ORCID Profile
0000-0002-0931-0051
Current Organisation
The University of Edinburgh
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Publisher: Informa UK Limited
Date: 20-10-2020
Publisher: Elsevier BV
Date: 11-2018
Publisher: Cold Spring Harbor Laboratory
Date: 11-04-2020
DOI: 10.1101/2020.04.06.20055517
Abstract: Dementia pathogenesis begins years before clinical symptom onset, necessitating the understanding of premorbid risk mechanisms. Here, we investigated potential pathogenic mechanisms by assessing DNA methylation associations with dementia risk factors in Alzheimer’s disease (AD)-free participants. Associations between dementia risk measures (family history, genetic risk score (GRS), and dementia risk scores (combining lifestyle, demographic and genetic factors) and whole-blood DNA methylation were assessed in discovery and replication s les (n=∼400 – ∼5,000) from Generation Scotland. AD genetic risk and two risk scores were associated with differential methylation. The GRS predominantly associated with methylation differences in cis but also identified a genomic region implicated in Parkinson’s disease. Loci associated with the risk scores were enriched for those previously associated with body mass index and alcohol consumption. Dementia risk measures show widespread association with blood-based methylation, which indicates differences in the processes affected by genetic and demographic/lifestyle risk factors.
Publisher: Cold Spring Harbor Laboratory
Date: 23-10-2019
DOI: 10.1101/815035
Abstract: The Apolipoprotein E ( APOE ) ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease, while the ε2 allele confers protection. Previous studies report differential DNA methylation of APOE between ε4 and ε2 carriers, but associations with epigenome-wide methylation have not previously been characterised. Using the EPIC array, we investigated epigenome-wide differences in whole blood DNA methylation patterns between Alzheimer’s disease-free APOE ε4 (n=2469) and ε2 (n=1118) carriers from the two largest single-cohort DNA methylation s les profiled to date. Using a discovery, replication and meta-analysis study design, methylation differences were identified using epigenome-wide association analysis and differentially methylated region (DMR) approaches. Results were explored using pathway and methylation quantitative trait loci (meQTL) analyses. We obtained replicated evidence for DNA methylation differences in a ~ 169kb region, which encompasses part of APOE and several upstream genes. Meta-analytic approaches identified DNA methylation differences outside of APOE: differentially methylated positions were identified in DHCR24, LDLR and ABCG1 (2.59 x 10 −100 ≤ P ≤2.44 x 10 −8 ) and DMRs were identified in SREBF2 and LDLR (1.63 x 10 −4 ≤ P ≤3.01 x 10 −2 ). Pathway and meQTL analyses implicated lipid-related processes and high density lipoprotein cholesterol was identified as a partial mediator of the methylation differences in ABCG1 and DHCR24 . APOE ε4 vs. ε2 carrier status is associated with epigenome-wide methylation differences in the blood. The loci identified are located in trans as well as cis to APOE and implicate genes involved in lipid homeostasis.
Publisher: American Thoracic Society
Date: 08-2022
Publisher: Springer Science and Business Media LLC
Date: 31-12-2019
DOI: 10.1186/S13073-019-0693-Z
Abstract: Advanced age is associated with cognitive and physical decline and is a major risk factor for a multitude of disorders. There is also a gap in life expectancy between males and females. DNA methylation differences have been shown to be associated with both age and sex. Here, we investigate age-by-sex differences in blood-based DNA methylation in an unrelated cohort of 2586 in iduals between the ages of 18 and 87 years, with replication in a further 4450 in iduals between the ages of 18 and 93 years. Linear regression models were applied, with stringent genome-wide significance thresholds ( p 3.6 × 10 −8 ) used in both the discovery and replication data. A second, highly conservative mixed linear model method that better controls the false-positive rate was also applied, using the same genome-wide significance thresholds. Using the linear regression method, 52 autosomal and 597 X-linked CpG sites, mapping to 251 unique genes, replicated with concordant effect size directions in the age-by-sex interaction analysis. The site with the greatest difference mapped to GAGE10 , an X-linked gene. Here, DNA methylation levels remained stable across the male adult age range (DNA methylation by age r = 0.02) but decreased across female adult age range (DNA methylation by age r = − 0.61). One site (cg23722529) with a significant age-by-sex interaction also had a quantitative trait locus (rs17321482) that is a genome-wide significant variant for prostate cancer. The mixed linear model method identified 11 CpG sites associated with the age-by-sex interaction. The majority of differences in age-associated DNA methylation trajectories between sexes are present on the X chromosome. Several of these differences occur within genes that have been implicated in sexually dimorphic traits.
Publisher: Springer Science and Business Media LLC
Date: 27-09-2018
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Mairead L. Bermingham.