Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus

• Published in: PloS one 2010-11, Vol.5 (11), p.e14040-e14040
• Main Authors: Bell, Christopher G, Finer, Sarah, Lindgren, Cecilia M, Wilson, Gareth A, Rakyan, Vardhman K, Teschendorff, Andrew E, Akan, Pelin, Stupka, Elia, Down, Thomas A, Prokopenko, Inga, Morison, Ian M, Mill, Jonathan, Pidsley, Ruth, Deloukas, Panos, Frayling, Timothy M, Hattersley, Andrew T, McCarthy, Mark I, Beck, Stephan, Hitman, Graham A
• Format: Article
• Language: English
• Subjects: Adult; Algorithms; Analysis; Animals; Base Sequence; Bayes Theorem; Bayesian analysis; Bioinformatics; Cancer; CpG islands; CpG Islands - genetics; Data analysis; Dentistry; Deoxyribonucleic acid; Diabetes; Diabetes and Endocrinology/Obesity; Diabetes and Endocrinology/Type 2 Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Disease; Disease susceptibility; DNA; DNA Methylation; Epigenetic inheritance; Epigenetics; Epigenomics; Evolution, Molecular; Female; Females; Gene expression; Gene Expression Profiling; Gene Frequency; Genetic aspects; Genetic Predisposition to Disease - genetics; Genetics; Genetics and Genomics/Comparative Genomics; Genetics and Genomics/Complex Traits; Genetics and Genomics/Epigenetics; Genetics and Genomics/Population Genetics; Genomes; Genomics; Genotype; Haplotypes; Haplotypes - genetics; Histones - metabolism; Humans; Immunoprecipitation; Loci; Medical research; Medicine; Methylation; Mutation; Obesity; Obesity - genetics; Oligonucleotide Array Sequence Analysis; Polymorphism, Single Nucleotide; Science; Sequence Analysis, DNA; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Susceptibility; Type 2 diabetes
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0014040

Recent multi-dimensional approaches to the study of complex disease have revealed powerful insights into how genetic and epigenetic factors may underlie their aetiopathogenesis. We examined genotype-epigenotype interactions in the context of Type 2 Diabetes (T2D), focussing on known regions of genomic susceptibility. We assayed DNA methylation in 60 females, stratified according to disease susceptibility haplotype using previously identified association loci. CpG methylation was assessed using methylated DNA immunoprecipitation on a targeted array (MeDIP-chip) and absolute methylation values were estimated using a Bayesian algorithm (BATMAN). Absolute methylation levels were quantified across LD blocks, and we identified increased DNA methylation on the FTO obesity susceptibility haplotype, tagged by the rs8050136 risk allele A (p = 9.40×10(-4), permutation p = 1.0×10(-3)). Further analysis across the 46 kb LD block using sliding windows localised the most significant difference to be within a 7.7 kb region (p = 1.13×10(-7)). Sequence level analysis, followed by pyrosequencing validation, revealed that the methylation difference was driven by the co-ordinated phase of CpG-creating SNPs across the risk haplotype. This 7.7 kb region of haplotype-specific methylation (HSM), encapsulates a Highly Conserved Non-Coding Element (HCNE) that has previously been validated as a long-range enhancer, supported by the histone H3K4me1 enhancer signature. This study demonstrates that integration of Genome-Wide Association (GWA) SNP and epigenomic DNA methylation data can identify potential novel genotype-epigenotype interactions within disease-associated loci, thus providing a novel route to aid unravelling common complex diseases.