pinecone/core-2020-05-10-deduplication huggingface dataset:
Pleiotropy Analysis of Quantitative Traits at Gene Level by Multivariate Functional Linear Models

In genetics, pleiotropy describes the genetic effect of a single gene on multiple phenotypic traits. A common approach is to analyze the phenotypic traits separately using univariate analyses and combine the test results through multiple comparisons. This approach may lead to low power. Multivariate functional linear models are developed to connect genetic variant data to multiple quantitative traits adjusting for covariates for a unified analysis. Three types of approximate F‐distribution tests based on Pillai–Bartlett trace, Hotelling–Lawley trace, and Wilks's Lambda are introduced to test for association between multiple quantitative traits and multiple genetic variants in one genetic region. The approximate F‐distribution tests provide much more significant results than those of F‐tests of univariate analysis and optimal sequence kernel association test (SKAT‐O). Extensive simulations were performed to evaluate the false positive rates and power performance of the proposed models and tests. We show that the approximate F‐distribution tests control the type I error rates very well. Overall, simultaneous analysis of multiple traits can increase power performance compared to an individual test of each trait. The proposed methods were applied to analyze (1) four lipid traits in eight European cohorts, and (2) three biochemical traits in the Trinity Students Study. The approximate F‐distribution tests provide much more significant results than those of F‐tests of univariate analysis and SKAT‐O for the three biochemical traits. The approximate F‐distribution tests of the proposed functional linear models are more sensitive than those of the traditional multivariate linear models that in turn are more sensitive than SKAT‐O in the univariate case. The analysis of the four lipid traits and the three biochemical traits detects more association than SKAT‐O in the univariate case
Polygenic Epidemiology

Much of the genetic basis of complex traits is present on current genotyping products, but the individual variants that affect the traits have largely not been identified. Several traditional problems in genetic epidemiology have recently been addressed by assuming a polygenic basis for disease and treating it as a single entity. Here I briefly review some of these applications, which collectively may be termed polygenic epidemiology. Methodologies in this area include polygenic scoring, linear mixed models, and linkage disequilibrium scoring. They have been used to establish a polygenic effect, estimate genetic correlation between traits, estimate how many variants affect a trait, stratify cases into subphenotypes, predict individual disease risks, and infer causal effects using Mendelian randomization. Polygenic epidemiology will continue to yield useful applications even while much of the specific variation underlying complex traits remains undiscovered.Peer-reviewedPublisher Versio
Exome copy number variation detection: Use of a pool of unrelated healthy tissue as reference sample

An increasing number of bioinformatic tools designed to detect CNVs (copy number variants) in tumor samples based on paired exome data where a matched healthy tissue constitutes the reference have been published in the recent years. The idea of using a pool of unrelated healthy DNA as reference has previously been formulated but not thoroughly validated. As of today, the gold standard for CNV calling is still aCGH but there is an increasing interest in detecting CNVs by exome sequencing. We propose to design a metric allowing the comparison of two CNV profiles, independently of the technique used and assessed the validity of using a pool of unrelated healthy DNA instead of a matched healthy tissue as reference in exome-based CNV detection. We compared the CNV profiles obtained with three different approaches (aCGH, exome sequencing with a matched healthy tissue as reference, exome sequencing with a pool of eight unrelated healthy tissue as reference) on three multiple myeloma samples. We show that the usual analyses performed to compare CNV profiles (deletion/amplification ratios and CNV size distribution) lack in precision when confronted with low LRR values, as they only consider the binary status of each CNV. We show that the metric-based distance constitutes a more accurate comparison of two CNV profiles. Based on these analyses, we conclude that a reliable picture of CNV alterations in multiple myeloma samples can be obtained from whole-exome sequencing in the absence of a matched healthy sample.Peer reviewe
Iterative Hard Thresholding for Model Selection in Genome-Wide
  Association Studies

A genome-wide association study (GWAS) correlates marker variation with trait
variation in a sample of individuals. Each study subject is genotyped at a
multitude of SNPs (single nucleotide polymorphisms) spanning the genome. Here
we assume that subjects are unrelated and collected at random and that trait
values are normally distributed or transformed to normality. Over the past
decade, researchers have been remarkably successful in applying GWAS analysis
to hundreds of traits. The massive amount of data produced in these studies
present unique computational challenges. Penalized regression with LASSO or MCP
penalties is capable of selecting a handful of associated SNPs from millions of
potential SNPs. Unfortunately, model selection can be corrupted by false
positives and false negatives, obscuring the genetic underpinning of a trait.
This paper introduces the iterative hard thresholding (IHT) algorithm to the
GWAS analysis of continuous traits. Our parallel implementation of IHT
accommodates SNP genotype compression and exploits multiple CPU cores and
graphics processing units (GPUs). This allows statistical geneticists to
leverage commodity desktop computers in GWAS analysis and to avoid
supercomputing. We evaluate IHT performance on both simulated and real GWAS
data and conclude that it reduces false positive and false negative rates while
remaining competitive in computational time with penalized regression. Source
code is freely available at https://github.com/klkeys/IHT.jl.Comment: 13 pages, 1 figure, 4 table
On the testing of Hardy-Weinberg proportions and equality of allele frequencies in males and females at biallelic genetic markers

Standard statistical tests for equality of allele frequencies in males and females and tests for Hardy-Weinberg equilibrium are tightly linked by their assumptions. Tests for equality of allele frequencies assume Hardy-Weinberg equilibrium, whereas the usual chi-square or exact test for Hardy-Weinberg equilibrium assume equality of allele frequencies in the sexes. In this paper, we propose ways to break this interdependence in assumptions of the two tests by proposing an omnibus exact test that can test both hypotheses jointly, as well as a likelihood ratio approach that permits these phenomena to be tested both jointly and separately. The tests are illustrated with data from the 1000 Genomes project.Peer ReviewedPostprint (author's final draft
Predictive accuracy of combined genetic and environmental risk scores.

Additional Supporting Information may be found online in the supporting information tab for this article.The substantial heritability of most complex diseases suggests that genetic data could provide useful risk prediction. To date the performance of genetic risk scores has fallen short of the potential implied by heritability, but this can be explained by insufficient sample sizes for estimating highly polygenic models. When risk predictors already exist based on environment or lifestyle, two key questions are to what extent can they be improved by adding genetic information, and what is the ultimate potential of combined genetic and environmental risk scores? Here, we extend previous work on the predictive accuracy of polygenic scores to allow for an environmental score that may be correlated with the polygenic score, for example when the environmental factors mediate the genetic risk. We derive common measures of predictive accuracy and improvement as functions of the training sample size, chip heritabilities of disease and environmental score, and genetic correlation between disease and environmental risk factors. We consider simple addition of the two scores and a weighted sum that accounts for their correlation. Using examples from studies of cardiovascular disease and breast cancer, we show that improvements in discrimination are generally small but reasonable degrees of reclassification could be obtained with current sample sizes. Correlation between genetic and environmental scores has only minor effects on numerical results in realistic scenarios. In the longer term, as the accuracy of polygenic scores improves they will come to dominate the predictive accuracy compared to environmental scores.This work is supported by the MRC (MR/K006215/1, MR/M026175/1).Peer-reviewedPublisher Versio
Assessing potential shared genetic aetiology between body mass index and sleep duration in 142,209 individuals

Observational studies find an association between increased body mass index (BMI) and short self‐reported sleep duration in adults. However, the underlying biological mechanisms that underpin these associations are unclear. Recent findings from the UK Biobank suggest a weak genetic correlation between BMI and self‐reported sleep duration. However, the potential shared genetic aetiology between these traits has not been examined using a comprehensive approach. To investigate this, we created a polygenic risk score (PRS) of BMI and examined its association with self‐reported sleep duration in a combination of individual participant data and summary‐level data, with a total sample size of 142,209 individuals. Although we observed a nonsignificant genetic correlation between BMI and sleep duration, using LD score regression (rg = −0.067 [SE = 0.039], P = 0.092) we found that a PRS of BMI is associated with a decrease in sleep duration (unstandardized coefficient = −1.75 min [SE = 0.67], P = 6.13 × 10−7), but explained only 0.02% of the variance in sleep duration. Our findings suggest that BMI and self‐reported sleep duration possess a small amount of shared genetic aetiology and other mechanisms must underpin these associations
Explosive expansion of a slowly-decompressed magma analog:evidence of delayed bubble nucleation

While ascending in the plumbing system of volcanoes, magma undergoes decompression at rates spanning several orders of magnitude and set by a number of factors internal and external to the volcano. Slow decompression generally results in an effusive or mildly explosive expansion of the magma, but counterexamples of sudden switches from effusive to explosive eruptive behaviour have been documented at various volcanoes worldwide. The  mechanisms involved in this behavior are currently debated, in particular regarding basaltic magmas. Here, we explore the interplay between decompression rate and vesiculation vigour by decompressing a magma analog obtained by dissolving pine resin into acetone in varying proportions. Our mixtures contain solid particles and upon decompression experience the nucleation of acetone bubbles. We find mixtures high in acetone, containing smaller and fewer solid particles, experience strong supersaturation and fragment for very slow decompressions, despite having low viscosity, while mixtures low in acetone, with more and larger solid particles degas efficiently. We interpret our results in terms of delayed bubble nucleation due to a lack of efficient nucleation sites. We discuss how a similar mechanism might induce violent, explosive expansion in volatile-rich and poorly crystalline low-silica magmas, by analogy to previous inferences for rhyolitic magmas
Seasonal moisture sources and the isotopic composition of precipitation, rivers, and carbonates across the Andes at 32º-35.5°S

Constraining the influence of different moisture sources across the flanks of mountain ranges is important for understanding tectonic, geomorphic, and paleoclimate problems at geologic timescales, as well as evaluating climate change and water resources on human time scales. The stable isotope compositions of stream waters and precipitation are an ideal tool for this task. This study reports the results of a 2 year monthly precipitation sampling campaign on the eastern flank of the Andes in the Mendoza Province of Argentina, which began in September 2008. A total of 104 precipitation samples spanning some 2500 m of relief from nine sites were analyzed for δD and δ18O. In addition, 81 samples from Andean rivers collected on both sides of the range in 2002 and 2007 were analyzed. We employ a Rayleigh isotope fractionation modeling approach to explore spatial and temporal variations in precipitation and river water compositions. The results indicate that precipitation on the eastern slopes of the Andes at ~33°S, at elevations above 2 km, is largely derived from a westerly, Pacific-source component and a mixture of easterly and westerly sources below 2 km. Further south at ~35°S, river water compositions exhibit a strong winter influence. At 33°S, rivers have an isotopic minimum of ~ −18? across the core of the range, which has an average elevation of 4000 m, and are topographically offset from similar isotopic values of precipitation by +1000 m. Comparison of precipitation and river water data with temperature-corrected δ18O estimates from pedogenic carbonates illustrates that carbonates capture the range of variability observed in modern precipitation and Rayleigh fractionation models.Fil: Hoke, Gregory D.. Syracuse University. Department of Earth Sciences; Estados UnidosFil: Aranibar, Julieta Nelida. Consejo Nacional de Investigaciones Científicas y Técnicas. Científico Tecnológico Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Viale, Maximiliano. Universidad de Chile. Departamento de Geofísica. Facultad de Ciencias Físicas y Matemáticas; Chile. Consejo Nacional de Investigaciones Científicas y Técnicas. Científico Tecnológico Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales; ArgentinaFil: Araneo, Diego Christian. Consejo Nacional de Investigaciones Científicas y Técnicas. Científico Tecnológico Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales; ArgentinaFil: Llano, Carina.  Museo de Historia Natural de San Rafael. Departamento de Antropología; Argentin
Mantle composition controls the development of an Oceanic Core Complex

The thickness and continuity of oceanic crust is variable. Slow-spreading ridge segments often contain areas of ‘amagmatic’ or tectonic extension, exposing areas of lower-crust and upper-mantle, and having little or no recent volcanism. These are interspersed with areas of ‘normal’ volcanic crust generated by ‘robust’ magmatic accretion. Tectonic spreading is accommodated by displacement on low-angle extensional detachment faults, forming Oceanic Core Complexes. Although ‘amagmatic’ extension appears to be common at slow spreading rates, little is known about the mechanisms that drive the transition from magmatic spreading. Here, we report results from a detailed study of the Mid-Atlantic Ridge (13°N–14°N) and show, paradoxically, that despite the presence of several Core Complexes, melt production remains similar along the present-day spreading axis, which erupts homogeneous ‘normal’ mid-ocean ridge basalt. However, melt production during formation of the older crust off-axis was derived from substantially lower degrees of melting of a heterogeneous mantle. During this magmatically restricted phase, melt production was limited by source composition. Small volumes of an enriched basalt (M1) were produced, derived from low-fraction melts of enriched compositional heterogeneities embedded in an otherwise compositionally depleted upper-mantle, which, in turn, erupted low-fraction incompatible-element-poor basalts (M2). As a consequence of low magma flux, the crust was thin and insufficient to fully accommodate seafloor spreading. Faulting of this thin crust resulted in the development of detachment faults and the formation of OCCs. Thus, we propose that periods of low melt production, resulting directly from depleted, heterogeneous mantle drives the transition from magmatic to amagmatic spreading
Timing, origin and emplacement dynamics of mass flows offshore of SE Montserrat in the last 110 ka: implications for landslide and tsunami hazards, eruption history, and volcanic island evolution

Mass flows on volcanic islands generated by volcanic lava dome collapse and by larger volume flank collapse, can be highly dangerous locally and may generate tsunamis that threaten a wider area. It is therefore important to understand their frequency, emplacement dynamics and relationship to volcanic eruption cycles. The best record of mass flow on volcanic islands may be found offshore, where most material is deposited, and where intervening hemipelagic sediment aids dating. Here we analyse what is arguably the most comprehensive sediment core data set collected offshore from a volcanic island. The cores are located southeast of Montserrat, on which the Soufriere Hills volcano has been erupting since 1995. The cores provide a record of mass flow events during the last 110 ka. Older mass flow deposits differ significantly from those generated by the repeated lava dome collapses observed since 1995. The oldest mass flow deposit originated through collapse of the basaltic South Soufriere Hills at 103-110 ka, some 20-30 ka after eruptions formed this volcanic centre. A ~1.8 km3 blocky debris avalanche deposit that extends from a chute in the island shelf records a particularly deep-seated failure. It likely formed from a collapse of almost equal amounts of volcanic edifice and coeval carbonate shelf, emplacing a mixed bioclastic-andesitic turbidite in a complex series of stages. This study illustrates how volcanic island growth and collapse involved extensive, large-volume submarine mass flows with highly variable composition. Run-out turbidites indicate that mass flows are emplaced either in multiple stages or as single events
The large-scale surface uplift in the Altiplano-Puna region of Bolivia: A parametric study of source characteristics and crustal rheology using finite element analysis

PublishedThis is the final version of the article. Available from the publisher via the DOI in this record.This paper focuses on the driving mechanism behind a 70 km wide region of ground uplift centered on
Uturuncu volcano, in the Altiplano-Puna region of southern Bolivia. We present a series of forward models
using finite element analysis to simultaneously test for first-order parameters that help constrain a viable
model for the observed maximum line of sight uplift rate of 1–2 cm/yr between 1992 and 2006. Stresses
from pressure sources with finite geometries are solved numerically, accounting for both homogeneous
and heterogeneous mechanical rock properties in elastic and viscoelastic rheologies. Crustal heterogeneity
is constrained by seismic velocity data that indicate the presence of a large low-velocity zone, the AltiplanoPuna
magma body, at depths of ~17 km below the surface. A viscoelastic rheology is employed to account
for time-dependent deformation and an inelastic crust. Comparing homogeneous and heterogeneous
models demonstrates the significant impact of a mechanically weak, source-depth layer, which alters
surface displacement patterns by buffering subsurface deformation. Elastic model results guide the source
parameters tested in the viscoelastic models and demonstrate a range of possible causative source
geometries. Our preferred model suggests that pressurization of a magma source extending upward from
the Altiplano-Puna magma body is causing the observed surface uplift and alludes to a continued increase
in this pressure to explain both the spatial and temporal patterns. We also demonstrate how a pressure-time
function plays a first-order role in explaining the observed temporal deformation patternThis work was supported by the Natural Environmental
Research Council (grant NE/G01843X/1), the European Union
Framework Program 7 (grant 282759, “VUELCO”) and the
Royal Society (University Research Fellowship). We thank
Matthew Pritchard, Ciro Del Negro and editor James Tyburczy
for their constructive review
Weathering geochemistry and Sr-Nd fingerprints of equatorial upper Nile and Congo muds

This study investigates processes of sediment generation in equatorial central Africa. An original, complete and integrated mineralogical-geochemical database on silt-sized sediments derived from different parent rocks (basalt, granite, gneiss, metapsammite, sandstone) along the East African Rift from 5°S in Tanzania to 5°N in Sudan is presented and used to assess the incidence of diverse factors controlling sediment composition (source-rock lithology, geomorphology, hydraulic sorting, grain size, recycling), with particular emphasis on chemical weathering
The geochemical and temporal evolution of the continental lithosphere and its relationship to continental-scale faulting: the Karakoram Fault, eastern Karakoram, NW Himalayas

[1] New laser ablation multicollector–inductively coupled plasma–mass spectrometry and isotope dilution-thermal ionization mass spectrometry U-Pb ages, coupled with Sm-Nd isotope and geochemical analysis, define the temporal and geochemical evolution of the continental lithosphere in the eastern Karakoram, India, NW Himalaya. Our analysis demonstrates that magmatism occurred between ~108 and 69 Ma and ~22 and 13 Ma. The new age data, coupled with geochemical examination of the granitoids, confirm a parallel evolution with the western Karakoram in Pakistan and supports a model of regional continental crustal thickening and related metamorphism. Middle to Late Cretaceous magmatism immediately adjacent to the Karakoram fault suggests that crustal melting and associated metamorphism are unrelated to shearing along the fault. Miocene leucogranite magmatism occurred almost exactly concomitant with the emplacement of the Baltoro batholith in Pakistan. These trans-Karakoram leucogranites also display similar geochemical evolution trends. Our new data clearly link the leucogranites along the fault to the regional Baltoro batholith and related metamorphic complexes to the west. This supports previous work suggesting that magmatism and metamorphism were not syn-kinematic with continental-scale faulting. The data demonstrate that the Karakoram fault could not have accommodated lateral offset in this region prior to ~16 Ma, limiting the long-term averaged slip rate to a maximum of ~10 mm/yr