Integrated DNA methylation analysis reveals a potential role for ANKRD30B in Williams syndrome

Abstract

Williams syndrome (WS) is a rare genetic disorder, caused by a microdeletion at the 7q11.23 region. WS exhibits a wide spectrum of features including hypersociability, which contrasts with social deficits typically associated with autism spectrum disorders. The phenotypic variability in WS likely involves epigenetic modifications; however, the nature of these events remains unclear. To better understand the role of epigenetics in WS phenotypes, we integrated DNA methylation and gene expression profiles in blood from patients with WS and controls. From these studies, 380 differentially methylated positions (DMPs), located throughout the genome, were identified. Systems-level analysis revealed multiple co-methylation modules linked to intermediate phenotypes of WS, with the top-scoring module related to neurogenesis and development of the central nervous system. Notably, ANKRD30B , a promising hub gene, was significantly hypermethylated in blood and downregulated in brain tissue from individuals with WS. Most CpG sites of ANKRD30B in blood were significantly correlated with brain regions. Furthermore, analyses of gene regulatory networks (GRNs) yielded master regulator transcription factors associated with WS. Taken together, this systems-level approach highlights the role of epigenetics in WS, and provides a possible explanation for the complex phenotypes observed in patients with WS.

Fish as Model Systems to Study Epigenetic Drivers in Human Self-Domestication and Neurodevelopmental Cognitive Disorders

“…DMRs identified using the Infinium ® HumanMethylation450 BeadChip array (Illumina, San Diego, CA, USA) in the blood of 20 WS patients vs. 15 healthy controls found DMRs intersecting 551 unique genes [ 54 ]. Differentially methylated cytosines (DMCs) were detected more recently in the blood of a larger sample of 90 WS patients vs. 34 healthy controls using the same array and these intersected with 143 unique genes [ 55 ]. The two gene lists were combined for further analysis as genes differentially methylated (DM) in WS, with a total of 624 different genes.…”

Epigenetic aging in Williams syndrome

“…The participants were already described in our previously published study (Kimura et al., 2020). Briefly, patients with WS were recruited from the pediatric neurology departments of Kyoto University Hospital, Osaka City General Hospital, and Todaiji Ryoiku Hospital for Children through the WS family support group in Japan.…”

“…Genome‐wide DNAm profiling was conducted using blood samples from 32 patients with WS and 32 controls using the Illumina Infinium 450K platform (450K array) as described previously (Kimura et al., 2020). The Beta Mixture Quantile Dilation method was used for the array normalization (Teschendorff et al., 2013).…”

“…In this study, we hypothesized that WS is associated with accelerated biological aging based on previously reported profiles of altered DNAm in the blood of patients with WS (Kimura et al, 2020;Strong et al, 2015). Our objective was to perform an epigenetic clock analysis, investigating DNAm GrimAge, DNAmTL, and other epigenetic clocks in the blood samples of patients with WS and controls.…”

Fish as model systems to study epigenetic drivers in human self-domestication and neurodevelopmental cognitive disorders

“…DMRs identified using the Infinium HumanMethylation 450 BeadChip array (Illumina) in the blood of 20 WS patients vs 15 healthy controls found DMRs intersecting 551 unique genes [51]. Differentially methylated cytosines (DMCs) were detected more recently in blood of a larger sample of 90 WS patients vs 34 healthy controls using the same array and these intersected with 143 unique genes [52]. The two gene lists were combined for further analysis as genes differentially methylated (DM) in WS, with a total of 624 different genes.…”