Identification of a new locus at 16q12 associated with time-to-asthma onset

Chloé Sarnowski, Pierre-Emmanuel Sugier, Raquel Granell, Debbie Jarvis, Marie-Hélène Dizier, Markus Ege, Medea Imboden, Catherine Laprise, Elza K. Khusnutdinova, Maxim B. Freidin, William O.C. Cookson, Miriam Moffatt, Mark Lathrop, Valérie Siroux, Ludmila M. Ogorodova, Alexandra S. Karunas, Alan James, Nicole M. Probst-Hensch, Erika von Mutius, Isabelle PinManolis Kogevinas, A. John Henderson, Florence Demenais, Emmanuelle Bouzigon

Research output: Contribution to journalArticle (Academic Journal)peer-review

20 Citations (Scopus)

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 × 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.

Original languageEnglish
Pages (from-to)1071-1080
Number of pages10
JournalJournal of Allergy and Clinical Immunology
Volume138
Issue number4
Early online date6 Apr 2016
DOIs
Publication statusPublished - Oct 2016

Keywords

  • Asthma
  • age-of-onset
  • genetics
  • genome-wide association study
  • survival analysis
  • conditional analysis
  • CYLD
  • NOD2

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