No abstract

Stress is defined as a state of threatened or perceived as threatened homeostasis. The well-tuned coordination of the stress response system is necessary for an organism to respond to external or internal stressors and re-establish homeostasis. Glucocorticoid hormones are the main effectors of stress response and aberrant glucocorticoid signaling has been associated with an increased risk for psychiatric and mood disorders, including schizophrenia, post-traumatic stress disorder and depression. Emerging evidence suggests that life-stress experiences can alter the epigenetic landscape and impact the function of genes involved in the regulation of stress response. More importantly, epigenetic changes induced by stressors persist over time, leading to increased susceptibility for a number of stress-related disorders. In this review, we discuss the role of glucocorticoids in the regulation of stress response, the mechanism through which stressful experiences can become biologically embedded through epigenetic alterations, and we underline potential associations between epigenetic changes and the development of stress-related disorders.

Objective: To estimate the prevalence of frailty using five different instruments in a cohort of older adults and explore the association between frailty and various risk factors. Method: 1,867 participants aged 65 years and above were included in the current retrospective cross-sectional study. Frailty was operationalized according to the Fried definition, the FRAIL Scale, the Frailty Index (FI), the Tilburg Frailty Indicator (TFI), and the Groningen Frailty Index (GFI). We explored the role of various frailty risk factors using logistic regression analyses. Results: The prevalence of frailty varied depending on the definition used (Fried definition = 4.1%, FRAIL Scale = 1.5%, FI = 19.7%, TFI = 24.5%, and GFI = 30.2%). The only risk factors consistently associated with frailty irrespectively of definition were education and age. Conclusion: The frailty prevalence reported in our study is similar or lower to that reported in other population studies. Qualitative differences between frailty definitions were observed.

The influence of genetic background on driver mutations is well established; however, the mechanisms by which the background interacts with Mendelian loci remains unclear. We performed a systematic secondary-variant burden analysis of two independent Bardet-Biedl syndrome (BBS) cohorts with known recessive biallelic pathogenic mutations in one of 17 BBS genes for each individual. We observed a significant enrichment of trans-acting rare nonsynonymous secondary variants compared to either population controls or to a cohort of individuals with a non-BBS diagnosis and recessive variants in the same gene set. Strikingly, we found a significant over-representation of secondary alleles in chaperonin-encoding genes, a finding corroborated by the observation of epistatic interactions involving this complex in vivo.These data indicate a complex genetic architecture for BBS that informs the biological properties of disease modules and presents a model paradigm for secondary-variant burden analysis in recessive disorders.A persistent hurdle in interrogating the role of genetic background in human genetic disorders is our limited understanding of the properties and distribution of contributory alleles. The challenge is particularly acute in rare disorders, in which the allele frequency of both causal variants and secondary contributory alleles (i.e. alleles in loci other than the primary locus) is often low; as such population-based studies are hampered by the lack of statistical power. At the same time, transitioning from a single-gene-centric to a systems-based disease architecture defined by biological modules can inform causality, penetrance and expressivity 1 . Bardet-Biedl syndrome, a model ciliopathy, represents an opportunity to study secondary-variant burden. We and others have shown previously that BBS patients can carry secondary pathogenic variants in known BBS genes 2 . In rare examples, such alleles can modify penetrance 3 , whereas, more commonly, they are thought to modulate expressivity 4,5 . However, initial population-based studies have failed to detect an enrichment for secondary alleles in trans (i.e. alleles in loci other than the primary locus), suggesting that either some of the examples were exceptions, or that the incidence, distribution, and frequency of such alleles might be different than assumed a priori 6 . Here, we studied two BBS cohorts with unambiguous recessive pathogenic mutations in 17 established BBS genes to measure a) whether there is enrichment for secondary variants beyond the driver locus; and b) if so, whether the excess variation is concentrated within discrete disease modules or whether it is randomly distributed.