Methylation Quantitative Trait Loci and Epigenetic Networks Underlying Asthma-Related Traits

• Activity Number: 495
• Type: Topic Contributed
• Date/Time: Wednesday, August 1, 2012 : 10:30 AM to 12:20 PM
• Sponsor: Biometrics Section
• Author(s): Liming Liang*+ and Saffron A.G. Willis-Owens and Kenny C.C. Wong and Aristea Binia and Gwyneth Davies and Julian M. Hopkin and Ivana Yang and Tomi M. Pastinen and David A. Schwartz and Goncalo Abecasis and G. Mark Lathrop and Miriam Moffatt and William O.C.M. Cookson
• Companies: Harvard School of Public Health and National Heart and Lung Institute, Imperial College and National Heart and Lung Institute, Imperial College and National Heart and Lung Institute, Imperial College and Swansea University, School of Medicine and Swansea University, School of Medicine and University of Colorado School of Medicine and National Jewish Health and McGill University and Genome Quebec Innovation Centre and University of Colorado School of Medicine and National Jewish Health and University of Michigan and CEA/Centre National de Genotypage and National Heart and Lung Institute, Imperial College and National Heart and Lung Institute, Imperial College
• Keywords: methylation QTL ; epigenetics ; network ; variance component model ; heritability ; asthma ; IgE

Abstract

Epigenetic variation in the methylation of DNA at CpG islands (CGI) is related to the regulation of transcription. The extent of epigenetic variation in the human genome and its relevance to common diseases are not known. We studied methylation status in asthmatic nuclear families genome-wide at 27,000 CGI in DNA from peripheral blood leukocytes (PBL). We show here that major components of variation in methylation quantitative trait loci (meQTL) included age, sex and the shared family environment. We observed true genetic influences (meSNPs) on methylation status at 10% of loci. In order to establish the utility of genome-wide meQTL association studies (GMAS) to common diseases we show mapping of meQTL with genome wide significance to multiple phenotypes. We found and replicated meQTL associations to the total serum IgE concentration (P<10-11) the top four of which accounted for 21.5% of the IgE variation, compared to 1-2% seen in GWAS studies of the same trait. Cigarette smoking showed replicated associations to loci influencing coagulation. Genome function is mediated through interactive networks of genes and regulatory elements, and we further show here the presence of strongly co-ordinated regulation of meQTL in the form of 30 scale-free meQTL correlation networks (meQTN). Enrichment analysis identified meQTN modules that could be attributed to peripheral blood neutrophils, lymphocytes, monocytes and eosinophils (P<10-81 to 10-350). These and other modules were enriched by loci associated to asthma and the total serum IgE (P<10-16 to 10-104). Hubs in these networks define potential therapeutic targets for manipulating cell-specific immune function in asthma and other common inflammatory diseases.