Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases

BACKGROUND: Clinical, pathological and genetic overlap between sporadic frontotemporal dementia (FTD), Alzheimer's disease (AD) and Parkinson's disease (PD) has been suggested; however, the relationship between these disorders is still not well understood. Here we evaluated genetic overlap between FTD, AD and PD to assess shared pathobiology and identify novel genetic variants associated with increased risk for FTD. METHODS: Summary statistics were obtained from the International FTD Genomics Consortium, International PD Genetics Consortium and International Genomics of AD Project (n>75 000 cases and controls). We used conjunction false discovery rate (FDR) to evaluate genetic pleiotropy and conditional FDR to identify novel FTD-associated SNPs. Relevant variants were further evaluated for expression quantitative loci. RESULTS: We observed SNPs within the HLA, MAPT and APOE regions jointly contributing to increased risk for FTD and AD or PD. By conditioning on polymorphisms associated with PD and AD, we found 11 loci associated with increased risk for FTD. Meta-analysis across two independent FTD cohorts revealed a genome-wide signal within the APOE region (rs6857, 3′-UTR=PVRL2, p=2.21×10–12), and a suggestive signal for rs1358071 within the MAPT region (intronic=CRHR1, p=4.91×10−7) with the effect allele tagging the H1 haplotype. Pleiotropic SNPs at the HLA and MAPT loci associated with expression changes in cis-genes supporting involvement of intracellular vesicular trafficking, immune response and endo/lysosomal processes. CONCLUSIONS: Our findings demonstrate genetic pleiotropy in these neurodegenerative diseases and indicate that sporadic FTD is a polygenic disorder where multiple pleiotropic loci with small effects contribute to increased disease risk

Alternative Promoters Influence Alternative Splicing at the Genomic Level

Background: More and more experiments have shown that transcription and mRNA processing are not two independent events but are tightly coupled to each other. Both promoter and transcription rate were found to influence alternative splicing. More than half of human genes have alternative promoters, but it is still not clear why there are so many alternative promoters and what their biological roles are. Methodology/Principal Findings: In this study, we explored whether there is a functional correlation between alternative promoters and alternative splicing by a genome-wide analysis of human and mouse genes. We constructed a large data set of genes with alternative promoter and alternative splicing annotations. By analyzing these genes, we showed that genes with alternative promoters tended to demonstrate alternative splicing compare to genes with single promoter, and, genes with more alternative promoters tend to have more alternative splicing variants. Furthermore, transcripts from different alternative promoters tended to splice differently. Conclusions/Significance: Thus at the genomic level, alternative promoters are positively correlated with alternativ

Medroxyprogesterone improves nocturnal breathing in postmenopausal women with chronic obstructive pulmonary disease

BACKGROUND: Progestins as respiratory stimulants in chronic obstructive pulmonary disease (COPD) have been investigated in males and during wakefulness. However, sleep and gender may influence therapeutic responses. We investigated the effects of a 2-week medroxyprogesterone acetate (MPA) therapy on sleep and nocturnal breathing in postmenopausal women. METHODS: A single-blind placebo-controlled trial was performed in 15 postmenopausal women with moderate to severe COPD. A 12-week trial included 2-week treatment periods with placebo and MPA (60 mg/d/14 days). All patients underwent a polysomnography with monitoring of SaO(2 )and transcutaneous PCO(2 )(tcCO(2)) at baseline, with placebo, with medroxyprogesterone acetate (MPA 60 mg/d/14 days), and three and six weeks after cessation of MPA. RESULTS: Thirteen patients completed the trial. At baseline, the average ± SD of SaO(2 )mean was 90.6 ± 3.2 % and the median of SaO(2 )nadir 84.8 % (interquartile range, IQR 6.1). MPA improved them by 1.7 ± 1.6 %-units (95 % confidence interval (CI) 0.56, 2.8) and by 3.9 %-units (IQR 4.9; 95% CI 0.24, 10.2), respectively. The average of tcCO(2 )median was 6.0 ± 0.9 kPa and decreased with MPA by 0.9 ± 0.5 kPa (95% CI -1.3, -0.54). MPA improved SaO(2 )nadir and tcCO(2 )median also during REM sleep. Three weeks after cessation of MPA, the SaO(2 )mean remained 1.4 ± 1.8 %-units higher than at baseline, the difference being not significant (95% CI -0.03, 2.8). SaO(2 )nadir was 2.7 %-units (IQR 4.9; 95% CI 0.06, 18.7) higher than at baseline. Increases in SaO(2 )mean and SaO(2 )nadir during sleep with MPA were inversely associated with baseline SaO(2 )mean (r = -0.70, p = 0.032) and baseline SaO(2 )nadir (r = -0.77, p = 0.008), respectively. Treatment response in SaO(2 )mean, SaO(2 )nadir and tcCO(2 )levels did not associate with pack-years smoked, age, BMI, spirometric results or sleep variables. CONCLUSION: MPA-induced respiratory improvement in postmenopausal women seems to be consistent and prolonged. The improvement was greater in patients with lower baseline SaO(2 )values. Long-term studies in females are warranted

A database of chlorophyll a in Australian waters

© The Author(s) 2018. Chlorophyll a is the most commonly used indicator of phytoplankton biomass in the marine environment. It is relatively simple and cost effective to measure when compared to phytoplankton abundance and is thus routinely included in many surveys. Here we collate 173, 333 records of chlorophyll a collected since 1965 from Australian waters gathered from researchers on regular coastal monitoring surveys and ocean voyages into a single repository. This dataset includes the chlorophyll a values as measured from samples analysed using spectrophotometry, fluorometry and high performance liquid chromatography (HPLC). The Australian Chlorophyll a database is freely available through the Australian Ocean Data Network portal (https://portal.aodn.org.au/). These data can be used in isolation as an index of phytoplankton biomass or in combination with other data to provide insight into water quality, ecosystem state, and relationships with other trophic levels such as zooplankton or fish

A database of marine phytoplankton abundance, biomass and species composition in Australian waters

There have been many individual phytoplankton datasets collected across Australia since the mid 1900s, but most are unavailable to the research community. We have searched archives, contacted researchers, and scanned the primary and grey literature to collate 3,621,847 records of marine phytoplankton species from Australian waters from 1844 to the present. Many of these are small datasets collected for local questions, but combined they provide over 170 years of data on phytoplankton communities in Australian waters. Units and taxonomy have been standardised, obviously erroneous data removed, and all metadata included. We have lodged this dataset with the Australian Ocean Data Network (http://portal.aodn.org.au/) allowing public access. The Australian Phytoplankton Database will be invaluable for global change studies, as it allows analysis of ecological indicators of climate change and eutrophication (e.g., changes in distribution; diatom:dinoflagellate ratios). In addition, the standardised conversion of abundance records to biomass provides modellers with quantifiable data to initialise and validate ecosystem models of lower marine trophic levels

The use of race, ethnicity and ancestry in human genetic research

Post-Human Genome Project progress has enabled a new wave of population genetic research, and intensified controversy over the use of race/ethnicity in this work. At the same time, the development of methods for inferring genetic ancestry offers more empirical means of assigning group labels. Here, we provide a systematic analysis of the use of race/ethnicity and ancestry in current genetic research. We base our analysis on key published recommendations for the use and reporting of race/ethnicity which advise that researchers: explain why the terms/categories were used and how they were measured, carefully define them, and apply them consistently. We studied 170 population genetic research articles from high impact journals, published 2008–2009. A comparative perspective was obtained by aligning study metrics with similar research from articles published 2001–2004. Our analysis indicates a marked improvement in compliance with some of the recommendations/guidelines for the use of race/ethnicity over time, while showing that important shortfalls still remain: no article using ‘race’, ‘ethnicity’ or ‘ancestry’ defined or discussed the meaning of these concepts in context; a third of articles still do not provide a rationale for their use, with those using ‘ancestry’ being the least likely to do so. Further, no article discussed potential socio-ethical implications of the reported research. As such, there remains a clear imperative for highlighting the importance of consistent and comprehensive reporting on human populations to the genetics/genomics community globally, to generate explicit guidelines for the uses of ancestry and genetic ancestry, and importantly, to ensure that guidelines are followed

Shared genetic risk between corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia

Corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and a subset of frontotemporal dementia (FTD) are neurodegenerative disorders characterized by tau inclusions in neurons and glia (tauopathies). Although clinical, pathological and genetic evidence suggests overlapping pathobiology between CBD, PSP, and FTD, the relationship between these disorders is still not well understood. Using summary statistics (odds ratios and p values) from large genome-wide association studies (total n = 14,286 cases and controls) and recently established genetic methods, we investigated the genetic overlap between CBD and PSP and CBD and FTD. We found up to 800-fold enrichment of genetic risk in CBD across different levels of significance for PSP or FTD. In addition to NSF (tagging the MAPT H1 haplotype), we observed that SNPs in or near MOBP, CXCR4, EGFR, and GLDC showed significant genetic overlap between CBD and PSP, whereas only SNPs tagging the MAPT haplotype overlapped between CBD and FTD. The risk alleles of the shared SNPs were associated with expression changes in cis-genes. Evaluating transcriptome levels across adult human brains, we found a unique neuroanatomic gene expression signature for each of the five overlapping gene loci (omnibus ANOVA p < 2.0 × 10−16). Functionally, we found that these shared risk genes were associated with protein interaction and gene co-expression networks and showed enrichment for several neurodevelopmental pathways. Our findings suggest: (1) novel genetic overlap between CBD and PSP beyond the MAPT locus; (2) strong ties between CBD and FTD through the MAPT clade, and (3) unique combinations of overlapping genes that may, in part, influence selective regional or neuronal vulnerability observed in specific tauopathies

Lysophosphatidic Acid Acyltransferase β (LPAATβ) Promotes the Tumor Growth of Human Osteosarcoma

Osteosarcoma is the most common primary malignancy of bone with poorly characterized molecular pathways important in its pathogenesis. Increasing evidence indicates that elevated lipid biosynthesis is a characteristic feature of cancer. We sought to investigate the role of lysophosphatidic acid acyltransferase β (LPAATβ, aka, AGPAT2) in regulating the proliferation and growth of human osteosarcoma cells. LPAATβ can generate phosphatidic acid, which plays a key role in lipid biosynthesis as well as in cell proliferation and survival. Although elevated expression of LPAATβ has been reported in several types of human tumors, the role of LPAATβ in osteosarcoma progression has yet to be elucidated.Endogenous expression of LPAATβ in osteosarcoma cell lines is analyzed by using semi-quantitative PCR and immunohistochemical staining. Adenovirus-mediated overexpression of LPAATβ and silencing LPAATβ expression is employed to determine the effect of LPAATβ on osteosarcoma cell proliferation and migration in vitro and osteosarcoma tumor growth in vivo. We have found that expression of LPAATβ is readily detected in 8 of the 10 analyzed human osteosarcoma lines. Exogenous expression of LPAATβ promotes osteosarcoma cell proliferation and migration, while silencing LPAATβ expression inhibits these cellular characteristics. We further demonstrate that exogenous expression of LPAATβ effectively promotes tumor growth, while knockdown of LPAATβ expression inhibits tumor growth in an orthotopic xenograft model of human osteosarcoma.Our results strongly suggest that LPAATβ expression may be associated with the aggressive phenotypes of human osteosarcoma and that LPAATβ may play an important role in regulating osteosarcoma cell proliferation and tumor growth. Thus, targeting LPAATβ may be exploited as a novel therapeutic strategy for the clinical management of osteosarcoma. This is especially attractive given the availability of selective pharmacological inhibitors

Genetic assessment of age-associated Alzheimer disease risk: Development and validation of a polygenic hazard score

BACKGROUND: Identifying individuals at risk for developing Alzheimer disease (AD) is of utmost importance. Although genetic studies have identified AD-associated SNPs in APOE and other genes, genetic information has not been integrated into an epidemiological framework for risk prediction. METHODS AND FINDINGS: Using genotype data from 17,008 AD cases and 37,154 controls from the International Genomics of Alzheimer’s Project (IGAP Stage 1), we identified AD-associated SNPs (at p < 10−5). We then integrated these AD-associated SNPs into a Cox proportional hazard model using genotype data from a subset of 6,409 AD patients and 9,386 older controls from Phase 1 of the Alzheimer’s Disease Genetics Consortium (ADGC), providing a polygenic hazard score (PHS) for each participant. By combining population-based incidence rates and the genotype-derived PHS for each individual, we derived estimates of instantaneous risk for developing AD, based on genotype and age, and tested replication in multiple independent cohorts (ADGC Phase 2, National Institute on Aging Alzheimer’s Disease Center [NIA ADC], and Alzheimer’s Disease Neuroimaging Initiative [ADNI], total n = 20,680). Within the ADGC Phase 1 cohort, individuals in the highest PHS quartile developed AD at a considerably lower age and had the highest yearly AD incidence rate. Among APOE ε3/3 individuals, the PHS modified expected age of AD onset by more than 10 y between the lowest and highest deciles (hazard ratio 3.34, 95% CI 2.62–4.24, p = 1.0 × 10−22). In independent cohorts, the PHS strongly predicted empirical age of AD onset (ADGC Phase 2, r = 0.90, p = 1.1 × 10−26) and longitudinal progression from normal aging to AD (NIA ADC, Cochran–Armitage trend test, p = 1.5 × 10−10), and was associated with neuropathology (NIA ADC, Braak stage of neurofibrillary tangles, p = 3.9 × 10−6, and Consortium to Establish a Registry for Alzheimer’s Disease score for neuritic plaques, p = 6.8 × 10−6) and in vivo markers of AD neurodegeneration (ADNI, volume loss within the entorhinal cortex, p = 6.3 × 10−6, and hippocampus, p = 7.9 × 10−5). Additional prospective validation of these results in non-US, non-white, and prospective community-based cohorts is necessary before clinical use. CONCLUSIONS: We have developed a PHS for quantifying individual differences in age-specific genetic risk for AD. Within the cohorts studied here, polygenic architecture plays an important role in modifying AD risk beyond APOE. With thorough validation, quantification of inherited genetic variation may prove useful for stratifying AD risk and as an enrichment strategy in therapeutic trials