Age-of-onset information helps identify 76 genetic variants associated with allergic disease.

Autor: Ferreira MAR; Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia., Vonk JM; University of Groningen, University Medical Center Groningen, Epidemiology, Groningen Research Institute for Asthma and COPD, Groningen, the Netherlands., Baurecht H; Department of Dermatology, Allergology and Venereology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.; Department of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany., Marenholz I; Max Delbrück Center (MDC) for Molecular Medicine, Berlin, Germany.; Clinic for Pediatric Allergy, Experimental and Clinical Research Center of Charité Universitätsmedizin Berlin and Max Delbrück Center, Berlin, Germany., Tian C; 23andMe, Inc., Mountain View, California, United States of America., Hoffman JD; Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America., Helmer Q; Department Biological Psychology, Netherlands Twin Register, Vrije University, Amsterdam, The Netherlands., Tillander A; Department of Medical Epidemiology and Biostatistics and the Swedish Twin Registry, Karolinska Institutet, Stockholm, Sweden., Ullemar V; Department of Medical Epidemiology and Biostatistics and the Swedish Twin Registry, Karolinska Institutet, Stockholm, Sweden., Lu Y; Department of Medical Epidemiology and Biostatistics and the Swedish Twin Registry, Karolinska Institutet, Stockholm, Sweden., Grosche S; Max Delbrück Center (MDC) for Molecular Medicine, Berlin, Germany.; Clinic for Pediatric Allergy, Experimental and Clinical Research Center of Charité Universitätsmedizin Berlin and Max Delbrück Center, Berlin, Germany.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Rüschendorf F; Max Delbrück Center (MDC) for Molecular Medicine, Berlin, Germany., Granell R; MRC Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, United Kingdom., Brumpton BM; MRC Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, United Kingdom.; K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.; Department of Thoracic Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway., Fritsche LG; K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America., Bhatta L; K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway., Gabrielsen ME; K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway., Nielsen JB; Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, United States of America.; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America., Zhou W; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America., Hveem K; K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway., Langhammer A; The HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway., Holmen OL; K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway., Løset M; K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.; Department of Dermatology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway., Abecasis GR; K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America., Willer CJ; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America.; Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, United States of America.; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America., Emami NC; Program in Biological and Medical Informatics, University of California, San Francisco, San Francisco, California, United States of America.; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, United States of America., Cavazos TB; Program in Biological and Medical Informatics, University of California, San Francisco, San Francisco, California, United States of America., Witte JS; Program in Biological and Medical Informatics, University of California, San Francisco, San Francisco, California, United States of America.; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, United States of America.; Institute for Human Genetics, University of California, San Francisco, San Francisco, California, United States of America.; Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, United States of America., Szwajda A; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden., Hinds DA; 23andMe, Inc., Mountain View, California, United States of America., Hübner N; Max Delbrück Center (MDC) for Molecular Medicine, Berlin, Germany., Weidinger S; Department of Dermatology, Allergology and Venereology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany., Magnusson PK; Department of Medical Epidemiology and Biostatistics and the Swedish Twin Registry, Karolinska Institutet, Stockholm, Sweden., Jorgenson E; Division of Research, Kaiser Permanente Northern California, Oakland, California, United States of America., Karlsson R; Department of Medical Epidemiology and Biostatistics and the Swedish Twin Registry, Karolinska Institutet, Stockholm, Sweden., Paternoster L; MRC Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, United Kingdom., Boomsma DI; Department Biological Psychology, Netherlands Twin Register, Vrije University, Amsterdam, The Netherlands., Almqvist C; Department of Medical Epidemiology and Biostatistics and the Swedish Twin Registry, Karolinska Institutet, Stockholm, Sweden.; Pediatric Allergy and Pulmonology Unit at Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden., Lee YA; Max Delbrück Center (MDC) for Molecular Medicine, Berlin, Germany.; Clinic for Pediatric Allergy, Experimental and Clinical Research Center of Charité Universitätsmedizin Berlin and Max Delbrück Center, Berlin, Germany., Koppelman GH; University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Pediatric Pulmonology and Pediatric Allergology, and University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, the Netherlands.
Jazyk: angličtina
Zdroj: PLoS genetics [PLoS Genet] 2020 Jun 30; Vol. 16 (6), pp. e1008725. Date of Electronic Publication: 2020 Jun 30 (Print Publication: 2020).
DOI: 10.1371/journal.pgen.1008725
Abstrakt: Risk factors that contribute to inter-individual differences in the age-of-onset of allergic diseases are poorly understood. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earliest age at which asthma, hay fever and/or eczema was first diagnosed and performed a genome-wide association study (GWAS) of this combined age-of-onset phenotype. We identified 50 variants with a significant independent association (P<3x10-8) with age-of-onset. Forty-five variants had comparable effects on the onset of the three individual diseases and 38 were also associated with allergic disease case-control status in an independent study (n = 222,484). We observed a strong negative genetic correlation between age-of-onset and case-control status of allergic disease (rg = -0.63, P = 4.5x10-61), indicating that cases with early disease onset have a greater burden of allergy risk alleles than those with late disease onset. Subsequently, a multivariate GWAS of age-of-onset and case-control status identified a further 26 associations that were missed by the univariate analyses of age-of-onset or case-control status only. Collectively, of the 76 variants identified, 18 represent novel associations for allergic disease. We identified 81 likely target genes of the 76 associated variants based on information from expression quantitative trait loci (eQTL) and non-synonymous variants, of which we highlight ADAM15, FOSL2, TRIM8, BMPR2, CD200R1, PRKCQ, NOD2, SMAD4, ABCA7 and UBE2L3. Our results support the notion that early and late onset allergic disease have partly distinct genetic architectures, potentially explaining known differences in pathophysiology between individuals.
Competing Interests: C. Tian and D. A. Hinds both report support from 23andMe during the conduct of the study. C. Almqvist received grant 2017-00641 from Swedish Research Council and Swedish Initiative for Research on Microdata in the Social And Medical Sciences (SIMSAM) framework grant (340-2013-5867) for this work. G. H. Koppelman's institution received grants from the Lung Foundation of The Netherlands, the Ubbo Emmius Foundation, TEVA (The Netherlands), GlaxoSmithKline, Vertex, and the Tetri Foundation for other works. L. Paternoster received grant MR/J012165/1 from the UK Medical Research Council for this work and personal fees from Merck. The rest of the authors declare that they have no relevant conflicts of interest.
Databáze: MEDLINE
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