Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus.
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 genom...
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Public Library of Science (PLoS)
2010-11-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0014040&type=printable |
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| author | Christopher G Bell Sarah Finer Cecilia M Lindgren Gareth A Wilson Vardhman K Rakyan Andrew E Teschendorff Pelin Akan Elia Stupka Thomas A Down Inga Prokopenko Ian M Morison Jonathan Mill Ruth Pidsley International Type 2 Diabetes 1q Consortium Panos Deloukas Timothy M Frayling Andrew T Hattersley Mark I McCarthy Stephan Beck Graham A Hitman |
| author_facet | Christopher G Bell Sarah Finer Cecilia M Lindgren Gareth A Wilson Vardhman K Rakyan Andrew E Teschendorff Pelin Akan Elia Stupka Thomas A Down Inga Prokopenko Ian M Morison Jonathan Mill Ruth Pidsley International Type 2 Diabetes 1q Consortium Panos Deloukas Timothy M Frayling Andrew T Hattersley Mark I McCarthy Stephan Beck Graham A Hitman |
| author_sort | Christopher G Bell |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-4d81a664453744d2912ef928bbd7afd7 |
| institution | DOAJ |
| issn | 1932-6203 |
| language | English |
| publishDate | 2010-11-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-4d81a664453744d2912ef928bbd7afd72025-08-20T03:07:21ZengPublic Library of Science (PLoS)PLoS ONE1932-62032010-11-01511e1404010.1371/journal.pone.0014040Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus.Christopher G BellSarah FinerCecilia M LindgrenGareth A WilsonVardhman K RakyanAndrew E TeschendorffPelin AkanElia StupkaThomas A DownInga ProkopenkoIan M MorisonJonathan MillRuth PidsleyInternational Type 2 Diabetes 1q ConsortiumPanos DeloukasTimothy M FraylingAndrew T HattersleyMark I McCarthyStephan BeckGraham A HitmanRecent 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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0014040&type=printable |
| spellingShingle | Christopher G Bell Sarah Finer Cecilia M Lindgren Gareth A Wilson Vardhman K Rakyan Andrew E Teschendorff Pelin Akan Elia Stupka Thomas A Down Inga Prokopenko Ian M Morison Jonathan Mill Ruth Pidsley International Type 2 Diabetes 1q Consortium Panos Deloukas Timothy M Frayling Andrew T Hattersley Mark I McCarthy Stephan Beck Graham A Hitman Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus. PLoS ONE |
| title | Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus. |
| title_full | Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus. |
| title_fullStr | Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus. |
| title_full_unstemmed | Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus. |
| title_short | Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus. |
| title_sort | integrated genetic and epigenetic analysis identifies haplotype specific methylation in the fto type 2 diabetes and obesity susceptibility locus |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0014040&type=printable |
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