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Sarnowski, Chloé; Sugier, Pierre-Emmanuel; Granell, Raquel; Jarvis, Debbie; Dizier, Marie-Hélène; Ege, Markus; Imboden, Medea; Laprise, Catherine; Khusnutdinova, Elza K.; Freidin, Maxim B.; Cookson, William O. C.; Moffatt, Miriam; Lathrop, Mark; Siroux, Valérie; Ogorodova, Ludmila M.; Karunas, Alexandra S.; James, Alan; Probst-Hensch, Nicole M.; Mutius, Erika von; Pin, Isabelle; Kogevinas, Manolis; Henderson, A. John; Demenais, Florence; Bouzigon, Emmanuelle (2016): Identification of a new locus at 16q12 associated with time to asthma onset. In: Journal of Allergy and Clinical Immunology, Vol. 138, No. 4: pp. 1071-1080
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Abstract

Background: Asthma is a heterogeneous disease in which age of onset plays an important role. Objective: We sought to identify the genetic variants associated with time to asthma onset (TAO). Methods: 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. Results: We detected 5 regions associated with TAO at the genome-wide significant level (P < 5 x 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)). Conclusion: 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.