Many studies have investigated the association between DNA methylation alterations and disease occurrences using two design paradigms, traditional case-control and disease-discordant twins. In the disease-discordant twin design, the affected twin serves as the case and the unaffected twin serves as the control. Theoretically the twin design takes advantage of controlling for the shared genetic make-up, but it is still highly debatable if and how much researchers may benefit from such a design over the traditional case-control design. In this study, we investigate and compare the power of both designs with simulations. A liability threshold model was used assuming that identical twins share the same genetic contribution with respect to the liability of complex human diseases. Varying ranges of parameters have been used to ensure that the simulation is close to real-world scenarios. Our results reveal that the disease-discordant twin design implies greater statistical power over the traditional case-control design. For diseases with moderate and high heritability (>0.3), the disease-discordant twin design allows for large sample size reductions compared to the ordinary case-control design. Our simulation results indicate that the discordant twin design is indeed a powerful tool for epigenetic association studies. Computer scripts are available at https://github.com/zickyls/EWAS-Twin-Simulation. Supplementary data are available at Bioinformatics online.

Background: Large numbers of autosomal sites are found differentially methylated in the aging genome. Due to analytical difficulties in dealing with sex differences in X-chromosome content and X-inactivation (XCI) in females, this has not been explored for the X chromosome. Methods: Using data from middle age to elderly individuals (age 55+ years) from two Danish cohorts of monozygotic twins and the Scottish Lothian Birth Cohort 1921, we conducted an X-chromosome-wide analysis of age-associated DNA methylation patterns with consideration of stably inferred XCI status. Results: Through analysing and comparing sex-specific X-linked DNA methylation changes over age late in life, we identified 123, 293 and 55 CpG sites significant (FDR < 0.05) only in males, only in females and in both sexes of Danish twins. All findings were significantly replicated in the two Danish twin cohorts. CpG sites escaping XCI are predominantly de-methylated with increasing age across cohorts. In contrast, CpGs highly methylated in both sexes are methylated even further with increasing age. Among the replicated sites in Danish samples, 16 (13%), 24 (8.2%) and 3 (5.5%) CpGs were further validated in LBC1921 (FDR < 0.05). Conclusions: The X-chromosome of whole blood leukocytes displays age- and sex-dependent DNA methylation patterns in relation to XCI across cohorts.

Objectives: To estimate the effects of baseline grip strength and cognition on the trajectory of functional limitation over time. Design: Longitudinal study of older adults participating in the Survey of Health, Ageing and Retirement in Europe (SHARE). Setting: Urban and rural households in 11 European countries and Israel. Participants: Individuals aged 50 and older from SHARE (2004–2015) (N=14,073; 52.5% female). Measurements: Outcomes were functional limitation scores from five panel wave. Main exposure variables were grip strength and cognitive measures including memory, verbal fluency, and numeracy at baseline. Basic demographic characteristics, life habits, and health status were considered as potential confounders. Mixed‐effect linear regression models were fitted. Results: Functional limitation increased significantly over time (follow‐up range 0.9–11.6 years) (β = 0.051, P < .001). Mixed‐effect linear regression models identified significant interactions between grip strength (β = −0.001, P < .001), numeracy (β = −0.012, P < .001), verbal fluency (β = −0.003, P < .001), word recall (β = −0.006, P < .001) and time on functional limitation. Conclusion: Stronger baseline grip strength and better cognition predicted a slower rate of increase in functional limitation over time in older adults. Grip strength and cognitive function appeared to be useful indicators of the functional limitation process and attested to their value in monitoring functional change in European older adults. J Am Geriatr Soc 67:93–99, 2019.

Hand grip strength is a measure of muscular strength and is used to study age-related loss of physical capacity. In order to explore the biological mechanisms that influence hand grip strength variation, an epigenome-wide association study (EWAS) of hand grip strength in 672 middle-aged and elderly monozygotic twins (age 55–90 years) was performed, using both individual and twin pair level analyses, the latter controlling the influence of genetic variation. Moreover, as measurements of hand grip strength performed over 8 years were available in the elderly twins (age 73–90 at intake), a longitudinal EWAS was conducted for this subsample. No genome-wide significant CpG sites or pathways were found, however two of the suggestive top CpG sites were mapped to the COL6A1 and CACNA1B genes, known to be related to muscular dysfunction. By investigating genomic regions using the comb-p algorithm, several differentially methylated regions in regulatory domains were identified as significantly associated to hand grip strength, and pathway analyses of these regions revealed significant pathways related to the immune system, autoimmune disorders, including diabetes type 1 and viral myocarditis, as well as negative regulation of cell differentiation. The genes contributing to the immunological pathways were HLA-B, HLA-C, HLA-DMA, HLA-DPB1, MYH10, ERAP1 and IRF8, while the genes implicated in the negative regulation of cell differentiation were IRF8, CEBPD, ID2 and BRCA1. In conclusion, this exploratory study suggests hand grip strength to associate with differentially methylated regions enriched in immunological and cell differentiation pathways, and hence merits further investigations.