New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Phase I study of STX 64 (667 Coumate) in Breast Cancer Patients: the First Study of a Steroid Sulphatase Inhibitor

Inhibition of steroid sulfatase (STS), the enzyme responsible for the hydrolysis of steroid sulfates, represents a potential novel treatment for postmenopausal women with hormone-dependent breast cancer. Estrone and DHEA are formed by this sulfatase pathway and can be converted to steroids (estradiol and androstenediol, respectively), which have potent estrogenic properties

Differing impact of the COVID-19 pandemic on youth’s mental health:: combined population and clinical study

Background: Identifying youths most at risk to COVID19-related mental illness will be essential to develop effective targeted interventions.Aims: To compare trajectories of mental health throughout the pandemic, in youths with and without prior mental illness, and identify youths most at risk to COVID-19-related mental illness.Methods: Data was collected from youths aged 18-26 years (N=669) from two existing cohorts: IMAGEN, a population-based cohort, and ESTRA/STRATIFY, clinical cohorts with pre-existing diagnoses of mental disorders. Repeated COVID-19 surveys and standardized mental health assessments were used to compare trajectories of mental health symptoms from prior to the pandemic through to the second lockdown.Results: Mental health trajectories differed significantly between cohorts. In the population cohort, depression and ED symptoms increased by 33.9% [95% CI, 31.78-36.57] and 15.6%, [95% CI, 15.39-15.68] during the pandemic, respectively. In contrast, these remained high over time in the clinical cohort. Conversely, trajectories of alcohol abuse were similar in both cohorts, decreasing continuously (15.2% decrease) during the pandemic. Pre-pandemic symptoms severity predicted the observed mental health trajectories in the population cohort. Surprisingly, being relatively healthy predicted the increases in depression and ED symptoms, and BMI. In contrast, youths initially at higher risks for depression or ED reported a lasting decrease.Conclusions: Healthier youths may be at greater risk of developing depressive or ED symptoms during the COVID-19 pandemic. Targeted mental health interventions considering prior diagnostic risk may be warranted to help youths cope with the challenges of psychosocial stress and reduce the associated health care burden.<br/

Cryptic diversity, molecular phylogeny and biogeography of the rock- and leaf litter-dwelling land snails of Belau (Republic of Palau, Oceania)

The endemic diplommatinid land snails (Caenogastropoda: Mollusca) of Belau (Republic of Palau, Micronesia) are an exceptionally diverse group of largely undescribed species distributed among rock and leaf litter habitats on most of Belau's 586 islands. Diplommatinid shell morphology (e.g. shell sculpture) reflects habitat type. In this study, I analysed a subset of the 90 diplommatinid species representing a broad geographical spread of islands in order to reveal the species' phylogenetic relationships and biogeography within the Belau archipelago. Diplommatinid species from the islands of Yap, Pohnpei, Kosrae and Guam are also included in the analysis. One nuclear (28S rRNA) and two mitochondrial (16S rRNA, COI) gene regions comprising 1906 bp were used for phylogenetic reconstruction. Results show that (i) the Belau Diplommatinidae are not monophyletic, as Guam and Yap species should be included as part of the radiation, (ii) Pohnpei and Kosrae species are highly divergent from Belau diplommatinids, (iii) there is little evidence for in situ radiation within individual Belau islands, (iv) spined and heavily calcified rock-dwelling species form a well-supported clade, and (v) Belau diplommatinid genera are in need of revision

Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol

Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98th or <2nd percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previous