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 Pin; Manolis Kogevinas; A. John Henderson; Florence Demenais; Emmanuelle Bouzigon

doi:10.1016/j.jaci.2016.03.018

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 Pin

Manolis Kogevinas, A. John Henderson, Florence Demenais, Emmanuelle Bouzigon

Bristol Medical School (PHS)

Research output: Contribution to journal › Article (Academic Journal) › peer-review

28 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 language	English
Pages (from-to)	1071-1080
Number of pages	10
Journal	Journal of Allergy and Clinical Immunology
Volume	138
Issue number	4
Early online date	6 Apr 2016
DOIs	https://doi.org/10.1016/j.jaci.2016.03.018
Publication status	Published - Oct 2016

Keywords

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

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10.1016/j.jaci.2016.03.018

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THE NATURAL HISTORY OF ASTHMA AND WHEEZING ILLNESSES FROM BIRTH TO ADOLESCENCE: DETERMINANTS OF THE REMISSION OF ASTHMA
Henderson, A. J. W. (Principal Investigator)
1/10/06 → 1/10/10
Project: Research
EXTENSION OF RD1321 VIA IOP.
Golding, J. (Principal Investigator)
1/02/01 → 1/02/06
Project: Research

Dr Raquel Granell
- Raquel.Granellbristol.acuk
- Applied Health Research - Senior Research Associate in Medical Statistics, Research Fellow in Primary Care
- Bristol Population Health Science Institute
Person: Academic , Member

Cite this

Sarnowski, C., Sugier, P.-E., Granell, R., Jarvis, D., Dizier, M.-H., Ege, M., Imboden, M., Laprise, C., Khusnutdinova, E. K., Freidin, M. B., Cookson, W. O. C., Moffatt, M., Lathrop, M., Siroux, V., Ogorodova, L. M., Karunas, A. S., James, A., Probst-Hensch, N. M., von Mutius, E., ... Bouzigon, E. (2016). Identification of a new locus at 16q12 associated with time-to-asthma onset. Journal of Allergy and Clinical Immunology, 138(4), 1071-1080. https://doi.org/10.1016/j.jaci.2016.03.018

@article{9c625ed884ef4a029174e9e9a43ae42c,

title = "Identification of a new locus at 16q12 associated with time-to-asthma onset",

abstract = "BackgroundAsthma is a heterogeneous disease in which age of onset plays an important role.ObjectiveWe sought to identify the genetic variants associated with time to asthma onset (TAO).MethodsWe 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.ResultsWe 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).ConclusionThe 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.",

keywords = "Asthma, age-of-onset, genetics, genome-wide association study, survival analysis, conditional analysis, CYLD, NOD2",

author = "Chlo{\'e} Sarnowski and Pierre-Emmanuel Sugier and Raquel Granell and Debbie Jarvis and Marie-H{\'e}l{\`e}ne Dizier and Markus Ege and Medea Imboden and Catherine Laprise and Khusnutdinova, \{Elza K.\} and Freidin, \{Maxim B.\} and Cookson, \{William O.C.\} and Miriam Moffatt and Mark Lathrop and Val{\'e}rie Siroux and Ogorodova, \{Ludmila M.\} and Karunas, \{Alexandra S.\} and Alan James and Probst-Hensch, \{Nicole M.\} and \{von Mutius\}, Erika and Isabelle Pin and Manolis Kogevinas and Henderson, \{A. John\} and Florence Demenais and Emmanuelle Bouzigon",

year = "2016",

month = oct,

doi = "10.1016/j.jaci.2016.03.018",

language = "English",

volume = "138",

pages = "1071--1080",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Elsevier Inc.",

number = "4",

}

Sarnowski, C, Sugier, P-E, Granell, R, Jarvis, D, Dizier, M-H, Ege, M, Imboden, M, Laprise, C, Khusnutdinova, EK, Freidin, MB, Cookson, WOC, Moffatt, M, Lathrop, M, Siroux, V, Ogorodova, LM, Karunas, AS, James, A, Probst-Hensch, NM, von Mutius, E, Pin, I, Kogevinas, M, Henderson, AJ, Demenais, F & Bouzigon, E 2016, 'Identification of a new locus at 16q12 associated with time-to-asthma onset', Journal of Allergy and Clinical Immunology, vol. 138, no. 4, pp. 1071-1080. https://doi.org/10.1016/j.jaci.2016.03.018

TY - JOUR

T1 - Identification of a new locus at 16q12 associated with time-to-asthma onset

AU - Sarnowski, Chloé

AU - Sugier, Pierre-Emmanuel

AU - Granell, Raquel

AU - Jarvis, Debbie

AU - Dizier, Marie-Hélène

AU - Ege, Markus

AU - Imboden, Medea

AU - Laprise, Catherine

AU - Khusnutdinova, Elza K.

AU - Freidin, Maxim B.

AU - Cookson, William O.C.

AU - Moffatt, Miriam

AU - Lathrop, Mark

AU - Siroux, Valérie

AU - Ogorodova, Ludmila M.

AU - Karunas, Alexandra S.

AU - James, Alan

AU - Probst-Hensch, Nicole M.

AU - von Mutius, Erika

AU - Pin, Isabelle

AU - Kogevinas, Manolis

AU - Henderson, A. John

AU - Demenais, Florence

AU - Bouzigon, Emmanuelle

PY - 2016/10

Y1 - 2016/10

N2 - BackgroundAsthma is a heterogeneous disease in which age of onset plays an important role.ObjectiveWe sought to identify the genetic variants associated with time to asthma onset (TAO).MethodsWe 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.ResultsWe 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).ConclusionThe 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.

AB - BackgroundAsthma is a heterogeneous disease in which age of onset plays an important role.ObjectiveWe sought to identify the genetic variants associated with time to asthma onset (TAO).MethodsWe 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.ResultsWe 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).ConclusionThe 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.

KW - Asthma

KW - age-of-onset

KW - genetics

KW - genome-wide association study

KW - survival analysis

KW - conditional analysis

KW - CYLD

KW - NOD2

U2 - 10.1016/j.jaci.2016.03.018

DO - 10.1016/j.jaci.2016.03.018

M3 - Article (Academic Journal)

C2 - 27130862

SN - 0091-6749

VL - 138

SP - 1071

EP - 1080

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 4

ER -

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

Abstract

Keywords

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THE NATURAL HISTORY OF ASTHMA AND WHEEZING ILLNESSES FROM BIRTH TO ADOLESCENCE: DETERMINANTS OF THE REMISSION OF ASTHMA

EXTENSION OF RD1321 VIA IOP.

Profiles

Dr Raquel Granell

Cite this