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. 2017 Feb 28;9(3):753-768.
doi: 10.18632/aging.101187.

Methylome-wide association study of whole blood DNA in the Norfolk Island isolate identifies robust loci associated with age

Miles C Benton  1 , Heidi G Sutherland  1 , Donia Macartney-Coxson  2 , Larisa M Haupt  1 , Rodney A Lea  1 , Lyn R Griffiths  1
Affiliations

Methylome-wide association study of whole blood DNA in the Norfolk Island isolate identifies robust loci associated with age

Miles C Benton et al. Aging (Albany NY). .

Abstract

Epigenetic regulation of various genomic functions, including gene expression, provide mechanisms whereby an organism can dynamically respond to changes in its environment and modify gene expression accordingly. One epigenetic mechanism implicated in human aging and age-related disorders is DNA methylation. Isolated populations such as Norfolk Island (NI) should be advantageous for the identification of epigenetic factors related to aging due to reduced genetic and environmental variation. Here we conducted a methylome-wide association study of age using whole blood DNA in 24 healthy female individuals from the NI genetic isolate (aged 24-47 years). We analysed 450K methylation array data using a machine learning approach (GLMnet) to identify age-associated CpGs. We identified 497 CpG sites, mapping to 422 genes, associated with age, with 11 sites previously associated with age. The strongest associations identified were for a single CpG site in MYOF and an extended region within the promoter of DDO. These hits were validated in curated public data from 2316 blood samples (MARMAL-AID). This study is the first to report robust age associations for MYOF and DDO, both of which have plausible functional roles in aging. This study also illustrates the value of genetic isolates to reveal new associations with epigenome-level data.

Keywords: DNA methylation; GLMnet; Norfolk Island; aging; epigenetics.

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Conflict of interest statement

CONFLICTS OF INTEREST

All authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Four promoter associated DDO CpG age-associations for the 24 healthy female Norfolk Island samples showing statistically significant reduction in methylation with age. Regression statistics are displayed within each panel.
Figure 2
Figure 2
Four DDO promoter CpG sites associated with human age in white blood cells from 2316 samples sourced from the MARMAL-AID methylation repository. Each association is fitted with an overall loess regression model, with the regression statistics shown in the top right of each panel. Points are coloured and shaped to represent both males (black, circles) and females (grey, triangles) separately.
Figure 3
Figure 3
Public blood data age categorised for 4 promoter associated DDO probes, portrayed in the same fashion as demonstrated in Bacalini et al., 2015. Mean methylation values in 10 age classes are reported for each CpG probe within the DDO promoter.
Figure 4
Figure 4
A single MYOF CpG site associated with age in: (A) the 24 healthy female Norfolk Island samples, and (B) 2316 public blood samples sourced from MARMAL-AID.
See this image and copyright information in PMC

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