Integrated analysis of genome-wide genetic and epigenetic association data for identification of disease mechanisms.
Many human diseases are multifactorial, involving multiple genetic and environmental factors impacting on one or more biological pathways. Much of the environmental effect is believed to be mediated through epigenetic changes. Although many genome-wide genetic and epigenetic association studies have been conducted for different diseases and traits, it is still far from clear to what extent the genomic loci and biological pathways identified in the genetic and epigenetic studies are shared. There is also a lack of statistical tools to assess these important aspects of disease mechanisms. In the present study, we describe a protocol for the integrated analysis of genome-wide genetic and epigenetic data based on permutation of a sum statistic for the combined effects in a locus or pathway. The method was then applied to published type 1 diabetes (T1D) genome-wide- and epigenome-wide-association studies data to identify genomic loci and biological pathways that are associated with T1D genetically and epigenetically. Through combined analysis, novel loci and pathways were also identified, which could add to our understanding of disease mechanisms of T1D as well as complex diseases in general.
MRC Centre of Epidemiology for Child Health; Institute of Child Health; University College London; London, UK.
Xiayi
X
Ke
MRC Centre of Epidemiology for Child Health; Institute of Child Health; University College London; London, UK.
Mario
M
Cortina-Borja
The Research Computing Group; Information Services Division; University College London; London, UK.
Bruno Cesar
BC
Silva
Blizard Institute of Cell and Molecular Science; Barts and The London School of Medicine and Dentistry; Queen Mary University of London; London, UK.
Robert
R
Lowe
Blizard Institute of Cell and Molecular Science; Barts and The London School of Medicine and Dentistry; Queen Mary University of London; London, UK.
Vardhman
V
Rakyan
UCL Genetics Institute; Department of Genetics, Environment and Evolution; University College London; London, UK.
David
D
Balding
D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D044127:Epigenesis, Genetic; D056726:Genetic Association Studies; D056426:Genetic Loci; D015894:Genome, Human; D006801:Humans
EWAS; GWAS; biological pathways; combined effect; integrated analysis; type 1 diabetes