Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing.

BACKGROUND: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. RESULTS: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. CONCLUSIONS: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape : A Large-Scale Genome-Wide Interaction Study

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age-and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to similar to 2.8M SNPs with BMI and WHRadjBMI in four strata (men 50y, women 50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR= 50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.Peer reviewe

Favourable outcomes of a preventive screening and counselling programme for older people in underprivileged areas in the Netherlands: The PRIMUS project.

An aging population is associated with an increased prevalence of diabetes, cardiovascular diseases and depression. Important aspects of programmes targeted at older people are: to reach those at risk, effective screening, optimising advice, and referral to local interventions. We examined the effect of a preventive health consultation (PRIMUS), a multi-behavioural screening programme for persons aged 55–74 years in primary care. In a multi-centre randomised controlled trial, the effects of participating in the PRIMUS intervention were compared to a comparison group receiving personalised summaries and advice by postal mail, both preceded by a health risk assessment via a questionnaire. The intervention consisted of a baseline health risk assessment, followed by a preventive health consultation (after 4 weeks), and a follow-up visit (2 weeks later) in the primary care centre. A newly developed web-based computer-tailored programme supported the nurse practitioner during the consultation. Main outcomes measures were awareness of, and compliance with referral advice for changing unhealthy lifestyles. The PRIMUS preventive health consultation was successful in older people at risk for cardio metabolic diseases compared to the comparison group (compliance: RR 1.43; 95% CI 1.12–1.79; p < 0.05). The intervention was less successful in older people at risk for mental health problems. This preventive health consultation for older people resulted in positive changes in unhealthy behaviours by optimising reach, raising awareness, motivating and assisting individuals to change, and referring to local interventions

Free space intra-datacenter interconnection utilizing 2D optical beam steering

We evaluate the performance and benefits of novel integrated Free-Space-Optics (FSO) transceivers, supporting optical beam steering at low power consumption with ns steering speed. A proper intra-datacenter network architecture is also presented.Peer Reviewe

Free space intra-datacenter interconnection utilizing 2D optical beam steering

We evaluate the performance and benefits of novel integrated Free-Space-Optics (FSO) transceivers, supporting optical beam steering at low power consumption with ns steering speed. A proper intra-datacenter network architecture is also presented.Peer ReviewedPostprint (published version