Biology subjects

Madden, R. A.

Publications and source records attributed to Madden, R. A..

3 recordsLinked to original sources

bioRxiv2023

Phenome-wide analysis identifies parent-of-origin effects on the human methylome associated with changes in the rate of aging

Variation in the rate at which humans age may be rooted in early life events acting through genomic regions that are influenced by such events and subsequently are related to health phenotypes in later life. The parent-of-origin-effect (POE)-regulated methylome includes regions either enriched for genetically controlled imprinting effects (the typical type of POE) or atypical POE introduced by environmental effects associated with parents. This part of the methylome is heavily influenced by early life events, making it a potential route connecting early environmental exposures, the epigenome and the rate of aging. Here, we aim to test the association of POE-influenced methylation of CpG dinucleotides (POE-CpG sites) with early and later environmental exposures and subsequently with health-related phenotypes and adult aging phenotypes. We do this by performing phenome-wide association analyses of the POE-influenced methylome using a large family-based population cohort (GS:SFHS, Ndiscovery=5,087, Nreplication=4,450). At the single CpG level, 92 associations of POE-CpGs with phenotypic variation were identified and replicated. Most of the associations were contributed by POE-CpGs belonging to the atypical class and the most strongly enriched associations were with aging (DNAmTL acceleration), intelligence and parental (maternal) smoking exposure phenotypes. We further found that a proportion of the atypical-POE-CpGs formed co-methylation networks (modules) which are associated with these phenotypes, with one of the aging-associated modules displaying increased internal module connectivity (strength of methylation correlation across constituent CpGs) with age. Atypical POE-CpGs also displayed high levels of methylation heterogeneity and epigenetic drift (i.e. information loss with age) and a strong correlation with CpGs contained within epigenetic clocks. These results identified associations between the atypical-POE-influenced methylome and aging and provided new evidence for the "early development of origin" hypothesis for aging in humans.

genetics↗

bioRxiv2021

Lifestyle and Genetic Factors Modify Parent-of-Origin Effects on the Human Methylome

Backgroundparent-of-origin effects (POE) play important roles in development and complex disease and thus understanding their regulation and associated molecular and phenotypic variation are warranted. Previous studies have mainly focused on the detection of genomic regions or phenotypes regulated by POE. Understanding whether POE may be modified by environmental or genetic exposures is important for understanding of the source of POE-associated variation, but only a few case studies addressing these modifiable POE exist. Methodsin order to understand this high order of POE regulation, we screened 101 genetic and environmental factors such as "predicted mRNA expression levels" of DNA methylation/imprinting machinery genes and early/late lifestyle/environmental exposures. POE-mQTL-modifier interaction models were proposed to test the potential of these factors to modify POE at DNA methylation using data from Generation Scotland: The Scottish Family Health Study(N=2315). Resultsa set of vulnerable/modifiable POE-CpGs were identified (modifiable-POE-regulated CpGs, N=3). Four factors, "lifetime smoking status" and "predicted mRNA expression levels" of TET2, SIRT1 and KDM1A, were found to significantly modify the POE on the three CpGs in both discovery and replication datasets. Importantly, the POE on one of the CpGs were modified by both genetic and environmental factors. We further identified plasma protein and health-related phenotypes associated with the methylation level of one of the identified CpGs. Conclusionsthe modifiable POE identified here revealed an important yet indirect path through which genetic background and environmental exposures introduce their effect on DNA methylation, motivating future comprehensive evaluation of the role of these modifiers in complex diseases. Key MessagesO_LIPrevious population studies showed that parent-origin-effects(POE) on human methylome can be widespread and affect health-related traits and diseases. C_LIO_LIWhether the POE remained stable throughout the life or can be modified by genetic or environmental factors were largely unknown. C_LIO_LIBy systematically screening 101 genetic and environmental factors in a large cohort(GS:SFHS) we provided the first population-level replicated evidence that those measuring lifestyle (smoking) and predicted expression of DNA methylation- or imprinting-machinery genes are amongst the factors that can modulate the POE of mQTLs for a set of CpG sites. C_LIO_LIWe found those modifiable-POE-regulated CpGs are also phenotypically relevant - one is associated with the plasma levels of CLEC4C and health-related phenotypes such as HDL levels. C_LIO_LIThe modifiable POE identified here revealed an important yet indirect path through which genetic background and environmental exposures introduce their effect on DNA methylation and their potential phenotypic consequences. This also provided a paradigm for further studies to explore how environmental and genetic effects can be integrated at methylation level. C_LI

genetics↗

bioRxiv2019

Birth weight predicts psychiatric and physical health, cognitive function, and DNA methylation differences in an adult population

BackgroundThe Developmental Origins of Adult Disease (DOAD) theory predicts that prenatal and early life events shape adult health outcomes. Birth weight is a useful indicator of the foetal experience, and has been associated with multiple adult health outcomes. DNA methylation (DNAm) is one plausible mechanism behind the relationship of birth weight to adult health. MethodsThe Generation Scotland study allows data linkage to historic Scottish birth cohorts, and birth records held through the NHS Information and Statistics Division. Data linkage with these sources yielded a sample of 4, 710 individuals. Health measures were related to birth weight in regression models. An epigenome-wide association study (EWAS) was performed in a subgroup (n=1, 395), relating adult DNAm from whole blood to birth weight, with replication in an independent sample (n=362). Associations between birth weight and epigenetic clocks were also assessed. FindingsHigher birth weight was significantly associated with reduced incidence of depression and osteoarthritis, higher body mass index, and higher general intelligence (absolute standardised effect size range 0{middle dot}04 to 0{middle dot}30, p(FDR)<0{middle dot}05). Meta-analysis of discovery and replication EWAS studies yielded one genome-wide significant CpG site (p=5{middle dot}97x10-9), cg00966482. Significant associations between birth weight and Grim Age (p=0{middle dot}0014) and DNAm-derived telomere length (p=3{middle dot}3x10-4) are also described. InterpretationOur results demonstrate associations between birth weight and adult health outcomes, with particularly striking effects for depression risk. It also provides support for an association between birth weight and DNAm, describing the first significant EWAS site associated with birth weight in an adult sample. FundingWellcome Trust Strategic Award 104036/Z/14/Z Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSThe associations between birth weight and various adult health outcomes have been well established. DNA methylation is a plausible mechanism through which early life experiences may continue to affect health throughout the lifecourse; however, evidence for birth weight associations with DNA methylation in adulthood has not yet been robustly established. This is likely due to small sample sizes of previous samples, as well as the use of poor-quality birth weight data, such as binary low/normal variables or retrospective self-report. Alternatively, work has attempted to describe the persistence into adulthood of DNA methylation at sites identified at birth. Added value of this studyWe investigated genome-wide differential DNA methylation patterns from whole blood using data linkage-derived, continuous birth weight data, in the largest reported adult sample (n=1, 395) with replication (n=362) and meta-analysis. Meta-analysis revealed one epigenome-wide significant CpG site, to our knowledge the first significant EWAS result reported for birth weight in a an adult sample. In addition, we found associations between birth weight and GrimAge and a DNA methylation-derived measure of telomere length, demonstrating accelerated biological ageing in lower birth weight individuals. Together, these results suggest differential methylation exists in adulthood related to birth weight, and this may be relevant to health and mortality. Implications of all the available evidenceAlthough CpG sites differentially methylated with birth weight at parturition may not remain so throughout life, the adult epigenome may still provide information on the impact of birth weight on health outcomes. The adult epigenome, therefore, may represent a useful archive of the foetal experience which results in birth weight variability, and this information may provide clinically useful information in mid-life.

genomics↗