Age-related changes in DNA methylation have been implicated in cellular senescence and longevity, yet the causes and functional consequences of these variants remain unclear. To elucidate the role of age-related epigenetic changes in healthy ageing and potential longevity, we tested for association between whole-blood DNA methylation patterns in 172 female twins aged 32 to 80 with age and age-related phenotypes. Twin-based DNA methylation levels at 26,690 CpG-sites showed evidence for mean genome-wide heritability of 18%, which was supported by the identification of 1,537 CpG-sites with methylation QTLs in cis at FDR 5%. We performed genome-wide analyses to discover differentially methylated regions (DMRs) for sixteen age-related phenotypes (ap-DMRs) and chronological age (a-DMRs). Epigenome-wide association scans (EWAS) identified age-related phenotype DMRs (ap-DMRs) associated with LDL (STAT5A), lung function (WT1), and maternal longevity (ARL4A, TBX20). In contrast, EWAS for chronological age identified hundreds of predominantly hyper-methylated age DMRs (490 a-DMRs at FDR 5%), of which only one (TBX20) was also associated with an age-related phenotype. Therefore, the majority of age-related changes in DNA methylation are not associated with phenotypic measures of healthy ageing in later life. We replicated a large proportion of a-DMRs in a sample of 44 younger adult MZ twins aged 20 to 61, suggesting that a-DMRs may initiate at an earlier age. We next explored potential genetic and environmental mechanisms underlying a-DMRs and ap-DMRs. Genome-wide overlap across cis-meQTLs, genotype-phenotype associations, and EWAS ap-DMRs identified CpG-sites that had cis-meQTLs with evidence for genotype-phenotype association, where the CpG-site was also an ap-DMR for the same phenotype. Monozygotic twin methylation difference analyses identified one potential environmentally-mediated ap-DMR associated with total cholesterol and LDL (CSMD1). Our results suggest that in a small set of genes DNA methylation may be a candidate mechanism of mediating not only environmental, but also genetic effects on age-related phenotypes.

https://www.epigenomicslab.com/wp-content/uploads/publications/2012%20-%20Epigenome-wide%20scans%20identify%20differentially%20methylated%20regions%20for%20age%20and%20age-related%20phenotypes%20in%20a%20healthy%20ageing%20population.pdf

Epigenome-Wide Scans Identify Differentially Methylated Regions for Age and Age-Related Phenotypes in a Healthy Ageing Population

Genetics of COPD and Emphysema

This thesis explores the contribution of twin studies, particularly those studies originating from the Danish Twin Registry, to the understanding of the aetiology of asthma. First, it is explored how twin studies have established the contribution of genetic and environmental factors to the variation in the susceptibility to asthma, and to the variation in several aspects of the clinical expression of the disease such as its age at onset, its symptomatology, its intermediate phenotypes , and its relationship with other atopic diseases. Next, it is explored how twin studies have corroborated theories explaining asthma’s recent increase in prevalence, and last, how these fit with the explanations of the epidemiological trends in other common chronic diseases of modernity. (Published: 1 September 2014) Citation: European Clinical Respiratory Journal 2014, 1 : 25535 - http://dx.doi.org/10.3402/ecrj.v1.25535

Exploring the origins of asthma: Lessons from twin studies

Heritability of forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and peak expiratory flow (PEF) has not been previously addressed in large twin studies. We evaluated the genetic contribution to individual differences observed in FEV1, FVC, and PEF using data from the largest population-based twin study on spirometry. Specially trained lay interviewers with previous experience in spirometric measurements tested 4,314 Danish twins (individuals), 46–68 years of age, in their homes using a hand-held spirometer, and their flow-volume curves were evaluated. Modern variance component sex-limitation models were applied to evaluate possible genetic differences between the sexes for FEV1, FVC, and PEF. Estimates were adjusted for age, height, and smoking. For FEV1, additive genetic effects of 61% (95% CI 56–65) were observed. For FVC, the additive genetic contribution was 26% (3–49%) and the dominant genetic contribution was 29% (4–54%). For PEF, our models showed an additive genetic contribution of 43% (31–52%) for men, but genetic influences were not significant in women. We found no significant differences between dizygotic same-sex twins and dizygotic opposite-sex twins for FEV1, FVC, and PEF, suggesting absence of qualitative genetic differences between the sexes. Sex-difference heritability for PEF suggested possible quantitative genetic differences between the sexes for this index. Genetic effects contributed significantly to individual differences observed in FEV1, FVC, and PEF. Qualitative sex differences were absent for all spirometric measures, while quantitative sex differences were observed only for PEF, with heritability being substantial in men but negligible in women.

/pdf/genetic-influences-on-pulmonary-function-a-large-sample-twin-11m4ppf4ib.pdf

Genetic Influences on Pulmonary Function: A Large Sample Twin Study

Background: The understanding of the influence of smoking and sex on lung function and symptoms is important for understanding diseases such as COPD. The influence of both genes and environment on lung function, smoking behaviour and the presence of respiratory symptoms has previously been demonstrated for each of these separately. Hence, smoking can influence lung function by co-varying not only as an environmental factor, but also by shared genetic pathways. Therefore, the objective was to evaluate heritability for different aspects of lung function, and to investigate how the estimates are affected by adjustments for smoking and respiratory symptoms. Methods: The current study is based on a selected sample of adult twins from the Swedish Twin Registry. Pairs were selected based on background data on smoking and respiratory symptoms collected by telephone interview. Lung function was measured as FEV1, VC and DLco. Pack years were quantified, and quantitative genetic analysis was performed on lung function data adjusting stepwise for sex, pack years and respiratory symptoms. Results: Fully adjusted heritability for VC was 59% and did not differ by sex, with smoking and symptoms explaining only a small part of the total variance. Heritabilities for FEV1 and DLco were sex specific. Fully adjusted estimates were10 and 15% in men and 46% and 39% in women, respectively. Adjustment for smoking and respiratory symptoms altered the estimates differently in men and women. For FEV1 and DLco, the variance explained by smoking and symptoms was larger in men. Further, smoking and symptoms explained genetic variance in women, but was primarily associated with shared environmental effects in men. Conclusion: Differences between men and women were found in how smoking and symptoms influence the variation in lung function. Pulmonary gas transfer variation related to the menstrual cycle has been shown before, and the findings regarding DLco in the present study indicates gender specific environmental susceptibility not shown before. As a consequence the results suggest that patients with lung diseases such as COPD could benefit from interventions that are sex specific.

/pdf/genetic-and-environmental-influence-on-lung-function-4g66t4zybq.pdf

Genetic and environmental influence on lung function impairment in Swedish twins

The interaction of genes and smoking on forced expiratory volume: a classic twin study.

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The interaction of genes and smoking on forced expiratory volume: a classic twin study.