RT Journal Article SR Electronic T1 A Bayesian approach for analysis of whole-genome bisulphite sequencing data identifies disease-associated changes in DNA methylation JF bioRxiv FD Cold Spring Harbor Laboratory SP 041715 DO 10.1101/041715 A1 Owen J.L. Rackham A1 Sarah R. Langley A1 Thomas Oates A1 Eleni Vradi A1 Nathan Harmston A1 Prashant K. Srivastava A1 Jacques Behmoaras A1 Petros Dellaportas A1 Leonardo Bottolo A1 Enrico Petretto YR 2017 UL http://biorxiv.org/content/early/2017/02/20/041715.abstract AB DNA methylation is a key epigenetic modification involved in gene regulation whose contribution to disease susceptibility remains to be fully understood. Here, we present a novel Bayesian smoothing approach (called ABBA) to detect differentially methylated regions (DMRs) from whole-genome bisulphite sequencing (WGBS). We also show how this approach can be leveraged to identify disease-associated changes in DNA methylation, suggesting mechanisms through which these alterations might affect disease. From a data modeling perspective, ABBA has the distinctive feature of automatically adapting to different correlation structures in CpG methylation levels across the genome whilst taking into account the distance between CpG sites as a covariate. Our simulation study shows that ABBA has greater power to detect DMRs than existing methods, providing an accurate identification of DMRs in the large majority of simulated cases. To empirically demonstrate the method’s efficacy in generating biological hypotheses, we performed WGBS of primary macrophages derived from an experimental rat system of glomerulonephritis and used ABBA to identify >1,000 disease-associated DMRs. Investigation of these DMRs revealed differential DNA methylation localized to a 600bp region in the promoter of the Ifitm3 gene. This was confirmed by ChIP-seq and RNA-seq analyses, showing differential transcription factor binding at the Ifitm3 promoter by JunD (an established determinant of glomerulonephritis) and a consistent change in Ifitm3 expression. Our ABBA analysis allowed us to propose a new role for Ifitm3 in the pathogenesis of glomerulonephritis via a mechanism involving promoter hypermethylation that is associated with Ifitm3 repression in the rat strain susceptible to glomerulonephritis.