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

Association between lifetime smoking and cutaneous squamous cell carcinoma:A 2-sample Mendelian randomization study

Background/Purpose: Cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies worldwide. While several environmental risk factors for cSCC are well established, there is conflicting evidence on cigarette smoking (and its potential causal effect) and cSCC risk. Furthermore, it is unclear if these potential associations represent causal, modifiable risk factors for cSCC development. This study aims to assess the nature of the associations between cigarette smoking traits (smoking initiation, amount smoked, and lifetime smoking exposure) and cSCC risk using two-sample Mendelian randomization analyses. Methods: Genetic instruments, based on common genetic variants associated with cigarette smoking traits (P &lt; 5 × 10−8), were derived from published genome-wide association studies (GWASs). For cSCC, we used GWAS summary statistics from the Kaiser Permanente GERA cohort (7701 cSCC cases and 60,167 controls; all non-Hispanic Whites). Results: We found modest evidence that genetically determined lifetime smoking was associated with cSCC (inverse-variance weighted method: OR[95% CI] = 1.47[1.09-1.98]; P =.012), suggesting it may be a causal risk factor for cSCC. We did not detect any evidence of association between genetically determined smoking initiation or amount smoked and cSCC risk. Conclusion: Study findings highlight the importance of smoking prevention and may support risk-stratified cSCC screening strategies based on carcinogen exposure and other genetic and clinical information.</p

Prevalence of actinic keratosis and skin cancer in a population of Dutch outdoor workers

Background: Outdoor work is associated with high and chronic exposure to solar ultraviolet radiation which might lead to an increased risk of developing skin (pre)malignancies. Prevalence of actinic keratosis (AK), basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC) and cutaneous melanoma (cM) in Dutch outdoor workers (OW) has not previously been investigated. Objective: This study compares the prevalence of premalignant lesions and skin tumours in OW and matched controls (non-OW). Methods: In a population-based cohort study, prevalence of premalignant lesions and skin tumours was investigated in a group of OW (n = 841) and controls matched 1:1 by age, sex, skin colour and tendency for sunburn. Skin examinations were conducted by physicians and skin cancer history was derived from the nationwide Dutch Pathology Registry. Information on OW was obtained through interviews. Conditional logistic regression models were used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for associations between OW and BCC, cSCC, cM and (number of) AK. Results: AK was found in 22.7% of OW and 22.9% of non-OW, BCC in 14% of OW and 15.7% of non-OW, cSCC in 4.9% of OW and 3.4% of non-OW, and cM in 1.9% of OW and 2% of non-OW. There was no significant association between OW and premalignant lesions and skin tumours, with exception for developing ≥4 AKs (OR 1.3 [95% CI 1.0–1.78]). Conclusions: This study reveals high prevalence of premalignant lesions and skin tumours in a Dutch population. No association between OW and the occurrence of premalignant lesions and skin tumours was found, however, multiple AKs were more prevalent in OW.</p

Prevalence of actinic keratosis and skin cancer in a population of Dutch outdoor workers

Background: Outdoor work is associated with high and chronic exposure to solar ultraviolet radiation which might lead to an increased risk of developing skin (pre)malignancies. Prevalence of actinic keratosis (AK), basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC) and cutaneous melanoma (cM) in Dutch outdoor workers (OW) has not previously been investigated. Objective: This study compares the prevalence of premalignant lesions and skin tumours in OW and matched controls (non-OW). Methods: In a population-based cohort study, prevalence of premalignant lesions and skin tumours was investigated in a group of OW (n = 841) and controls matched 1:1 by age, sex, skin colour and tendency for sunburn. Skin examinations were conducted by physicians and skin cancer history was derived from the nationwide Dutch Pathology Registry. Information on OW was obtained through interviews. Conditional logistic regression models were used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for associations between OW and BCC, cSCC, cM and (number of) AK. Results: AK was found in 22.7% of OW and 22.9% of non-OW, BCC in 14% of OW and 15.7% of non-OW, cSCC in 4.9% of OW and 3.4% of non-OW, and cM in 1.9% of OW and 2% of non-OW. There was no significant association between OW and premalignant lesions and skin tumours, with exception for developing ≥4 AKs (OR 1.3 [95% CI 1.0–1.78]). Conclusions: This study reveals high prevalence of premalignant lesions and skin tumours in a Dutch population. No association between OW and the occurrence of premalignant lesions and skin tumours was found, however, multiple AKs were more prevalent in OW.</p