Heterogeneous nickel isotopic compositions in the terrestrial mantle – Part 1: Ultramafic lithologies

High precision nickel stable isotopic compositions (δ⁶⁰/⁵⁸Ni) are reported for 22 peridotite xenoliths from the USA (Kilbourne Hole, New Mexico), Tanzania, and Cameroon. For a subset of these, δ⁶⁰/⁵⁸Ni is also reported for their constituent mineral separates (olivine, orthopyroxene, clinopyroxene, and spinel). Bulk peridotites show significant heterogeneity in Ni isotopic composition, ranging from +0.02‰ to +0.26‰. Unmetasomatised fertile peridotites from three localities, define an average δ⁶⁰/⁵⁸Ni of +0.19±0.09‰ (n = 18). This value is comparable to previous estimates for the δ⁶⁰/⁵⁸Ni of the bulk silicate earth (BSE), but is unlikely to be representative, given observed heterogeneity, presented here and elsewhere. Samples with reaction rims and interstitial glass (interpreted as petrographic indications of minor metasomatism) were excluded from this average; their Ni isotopic compositions extend to lighter values, spanning nearly the entire range observed in peridotite worldwide. Dunites (n = 2) are lighter in δ⁶⁰/⁵⁸Ni than lherzolites and harzburgites from the same location, and pyroxenites (n = 5) range from +0.16‰ to as light as −0.38‰. The δ⁶⁰/⁵⁸Ni in the Kilbourne Hole xenoliths correlate negatively with bulk-rock Fe concentration and positively with ¹⁴³Nd/¹⁴⁴Nd, providing evidence that light δ⁶⁰/⁵⁸Ni is associated with mantle fertility and enrichment. The trend between δ⁶⁰/⁵⁸Ni and Fe concentration in bulk rocks appears to be global, replicated across the peridotites in this work from other localities, and in literature data. The inter-mineral fractionations are small; the maximum difference between heaviest and lightest phase is 0.12‰. This provides evidence that bulk rock δ⁶⁰/⁵⁸Nii variation does not result from differences in modal mineralogy, fractional crystallization or degrees of partial melting. The δ⁶⁰/⁵⁸Ni fractionation appears to be an equilibrium effect and usually is in the decreasing order spinel > olivine = orthopyroxene > clinopyroxene. However, the fractionation between clinopyroxene and orthopyroxene varies in magnitude and sign, and is correlated with pyroxene Si/Fe positively, and Fe/Mg negatively. The magnitude of inter-pyroxene fractionation also correlates with other pyroxene compositional ratios (e.g. La/Sm_clinopyroxene); as well as bulk rock δ⁶⁰/⁵⁸Ni, and [U]. These data provide evidence that Ni isotopes fractionate at the bulk rock and mineral scale in response to mantle enrichment processes, possibly related to recycling of isotopically light subducted components

Heterogeneous nickel isotope compositions of the terrestrial mantle – Part 2: Mafic lithologies

We report stable Ni isotope compositions (δ⁶⁰/⁵⁸Ni, relative to SRM986) for mafic lavas with a range of -0.16 ‰ to +0.20 ‰ (n=44), similar to that of peridotite samples. Ocean island basalts (OIB) have been analysed from Iceland (n=6), the Azores (n=3), the Galápagos Islands (n=2), and Lōʻihi, Hawaii (n=1). Samples from Iceland (average δ⁶⁰/⁵⁸Ni = +0.13±0.16‰, 2s, n=7) display the greatest range in Ni isotope compositions from a single OIB location in this work, of +0.01 ‰ to +0.23 ‰. Samples from the Azores (average δ⁶⁰/⁵⁸Ni = -0.10±0.10 ‰, 2s) and Galápagos (average δ⁶⁰/⁵⁸Ni = -0.01±0.04 ‰, 2s) are generally isotopically lighter. The single Lōʻihi sample has a δ⁶⁰/⁵⁸Ni of +0.17 ‰. The lightest analysed bulk rock δ⁶⁰/⁵⁸Ni in this work, -0.16 ‰, is from the Azores island, Pico. Enriched mid ocean ridge basalts (E-MORB), which have (La/Sm)_N>1, are isotopically lighter than normal type MORB (N-MORB), as shown by data from the Mid Atlantic Ridge (n=9) and East Pacific Rise (n=3). All E-MORB average δ60/58Ni = +0.00±0.06 ‰ (2s, n=7), whereas N-MORB average δ60/58Ni = +0.14±0.10 ‰ (2s, n=5). A suite of 15 mafic samples from the Cameroon Line, comprising lithologies ranging from nephelinites to hypersthene-normative basalts, have Ni isotope compositions that are identical within analytical uncertainty (average δ⁶⁰/⁵⁸Ni = +0.08±0.06 ‰, 2s). Similarly, MORB samples display no relationship between δ⁶⁰/⁵⁸Ni and geochemical indicators of degree of partial melting or fractional crystallisation. Host lavas for two previously analysed ultramafic xenolith suites have δ⁶⁰/⁵⁸Ni identical to the average δ⁶⁰/⁵⁸Ni of their respective xenolith suites. This is consistent with previously published evidence from peridotites and komatiites that Ni isotopes are not greatly fractionated by melting. Therefore, mafic rocks may preserve the δ⁶⁰/⁵⁸Ni of their mantle source. Sampling a greater volume of mantle, their average Ni isotope composition +0.07±0.17 ‰ (2s, n=44) may also be a better representation of the Bulk Silicate Earth (BSE), than estimates based purely on peridotites. The δ⁶⁰/⁵⁸Ni of MORB co-varies with La/Sm, Rb/Sr, europium anomaly (Eu/Eu*), and K₂O/(K₂O+Na₂O). The relationships between these parameters and δ⁶⁰/⁵⁸Ni are consistent with mixing between two model endmembers. One could be depleted MORB or depleted MORB mantle (DMM) with a relatively heavy Ni isotope composition; the other a more enriched endmember that has isotopically lighter δ⁶⁰/⁵⁸Ni. The link between lighter δ⁶⁰/⁵⁸Ni and enriched lithologies in the mantle is further supported by published evidence of light Ni isotope compositions associated with some pyroxenite xenoliths. However, the curvature of the apparent mixing arrays defined by basalts is hard to reconcile with admixing of geochemically enriched but isotopically fractionated oceanic crustal lithologies. High [Ni] enriched magmas such as kimberlites may be a closer match to the enriched endmember. However, this needs further study

Expert appraisal of criteria for assessing gaming disorder : An international Delphi study

© 2021 The Authors. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (CC-BY-NC-ND - https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.Background and aims: Following the recognition of ‘internet gaming disorder’ (IGD) as a condition requiring further study by the DSM-5, ‘gaming disorder’ (GD) was officially included as a diagnostic entity by the World Health Organization (WHO) in the 11th revision of the International Classification of Diseases (ICD-11). However, the proposed diagnostic criteria for gaming disorder remain the subject of debate, and there has been no systematic attempt to integrate the views of different groups of experts. To achieve a more systematic agreement on this new disorder, this study employed the Delphi expert consensus method to obtain expert agreement on the diagnostic validity, clinical utility and prognostic value of the DSM-5 criteria and ICD-11 clinical guidelines for GD. Methods: A total of 29 international experts with clinical and/or research experience in GD completed three iterative rounds of a Delphi survey. Experts rated proposed criteria in progressive rounds until a pre-determined level of agreement was achieved. Results: For DSM-5 IGD criteria, there was an agreement both that a subset had high diagnostic validity, clinical utility and prognostic value and that some (e.g. tolerance, deception) had low diagnostic validity, clinical utility and prognostic value. Crucially, some DSM-5 criteria (e.g. escapism/mood regulation, tolerance) were regarded as incapable of distinguishing between problematic and non-problematic gaming. In contrast, ICD-11 diagnostic guidelines for GD (except for the criterion relating to diminished non-gaming interests) were judged as presenting high diagnostic validity, clinical utility and prognostic value. Conclusions: This Delphi survey provides a foundation for identifying the most diagnostically valid and clinically useful criteria for GD. There was expert agreement that some DSM-5 criteria were not clinically relevant and may pathologize non-problematic patterns of gaming, whereas ICD-11 diagnostic guidelines are likely to diagnose GD adequately and avoid pathologizing.Peer reviewe

Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease.

OBJECTIVE: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease. METHODS: We performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers. RESULTS: A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E-07; age-at-onset top variant: p value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset. INTERPRETATION: This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021;90:82-94

Height, selected genetic markers and prostate cancer risk:Results from the PRACTICAL consortium

Background: Evidence on height and prostate cancer risk is mixed, however, recent studies with large data sets support a possible role for its association with the risk of aggressive prostate cancer. Methods: We analysed data from the PRACTICAL consortium consisting of 6207 prostate cancer cases and 6016 controls and a subset of high grade cases (2480 cases). We explored height, polymorphisms in genes related to growth processes as main effects and their possible interactions. Results: The results suggest that height is associated with high-grade prostate cancer risk. Men with height 4180cm are at a 22% increased risk as compared to men with height o173cm (OR 1.22, 95% CI 1.01–1.48). Genetic variants in the growth pathway gene showed an association with prostate cancer risk. The aggregate scores of the selected variants identified a significantly increased risk of overall prostate cancer and high-grade prostate cancer by 13% and 15%, respectively, in the highest score group as compared to lowest score group. Conclusions: There was no evidence of gene-environment interaction between height and the selected candidate SNPs. Our findings suggest a role of height in high-grade prostate cancer. The effect of genetic variants in the genes related to growth is seen in all cases and high-grade prostate cancer. There is no interaction between these two exposures.</p

Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10−15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62–4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Peer reviewe