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  • 1. Auer-Grumbach, Michaela
    et al.
    Toegel, Stefan
    Schabhuettl, Maria
    Weinmann, Daniela
    Chiari, Catharina
    Bennett, David L. H.
    Beetz, Christian
    Klein, Dennis
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Boehme, Ilka
    Fink-Puches, Regina
    Gonzalez, Michael
    Harms, Matthew B.
    Motley, William
    Reilly, Mary M.
    Renner, Wilfried
    Rudnik-Schoeneborn, Sabine
    Schlotter-Weigel, Beate
    Themistocleous, Andreas C.
    Weishaupt, Jochen H.
    Ludolph, Albert C.
    Wieland, Thomas
    Tao, Feifei
    Abreu, Lisa
    Windhager, Reinhard
    Zitzelsberger, Manuela
    Strom, Tim M.
    Walther, Thomas
    Scherer, Steven S.
    Zuchner, Stephan
    Martini, Rudolf
    Senderek, Jan
    Rare Variants in MME, Encoding Metalloprotease Neprilysin, Are Linked to Late-Onset Autosomal-Dominant Axonal Polyneuropathies2016In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 99, no 3, p. 607-623Article in journal (Refereed)
    Abstract [en]

    Axonal polyneuropathies are a frequent cause of progressive disability in the elderly. Common etiologies comprise diabetes mellitus, paraproteinaemia, and inflammatory disorders, but often the underlying causes remain elusive. Late-onset axonal Charcot-Marie-Tooth neuropathy (CMT2) is an autosomal-dominantly inherited condition that manifests in the second half of life and is genetically largely unexplained. We assumed age-dependent penetrance of mutations in a so far unknown gene causing late-onset CMT2. We screened 51 index case subjects with late-onset CMT2 for mutations by whole-exome (WES) and Sanger sequencing and subsequently queried WES repositories for further case subjects carrying mutations in the identified candidate gene. We studied nerve pathology and tissue levels and function of the abnormal protein in order to explore consequences of the mutations. Altogether, we observed heterozygous rare loss-of-function and missense mutations in MME encoding the metalloprotease neprilysin in 19 index case subjects diagnosed with axonal polyneuropathies or neurodegenerative conditions involving the peripheral nervous system. MME mutations segregated in an autosomal-dominant fashion with age-related incomplete penetrance and some affected individuals were isolated case subjects. We also found that MME mutations resulted in strongly decreased tissue availability of neprilysin and impaired enzymatic activity. Although neprilysin is known to degrade beta-amyloid, we observed no increased amyloid deposition or increased incidence of dementia in individuals with MME mutations. Detection of MME mutations is expected to increase the diagnostic yield in late-onset polyneuropathies, and it will be tempting to explore whether substances that can elevate neprilysin activity could be a rational option for treatment.

  • 2.
    Bhattacharjee, Samsiddhi
    et al.
    Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 6120 Executive Boulevard, Rockville, Maryland 20852, USA.
    Rajaraman, Preetha
    Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 6120 Executive Boulevard, Rockville, Maryland 20852, USA.
    Jacobs, Kevin B
    Core Genotyping Facility, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 8717 Grovemont Circle, Gaithersburg, Maryland 20877, USA.
    Wheeler, William A
    Information Management Services, Rockville, MD 20852, USA.
    Melin, Beatrice S
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hartge, Patricia
    Epidemiology and Biostatistics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
    GliomaScan Consortium,
    GliomaScan Consortium investigators and affiliations are available in the Supplemental Data.
    Yeager, Meredith
    Core Genotyping Facility, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 8717 Grovemont Circle, Gaithersburg, Maryland 20877, USA.
    Chung, Charles C
    Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
    Chanock, Stephen J
    Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
    Chatterjee, Nilanjan
    Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 6120 Executive Boulevard, Rockville, Maryland 20852, USA.
    A subset-based approach improves power and interpretation for the combined analysis of genetic association studies of heterogeneous traits2012In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 90, no 5, p. 821-835Article in journal (Refereed)
    Abstract [en]

    Pooling genome-wide association studies (GWASs) increases power but also poses methodological challenges because studies are often heterogeneous. For example, combining GWASs of related but distinct traits can provide promising directions for the discovery of loci with small but common pleiotropic effects. Classical approaches for meta-analysis or pooled analysis, however, might not be suitable for such analysis because individual variants are likely to be associated with only a subset of the traits or might demonstrate effects in different directions. We propose a method that exhaustively explores subsets of studies for the presence of true association signals that are in either the same direction or possibly opposite directions. An efficient approximation is used for rapid evaluation of p values. We present two illustrative applications, one for a meta-analysis of separate case-control studies of six distinct cancers and another for pooled analysis of a case-control study of glioma, a class of brain tumors that contains heterogeneous subtypes. Both the applications and additional simulation studies demonstrate that the proposed methods offer improved power and more interpretable results when compared to traditional methods for the analysis of heterogeneous traits. The proposed framework has applications beyond genetic association studies.

  • 3. Blaydon, Diana C
    et al.
    Lind, Lisbet K
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Plagnol, Vincent
    Linton, Kenneth J
    Smith, Francis JD
    Wilson, Neil J
    McLean, WH Irwin
    Munro, Colin S
    South, Andrew P
    Leigh, Irene M
    O'Toole, Edel A
    Lundström, Anita
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Kelsell, David P
    Mutations in AQP5, encoding a water-channel protein, cause autosomal-dominant diffuse nonepidermolytic palmoplantar keratoderma2013In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 93, no 2, p. 330-335Article in journal (Refereed)
  • 4. Han, Buhm
    et al.
    Diogo, Dorothee
    Eyre, Steve
    Kallberg, Henrik
    Zhernakova, Alexandra
    Bowes, John
    Padyukov, Leonid
    Okada, Yukinori
    Gonzalez-Gay, Miguel A.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Martin, Javier
    Huizinga, Tom W. J.
    Plenge, Robert M.
    Worthington, Jane
    Gregersen, Peter K.
    Klareskog, Lars
    de Bakker, Paul I. W.
    Raychaudhuri, Soumya
    Fine Mapping Seronegative and Seropositive Rheumatoid Arthritis to Shared and Distinct HLA Alleles by Adjusting for the Effects of Heterogeneity2014In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 94, no 4, p. 522-532Article in journal (Refereed)
    Abstract [en]

    Despite progress in defining human leukocyte antigen (HLA) alleles for anti-citrullinated-protein-autoantibody-positive (ACPA(+)) rheumatoid arthritis (RA), identifying HLA alleles for ACPA-negative (ACPA(-)) RA has been challenging because of clinical heterogeneity within clinical cohorts. We imputed 8,961 classical HLA alleles, amino acids, and SNPs from Immunochip data in a discovery set of 2,406 ACPA(-) RA case and 13,930 control individuals. We developed a statistical approach to identify and adjust for clinical heterogeneity within ACPA RA and observed independent associations for serine and leucine at position 11 in HLA-DR beta 1 (p = 1.4 x 10 (13), odds ratio [OR] = 1.30) and for aspartate at position 9 in HLA-B (p = 2.7 x 10(-12), OR = 1.39) within the peptide binding grooves. These amino acid positions induced associations at HLA-DRB1*03 (encoding serine at 11) and HLA-B*08 (encoding aspartate at 9). We validated these findings in an independent set of 427 ACPA(-) case subjects, carefully phenotyped with a highly sensitive ACPA assay, and 1,691 control subjects (HLA-DR beta 1 Ser11+Leu11: p = 5.8 x 10(-4), OR = 1.28; HLA-B Asp9: p = 2.6 x 10(-3), OR = 1.34). Although both amino acid sites drove risk of ACPA(+) and ACPA(-) disease, the effects of individual residues at HLA-DR beta 1 position 11 were distinct (p < 2.9 x 10(-107)). We also identified an association with ACPA(+) RA at HLA-A position 77 (p = 2.7 x 10(-8), OR = 0.85) in 7,279 ACPA(+) RA case and 15,870 control subjects. These results contribute to mounting evidence that ACPA(+) and ACPA(-) RA are genetically distinct and potentially have separate autoantigens contributing to pathogenesis. We expect that our approach might have broad applications in analyzing clinical conditions with heterogeneity at both major histocompatibility complex (MHC) and non-MHC regions.

  • 5. Kapferer-Seebacher, Ines
    et al.
    Pepin, Melanie
    Werner, Roland
    Aitman, Timothy J
    Nordgren, Ann
    Stoiber, Heribert
    Thielens, Nicole
    Gaboriaud, Christine
    Amberger, Albert
    Schossig, Anna
    Gruber, Robert
    Giunta, Cecilia
    Bamshad, Michael
    Björck, Erik
    Chen, Christina
    Chitayat, David
    Dorschner, Michael
    Schmitt-Egenolf, Marcus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Hale, Christopher J
    Hanna, David
    Hennies, Hans Christian
    Heiss-Kisielewsky, Irene
    Lindstrand, Anna
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology.
    Mitchell, Anna L
    Nickerson, Deborah A
    Reinstein, Eyal
    Rohrbach, Marianne
    Romani, Nikolaus
    Schmuth, Matthias
    Silver, Rachel
    Taylan, Fulya
    Vandersteen, Anthony
    Vandrovcova, Jana
    Weerakkody, Ruwan
    Yang, Margaret
    Pope, F Michael
    Byers, Peter H
    Zschocke, Johannes
    Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement2016In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 99, no 5, p. 1005-1014Article in journal (Refereed)
    Abstract [en]

    Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, and mild skin findings. A locus was mapped to an approximately 5.8 Mb region at 12p13.1 but no candidate gene was identified. In an international consortium we recruited 19 independent families comprising 107 individuals with pEDS to identify the locus, characterize the clinical details in those with defined genetic causes, and try to understand the physiological basis of the condition. In 17 of these families, we identified heterozygous missense or in-frame insertion/deletion mutations in C1R (15 families) or C1S (2 families), contiguous genes in the mapped locus that encode subunits C1r and C1s of the first component of the classical complement pathway. These two proteins form a heterotetramer that then combines with six C1q subunits. Pathogenic variants involve the subunit interfaces or inter-domain hinges of C1r and C1s and are associated with intracellular retention and mild endoplasmic reticulum enlargement. Clinical features of affected individuals in these families include rapidly progressing periodontitis with onset in the teens or childhood, a previously unrecognized lack of attached gingiva, pretibial hyperpigmentation, skin and vascular fragility, easy bruising, and variable musculoskeletal symptoms. Our findings open a connection between the inflammatory classical complement pathway and connective tissue homeostasis.

  • 6. Lee, YA
    et al.
    Rüschendorf, F
    Windemuth, C
    Schmitt-Egenolf, Marcus
    Department of Dermatology, Norwegian University of Science and Technology, Trondheim, Norway.
    Stadelmann, A
    Nürnberg, G
    Ständer, M
    Wienker, TF
    Reis, A
    Traupe, H
    Genomewide scan in german families reveals evidence for a novel psoriasis-susceptibility locus on chromosome 19p132000In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 67, no 4, p. 1020-1024Article in journal (Refereed)
    Abstract [en]

    Psoriasis is a common chronic inflammatory skin disease with a strong genetic component. Few psoriasis-susceptibility loci have been reported, and only two have been confirmed in independent data sets. This article reports results of a genomewide scan that was performed, using 370 microsatellite markers, for psoriasis-susceptibility loci in 32 German extended families, comprising 162 affected and 195 unaffected individuals. Nonparametric linkage analysis of all families provided strong evidence for a novel psoriasis-susceptibility locus on chromosome 19p (Zlr=3.50; P=.0002). Parametric analysis revealed a heterogeneity LOD score of 4.06, corresponding to a genomewide significance level of.037, under the assumption of a recessive model with high disease-allele frequency and 66% as the proportion of linked families. This study confirms linkage of psoriasis to the HLA region on chromosome 6p and suggests additional regions on chromosomes 8q and 21q for further investigations.

  • 7. Lindholm, E
    et al.
    Ekholm, B
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Shaw, S
    Jalonen, P
    Johansson, G
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Pettersson, U
    Sherrington, R
    Adolfsson, R
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Jazin, E
    A schizophrenia-susceptibility locus at 6q25, in one of the world´s largest reported pedigree2001In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 69, no 1, p. 96-105Article in journal (Refereed)
    Abstract [en]

    We have completed a genome scan of a 12-generation, 3,400-member pedigree with schizophrenia. Samples from 210 individuals were collected from the pedigree. We performed an "affecteds-only" genome-scan analysis using 43 members of the pedigree. The affected individuals included 29 patients with schizophrenia, 10 with schizoaffective disorders, and 4 with psychosis not otherwise specified. Two sets of white-European allele frequencies were used-one from a Swedish control population (46 unrelated individuals) and one from the pedigree (210 individuals). All analyses pointed to the same region: D6S264, located at 6q25.2, showed a maximum LOD score of 3.45 when allele frequencies in the Swedish control population were used, compared with a maximum LOD score of 2.59 when the pedigree's allele frequencies were used. We analyzed additional markers in the 6q25 region and found a maximum LOD score of 6.6 with marker D6S253, as well as a 6-cM haplotype (markers D6S253-D6S264) that segregated, after 12 generations, with the majority of the affected individuals. Multipoint analysis was performed with the markers in the 6q25 region, and a maximum LOD score of 7.7 was obtained. To evaluate the significance of the genome scan, we simulated the complete analysis under the assumption of no linkage. The results showed that a LOD score >2.2 should be considered as suggestive of linkage, whereas a LOD score >3.7 should be considered as significant. These results suggest that a common ancestral region was inherited by the affected individuals in this large pedigree.

  • 8. Machiela, Mitchell J.
    et al.
    Zhou, Weiyin
    Sampson, Joshua N.
    Dean, Michael C.
    Jacobs, Kevin B.
    Black, Amanda
    Brinton, Louise A.
    Chang, I-Shou
    Chen, Chu
    Chen, Constance
    Chen, Kexin
    Cook, Linda S.
    Bou, Marta Crous
    De Vivo, Immaculata
    Doherty, Jennifer
    Friedenreich, Christine M.
    Gaudet, Mia M.
    Haiman, Christopher A.
    Hankinson, Susan E.
    Hartge, Patricia
    Henderson, Brian E.
    Hong, Yun-Chul
    Hosgood, H. Dean, III
    Hsiung, Chao A.
    Hu, Wei
    Hunter, David J.
    Jessop, Lea
    Kim, Hee Nam
    Kim, Yeul Hong
    Kim, Young Tae
    Klein, Robert
    Kraft, Peter
    Lan, Qing
    Lin, Dongxin
    Liu, Jianjun
    Le Marchand, Loic
    Liang, Xiaolin
    Lissowska, Jolanta
    Lu, Lingeng
    Magliocco, Anthony M.
    Matsuo, Keitaro
    Olson, Sara H.
    Orlow, Irene
    Park, Jae Yong
    Pooler, Loreall
    Prescott, Jennifer
    Rastogi, Radhai
    Risch, Harvey A.
    Schumacher, Fredrick
    Seow, Adeline
    Setiawan, Veronica Wendy
    Shen, Hongbing
    Sheng, Xin
    Shin, Min-Ho
    Shu, Xiao-Ou
    VanDen Berg, David
    Wang, Jiu-Cun
    Wentzensen, Nicolas
    Wong, Maria Pik
    Wu, Chen
    Wu, Tangchun
    Wu, Yi-Long
    Xia, Lucy
    Yang, Hannah P.
    Yang, Pan-Chyr
    Zheng, Wei
    Zhou, Baosen
    Abnet, Christian C.
    Albanes, Demetrius
    Aldrich, Melinda C.
    Amos, Christopher
    Amundadottir, Laufey T.
    Berndt, Sonja I.
    Blot, William J.
    Bock, Cathryn H.
    Bracci, Paige M.
    Burdett, Laurie
    Buring, Julie E.
    Butler, Mary A.
    Carreon, Tania
    Chatterjee, Nilanjan
    Chung, Charles C.
    Cook, Michael B.
    Cullen, Michael
    Davis, Faith G.
    Ding, Ti
    Duell, Eric J.
    Epstein, Caroline G.
    Fan, Jin-Hu
    Figueroa, Jonine D.
    Fraumeni, Joseph F., Jr.
    Freedman, Neal D.
    Fuchs, Charles S.
    Gao, Yu-Tang
    Gapstur, Susan M.
    Patino-Garcia, Ana
    Garcia-Closas, Montserrat
    Gaziano, J. Michael
    Giles, Graham G.
    Gillanders, Elizabeth M.
    Giovannucci, Edward L.
    Goldin, Lynn
    Goldstein, Alisa M.
    Greene, Mark H.
    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.
    Harris, Curtis C.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Holly, Elizabeth A.
    Hoover, Robert N.
    Hu, Nan
    Hutchinson, Amy
    Jenab, Mazda
    Johansen, Christoffer
    Khaw, Kay-Tee
    Koh, Woon-Puay
    Kolonel, Laurence N.
    Kooperberg, Charles
    Krogh, Vittorio
    Kurtz, Robert C.
    LaCroix, Andrea
    Landgren, Annelie
    Landi, Maria Teresa
    Li, Donghui
    Liao, Linda M.
    Malats, Nuria
    McGlynn, Katherine A.
    McNeill, Lorna H.
    McWilliams, Robert R.
    Melin, Beatrice S.
    Mirabello, Lisa
    Peplonska, Beata
    Peters, Ulrike
    Petersen, Gloria M.
    Prokunina-Olsson, Ludmila
    Purdue, Mark
    Qiao, You-Lin
    Rabe, Kari G.
    Rajaraman, Preetha
    Real, Francisco X.
    Riboli, Elio
    Rodriguez-Santiago, Benjamin
    Rothman, Nathaniel
    Ruder, Avima M.
    Savage, Sharon A.
    Schwartz, Ann G.
    Schwartz, Kendra L.
    Sesso, Howard D.
    Severi, Gianluca
    Silverman, Debra T.
    Spitz, Margaret R.
    Stevens, Victoria L.
    Stolzenberg-Solomon, Rachael
    Stram, Daniel
    Tang, Ze-Zhong
    Taylor, Philip R.
    Teras, Lauren R.
    Tobias, Geoffrey S.
    Viswanathan, Kala
    Wacholder, Sholom
    Wang, Zhaoming
    Weinstein, Stephanie J.
    Wheeler, William
    White, Emily
    Wiencke, John K.
    Wolpin, Brian M.
    Wu, Xifeng
    Wunder, Jay S.
    Yu, Kai
    Zanetti, Krista A.
    Zeleniuch-Jacquotte, Anne
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Ziegler, Regina G.
    De Andrade, Mariza
    Barnes, Kathleen C.
    Beaty, Terri H.
    Bierut, Laura J.
    Desch, Karl C.
    Doheny, Kimberly F.
    Feenstra, Bjarke
    Ginsburg, David
    Heit, John A.
    Kang, Jae H.
    Laurie, Cecilia A.
    Li, Jun Z.
    Lowe, William L.
    Marazita, Mary L.
    Melbye, Mads
    Mirel, Daniel B.
    Murray, Jeffrey C.
    Nelson, Sarah C.
    Pasquale, Louis R.
    Rice, Kenneth
    Wiggs, Janey L.
    Wise, Anastasia
    Tucker, Margaret
    Perez-Jurado, Luis A.
    Laurie, Cathy C.
    Caporaso, Neil E.
    Yeager, Meredith
    Chanock, Stephen J.
    Characterization of Large Structural Genetic Mosaicism in Human Autosomes2015In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 96, no 3, p. 487-497Article in journal (Refereed)
    Abstract [en]

    Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 x 3 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.

  • 9. Mochel, Fanny
    et al.
    Knight, Melanie A
    Tong, Wing-Hang
    Hernandez, Dena
    Ayyad, Karen
    Taivassalo, Tanja
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Singleton, Andrew
    Rouault, Tracey A
    Fischbeck, Kenneth H
    Haller, Ronald G
    Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance2008In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 82, no 3, p. 652-660Article in journal (Refereed)
    Abstract [en]

    A myopathy with severe exercise intolerance and myoglobinuria has been described in patients from northern Sweden, with associated deficiencies of succinate dehydrogenase and aconitase in skeletal muscle. We identified the gene for the iron-sulfur cluster scaffold protein ISCU as a candidate within a region of shared homozygosity among patients with this disease. We found a single mutation in ISCU that likely strengthens a weak splice acceptor site, with consequent exon retention. A marked reduction of ISCU mRNA and mitochondrial ISCU protein in patient muscle was associated with a decrease in the iron regulatory protein IRP1 and intracellular iron overload in skeletal muscle, consistent with a muscle-specific alteration of iron homeostasis in this disease. ISCU interacts with the Friedreich ataxia gene product frataxin in iron-sulfur cluster biosynthesis. Our results therefore extend the range of known human diseases that are caused by defects in iron-sulfur cluster biogenesis.

  • 10.
    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.

  • 11. Sung, Yun J.
    et al.
    Winkler, Thomas W.
    de las Fuentes, Lisa
    Bentley, Amy R.
    Brown, Michael R.
    Kraja, Aldi T.
    Schwander, Karen
    Ntalla, Ioanna
    Guo, Xiuqing
    Franceschini, Nora
    Lu, Yingchang
    Cheng, Ching-Yu
    Sim, Xueling
    Vojinovic, Dina
    Marten, Jonathan
    Musani, Solomon K.
    Li, Changwei
    Feitosa, Mary F.
    Kilpelainen, Tuomas O.
    Richard, Melissa A.
    Noordam, Raymond
    Aslibekyan, Stella
    Aschard, Hugues
    Bartz, Traci M.
    Dorajoo, Rajkumar
    Liu, Yongmei
    Manning, Alisa K.
    Rankinen, Tuomo
    Smith, Albert Vernon
    Tajuddin, Salman M.
    Tayo, Bamidele O.
    Warren, Helen R.
    Zhao, Wei
    Zhou, Yanhua
    Matoba, Nana
    Sofer, Tamar
    Alver, Maris
    Amini, Marzyeh
    Boissel, Mathilde
    Chai, Jin Fang
    Chen, Xu
    Divers, Jasmin
    Gandin, Ilaria
    Gao, Chuan
    Giulianini, Franco
    Goel, Anuj
    Harris, Sarah E.
    Hartwig, Fernando Pires
    Horimoto, Andrea R. V. R.
    Hsu, Fang-Chi
    Jackson, Anne U.
    Kahonen, Mika
    Kasturiratne, Anuradhani
    Kuhnel, Brigitte
    Leander, Karin
    Lee, Wen-Jane
    Lin, Keng-Hung
    Luan, Jian' an
    McKenzie, Colin A.
    Meian, He
    Nelson, Christopher P.
    Rauramaa, Rainer
    Schupf, Nicole
    Scott, Robert A.
    Sheu, Wayne H. H.
    Stancakova, Alena
    Takeuchi, Fumihiko
    van der Most, Peter J.
    Varga, Tibor V.
    Wang, Heming
    Wang, Yajuan
    Ware, Erin B.
    Weiss, Stefan
    Wen, Wanqing
    Yanek, Lisa R.
    Zhang, Weihua
    Zhao, Jing Hua
    Afaq, Saima
    Alfred, Tamuno
    Amin, Najaf
    Arking, Dan
    Aung, Tin
    Barr, R. Graham
    Bielak, Lawrence F.
    Boerwinkle, Eric
    Bottinger, Erwin P.
    Braund, Peter S.
    Brody, Jennifer A.
    Broeckel, Ulrich
    Cabrera, Claudia P.
    Cade, Brian
    Caizheng, Yu
    Campbell, Archie
    Canouil, Mickael
    Chakravarti, Aravinda
    Chauhan, Ganesh
    Christensen, Kaare
    Cocca, Massimiliano
    Collins, Francis S.
    Connell, John M.
    de Mutsert, Renee
    de Silva, H. Janaka
    Debette, Stephanie
    Dorr, Marcus
    Duan, Qing
    Eaton, Charles B.
    Ehret, Georg
    Evangelou, Evangelos
    Faul, Jessica D.
    Fisher, Virginia A.
    Forouhi, Nita G.
    Franco, Oscar H.
    Friedlander, Yechiel
    Gao, He
    Gigante, Bruna
    Graff, Misa
    Gu, C. Charles
    Gu, Dongfeng
    Gupta, Preeti
    Hagenaars, Saskia P.
    Harris, Tamara B.
    He, Jiang
    Heikkinen, Sami
    Heng, Chew-Kiat
    Hirata, Makoto
    Hofman, Albert
    Howard, Barbara V.
    Hunt, Steven
    Irvin, Marguerite R.
    Jia, Yucheng
    Joehanes, Roby
    Justice, Anne E.
    Katsuya, Tomohiro
    Kaufman, Joel
    Kerrison, Nicola D.
    Khor, Chiea Chuen
    Koh, Woon-Puay
    Koistinen, Heikki A.
    Komulainen, Pirjo
    Kooperberg, Charles
    Krieger, Jose E.
    Kubo, Michiaki
    Kuusisto, Johanna
    Langefeld, Carl D.
    Langenberg, Claudia
    Launer, Lenore J.
    Lehne, Benjamin
    Lewis, Cora E.
    Li, Yize
    Lim, Sing Hui
    Lin, Shiow
    Liu, Ching-Ti
    Liu, Jianjun
    Liu, Jingmin
    Liu, Kiang
    Liu, Yeheng
    Loh, Marie
    Lohman, Kurt K.
    Long, Jirong
    Louie, Tin
    Magi, Reedik
    Mahajan, Anubha
    Meitinger, Thomas
    Metspalu, Andres
    Milani, Lili
    Momozawa, Yukihide
    Morris, Andrew P.
    Mosley, Thomas H., Jr.
    Munson, Peter
    Murray, Alison D.
    Nalls, Mike A.
    Nasri, Ubaydah
    Norris, Jill M.
    North, Kari
    Ogunniyi, Adesola
    Padmanabhan, Sandosh
    Palmas, Walter R.
    Palmer, Nicholette D.
    Pankow, James S.
    Pedersen, Nancy L.
    Peters, Annette
    Peyser, Patricia A.
    Polasek, Ozren
    Raitakari, Olli T.
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Rice, Treva K.
    Ridker, Paul M.
    Robino, Antonietta
    Robinson, Jennifer G.
    Rose, Lynda M.
    Rudan, Igor
    Sabanayagam, Charumathi
    Salako, Babatunde L.
    Sandow, Kevin
    Schmidt, Carsten O.
    Schreiner, Pamela J.
    Scott, William R.
    Seshadri, Sudha
    Sever, Peter
    Sitlani, Colleen M.
    Smith, Jennifer A.
    Snieder, Harold
    Starr, John M.
    Strauch, Konstantin
    Tang, Hua
    Taylor, Kent D.
    Teo, Yik Ying
    Tham, Yih Chung
    Ultterlinden, Andre G.
    Waldenberger, Melanie
    Wang, Lihua
    Wang, Ya X.
    Bin Wei, Wen
    Williams, Christine
    Wilson, Gregory
    Wojczynski, Mary K.
    Yao, Jie
    Yuan, Jian-Min
    Zonderman, Alan B.
    Becker, Diane M.
    Boehnke, Michael
    Bowden, Donald W.
    Chambers, John C.
    Chen, Yii-Der Ida
    de Faire, Ulf
    Deary, Ian J.
    Esko, Tonu
    Farrall, Martin
    Forrester, Terrence
    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, Lund University, Malmö, Sweden; Harvard T.H. Chan School of Public Health, Department of Nutrition, Harvard University, Boston, MA, USA.
    Freedman, Barry I.
    Froguel, Philippe
    Gasparini, Paolo
    Gieger, Christian
    Horta, Bernardo Lessa
    Hung, Yi-Jen
    Jonas, Jost B.
    Kato, Norihiro
    Kooner, Jaspal S.
    Laakso, Markku
    Lehtimaki, Terho
    Liang, Kae-Woei
    Magnusson, Patrik K. E.
    Newman, Anne B.
    Oldehinkel, Albertine J.
    Pereira, Alexandre C.
    Redline, Susan
    Rettig, Rainer
    Samani, Nilesh J.
    Scott, James
    Shu, Xiao-Ou
    van der Harst, Pim
    Wagenknecht, Lynne E.
    Wareham, Nicholas J.
    Watkins, Hugh
    Weir, David R.
    Wickremasinghe, Ananda R.
    Wu, Tangchun
    Zheng, Wei
    Kamatani, Yoichiro
    Laurie, Cathy C.
    Bouchard, Claude
    Cooper, Richard S.
    Evans, Michele K.
    Gudnason, Vilmundur
    Kardia, Sharon L. R.
    Kritchevsky, Stephen B.
    Levy, Daniel
    O'Connell, Jeff R.
    Psaty, Bruce M.
    van Dam, Rob M.
    Sims, Mario
    Arnett, Donna K.
    Mook-Kanamori, Dennis O.
    Kelly, Tanika N.
    Fox, Ervin R.
    Hayward, Caroline
    Fornage, Myriam
    Rotimi, Charles N.
    Province, Michael A.
    van Duijn, Cornelia M.
    Tai, E. Shyong
    Wong, Tien Yin
    Loos, Ruth J. F.
    Reiner, Alex P.
    Rotter, Jerome I.
    Zhu, Xiaofeng
    Bierut, Laura J.
    Gauderman, W. James
    Caulfield, Mark J.
    Elliott, Paul
    Rice, Kenneth
    Munroe, Patricia B.
    Morrison, Alanna C.
    Cupples, L. Adrienne
    Rao, Dabeeru C.
    Chasman, Daniel I.
    A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure2018In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 102, no 3, p. 375-400Article in journal (Refereed)
    Abstract [en]

    Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined similar to 18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 x 10(-8)) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 x 10(-8)). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling MSRA, EBF2).

  • 12. Venken, Tine
    et al.
    Claes, Stephan
    Sluijs, Samuël
    Paterson, Andrew D
    van Duijn, Cornelia
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Del-Favero, Jurgen
    Van Broeckhoven, Christine
    Genomewide scan for affective disorder susceptibility loci in families of a northern Swedish isolated population2005In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 76, no 2, p. 237-248Article in journal (Refereed)
    Abstract [en]

    We analyzed nine multigenerational families with ascertained affective spectrum disorders in northern Sweden's geographically isolated population of Vasterbotten. This northern Swedish population, which originated from a limited number of early settlers similar to8,000 years ago, is genetically more homogeneous than outbred populations. In a genomewide linkage analysis, we identified three chromosomal loci with multipoint LOD scores (MPLOD) greater than or equal to2 at 9q31.1-q34.1 (MPLOD 3.24), 6q22.2-q24.2 (MPLOD 2.48), and 2q33-q36 (MPLOD 2.26) under a recessive affected-only model. Follow-up genotyping with application of a 2-cM density simple-tandem-repeat (STR) map confirmed linkage at 9q31.1-q34.1 (MPLOD 3.22), 6q23-q24 (MPLOD 3.25), and 2q33-q36 (MPLOD 2.2). In an initial analysis aimed at identification of the underlying susceptibility genes, we focused our attention on the 9q locus. We fine mapped this region at a 200-kb STR density, with the result of an MPLOD of 3.70. Genealogical studies showed that three families linked to chromosome 9q descended from common founder couples similar to10 generations ago. In this similar to10-generation pedigree, a common ancestral haplotype was inherited by the patients, which reduced the 9q candidate region to 1.6 Mb. Further, the shared haplotype was observed in 4.2% of patients with bipolar disorder with alternating episodes of depression and mania, but it was not observed in control individuals in a patient-control sample from the Vasterbotten isolate. These results suggest a susceptibility locus on 9q31-q33 for affective disorder in this common ancestral region.

  • 13. Williams, N M
    et al.
    Norton, N
    Williams, H
    Ekholm, B
    Umeå University, Faculty of Medicine, Clinical Sciences.
    Hamshere, M L
    Lindblom, Y
    Umeå University, Faculty of Medicine, Clinical Sciences, Psychiatry.
    Chowdari, K V
    Cardno, A G
    Zammit, S
    Jones, L A
    Murphy, K C
    Sanders, R D
    McCarthy, G
    Gray, M Y
    Jones, G
    Holmans, P
    Nimgaonkar, V
    Adolfson, R
    Umeå University, Faculty of Medicine, Clinical Sciences, Psychiatry.
    Osby, U
    Terenius, L
    Sedvall, G
    O'Donovan, M C
    Owen, M J
    A systematic genomewide linkage study in 353 sib pairs with schizophrenia.2003In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 73, no 6, p. 1355-1367Article in journal (Refereed)
    Abstract [en]

    We undertook a genomewide linkage study in a total of 353 affected sib pairs (ASPs) with schizophrenia. Our sample consisted of 179 ASPs from the United Kingdom, 134 from Sweden, and 40 from the United States. We typed 372 microsatellite markers at approximately 10-cM intervals. Our strongest finding was a LOD score of 3.87 on chromosome 10q25.3-q26.3, with positive results being contributed by all three samples and a LOD-1 interval of 15 cM. This finding achieved genomewide significance (P<.05), on the basis of simulation studies. We also found two regions, 17p11.2-q25.1 (maximum LOD score [MLS] = 3.35) and 22q11 (MLS = 2.29), in which the evidence for linkage was highly suggestive. Linkage to all of these regions has been supported by other studies. Moreover, we found strong evidence for linkage (genomewide P<.02) to 17p11.2-q25.1 in a single pedigree with schizophrenia. In our view, the evidence is now sufficiently compelling to undertake detailed mapping studies of these three regions.

1 - 13 of 13
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