Amplification of the epigenetic (gestational) age acceleration signal

ABSTRACTBackgroundEpigenetic (gestational) age acceleration (E(G)AA) is associated with environmental exposures and health outcomes in humans. However, E(G)AA is the residual term from a regression of epigenetic age (outcome) on chronological (gestational) age (predictor) and therefore strongly obscured by ‘noise’ from multiple sources. Here, we propose a simple procedure, based on regression, principal component analysis (PCA), and the Lasso, that amplifies E(G)AA signals. More specifically, we first regress given (gestational) age against each CpG used for epigenetic (gestational) age prediction. The CpGs are typically taken from one of several epigenetic clocks available. PCA is subsequently performed on the resulting matrix of residual vectors for each CpG as it projects the E(G)AA signal onto perpendicular principal components (PCs), thereby separating ‘signal’ from noise. Finally, we use the Lasso to select PCs associated with an outcome of interest. We apply our method to previous studies: EAA in patients with Down’s syndrome and Werner’s syndrome and EGAA of newborns exposed to prenatal smoking as well as associations with maternal BMI.ResultsThe extracted EAA components computed using our proposed procedure revealed a significant association with Down’s syndrome (PB<0.05, Bonferroni adjusted for multiple testing) as well as for Werner’s Syndrome (PB<0.05). For EGAA we find a significant association with maternal prenatal smoking (PB<0.05, also Bonferroni adjusted) and maternal BMI (PB<0.05). Additionally, by examining the loadings of the PCs of interest, and contrary to residual EGAA, our method can identify implicated CpGs.ConclusionsOur findings suggest that our proposed procedure leads to a remarkable amplification of the E(G)AA signal. Furthermore, our method reveals that E(G)AA is a composite signal that can be driven by multiple independent factors.

Werner’s Syndrome: Understanding the Phenotype of Premature Aging—First Case Described in Colombia

Werner’s syndrome (WS) is an autosomal recessive genetic disease, which is mainly characterized by scleroderma-like skin changes, juvenile cataracts, short stature, and signs of premature aging. We report a case of a 48-year-old male patient, who presents with cardinal signs of WS including high-pitched voice, sclerotic skin lesions mainly on feet, premature greying of scalp hair, bilateral cataracts, and “bird-like” facial appearance. In addition, the patient presents other clinical characteristics observed in patients with WS such as short stature, type 2 diabetes mellitus, hypogonadism, parental consanguinity, and a history of a sibling with similar clinical characteristics. WRN gene sequencing identified the homozygous pathogenic variant NM_00553.4: c.2581C>T (NP_000544.2: pGln861Ter). This is the first case of WS reported in the Colombian population. We report this case to avoid misdiagnosis of this infrequent condition and allow timely identification of potential complications associated with premature aging, especially malignancies, cardiovascular and metabolic diseases.