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| 3. |
- Fresard, Laure, et al.
(författare)
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Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
- 2019
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Ingår i: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:6, s. 911-919
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Tidskriftsartikel (refereegranskat)abstract
- It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
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| 4. |
- Levy, Rebecca C., et al.
(författare)
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The Morpho-kinematic Architecture of Super Star Clusters in the Center of NGC 253
- 2022
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 1538-4357 .- 0004-637X. ; 935:1
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Tidskriftsartikel (refereegranskat)abstract
- The center of the nearby galaxy NGC 253 hosts a population of more than a dozen super star clusters (SSCs) that are still in the process of forming. The majority of the star formation of the burst is concentrated in these SSCs, and the starburst is powering a multiphase outflow from the galaxy. In this work, we measure the 350 GHz dust continuum emission toward the center of NGC 253 at 47 mas (0.8 pc) resolution using data from the Atacama Large Millimeter/submillimeter Array. We report the detection of 350 GHz (dust) continuum emission in the outflow for the first time, associated with the prominent South-West streamer. In this feature, the dust emission has a width of approximate to 8 pc, is located at the outer edge of the CO emission, and corresponds to a molecular gas mass of similar to(8-17)x10(6) M (circle dot). In the starburst nucleus, we measure the resolved radial profiles, sizes, and molecular gas masses of the SSCs. Compared to previous work at the somewhat lower spatial resolution, the SSCs here break apart into smaller substructures with radii 0.4-0.7 pc. In projection, the SSCs, dust, and dense molecular gas appear to be arranged as a thin, almost linear, structure roughly 155 pc in length. The morphology and kinematics of this structure can be well explained as gas following x (2) orbits at the center of a barred potential. We constrain the morpho-kinematic arrangement of the SSCs themselves, finding that an elliptical, angular-momentum-conserving ring is a good description of both the morphology and kinematics of the SSCs.
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| 5. |
- Ntalla, Ioanna, et al.
(författare)
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Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N=293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
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| 6. |
- Peloso, Gina M, et al.
(författare)
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Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks.
- 2014
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 94:2, s. 223-232
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Tidskriftsartikel (refereegranskat)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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| 7. |
- Bolatto, Alberto D., et al.
(författare)
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ALMA Imaging of a Galactic Molecular Outflow in NGC 4945
- 2021
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 1538-4357 .- 0004-637X. ; 923:1
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Tidskriftsartikel (refereegranskat)abstract
- We present the ALMA detection of molecular outflowing gas in the central regions of NGC 4945, one of the nearest starbursts and also one of the nearest hosts of an active galactic nucleus (AGN). We detect four outflow plumes in CO J= 3 - 2 at similar to 0.3 resolution that appear to correspond to molecular gas located near the edges of the known ionized outflow cone and its (unobserved) counterpart behind the disk. The fastest and brightest of these plumes has emission reaching observed line-of-sight projected velocities of over 450 km s(-1) beyond systemic, equivalent to an estimated physical outflow velocity v greater than or similar to 600 km s(-1) for the fastest emission. Most of these plumes have corresponding emission in HCN or HCO + J= 4 - 3. We discuss a kinematic model for the outflow emission where the molecular gas has the geometry of the ionized gas cone and shares the rotation velocity of the galaxy when ejected. We use this model to explain the velocities we observe, constrain the physical speed of the ejected material, and account for the fraction of outflowing gas that is not detected due to confusion with the galaxy disk. We estimate a total molecular mass outflow rate (M) over dot(mol) similar to 20 M-circle dot yr(-1) flowing through a surface within 100 pc of the disk midplane, likely driven by a combination of the central starburst and AGN.
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| 8. |
- Emig, Kimberly L., et al.
(författare)
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Super Star Clusters in the Central Starburst of NGC 4945
- 2020
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 1538-4357 .- 0004-637X. ; 903:1
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Tidskriftsartikel (refereegranskat)abstract
- The nearby (3.8Mpc) galaxy NGC 4945 hosts a nuclear starburst and Seyfert type 2 active galactic nucleus (AGN). We use the Atacama Large Millimeter/submillimeter Array (ALMA) to image the 93 GHz (3.2 mm) free-free continuum and hydrogen recombination line emission (H40 alpha and H42 alpha) at 2.2 pc (0 12) resolution. Our observations reveal 27 bright, compact sources with FWHM sizes of 1.4-4.0 pc, which we identify as candidate super star clusters. Recombination line emission, tracing the ionizing photon rate of the candidate clusters, is detected in 15 sources, six of which have a significant synchrotron component to the 93 GHz continuum. Adopting an age of similar to 5Myr, the stellar masses implied by the ionizing photon luminosities are log(10) (M*/M-circle dot) approximate to 4.7-6.1. We fit a slope to the cluster mass distribution and find beta = -1.8 +/-.0.4. The gas masses associated with these clusters, derived from the dust continuum at 350 GHz, are typically an order of magnitude lower than the stellar mass. These candidate clusters appear to have already converted a large fraction of their dense natal material into stars and, given their small freefall times of similar to 0.05 Myr, are surviving an early volatile phase. We identify a pointlike source in 93 GHz continuum emission that is presumed to be the AGN. We do not detect recombination line emission from the AGN and place an upper limit on the ionizing photons that leak into the starburst region of Q(0).<.10(52) s(-1).
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| 9. |
- Levy, Rebecca C., et al.
(författare)
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Outflows from Super Star Clusters in the Central Starburst of NGC 253
- 2021
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 1538-4357 .- 0004-637X. ; 912:1
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Tidskriftsartikel (refereegranskat)abstract
- Young massive clusters play an important role in the evolution of their host galaxies, and feedback from the high-mass stars in these clusters can have profound effects on the surrounding interstellar medium. The nuclear starburst in the nearby galaxy NGC 253 at a distance of 3.5 Mpc is a key laboratory in which to study star formation in an extreme environment. Previous high-resolution (1.9 pc) dust continuum observations from the Atacama Large Millimeter/submillimeter Array (ALMA) discovered 14 compact, massive super star clusters (SSCs) still in formation. We present here ALMA data at 350 GHz with 28 mas (0.5 pc) resolution. We detect blueshifted absorption and redshifted emission (P-Cygni profiles) toward three of these SSCs in multiple lines, including CS 7-6 and (HCN)-C-13 4-3, which represent direct evidence for previously unobserved outflows. The mass contained in these outflows is a significant fraction of the cluster gas masses, which suggests we are witnessing a short but important phase. Further evidence of this is the finding of a molecular shell around the only SSC visible at near-IR wavelengths. We model the P-Cygni line profiles to constrain the outflow geometry, finding that the outflows must be nearly spherical. Through a comparison of the outflow properties with predictions from simulations, we find that none of the available mechanisms completely explains the observations, although dust-reprocessed radiation pressure and O star stellar winds are the most likely candidates. The observed outflows will have a very substantial effect on the clusters' evolution and star formation efficiency.
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| 10. |
- Jakobsdottir, Johanna, et al.
(författare)
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Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease
- 2016
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 12:10
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Tidskriftsartikel (refereegranskat)abstract
- We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (similar to 0.5% versus < 0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES substudy, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5-15.9), p = 6.6x10(-9)]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the beta-amyloid cascade.
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