Genetic study of cognitive function

Dissecting the genetics of Alzheimer’s disease (AD) and Parkinson’s disease (PD) has contributed significantly to our understanding of the pathogenesis of neurodegeneration in these two complex disorders. For AD, three highly penetrant genes (APP, PSEN1 and PSEN2) and one susceptibility gene (APOE) have been identified. For PD, seven genes (SNCA, Parkin, UCHL1, NR4A2, DJ1, PINK1 and LRRK2) have been found. These genes explain only a small proportion of AD and PD patients and are mostly associated with an early onset presentation of the disease. APOE remains the only common gene, which increases the risk of both rare early and late onset AD. The ongoing challenge is to unravel the genetics of the most frequent forms of these complex disorders. In the present paper, we briefl y review the state of the art in the genetics of AD and PD. We also discuss the prospects of finding new genes associated with common forms of these diseases in light of two hypotheses concerning the genetic variation of complex diseases: common disease/ common variants and common disease/rare variants

Predicting keratinocyte carcinoma in patients with actinic keratosis: development and internal validation of a multivariable risk-prediction model

Background: Patients with actinic keratosis (AK) are at increased risk for developing keratinocyte carcinoma (KC) but predictive factors and their risk rates are unknown. Objectives: To develop and internally validate a prediction model to calculate the absolute risk of a first KC in patients with AK. Methods: The risk-prediction model was based on the prospective population-based Rotterdam Study cohort. We hereto analysed the data of participants with at least one AK lesion at cohort baseline using a multivariable Cox proportional hazards model and included 13 a priori defined candidate predictor variables considering phenotypic, genetic and lifestyle risk factors. KCs were identified by linkage of the data with the Dutch Pathology Registry. Results: Of the 1169 AK participants at baseline, 176 (15·1%) developed a KC after a median follow-up of 1·8 years. The final model with significant predictors was obtained after backward stepwise selection and comprised the presence of four to nine AKs [hazard ratio (HR) 1·68, 95% confidence interval (CI) 1·17–2·42], 10 or more AKs (HR 2·44, 95% CI 1·65–3·61), AK localization on the upper extremities (HR 0·75, 95% CI 0·52–1·08) or elsewhere except the head (HR 1·40, 95% CI 0·98–2·01) and coffee consumption (HR 0·92, 95% CI 0·84–1·01). Evaluat

The Skin and Nose Microbiome and Its Association with Filaggrin Gene Mutations in Pediatric Atopic Dermatitis

BACKGROUND: Interactions between the skin barrier, immune system, and microbiome underlie the development of atopic dermatitis (AD). OBJECTIVE: To investigate the skin and nasal microbiome in relation to filaggrin gene (FLG) mutations. METHODS: A cross-sectional study including 77 children with difficult-to-treat AD. The entire encoding region of FLG was screened for mutations using single molecule molecular inversion probes and next-generation sequencing. Bacterial swabs from the anterior nares, lesional and nonlesional skin were analyzed using 16S rRNA sequencing. For skin samples, additional qPCR was performed for Staphylococcus aureus and Staphylococcus epidermidis. RESULTS: The prevalence of patients with a mutation in FLG was 40%, including 10 different mutations. Analyzing bacterial swabs from all three niches showed a significant effect for both niche and FLG mutation status on the overall microbiome composition. Using a subset analysis to test the effect of FLG mutation status per niche separately did not show a significant association to the microbiome. Shannon diversity and S. aureus abundance were significantly affected by the niche, but not by the presence of an FLG mutation. CONCLUSIONS: Our results suggest only a minor role for FLG mutation status on the overall microbiome, which is rather caused by differences in the present genera than by microbe richness and evenness