Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, ...issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible.
Bone loss caused by ionizing radiation is a potential health concern for radiotherapy patients, radiation workers and astronauts. In animal studies, exposure to ionizing radiation increases oxidative ...damage in skeletal tissues, and results in an imbalance in bone remodeling initiated by increased bone-resorbing osteoclasts. Therefore, we evaluated various candidate interventions with antioxidant or anti-inflammatory activities (antioxidant cocktail, dihydrolipoic acid, ibuprofen, dried plum) both for their ability to blunt the expression of resorption-related genes in marrow cells after irradiation with either gamma rays (photons, 2 Gy) or simulated space radiation (protons and heavy ions, 1 Gy) and to prevent bone loss. Dried plum was most effective in reducing the expression of genes related to bone resorption (Nfe2l2, Rankl, Mcp1, Opg, TNF-α) and also preventing later cancellous bone decrements caused by irradiation with either photons or heavy ions. Thus, dietary supplementation with DP may prevent the skeletal effects of radiation exposures either in space or on Earth.
Twin and family studies have shown that same-sex sexual behavior is partly genetically influenced, but previous searches for specific genes involved have been underpowered. We performed a genome-wide ...association study (GWAS) on 477,522 individuals, revealing five loci significantly associated with same-sex sexual behavior. In aggregate, all tested genetic variants accounted for 8 to 25% of variation in same-sex sexual behavior, only partially overlapped between males and females, and do not allow meaningful prediction of an individual's sexual behavior. Comparing these GWAS results with those for the proportion of same-sex to total number of sexual partners among nonheterosexuals suggests that there is no single continuum from opposite-sex to same-sex sexual behavior. Overall, our findings provide insights into the genetics underlying same-sex sexual behavior and underscore the complexity of sexuality.
Mountain social‐ecological systems (MtSES) are vital to humanity, providing ecosystem services to over half the planet's human population. Despite their importance, there has been no global ...assessment of threats to MtSES, even as they face unprecedented challenges to their sustainability. With survey data from 57 MtSES sites worldwide, we test a conceptual model of the types and scales of stressors and ecosystem services in MtSES and explore their distinct configurations according to their primary economic orientation and land use. We find that MtSES worldwide are experiencing both gradual and abrupt climatic, economic, and governance changes, with policies made by outsiders as the most ubiquitous challenge. Mountains that support primarily subsistence‐oriented livelihoods, especially agropastoral systems, deliver abundant services but are also most at risk. Moreover, transitions from subsistence‐ to market‐oriented economies are often accompanied by increased physical connectedness, reduced diversity of cross‐scale ecosystem services, lowered importance of local knowledge, and shifting vulnerabilities to threats. Addressing the complex challenges facing MtSES and catalyzing transformations to MtSES sustainability will require cross‐scale partnerships among researchers, stakeholders, and decision makers to jointly identify desired futures and adaptation pathways, assess trade‐offs in prioritizing ecosystem services, and share best practices for sustainability. These transdisciplinary approaches will allow local stakeholders, researchers, and practitioners to jointly address MtSES knowledge gaps while simultaneously focusing on critical issues of poverty and food security.
Plain Language Summary
Mountain ecosystems and the human communities that inhabit them deliver critical resources—such as fresh water and timber—to over half the planet's human population. Despite their importance, there has been no global assessment of threats to mountain systems, even as they face unprecedented challenges to their sustainability. With survey data from 57 mountain sites worldwide, we test our understanding of the types of stresses that are threatening mountain systems as well as the resources and benefits that come from mountains. We find that mountain systems worldwide are experiencing both gradual and abrupt climatic, economic, and governance changes. One of the most ubiquitous challenges facing mountain systems is that policies directly affecting mountain systems are being made by those living outside of the mountains themselves. Mountains that support primarily subsistence‐oriented livelihoods in the developing world, especially mixed agriculture and animal husbandry systems, deliver abundant services but are also most at risk. Addressing the complex challenges facing mountain systems will require partnerships among researchers, stakeholders, and decision makers to jointly identify the types of futures they desire and the actions to achieve these. This approach will address knowledge gaps in mountains while simultaneously focusing on critical issues of poverty and food security.
Key Points
Mountain social‐ecological systems (MtSES) worldwide face climatic, economic, and governance threats; policies made by outsiders are a critical challenge
Mountains that support subsistence‐oriented livelihoods deliver abundant cross‐scale ecosystems services, but these MtSES are also most threatened
Addressing threats to MtSES requires the united effort of policymakers, land users, scientists, and practitioners at local to global scales
Major depression is a debilitating psychiatric illness that is typically associated with low mood and anhedonia. Depression has a heritable component that has remained difficult to elucidate with ...current sample sizes due to the polygenic nature of the disorder. To maximize sample size, we meta-analyzed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 genesets associated with depression, including both genes and gene pathways associated with synaptic structure and neurotransmission. An enrichment analysis provided further evidence of the importance of prefrontal brain regions. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant after multiple testing correction. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding etiology and developing new treatment approaches.
In order to systematically describe the Parkinson's disease phenome, we performed a series of 832 cross-sectional case-control analyses in a large database. Responses to 832 online survey-based ...phenotypes including diseases, medications, and environmental exposures were analyzed in 23andMe research participants. For each phenotype, survey respondents were used to construct a cohort of Parkinson's disease cases and age-matched and sex-matched controls, and an association test was performed using logistic regression. Cohorts included a median of 3899 Parkinson's disease cases and 49,808 controls, all of European ancestry. Highly correlated phenotypes were removed and the novelty of each significant association was systematically assessed (assigned to one of four categories: known, likely, unclear, or novel). Parkinson's disease diagnosis was associated with 122 phenotypes. We replicated 27 known associations and found 23 associations with a strong a priori link to a known association. We discovered 42 associations that have not previously been reported. Migraine, obsessive-compulsive disorder, and seasonal allergies were associated with Parkinson's disease and tend to occur decades before the typical age of diagnosis for Parkinson's disease. The phenotypes that currently comprise the Parkinson's disease phenome have mostly been explored in relatively small purpose-built studies. Using a single large dataset, we have successfully reproduced many of these established associations and have extended the Parkinson's disease phenome by discovering novel associations. Our work paves the way for studies of these associated phenotypes that explore shared molecular mechanisms with Parkinson's disease, infer causal relationships, and improve our ability to identify individuals at high-risk of Parkinson's disease.
Insomnia is the second most prevalent mental disorder, with no sufficient treatment available. Despite substantial heritability, insight into the associated genes and neurobiological pathways remains ...limited. Here, we use a large genetic association sample (n = 1,331,010) to detect novel loci and gain insight into the pathways, tissue and cell types involved in insomnia complaints. We identify 202 loci implicating 956 genes through positional, expression quantitative trait loci, and chromatin mapping. The meta-analysis explained 2.6% of the variance. We show gene set enrichments for the axonal part of neurons, cortical and subcortical tissues, and specific cell types, including striatal, hypothalamic, and claustrum neurons. We found considerable genetic correlations with psychiatric traits and sleep duration, and modest correlations with other sleep-related traits. Mendelian randomization identified the causal effects of insomnia on depression, diabetes, and cardiovascular disease, and the protective effects of educational attainment and intracranial volume. Our findings highlight key brain areas and cell types implicated in insomnia, and provide new treatment targets.
Data collected between 1974 and 2016 from snow pits and core samples from two Peruvian ice fields demonstrate the effect of the recent warming over the tropical Andes, augmented by El Niño, on the ...preservation of the climate record. As the 0°C isotherm is approaching the summit of the Quelccaya ice cap in the Andes of southern Peru (5,670 meters above sea level (masl)), the distinctive seasonal δ18O oscillations in the fresh snow deposited within each thermal year are attenuated at depth due to melting and percolation through the firn. This has become increasingly pronounced over 43 years. In the Andes of northern Peru, the ice field on the col of Nevado Huascarán (6050 masl) has retained its seasonal δ18O variations at depth due to its higher elevation. During the 2015/2016 El Niño, snow on Quelccaya and Huascarán was isotopically (δ18O) enriched and the net sum of accumulation over the previous year (NSA) was below the mean for non–El Niño years, particularly on Quelccaya (up to 64% below the mean) which was more pronounced than the NSA decrease during the comparable 1982/1983 El Niño. Interannual large‐scale oceanic and middle to upper‐level atmospheric temperatures influence δ18O in precipitation on both ice fields, although the influences are variably affected by strong El Niño–Southern Oscillation events, especially on Quelccaya. The rate of ice wastage along Quelccaya's margin was dramatically higher during 2015/2016 compared with that of the previous 15 years, suggesting that warming from future El Niños may accelerate mass loss on Peruvian glaciers.
Key Points
Midtropospheric warming in the Peruvian Andes is destroying climate signals preserved in glaciers and driving glacier retreat
The impact of the 2015/2016 El Niño on Quelccaya ice cap was more pronounced than for previous events in the last four decades
Peruvian Andes snow δ18O is linked to tropical Pacific SSTs, regional 500 mb temperatures, and convection
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