Methylome-wide Association Study of Whole Blood DNA in the Norfolk Island Isolate Identifies Robust Loci Associated with Age

Overview

Journal Aging (Albany NY)

Specialty Geriatrics

Date 2017 Mar 4

PMID 28255110

Citations 23

Authors

Miles C Benton

Heidi G Sutherland

Donia Macartney-Coxson

Larisa M Haupt

Rodney A Lea

Lyn R Griffiths

Affiliations

Soon will be listed here.

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 and an extended region within the promoter of . 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 and , 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.

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References

Benton M, Stuart S, Bellis C, Macartney-Coxson D, Eccles D, Curran J . 'Mutiny on the Bounty': the genetic history of Norfolk Island reveals extreme gender-biased admixture. Investig Genet. 2015; 6:11. PMC: 4558825. DOI: 10.1186/s13323-015-0028-9. View

Zhuang J, Widschwendter M, Teschendorff A . A comparison of feature selection and classification methods in DNA methylation studies using the Illumina Infinium platform. BMC Bioinformatics. 2012; 13:59. PMC: 3364843. DOI: 10.1186/1471-2105-13-59. View

Florath I, Butterbach K, Muller H, Bewerunge-Hudler M, Brenner H . Cross-sectional and longitudinal changes in DNA methylation with age: an epigenome-wide analysis revealing over 60 novel age-associated CpG sites. Hum Mol Genet. 2013; 23(5):1186-201. PMC: 3919014. DOI: 10.1093/hmg/ddt531. View

Cristino L, Luongo L, Squillace M, Paolone G, Mango D, Piccinin S . d-Aspartate oxidase influences glutamatergic system homeostasis in mammalian brain. Neurobiol Aging. 2015; 36(5):1890-902. DOI: 10.1016/j.neurobiolaging.2015.02.003. View

Ali O, Cerjak D, Kent Jr J, James R, Blangero J, Carless M . An epigenetic map of age-associated autosomal loci in northern European families at high risk for the metabolic syndrome. Clin Epigenetics. 2015; 7:12. PMC: 4372177. DOI: 10.1186/s13148-015-0048-6. View

Miceli-Richard C, Wang-Renault S, Boudaoud S, Busato F, Lallemand C, Bethune K . Overlap between differentially methylated DNA regions in blood B lymphocytes and genetic at-risk loci in primary Sjögren's syndrome. Ann Rheum Dis. 2015; 75(5):933-40. PMC: 4853580. DOI: 10.1136/annrheumdis-2014-206998. View

Millay D, Maillet M, Roche J, Sargent M, McNally E, Bloch R . Genetic manipulation of dysferlin expression in skeletal muscle: novel insights into muscular dystrophy. Am J Pathol. 2009; 175(5):1817-23. PMC: 2774048. DOI: 10.2353/ajpath.2009.090107. View

Langmead B, Salzberg S . Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012; 9(4):357-9. PMC: 3322381. DOI: 10.1038/nmeth.1923. View

Bjornsson H, Sigurdsson M, Daniele Fallin M, Irizarry R, Aspelund T, Cui H . Intra-individual change over time in DNA methylation with familial clustering. JAMA. 2008; 299(24):2877-83. PMC: 2581898. DOI: 10.1001/jama.299.24.2877. View

10.

Zaar K, Schad A, Volkl A, Baumgart E, Fahimi H . Cellular and subcellular distribution of D-aspartate oxidase in human and rat brain. J Comp Neurol. 2002; 450(3):272-82. DOI: 10.1002/cne.10320. View

11.

Punzo D, Errico F, Cristino L, Sacchi S, Keller S, Belardo C . Age-Related Changes in D-Aspartate Oxidase Promoter Methylation Control Extracellular D-Aspartate Levels and Prevent Precocious Cell Death during Brain Aging. J Neurosci. 2016; 36(10):3064-78. PMC: 6601755. DOI: 10.1523/JNEUROSCI.3881-15.2016. View

12.

Chen J, Bardes E, Aronow B, Jegga A . ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucleic Acids Res. 2009; 37(Web Server issue):W305-11. PMC: 2703978. DOI: 10.1093/nar/gkp427. View

13.

Waldmann P, Meszaros G, Gredler B, Fuerst C, Solkner J . Evaluation of the lasso and the elastic net in genome-wide association studies. Front Genet. 2013; 4:270. PMC: 3850240. DOI: 10.3389/fgene.2013.00270. View

14.

Furst R, Kliem H, Meyer H, Ulbrich S . A differentially methylated single CpG-site is correlated with estrogen receptor alpha transcription. J Steroid Biochem Mol Biol. 2012; 130(1-2):96-104. DOI: 10.1016/j.jsbmb.2012.01.009. View

15.

Flores K, Wolschin F, Corneveaux J, Allen A, Huentelman M, Amdam G . Genome-wide association between DNA methylation and alternative splicing in an invertebrate. BMC Genomics. 2012; 13:480. PMC: 3526459. DOI: 10.1186/1471-2164-13-480. View

16.

Mackey D, Sherwin J, Kearns L, Ma Y, Kelly J, Chu B . The Norfolk Island Eye Study (NIES): rationale, methodology and distribution of ocular biometry (biometry of the bounty). Twin Res Hum Genet. 2011; 14(1):42-52. DOI: 10.1375/twin.14.1.42. View

17.

Abraham G, Kowalczyk A, Zobel J, Inouye M . SparSNP: fast and memory-efficient analysis of all SNPs for phenotype prediction. BMC Bioinformatics. 2012; 13:88. PMC: 3483007. DOI: 10.1186/1471-2105-13-88. View

18.

Friedman J, Hastie T, Tibshirani R . Regularization Paths for Generalized Linear Models via Coordinate Descent. J Stat Softw. 2010; 33(1):1-22. PMC: 2929880. View

19.

Fleischer T, Frigessi A, Johnson K, Edvardsen H, Touleimat N, Klajic J . Genome-wide DNA methylation profiles in progression to in situ and invasive carcinoma of the breast with impact on gene transcription and prognosis. Genome Biol. 2014; 15(8):435. PMC: 4165906. DOI: 10.1186/PREACCEPT-2333349012841587. View

20.

Bacalini M, Boattini A, Gentilini D, Giampieri E, Pirazzini C, Giuliani C . A meta-analysis on age-associated changes in blood DNA methylation: results from an original analysis pipeline for Infinium 450k data. Aging (Albany NY). 2015; 7(2):97-109. PMC: 4359692. DOI: 10.18632/aging.100718. View