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

Desenvolvimento de porta-enxertos de umbuzeiro em resposta à adubação com nitrogênio e fósforo ‘Umbuzeiro’ rootstocks development as a answer for fertilization with nitrogen and phosphorous

A adubação, notadamente com nitrogênio e fósforo, é fundamental no estádio de desenvolvimento inicial de mudas de frutíferas. Porém, existem poucas informações científicas com respeito do umbuzeiro. Assim, objetivou-se avaliar o efeito de doses de nitrogênio e fósforo no desenvolvimento de porta-enxertos de umbuzeiro (Spondias tuberosa Arr. Câm.). O experimento foi conduzido sob telado, na Universidade Federal de Sergipe, em um delineamento em blocos ao acaso, em esquema fatorial 4 x 4, sendo quatro níveis de nitrogênio e quatro de fósforo (0, 50, 100 e 150kg ha-1 de N e P2O5, respectivamente na forma de uréia e superfosfato simples, em quatro repetições. O maior ganho em altura (12,52cm) foi obtido com as doses de 97,58kg ha-1 de N, enquanto o maior incremento no diâmetro do colo (2,18mm) foi obtido com as doses de 150kg ha-1 de N e 150kg ha-1 de P2O5. O maior número de folhas foi observado na presença de 126,03kg ha-1 de N e 150kg ha-1 de P2O5. A maior produção de massa seca da parte aérea total foi constatada na dose de 98,71kg ha-1 de N e 150kg ha-1 de P2O5. A área foliar cresceu linearmente para ambos fatores As adubações estudadas contribuem de forma positiva para a formação de mudas de umbuzeiro, podendo antecipar a formação de porta-enxertos para algumas fruteiras do gênero Spondias. Doses de fósforo a partir de 150kg ha-1 não são recomendadas quando se pretende produzir picles, a partir do xilopódio do umbuzeiro.<br>The fertilization, notable with nitrogen and phosphorous, is fundamental on initial development stadium on fruits nursery trees. However, there is little scientific information about ‘umbuzeiro’. This work had as objective to evaluate the effect of nitrogen and phosphorous’ doses on ‘umbuzeiro’ rootstocks (Spondias tuberosa Arr. Câm.). The experiment was carried out under nursery at ‘Universidade Federal de Sergipe’ being used experimental design of randomized blocks in factorial 4X4 with four levels of nitrogen and four levels of phosphorous (0, 50, 100 and 150kg ha-1 of N and P2O5) respectively under urea form and simple superphosphate, with four replications. The higher rootstock (12.52cm) was obtained with doses of 97.58kg ha-1 of N, the higher stem diameter (2.18mm) was obtained with doses of 150kg ha-1 of N and 150kg ha-1 of P2O5. The major number of leaves was observed on presence of 126.03kg ha-1 of N and 150kg ha-1 of P2O5. The major dry matter production of total aerial plant was verified with a dose of 98.71kg ha-1 of N and 150kg ha-1 of P2O5. The leaf area presented a linear grown for both factors. The nitrogen and phosphorous fertilization contribute as positive performance on ‘umbuzeiro’ doing the rootstocks development anticipated for some fruit trees of the Spondias genus. Phosphorous’ doses from 150kg ha-1 were not recommended for pickles production using ‘umbuzeiro’ xylopodium

A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson's disease

Item does not contain fulltextParkinson's disease (PD) is the second most common neurodegenerative disease affecting 1-2% in people >60 and 3-4% in people >80. Genome-wide association (GWA) studies have now implicated significant evidence for association in at least 18 genomic regions. We have studied a large PD-meta analysis and identified a significant excess of SNPs (P < 1 x 10(-16)) that are associated with PD but fall short of the genome-wide significance threshold. This result was independent of variants at the 18 previously implicated regions and implies the presence of additional polygenic risk alleles. To understand how these loci increase risk of PD, we applied a pathway-based analysis, testing for biological functions that were significantly enriched for genes containing variants associated with PD. Analysing two independent GWA studies, we identified that both had a significant excess in the number of functional categories enriched for PD-associated genes (minimum P = 0.014 and P = 0.006, respectively). Moreover, 58 categories were significantly enriched for associated genes in both GWA studies (P < 0.001), implicating genes involved in the 'regulation of leucocyte/lymphocyte activity' and also 'cytokine-mediated signalling' as conferring an increased susceptibility to PD. These results were unaltered by the exclusion of all 178 genes that were present at the 18 genomic regions previously reported to be strongly associated with PD (including the HLA locus). Our findings, therefore, provide independent support to the strong association signal at the HLA locus and imply that the immune-related genetic susceptibility to PD is likely to be more widespread in the genome than previously appreciated

Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause inherited Parkinson disease (PD), and common variants around LRRK2 are a risk factor for sporadic PD. Using protein–protein interaction arrays, we identified BCL2-associated athanogene 5, Rab7L1 (RAB7, member RAS oncogene family-like 1), and Cyclin-G–associated kinase as binding partners of LRRK2. The latter two genes are candidate genes for risk for sporadic PD identified by genome-wide association studies. These proteins form a complex that promotes clearance of Golgi-derived vesicles through the autophagy–lysosome system both in vitro and in vivo. We propose that three different genes for PD have a common biological function. More generally, data integration from multiple unbiased screens can provide insight into human disease mechanisms

Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson&apos;s disease

We conducted a meta-analysis of Parkinson&apos;s disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson&apos;s disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55-4.30; P = 2 × 10-16). We also show six risk loci associated with proximal gene expression or DNA methylation. © 2014 Nature America, Inc. All rights reserved