An epigenome-wide association study of sex-specific chronological ageing

Background 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 investigat...

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Vydáno v:	Genome medicine Ročník 12; číslo 1; s. 1 - 11
Hlavní autoři:	McCartney, Daniel L., Zhang, Futao, Hillary, Robert F., Zhang, Qian, Stevenson, Anna J., Walker, Rosie M., Bermingham, Mairead L., Boutin, Thibaud, Morris, Stewart W., Campbell, Archie, Murray, Alison D., Whalley, Heather C., Porteous, David J., Hayward, Caroline, Evans, Kathryn L., Chandra, Tamir, Deary, Ian J., McIntosh, Andrew M., Yang, Jian, Visscher, Peter M., McRae, Allan F., Marioni, Riccardo E.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London BioMed Central 31.12.2019 BioMed Central Ltd Springer Nature B.V BMC
Témata:	Adult Age Aged Ageing Aging Aging - genetics Analysis Bioinformatics Biomedical and Life Sciences Biomedicine Blood Cancer Research Chromosomes, Human, X - genetics Cognitive ability CpG Islands Deoxyribonucleic acid Disease DNA DNA Methylation Epigenetics Female Gene Expression Regulation Gene mapping Generation Scotland Genes Genome-Wide Association Study Genomes Genomics Health aspects Human Genetics Humans Life expectancy Life span Linear Models Male Medicine/Public Health Metabolomics Methylation Middle Aged Mortality Prostate cancer Quality control Quantitative Trait Loci Regression analysis Replication Risk factors Sex Sex Characteristics Sex differences Sexual dimorphism Software Studies Systems Biology X chromosome United Kingdom United Kingdom > UK Scotland DNA methylation Sexual dimorphism Generation Scotland Ageing X chromosome
ISSN:	1756-994X, 1756-994X
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Shrnutí:	Background 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 individuals between the ages of 18 and 87 years, with replication in a further 4450 individuals between the ages of 18 and 93 years. Methods 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. Results 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. Conclusion 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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1756-994X 1756-994X
DOI:	10.1186/s13073-019-0693-z