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  • 201.
    Olsson, Malin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Familial amyloidosis with polyneuropathy: studies of genetic factors modifying the phenotype of the disease2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background. Familial Amyloidosis with Polyneuropathy (FAP) is an autosomal dominantly inherited systemic amyloid disease. The disease is caused by mutations in the transthyretin (TTR) gene, where close to 100 different amyloidogenic mutations have been identified. FAP is found worldwide, but endemic areas with a high frequency of patients are found in Portugal, Japan and northern Sweden. Cases from these endemic areas all share the same TTR c.148G>A, p.V50M ("V30M") mutation, but the phenotype of the disease varies between the areas, and also within the endemic areas. The mean onset of the disease is two decades earlier in Portugal and Japan compared to Sweden, but late as well as early age at onset cases occur within all the populations. Interestingly, the different populations all display a maternal anticipation, where an earlier onset is observed for those individuals who inherit the trait from their mother. Since substantial variation in the phenotype is observed for different populations, epigenetic/genetic and/or environmental factors must exert a significant impact on the penetrance of the disease. Amyloid formation is caused by conformational changes of proteins, which facilitates their assembly into fibrils, amyloid. Oxidative stress can mediate conformational changes of proteins and since the mitochondria regulate oxidative processes within the cell, mitochondrial function may affect amyloid formation. The mitochondrial DNA is a non-nuclear DNA, which is entirely maternally inherited, and therefore could be related to the observed maternal anticipation of the disease. In addition, differences within the surrounding regions of the TTR gene may have an impact on the transcription of the gene and thereby on the expression of the different alleles.

    Material and methods. DNA from early and late onset V30M cases and from non-carriers (the latter utilised as controls) from Swedish, French, Japanese and Portuguese populations were analysed. In addition, DNA from healthy Swedish V30M carriers was analysed. Conventional analytical methods were employed, such as PCR, sequencing and genotyping. Conventional statistical methods used were t-test, Chi-squared test and maximum likelihood.

    Results. The study of V30M carrier frequency in two counties (Lycksele and Skellefteå) within the Swedish endemic area revealed a carrier frequency of 2.14% and 2.54%, respectively. The mitochondrial haplogroup analysis showed that in populations with generally late onset (French and Swedish), the haplogroup distribution of late onset cases resembled that of the controls derived from the same area, whereas haplogroup distribution for early onset patients was significantly different. The most pronounced difference was for the rare haplogroup K, of which early onset cases had a higher frequency than the controls. Analysis of the Portuguese population, with predominantly early onset, showed that haplogroup distribution for early onset cases were similar to the Portuguese control group, which had a different distribution than the Swedish control group. By analysis of pedigrees from Swedish and Portuguese patients it could be shown that mitochondrial genetic variation entirely could explain maternal anticipation in the Portuguese patients, whereas for Swedish patients, an additional parent of origin effect is present. Our analysis of the TTR gene disclosed a polymorphism (rs62093482) in the 3'UTR region of the Swedish patients. This polymorphism was found in all V30M carriers, irrespective of symptoms. In addition, homozygous TTR V30M carriers were homozygous also for the polymorphism. Since Swedish patients share a common founder this polymorphism thus is localised on the V30M allele. This polymorphism was found in only 4% of the Swedish controls. French controls showed the same frequency, but none of the French V30M patients displayed the polymorphism. In the Japanese population the polymorphism was not present at all. Interestingly, this polymorphism generates a potential binding site for microRNA and thereby possibly could down-regulate the expression of the mutated TTR allele.

    Conclusions. The carrier frequency in the endemic area is remarkably high, above 2% in the Lycksele and Skellefteå areas. The prevailing haplogroup distributions in the different endemic areas are consistent between the general population and the patient group with the predominant phenotype of that area. Mitochondrial genetic differences may explain maternal anticipation in Portuguese patients, and have an influence in Swedish patients. A polymorphism in the 3'UTR regulatory region of the mutated TTR allele is found in all Swedish patients. This polymorphism may down-regulate TTR V30M expression and thereby contribute to the late onset of the disease noted in the Swedish population.

  • 202.
    Olsson, Malin
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Planté-Bordeneuve, V
    Jonasson, J
    Lång, K
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mitochondrial haplogroup is associated with the phenotype of familial amyloidosis with polyneuropathy in Swedish and French patients2009In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 75, no 2, p. 163-168Article in journal (Refereed)
    Abstract [en]

    Familial amyloidotic polyneuropathy (FAP) is a monogenic disease caused by mutations in the transthyretin (TTR) gene. The phenotype of the most common TTR mutation, V30M, varies within and between populations. Oxidative stress and protein misfolding are cellular processes involved in the development of FAP. Because the mitochondria are important for both these processes, we investigated if mitochondrial haplogroups are related to age at onset of the disease in Swedish and French FAP patients. Mitochondrial haplogroup analysis was performed on 25 early-onset (below 40 years) and 29 late-onset (above 51 years) Swedish FAP patients. DNA from 249 Swedish individuals served as controls. In addition, 6 early-onset and 17 late-onset French FAP patients were examined with 25 French controls. The haplogroup distribution among late-onset Swedish and French cases was similar to that found in the general populations, whereas among early-onset cases a different haplogroup distribution was seen. The relatively rare haplogroup K was significantly more common among early-onset cases. Our findings substantiate the suggestion that a genetic component, still to be found, affecting mitochondrial function has an impact on the amyloid generating process in transthyretin amyloidosis.

  • 203.
    Olsson, Malin
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Jonasson, Jenni
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Cederquist, Kristina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Frequency of the transthyretin Val30Met mutation in the northern Swedish population2014In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 21, no 1, p. 18-20Article in journal (Other academic)
    Abstract [en]

    By genotyping a large number of samples from the Northern Sweden Health and Disease Study cohort, a carrier frequency could be determined for the Skelleftea and Lycksele populations. A previous study of the amyloidogenic transthyretin mutation TTRV30M in Northern Sweden's endemic area has shown a large variation in carrier frequency and penetrance of the trait within the area. However, the estimations have been based on a small sample size within the different regions in the area and therefore, the wide variation in TTRV30M carrier frequency observed between the Lycksele and Skelleftea populations are uncertain. Based on a total of 3460 samples, the estimated overall carrier frequency in the two regions was 1.82% with a carrier frequency in the Skelleftea and Lycksele population of 1.63% and 2.02%, respectively. Thus, the previously reported extremely high frequency in the Lycksele region compared to that of the Skelleftea region could not be substantiated. However, it does not change the previous finding of a surprisingly higher carrier frequency in the population from endemic area of Northern Sweden compared to that reported from endemic areas in Portugal.

  • 204.
    Olsson, Malin
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Norgren, Nina
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Obayashi, Konen
    Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
    Plante-Bordeneuve, Violaine
    Service de Neurologie, CHU Henri Mondor, Créteil, France.
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Cederquist, Kristina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Jonasson, Jenni
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    A possible role for miRNA silencing in disease phenotype variation in Swedish transthyretin V30M carriers2010In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 11, p. 130-Article in journal (Refereed)
    Abstract [en]

    Our results are the first to show the presence of a 3'UTR polymorphism on the V30M haplotype in Swedish carriers, which can serve as a miRNA binding site potentially leading to down-regulated expression from the mutated TTR allele. This finding may be related to the low penetrance and high age at onset of the disease observed in the Swedish patient population.

  • 205.
    Olsson, Malin
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Norgren, Nina
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Saraiva, Maria J
    Cederquist, Kristina
    Jonasson, Jenni
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Distribution of mitochondrial DNA haplogroups in Portuguese familial amyloidosis with polyneuropathy (FAP) patientsManuscript (preprint) (Other academic)
  • 206. Ostrom, Quinn T.
    et al.
    Coleman, Warren
    Huang, William
    Rubin, Joshua B.
    Lathia, Justin D.
    Berens, Michael E.
    Speyer, Gil
    Liao, Peter
    Wrensch, Margaret R.
    Eckel-Passow, Jeanette E.
    Armstrong, Georgina
    Rice, Terri
    Wiencke, John K.
    McCoy, Lucie S.
    Hansen, Helen M.
    Amos, Christopher I.
    Bernstein, Jonine L.
    Claus, Elizabeth B.
    Houlston, Richard S.
    Il'yasova, Dora
    Jenkins, Robert B.
    Johansen, Christoffer
    Lachance, Daniel H.
    Lai, Rose K.
    Merrell, Ryan T.
    Olson, Sara H.
    Sadetzki, Siegal
    Schildkraut, Joellen M.
    Shete, Sanjay
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Rajaraman, Preetha
    Chanock, Stephen J.
    Linet, Martha S.
    Wang, Zhaoming
    Yeager, Meredith
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Bondy, Melissa L.
    Barnholtz-Sloan, Jill S.
    Freeman, Laura E. Beane
    Koutros, Stella
    Albanes, Demetrius
    Visvanathan, Kala
    Stevens, Victoria L.
    Henriksson, Roger
    Michaud, Dominique S.
    Feychting, Maria
    Ahlbom, Anders
    Giles, Graham G.
    Milne, Roger
    McKean-Cowdin, Roberta
    Le Marchand, Loic
    Stampfer, Meir
    Ruder, Avima M.
    Carreon, Tania
    Hallmans, Goran
    Zeleniuch-Jacquotte, Anne
    Gaziano, J. Michael
    Sesso, Howard D.
    Purdue, Mark P.
    White, Emily
    Peters, Ulrike
    Buring, Julie
    Sex-specific gene and pathway modeling of inherited glioma risk2019In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 21, no 1, p. 71-82Article in journal (Refereed)
    Abstract [en]

    Background To date, genome-wide association studies (GWAS) have identified 25 risk variants for glioma, explaining 30% of heritable risk. Most histologies occur with significantly higher incidence in males, and this difference is not explained by currently known risk factors. A previous GWAS identified sex-specific glioma risk variants, and this analysis aims to further elucidate risk variation by sex using gene- and pathway-based approaches. Methods Results from the Glioma International Case-Control Study were used as a testing set, and results from 3 GWAS were combined via meta-analysis and used as a validation set. Using summary statistics for nominally significant autosomal SNPs (P < 0.01 in a previous meta-analysis) and nominally significant X-chromosome SNPs (P < 0.01), 3 algorithms (Pascal, BimBam, and GATES) were used to generate gene scores, and Pascal was used to generate pathway scores. Results were considered statistically significant in the discovery set when P < 3.3 x 10(-6) and in the validation set when P < 0.001 in 2 of 3 algorithms. Results Twenty-five genes within 5 regions and 19 genes within 6 regions reached statistical significance in at least 2 of 3 algorithms in males and females, respectively. EGFR was significantly associated with all glioma and glioblastoma in males only and a female-specific association in TERT, all of which remained nominally significant after conditioning on known risk loci. There were nominal associations with the BioCarta telomeres pathway in both males and females. Conclusions These results provide additional evidence that there may be differences by sex in genetic risk for glioma. Additional analyses may further elucidate the biological processes through which this risk is conferred.

  • 207.
    Park, Hyun-Sook
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Östberg, Yngve
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Johansson, Jörgen
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Wagner, E Gerhart
    Uhlin, Bernt Eric
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Novel role for a bacterial nucleoid protein in translation of mRNAs with suboptimal ribosome-binding sites2010In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 24, no 13, p. 1345-1350Article in journal (Refereed)
    Abstract [en]

    In Escherichia coli, the major nucleoid protein H-NS limits transcription by acting as a repressor or transcriptional silencer, presumably by its ability to close the looped chromosome domains in the nucleoid through DNA-protein-DNA bridging. Here, we demonstrate the direct involvement of H-NS as a positive factor stimulating translation of the malT mRNA. In vitro studies showed that H-NS facilitates a repositioning of the 30S preinitiation complex on the malT mRNA. H-NS stimulation of translation depended on the AU-rich -35 to -40 region of the mRNA. Several additional examples were found demonstrating a novel function for H-NS in translation of genes with suboptimal ribosome-binding sequences.

  • 208.
    Persson-Sjögren, Solveig
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Expression of the NK-1 receptor on islet cells and invading immune cells in the non-obese diabetic mouse2005In: Journal of Autoimmunity, ISSN 0896-8411, Vol. 24, no 4, p. 269-279Article in journal (Refereed)
    Abstract [en]

    The underlying mechanistic causes of immune cell infiltration in the islets of Langerhans and beta cell failure in the non-obese diabetic (NOD) mouse is still to be completely revealed. Substance P (SP) is a substance known to have pro-inflammatory, endocrine, neuromodulatory and trophic effects, and its preferred receptor, the neurokinin receptor 1 (NK-1 R), is reported to be involved in extravasation of granulocytes and in inflammation and tissue derangement. Therefore, we have investigated the expression of NK-1 R during development of insulitis in the NOD mouse. We show that the magnitude of immunoreactivity scoring NK-1 R expression in the islets was increased in the 12-week-old NOD mouse. Expression of NK-1 R co-localized with expression of glucagon. In line with this expression pattern, we did not detect any effect of SP on glucose-induced insulin release. NK-1 R expression was particularly observed in islet cells in association with the clusters of immune cells. Expression of NK-1 R was also demonstrated in a fraction of the infiltrating B and T lymphocytes, as well as on infiltrating macrophages and dendritic cells. The observations show that the level of NK-1 R expression is increased in 12-week-old NOD mice, being correlated with the occurrence of islet mononuclear infiltration. Our data suggest that SP may act as a chemoattractant, contributing to the pathogenic mononuclear infiltration process in the NOD mouse. On the whole, the observations suggest that SP and the NK-1 R to certain extents are involved in the changes that occur during the development of insulitis in the NOD mouse.

  • 209.
    Pettersson, Ulrika
    et al.
    Bone research group, Institution of Medical Sciences, University of Aberdeen .
    Albagha, Omar M E
    Bone research group, Institution of Medical Sciences, University of Aberdeen .
    Mirolo, Max
    Institute of Biomedical technology, CNR, Via Fratelli Cervi, Milano, Italy.
    Taranta, Anna
    Department of Experimental Medicine, University of L'Aquila, Italy.
    Frattini, Annalisa
    Institute of Biomedical technology, CNR, Via Fratelli Cervi, Milano, Italy.
    McGuigan, Fiona E A
    Bone research group, Institution of Medical Sciences, University of Aberdeen .
    Vezzoni, Paolo
    Institute of Biomedical technology, CNR, Via Fratelli Cervi, Milano, Italy.
    Teti, Anna
    Institute of Biomedical technology, CNR, Via Fratelli Cervi, Milano, Italy.
    van Hul, Wim
    Department of Medical Genetics, University Hospital of Antwerp, Belgium.
    Reid, David M
    Bone research group, Institution of Medical Sciences, University of Aberdeen .
    Villa, Anna
    Ralston, Stuart H
    Bone research group, Institution of Medical Sciences, University of Aberdeen .
    Polymorphisms of the CLCN7 gene are associated with BMD in women.2005In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 20, no 11, p. 1960-7Article in journal (Refereed)
    Abstract [en]

    UNLABELLED: Here we show that a common polymorphism causing a valine to methionine amino acid substitution at codon 418 (V418M) in the CLCN7 gene is associated with femoral neck BMD in women. Our study adds to accumulating evidence that shows that common allelic variants in monogenic bone disease genes often contribute to BMD regulation in normal subjects.

    INTRODUCTION: The CLCN7 gene is a strong candidate for regulation of BMD, because mutations in CLCN7 cause some forms of osteopetrosis, a disease characterized by impaired osteoclast function and increased BMD. In this study, we sought to determine whether common allelic variation within CLCN7 was associated with BMD in the normal population.

    MATERIALS AND METHODS: We conducted mutation screening of the exons and intron-exon boundaries in CLCN7 by DNA sequencing in 50 normal subjects. We conducted an association study between common polymorphisms in CLCN7 and haplotypes defined by these polymorphisms and BMD values at the lumbar spine and femoral neck in a population-based cohort study of 1077 Scottish women 45-55 years of age.

    RESULTS: We identified 24 polymorphisms, but most were rare and only 4 had allele frequencies of >5%. These were a conservative single nucleotide polymorphism (SNP) in exon 1 (rs3751884), a 50-bp tandem repeat polymorphism within intron 8, and two SNPs within exon 15 (rs12926089 and rs12926669), of which one (rs12926669) predicts an amino acid change from valine to methionine at codon 418 (V418M). The exon 15 SNPs were in strong linkage disequilibrium and were both associated with femoral neck BMD (p = 0.001-0.003). None of the other polymorphisms were associated with BMD, and long-range haplotypes showed a much weaker association with BMD than the exon 15 SNPs. The V418M polymorphism was an independent predictor of femoral neck BMD on multiple regression analysis accounting for 1% of the variance in BMD at this site.

    CONCLUSIONS: Our study indicates that the V418M polymorphism of CLCN7 contributes to the genetic regulation of femoral neck BMD in women and adds to accumulating evidence that indicates that subtle polymorphic variation in genes that cause monogenic bone diseases also contribute to regulation of BMD in normal subjects.

  • 210.
    Pettersson-Kymmer, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hanson, Aimee L
    Madeleine, Margaret M
    Wang, Sophia S
    Schwartz, Stephen M
    Newell, Felicity
    Pettersson-Kymmer, Ulrika
    Hemminki, Kari
    Tiews, Sven
    Steinberg, Winfried
    Rader, Janet S
    Castro, Felipe
    Safaeian, Mahboobeh
    Franco, Eduardo L
    Coutlée, François
    Ohlsson, Claes
    Cortes, Adrian
    Marshall, Mhairi
    Mukhopadhyay, Pamela
    Cremin, Katie
    Johnson, Lisa G
    Garland, Suzanne M
    Tabrizi, Sepehr N
    Wentzensen, Nicolas
    Sitas, Freddy
    Trimble, Cornelia
    Little, Julian
    Cruickshank, Maggie
    Frazer, Ian H
    Hildesheim, Allan
    Brown, Matthew A
    Duncan, Emma L
    Sun, YingPu
    Leo, Paul J
    HLA and KIR Associations of Cervical Neoplasia2018In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 218, no 12, p. 2006-2015Article in journal (Refereed)
    Abstract [en]

    Background: Cervical cancer is the fourth most common cancer in women, and we recently reported human leukocyte antigen (HLA) alleles showing strong associations with cervical neoplasia risk and protection. HLA ligands are recognised by killer immunoglobulin-like receptors (KIRs) expressed on a range of immune cell subsets, governing their proinflammatory activity. We hypothesized that the inheritance of particular HLA-KIR combinations would increase cervical neoplasia risk.

    Methods: Here, we used HLA and KIR dosages imputed from SNP genotype data from 2,143 cervical neoplasia cases and 13,858 healthy controls of European decent.

    Results: Four novel HLA alleles were identified in association with cervical neoplasia: HLA-DRB3*9901 (OR=1.24, P=2.49×10-9), HLA-DRB5*0101 (OR=1.29, P=2.26×10-8), HLA-DRB5*9901 (OR=0.77, P=1.90×10-9) and HLA-DRB3*0301 (OR=0.63, P=4.06×10-5), due to their linkage disequilibrium with known cervical neoplasia-associated HLA-DRB1 alleles. We also found homozygosity of HLA-C1 group alleles is a protective factor for HPV16-related cervical neoplasia (C1/C1, OR=0.79, P=0.005). This protective association was restricted to carriers of either KIR2DL2 (OR=0.67, P=0.00045) or KIR2DS2 (OR=0.69, P=0.0006).

    Conclusions: Our findings suggest that HLA-C1 group alleles play a role in protecting against HPV16-related cervical neoplasia, mainly through a KIR-mediated mechanism.

  • 211.
    Petzold, Katja
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Al-Hashimi, Hashim M
    RNA structure: adding a second dimension2011In: Nature Chemistry, ISSN 1755-4330, E-ISSN 1755-4349, Vol. 3, no 12, p. 913-915Article in journal (Refereed)
  • 212. Pihlstrøm, Lasse
    et al.
    Rengmark, Aina
    Bjørnarå, Kari Anne
    Dizdar, Nil
    Fardell, Camilla
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Holmberg, Björn
    Larsen, Jan Petter
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nissbrandt, Hans
    Tysnes, Ole-Bjørn
    Dietrichs, Espen
    Toft, Mathias
    Fine mapping and resequencing of the PARK16 locus in Parkinson's disease2015In: Journal of Human Genetics, ISSN 1434-5161, E-ISSN 1435-232X, Vol. 60, no 7, p. 357-362Article in journal (Refereed)
    Abstract [en]

    The PARK16 locus, spanning five genes on chromosome 1, was among the first genetic regions to show genome-wide association in Parkinson's disease (PD). Subsequent investigations have found variability in PARK16 top-hits and association patterns across populations, and the implicated genes and mechanisms are currently unclear. In the present study, we aimed to explore the contribution of PARK16 variability to PD risk in a Scandinavian population. We genotyped 17 single-nucleotide polymorphisms in a case-control sample set of 2570 individuals from Norway and Sweden to fine map the locus. Targeted resequencing of the full coding regions of SLC45A3, NUCKS1, RAB7L1, SLC41A1 and PM20D1 was performed in DNA pools from a subset of 387 patient samples. We find evidence for an association with PD for rs1775143 as well as a haplotype located around the 5' region of RAB7L1, implicating variants which are not in high linkage disequilibrium with the strongest signal from a recent large meta-analysis in Caucasians. We also provide suggestive support for epistasis between RAB7L1 and LRRK2 as previously hypothesized by others. Comparing our results with previous work, allelic heterogeneity at PARK16 appears likely, and further studies are warranted to disentangle the complex patterns of association and pinpoint the functionally relevant variants.

  • 213. Plagens, Andre
    et al.
    Richter, Hagen
    Charpentier, Emmanuelle
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Randau, Lennart
    DNA and RNA interference mechanisms by CRISPR-Cas surveillance complexes2015In: FEMS Microbiology Reviews, ISSN 0168-6445, E-ISSN 1574-6976, Vol. 39, no 3, p. 442-463Article, review/survey (Refereed)
    Abstract [en]

    The CRISPR (clustered regularly interspaced short palindromic repeats)-Cas (CRISPR-associated) adaptive immune systems use small guide RNAs, the CRISPR RNAs (crRNAs), to mark foreign genetic material, e.g. viral nucleic acids, for degradation. Archaea and bacteria encode a large variety of Cas proteins that bind crRNA molecules and build active ribonucleoprotein surveillance complexes. The evolution of CRISPR-Cas systems has resulted in a diversification of cas genes and a classification of the systems into three types and additional subtypes characterized by distinct surveillance and interfering complexes. Recent crystallographic and biochemical advances have revealed detailed insights into the assembly and DNA/RNA targeting mechanisms of the various complexes. Here, we review our knowledge on the molecular mechanism involved in the DNA and RNA interference stages of type I (Cascade: CRISPR-associated complex for antiviral defense), type II (Cas9) and type III (Csm, Cmr) CRISPR-Cas systems. We further highlight recently reported structural and mechanistic themes shared among these systems.

  • 214. Poveda, Alaitz
    et al.
    Chen, Yan
    Brändström, Anders
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR).
    Engberg, Elisabeth
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR).
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Clinical Research Centre, Lund University, Jan Waldenströms gata 35, Building 91, Skåne University Hospital, SE-20502 Malmö, Sweden.
    Kurbasic, Azra
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Clinical Research Centre, Lund University, Jan Waldenströms gata 35, Building 91, Skåne University Hospital, SE-20502 Malmö, Sweden; Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
    The heritable basis of gene-environment interactions in cardiometabolic traits2017In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, no 3, p. 442-452Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis Little is known about the heritable basis of gene-environment interactions in humans. We therefore screened multiple cardiometabolic traits to assess the probability that they are influenced by genotype-environment interactions.

    Methods Fourteen established environmental risk exposures and 11 cardiometabolic traits were analysed in the VIKING study, a cohort of 16,430 Swedish adults from 1682 extended pedigrees with available detailed genealogical, phenotypic and demographic information, using a maximum likelihood variance decomposition method in Sequential Oligogenic Linkage Analysis Routines software.

    Results All cardiometabolic traits had statistically significant heritability estimates, with narrow-sense heritabilities (h (2)) ranging from 24% to 47%. Genotype-environment interactions were detected for age and sex (for the majority of traits), physical activity (for triacylglycerols, 2 h glucose and diastolic BP), smoking (for weight), alcohol intake (for weight, BMI and 2 h glucose) and diet pattern (for weight, BMI, glycaemic traits and systolic BP). Genotype-age interactions for weight and systolic BP, genotype-sex interactions for BMI and triacylglycerols and genotype-alcohol intake interactions for weight remained significant after multiple test correction.

    Conclusion/hypothesis Age, sex and alcohol intake are likely to be major modifiers of genetic effects for a range of cardiometabolic traits. This information may prove valuable for studies that seek to identify specific loci that modify the effects of lifestyle in cardiometabolic disease.

  • 215. Purdue, Mark P
    et al.
    Johansson, Mattias
    International Agency for Research on Cancer (IARC), Lyon, France.
    Zelenika, Diana
    Toro, Jorge R
    Scelo, Ghislaine
    Moore, Lee E
    Prokhortchouk, Egor
    Wu, Xifeng
    Kiemeney, Lambertus A
    Gaborieau, Valerie
    Jacobs, Kevin B
    Chow, Wong-Ho
    Zaridze, David
    Matveev, Vsevolod
    Lubinski, Jan
    Trubicka, Joanna
    Szeszenia-Dabrowska, Neonila
    Lissowska, Jolanta
    Rudnai, Péter
    Fabianova, Eleonora
    Bucur, Alexandru
    Bencko, Vladimir
    Foretova, Lenka
    Janout, Vladimir
    Boffetta, Paolo
    Colt, Joanne S
    Davis, Faith G
    Schwartz, Kendra L
    Banks, Rosamonde E
    Selby, Peter J
    Harnden, Patricia
    Berg, Christine D
    Hsing, Ann W
    Grubb, Robert L
    Boeing, Heiner
    Vineis, Paolo
    Clavel-Chapelon, Françoise
    Palli, Domenico
    Tumino, Rosario
    Krogh, Vittorio
    Panico, Salvatore
    Duell, Eric J
    Quirós, José Ramón
    Sanchez, Maria-José
    Navarro, Carmen
    Ardanaz, Eva
    Dorronsoro, Miren
    Khaw, Kay-Tee
    Allen, Naomi E
    Bueno-de-Mesquita, H Bas
    Peeters, Petra H M
    Trichopoulos, Dimitrios
    Linseisen, Jakob
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Overvad, Kim
    Tjønneland, Anne
    Romieu, Isabelle
    Riboli, Elio
    Mukeria, Anush
    Shangina, Oxana
    Stevens, Victoria L
    Thun, Michael J
    Diver, W Ryan
    Gapstur, Susan M
    Pharoah, Paul D
    Easton, Douglas F
    Albanes, Demetrius
    Weinstein, Stephanie J
    Virtamo, Jarmo
    Vatten, Lars
    Hveem, Kristian
    Njølstad, Inger
    Tell, Grethe S
    Stoltenberg, Camilla
    Kumar, Rajiv
    Koppova, Kvetoslava
    Cussenot, Olivier
    Benhamou, Simone
    Oosterwijk, Egbert
    Vermeulen, Sita H
    Aben, Katja K H
    van der Marel, Saskia L
    Ye, Yuanqing
    Wood, Christopher G
    Pu, Xia
    Mazur, Alexander M
    Boulygina, Eugenia S
    Chekanov, Nikolai N
    Foglio, Mario
    Lechner, Doris
    Gut, Ivo
    Heath, Simon
    Blanche, Hélène
    Hutchinson, Amy
    Thomas, Gilles
    Wang, Zhaoming
    Yeager, Meredith
    Fraumeni, Joseph F
    Skryabin, Konstantin G
    McKay, James D
    Rothman, Nathaniel
    Chanock, Stephen J
    Lathrop, Mark
    Brennan, Paul
    Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.32011In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 43, no 1, p. 60-65Article in journal (Refereed)
    Abstract [en]

    We conducted a two-stage genome-wide association study of renal cell carcinoma (RCC) in 3,772 affected individuals (cases) and 8,505 controls of European background from 11 studies and followed up 6 SNPs in 3 replication studies of 2,198 cases and 4,918 controls. Two loci on the regions of 2p21 and 11q13.3 were associated with RCC susceptibility below genome-wide significance. Two correlated variants (r² = 0.99 in controls), rs11894252 (P = 1.8 × 10⁻⁸) and rs7579899 (P = 2.3 × 10⁻⁹), map to EPAS1 on 2p21, which encodes hypoxia-inducible-factor-2 alpha, a transcription factor previously implicated in RCC. The second locus, rs7105934, at 11q13.3, contains no characterized genes (P = 7.8 × 10⁻¹⁴). In addition, we observed a promising association on 12q24.31 for rs4765623, which maps to SCARB1, the scavenger receptor class B, member 1 gene (P = 2.6 × 10⁻⁸). Our study reports previously unidentified genomic regions associated with RCC risk that may lead to new etiological insights.

  • 216. Randall, Joshua C
    et al.
    Winkler, Thomas W
    Kutalik, Zoltán
    Berndt, Sonja I
    Jackson, Anne U
    Monda, Keri L
    Kilpeläinen, Tuomas O
    Esko, Tõnu
    Mägi, Reedik
    Li, Shengxu
    Workalemahu, Tsegaselassie
    Feitosa, Mary F
    Croteau-Chonka, Damien C
    Day, Felix R
    Fall, Tove
    Ferreira, Teresa
    Gustafsson, Stefan
    Locke, Adam E
    Mathieson, Iain
    Scherag, Andre
    Vedantam, Sailaja
    Wood, Andrew R
    Liang, Liming
    Steinthorsdottir, Valgerdur
    Thorleifsson, Gudmar
    Dermitzakis, Emmanouil T
    Dimas, Antigone S
    Karpe, Fredrik
    Min, Josine L
    Nicholson, George
    Clegg, Deborah J
    Person, Thomas
    Krohn, Jon P
    Bauer, Sabrina
    Buechler, Christa
    Eisinger, Kristina
    Bonnefond, Amélie
    Froguel, Philippe
    Hottenga, Jouke-Jan
    Prokopenko, Inga
    Waite, Lindsay L
    Harris, Tamara B
    Smith, Albert Vernon
    Shuldiner, Alan R
    McArdle, Wendy L
    Caulfield, Mark J
    Munroe, Patricia B
    Grönberg, Henrik
    Chen, Yii-Der Ida
    Li, Guo
    Beckmann, Jacques S
    Johnson, Toby
    Thorsteinsdottir, Unnur
    Teder-Laving, Maris
    Khaw, Kay-Tee
    Wareham, Nicholas J
    Zhao, Jing Hua
    Amin, Najaf
    Oostra, Ben A
    Kraja, Aldi T
    Province, Michael A
    Cupples, L Adrienne
    Heard-Costa, Nancy L
    Kaprio, Jaakko
    Ripatti, Samuli
    Surakka, Ida
    Collins, Francis S
    Saramies, Jouko
    Tuomilehto, Jaakko
    Jula, Antti
    Salomaa, Veikko
    Erdmann, Jeanette
    Hengstenberg, Christian
    Loley, Christina
    Schunkert, Heribert
    Lamina, Claudia
    Wichmann, H Erich
    Albrecht, Eva
    Gieger, Christian
    Hicks, Andrew A
    Johansson, Asa
    Pramstaller, Peter P
    Kathiresan, Sekar
    Speliotes, Elizabeth K
    Penninx, Brenda
    Hartikainen, Anna-Liisa
    Jarvelin, Marjo-Riitta
    Gyllensten, Ulf
    Boomsma, Dorret I
    Campbell, Harry
    Wilson, James F
    Chanock, Stephen J
    Farrall, Martin
    Goel, Anuj
    Medina-Gomez, Carolina
    Rivadeneira, Fernando
    Estrada, Karol
    Uitterlinden, André G
    Hofman, Albert
    Zillikens, M Carola
    den Heijer, Martin
    Kiemeney, Lambertus A
    Maschio, Andrea
    Hall, Per
    Tyrer, Jonathan
    Teumer, Alexander
    Völzke, Henry
    Kovacs, Peter
    Tönjes, Anke
    Mangino, Massimo
    Spector, Tim D
    Hayward, Caroline
    Rudan, Igor
    Hall, Alistair S
    Samani, Nilesh J
    Attwood, Antony Paul
    Sambrook, Jennifer G
    Hung, Joseph
    Palmer, Lyle J
    Lokki, Marja-Liisa
    Sinisalo, Juha
    Boucher, Gabrielle
    Huikuri, Heikki
    Lorentzon, Mattias
    Ohlsson, Claes
    Eklund, Niina
    Eriksson, Johan G
    Barlassina, Cristina
    Rivolta, Carlo
    Nolte, Ilja M
    Snieder, Harold
    Van der Klauw, Melanie M
    Van Vliet-Ostaptchouk, Jana V
    Gejman, Pablo V
    Shi, Jianxin
    Jacobs, Kevin B
    Wang, Zhaoming
    Bakker, Stephan J L
    Mateo Leach, Irene
    Navis, Gerjan
    van der Harst, Pim
    Martin, Nicholas G
    Medland, Sarah E
    Montgomery, Grant W
    Yang, Jian
    Chasman, Daniel I
    Ridker, Paul M
    Rose, Lynda M
    Lehtimäki, Terho
    Raitakari, Olli
    Absher, Devin
    Iribarren, Carlos
    Basart, Hanneke
    Hovingh, Kees G
    Hyppönen, Elina
    Power, Chris
    Anderson, Denise
    Beilby, John P
    Hui, Jennie
    Jolley, Jennifer
    Sager, Hendrik
    Bornstein, Stefan R
    Schwarz, Peter E H
    Kristiansson, Kati
    Perola, Markus
    Lindström, Jaana
    Swift, Amy J
    Uusitupa, Matti
    Atalay, Mustafa
    Lakka, Timo A
    Rauramaa, Rainer
    Bolton, Jennifer L
    Fowkes, Gerry
    Fraser, Ross M
    Price, Jackie F
    Fischer, Krista
    Krjutå Kov, Kaarel
    Metspalu, Andres
    Mihailov, Evelin
    Langenberg, Claudia
    Luan, Jian'an
    Ong, Ken K
    Chines, Peter S
    Keinanen-Kiukaanniemi, Sirkka M
    Saaristo, Timo E
    Edkins, Sarah
    Franks, Paul W
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Shungin, Dmitry
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Morris, Andrew David
    Palmer, Colin N A
    Erbel, Raimund
    Moebus, Susanne
    Nöthen, Markus M
    Pechlivanis, Sonali
    Hveem, Kristian
    Narisu, Narisu
    Hamsten, Anders
    Humphries, Steve E
    Strawbridge, Rona J
    Tremoli, Elena
    Grallert, Harald
    Thorand, Barbara
    Illig, Thomas
    Koenig, Wolfgang
    Müller-Nurasyid, Martina
    Peters, Annette
    Boehm, Bernhard O
    Kleber, Marcus E
    März, Winfried
    Winkelmann, Bernhard R
    Kuusisto, Johanna
    Laakso, Markku
    Arveiler, Dominique
    Cesana, Giancarlo
    Kuulasmaa, Kari
    Virtamo, Jarmo
    Yarnell, John W G
    Kuh, Diana
    Wong, Andrew
    Lind, Lars
    de Faire, Ulf
    Gigante, Bruna
    Magnusson, Patrik K E
    Pedersen, Nancy L
    Dedoussis, George
    Dimitriou, Maria
    Kolovou, Genovefa
    Kanoni, Stavroula
    Stirrups, Kathleen
    Bonnycastle, Lori L
    Njølstad, Inger
    Wilsgaard, Tom
    Ganna, Andrea
    Rehnberg, Emil
    Hingorani, Aroon
    Kivimaki, Mika
    Kumari, Meena
    Assimes, Themistocles L
    Barroso, Inês
    Boehnke, Michael
    Borecki, Ingrid B
    Deloukas, Panos
    Fox, Caroline S
    Frayling, Timothy
    Groop, Leif C
    Haritunians, Talin
    Hunter, David
    Ingelsson, Erik
    Kaplan, Robert
    Mohlke, Karen L
    O'Connell, Jeffrey R
    Schlessinger, David
    Strachan, David P
    Stefansson, Kari
    van Duijn, Cornelia M
    Abecasis, Gonçalo R
    McCarthy, Mark I
    Hirschhorn, Joel N
    Qi, Lu
    Loos, Ruth J F
    Lindgren, Cecilia M
    North, Kari E
    Heid, Iris M
    Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits2013In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 6, p. e1003500-Article in journal (Refereed)
    Abstract [en]

    Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.

  • 217.
    Rasmuson, Marianne
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Genealogy and gene trees2008In: Hereditas, ISSN 0018-0661, E-ISSN 1601-5223, Vol. 145, no 1, p. 20-27Article in journal (Refereed)
    Abstract [en]

    Heredity can be followed in persons or in genes. Persons can be identified only a few generations back, but simplified models indicate that universal ancestors to all now living persons have occurred in the past. Genetic variability can be characterized as variants of DNA sequences. Data are available only from living persons, but from the pattern of variation gene trees can be inferred by means of coalescence models. The merging of lines backwards in time leads to a MRCA (most recent common ancestor). The time and place of living for this inferred person can give insights in human evolutionary history. Demographic processes are incorporated in the model, but since culture and customs are known to influence demography the models used ought to be tested against available genealogy. The Icelandic data base offers a possibility to do so and points to some discrepancies. Mitochondrial DNA and Y chromosome patterns give a rather consistent view of human evolutionary history during the latest 100 000 years but the earlier epochs of human evolution demand gene trees with longer branches. The results of such studies reveal as yet unsolved problems about the sources of our genome.

  • 218.
    Rawcliffe, Denise
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Muscle Specific Aberrant Splicing of Mutated ISCU in Hereditary Myopathy with Lactic Acidosis2013Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
  • 219.
    Rawcliffe, Denise F. R.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    The regulation of incorrect splicing of ISCU in hereditary myopathy with lactic acidosis2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Patients suffering from hereditary myopathy with lactic acidosis (HML) can be found in the northern Swedish counties of Ångermanland and Västerbotten. HML is a rare autosomal recessive disease where patients display a low tolerance to exercise at an early age. Exercise can trigger symptoms such as palpitations, tachycardia, muscle cramps and dyspnoea. Extensive exercise or strict diets can result in myoglobinuria and life-threatening levels of lactic acid. The disease is caused by a nonsense G > C mutation (c.418 + 328G < C) in the last intron of the iron-sulphur (FeS) cluster assembly gene (ISCU), resulting in nonsense-mediated decay (NMD) of the transcript due to incorrect splicing. The ISCU protein is involved in the assembly of FeS clusters, which are essential cofactors for a wide range of proteins. Patient muscles display decreased levels of several FeS cluster proteins: mitochondrial aconitase in the tricarboxylic acid (TCA) cycle and Complex I, II (succinate dehydrogenase [SDH]) and III in the electron transport chain (ETC). The incorrect splicing of ISCU occurs to the highest extent in HML patient skeletal muscle, restricting the loss of ISCU protein to muscles, thereby preventing a more severe phenotype.

    We found that the incorrect splicing occurs to the highest extent in slow-fibre muscle, which may be caused by the serine/arginine-rich splicing factor (SRSF3) as it is expressed at higher levels in slow-fibre muscle compared to other muscles, and since it is able to activate the incorrect splicing of ISCU. Following muscle, there is a gradual decrease of the incorrect splicing in heart, brain, liver and kidney, which is negatively correlated with the levels of the splicing inhibitor polypyrimidine-tract binding protein 1 (PTBP1). Overexpression of PTBP1 in HML patient myoblasts resulted in a drastic decrease in the incorrect splicing, while a PTBP1 knockdown had the opposite effect. Our results suggest that PTBP1 acts as a dominant inhibitor of the incorrect splicing and is likely the main cause for the tissue-specific splicing of ISCU in HML. We also identified RBM39 and MBNL1 as activators of the incorrect splicing of ISCU, which, together with the low levels of PTBP1, could explain the high levels of incorrect splicing in muscle.

    Since almost 95% of all human gene transcripts are alternatively spliced, it is not surprising that a wide range of diseases are caused by mutations that affect splicing. Further knowledge of the function of splicing, such as tissue-specific splicing, can provide vital information for the development of therapies for diseases caused by splicing.

  • 220.
    Rawcliffe, Denise F. R.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Johansson, Malin
    Österman, Lennart
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    MBNL1 and RBM39 can activate the incorrect splicing of ISCU and the aberrant transcript is a target for nonsense-mediated decayManuscript (preprint) (Other academic)
  • 221.
    Rawcliffe, Denise F. R.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Österman, Lennart
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Lindsten, Hans
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience, Umeå University Hospital, Umeå, Sweden .
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    The High Level of Aberrant Splicing of ISCU in Slow-Twitch Muscle May Involve the Splicing Factor SRSF32016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, article id e0165453Article in journal (Refereed)
    Abstract [en]

    Hereditary myopathy with lactic acidosis (HML) is an autosomal recessive disease caused by an intronic one-base mutation in the iron-sulfur cluster assembly (ISCU) gene, resulting in aberrant splicing. The incorrectly spliced transcripts contain a 100 or 86 bp intron sequence encoding a non-functional ISCU protein, which leads to defects in several Fe-S containing proteins in the respiratory chain and the TCA cycle. The symptoms in HML are restricted to skeletal muscle, and it has been proposed that this effect is due to higher levels of incorrectly spliced ISCU in skeletal muscle compared with other energy-demanding tissues. In this study, we confirm that skeletal muscle contains the highest levels of incorrect ISCU splice variants compared with heart, brain, liver and kidney using a transgenic mouse model expressing human HML mutated ISCU. We also show that incorrect splicing occurs to a significantly higher extent in the slow-twitch soleus muscle compared with the gastrocnemius and quadriceps. The splicing factor serine/arginine-rich splicing factor 3 (SRSF3) was identified as a potential candidate for the slow fiber specific regulation of ISCU splicing since this factor was expressed at higher levels in the soleus compared to the gastrocnemius and quadriceps. We identified an interaction between SRSF3 and the ISCU transcript, and by overexpressing SRSF3 in human myoblasts we observed increased levels of incorrectly spliced ISCU, while knockdown of SRSF3 resulted in decreased levels. We therefore suggest that SRSF3 may participate in the regulation of the incorrect splicing of mutant ISCU and may, at least partially, explain the muscle-specific symptoms of HML.

  • 222.
    Rawcliffe, Denise F. R.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Österman, Lennart
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Nordin, Angelica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    PTBP1 acts as a dominant repressor of the aberrant tissue-specific splicing of ISCU in hereditary myopathy with lactic acidosis2018In: Molecular Genetics & Genomic Medicine, ISSN 2324-9269, Vol. 6, no 6, p. 887-897Article in journal (Refereed)
    Abstract [en]

    Background: Hereditary myopathy with lactic acidosis (HML) is an autosomal recessive disease caused by an intron mutation in the iron-sulfur cluster assembly (ISCU) gene. The mutation results in aberrant splicing, where part of the intron is retained in the final mRNA transcript, giving rise to a truncated nonfunctional ISCU protein. Using an ISCU mini-gene system, we have previously shown that PTBP1 can act as a repressor of the mis-splicing of ISCU, where overexpression of PTBP1 resulted in a decrease of the incorrect splicing. In this study, we wanted to, in more detail, analyze the role of PTBP1 in the regulation of endogenous ISCU mis-splicing.

    Methods: Overexpression and knockdown of PTBP1 was performed in myoblasts from two HML patients and a healthy control. Quantification of ISCU mis-splicing was done by qRTPCR. Biotinylated ISCU RNA, representing wildtype and mutant intron sequence, was used in a pull-down assay with nuclear extracts from myoblasts. Levels of PTBP1 in human cell lines and mice tissues were analyzed by qRTPCR and western blot.

    Results: PTBP1 overexpression in HML patient myoblasts resulted in a substantial decrease of ISCU mis-splicing while knockdown of PTBP1 resulted in a drastic increase. The effect could be observed in both patient and control myoblasts. We could also show that PTBP1 interacts with both the mutant and wild-type ISCU intron sequence, but with a higher affinity to the mutant sequence. Furthermore, low levels of PTBP1 among examined mouse tissues correlated with high levels of incorrect splicing of ISCU.

    Conclusion: Our results show that PTBP1 acts as a dominant repressor of ISCU mis-splicing. We also show an inverse correlation between the levels of PTBP1 and ISCU mis-splicing, suggesting that the high level of mis-splicing in the skeletal muscle is primarily due to the low levels of PTBP1.

  • 223. Renard, Marjolijn
    et al.
    Callewaert, Bert
    Baetens, Machteld
    Campens, Laurence
    MacDermot, Kay
    Fryns, Jean-Pierre
    Bonduelle, Maryse
    Dietz, Harry C.
    Gaspar, Isabel Mendes
    Cavaco, Diogo
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Schrander-Stumpel, Constance
    Coucke, Paul
    Loeys, Bart
    De Paepe, Anne
    De Backer, Julie
    Novel MYH11 and ACTA2 mutations reveal a role for enhanced TGF beta signaling in FTAAD2013In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 165, no 2, p. 314-321Article in journal (Refereed)
    Abstract [en]

    Background: Thoracic aortic aneurysm/dissection (TAAD) is a common phenotype that may occur as an isolated manifestation or within the constellation of a defined syndrome. In contrast to syndromic TAAD, the elucidation of the genetic basis of isolated TAAD has only recently started. To date, defects have been found in genes encoding extracellular matrix proteins (fibrillin-1, FBN1; collagen type III alpha 1, COL3A1), proteins involved in transforming growth factor beta (TGF beta) signaling (TGF beta receptor 1 and 2, TGFBR1/2; and SMAD3) or proteins that build up the contractile apparatus of aortic smooth muscle cells (myosin heavy chain 11, MYH11; smooth muscle actin alpha 2, ACTA2; and MYLK).

    Methods and result: In 110 non-syndromic TAAD patients that previously tested negative for FBN1 or TGFBR1/2 mutations, we identified 7 ACTA2 mutations in a cohort of 43 familial TAAD patients, including 2 premature truncating mutations. Sequencing of MYH11 revealed an in frame splice-site alteration in one out of two probands with TAA(D) associated with PDA but none in the series of 22 probands from the cohort of 110 patients with non-syndromic TAAD. Interestingly, immunohistochemical staining of aortic biopsies of a patient and a family member with MYH11 and patients with ACTA2 missense mutations showed upregulation of the TGF beta signaling pathway.

    Conclusions: MYH11 mutations are rare and typically identified in patients with TAAD associated with PDA. ACTA2 mutations were identified in 16% of a cohort presenting familial TAAD. Different molecular defects in TAAD may account for a different pathogenic mechanism of enhanced TGF beta signaling.

    (C) 2011 Elsevier Ireland Ltd. All rights reserved.

  • 224.
    Rentoft, Matilda
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Svensson, Daniel
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sjödin, Andreas
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Division of CBRN Security and Defence, FOI–Swedish Defence Research Agency, SE Umeå, Sweden.
    Olason, Pall I.
    Sjöström, Olle
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Unit of research, education and development, Region Jämtland Härjedalen, SE Östersund, Sweden.
    Nylander, Carin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Osterman, Pia
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Sjögren, Rickard
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Netotea, Sergiu
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Science for Life Laboratory, Department of Biology and Biological Engineering, Chalmers University of Technology, SE Göteborg, Sweden.
    Wibom, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Cederquist, Kristina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Chabes, Andrei
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johansson, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    A geographically matched control population efficiently limits the number of candidate disease-causing variants in an unbiased whole-genome analysis2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 3, article id e0213350Article in journal (Refereed)
    Abstract [en]

    Whole-genome sequencing is a promising approach for human autosomal dominant disease studies. However, the vast number of genetic variants observed by this method constitutes a challenge when trying to identify the causal variants. This is often handled by restricting disease studies to the most damaging variants, e.g. those found in coding regions, and overlooking the remaining genetic variation. Such a biased approach explains in part why the genetic causes of many families with dominantly inherited diseases, in spite of being included in whole-genome sequencing studies, are left unsolved today. Here we explore the use of a geographically matched control population to minimize the number of candidate disease-causing variants without excluding variants based on assumptions on genomic position or functional predictions. To exemplify the benefit of the geographically matched control population we apply a typical disease variant filtering strategy in a family with an autosomal dominant form of colorectal cancer. With the use of the geographically matched control population we end up with 26 candidate variants genome wide. This is in contrast to the tens of thousands of candidates left when only making use of available public variant datasets. The effect of the local control population is dual, it (1) reduces the total number of candidate variants shared between affected individuals, and more importantly (2) increases the rate by which the number of candidate variants are reduced as additional affected family members are included in the filtering strategy. We demonstrate that the application of a geographically matched control population effectively limits the number of candidate disease-causing variants and may provide the means by which variants suitable for functional studies are identified genome wide.

  • 225. Rothman, Nathaniel
    et al.
    Garcia-Closas, Montserrat
    Chatterjee, Nilanjan
    Malats, Nuria
    Wu, Xifeng
    Figueroa, Jonine D
    Real, Francisco X
    Van Den Berg, David
    Matullo, Giuseppe
    Baris, Dalsu
    Thun, Michael
    Kiemeney, Lambertus A
    Vineis, Paolo
    De Vivo, Immaculata
    Albanes, Demetrius
    Purdue, Mark P
    Rafnar, Thorunn
    Hildebrandt, Michelle A T
    Kiltie, Anne E
    Cussenot, Olivier
    Golka, Klaus
    Kumar, Rajiv
    Taylor, Jack A
    Mayordomo, Jose I
    Jacobs, Kevin B
    Kogevinas, Manolis
    Hutchinson, Amy
    Wang, Zhaoming
    Fu, Yi-Ping
    Prokunina-Olsson, Ludmila
    Burdett, Laurie
    Yeager, Meredith
    Wheeler, William
    Tardón, Adonina
    Serra, Consol
    Carrato, Alfredo
    García-Closas, Reina
    Lloreta, Josep
    Johnson, Alison
    Schwenn, Molly
    Karagas, Margaret R
    Schned, Alan
    Andriole, Gerald
    Grubb, Robert
    Black, Amanda
    Jacobs, Eric J
    Diver, W Ryan
    Gapstur, Susan M
    Weinstein, Stephanie J
    Virtamo, Jarmo
    Cortessis, Victoria K
    Gago-Dominguez, Manuela
    Pike, Malcolm C
    Stern, Mariana C
    Yuan, Jian-Min
    Hunter, David J
    McGrath, Monica
    Dinney, Colin P
    Czerniak, Bogdan
    Chen, Meng
    Yang, Hushan
    Vermeulen, Sita H
    Aben, Katja K
    Witjes, J Alfred
    Makkinje, Remco R
    Sulem, Patrick
    Besenbacher, Soren
    Stefansson, Kari
    Riboli, Elio
    Brennan, Paul
    Panico, Salvatore
    Navarro, Carmen
    Allen, Naomi E
    Bueno-de-Mesquita, H Bas
    Trichopoulos, Dimitrios
    Caporaso, Neil
    Landi, Maria Teresa
    Canzian, Federico
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Tjonneland, Anne
    Clavel-Chapelon, Francoise
    Bishop, David T
    Teo, Mark T W
    Knowles, Margaret A
    Guarrera, Simonetta
    Polidoro, Silvia
    Ricceri, Fulvio
    Sacerdote, Carlotta
    Allione, Alessandra
    Cancel-Tassin, Geraldine
    Selinski, Silvia
    Hengstler, Jan G
    Dietrich, Holger
    Fletcher, Tony
    Rudnai, Peter
    Gurzau, Eugen
    Koppova, Kvetoslava
    Bolick, Sophia C E
    Godfrey, Ashley
    Xu, Zongli
    Sanz-Velez, José I
    D García-Prats, María
    Sanchez, Manuel
    Valdivia, Gabriel
    Porru, Stefano
    Benhamou, Simone
    Hoover, Robert N
    Fraumeni, Joseph F
    Silverman, Debra T
    Chanock, Stephen J
    A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci2010In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 42, no 11, p. 978-984Article in journal (Refereed)
    Abstract [en]

    We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis.

  • 226. Rukh, G
    et al.
    Ahmad, S
    Ericson, U
    Hindy, G
    Stocks, Tanja
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Renström, F
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Almgren, P
    Nilsson, P M
    Melander, O
    Franks, Paul W
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Orho-Melander, M
    Inverse relationship between a genetic risk score of 31 BMI loci and weight change before and after reaching middle age2016In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 40, no 2, p. 252-259Article in journal (Refereed)
    Abstract [en]

    BACKGROUND/OBJECTIVE: Genome-wide-association studies have identified numerous body mass index (BMI)-associated variants, but it is unclear how these relate to weight gain in adults at different ages.

    METHODS: We examined the association of a genetic risk score (GRS), consisting of 31 BMI-associated variants, with an annual weight change (AWC) and a substantial weight gain (SWG) of 10% by comparing self-reported weight at 20 years (y) with baseline weight (mean: 58 y; s.d.: 8 y) in 21407 participants from the Malmö Diet and Cancer Study (MDCS), and comparing baseline weight to weight at follow-up (mean: 73 y; s.d.: 6 y) among 2673 participants. Association between GRS and AWG and SWG was replicated in 4327 GLACIER (Gene x Lifestyle interactions And Complex traits Involved in Elevated disease Risk) participants (mean: 45 y; s.d.: 7 y) with 10 y follow-up. Cohort-specific results were pooled by fixed-effect meta-analyses.

    RESULTS: In MDCS, the GRS was associated with increased AWC (β: 0.003; s.e: 0.01; P: 7 × 10(-8)) and increased odds for SWG (odds ratio (OR) 1.01 (95% confidence interval (CI): 1.00, 1.02); P: 0.013) per risk-allele from age 20y, but unexpectedly with decreased AWC (β: -0.006; s.e: 0.002; P: 0.009) and decreased odds for SWG OR 0.96 (95% CI: 0.93, 0.98); P: 0.001) between baseline and follow-up. Effect estimates from age 20 y to baseline differed significantly from those from baseline to follow-up (P: 0.0002 for AWC and P: 0.0001 for SWG). Similar to MDCS, the GRS was associated with decreased odds for SWG OR 0.98 (95% CI: 0.96, 1.00); P: 0.029) from baseline to follow-up in GLACIER. In meta-analyses (n=7000), the GRS was associated with decreased AWC (β: -0.005; s.e.m. 0.002; P: 0.002) and decreased odds for SWG OR 0.97 (95% CI: 0.96, 0.99); P: 0.001) per risk-allele.

    CONCLUSIONS: Our results provide convincing evidence for a paradoxical inversed relationship between a high number of BMI-associated risk-alleles and less weight gain during and after middle-age, in contrast to the expected increased weight gain seen in younger age.

  • 227.
    Sahlman, Janne
    et al.
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Inkinen, Ritva
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Hirvonen, Teemu
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Lammi, Pirkko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Nieminen, Jyrki
    Department of Surgery, Tampere University Hospital, Tampere, Finland.
    Lapveteläinen, Tuomo
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Prockop, Darwin
    Center for Gene Therapy, School of Medicine, MCP Hahnemann University, Philadelphia, Pennsylvania, USA.
    Arita, Machiko
    Center for Gene Therapy, School of Medicine, MCP Hahnemann University, Philadelphia, Pennsylvania, USA.
    Li, Shi-Wu
    Center for Gene Therapy, School of Medicine, MCP Hahnemann University, Philadelphia, Pennsylvania, USA.
    Hyttinen, Mika
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Helminen, Heikki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Puustjärvi, Kaija
    Department of Physical Medicine and Rehabilitation, Kuopio University Hospital, Kuopio, Finland.
    Premature vertebral endplate ossification and mild disc degeneration in mice after inactivation of one allele belonging to the Col2a1 gene for Type II collagen.2001In: Spine, ISSN 0362-2436, E-ISSN 1528-1159, Vol. 26, no 23, p. 2558-2565, article id 11725236Article in journal (Refereed)
    Abstract [en]

    STUDY DESIGN: Skeletal tissues of mice with an inactivated allele of the Col2a1 gene for Type II collagen ("heterozygous knockout") were studied.

    OBJECTIVE: To determine whether a heterozygous inactivation of the Col2a1 gene has a role in the etiology of spine disorders such as disc degeneration.

    SUMMARY OF BACKGROUND DATA: Mutations in the COL2A1, COL11A1, COL11A2, and COL9A2 genes have been linked to spine disorders. However, the mechanism by which genetic factors lead to disc degeneration still are largely unknown.

    METHODS: Spine tissues were studied using radiograph analyses; conventional, quantitative, and polarized light microscopy; immunohistochemistry for the major extracellular components, and in situ hybridization for procollagens alpha1(I) and alpha1(II). Voluntary running activity also was monitored in half of the mice.

    RESULTS: As the findings showed, 1-month-old heterozygous knockout mice had shorter limb bones, skulls, and spines, as well as thicker and more irregular vertebral endplates, which calcified earlier than in the control mice. They also had a lower concentration of glycosaminoglycans in the anulus fibrosus, in the endplates, and in the vertebral bone than the controls. These features in the heterozygous knockout mice were compensated by the age of 15 months. However, the long bones and skulls of the mature heterozygous mice remained shorter than those of the controls. Gene-deficient mice used the running wheel less. However, physical exercise did not induce any marked structural changes in the skeleton.

    CONCLUSION: Mice with heterozygous knockout of Col2a1 show subtle early skeletal manifestations that bear some resemblance to those of human spine disorders.

  • 228. Salmela, Elina
    et al.
    Lappalainen, Tuuli
    Fransson, Ingegerd
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Dahlman-Wright, Karin
    Fiebig, Andreas
    Sistonen, Pertti
    Savontaus, Marja-Liisa
    Schreiber, Stefan
    Kere, Juha
    Lahermo, Paivi
    Genome-wide analysis of single nucleotide polymorphisms uncovers population structure in Northern Europe2008In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 3, no 10, article id e3519Article in journal (Refereed)
    Abstract [en]

    Background: Genome-wide data provide a powerful tool for inferring patterns of genetic variation and structure of human populations.

    Principal Findings: In this study, we analysed almost 250,000 SNPs from a total of 945 samples from Eastern and Western Finland, Sweden, Northern Germany and Great Britain complemented with HapMap data. Small but statistically significant differences were observed between the European populations (F(ST) = 0.0040, p < 10(-4)), also between Eastern and Western Finland (F(ST) = 0.0032, p < 10(-3)). The latter indicated the existence of a relatively strong autosomal substructure within the country, similar to that observed earlier with smaller numbers of markers. The Germans and British were less differentiated than the Swedes, Western Finns and especially the Eastern Finns who also showed other signs of genetic drift. This is likely caused by the later founding of the northern populations, together with subsequent founder and bottleneck effects, and a smaller population size. Furthermore, our data suggest a small eastern contribution among the Finns, consistent with the historical and linguistic background of the population.

    Significance: Our results warn against a priori assumptions of homogeneity among Finns and other seemingly isolated populations. Thus, in association studies in such populations, additional caution for population structure may be necessary. Our results illustrate that population history is often important for patterns of genetic variation, and that the analysis of hundreds of thousands of SNPs provides high resolution also for population genetics.

  • 229. Salmela, Elina
    et al.
    Lappalainen, Tuuli
    Liu, Jianjun
    Sistonen, Pertti
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Schreiber, Stefan
    Savontaus, Marja-Liisa
    Czene, Kamila
    Lahermo, Päivi
    Hall, Per
    Kere, Juha
    Swedish population substructure revealed by genome-wide single nucleotide polymorphism data2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 2, p. e16747-Article in journal (Refereed)
    Abstract [en]

    The use of genome-wide single nucleotide polymorphism (SNP) data has recently proven useful in the study of human population structure. We have studied the internal genetic structure of the Swedish population using more than 350,000 SNPs from 1525 Swedes from all over the country genotyped on the Illumina HumanHap550 array. We have also compared them to 3212 worldwide reference samples, including Finns, northern Germans, British and Russians, based on the more than 29,000 SNPs that overlap between the Illumina and Affymetrix 250K Sty arrays. The Swedes--especially southern Swedes--were genetically close to the Germans and British, while their genetic distance to Finns was substantially longer. The overall structure within Sweden appeared clinal, and the substructure in the southern and middle parts was subtle. In contrast, the northern part of Sweden, Norrland, exhibited pronounced genetic differences both within the area and relative to the rest of the country. These distinctive genetic features of Norrland probably result mainly from isolation by distance and genetic drift caused by low population density. The internal structure within Sweden (F(ST) = 0.0005 between provinces) was stronger than that in many Central European populations, although smaller than what has been observed for instance in Finland; importantly, it is of the magnitude that may hamper association studies with a moderate number of markers if cases and controls are not properly matched geographically. Overall, our results underline the potential of genome-wide data in analyzing substructure in populations that might otherwise appear relatively homogeneous, such as the Swedes.

  • 230. Sandahl, Julie Damgaard
    et al.
    Coenen, Eva A.
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Harbott, Jochen
    Johansson, Bertil
    Kerndrup, Gitte
    Adachi, Souichi
    Auvrignon, Anne
    Beverloo, H. Berna
    Cayuela, Jean-Michel
    Chilton, Lucy
    Fornerod, Maarten
    de Haas, Valerie
    Harrison, Christine J.
    Inaba, Hiroto
    Kaspers, Gertjan J. L.
    Liang, Der-Cherng
    Locatelli, Franco
    Masetti, Riccardo
    Perot, Christine
    Raimondi, Susana C.
    Reinhardt, Katarina
    Tomizawa, Daisuke
    von Neuhoff, Nils
    Zecca, Marco
    Zwaan, C. Michel
    van den Heuvel-Eibrink, Marry M.
    Hasle, Henrik
    t(6;9)(p22; q34)/DEK-NUP214-rearranged pediatric myeloid leukemia: an international study of 62 patients2014In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 99, no 5, p. 865-872Article in journal (Refereed)
    Abstract [en]

    Acute myeloid leukemia with t(6; 9)(p22; q34) is listed as a distinct entity in the 2008 World Health Organization classification, but little is known about the clinical implications of t(6; 9)-positive myeloid leukemia in children. This international multicenter study presents the clinical and genetic characteristics of 62 pediatric patients with t(6; 9)/DEKNUP214-rearranged myeloid leukemia; 54 diagnosed as having acute myeloid leukemia, representing <1% of all childhood acute myeloid leukemia, and eight as having myelodysplastic syndrome. The t(6; 9)/DEK-NUP214 was associated with relatively late onset (median age 10.4 years), male predominance (sex ratio 1.7), French-American-British M2 classification (54%), myelodysplasia (100%), and FLT3-ITD (42%). Outcome was substantially better than previously reported with a 5-year event-free survival of 32%, 5-year overall survival of 53%, and a 5-year cumulative incidence of relapse of 57%. Hematopoietic stem cell transplantation in first complete remission improved the 5-year event-free survival compared with chemotherapy alone (68% versus 18%; P<0.01) but not the overall survival (68% versus 54%; P=0.48). The presence of FLT3-ITD had a non-significant negative effect on 5-year overall survival compared with non-mutated cases (22% versus 62%; P=0.13). Gene expression profiling showed a unique signature characterized by significantly higher expression of EYA3, SESN1, PRDM2/RIZ, and HIST2H4 genes. In conclusion, t(6; 9)/DEK-NUP214 represents a unique subtype of acute myeloid leukemia with a high risk of relapse, high frequency of FLT3-ITD, and a specific gene expression signature.

  • 231. Santucci-Pereira, Julia
    et al.
    Zeleniuch-Jacquotte, Anne
    Afanasyeva, Yelena
    Zhong, Hua
    Slifker, Michael
    Peri, Suraj
    Ross, Eric A
    López de Cicco, Ricardo
    Zhai, Yubo
    Nguyen, Theresa
    Sheriff, Fathima
    Russo, Irma H
    Su, Yanrong
    Arslan, Alan A
    Bordas, Pal
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Åhman, Janet
    Landström Eriksson, Anna Stina
    Johansson, Robert
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Toniolo, Paolo
    Russo, Jose
    Genomic signature of parity in the breast of premenopausal women2019In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 21, no 1, article id 46Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Full-term pregnancy (FTP) at an early age confers long-term protection against breast cancer. Previously, we reported that a FTP imprints a specific gene expression profile in the breast of postmenopausal women. Herein, we evaluated gene expression changes induced by parity in the breast of premenopausal women.

    METHODS: Gene expression profiling of normal breast tissue from 30 nulliparous (NP) and 79 parous (P) premenopausal volunteers was performed using Affymetrix microarrays. In addition to a discovery/validation analysis, we conducted an analysis of gene expression differences in P vs. NP women as a function of time since last FTP. Finally, a laser capture microdissection substudy was performed to compare the gene expression profile in the whole breast biopsy with that in the epithelial and stromal tissues.

    RESULTS: Discovery/validation analysis identified 43 differentially expressed genes in P vs. NP breast. Analysis of expression as a function of time since FTP revealed 286 differentially expressed genes (238 up- and 48 downregulated) comparing all P vs. all NP, and/or P women whose last FTP was less than 5 years before biopsy vs. all NP women. The upregulated genes showed three expression patterns: (1) transient: genes upregulated after FTP but whose expression levels returned to NP levels. These genes were mainly related to immune response, specifically activation of T cells. (2) Long-term changing: genes upregulated following FTP, whose expression levels decreased with increasing time since FTP but did not return to NP levels. These were related to immune response and development. (3) Long-term constant: genes that remained upregulated in parous compared to nulliparous breast, independently of time since FTP. These were mainly involved in development/cell differentiation processes, and also chromatin remodeling. Lastly, we found that the gene expression in whole tissue was a weighted average of the expression in epithelial and stromal tissues.

    CONCLUSIONS: Genes transiently activated by FTP may have a role in protecting the mammary gland against neoplastically transformed cells through activation of T cells. Furthermore, chromatin remodeling and cell differentiation, represented by the genes that are maintained upregulated long after the FTP, may be responsible for the lasting preventive effect against breast cancer.

  • 232.
    Schwartz, Yuri B.
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Pirrotta, Vincenzo
    A new world of Polycombs: unexpected partnerships and emerging functions2013In: Nature reviews genetics, ISSN 1471-0056, E-ISSN 1471-0064, Vol. 14, no 12, p. 853-864Article, review/survey (Refereed)
    Abstract [en]

    Polycomb group (PcG) proteins are epigenetic repressors that are essential for the transcriptional control of cell differentiation and development. PcG-mediated repression is associated with specific post-translational histone modifications and is thought to involve both biochemical and physical modulation of chromatin structure. Recent advances show that PcG complexes comprise a multiplicity of variants and are far more biochemically diverse than previously thought. The importance of these new PcG complexes for normal development and disease, their targeting mechanisms and their shifting roles in the course of differentiation are now the subject of investigation and the focus of this Review.

  • 233.
    Selander, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    In vivo and in vitro approaches to induce beta cells from stem and progenitor cells2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Diabetes or diabetes mellitus which is the correct medical term is a medical condition were the affected person lack the ability to regulate his or her blood glucose levels. This inability is directly due to the fact that the insulin producing cells, residing in the pancreas, can’t meet the body’s demand for insulin. It is estimated that close to 200 million people are suffering from diabetes today and this number is predicted to double within 20 years. Of the approximately 200 million people suffering from diabetes today approximately 20 million are in dependent on daily injections of insulin. Being dependent on exogenous insulin is not only an inconvenience it also increase the risk for several medical complications such as stroke, heart disorders, kidney failure, retinopathy, atherosclerosis and impaired wound healing. The major risk factor for all these complications is long periods of high blood sugar levels that is damaging to thin blood vessels and nerves.  Even in the best of situations the blood sugar levels of a diabetic with need for daily insulin injections can never be as well controlled as in a healthy individual.

    Increased understanding in the developmental processes behind the formation of the pancreas, and more specifically the insulin producing β-cells could result in new treatments for diabetics. By imitating the in vivo conditions generating pancreatic development scientist are now able to induce embryonic stem cells to differentiate into pancreatic progenitors as well as insulin producing β-cells in vitro. These in vitro generated pancreatic cells might in the future serve as a donor source for transplantations, thereby restoring the insulin producing capability of diabetic patients. An alternative approach to restore insulin production in diabetics is to influence cells in the pancreas to generate more insulin producing cells. To successfully achieve this, what cell types have the capacity to generate β-cells needs to be appreciated.

    In this thesis papers concerning in vitro differentiating of embryonic stem cells towards a pancreatic fate as well as in vivo studies in basic pancreas development are presented and discussed.

  • 234.
    Shungin, Dmitry
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit, Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA, United States of America.
    Deng, Wei Q.
    Varga, Tibor V.
    Luan, Jian'an
    Mihailov, Evelin
    Metspalu, Andres
    Morris, Andrew P.
    Forouhi, Nita G.
    Lindgren, Cecilia
    Magnusson, Patrik K. E.
    Pedersen, Nancy L.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Chu, Audrey Y.
    Justice, Anne E.
    Graff, Mariaelisa
    Winkler, Thomas W.
    Rose, Lynda M.
    Langenberg, Claudia
    Cupples, L. Adrienne
    Ridker, Paul M.
    Wareham, Nicholas J.
    Ong, Ken K.
    Loos, Ruth J. F.
    Chasman, Daniel I.
    Ingelsson, Erik
    Kilpeläinen, Tuomas O.
    Scott, Robert A.
    Mägi, Reedik
    Paré, Guillaume
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit, Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden.
    Ranking and characterization of established BMI and lipid associated loci as candidates for gene-environment interactions2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 6, article id e1006812Article in journal (Refereed)
    Abstract [en]

    Phenotypic variance heterogeneity across genotypes at a single nucleotide polymorphism (SNP) may reflect underlying gene-environment (GxE) or gene-gene interactions. We modeled variance heterogeneity for blood lipids and BMI in up to 44,211 participants and investigated relationships between variance effects (P-v), GxE interaction effects (with smoking and physical activity), and marginal genetic effects (P-m). Correlations between P-v and P-m were stronger for SNPs with established marginal effects (Spearman's rho = 0.401 for triglycerides, and rho = 0.236 for BMI) compared to all SNPs. When P-v and P-m were compared for all pruned SNPs, only BMI was statistically significant (Spearman's rho = 0.010). Overall, SNPs with established marginal effects were overrepresented in the nominally significant part of the P-v distribution (P-binomial < 0.05). SNPs from the top 1% of the P-m distribution for BMI had more significant P-v values (Pmann-Whitney = 1.46x10(-5)), and the odds ratio of SNPs with nominally significant (< 0.05) P-m and P-v was 1.33 (95% CI: 1.12, 1.57) for BMI. Moreover, BMI SNPs with nominally significant GxE interaction P-values (Pint < 0.05) were enriched with nominally significant P-v values (P-binomial = 8.63x10(-9) and 8.52x10(-7) for SNP x smoking and SNP x physical activity, respectively). We conclude that some loci with strong marginal effects may be good candidates for GxE, and variance-based prioritization can be used to identify them.

  • 235.
    Sikström, Carin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    The transferrin polymorphism: population genetics and associations with reproductive hazards and disease1994Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Human serum transferrin (TF) carries iron from the intestine, reticuloendothelial system and liver parenchymal cells to proliferating cells in the body. TF is highly polymorphic, and previous findings of associations between TF types and reproductive hazards in different species suggest that the TF polymorphism may be involved in natural selection and susceptibility to disease.

    The aims of this thesis were:

    to examine the TF polymorphism in Finns, Swedes and Swedish Saamis and variations of TF allele frequencies between 23 North-Swedish subpopulations.

    to study TF types in relation to spontaneous abortion and disease.

    to investigate the relationship between TF types, iron-binding capacity and body iron stores in an attempt to elucidate the mechanism through which TF types may be involved in spontaneous abortion and disease.

    The following results were found:

    1        Significant allele frequency differences were found between Finns, Swedes and Saamis. Finns had a lower TF*C2 frequency compared to Saamis and Swedes and the highest TF*C3 frequency so far observed in the world. Saamis had a very low TF*C3, and originally they probably lacked this allele. A significant heterogeneity between 23 subpopulations in northern Sweden was found for all TF alleles, and the geographical picture of TF*C3 and rare allele frequencies showed dines, which could be interpreted in terms of Finnish influence.

    2        A significantly increased frequency of TF*C2 and especially the TF C2 type was found among mothers with a history of previous spontaneous abortion.

    3        In patients with occupational photodermatosis of the face a highly significant increase of TF*C2 was found.

    4        A highly significant association was found between TF*C3 and myocardial infarction. There was also an association with the TF C2 type, but with marginal significance.

    5        In patients with hereditary hemochromatosis and thus extreme iron overload the frequency of TF*C1 was significantly increased, and this association was more pronounced in HLA-A3 associated hemochromatosis.

    6        No significant relationship was found between TF types and serum iron, total iron binding capacity (TIBC), transferrin saturation and serum ferritin, thus the adverse effects of TF C2 and C3 appear to be independent of iron-binding and body iron stores.

  • 236. Smeland, Olav B.
    et al.
    Kauppi, Karolina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Wang, Yunpeng
    Hill, W. David
    Davies, Gail
    Frei, Oleksandr
    Li, Wen
    Eriksen, Jon A.
    Witoelar, Aree
    Bettella, Francesco
    Fan, Chun C.
    Thompson, Wes
    Chen, Chi-Hua
    Djurovic, Srdjan
    Deary, Ian J.
    Dale, Anders M.
    Andreassen, Ole A.
    Shared genetic variants between schizophrenia and general cognitive function indicate common molecular genetic mechanisms2017In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 27, p. S410-S410Article in journal (Other academic)
    Abstract [en]

    Background: Schizophrenia (SCZ) is a severe mental disorder characterized by widespread cognitive impairments including deficits in learning, memory, processing speed, attention and executive functioning. Although cognitive deficits are a strong predictor of functional outcome in SCZ, current treatment strategies largely fail to ameliorate these impairments. Thus, in order to develop more efficient treatment strategies in SCZ, a better understanding of the pathogenesis of these cognitive deficits is needed. Given that both SCZ and cognitive ability are substantially heritable, we here aimed to determine whether SCZ share genetic influences with general cognitive function (COG), a phenotype that captures the shared variation in performance across several cognitive domains. Methods: We analyzed GWAS results in the form of summary statistics (p-values and z-scores) from SCZ (the Psychiatric Genomics Consortium; n=82 315) and COG (CHARGE Consortium; n=53 949). We applied a conditional false discovery rate (FDR) framework. By leveraging SNP-associations in a secondary trait (SCZ or COG), the conditional FDR approach increases power to detect loci in the primary trait (COG or SCZ), regardless of the directions of allelic effects of the risk loci. We then applied the conjunction FDR to identify shared loci between the phenotypes. The conjunction FDR is defined as the maximum of the conditional FDRs for both directions, and we used an overall FDR threshold of 0.05. Results: To visualize pleiotropic enrichment, we constructed conditional Q-Q plots which indicate substantial polygenetic overlap between SCZ and COG. For progressively stringent p-value thresholds for SCZ SNPs, we found approximately 150-fold enrichment for COG. For progressively stringent p-value thresholds for COG SNPs, we found approximately 100-fold enrichment for SCZ. We then used the conjunction FDR and identified fourteen independent loci shared between SCZ and COG. The majority of the shared loci show inverse associations in SCZ and COG, in line with the observed cognitive dysfunction in SCZ. Discussion: Our preliminary findings indicate shared molecular genetic mechanisms between SCZ and COG, which may provide important new insights into the pathogenesis of cognitive dysfunction in SCZ.

  • 237. Sofer, Tamar
    et al.
    Zheng, Xiuwen
    Gogarten, Stephanie M.
    Laurie, Cecelia A.
    Grinde, Kelsey
    Shaffer, John R.
    Shungin, Dmitry
    Umeå University, Faculty of Medicine, Department of Odontology. Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
    O'Connell, Jeffrey R.
    Durazo-Arvizo, Ramon A.
    Raffield, Laura
    Lange, Leslie
    Musani, Solomon
    Vasan, Ramachandran S.
    Cupples, L. Adrienne
    Reiner, Alexander P.
    Laurie, Cathy C.
    Rice, Kenneth M.
    A fully adjusted two-stage procedure for rank-normalization in genetic association studies2019In: Genetic Epidemiology, ISSN 0741-0395, E-ISSN 1098-2272, Vol. 43, no 3, p. 263-275Article in journal (Refereed)
    Abstract [en]

    When testing genotype–phenotype associations using linear regression, departure of the trait distribution from normality can impact both Type I error rate control and statistical power, with worse consequences for rarer variants. Because genotypes are expected to have small effects (if any) investigators now routinely use a two‐stage method, in which they first regress the trait on covariates, obtain residuals, rank‐normalize them, and then use the rank‐normalized residuals in association analysis with the genotypes. Potential confounding signals are assumed to be removed at the first stage, so in practice, no further adjustment is done in the second stage. Here, we show that this widely used approach can lead to tests with undesirable statistical properties, due to both combination of a mis‐specified mean–variance relationship and remaining covariate associations between the rank‐normalized residuals and genotypes. We demonstrate these properties theoretically, and also in applications to genome‐wide and whole‐genome sequencing association studies. We further propose and evaluate an alternative fully adjusted two‐stage approach that adjusts for covariates both when residuals are obtained and in the subsequent association test. This method can reduce excess Type I errors and improve statistical power.

  • 238. Sparks, Justin L
    et al.
    Chon, Hyongi
    Cerritelli, Susana M
    Kunkel, Thomas A
    Johansson, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Crouch, Robert J
    Burgers, Peter M
    RNase H2-Initiated Ribonucleotide Excision Repair2012In: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 47, no 6, p. 980-986Article in journal (Refereed)
    Abstract [en]

    Ribonucleotides are incorporated into DNA by the replicative DNA polymerases at frequencies of about 2 per kb, which makes them by far the most abundant form of potential DNA damage in the cell. Their removal is essential for restoring a stable intact chromosome. Here, we present a complete biochemical reconstitution of the ribonucleotide excision repair (RER) pathway with enzymes purified from Saccharomyces cerevisiae. RER is most efficient when the ribonucleotide is incised by RNase H2, and further excised by the flap endonuclease FEN1 with strand displacement synthesis carried out by DNA polymerase δ, the PCNA clamp, its loader RFC, and completed by DNA ligase I. We observed partial redundancy for several of the enzymes in this pathway. Exo1 substitutes for FEN1 and Pol ε for Pol δ with reasonable efficiency. However, RNase H1 fails to substitute for RNase H2 in the incision step of RER.

  • 239. Speedy, Helen E.
    et al.
    Di Bernardo, Maria Chiara
    Sava, Georgina P.
    Dyer, Martin J. S.
    Holroyd, Amy
    Wang, Yufei
    Sunter, Nicola J.
    Mansouri, Larry
    Juliusson, Gunnar
    Smedby, Karin E.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jayne, Sandrine
    Majid, Aneela
    Dearden, Claire
    Hall, Andrew G.
    Mainou-Fowler, Tryfonia
    Jackson, Graham H.
    Summerfield, Geoffrey
    Harris, Robert J.
    Pettitt, Andrew R.
    Allsup, David J.
    Bailey, James R.
    Pratt, Guy
    Pepper, Chris
    Fegan, Chris
    Rosenquist, Richard
    Catovsky, Daniel
    Allan, James M.
    Houlston, Richard S.
    A genome-wide association study identifies multiple susceptibility loci for chronic lymphocytic leukemia2014In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 46, no 1, p. 56-+Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) of chronic lymphocytic leukemia (CLL) have shown that common genetic variation contributes to the heritable risk of CLL. To identify additional CLL susceptibility loci, we conducted a GWAS and performed a meta-analysis with a published GWAS totaling 1,739 individuals with CLL (cases) and 5,199 controls with validation in an additional 1,144 cases and 3,151 controls. A combined analysis identified new susceptibility loci mapping to 3q26.2 (rs10936599, P = 1.74 x 10(-9)), 4q26 (rs6858698, P = 3.07 x 10(-9)), 6q25.2 (IPCEF1, rs2236256, P = 1.50 x 10(-10)) and 7q31.33 (POT1, rs17246404, P = 3.40 x 10(-8)). Additionally, we identified a promising association at 5p15.33 (CLPTM1L, rs31490, P = 1.72 x 10(-7)) and validated recently reported putative associations at 5p15.33 (TERT, rs10069690, P = 1.12 x 10(-10)) and 8q22.3 (rs2511714, P = 2.90 x 10(-9)). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CLL.

  • 240. Stahl, Eli A.
    et al.
    Breen, Gerome
    Forstner, Andreas J
    McQuillin, Andrew
    Ripke, Stephan
    Trubetskoy, Vassily
    Mattheisen, Manuel
    Wang, Yunpeng
    Coleman, Jonathan R I
    Gaspar, Héléna A
    de Leeuw, Christiaan A
    Steinberg, Stacy
    Pavlides, Jennifer M Whitehead
    Trzaskowski, Maciej
    Byrne, Enda M
    Pers, Tune H
    Holmans, Peter A
    Richards, Alexander L
    Abbott, Liam
    Agerbo, Esben
    Akil, Huda
    Albani, Diego
    Alliey-Rodriguez, Ney
    Als, Thomas D
    Anjorin, Adebayo
    Antilla, Verneri
    Awasthi, Swapnil
    Badner, Judith A
    Bækvad-Hansen, Marie
    Barchas, Jack D
    Bass, Nicholas
    Bauer, Michael
    Belliveau, Richard
    Bergen, Sarah E
    Pedersen, Carsten Bøcker
    Bøen, Erlend
    Boks, Marco P
    Boocock, James
    Budde, Monika
    Bunney, William
    Burmeister, Margit
    Bybjerg-Grauholm, Jonas
    Byerley, William
    Casas, Miquel
    Cerrato, Felecia
    Cervantes, Pablo
    Chambert, Kimberly
    Charney, Alexander W
    Chen, Danfeng
    Churchhouse, Claire
    Clarke, Toni-Kim
    Coryell, William
    Craig, David W
    Cruceanu, Cristiana
    Curtis, David
    Czerski, Piotr M
    Dale, Anders M
    de Jong, Simone
    Degenhardt, Franziska
    Del-Favero, Jurgen
    DePaulo, J Raymond
    Djurovic, Srdjan
    Dobbyn, Amanda L
    Dumont, Ashley
    Elvsåshagen, Torbjørn
    Escott-Price, Valentina
    Fan, Chun Chieh
    Fischer, Sascha B
    Flickinger, Matthew
    Foroud, Tatiana M
    Forty, Liz
    Frank, Josef
    Fraser, Christine
    Freimer, Nelson B
    Frisén, Louise
    Gade, Katrin
    Gage, Diane
    Garnham, Julie
    Giambartolomei, Claudia
    Pedersen, Marianne Giørtz
    Goldstein, Jaqueline
    Gordon, Scott D
    Gordon-Smith, Katherine
    Green, Elaine K
    Green, Melissa J
    Greenwood, Tiffany A
    Grove, Jakob
    Guan, Weihua
    Guzman-Parra, José
    Hamshere, Marian L
    Hautzinger, Martin
    Heilbronner, Urs
    Herms, Stefan
    Hipolito, Maria
    Hoffmann, Per
    Holland, Dominic
    Huckins, Laura
    Jamain, Stéphane
    Johnson, Jessica S
    Juréus, Anders
    Kandaswamy, Radhika
    Karlsson, Robert
    Kennedy, James L
    Kittel-Schneider, Sarah
    Knowles, James A
    Kogevinas, Manolis
    Koller, Anna C
    Kupka, Ralph
    Lavebratt, Catharina
    Lawrence, Jacob
    Lawson, William B
    Leber, Markus
    Lee, Phil H
    Levy, Shawn E
    Li, Jun Z
    Liu, Chunyu
    Lucae, Susanne
    Maaser, Anna
    MacIntyre, Donald J
    Mahon, Pamela B
    Maier, Wolfgang
    Martinsson, Lina
    McCarroll, Steve
    McGuffin, Peter
    McInnis, Melvin G
    McKay, James D
    Medeiros, Helena
    Medland, Sarah E
    Meng, Fan
    Milani, Lili
    Montgomery, Grant W
    Morris, Derek W
    Mühleisen, Thomas W
    Mullins, Niamh
    Nguyen, Hoang
    Nievergelt, Caroline M
    Nordin Adolfsson, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nwulia, Evaristus A
    O'Donovan, Claire
    Loohuis, Loes M Olde
    Ori, Anil P S
    Oruc, Lilijana
    Ösby, Urban
    Perlis, Roy H
    Perry, Amy
    Pfennig, Andrea
    Potash, James B
    Purcell, Shaun M
    Regeer, Eline J
    Reif, Andreas
    Reinbold, Céline S
    Rice, John P
    Rivas, Fabio
    Rivera, Margarita
    Roussos, Panos
    Ruderfer, Douglas M
    Ryu, Euijung
    Sánchez-Mora, Cristina
    Schatzberg, Alan F
    Scheftner, William A
    Schork, Nicholas J
    Shannon Weickert, Cynthia
    Shehktman, Tatyana
    Shilling, Paul D
    Sigurdsson, Engilbert
    Slaney, Claire
    Smeland, Olav B
    Sobell, Janet L
    Søholm Hansen, Christine
    Spijker, Anne T
    St Clair, David
    Steffens, Michael
    Strauss, John S
    Streit, Fabian
    Strohmaier, Jana
    Szelinger, Szabolcs
    Thompson, Robert C
    Thorgeirsson, Thorgeir E
    Treutlein, Jens
    Vedder, Helmut
    Wang, Weiqing
    Watson, Stanley J
    Weickert, Thomas W
    Witt, Stephanie H
    Xi, Simon
    Xu, Wei
    Young, Allan H
    Zandi, Peter
    Zhang, Peng
    Zöllner, Sebastian
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Agartz, Ingrid
    Alda, Martin
    Backlund, Lena
    Baune, Bernhard T
    Bellivier, Frank
    Berrettini, Wade H
    Biernacka, Joanna M
    Blackwood, Douglas H R
    Boehnke, Michael
    Børglum, Anders D
    Corvin, Aiden
    Craddock, Nicholas
    Daly, Mark J
    Dannlowski, Udo
    Esko, Tõnu
    Etain, Bruno
    Frye, Mark
    Fullerton, Janice M
    Gershon, Elliot S
    Gill, Michael
    Goes, Fernando
    Grigoroiu-Serbanescu, Maria
    Hauser, Joanna
    Hougaard, David M
    Hultman, Christina M
    Jones, Ian
    Jones, Lisa A
    Kahn, René S
    Kirov, George
    Landén, Mikael
    Leboyer, Marion
    Lewis, Cathryn M
    Li, Qingqin S
    Lissowska, Jolanta
    Martin, Nicholas G
    Mayoral, Fermin
    McElroy, Susan L
    McIntosh, Andrew M
    McMahon, Francis J
    Melle, Ingrid
    Metspalu, Andres
    Mitchell, Philip B
    Morken, Gunnar
    Mors, Ole
    Mortensen, Preben Bo
    Müller-Myhsok, Bertram
    Myers, Richard M
    Neale, Benjamin M
    Nimgaonkar, Vishwajit
    Nordentoft, Merete
    Nöthen, Markus M
    O'Donovan, Michael C
    Oedegaard, Ketil J
    Owen, Michael J
    Paciga, Sara A
    Pato, Carlos
    Pato, Michele T
    Posthuma, Danielle
    Ramos-Quiroga, Josep Antoni
    Ribasés, Marta
    Rietschel, Marcella
    Rouleau, Guy A
    Schalling, Martin
    Schofield, Peter R
    Schulze, Thomas G
    Serretti, Alessandro
    Smoller, Jordan W
    Stefansson, Hreinn
    Stefansson, Kari
    Stordal, Eystein
    Sullivan, Patrick F
    Turecki, Gustavo
    Vaaler, Arne E
    Vieta, Eduard
    Vincent, John B
    Werge, Thomas
    Nurnberger, John I
    Wray, Naomi R
    Di Florio, Arianna
    Edenberg, Howard J
    Cichon, Sven
    Ophoff, Roel A
    Scott, Laura J
    Andreassen, Ole A
    Kelsoe, John
    Sklar, Pamela
    Genome-wide association study identifies 30 loci associated with bipolar disorder2019In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 5, p. 793-803Article in journal (Refereed)
    Abstract [en]

    Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.

  • 241.
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Clinical and genetic studies of three inherited skeletal disorders2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Mutations in genes of importance for cartilage development may lead to skeletal malformations, chondroskeletal dysfunction and increased susceptibility to degenerative joint disease. Characterization of these mutations and identification of molecular pathways for the corresponding gene products have contributed to our understanding of mechanisms regulating skeletal patterning, endochondral ossification and joint formation.

    A five generation family segregating autosomal dominant osteochondritis dissecans (OCD) was identified. Affected family members presented with OCD in knees, hips and elbows, short stature, and early osteoarthritis. A genome wide scan and a multipoint linkage analysis identified aggrecan (ACAN) as a prime candidate gene. DNA sequence analysis of the ACAN-gene revealed heterozygosity for a missense mutation (c.6907G>A) in affected subjects, resulting in a p.V2303M substitution in the aggrecan G3 domain C-type lectin. This domain is important for the interaction with other proteins in the cartilage extracellular matrix. To determine the effect of the V2303M substitution on secretion and interaction, we performed binding studies with recombinant mutated and wild type G3 proteins. We found decreased affinity or complete loss of interaction between V2303M aggrecan and fibulin1, fibulin2 and tenascin-R. Analysis of articular cartilage from an affected family member confirmed that V2303M aggrecan is produced and present.

    In search for gene mutations associated with multiple epiphyseal dysplasia (MED) we considered the ACAN-gene a likely candidate. The ACAN-gene was analysed in 39 individuals with MED and screened negative for mutations in six previously known MED genes. Sequence analysis revealed a heterozygous missense mutation (c.1448G>T) in one adult male and compound heterozygous missense mutations (c.1366T>C and c.836G>A) in a five year old boy with healthy parents, each of them carrier for one of the mutations.

    A large family segregating autosomal dominant brachymesophalangia and OCD in finger joints was characterised. The clinical presentation in six affected family members was consistent with the diagnosis Brachydactyly type A1, in this family characterized by shortening of the middle phalanges, short ulnar styloid process, flattening of the metacarpal heads and mild osteoarthritis. The condition may be caused by mutations in the Indian hedgehog gene (IHH) or a yet unidentified gene on chromosome 5p13. Sequence analysis of the IHH-gene in affected individuals revealed a novel C to T transition (c.472C>T) leading to a p.158Arg>Cys substitution. Residue 158 in IHH is highly conserved throughout evolution and molecular structure modelling of IHH suggests that the R158C substitution leads to a conformational change at the site of interaction with the IHH-receptor. This supports that the substitution causes Brachydactyly type A1 in this family.

    In summary, we report on the clinical, radiological and molecular genetic characteristics of the three skeletal disorders OCD, MED and BDA1. Our results provide a novel molecular mechanism in the pathophysiology of familial osteochondritis dissecans confirming the importance of aggrecan C-type lectin for cartilage function. We also show that ACAN-gene mutations may be associated with MED extending the spectrum of skeletal dysplasias associated with the aggrecan gene. Finally, we report on a novel missense mutation in a conserved region of the IHH-gene associated with BDA1.

  • 242.
    Stattin, Eva-Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Henning, Petra
    Klar, Joakim
    McDermott, Emma
    Stecksen-Blicks, Christina
    Umeå University, Faculty of Medicine, Department of Odontology.
    Sandström, Per-Erik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Kellgren, Therese G
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Rydén, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Lönnerholm, Torsten
    Ameur, Adam
    Helfrich, Miep H
    Coxon, Fraser P
    Dahl, Niklas
    Wikström, Johan
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology. Centre for Bone and Arthritis Research, Department of internal medicine and clinical nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 3012Article in journal (Refereed)
    Abstract [en]

    Autosomal recessive osteopetrosis (ARO) is a heterogeneous disorder, characterized by defective osteoclastic resorption of bone that results in increased bone density. We have studied nine individuals with an intermediate form of ARO, from the county of Västerbotten in Northern Sweden. All afflicted individuals had an onset in early infancy with optic atrophy, and in four patients anemia was present at diagnosis. Tonsillar herniation, foramen magnum stenosis, and severe osteomyelitis of the jaw were common clinical features. Whole exome sequencing, verified by Sanger sequencing, identified a splice site mutation c.212 + 1 G > T in the SNX10 gene encoding sorting nexin 10. Sequence analysis of the SNX10 transcript in patients revealed activation of a cryptic splice site in intron 4 resulting in a frame shift and a premature stop (p.S66Nfs * 15). Haplotype analysis showed that all cases originated from a single mutational event, and the age of the mutation was estimated to be approximately 950 years. Functional analysis of osteoclast progenitors isolated from peripheral blood of patients revealed that stimulation with receptor activator of nuclear factor kappa-B ligand (RANKL) resulted in a robust formation of large, multinucleated osteoclasts which generated sealing zones; however these osteoclasts exhibited defective ruffled borders and were unable to resorb bone in vitro.

  • 243.
    Stattin, Eva-Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Westin, Ida Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Cederquist, Kristina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jonasson, Jenni
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jonsson, Björn-Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Norberg, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Krantz, Peter
    Wisten, Aase
    Genetic screening in sudden cardiac death in the young can save future lives2016In: International journal of legal medicine (Print), ISSN 0937-9827, E-ISSN 1437-1596, Vol. 130, no 1, p. 59-66Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Autopsy of sudden cardiac death (SCD) in the young shows a structurally and histologically normal heart in about one third of cases. Sudden death in these cases is believed to be attributed in a high percentage to inherited arrhythmogenic diseases. The purpose of this study was to investigate the value of performing post-mortem genetic analysis for autopsy-negative sudden unexplained death (SUD) in 1 to 35 year olds.

    METHODS AND RESULTS: From January 2009 to December 2011, samples from 15 cases suffering SUD were referred to the Department of Clinical Genetics, Umeå University Hospital, Sweden, for molecular genetic evaluation. PCR and bidirectional Sanger sequencing of genes important for long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome type 1 (BrS1), and catecholaminergic polymorphic ventricular tachycardia (CPVT) (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, and RYR2) was performed. Multiplex ligation-dependent probe amplification (MLPA) was used to detect large deletions or duplications in the LQTS genes. Six pathogenic sequence variants (four LQTS and two CPVT) were discovered in 15 SUD cases (40%). Ten first-degree family members were found to be mutation carriers (seven LQTS and three CPVT).

    CONCLUSION: Cardiac ion channel genetic testing in autopsy-negative sudden death victims has a high diagnostic yield, with identification of the disease in 40 of families. First-degree family members should be offered predictive testing, clinical evaluation, and treatment with the ultimate goal to prevent sudden death.

  • 244.
    Stattin, Eva-Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Wiklund, Fredrik
    Lindblom, Karin
    Onnerfjord, Patrik
    Jonsson, Björn-Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Tegner, Yelverton
    Sasaki, Takako
    Struglics, André
    Lohmander, Stefan
    Dahl, Niklas
    Heinegård, Dick
    Aspberg, Anders
    A missense mutation in the aggrecan C-type lectin domain disrupts extracellular matrix interactions and causes dominant familial osteochondritis dissecans2010In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 86, no 2, p. 126-137Article in journal (Refereed)
    Abstract [en]

    Osteochondritis dissecans is a disorder in which fragments of articular cartilage and subchondral bone dislodge from the joint surface. We analyzed a five-generation family in which affected members had autosomal-dominant familial osteochondritis dissecans. A genome-wide linkage analysis identified aggrecan (ACAN) as a prime candidate gene for the disorder. Sequence analysis of ACAN revealed heterozygosity for a missense mutation (c.6907G > A) in affected individuals, resulting in a p.V2303M amino acid substitution in the aggrecan G3 domain C-type lectin, which mediates interactions with other proteins in the cartilage extracellular matrix. Binding studies with recombinant mutated and wild-type G3 proteins showed loss of fibulin-1, fibulin-2, and tenascin-R interactions for the V2303M protein. Mass spectrometric analyses of aggrecan purified from patient cartilage verified that V2303M aggrecan is produced and present in the tissue. Our results provide a molecular mechanism for the etiology of familial osteochondritis dissecans and show the importance of the aggrecan C-type lectin interactions for cartilage function in vivo.

  • 245.
    Stocks, Tanja
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Ängquist, Lars
    Hager, Joerg
    Charon, Celine
    Hoist, Claus
    Martinez, J Alfredo
    Saris, Wim HM
    Astrup, Arne
    Sorensen, Thorkild IA
    Larsen, Lesli H
    TFAP2B-dietary protein and glycemic index interactions and weight maintenance after weight loss in the DiOGenes trial2013In: Human Heredity, ISSN 0001-5652, E-ISSN 1423-0062, Vol. 75, no 2-4, p. 213-219Article in journal (Refereed)
    Abstract [en]

    Background: TFAP2B rs987237 is associated with obesity and has shown interaction with the dietary fat-to-carbohydrate ratio, which has an effect on weight loss. We investigated interactions between rs987237 and protein-to-carbohydrate ratio or glycemic index (GI) in relation to weight maintenance after weight loss.

    Methods: This study included 742 obese individuals from 8 European countries who participated in the Diet, Obesity, and Genes (DiOGenes) trial, lost >= 8% of their initial body weight during an 8-week low-calorie diet and were randomized to one of 5 ad libitum diets with a fixed energy percentage from fat: either low-protein/low-GI, low-protein/high-GI, high-protein/low-GI, or high-protein/high-GI diets, or a control diet for a 6-month weight maintenance period. Using linear regression analyses and additive genetic models, we investigated main and dietary interaction effects of TFAP2B rs987237 in relation to weight maintenance.

    Results: In total, 468 completers of the trial were genotyped for rs987237. High-protein diets were beneficial for weight maintenance in the AA genotype group (67% of participants), but in the AG and GG groups no differences were observed for low- or high-protein diets. On the high-protein diet, carriers of the obesity risk allele (G allele) regained 1.84 kg (95% CI: 0.02; 3.67, p = 0.047) more body weight per risk allele than individuals on a low-protein diet. There was no interaction effect between rs987237 and GI on weight maintenance.

    Conclusion: TFAP2B rs987237 and dietary protein/carbohydrate interacted to modify weight maintenance. Considering the carbohydrate proportion of the diet, the interaction was different from the previously reported rs987237-fat-to-carbohydrate ratio interaction for weight loss. Thus, TFAP2B-macronutrient interactions might diverge depending on the nutritional state.

    (C) 2013 S. Karger AG, Basel

  • 246. Stone, Jana E
    et al.
    Kumar, Dinesh
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Binz, Sara K
    Inase, Aki
    Iwai, Shigenori
    Chabes, Andrei
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Burgers, Peter M
    Kunkel, Thomas A
    Lesion bypass by S. cerevisiae Pol ζ alone2011In: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, Vol. 10, no 8, p. 826-834Article in journal (Refereed)
    Abstract [en]

    DNA polymerase zeta (Pol ζ) participates in translesion synthesis (TLS) of DNA adducts that stall replication fork progression. Previous studies have led to the suggestion that the primary role of Pol ζ in TLS is to extend primers created when another DNA polymerase inserts nucleotides opposite lesions. Here we test the non-exclusive possibility that Pol ζ can sometimes perform TLS in the absence of any other polymerase. To do so, we quantified the efficiency with which S. cerevisiae Pol ζ bypasses abasic sites, cis-syn cyclobutane pyrimidine dimers and (6-4) photoproducts. In reactions containing dNTP concentrations that mimic those induced by DNA damage, a Pol ζ derivative with phenylalanine substituted for leucine 979 at the polymerase active site bypasses all three lesions at efficiencies between 27 and 73%. Wild-type Pol ζ also bypasses these lesions, with efficiencies that are lower and depend on the sequence context in which the lesion resides. The results are consistent with the hypothesis that, in addition to extending aberrant termini created by other DNA polymerases, Pol ζ has the potential to be the sole DNA polymerase involved in TLS.

  • 247. Stray-Pedersen, Asbjorg
    et al.
    Sorte, Hanne Sormo
    Samarakoon, Pubudu
    Gambin, Tomasz
    Chinn, Ivan K.
    Akdemir, Zeynep H. Coban
    Erichsen, Hans Christian
    Forbes, Lisa R.
    Gu, Shen
    Yuan, Bo
    Jhangiani, Shalini N.
    Muzny, Donna M.
    Rodningen, Olaug Kristin
    Sheng, Ying
    Nicholas, Sarah K.
    Noroski, Lenora M.
    Seeborg, Filiz O.
    Davis, Carla M.
    Canter, Debra L.
    Mace, Emily M.
    Vece, Timothy J.
    Allen, Carl E.
    Abhyankar, Harshal A.
    Boone, Philip M.
    Beck, Christine R.
    Wiszniewski, Wojciech
    Fevang, Borre
    Aukrust, Pal
    Tjonnfjord, Geir E.
    Gedde-Dahl, Tobias
    Hjorth-Hansen, Henrik
    Dybedal, Ingunn
    Nordoy, Ingvild
    Jorgensen, Silje F.
    Abrahamsen, Tore G.
    Overland, Torstein
    Bechensteen, Anne Grete
    Skogen, Vegard
    Osnes, Liv T. N.
    Kulseth, Mari Ann
    Prescott, Trine E.
    Rustad, Cecilie F.
    Heimdal, Ketil R.
    Belmont, John W.
    Rider, Nicholas L.
    Chinen, Javier
    Cao, Tram N.
    Smith, Eric A.
    Soledad Caldirola, Maria
    Bezrodnik, Liliana
    Lugo Reyes, Saul Oswaldo
    Espinosa Rosales, Francisco J.
    Guerrero-Cursaru, Nina Denisse
    Pedroza, Luis Alberto
    Poli, Cecilia M.
    Franco, Jose L.
    Trujillo Vargas, Claudia M.
    Aldave Becerra, Juan Carlos
    Wright, Nicola
    Issekutz, Thomas B.
    Issekutz, Andrew C.
    Abbott, Jordan
    Caldwell, Jason W.
    Bayer, Diana K.
    Chan, Alice Y.
    Aiuti, Alessandro
    Cancrini, Caterina
    Holmberg, Eva
    West, Christina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Burstedt, Magnus
    Karaca, Ender
    Yesil, Gozde
    Artac, Hasibe
    Bayram, Yavuz
    Atik, Mehmed Musa
    Eldomery, Mohammad K.
    Ehlayel, Mohammad S.
    Jolles, Stephen
    Flato, Berit
    Bertuch, Alison A.
    Hanson, I. Celine
    Zhang, Victor W.
    Wong, Lee-Jun
    Hu, Jianhong
    Walkiewicz, Magdalena
    Yang, Yaping
    Eng, Christine M.
    Boerwinkle, Eric
    Gibbs, Richard A.
    Shearer, William T.
    Lyle, Robert
    Orange, Jordan S.
    Lupski, James R.
    Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders2017In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 139, no 1, p. 232-245Article in journal (Refereed)
    Abstract [en]

    Background: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. Objective: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs. Methods: Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. Results: A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/ 110) and management was directly altered in nearly a quarter (26/ 110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. Conclusion: This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.

  • 248.
    Ström, Anna-Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neurophysiology.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    A role for both wild-type and expanded ataxin-7 in transcriptional regulation2005In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 20, no 3, p. 646-655Article in journal (Refereed)
    Abstract [en]

    Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disease primarily affecting the brainstem, retina and Purkinje cells of the cerebellum. The disease is caused by a polyglutamine expansion in ataxin-7, a protein found in two complexes TFTC and STAGA, involved in transcriptional regulation. Transcriptional dysregulation has been implicated in the pathology of several polyglutamine diseases. In this paper, we analyzed the effect of both wild-type and expanded ataxin-7 on transcription driven by the co-activator CBP and the Purkinje cell expressed nuclear receptor RORα1. We could show that transcription mediated by both CBP and RORα1 was repressed by expanded ataxin-7. Interestingly, repression of transcription could also be observed with wild-type full-length ataxin-7, not only on CBP- and RORα1-mediated transcription, but also on basal transcription. The repression could be counteracted by inhibition of deacetylation, suggesting that ataxin-7 may act as a repressor of transcription by inhibiting the acetylation activity of TFTC and STAGA.

  • 249.
    Ström, Anna-Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Identification and characterization of Spinocerebellar Ataxia Type 7 (SCA7) isoform SCA7b in mice2005In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1731, no 3, p. 149-153Article in journal (Refereed)
    Abstract [en]

    Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disease primarily affecting the cerebellum, brainstem and retina. The disease is caused by a polyglutamine expansion in ataxin-7, a protein with largely unknown function. To improve our knowledge of the expression and function of wild-type and expanded ataxin-7, we looked for alternative SCA7 transcripts in mice. We identified a murine SCA7 isoform (SCA7b) containing an uncharacterized exon homologous to the newly identified human exon 12b. Northern blot analysis revealed three exon 12b containing transcripts with molecular sizes of 7.5, 4.4 and 3.0 kb in mice. This contrasted with the situation in humans, where only one exon 12b-containing transcript was observed. Furthermore, Northern blot of the human 4.4 kb SCA7b isoform predominantly showed expression in the brain, while expression of both the murine 7.5-kb and the 4.4-kb transcripts were observed in several tissues including brain, heart, liver, kidney and testis. Quantitative real-time RT-PCR analysis revealed that in muscle and heart SCA7b is the predominant SCA7 isoform, while in brain equal levels of SCA7a and SCA7b was observed. Insertion of exon 12b into the murine SCA7 ORF resulted in a frame-shift that gave rise to an alternative ataxin-7 protein (ataxin-7b). The novel 58-amino acid C-terminus in ataxin-7b directed the protein to a more cytoplasmic location.

  • 250.
    Suhr, Ole B.
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Coelho, Teresa
    Buades, Juan
    Pouget, Jean
    Conceicao, Isabel
    Berk, John
    Schmidt, Hartmut
    Waddington-Cruz, Marcia
    Campistol, Josep M.
    Bettencourt, Brian R.
    Vaishnaw, Akshay
    Gollob, Jared
    Adams, David
    Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study2015In: Orphanet Journal of Rare Diseases, ISSN 1750-1172, E-ISSN 1750-1172, Vol. 10, article id 109Article in journal (Refereed)
    Abstract [en]

    Background: Transthyretin-mediated amyloidosis is an inherited, progressively debilitating disease caused by mutations in the transthyretin gene. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of patisiran (ALN-TTR02), a small interfering RNA encapsulated within lipid nanoparticles, in patients with transthyretin-mediated familial amyloid polyneuropathy (FAP). Methods: In this phase II study, patients with FAP were administered 2 intravenous infusions of patisiran at one of the following doses: 0.01 (n = 4), 0.05 (n = 3), 0.15 (n = 3), or 0.3 (n = 7) mg/kg every 4 weeks (Q4W), or 0.3 mg/kg (n = 12) every 3 weeks (Q3W). Results: Of 29 patients in the intent-to-treat population, 26 completed the study. Administration of patisiran led to rapid, dose-dependent, and durable knockdown of transthyretin, with the maximum effect seen with patisiran 0.3 mg/kg; levels of mutant and wild-type transthyretin were reduced to a similar extent in Val30Met patients. A mean level of knockdown exceeding 85 % after the second dose, with maximum knockdown of 96 %, was observed for the Q3W dose. The most common treatment-related adverse event (AE) was mild-to-moderate infusion-related reactions in 10.3 % of patients. Four serious AEs (SAEs) were reported in 1 patient administered 0.3 mg/kg Q3W (urinary tract infection, sepsis, nausea, vomiting), and 1 patient administered 0.3 mg/kg Q4W had 1 SAE (extravasation-related cellulitis). Conclusions: Patisiran was generally well tolerated and resulted in significant dose-dependent knockdown of transthyretin protein in patients with FAP. Patisiran 0.3 mg/kg Q3W is currently in phase III development.

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