title: Identification of a new locus at 16q12 associated with time to asthma onset.
abstract: Asthma is a heterogeneous disease in which age of onset plays an important role.
  
  
  
  We sought to identify the genetic variants associated with time to asthma onset (TAO).
  
  
  
  We conducted a large-scale meta-analysis of 9 genome-wide association studies of TAO (total of 5462 asthmatic patients with a broad range of age of asthma onset and 8424 control subjects of European ancestry) performed by using survival analysis techniques.
  
  
  
  We detected 5 regions associated with TAO at the genome-wide significant level (P < 5 × 10-8). We evidenced a new locus in the 16q12 region (near cylindromatosis turban tumor syndrome gene [CYLD]) and confirmed 4 asthma risk regions: 2q12 (IL-1 receptor-like 1 [IL1RL1]), 6p21 (HLA-DQA1), 9p24 (IL33), and 17q12-q21 (zona pellucida binding protein 2 [ZPBP2]-gasdermin A [GSDMA]). Conditional analyses identified 2 distinct signals at 9p24 (both upstream of IL33) and 17q12-q21 (near ZPBP2 and within GSDMA). Together, these 7 distinct loci explained 6.0% of the variance in TAO. In addition, we showed that genetic variants at 9p24 and 17q12-q21 were strongly associated with an earlier onset of childhood asthma (P ≤ .002), whereas the 16q12 single nucleotide polymorphism was associated with later asthma onset (P = .04). A high burden of disease risk alleles at these loci was associated with earlier age of asthma onset (4 vs 9-12 years, P = 10-4).
  
  
  
  The new susceptibility region for TAO at 16q12 harbors variants that correlate with the expression of CYLD and nucleotide-binding oligomerization domain 2 (NOD2), 2 strong candidates for asthma. This study demonstrates that incorporating the variability of age of asthma onset in asthma modeling is a helpful approach in the search for disease susceptibility genes.
authors.affiliation: Inserm, UMR-946, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France.
authors.forename: Chloé
authors.initials: C
authors.lastname: Sarnowski
authors.affiliation: Inserm, UMR-946, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France.
authors.forename: Pierre-Emmanuel
authors.initials: PE
authors.lastname: Sugier
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Raquel
authors.initials: R
authors.lastname: Granell
authors.affiliation: Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College, London, United Kingdom; MRC-PHE Centre for Environment & Health, London, United Kingdom.
authors.forename: Debbie
authors.initials: D
authors.lastname: Jarvis
authors.affiliation: Inserm, UMR-946, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France.
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Dizier
authors.affiliation: Dr von Hauner Children's Hospital, Ludwig Maximilian University, Munich, Germany; Comprehensive Pneumology Center Munich (CPC-M), German Center for Lung Research, Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Ege
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland; University of Basel, Basel, Switzerland.
authors.forename: Medea
authors.initials: M
authors.lastname: Imboden
authors.affiliation: Département des sciences fondamentales, Université du Québec à Chicoutimi, Saguenay, Quebec, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Laprise
authors.affiliation: Institute of Biochemistry and Genetics, Ufa Scientific Centre, Russian Academy of Sciences, Ufa, Russia; Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, Russia.
authors.forename: Elza K
authors.initials: EK
authors.lastname: Khusnutdinova
authors.affiliation: Research Institute for Medical Genetics, Tomsk, Russia.
authors.forename: Maxim B
authors.initials: MB
authors.lastname: Freidin
authors.affiliation: National Heart Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: William O C
authors.initials: WOC
authors.lastname: Cookson
authors.affiliation: National Heart Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Miriam
authors.initials: M
authors.lastname: Moffatt
authors.affiliation: McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.affiliation: Université Grenoble Alpes, IAB, Team of Environmental Epidemiology applied to Reproduction and Respiratory Health, Grenoble, France; Inserm, IAB, Team of Environmental Epidemiology applied to Reproduction and Respiratory Health, Grenoble, France; CHU de Grenoble, IAB, Team of Environmental Epidemiology applied to Reproduction and Respiratory Health, Grenoble, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Siroux
authors.affiliation: Siberian State Medical University, Tomsk, Russia.
authors.forename: Ludmila M
authors.initials: LM
authors.lastname: Ogorodova
authors.affiliation: Institute of Biochemistry and Genetics, Ufa Scientific Centre, Russian Academy of Sciences, Ufa, Russia; Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, Russia.
authors.forename: Alexandra S
authors.initials: AS
authors.lastname: Karunas
authors.affiliation: Busselton Population Medical Research Institute, Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Nedlands, and the School of Population Health, University of Western Australia, Crawley, Australia.
authors.forename: Alan
authors.initials: A
authors.lastname: James
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland; University of Basel, Basel, Switzerland.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Probst-Hensch
authors.affiliation: Dr von Hauner Children's Hospital, Ludwig Maximilian University, Munich, Germany; Comprehensive Pneumology Center Munich (CPC-M), German Center for Lung Research, Munich, Germany.
authors.forename: Erika
authors.initials: E
authors.lastname: von Mutius
authors.affiliation: Université Grenoble Alpes, IAB, Team of Environmental Epidemiology applied to Reproduction and Respiratory Health, Grenoble, France; Inserm, IAB, Team of Environmental Epidemiology applied to Reproduction and Respiratory Health, Grenoble, France; CHU de Grenoble, Pediatrics, Grenoble, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Pin
authors.affiliation: Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Manolis
authors.initials: M
authors.lastname: Kogevinas
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: A John
authors.initials: AJ
authors.lastname: Henderson
authors.affiliation: Inserm, UMR-946, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Demenais
authors.affiliation: Inserm, UMR-946, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France. Electronic address: emmanuelle.bouzigon@inserm.fr.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Bouzigon
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D001249:Asthma / Q000235:genetics*; D002648:Child; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D000074749:Deubiquitinating Enzyme CYLD; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D025521:Tumor Suppressor Proteins; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD
keywords: Asthma; CYLD; NOD2; age of onset; conditional analysis; genetics; genome-wide association study; survival analysis