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Author (up) Ferreira, M.A.; Vonk, J.M.; Baurecht, H.; Marenholz, I.; Tian, C.; Hoffman, J.D.; Helmer, Q.; Tillander, A.; Ullemar, V.; van Dongen, J.; Lu, Y.; Ruschendorf, F.; Esparza-Gordillo, J.; Medway, C.W.; Mountjoy, E.; Burrows, K.; Hummel, O.; Grosche, S.; Brumpton, B.M.; Witte, J.S.; Hottenga, J.-J.; Willemsen, G.; Zheng, J.; Rodriguez, E.; Hotze, M.; Franke, A.; Revez, J.A.; Beesley, J.; Matheson, M.C.; Dharmage, S.C.; Bain, L.M.; Fritsche, L.G.; Gabrielsen, M.E.; Balliu, B.; Nielsen, J.B.; Zhou, W.; Hveem, K.; Langhammer, A.; Holmen, O.L.; Loset, M.; Abecasis, G.R.; Willer, C.J.; Arnold, A.; Homuth, G.; Schmidt, C.O.; Thompson, P.J.; Martin, N.G.; Duffy, D.L.; Novak, N.; Schulz, H.; Karrasch, S.; Gieger, C.; Strauch, K.; Melles, R.B.; Hinds, D.A.; Hubner, N.; Weidinger, S.; Magnusson, P.K.E.; Jansen, R.; Jorgenson, E.; Lee, Y.-A.; Boomsma, D.I.; Almqvist, C.; Karlsson, R.; Koppelman, G.H.; Paternoster, L.
Title Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology Type Meta-Analysis
Year 2017 Publication Nature Genetics Abbreviated Journal Nat Genet
Volume 49 Issue 12 Pages 1752-1757
Keywords Asthma/*genetics; Eczema/*genetics; Genetic Predisposition to Disease/*genetics; Genome-Wide Association Study/methods; Humans; Hypersensitivity/*genetics; Phenotype; Polymorphism, Single Nucleotide; Rhinitis, Allergic, Seasonal/*genetics; Risk Factors
Abstract Asthma, hay fever (or allergic rhinitis) and eczema (or atopic dermatitis) often coexist in the same individuals, partly because of a shared genetic origin. To identify shared risk variants, we performed a genome-wide association study (GWAS; n = 360,838) of a broad allergic disease phenotype that considers the presence of any one of these three diseases. We identified 136 independent risk variants (P < 3 x 10(-8)), including 73 not previously reported, which implicate 132 nearby genes in allergic disease pathophysiology. Disease-specific effects were detected for only six variants, confirming that most represent shared risk factors. Tissue-specific heritability and biological process enrichment analyses suggest that shared risk variants influence lymphocyte-mediated immunity. Six target genes provide an opportunity for drug repositioning, while for 36 genes CpG methylation was found to influence transcription independently of genetic effects. Asthma, hay fever and eczema partly coexist because they share many genetic risk variants that dysregulate the expression of immune-related genes.
Address MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK
Corporate Author LifeLines Cohort Study Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 1061-4036 ISBN Medium
Area Expedition Conference
Notes PMID:29083406 Approved no
Call Number HUNT @ maria.stuifbergen @ Serial 1903
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Author (up) Liu, J.Z.; Hov, J.R.; Folseraas, T.; Ellinghaus, E.; Rushbrook, S.M.; Doncheva, N.T.; Andreassen, O.A.; Weersma, R.K.; Weismuller, T.J.; Eksteen, B.; Invernizzi, P.; Hirschfield, G.M.; Gotthardt, D.N.; Pares, A.; Ellinghaus, D.; Shah, T.; Juran, B.D.; Milkiewicz, P.; Rust, C.; Schramm, C.; Muller, T.; Srivastava, B.; Dalekos, G.; Nothen, M.M.; Herms, S.; Winkelmann, J.; Mitrovic, M.; Braun, F.; Ponsioen, C.Y.; Croucher, P.J.P.; Sterneck, M.; Teufel, A.; Mason, A.L.; Saarela, J.; Leppa, V.; Dorfman, R.; Alvaro, D.; Floreani, A.; Onengut-Gumuscu, S.; Rich, S.S.; Thompson, W.K.; Schork, A.J.; Naess, S.; Thomsen, I.; Mayr, G.; Konig, I.R.; Hveem, K.; Cleynen, I.; Gutierrez-Achury, J.; Ricano-Ponce, I.; van Heel, D.; Bjornsson, E.; Sandford, R.N.; Durie, P.R.; Melum, E.; Vatn, M.H.; Silverberg, M.S.; Duerr, R.H.; Padyukov, L.; Brand, S.; Sans, M.; Annese, V.; Achkar, J.-P.; Boberg, K.M.; Marschall, H.-U.; Chazouilleres, O.; Bowlus, C.L.; Wijmenga, C.; Schrumpf, E.; Vermeire, S.; Albrecht, M.; Rioux, J.D.; Alexander, G.; Bergquist, A.; Cho, J.; Schreiber, S.; Manns, M.P.; Farkkila, M.; Dale, A.M.; Chapman, R.W.; Lazaridis, K.N.; Franke, A.; Anderson, C.A.; Karlsen, T.H.
Title Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis Type Journal Article
Year 2013 Publication Nature Genetics Abbreviated Journal Nat Genet
Volume 45 Issue 6 Pages 670-675
Keywords Case-Control Studies; Cholangitis, Sclerosing/*genetics/immunology; Gene Frequency; Genetic Loci/immunology; Genetic Pleiotropy; Genome-Wide Association Study; Genotyping Techniques; Humans; Linkage Disequilibrium; Oligonucleotide Array Sequence Analysis; Polymorphism, Single Nucleotide; Risk Factors
Abstract Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases.
Address Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
Corporate Author International PSC Study Group Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 1061-4036 ISBN Medium
Area Expedition Conference
Notes PMID:23603763; PMC3667736 Approved no
Call Number HUNT @ maria.stuifbergen @ Serial 1427
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Author (up) Webb, T.R.; Erdmann, J.; Stirrups, K.E.; Stitziel, N.O.; Masca, N.G.D.; Jansen, H.; Kanoni, S.; Nelson, C.P.; Ferrario, P.G.; Konig, I.R.; Eicher, J.D.; Johnson, A.D.; Hamby, S.E.; Betsholtz, C.; Ruusalepp, A.; Franzen, O.; Schadt, E.E.; Bjorkegren, J.L.M.; Weeke, P.E.; Auer, P.L.; Schick, U.M.; Lu, Y.; Zhang, H.; Dube, M.-P.; Goel, A.; Farrall, M.; Peloso, G.M.; Won, H.-H.; Do, R.; van Iperen, E.; Kruppa, J.; Mahajan, A.; Scott, R.A.; Willenborg, C.; Braund, P.S.; van Capelleveen, J.C.; Doney, A.S.F.; Donnelly, L.A.; Asselta, R.; Merlini, P.A.; Duga, S.; Marziliano, N.; Denny, J.C.; Shaffer, C.; El-Mokhtari, N.E.; Franke, A.; Heilmann, S.; Hengstenberg, C.; Hoffmann, P.; Holmen, O.L.; Hveem, K.; Jansson, J.-H.; Jockel, K.-H.; Kessler, T.; Kriebel, J.; Laugwitz, K.L.; Marouli, E.; Martinelli, N.; McCarthy, M.I.; Van Zuydam, N.R.; Meisinger, C.; Esko, T.; Mihailov, E.; Escher, S.A.; Alver, M.; Moebus, S.; Morris, A.D.; Virtamo, J.; Nikpay, M.; Olivieri, O.; Provost, S.; AlQarawi, A.; Robertson, N.R.; Akinsansya, K.O.; Reilly, D.F.; Vogt, T.F.; Yin, W.; Asselbergs, F.W.; Kooperberg, C.; Jackson, R.D.; Stahl, E.; Muller-Nurasyid, M.; Strauch, K.; Varga, T.V.; Waldenberger, M.; Zeng, L.; Chowdhury, R.; Salomaa, V.; Ford, I.; Jukema, J.W.; Amouyel, P.; Kontto, J.; Nordestgaard, B.G.; Ferrieres, J.; Saleheen, D.; Sattar, N.; Surendran, P.; Wagner, A.; Young, R.; Howson, J.M.M.; Butterworth, A.S.; Danesh, J.; Ardissino, D.; Bottinger, E.P.; Erbel, R.; Franks, P.W.; Girelli, D.; Hall, A.S.; Hovingh, G.K.; Kastrati, A.; Lieb, W.; Meitinger, T.; Kraus, W.E.; Shah, S.H.; McPherson, R.; Orho-Melander, M.; Melander, O.; Metspalu, A.; Palmer, C.N.A.; Peters, A.; Rader, D.J.; Reilly, M.P.; Loos, R.J.F.; Reiner, A.P.; Roden, D.M.; Tardif, J.-C.; Thompson, J.R.; Wareham, N.J.; Watkins, H.; Willer, C.J.; Samani, N.J.; Schunkert, H.; Deloukas, P.; Kathiresan, S.
Title Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease Type Journal Article
Year 2017 Publication Journal of the American College of Cardiology Abbreviated Journal J Am Coll Cardiol
Volume 69 Issue 7 Pages 823-836
Keywords Case-Control Studies; Coronary Artery Disease/epidemiology/*genetics; Female; Gene Frequency; *Genetic Loci; *Genetic Pleiotropy; Genome-Wide Association Study; Humans; Male; Odds Ratio; Polymorphism, Single Nucleotide; cholesteryl ester transfer protein; expression quantitative trait loci; genetics; genome-wide association; single nucleotide polymorphism
Abstract BACKGROUND: Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. OBJECTIVES: This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. METHODS: In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. RESULTS: We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 x 10(-4) with a range of other diseases/traits. CONCLUSIONS: We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.
Address Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts; Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts
Corporate Author Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 0735-1097 ISBN Medium
Area Expedition Conference
Notes PMID:28209224; PMCID:PMC5314135 Approved no
Call Number HUNT @ maria.stuifbergen @ Serial 2030
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