Biology subjects

Baglietto, L.

Publications and source records attributed to Baglietto, L..

5 recordsLinked to original sources

bioRxiv2019

Smoking and blood DNA methylation: novel associations, replication of previous findings and assessment of reversibility

We conducted a genome-wide association study of blood DNA methylation and smoking, attempted replication of previously discovered associations, and assessed the reversibility of smoking-associated methylation changes. DNA methylation was measured in baseline peripheral blood samples for 5,044 participants in the Melbourne Collaborative Cohort Study. For 1,032 participants, these measures were repeated using blood samples collected at follow-up, a median of 11 years later. A cross-sectional analysis of the association between smoking and DNA methylation and a longitudinal analysis of changes in smoking status and changes in DNA methylation were conducted. We used our cross-sectional analysis to replicate previously reported associations for current (N=3,327) and former (N=172) smoking. A comprehensive smoking index accounting for the bioactivity of smoking and several aspects of smoking history was constructed to assess the reversibility of smoking-induced methylation changes. We identified 4,496 cross-sectional associations at P<10-7, including 3,296 that were novel. We replicated the majority (90%) of previously reported associations for current and former smokers. In our data, we observed for former smokers a substantial degree of return to the methylation levels of never smokers, compared with current smokers (median: 74%, IQR=63-86%). Consistent with this, we found wide-ranging estimates for the half-life parameter of the comprehensive smoking index. Longitudinal analyses identified 368 sites at which methylation changed upon smoking cessation. Our study provides evidence of many novel associations between smoking and DNA methylation at CpGs across the genome, replicates the vast majority of previously reported associations, and indicates wide-ranging reversibility rates for smoking-induced methylation changes.

genomics↗

bioRxiv2018

Genome-wide association study of peripheral blood DNA methylation and conventional mammographic density measures

Age- and body mass index (BMI)-adjusted mammographie density is one the strongest breast cancer risk factors. DNA methylation is a molecular mechanism that could underlie interindividual variation in mammographic density. We aimed to investigate the association between breast cancer risk-predicting mammographic density measures and blood DNA methylation. For 436 women from the Australian Mammographic Density Twins and Sisters Study and 591 women from the Melbourne Collaborative Cohort Study, mammographic density (dense area, non-dense area and percentage dense area) defined by the conventional brightness threshold was measured using the CUMULUS software, and peripheral blood DNA methylation was measured using the HumanMethylation450 (HM450) BeadChip assay. Associations between DNA methylation at >400,000 sites and mammographic density measures adjusted for age and BMI were assessed within each cohort and pooled using fixed-effect meta-analysis. Associations with methylation at genetic loci known to be associated with mammographic density were also examined. We found no genome-wide significant(P<10-7)association for any mammographic density measure from the meta-analysis, or from the cohort-specific analyses. None of the 299 methylation sites located at genetic loci associated with mammographic density was associated with any mammographic density measure after adjusting for multiple testing (all P>0.05/299 = 1.7 x 10-4). In summary, our study did not detect associations between blood DNA methylation, as measured by the HM450 assay, and conventional mammographic density measures that predict breast cancer risk.

epidemiology↗

bioRxiv2018

Alcohol consumption is associated with widespread changes in blood DNA methylation: analysis of cross-sectional and longitudinal data

BackgroundDNA methylation may be one of the mechanisms by which alcohol consumption is associated with the risk of disease. We conducted a large-scale, cross-sectional, genome-wide DNA methylation association study of alcohol consumption and a longitudinal analysis of repeated measurements taken several years apart.\n\nMethodsUsing the Illumina Infinium HumanMethylation450 BeadChip, DNA methylation measures were determined using baseline peripheral blood samples from 5,606 adult Melbourne Collaborative Cohort Study (MCCS) participants. For a subset of 1,088 of them, these measures were repeated using blood samples collected at follow-up, a median of 11 years later. Associations between alcohol intake and blood DNA methylation were assessed using linear mixed-effects regression models adjusted for batch effects and potential confounders. Independent data from the LOLIPOP (N=4,042) and KORA (N=1,662) cohorts were used to replicate associations discovered in the MCCS.\n\nResultsCross-sectional analyses identified 1,414 CpGs associated with alcohol intake at P<10-7, 1,243 of which had not been reported previously. Of these 1,243 novel associations, 1,078 were replicated (P<0.05) using LOLIPOP and KORA data. Using the MCCS data, we also replicated (P<0.05) 403 of 518 associations that had been reported previously. Interaction analyses suggested that associations were stronger for women, non-smokers, and participants genetically predisposed to consume less alcohol. Of the 1,414 CpGs, 530 were differentially methylated (P<0.05) in former compared with current drinkers. Longitudinal associations between the change in alcohol intake and the change in methylation were observed for 513 of the 1,414 cross-sectional associations.\n\nConclusionOur study indicates that, for middle-aged and older adults, alcohol intake is associated with widespread changes in DNA methylation across the genome. Longitudinal analyses showed that the methylation status of alcohol-associated CpGs may change with changes in alcohol consumption.

epidemiology↗

bioRxiv2018

Appraising the causal relevance of DNA methylation for risk of lung cancer

DNA methylation changes in peripheral blood have been identified in relation to lung cancer risk. However, the causal nature of these associations remains to be fully elucidated. Meta-analysis of four epigenome-wide association studies (918 cases, 918 controls) revealed differential methylation at 16 CpG sites (FDR < 0.05) in relation to lung cancer risk. A two-sample Mendelian randomization analysis, using genetic instruments for methylation at 14 of the 16 CpG sites, and 29,863 cases and 55,586 controls from the TRICL-ILCCO lung cancer consortium, was performed to appraise the causal role of methylation at these sites on lung cancer. This approach provided little evidence that DNA methylation in peripheral blood at the 14 CpG sites play a causal role in lung cancer development, including for cg05575921 AHRR, where methylation is strongly associated with lung cancer risk. Further studies are needed to investigate the causal role played by DNA methylation in lung tissue.

epidemiology↗

bioRxiv2017

An epigenome-wide association study of educational attainment (n = 10,767)

The epigenome has been shown to be influenced by biological factors, such as disease status, and environmental factors, such as smoking, alcohol consumption, and body mass index. Although there is a widespread perception that environmental influences on the epigenome are pervasive and profound, there has been little evidence to date in humans with respect to environmental factors that are biologically distal. Here, we provide evidence on the associations between epigenetic modifications--in our case, CpG methylation--and educational attainment (EA), a biologically distal environmental factor that is arguably among of the most important life-shaping experiences for individuals. Specifically, we report the results of an epigenome-wide association study meta-analysis of EA based on data from 27 cohort studies with a total of 10,767 individuals. While we find that 9 CpG probes are significantly associated with EA, only two remain associated when we restrict the sample to never-smokers. These two are known to be strongly associated with maternal smoking during pregnancy, and thus their association with EA could be due to correlation between EA and maternal smoking. Moreover, their effect sizes on EA are far smaller than the known associations between CpG probes and biologically proximal environmental factors. Two analyses that combine the effects of many probes--polygenic methylation score and epigenetic-clock analyses--both suggest small associations with EA. If our findings regarding EA can be generalized to other biologically distal environmental factors, then they cast doubt on the hypothesis that such factors have large effects on the epigenome.

genetics↗