Altered DNA methylation profiles in blood from patients with sporadic Creutzfeldt–Jakob disease

Abstract

Prion diseases are fatal and transmissible neurodegenerative disorders caused by the misfolding and aggregation of prion protein. Although recent studies have implicated epigenetic variation in common neurodegenerative disorders, no study has yet explored their role in human prion diseases. Here we profiled genome-wide blood DNA methylation in the most common human prion disease, sporadic Creutzfeldt–Jakob disease (sCJD). Our case–control study (n = 219), when accounting for differences in cell type composition between individuals, identified 38 probes at genome-wide significance (p < 1.24 × 10–7). Nine of these sites were taken forward in a replication study, performed in an independent case–control (n = 186) cohort using pyrosequencing. Sites in or close to FKBP5, AIM2 (2 probes), UHRF1, KCNAB2 successfully replicated. The blood-based DNA methylation signal was tissue- and disease-specific, in that the replicated probe signals were unchanged in case–control studies using sCJD frontal-cortex (n = 84), blood samples from patients with Alzheimer’s disease, and from inherited and acquired prion diseases. Machine learning algorithms using blood DNA methylation array profiles accurately distinguished sCJD patients and controls. Finally, we identified sites whose methylation levels associated with prolonged survival in sCJD patients. Altogether, this study has identified a peripheral DNA methylation signature of sCJD with a variety of potential biomarker applications.

Genotype by environment interactions for chronic wasting disease in farmed US white-tailed deer

“…Beyond ARSB and its association with MPS, we also noted 24 positional candidate genes related to 26 additional EMMAX GxE signals ( P -value ≤ 5E-05; Supplementary Table 2 , Fig. 1 ); the majority of which have previously been associated with Parkinson’s disease ( SMYD4 , WARS2 , IFNGR1 , PLPP4 , ASCL1 , FAM120A ), Alzheimer’s disease ( TBX15 , IFNGR , PTP4A1 , AIM2 , SLC10A2 , COL25A1 , ASCL1 , EPHB1 , UMAD1 , VNN3 , COL27A1 , RNF144B , SDK2 ), and various prion diseases ( IFNGR , SEC23IP , EPHA3 , EFNB2 , ELOVL4 , DOCK5 , COL27A1 ) including scrapie, bovine spongiform encephalopathy, and Creutzfeldt–Jakob disease ( Ide et al 2005 ; Julius 2008 ; Hashioka et al 2009 ; Tong et al 2010 ; Tian et al 2013 ; Woodling et al 2014 ; Majer 2015 ; Freeman and Ting 2016 ; Vélez et al 2016 ; Watson et al 2016 ; Mez et al 2017 ; Su et al 2018 ; Choubey 2019 ; Dabin 2019 ; Hirsch et al 2019 ; Liu et al 2019 ; Majer et al 2019 ; Meyer et al 2019 ; Thatra 2019 ; Bellenguez et al 2020 ; Dabin et al 2020 ; Donaldson et al 2020 ; Martinelli et al 2020 ; Wang et al 2020 ; Vastrad and Vastrad 2021 ). Notably, the EMMAX GxE mixed model solutions were also robust to the inclusion of additional fixed effect covariates (i.e.…”

Genome-Wide Methylation Profiling in the Thalamus of Scrapie Sheep

“…To the best of our knowledge, and in contrast to AD ( 38 ), PD ( 41 ), and ALS ( 42 ), only one study has analyzed the genome-wide methylation profile in prion diseases, and this was performed in peripheral blood of sCJD patients ( 23 ). We report here the first WGBS study carried out in the CNS of any prion disease model.…”

“…However, methylation has not been observed in the promoter of the rat PRNP gene, at least in PC12 cells ( 22 ). Regarding prion diseases, DNA methylation studies at a genomic level have only been performed in blood from patients with sporadic Creutzfeldt–Jakob disease (sCJD), the most common human prion disease ( 23 ). To the best of our knowledge, no genome-wide DNA methylation studies have yet been reported in the CNS of any prion disease models or naturally infected cases.…”

Prion protein gene mutation detection using long-read Nanopore sequencing

“…Final DNA samples were stored at 4 °C until needed. DNA extraction from CJD brain samples was carried out in a Biosafety Level 3 facility as previously published 49 .…”