Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition

Controls of Initial Wood Decomposition on and in Forest Soils Using Standard Material

Forest ecosystems sequester approximately half of the world’s organic carbon (C), most of it in the soil. The amount of soil C stored depends on the input and decomposition rate of soil organic matter (OM), which is controlled by the abundance and composition of the microbial and invertebrate communities, soil physico-chemical properties, and (micro)-climatic conditions. Although many studies have assessed how these site-specific climatic and soil properties affect the decomposition of fresh OM, differences in the type and quality of the OM substrate used, make it difficult to compare and extrapolate results across larger scales. Here, we used standard wood stakes made from aspen (Populus tremuloides Michx.) and loblolly pine (Pinus taeda L.) to explore how climate and abiotic soil properties affect wood decomposition across 44 unharvested forest stands located across the northern hemisphere. Stakes were placed in three locations: (i) on top of the surface organic horizons (surface), (ii) at the interface between the surface organic horizons and mineral soil (interface), and (iii) into the mineral soil (mineral). Decomposition rates of both wood species was greatest for mineral stakes and lowest for stakes placed on the surface organic horizons, but aspen stakes decomposed faster than pine stakes. Our models explained 44 and 36% of the total variation in decomposition for aspen surface and interface stakes, but only 0.1% (surface), 12% (interface), 7% (mineral) for pine, and 7% for mineral aspen stakes. Generally, air temperature was positively, precipitation negatively related to wood stake decomposition. Climatic variables were stronger predictors of decomposition than soil properties (surface C:nitrogen ratio, mineral C concentration, and pH), regardless of stake location or wood species. However, climate-only models failed in explaining wood decomposition, pointing toward the importance of including local-site properties when predicting wood decomposition. The difficulties we had in explaining the variability in wood decomposition, especially for pine and mineral soil stakes, highlight the need to continue assessing drivers of decomposition across large global scales to better understand and estimate surface and belowground C cycling, and understand the drivers and mechanisms that affect C pools, CO2 emissions, and nutrient cycles

The Great Lakes: Nutrients, sediments, persistent pollutants, and policy perspectives for a sustainable future

The Chapter 4.17 has described the geological evolution of the Great Lakes and their hydrology and introduced selected features of lake physics, chemistry, and biology. In this chapter, two of the most important pollutant classes in the Great Lakes, nutrients and persistent bioaccumulative toxins, and biogeochemically mediated interactions between water, atmosphere, and lake sediments are examined. Next, the role of satellite remote sensing in enhancing our understanding these features of lake behavior is reviewed. Finally, policy and the regulatory environment, the bases for management of sustainable futures is looked at. As with the previous chapter, two key points are emphasized: (1) we should look to nature before the fact for help in differentiating sustainable and unsustainable practices and (2) it is critical that we increase our awareness of those things that ‘we don\u27t know we don\u27t know’ about the response of the Great Lakes to human perturbation. Adoption of an outlook that embraces an ethic, sensitivity, and understanding represents an excellent start to ensuring a sustainable future for these Great Lakes

Mutation analysis of patients with neurodegenerative disorders using NeuroX array

Genetic analyses of patients with neurodegenerative disorders have identified multiple genes that need to be investigated for the presence of damaging variants. However, mutation analysis by Sanger sequencing is costly and time consuming. We tested the utility of a recently designed semi-custom genome-wide array (NeuroX; Illumina, Inc) tailored to study neurodegenerative diseases (e.g., mutation screening). We investigated 192 patients with 4 different neurodegenerative disorders for the presence of rare damaging variations in 77 genes implicated in these diseases. Several causative mutations were identified and confirmed by Sanger sequencing, including PSEN1 p.M233T responsible for Alzheimer's disease in a large Italian family, as well as SOD1 p.A4V and p.I113T in patients with amyotrophic lateral sclerosis. In total, we identified 78 potentially damaging rare variants (frequency <1%), including ABCA7 p.L400V in a family with Alzheimer's disease and LRRK2 p.R1514Q in 6 of 98 patients with Parkinson's disease (6.1%). In conclusion, NeuroX appears to be helpful for rapid and accurate mutation screening, although further development may be still required to improve some current caveats.Fil: Ghani, Mahdi. University of Toronto; CanadáFil: Lang, Anthony E.. University of Toronto; Canadá. Toronto Western Hospital; CanadáFil: Zinman, Lorne. University of Toronto; Canadá. Sunnybrook Health Sciences Centre; CanadáFil: Nacmias, Benedetta. Università degli Studi di Firenze; ItaliaFil: Sorbi, Sandro. Università degli Studi di Firenze; ItaliaFil: Bessi, Valentina. Università degli Studi di Firenze; ItaliaFil: Tedde, Andrea. Università degli Studi di Firenze; ItaliaFil: Tartaglia, Maria Carmela. University of Toronto; CanadáFil: Surace, Ezequiel Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha Contra las Enfermedades Neurológicas de la Infancia. Instituto de Investigaciones Neurológicas "Raúl Carrea"; ArgentinaFil: Sato, Christine. University of Toronto; CanadáFil: Moreno, Danielle. University of Toronto; CanadáFil: Xi, Zhengrui. University of Toronto; CanadáFil: Hung, Rachel. University of Toronto; CanadáFil: Nalls, Mike A.. National Institute on Aging; Estados UnidosFil: Singleton, Andrew. National Institute on Aging; Estados UnidosFil: George Hyslop, Peter St.. University of Toronto; Canadá. University of Cambridge; Reino UnidoFil: Savchenko, Ekaterina. University of Toronto; Canad

Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease

A locus segregating with familial Alzheimer's disease (AD) has been mapped to chromosome 21, close to the amyloid precursor protein (APP) gene. Recombinants between the APP gene and the AD locus have been reported which seemed to exclude it as the site of the mutation causing familial AD. But recent genetic analysis of a large number of AD families has demonstrated that the disease is heterogeneous. Families with late-onset AD do not show linkage to chromosome 21 markers. Some families with early-onset AD show linkage to chromosome 21 markers, but some do not. This has led to the suggestion that there is non-allelic genetic heterogeneity even within early onset familial AD. To avoid the problems that heterogeneity poses for genetic analysis, we have examined the cosegregation of AD and markers along the long arm of chromosome 21 in a single family with AD confirmed by autopsy. Here we demonstrate that in this kindred, which shows linkage to chromosome 21 markers, there is a point mutation in the APP gene. This mutation causes an amino-acid substitution (Val----Ile) close to the carboxy terminus of the beta-amyloid peptide. Screening other cases of familial AD revealed a second unrelated family in which this variant occurs. This suggests that some cases of AD could be caused by mutations in the APP gene

Shared genetic contribution to ischemic stroke and Alzheimer's disease:Ischemic Stroke and Alzheimer's Disease

Objective: Increasing evidence suggests epidemiological and pathological links between Alzheimer's disease (AD) and ischemic stroke (IS). We investigated the evidence that shared genetic factors underpin the two diseases. Methods: Using genome‐wide association study (GWAS) data from METASTROKE + (15,916 IS cases and 68,826 controls) and the International Genomics of Alzheimer's Project (IGAP; 17,008 AD cases and 37,154 controls), we evaluated known associations with AD and IS. On the subset of data for which we could obtain compatible genotype‐level data (4,610 IS cases, 1,281 AD cases, and 14,320 controls), we estimated the genome‐wide genetic correlation (rG) between AD and IS, and the three subtypes (cardioembolic, small vessel, and large vessel), using genome‐wide single‐nucleotide polymorphism (SNP) data. We then performed a meta‐analysis and pathway analysis in the combined AD and small vessel stroke data sets to identify the SNPs and molecular pathways through which disease risk may be conferred. Results: We found evidence of a shared genetic contribution between AD and small vessel stroke (rG [standard error] = 0.37 [0.17]; p  = 0.011). Conversely, there was no evidence to support shared genetic factors in AD and IS overall or with the other stroke subtypes. Of the known GWAS associations with IS or AD, none reached significance for association with the other trait (or stroke subtypes). A meta‐analysis of AD IGAP and METASTROKE + small vessel stroke GWAS data highlighted a region (ATP5H/KCTD2/ICT1) associated with both diseases (p  = 1.8 × 10−8). A pathway analysis identified four associated pathways involving cholesterol transport and immune response. Interpretation: Our findings indicate shared genetic susceptibility to AD and small vessel stroke and highlight potential causal pathways and loci. Ann Neurol 2016;79:739–74