Phenome-wide analyses identify an association between the parent-of-origin effects dependent methylome and the rate of aging in humans.

BACKGROUND: The variation in the rate at which humans age may be rooted in early events acting through the 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 enriched for genetically controlled imprinting effects (the typical type of POE) and regions influenced by environmental effects associated with parents (the atypical POE). This part of the methylome is heavily influenced by early events, making it a potential route connecting early exposures, the epigenome, and aging. We aim to test the association of POE-CpGs with early and later exposures and subsequently with health-related phenotypes and adult aging. RESULTS: We perform a phenome-wide association analysis for the POE-influenced methylome using GS:SFHS (Ndiscovery = 5087, Nreplication = 4450). We identify and replicate 92 POE-CpG-phenotype associations. Most of the associations are contributed by the POE-CpGs belonging to the atypical class where the most strongly enriched associations are with aging (DNAmTL acceleration), intelligence, and parental (maternal) smoking exposure phenotypes. A proportion of the atypical POE-CpGs form co-methylation networks (modules) which are associated with these phenotypes, with one of the aging-associated modules displaying increased within-module methylation connectivity with age. The atypical POE-CpGs also display high levels of methylation heterogeneity, fast information loss with age, and a strong correlation with CpGs contained within epigenetic clocks. CONCLUSIONS: These results identify the association between the atypical POE-influenced methylome and aging and provide new evidence for the "early development of origin" hypothesis for aging in humans.

Structural brain correlates of childhood trauma with replication across two large, independent community-based samples.

INTRODUCTION: Childhood trauma and adversity are common across societies and have strong associations with physical and psychiatric morbidity throughout the life-course. One possible mechanism through which childhood trauma may predispose individuals to poor psychiatric outcomes is via associations with brain structure. This study aimed to elucidate the associations between childhood trauma and brain structure across two large, independent community cohorts. METHODS: The two samples comprised (i) a subsample of Generation Scotland (n=1,024); and (ii) individuals from UK Biobank (n=27,202). This comprised n=28,226 for mega-analysis. MRI scans were processed using Free Surfer, providing cortical, subcortical, and global brain metrics. Regression models were used to determine associations between childhood trauma measures and brain metrics and psychiatric phenotypes. RESULTS: Childhood trauma associated with lifetime depression across cohorts (OR 1.06 GS, 1.23 UKB), and related to early onset and recurrent course within both samples. There was evidence for associations between childhood trauma and structural brain metrics. This included reduced global brain volume, and reduced cortical surface area with highest effects in the frontal (ß=-0.0385, SE=0.0048, p(FDR)=5.43x10-15) and parietal lobes (ß=-0.0387, SE=0.005, p(FDR)=1.56x10-14). At a regional level the ventral diencephalon (VDc) displayed significant associations with childhood trauma measures across both cohorts and at mega-analysis (ß=-0.0232, SE=0.0039, p(FDR)=2.91x10-8). There were also associations with reduced hippocampus, thalamus, and nucleus accumbens volumes. DISCUSSION: Associations between childhood trauma and reduced global and regional brain volumes were found, across two independent UK cohorts, and at mega-analysis. This provides robust evidence for a lasting effect of childhood adversity on brain structure.

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.

Developing Bottom-Up Induced Pluripotent Stem Cell Derived Solid Tumor Models Using Precision Genome Editing Technologies.

Advances in genome and tissue engineering have spurred significant progress and opportunity for innovation in cancer modeling. Human induced pluripotent stem cells (iPSCs) are an established and powerful tool to study cellular processes in the context of disease-specific genetic backgrounds; however, their application to cancer has been limited by the resistance of many transformed cells to undergo successful reprogramming. Here, we review the status of human iPSC modeling of solid tumors in the context of genetic engineering, including how base and prime editing can be incorporated into "bottom-up" cancer modeling, a term we coined for iPSC-based cancer models using genetic engineering to induce transformation. This approach circumvents the need to reprogram cancer cells while allowing for dissection of the genetic mechanisms underlying transformation, progression, and metastasis with a high degree of precision and control. We also discuss the strengths and limitations of respective engineering approaches and outline experimental considerations for establishing future models.

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

BACKGROUND: parent-of-origin effects (POE) play important roles in complex disease and thus understanding their regulation and associated molecular and phenotypic variation are warranted. Previous studies 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 modifiable POE exist. METHODS: in 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 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). FINDINGS: a 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. We further identified plasma protein and health-related phenotypes associated with the methylation level of one of the identified CpGs. INTERPRETATION: the 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. FUNDING: NSFC (81971270),H2020-MSCA-ITN(721815), Wellcome (204979/Z/16/Z,104036/Z/14/Z), MRC (MC_UU_00007/10, MC_PC_U127592696), CSO (CZD/16/6,CZB/4/276, CZB/4/710), SFC (HR03006), EUROSPAN (LSHG-CT-2006-018947), BBSRC (BBS/E/D/30002276), SYSU, Arthritis Research UK, NHLBI, NIH.

Birth weight associations with DNA methylation differences in an adult population.

The Developmental Origins of Health and Disease (DOHaD) 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. Through data linkage between Generation Scotland and historic Scottish birth cohorts, and birth records held through the NHS Information and Statistics Division, a sample of 1,757 individuals with available birth weight and DNAm data was derived. Epigenome-wide association studies (EWAS) were performed in two independently generated DNAm subgroups (nSet1 = 1,395, nSet2 = 362), relating adult DNAm from whole blood to birth weight. Meta-analysis yielded one genome-wide significant CpG site (p = 5.97x10-9), cg00966482. There was minimal evidence for attenuation of the effect sizes for the lead loci upon adjustment for numerous potential confounder variables (body mass index, educational attainment, and socioeconomic status). Associations between birth weight and epigenetic measures of biological age were also assessed. Associations between lower birth weight and higher Grim Age acceleration (p(FDR) = 3.6x10-3) and shorter DNAm-derived telomere length (p(FDR) = 1.7x10-3) are described, although results for three other epigenetic clocks were null. Our results provide support for an association between birth weight and DNAm both locally at one CpG site, and globally via biological ageing estimates.