Genetic variability in response to Aβ deposition influences Alzheimer's risk

Genetic analysis of late-onset Alzheimer's disease risk has previously identified a network of largely microglial genes that form a transcriptional network. In transgenic mouse models of amyloid deposition we have previously shown that the expression of many of the mouse orthologs of these genes are co-ordinately up-regulated by amyloid deposition. Here we investigate whether systematic analysis of other members of this mouse amyloid-responsive network predicts other Alzheimer's risk loci. This statistical comparison of the mouse amyloid-response network with Alzheimer's disease genome-wide association studies identifies 5 other genetic risk loci for the disease (OAS1, CXCL10, LAPTM5, ITGAM and LILRB4). This work suggests that genetic variability in the microglial response to amyloid deposition is a major determinant for Alzheimer's risk

Identification of Candidate Parkinson Disease Genes by Integrating Genome-Wide Association Study, Expression, and Epigenetic Data Sets

Importance Substantial genome-wide association study (GWAS) work in Parkinson disease (PD) has led to the discovery of an increasing number of loci shown reliably to be associated with increased risk of disease. Improved understanding of the underlying genes and mechanisms at these loci will be key to understanding the pathogenesis of PD. / Objective To investigate what genes and genomic processes underlie the risk of sporadic PD. / Design and Setting This genetic association study used the bioinformatic tools Coloc and transcriptome-wide association study (TWAS) to integrate PD case-control GWAS data published in 2017 with expression data (from Braineac, the Genotype-Tissue Expression [GTEx], and CommonMind) and methylation data (derived from UK Parkinson brain samples) to uncover putative gene expression and splicing mechanisms associated with PD GWAS signals. Candidate genes were further characterized using cell-type specificity, weighted gene coexpression networks, and weighted protein-protein interaction networks. / Main Outcomes and Measures It was hypothesized a priori that some genes underlying PD loci would alter PD risk through changes to expression, splicing, or methylation. Candidate genes are presented whose change in expression, splicing, or methylation are associated with risk of PD as well as the functional pathways and cell types in which these genes have an important role. / Results Gene-level analysis of expression revealed 5 genes (WDR6 [OMIM 606031], CD38 [OMIM 107270], GPNMB [OMIM 604368], RAB29 [OMIM 603949], and TMEM163 [OMIM 618978]) that replicated using both Coloc and TWAS analyses in both the GTEx and Braineac expression data sets. A further 6 genes (ZRANB3 [OMIM 615655], PCGF3 [OMIM 617543], NEK1 [OMIM 604588], NUPL2 [NCBI 11097], GALC [OMIM 606890], and CTSB [OMIM 116810]) showed evidence of disease-associated splicing effects. Cell-type specificity analysis revealed that gene expression was overall more prevalent in glial cell types compared with neurons. The weighted gene coexpression performed on the GTEx data set showed that NUPL2 is a key gene in 3 modules implicated in catabolic processes associated with protein ubiquitination and in the ubiquitin-dependent protein catabolic process in the nucleus accumbens, caudate, and putamen. TMEM163 and ZRANB3 were both important in modules in the frontal cortex and caudate, respectively, indicating regulation of signaling and cell communication. Protein interactor analysis and simulations using random networks demonstrated that the candidate genes interact significantly more with known mendelian PD and parkinsonism proteins than would be expected by chance. / Conclusions and Relevance Together, these results suggest that several candidate genes and pathways are associated with the findings observed in PD GWAS studies

Tratamento farmacológico da distimia: avaliação crítica da evidência científica Pharmacological treatment of dysthymia: a critical appraisal of the evidence

Distimia é um transtorno depressivo de natureza crônica, mas de menor gravidade que a depressão maior, cujos sintomas persistem por mais ou menos dois anos. Este artigo aborda aspectos relativos à eficácia do tratamento farmacológico na distimia, a partir de resultados de revisões sistemáticas recentemente concluídas. Em termos de eficácia, os resultados foram similares para as diferentes classes de drogas, tais como tricíclicos (ADT), inibidores seletivos da recaptação da serotonina (ISRS), inibidores da mono-amino-oxidase (IMAO) e outras drogas (sulpirida, amineptina, e ritanserina). Os pacientes tomando tricíclicos relataram um maior número de efeitos adversos, comparado com placebo. Em resumo, o tratamento farmacológico da distimia é eficaz, sem efeito diferencial entre os diversos antidepressivos. O uso de tricíclicos está associado à maior ocorrência de efeitos adversos e de desistências. Apesar de a distimia ser uma doença crônica, existe ainda informação limitada sobre a qualidade de vida dos pacientes e sobre o tratamento a médio e longo prazo.<br>Dysthymia is a depressive disorder of chronic nature but of less severity than major depression, in which depressive symptoms are more or less continuous for at least two years. This paper discusses the role of pharmacological treatment for dysthymia. Similar results are found in terms of efficacy for different groups of drugs, such as tricyclic (TCA), selective serotonin reuptake inhibitors (SSRI), monoamine oxidase inhibitors (MAOI) and other drugs (sulpiride, amineptine, and ritanserin). Patients treated on TCA are more likely to report adverse events, comparing with placebo. In conclusion, pharmacological treatment seems to be effective in the treatment of dysthymia with no differences between and within class of drugs. Although dysthymia is a chronic condition, there remains little information on quality of life and medium or long-term outcome

Acute exercise and hormones related to appetite regulation: a meta-analysis

Background Understanding of the impact of an acute bout of exercise on hormones involved in appetite regulation may provide insight into some of the mechanisms that regulate energy balance. In resting conditions, acylated ghrelin is known to stimulate food intake, while hormones such as peptide YY (PYY), pancreatic polypeptide (PP) and glucagon-like peptide 1 (GLP-1) are known to suppress food intake