Uncovering Networks from Genome-Wide Association Studies via Circular Genomic Permutation

Genome-wide association studies (GWAS) aim to detect single nucleotide polymorphisms (SNP) associated with trait variation. However, due to the large number of tests, standard analysis techniques impose highly stringent significance thresholds, leaving potentially associated SNPs undetected, and much of the trait genetic variation unexplained. Pathway- and network-based methodologies applied to GWAS aim to detect associations missed by standard single-marker approaches. The complex and non-random architecture of the genome makes it a challenge to derive an appropriate testing framework for such methodologies. We developed a rapid and simple permutation approach that uses GWAS SNP association results to establish the significance of pathway associations while accounting for the linkage disequilibrium structure of SNPs and the clustering of functionally related elements in the genome. All SNPs used in the GWAS are placed in a “circular genome” according to their location. Then the complete set of SNP association P values are permuted by rotation with respect to the genomic locations of the SNPs. Once these “simulated” P values are assigned, the joint gene P values are calculated using Fisher’s combination test, and the association of pathways is tested using the hypergeometric test. The circular genomic permutation approach was applied to a human genome-wide association dataset. The data consists of 719 individuals from the ORCADES study genotyped for ∼300,000 SNPs and measured for 51 traits ranging from physical to biochemical measurements. KEGG pathways (n = 225) were used as the sets of pathways to be tested. Our results demonstrate that the circular genomic permutations provide robust association P values. The non-permuted hypergeometric analysis generates ∼1400 pathway-trait combination results with an association P value more significant than P ≤ 0.05, whereas applying circular genomic permutation reduces the number of significant results to a more credible 40% of that value. The circular permutation software (“genomicper”) is available as an R package at http://cran.r-project.org/

Gravitational Radiation from the Coalescence of Binary Neutron Stars: Effects Due to the Equation of State, Spin, and Mass Ratio

We calculate the gravitational radiation produced by the coalescence of inspiraling binary neutron stars in the Newtonian regime using 3-dimensional numerical simulations. The stars are modeled as polytropes and start out in the point-mass regime at wide separation. The hydrodynamic integration is performed using smooth particle hydrodynamics (SPH) with Newtonian gravity, and the gravitational radiation is calculated using the quadrupole approximation. We have run a number of simulations varying the neutron star radii, equations of state, spins, and mass ratio. The resulting gravitational waveforms and spectra are rich in information about the hydrodynamics of coalescence, and show characteristic dependence on GM/Rc^2, the equation of state, and the mass ratio.Comment: 39 pages, uses Latex 2.09. To be published in the Dec. 15, 1996 issue of Physical Review D. 16 Figures (bitmapped). Originals available in compressed Postscript format at ftp://zonker.drexel.edu/papers/PAPER2

Search for gravitational wave bursts in LIGO's third science run

We report on a search for gravitational wave bursts in data from the three LIGO interferometric detectors during their third science run. The search targets subsecond bursts in the frequency range 100-1100 Hz for which no waveform model is assumed, and has a sensitivity in terms of the root-sum-square (rss) strain amplitude of hrss ~ 10^{-20} / sqrt(Hz). No gravitational wave signals were detected in the 8 days of analyzed data.Comment: 12 pages, 6 figures. Amaldi-6 conference proceedings to be published in Classical and Quantum Gravit

Delivery of Dark Material to Vesta via Carbonaceous Chondritic Impacts

NASA's Dawn spacecraft observations of asteroid (4) Vesta reveal a surface with the highest albedo and color variation of any asteroid we have observed so far. Terrains rich in low albedo dark material (DM) have been identified using Dawn Framing Camera (FC) 0.75 {\mu}m filter images in several geologic settings: associated with impact craters (in the ejecta blanket material and/or on the crater walls and rims); as flow-like deposits or rays commonly associated with topographic highs; and as dark spots (likely secondary impacts) nearby impact craters. This DM could be a relic of ancient volcanic activity or exogenic in origin. We report that the majority of the spectra of DM are similar to carbonaceous chondrite meteorites mixed with materials indigenous to Vesta. Using high-resolution seven color images we compared DM color properties (albedo, band depth) with laboratory measurements of possible analog materials. Band depth and albedo of DM are identical to those of carbonaceous chondrite xenolith-rich howardite Mt. Pratt (PRA) 04401. Laboratory mixtures of Murchison CM2 carbonaceous chondrite and basaltic eucrite Millbillillie also show band depth and albedo affinity to DM. Modeling of carbonaceous chondrite abundance in DM (1-6 vol%) is consistent with howardite meteorites. We find no evidence for large-scale volcanism (exposed dikes/pyroclastic falls) as the source of DM. Our modeling efforts using impact crater scaling laws and numerical models of ejecta reaccretion suggest the delivery and emplacement of this DM on Vesta during the formation of the ~400 km Veneneia basin by a low-velocity (<2 km/sec) carbonaceous impactor. This discovery is important because it strengthens the long-held idea that primitive bodies are the source of carbon and probably volatiles in the early Solar System.Comment: Icarus (Accepted) Pages: 58 Figures: 15 Tables:

Analysis of LIGO data for gravitational waves from binary neutron stars

We report on a search for gravitational waves from coalescing compact binary systems in the Milky Way and the Magellanic Clouds. The analysis uses data taken by two of the three LIGO interferometers during the first LIGO science run and illustrates a method of setting upper limits on inspiral event rates using interferometer data. The analysis pipeline is described with particular attention to data selection and coincidence between the two interferometers. We establish an observational upper limit of $\mathcal{R}<$1.7 \times 10^{2}$per year per Milky Way Equivalent Galaxy (MWEG), with 90coalescence rate of binary systems in which each component has a mass in the range 1--3$M_\odot$.Comment: 17 pages, 9 figure

Detector Description and Performance for the First Coincidence Observations between LIGO and GEO

For 17 days in August and September 2002, the LIGO and GEO interferometer gravitational wave detectors were operated in coincidence to produce their first data for scientific analysis. Although the detectors were still far from their design sensitivity levels, the data can be used to place better upper limits on the flux of gravitational waves incident on the earth than previous direct measurements. This paper describes the instruments and the data in some detail, as a companion to analysis papers based on the first data.Comment: 41 pages, 9 figures 17 Sept 03: author list amended, minor editorial change

Search for Gravitational Waves from Primordial Black Hole Binary Coalescences in the Galactic Halo

We use data from the second science run of the LIGO gravitational-wave detectors to search for the gravitational waves from primordial black hole (PBH) binary coalescence with component masses in the range 0.2--$1.0 M_\odot$. The analysis requires a signal to be found in the data from both LIGO observatories, according to a set of coincidence criteria. No inspiral signals were found. Assuming a spherical halo with core radius 5 kpc extending to 50 kpc containing non-spinning black holes with masses in the range 0.2--$1.0 M_\odot$, we place an observational upper limit on the rate of PBH coalescence of 63 per year per Milky Way halo (MWH) with 90% confidence.Comment: 7 pages, 4 figures, to be submitted to Phys. Rev.

Local exome sequences facilitate imputation of less common variants and increase power of genome wide association studies

The analysis of less common variants in genome-wide association studies promises to elucidate complex trait genetics but is hampered by low power to reliably detect association. We show that addition of population-specific exome sequence data to global reference data allows more accurate imputation, particularly of less common SNPs (minor allele frequency 1–10%) in two very different European populations. The imputation improvement corresponds to an increase in effective sample size of 28–38%, for SNPs with a minor allele frequency in the range 1–3%

Cascade oxime formation, cyclization to a nitrone, and intermolecular dipolar cycloaddition.

Simple haloaldehydes, including enolisable aldehydes, were found to be suitable for the formation of cyclic products by cascade (domino) condensation, cyclisation, dipolar cycloaddition chemistry. This multi-component reaction approach to heterocyclic compounds was explored by using hydroxylamine, a selection of aldehydes, and a selection of activated dipolarophiles. Initial condensation gives intermediate oximes that undergo cyclisation with displacement of halide to give intermediate nitrones; these nitrones undergo in situ intermolecular dipolar cycloaddition reactions to give isoxazolidines. The cycloadducts from using dimethyl fumarate were treated with zinc/acetic acid to give lactam products and this provides an easy way to prepare pyrrolizinones, indolizinones, and pyrrolo[2,1-a]isoquinolinones. The chemistry is illustrated with a very short synthesis of the pyrrolizidine alkaloid macronecine and a formal synthesis of petasinecine

Genomic Runs of Homozygosity Record Population History and Consanguinity

The human genome is characterised by many runs of homozygous genotypes, where identical haplotypes were inherited from each parent. The length of each run is determined partly by the number of generations since the common ancestor: offspring of cousin marriages have long runs of homozygosity (ROH), while the numerous shorter tracts relate to shared ancestry tens and hundreds of generations ago. Human populations have experienced a wide range of demographic histories and hold diverse cultural attitudes to consanguinity. In a global population dataset, genome-wide analysis of long and shorter ROH allows categorisation of the mainly indigenous populations sampled here into four major groups in which the majority of the population are inferred to have: (a) recent parental relatedness (south and west Asians); (b) shared parental ancestry arising hundreds to thousands of years ago through long term isolation and restricted effective population size (N(e)), but little recent inbreeding (Oceanians); (c) both ancient and recent parental relatedness (Native Americans); and (d) only the background level of shared ancestry relating to continental N(e) (predominantly urban Europeans and East Asians; lowest of all in sub-Saharan African agriculturalists), and the occasional cryptically inbred individual. Moreover, individuals can be positioned along axes representing this demographic historic space. Long runs of homozygosity are therefore a globally widespread and under-appreciated characteristic of our genomes, which record past consanguinity and population isolation and provide a distinctive record of the demographic history of an individual's ancestors. Individual ROH measures will also allow quantification of the disease risk arising from polygenic recessive effects