Asthma One child in 10 in the EU Childhood asthma costs the EU 3 Billion p.a. Adult and industrial asthma also 3 Billion Abnormal airway mucosa Intermittent inflammation Association with atopy (incomplete) Rural environment protective Rich microbial environment protective Familial Strong maternal effects Birth order effects

Asthma and GABRIEL Aim of GABRIEL –To systematically identify the genetic and environmental factors that control asthma risk Senior Partners –Imperial College London –University Children's Hospital Munich –CEA / Centre National de Genotypage Paris 37 Partners 19 Countries –EU contribution 11.5M 4 years –Total spend 25M

GABRIEL Genetics Phase I genome-wide association study 1000 children 1200 controls Phase II genome-wide association study 11,000 asthmatics 15,000 controls Adult, childhood, industrial and severe asthma Additional 4.3 million from the Wellcome Trust Phase III Genetic epidemiology in 40,000 subjects from exiting population surveys Phase IV Genomic epidemiology: global gene expression in 2000 children from different environments

Genome-wide Association Asthma 938 cases and 1244 controls: UK, Germany and Austria 317,000 markers Moffatt, Kabesch and Liang et al. Nature 2007

Chr 17 and age of onset Emmanuelle Bouzigon et al NEJM 2008

Chr 17 ORMDL3 SNPs Population attributable risk 30% OR ~1.8 in population samples Associated with severity Not associated with atopy Not associated with adult-onset asthma

GABRIEL Phase II GWAS

Global gene expression 30,000 human genes Measure their level of expression simultaneously Extraordinary insight into the function of cells and tissues Genome wide association study of gene expression Dixon, Liang, Moffatt et al Nature Genetics 2007

Genomic Epidemiology: Global gene expression in Populations 225 subjects from von Mutius Advanced Surveys

Metagenomics Genetics and genomics of bacteria Molecular detection of bacteria by sequencing their 16S rRNA genes

Phylogeny of bronchial bacteria

Airway bacterial flora in health and disease P < P < P < P < P < 0.05

Future Needs Complete the identification of asthma genes –Build on current collaboration Copy number variation Resequencing Epigenetics Elucidate the function of asthma genes Investigate genes identified by genome-wide studies Identify targets and build models for new therapies Dissect the interaction between genes and environment Genetic Epidemiology –Phenotypes –Life-course –Exposures Genomic Epidemiology –Children from the advanced surveys –Other Populations and environments Developing biomarkers –Proteomics, metabolomics Metagenomics of airway bacteria Larger studies Investigate functional effects of different bacteria

Future Needs Identify environmental factors protective against asthma Building on samples and knowledge from Advanced Surveys Provide tools for genomic epidemiology and metagenomics