution posits that recombination is suppressed between emerging X and Y chromosomes in order to resolve sexual conflict. Here we test this model using whole genome and transcriptome resequencing data in the guppy, a model for sexual selection with many Y-linked colour traits. We show that although the nascent Y chromosome encompasses nearly half of the linkage group, there has been no perceptible degradation of Y chromosome gene content or activity. Using replicate wild populations with differing levels of sexually antagonistic selection for colour, we also show that sexual selection leads to greater expansion of the non-recombining region and increased Y chromosome divergence. These results provide empirical support for longstanding models of sex chromosome catalysis, and suggest an important role for sexual selection and sexual conflict in genome evolution.

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