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1.
  • Niemi, MEK, et al. (author)
  • 2021
  • swepub:Mat__t
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2.
  • Ramdas, S., et al. (author)
  • A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids
  • 2022
  • In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 109:8, s. 1366-1387
  • Journal article (peer-reviewed)abstract
    • A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.
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4.
  • Recio-Blanco, A., et al. (author)
  • Gaia Data Release 3: Chemical cartography of the Milky Way
  • 2023
  • In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 674
  • Journal article (peer-reviewed)abstract
    • Context. The motion of stars has been used to reveal details of the complex history of the Milky Way, in constant interaction with its environment. Nevertheless, to reconstruct the Galactic history puzzle in its entirety, the chemo-physical characterisation of stars is essential. Previous Gaia data releases were supported by a smaller, heterogeneous, and spatially biased mixture of chemical data from ground-based observations.Aims. Gaia Data Release 3 opens a new era of all-sky spectral analysis of stellar populations thanks to the nearly 5.6 million stars observed by the Radial Velocity Spectrometer (RVS) and parametrised by the GSP-Spec module. In this work, we aim to demonstrate the scientific quality of Gaia s Milky Way chemical cartography through a chemo-dynamical analysis of disc and halo populations.Methods. Stellar atmospheric parameters and chemical abundances provided by Gaia DR3 spectroscopy are combined with DR3 radial velocities and EDR3 astrometry to analyse the relationships between chemistry and Milky Way structure, stellar kinematics, and orbital parameters.Results. The all-sky Gaia chemical cartography allows a powerful and precise chemo-dynamical view of the Milky Way with unprecedented spatial coverage and statistical robustness. First, it reveals the strong vertical symmetry of the Galaxy and the flared structure of the disc. Second, the observed kinematic disturbances of the disc seen as phase space correlations and kinematic or orbital substructures are associated with chemical patterns that favour stars with enhanced metallicities and lower [α/Fe] abundance ratios compared to the median values in the radial distributions. This is detected both for young objects that trace the spiral arms and older populations. Several α, iron-peak elements and at least one heavy element trace the thin and thick disc properties in the solar cylinder. Third, young disc stars show a recent chemical impoverishment in several elements. Fourth, the largest chemo-dynamical sample of open clusters analysed so far shows a steepening of the radial metallicity gradient with age, which is also observed in the young field population. Finally, the Gaia chemical data have the required coverage and precision to unveil galaxy accretion debris and heated disc stars on halo orbits through their [α/Fe] ratio, and to allow the study of the chemo-dynamical properties of globular clusters. Conclusions. Gaia DR3 chemo-dynamical diagnostics open new horizons before the era of ground-based wide-field spectroscopic surveys. They unveil a complex Milky Way that is the outcome of an eventful evolution, shaping it to the present day.
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5.
  • Vallenari, A., et al. (author)
  • Gaia Data Release 3: Summary of the content and survey properties
  • 2023
  • In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 674
  • Journal article (peer-reviewed)abstract
    • Context. We present the third data release of the European Space Agency's Gaia mission, Gaia DR3. This release includes a large variety of new data products, notably a much expanded radial velocity survey and a very extensive astrophysical characterisation of Gaia sources.Aims. We outline the content and the properties of Gaia DR3, providing an overview of the main improvements in the data processing in comparison with previous data releases (where applicable) and a brief discussion of the limitations of the data in this release.Methods. The Gaia DR3 catalogue is the outcome of the processing of raw data collected with the Gaia instruments during the first 34 months of the mission by the Gaia Data Processing and Analysis Consortium.Results. The Gaia DR3 catalogue contains the same source list, celestial positions, proper motions, parallaxes, and broad band photometry in the G, GBP, and G(RP) pass-bands already present in the Early Third Data Release, Gaia EDR3. Gaia DR3 introduces an impressive wealth of new data products. More than 33 million objects in the ranges G(RVS) < 14 and 3100 < T-eff < 14 500, have new determinations of their mean radial velocities based on data collected by Gaia. We provide GRVS magnitudes for most sources with radial velocities, and a line broadening parameter is listed for a subset of these. Mean Gaia spectra are made available to the community. The Gaia DR3 catalogue includes about 1 million mean spectra from the radial velocity spectrometer, and about 220 million low-resolution blue and red prism photometer BP /RP mean spectra. The results of the analysis of epoch photometry are provided for some 10 million sources across 24 variability types. Gaia DR3 includes astrophysical parameters and source class probabilities for about 470 million and 1500 million sources, respectively, including stars, galaxies, and quasars. Orbital elements and trend parameters are provided for some 800 000 astrometric, spectroscopic and eclipsing binaries. More than 150 000 Solar System objects, including new discoveries, with preliminary orbital solutions and individual epoch observations are part of this release. Reflectance spectra derived from the epoch BP /RP spectral data are published for about 60 000 asteroids. Finally, an additional data set is provided, namely the Gaia Andromeda Photometric Survey, consisting of the photometric time series for all sources located in a 5:5 degree radius field centred on the Andromeda galaxy.Conclusions. This data release represents a major advance with respect to Gaia DR2 and Gaia EDR3 because of the unprecedented quantity, quality, and variety of source astrophysical data. To date this is the largest collection of all-sky spectrophotometry, radial velocities, variables, and astrophysical parameters derived from both low- and high-resolution spectra and includes a spectrophotometric and dynamical survey of SSOs of the highest accuracy. The non-single star content surpasses the existing data by orders of magnitude. The quasar host and galaxy light profile collection is the first such survey that is all sky and space based. The astrophysical information provided in Gaia DR3 will unleash the full potential of Gaia's exquisite astrometric, photometric, and radial velocity surveys.
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6.
  • Klioner, S. A., et al. (author)
  • Gaia Early Data Release 3: The celestial reference frame (Gaia-CRF3)
  • 2022
  • In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 667
  • Journal article (peer-reviewed)abstract
    • Context. Gaia-CRF3 is the celestial reference frame for positions and proper motions in the third release of data from the Gaia mission, Gaia DR3 (and for the early third release, Gaia EDR3, which contains identical astrometric results). The reference frame is defined by the positions and proper motions at epoch 2016.0 for a specific set of extragalactic sources in the (E)DR3 catalogue.Aims. We describe the construction of Gaia-CRF3 and its properties in terms of the distributions in magnitude, colour, and astrometric quality.Methods. Compact extragalactic sources in Gaia DR3 were identified by positional cross-matching with 17 external catalogues of quasi-stellar objects (QSO) and active galactic nuclei (AGN), followed by astrometric filtering designed to remove stellar contaminants. Selecting a clean sample was favoured over including a higher number of extragalactic sources. For the final sample, the random and systematic errors in the proper motions are analysed, as well as the radio-optical offsets in position for sources in the third realisation of the International Celestial Reference Frame (ICRF3).Results. Gaia-CRF3 comprises about 1.6 million QSO-like sources, of which 1.2 million have five-parameter astrometric solutions in Gaia DR3 and 0.4 million have six-parameter solutions. The sources span the magnitude range G = 13-21 with a peak density at 20.6 mag, at which the typical positional uncertainty is about 1 mas. The proper motions show systematic errors on the level of 12 μas yr-1 on angular scales greater than 15 deg. For the 3142 optical counterparts of ICRF3 sources in the S/X frequency bands, the median offset from the radio positions is about 0.5 mas, but it exceeds 4 mas in either coordinate for 127 sources. We outline the future of Gaia-CRF in the next Gaia data releases. Appendices give further details on the external catalogues used, how to extract information about the Gaia-CRF3 sources, potential (Galactic) confusion sources, and the estimation of the spin and orientation of an astrometric solution.
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8.
  • De Ridder, J., et al. (author)
  • Gaia Data Release 3: Pulsations in main sequence OBAF-type stars
  • 2023
  • In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 674
  • Journal article (peer-reviewed)abstract
    • Context. The third Gaia data release provides photometric time series covering 34 months for about 10 million stars. For many of those stars, a characterisation in Fourier space and their variability classification are also provided. This paper focuses on intermediate- to high-mass (IHM) main sequence pulsators (M ≥  1.3 M⊙) of spectral types O, B, A, or F, known as β Cep, slowly pulsating B (SPB), δ Sct, and γ Dor stars. These stars are often multi-periodic and display low amplitudes, making them challenging targets to analyse with sparse time series.Aims. We investigate the extent to which the sparse Gaia DR3 data can be used to detect OBAF-type pulsators and discriminate them from other types of variables. We aim to probe the empirical instability strips and compare them with theoretical predictions. The most populated variability class is that of the δ Sct variables. For these stars, we aim to confirm their empirical period-luminosity (PL) relation, and verify the relation between their oscillation amplitude and rotation.Methods. All datasets used in this analysis are part of the Gaia DR3 data release. The photometric time series were used to perform a Fourier analysis, while the global astrophysical parameters necessary for the empirical instability strips were taken from the Gaia DR3 gspphot tables, and the v sin i data were taken from the Gaia DR3 esphs tables. The δ Sct PL relation was derived using the same photometric parallax method as the one recently used to establish the PL relation for classical Cepheids using Gaia data.Results. We show that for nearby OBAF-type pulsators, the Gaia DR3 data are precise and accurate enough to pinpoint them in the Hertzsprung-Russell (HR) diagram. We find empirical instability strips covering broader regions than theoretically predicted. In particular, our study reveals the presence of fast rotating gravity-mode pulsators outside the strips, as well as the co-existence of rotationally modulated variables inside the strips as reported before in the literature. We derive an extensive period–luminosity relation for δ Sct stars and provide evidence that the relation features different regimes depending on the oscillation period. We demonstrate how stellar rotation attenuates the amplitude of the dominant oscillation mode of δ Sct stars.Conclusions. The Gaia DR3 time-series photometry already allows for the detection of the dominant (non-)radial oscillation mode in about 100 000 intermediate- and high-mass dwarfs across the entire sky. This detection capability will increase as the time series becomes longer, allowing the additional delivery of frequencies and amplitudes of secondary pulsation modes.
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9.
  • Drimmel, R., et al. (author)
  • Gaia Data Release 3: Mapping the asymmetric disc of the Milky Way
  • 2023
  • In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 674
  • Journal article (peer-reviewed)abstract
    • Context. With the most recent Gaia data release, the number of sources with complete 6D phase space information (position and velocity) has increased to well over 33 million stars, while stellar astrophysical parameters are provided for more than 470 million sources, and more than 11 million variable stars are identified.Aims. Using the astrophysical parameters and variability classifications provided in Gaia DR3, we selected various stellar populations to explore and identify non-axisymmetric features in the disc of the Milky Way in configuration and velocity space.Methods. Using more about 580 000 sources identified as hot OB stars, together with 988 known open clusters younger than 100 Myr, we mapped the spiral structure associated with star formation 4−5 kpc from the Sun. We selected over 2800 Classical Cepheids younger than 200 Myr that show spiral features extending as far as 10 kpc from the Sun in the outer disc. We also identified more than 8.7 million sources on the red giant branch (RGB), of which 5.7 million have line-of-sight velocities. This later sample allows the velocity field of the Milky Way to be mapped as far as 8 kpc from the Sun, including the inner disc.Results. The spiral structure revealed by the young populations is consistent with recent results using Gaia EDR3 astrometry and source lists based on near-infrared photometry, showing the Local (Orion) Arm to be at least 8 kpc long, and an outer arm consistent with what is seen in HI surveys, which seems to be a continuation of the Perseus arm into the third quadrant. The subset of RGB stars with velocities clearly reveals the large-scale kinematic signature of the bar in the inner disc, as well as evidence of streaming motions in the outer disc that might be associated with spiral arms or bar resonances. A local comparison of the velocity field of the OB stars reveals similarities and differences with the RGB sample.Conclusions. This cursory study of Gaia DR3 data shows there is a rich bounty of kinematic information to be explored more deeply, which will undoubtedly lead us to a clearer understanding of the dynamical nature of the non-axisymmetric structures of the Milky Way.
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10.
  • Galluccio, L., et al. (author)
  • Gaia Data Release 3: Reflectance spectra of Solar System small bodies
  • 2023
  • In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 674
  • Journal article (peer-reviewed)abstract
    • Context. The Gaia mission of the European Space Agency (ESA) has been routinely observing Solar System objects (SSOs) since the beginning of its operations in August 2014. The Gaia data release three (DR3) includes, for the first time, the mean reflectance spectra of a selected sample of 60 518 SSOs, primarily asteroids, observed between August 5, 2014, and May 28, 2017. Each reflectance spectrum was derived from measurements obtained by means of the Blue and Red photometers (BP/RP), which were binned in 16 discrete wavelength bands. For every spectrum, the DR3 also contains additional information about the data quality for each band.Aims. We describe the processing of the Gaia spectral data of SSOs, explaining both the criteria used to select the subset of asteroid spectra published in Gaia DR3, and the different steps of our internal validation procedures. In order to further assess the quality of Gaia SSO reflectance spectra, we carried out external validation against SSO reflectance spectra obtained from ground-based and space-borne telescopes and available in the literature; we present our validation approach.Methods. For each selected SSO, an epoch reflectance was computed by dividing the calibrated spectrum observed by the BP/RP at each transit on the focal plane by the mean spectrum of a solar analogue. The latter was obtained by averaging the Gaia spectral measurements of a selected sample of stars known to have very similar spectra to that of the Sun. Finally, a mean of the epoch reflectance spectra was calculated in 16 spectral bands for each SSO.Results. Gaia SSO reflectance spectra are in general agreement with those obtained from a ground-based spectroscopic campaign specifically designed to cover the same spectral interval as Gaia and mimic the illumination and observing geometry characterising Gaia SSO observations. In addition, the agreement between Gaia mean reflectance spectra and those available in the literature is good for bright SSOs, regardless of their taxonomic spectral class. We identify an increase in the spectral slope of S-type SSOs with increasing phase angle. Moreover, we show that the spectral slope increases and the depth of the 1 μm absorption band decreases for increasing ages of S-type asteroid families. The latter can be interpreted as proof of progressive ageing of S-type asteroid surfaces due to their exposure to space weathering effects.
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11.
  • Lindegren, L., et al. (author)
  • Gaia Data Release 3: A golden sample of astrophysical parameters
  • 2023
  • In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 674
  • Journal article (peer-reviewed)abstract
    • Context. Gaia Data Release 3 (DR3) provides a wealth of new data products for the astronomical community to exploit, including astrophysical parameters for half a billion stars. In this work, we demonstrate the high quality of these data products and illustrate their use in different astrophysical contexts.Aims. We produce homogeneous samples of stars with high-quality astrophysical parameters by exploiting Gaia DR3, while focusing on many regimes across the Hertzsprung-Russell (HR) diagram; spectral types OBA, FGKM, and ultracool dwarfs (UCDs). We also focus on specific subsamples of particular interest to the community: solar analogues, carbon stars, and the Gaia spectrophotometric standard stars (SPSS).Methods. We query the astrophysical parameter tables along with other tables in Gaia DR3 to derive the samples of the stars of interest. We validate our results using the Gaia catalogue itself and by comparison with external data.Results. We produced six homogeneous samples of stars with high-quality astrophysical parameters across the HR diagram for the community to exploit. We first focus on three samples that span a large parameter space: young massive disc stars (OBA; about 3 Million), FGKM spectral type stars (about 3 Million), and UCDs (about 20 000). We provide these sources along with additional information (either a flag or complementary parameters) as tables that are made available in the Gaia archive. We also identify 15 740 bone fide carbon stars and 5863 solar analogues, and provide the first homogeneous set of stellar parameters of the SPSS sample. We demonstrate some applications of these samples in different astrophysical contexts. We use a subset of the OBA sample to illustrate its usefulness in analysing the Milky Way rotation curve. We then use the properties of the FGKM stars to analyse known exoplanet systems. We also analyse the ages of some unseen UCD-companions to the FGKM stars. We additionally predict the colours of the Sun in various passbands (Gaia, 2MASS, WISE) using the solar-analogue sample.Conclusions. Gaia DR3 contains a wealth of new high-quality astrophysical parameters for the community to exploit.
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12.
  • Montegriffo, P., et al. (author)
  • Gaia Data Release 3: The Galaxy in your preferred colours: Synthetic photometry from Gaia low-resolution spectra
  • 2023
  • In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 674
  • Journal article (peer-reviewed)abstract
    • Gaia Data Release 3 provides novel flux-calibrated low-resolution spectrophotometry for ≅220 million sources in the wavelength range 330 nm ≤ λ ≤ 1050 nm (XP spectra). Synthetic photometry directly tied to a flux in physical units can be obtained from these spectra for any passband fully enclosed in this wavelength range. We describe how synthetic photometry can be obtained from XP spectra, illustrating the performance that can be achieved under a range of different conditions - for example passband width and wavelength range - as well as the limits and the problems affecting it. Existing top-quality photometry can be reproduced within a few per cent over a wide range of magnitudes and colour, for wide and medium bands, and with up to millimag accuracy when synthetic photometry is standardised with respect to these external sources. Some examples of potential scientific application are presented, including the detection of multiple populations in globular clusters, the estimation of metallicity extended to the very metal-poor regime, and the classification of white dwarfs. A catalogue providing standardised photometry for ≅2.2×108 sources in several wide bands of widely used photometric systems is provided (Gaia Synthetic Photometry Catalogue; GSPC) as well as a catalogue of ≅105 white dwarfs with DA/non-DA classification obtained with a Random Forest algorithm (Gaia Synthetic Photometry Catalogue for White Dwarfs; GSPC-WD).
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13.
  • Lindegren, L., et al. (author)
  • Gaia Data Release 3: The extragalactic content
  • 2023
  • In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 674
  • Journal article (peer-reviewed)abstract
    • The Gaia Galactic survey mission is designed and optimized to obtain astrometry, photometry, and spectroscopy of nearly two billion stars in our Galaxy. Yet as an all-sky multi-epoch survey, Gaia also observes several million extragalactic objects down to a magnitude of G 21 mag. Due to the nature of the Gaia onboard-selection algorithms, these are mostly point-source-like objects. Using data provided by the satellite, we have identified quasar and galaxy candidates via supervised machine learning methods, and estimate their redshifts using the low resolution BP/RP spectra. We further characterise the surface brightness profiles of host galaxies of quasars and of galaxies from pre-defined input lists. Here we give an overview of the processing of extragalactic objects, describe the data products in Gaia DR3, and analyse their properties. Two integrated tables contain the main results for a high completeness, but low purity (50-70%), set of 6.6 million candidate quasars and 4.8 million candidate galaxies. We provide queries that select purer sub-samples of these containing 1.9 million probable quasars and 2.9 million probable galaxies (both 95% purity). We also use high quality BP/RP spectra of 43 thousand high probability quasars over the redshift range 0.05-4.36 to construct a composite quasar spectrum spanning restframe wavelengths from 72 1000 nm.
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14.
  • Schultheis, M., et al. (author)
  • Gaia Data Release 3: Exploring and mapping the diffuse interstellar band at 862 nm
  • 2023
  • In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 674
  • Journal article (peer-reviewed)abstract
    • Context. Diffuse interstellar bands (DIBs) are common interstellar absorption features in spectroscopic observations but their origins remain unclear. DIBs play an important role in the life cycle of the interstellar medium (ISM) and can also be used to trace Galactic structure.Aims. Here, we demonstrate the capacity of the Gaia-Radial Velocity Spectrometer (RVS) in Gaia DR3 to reveal the spatial distribution of the unknown molecular species responsible for the most prominent DIB at 862 nm in the RVS passband, exploring the Galactic ISM within a few kiloparsecs from the Sun.Methods. The DIBs are measured within the GSP-Spec module using a Gaussian profile fit for cool stars and a Gaussian process for hot stars. In addition to the equivalent widths and their uncertainties, Gaia DR3 provides their characteristic central wavelength, width, and quality flags.Results. We present an extensive sample of 476 117 individual DIB measurements obtained in a homogeneous way covering the entire sky. We compare spatial distributions of the DIB carrier with interstellar reddening and find evidence that DIB carriers are present in a local bubble around the Sun which contains nearly no dust. We characterised the DIB equivalent width with a local density of 0.19 ± 0.04 kpc1 and a scale height of 98.60 8.46+11.10 pc. The latter is smaller than the dust scale height, indicating that DIBs are more concentrated towards the Galactic plane. We determine the rest-frame wavelength with unprecedented precision (?0 = 8620.86 ± 0.019 in air) and reveal a remarkable correspondence between the DIB velocities and the CO gas velocities, suggesting that the 862 nm DIB carrier is related to macro-molecules. Conclusions. We demonstrate the unique capacity of Gaia to trace the spatial structure of the Galactic ISM using the 862 nm DIB.
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15.
  • Krone-Martins, A., et al. (author)
  • Gaia Focused Product Release: A catalogue of sources around quasars to search for strongly lensed quasars
  • 2024
  • In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 685
  • Journal article (peer-reviewed)abstract
    • Context. Strongly lensed quasars are fundamental sources for cosmology. The Gaia space mission covers the entire sky with the unprecedented resolution of 0.18âà € ³ in the optical, making it an ideal instrument to search for gravitational lenses down to the limiting magnitude of 21. Nevertheless, the previous Gaia Data Releases are known to be incomplete for small angular separations such as those expected for most lenses.Aims. We present the Data Processing and Analysis Consortium GravLens pipeline, which was built to analyse all Gaia detections around quasars and to cluster them into sources, thus producing a catalogue of secondary sources around each quasar. We analysed the resulting catalogue to produce scores that indicate source configurations that are compatible with strongly lensed quasars.Methods. GravLens uses the DBSCAN unsupervised clustering algorithm to detect sources around quasars. The resulting catalogue of multiplets is then analysed with several methods to identify potential gravitational lenses. We developed and applied an outlier scoring method, a comparison between the average BP and RP spectra of the components, and we also used an extremely randomised tree algorithm. These methods produce scores to identify the most probable configurations and to establish a list of lens candidates.Results. We analysed the environment of 3 760 032 quasars. A total of 4 760 920 sources, including the quasars, were found within 6âà € ³ of the quasar positions. This list is given in the Gaia archive. In 87% of cases, the quasar remains a single source, and in 501 385 cases neighbouring sources were detected. We propose a list of 381 lensed candidates, of which we identified 49 as the most promising ones. Beyond these candidates, the associate tables in this Focused Product Release allow the entire community to explore the unique Gaia data for strong lensing studies further.
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16.
  • David, P., et al. (author)
  • Gaia Focused Product Release: Asteroid orbital solution : Properties and assessment
  • 2023
  • In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 680
  • Journal article (peer-reviewed)abstract
    • Context. We report the exploitation of a sample of Solar System observations based on data from the third Gaia Data Release (Gaia DR3) of nearly 157 000 asteroids. It extends the epoch astrometric solution over the time coverage planned for the Gaia DR4, which is not expected before the end of 2025. This data set covers more than one full orbital period for the vast majority of these asteroids. The orbital solutions are derived from the Gaia data alone over a relatively short arc compared to the observation history of many of these asteroids.Aims. The work aims to produce orbital elements for a large set of asteroids based on 66 months of accurate astrometry provided by Gaia and to assess the accuracy of these orbital solutions with a comparison to the best available orbits derived from independent observations. A second validation is performed with accurate occultation timings.Methods. We processed the raw astrometric measurements of Gaia to obtain astrometric positions of moving objects with 1D sub-mas accuracy at the bright end. For each asteroid that we matched to the data, an orbit fitting was attempted in the form of the best fit of the initial conditions at the median epoch. The force model included Newtonian and relativistic accelerations to derive the observation equations, which were solved with a linear least-squares fit.Results. Orbits are provided in the form of state vectors in the International Celestial Reference Frame for 156 764 asteroids, including near-Earth objects, main-belt asteroids, and Trojans. For the asteroids with the best observations, the (formal) relative uncertainty σa/a is better than 10-10. Results are compared to orbits available from the Jet Propulsion Laboratory and MPC. Their orbits are based on much longer data arcs, but from positions of lower quality. The relative differences in semi-major axes have a mean of 5 × 10-10 and a scatter of 5 × 10-9
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18.
  • Panuzzo, P., et al. (author)
  • Discovery of a dormant 33 solar-mass black hole in pre-release Gaia astrometry
  • 2024
  • In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 686
  • Journal article (peer-reviewed)abstract
    • Context. Gravitational waves from black-hole (BH) merging events have revealed a population of extra-galactic BHs residing in short-period binaries with masses that are higher than expected based on most stellar evolution models-And also higher than known stellar-origin black holes in our Galaxy. It has been proposed that those high-mass BHs are the remnants of massive metal-poor stars.Aims. Gaia astrometry is expected to uncover many Galactic wide-binary systems containing dormant BHs, which may not have been detected before. The study of this population will provide new information on the BH-mass distribution in binaries and shed light on their formation mechanisms and progenitors.Methods. As part of the validation efforts in preparation for the fourth Gaia data release (DR4), we analysed the preliminary astrometric binary solutions, obtained by the Gaia Non-Single Star pipeline, to verify their significance and to minimise false-detection rates in high-mass-function orbital solutions.Results. The astrometric binary solution of one source, Gaia BH3, implies the presence of a 32.70a ±a 0.82aM- BH in a binary system with a period of 11.6 yr. Gaia radial velocities independently validate the astrometric orbit. Broad-band photometric and spectroscopic data show that the visible component is an old, very metal-poor giant of the Galactic halo, at a distance of 590 pc.Conclusions. The BH in the Gaia BH3 system is more massive than any other Galactic stellar-origin BH known thus far. The low metallicity of the star companion supports the scenario that metal-poor massive stars are progenitors of the high-mass BHs detected by gravitational-wave telescopes. The Galactic orbit of the system and its metallicity indicate that it might belong to the Sequoia halo substructure. Alternatively, and more plausibly, it could belong to the ED-2 stream, which likely originated from a globular cluster that had been disrupted by the Milky Way.
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19.
  • Trabucchi, M., et al. (author)
  • Gaia Focused Product Release: Radial velocity time series of long-period variables
  • 2023
  • In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 680
  • Journal article (peer-reviewed)abstract
    • Context. The third Gaia Data Release (DR3) provided photometric time series of more than 2 million long-period variable (LPV) candidates. Anticipating the publication of full radial-velocity data planned with Data Release 4, this Focused Product Release (FPR) provides radial-velocity time series for a selection of LPV candidates with high-quality observations.Aims. We describe the production and content of the Gaia catalog of LPV radial-velocity time series, and the methods used to compute the variability parameters published as part of the Gaia FPR.Methods. Starting from the DR3 catalog of LPV candidates, we applied several filters to construct a sample of sources with high-quality radial-velocity measurements. We modeled their radial-velocity and photometric time series to derive their periods and amplitudes, and further refined the sample by requiring compatibility between the radial-velocity period and at least one of the G, GBP, or GRP photometric periods.Results. The catalog includes radial-velocity time series and variability parameters for 9614 sources in the magnitude range 6 ≲ G/mag ≲ 14, including a flagged top-quality subsample of 6093 stars whose radial-velocity periods are fully compatible with the values derived from the G, GBP, and GRP photometric time series. The radial-velocity time series contain a mean of 24 measurements per source taken unevenly over a duration of about three years. We identify the great majority of the sources (88%) as genuine LPV candidates, with about half of them showing a pulsation period and the other half displaying a long secondary period. The remaining 12% of the catalog consists of candidate ellipsoidal binaries. Quality checks against radial velocities available in the literature show excellent agreement. We provide some illustrative examples and cautionary remarks.Conclusions. The publication of radial-velocity time series for almost ten thousand LPV candidates constitutes, by far, the largest such database available to date in the literature. The availability of simultaneous photometric measurements gives a unique added value to the Gaia catalog.
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20.
  • Weingrill, K., et al. (author)
  • Gaia Focused Product Release: Sources from Service Interface Function image analysis: Half a million new sources in omega Centauri
  • 2023
  • In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 680
  • Journal article (peer-reviewed)abstract
    • Context. Gaia's readout window strategy is challenged by very dense fields in the sky. Therefore, in addition to standard Gaia observations, full Sky Mapper (SM) images were recorded for nine selected regions in the sky. A new software pipeline exploits these Service Interface Function (SIF) images of crowded fields (CFs), making use of the availability of the full two-dimensional (2D) information. This new pipeline produced half a million additional Gaia sources in the region of the omega Centauri (ω Cen) cluster, which are published with this Focused Product Release. We discuss the dedicated SIF CF data reduction pipeline, validate its data products, and introduce their Gaia archive table.Aims. Our aim is to improve the completeness of the Gaia source inventory in a very dense region in the sky, ω Cen.Methods. An adapted version of Gaia's Source Detection and Image Parameter Determination software located sources in the 2D SIF CF images. These source detections were clustered and assigned to new SIF CF or existing Gaia sources by Gaia s cross-match software. For the new sources, astrometry was calculated using the Astrometric Global Iterative Solution software, and photometry was obtained in the Gaia DR3 reference system. We validated the results by comparing them to the public Gaia DR3 catalogue and external Hubble Space Telescope data.Results. With this Focused Product Release, 526 587 new sources have been added to the Gaia catalogue in ω Cen. Apart from positions and brightnesses, the additional catalogue contains parallaxes and proper motions, but no meaningful colour information. While SIF CF source parameters generally have a lower precision than nominal Gaia sources, in the cluster centre they increase the depth of the combined catalogue by three magnitudes and improve the source density by a factor of ten.Conclusions. This first SIF CF data publication already adds great value to the Gaia catalogue. It demonstrates what to expect for the fourth Gaia catalogue, which will contain additional sources for all nine SIF CF regions.
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21.
  • Lindegren, Lennart, et al. (author)
  • Gaia Early Data Release 3 : The Gaia Catalogue of Nearby Stars
  • 2021
  • In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 649
  • Journal article (peer-reviewed)abstract
    • Aims. We produce a clean and well-characterised catalogue of objects within 100 pc of the Sun from the Gaia Early Data Release 3. We characterise the catalogue through comparisons to the full data release, external catalogues, and simulations. We carry out a first analysis of the science that is possible with this sample to demonstrate its potential and best practices for its use.Methods. Theselection of objects within 100 pc from the full catalogue used selected training sets, machine-learning procedures, astrometric quantities, and solution quality indicators to determine a probability that the astrometric solution is reliable. The training set construction exploited the astrometric data, quality flags, and external photometry. For all candidates we calculated distance posterior probability densities using Bayesian procedures and mock catalogues to define priors. Any object with reliable astrometry and a non-zero probability of being within 100 pc is included in the catalogue.Results. We have produced a catalogue of 331 312 objects that we estimate contains at least 92% of stars of stellar type M9 within 100 pc of the Sun. We estimate that 9% of the stars in this catalogue probably lie outside 100 pc, but when the distance probability function is used, a correct treatment of this contamination is possible. We produced luminosity functions with a high signal-to-noise ratio for the main-sequence stars, giants, and white dwarfs. We examined in detail the Hyades cluster, the white dwarf population, and wide-binary systems and produced candidate lists for all three samples. We detected local manifestations of several streams, superclusters, and halo objects, in which we identified 12 members of Gaia Enceladus. We present the first direct parallaxes of five objects in multiple systems within 10 pc of the Sun.Conclusions. We provide the community with a large, well-characterised catalogue of objects in the solar neighbourhood. This is a primary benchmark for measuring and understanding fundamental parameters and descriptive functions in astronomy.
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22.
  • Schultheis, M., et al. (author)
  • Gaia Focused Product Release: Spatial distribution of two diffuse interstellar bands
  • 2023
  • In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 680
  • Journal article (peer-reviewed)abstract
    • Diffuse interstellar bands (DIBs) are absorption features seen in optical and infrared spectra of stars and extragalactic objects that are probably caused by large and complex molecules in the galactic interstellar medium (ISM). Here we investigate the Galactic distribution and properties of two DIBs identified in almost six million stellar spectra collected by the Gaia Radial Velocity Spectrometer. These measurements constitute a part of the Gaia Focused Product Release to be made public between the Gaia DR3 and DR4 data releases. In order to isolate the DIB signal from the stellar features in each individual spectrum, we identified a set of 160 000 spectra at high Galactic latitudes (|b| ≥ 65) covering a range of stellar parameters which we consider to be the DIB-free reference sample. Matching each target spectrum to its closest reference spectra in stellar parameter space allowed us to remove the stellar spectrum empirically, without reference to stellar models, leaving a set of six million ISM spectra. Using the star's parallax and sky coordinates, we then allocated each ISM spectrum to a voxel (VOlume piXEL) on a contiguous three-dimensional grid with an angular size of 1.8 (level 5 HEALPix) and 29 unequally sized distance bins. Identifying the two DIBs at 862.1 nm (λ862.1) and 864.8 nm (λ864.8) in the stacked spectra, we modelled their shapes and report the depth, central wavelength, width, and equivalent width (EW) for each, along with confidence bounds on these measurements. We then explored the properties and distributions of these quantities and compared them with similar measurements from other surveys. Our main results are as follows: (1) the strength and spatial distribution of the DIB λ862.1 are very consistent with what was found in Gaia DR3, but for this work we attained a higher signal-to-noise ratio in the stacked spectra to larger distances, which allowed us to trace DIBs in the outer spiral arm and beyond the Scutum-Centaurus spiral arm; (2) we produced an all-sky map below ±65 of Galactic latitude to ∼4000 pc of both DIB features and their correlations; (3) we detected the signals of DIB λ862.1 inside the Local Bubble (≲200 pc); and (4) there is a reasonable correlation with the dust reddening found from stellar absorption and EWs of both DIBs with a correlation coefficient of 0.90 for λ862.1 and 0.77 for λ864.8.
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23.
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24.
  • Bellenguez, C, et al. (author)
  • New insights into the genetic etiology of Alzheimer's disease and related dementias
  • 2022
  • In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:4, s. 412-436
  • Journal article (peer-reviewed)abstract
    • Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
  •  
25.
  • Barausse, Enrico, et al. (author)
  • Prospects for fundamental physics with LISA
  • 2020
  • In: General Relativity and Gravitation. - : SPRINGER/PLENUM PUBLISHERS. - 0001-7701 .- 1572-9532. ; 52:8
  • Journal article (other academic/artistic)abstract
    • In this paper, which is of programmatic rather than quantitative nature, we aim to further delineate and sharpen the future potential of the LISA mission in the area of fundamental physics. Given the very broad range of topics that might be relevant to LISA,we present here a sample of what we view as particularly promising fundamental physics directions. We organize these directions through a "science-first" approach that allows us to classify how LISA data can inform theoretical physics in a variety of areas. For each of these theoretical physics classes, we identify the sources that are currently expected to provide the principal contribution to our knowledge, and the areas that need further development. The classification presented here should not be thought of as cast in stone, but rather as a fluid framework that is amenable to change with the flow of new insights in theoretical physics.
  •  
26.
  • Kanoni, Stavroula, et al. (author)
  • Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
  • 2022
  • In: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
  • Journal article (peer-reviewed)abstract
    • Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
  •  
27.
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28.
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29.
  • Marouli, Eirini, et al. (author)
  • Rare and low-frequency coding variants alter human adult height
  • 2017
  • In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
  • Journal article (peer-reviewed)abstract
    • Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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30.
  • Turcot, Valerie, et al. (author)
  • Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
  • 2018
  • In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41
  • Journal article (peer-reviewed)abstract
    • Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
  •  
31.
  • Wessel, Jennifer, et al. (author)
  • Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
  • 2015
  • In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
  • Journal article (peer-reviewed)abstract
    • Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF = 1.4%) with lower FG (beta = -0.09 +/- 0.01 mmol l(-1), P = 3.4 x 10(-12)), T2D risk (OR[95% CI] = 0.86[0.76-0.96], P = 0.010), early insulin secretion (beta = -0.07 +/- 0.035 pmol(insulin) mmol(glucose)(-1), P = 0.048), but higher 2-h glucose (beta = 0.16 +/- 0.05 mmol l(-1), P = 4.3 x 10(-4)). We identify a gene-based association with FG at G6PC2 (p(SKAT) = 6.8 x 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF = 20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (beta = 0.02 +/- 0.004 mmol l(-1), P = 1.3 x 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
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32.
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33.
  • Justice, Anne E., et al. (author)
  • Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
  • 2019
  • In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:3, s. 452-469
  • Journal article (peer-reviewed)abstract
    • Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF >= 5%) and nine low-frequency or rare (MAF < 5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
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34.
  • Mahajan, Anubha, et al. (author)
  • Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes
  • 2018
  • In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:4, s. 559-571
  • Journal article (peer-reviewed)abstract
    • We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10−7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent ‘false leads’ with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.
  •  
35.
  • Eicher, John D., et al. (author)
  • Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals
  • 2016
  • In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 99:1, s. 40-55
  • Journal article (peer-reviewed)abstract
    • Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common(ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV(PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.
  •  
36.
  • Teslovich, Tanya M., et al. (author)
  • Biological, clinical and population relevance of 95 loci for blood lipids
  • 2010
  • In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 466:7307, s. 707-713
  • Journal article (peer-reviewed)abstract
    • Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P<5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
  •  
37.
  • Do, Ron, et al. (author)
  • Common variants associated with plasma triglycerides and risk for coronary artery disease
  • 2013
  • In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1345-
  • Journal article (peer-reviewed)abstract
    • Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 x 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
  •  
38.
  • Lange, Leslie A, et al. (author)
  • Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol.
  • 2014
  • In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 94:2, s. 233-245
  • Journal article (peer-reviewed)abstract
    • Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.
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39.
  • Willer, Cristen J., et al. (author)
  • Discovery and refinement of loci associated with lipid levels
  • 2013
  • In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1274-1283
  • Journal article (peer-reviewed)abstract
    • Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 x 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
  •  
40.
  • Scott, Robert A., et al. (author)
  • A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease
  • 2016
  • In: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 8:341
  • Journal article (peer-reviewed)abstract
    • Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.
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41.
  • Webb, Thomas R., et al. (author)
  • Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease
  • 2017
  • In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 69:7, s. 823-836
  • Journal article (peer-reviewed)abstract
    • BACKGROUND Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits.OBJECTIVES This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci.METHODS In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs.RESULTS We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 x 10(-4) with a range of other diseases/traits.CONCLUSIONS We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.
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42.
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43.
  • Peloso, Gina M, et al. (author)
  • Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks.
  • 2014
  • In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 94:2, s. 223-232
  • Journal article (peer-reviewed)abstract
    • Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121(∗)], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.
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44.
  • Stitziel, Nathan O., et al. (author)
  • Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease
  • 2016
  • In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 374:12, s. 1134-1144
  • Journal article (peer-reviewed)abstract
    • BACKGROUND The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets. METHODS Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes. RESULTS We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P = 4.2x10(-10)) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P = 4.0x10(-8)), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P = 0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P = 0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P = 2.0x10(-4)) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P = 2.5x10(-7)). CONCLUSIONS We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease.
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45.
  • Crosby, Jacy, et al. (author)
  • Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease
  • 2014
  • In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 371:1, s. 22-31
  • Journal article (peer-reviewed)abstract
    • Background Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype. Methods We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons. Results An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G -> A and IVS3+1G -> T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1x10(-20)), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P = 8x10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P = 4x10(-6)). Conclusions Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.)
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46.
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47.
  • Huffman, JE, et al. (author)
  • Multi-ancestry fine mapping implicates OAS1 splicing in risk of severe COVID-19
  • 2022
  • In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:2, s. 125-
  • Journal article (peer-reviewed)abstract
    • The OAS1/2/3 cluster has been identified as a risk locus for severe COVID-19 among individuals of European ancestry, with a protective haplotype of approximately 75 kilobases (kb) derived from Neanderthals in the chromosomal region 12q24.13. This haplotype contains a splice variant of OAS1, which occurs in people of African ancestry independently of gene flow from Neanderthals. Using trans-ancestry fine-mapping approaches in 20,779 hospitalized cases, we demonstrate that this splice variant is likely to be the SNP responsible for the association at this locus, thus strongly implicating OAS1 as an effector gene influencing COVID-19 severity.
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48.
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49.
  • Huffman, J, et al. (author)
  • Alternative splicing of OAS1 alters the risk for severe COVID-19
  • 2021
  • In: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory.
  • Journal article (other academic/artistic)abstract
    • A locus containing OAS1/2/3 has been identified as a risk locus for severe COVID-19 among Europeans ancestry individuals, with a protective haplotype of ∼75 kilobases derived from Neanderthals. Here, we show that among several potentially causal variants at this locus, a splice variant of OAS1 occurs in people of African ancestry independently of the Neanderthal haplotype and confers protection against COVID-19 of a magnitude similar to that seen in individuals without African ancestry.
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50.
  • Kathiresan, Sekar, et al. (author)
  • Common variants at 30 loci contribute to polygenic dyslipidemia
  • 2009
  • In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:1, s. 56-65
  • Journal article (peer-reviewed)abstract
    • Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 x 10(-8)), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10(-15) for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.
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