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


Autoři: Manuel A. R. Ferreira aff001;  Judith M. Vonk aff002;  Hansjörg Baurecht aff003;  Ingo Marenholz aff005;  Chao Tian aff007;  Joshua D. Hoffman aff008;  Quinta Helmer aff009;  Annika Tillander aff010;  Vilhelmina Ullemar aff010;  Yi Lu aff010;  Sarah Grosche aff005;  Franz Rüschendorf aff005;  Raquel Granell aff012;  Ben M. Brumpton aff012;  Lars G. Fritsche aff013;  Laxmi Bhatta aff013;  Maiken E. Gabrielsen aff013;  Jonas B. Nielsen aff016;  Wei Zhou aff017;  Kristian Hveem aff013;  Arnulf Langhammer aff018;  Oddgeir L. Holmen aff013;  Mari Løset aff013;  Gonçalo R. Abecasis aff013;  Cristen J. Willer aff015;  Nima C. Emami aff020;  Taylor B. Cavazos aff020;  John S. Witte aff020;  Agnieszka Szwajda aff024aff007;  ;  David A. Hinds aff007;  Norbert Hübner aff005;  Stephan Weidinger aff003;  Patrik KE Magnusson aff010;  Eric Jorgenson aff025;  Robert Karlsson aff010;  Lavinia Paternoster aff012;  Dorret I. Boomsma aff009;  Catarina Almqvist aff010;  Young-Ae Lee aff005;  Gerard H. Koppelman aff027
Působiště autorů: Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia aff001;  Epidemiology, University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, the Netherlands aff002;  University of Groningen, University Medical Center Groningen, Epidemiology, Groningen Research Institute for Asthma and COPD, Groningen, the Netherlands aff002;  Department of Dermatology, Allergology and Venereology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany aff003;  Department of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany aff004;  Max Delbrück Center (MDC) for Molecular Medicine, Berlin, Germany aff005;  Clinic for Pediatric Allergy, Experimental and Clinical Research Center of Charité Universitätsmedizin Berlin and Max Delbrück Center, Berlin, Germany aff006;  23andMe, Inc., Mountain View, California, United States of America aff007;  Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America aff008;  Department Biological Psychology, Netherlands Twin Register, Vrije University, Amsterdam, The Netherlands aff009;  Department of Medical Epidemiology and Biostatistics and the Swedish Twin Registry, Karolinska Institutet, Stockholm, Sweden aff010;  CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria aff011;  MRC Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, United Kingdom aff012;  K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway aff013;  Department of Thoracic Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway aff014;  Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America aff015;  Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, United States of America aff016;  Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America aff017;  The HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway aff018;  Department of Dermatology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway aff019;  Program in Biological and Medical Informatics, University of California, San Francisco, San Francisco, California, United States of America aff020;  Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, United States of America aff021;  Institute for Human Genetics, University of California, San Francisco, San Francisco, California, United States of America aff022;  Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, United States of America aff023;  Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden aff024;  Division of Research, Kaiser Permanente Northern California, Oakland, California, United States of America aff025;  Pediatric Allergy and Pulmonology Unit at Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden aff026;  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, aff027;  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, aff027;  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, aff027;  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, aff027;  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, aff027;  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, aff027;  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, aff027;  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, aff027;  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, aff027;  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, aff027;  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, aff027;  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, aff027;  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, aff027;  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, aff027;  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, aff027;  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, aff027;  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, aff027;  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, aff027;  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, aff027;  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, aff027;  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, aff027
Vyšlo v časopise: Age-of-onset information helps identify 76 genetic variants associated with allergic disease. PLoS Genet 16(6): e32767. doi:10.1371/journal.pgen.1008725
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008725

Souhrn

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.

Klíčová slova:

Allergic diseases – Allergic rhinitis – Asthma – Eczema – Food allergies – Genetics of disease – Genome-wide association studies – Medical risk factors


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2020 Číslo 6

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