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- Clark, DW, et al.
(författare)
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Associations of autozygosity with a broad range of human phenotypes
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4957-
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Tidskriftsartikel (refereegranskat)abstract
- In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
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- Reinbold, C. S., et al.
(författare)
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Analysis of the Influence of microRNAs in Lithium Response in Bipolar Disorder
- 2018
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Ingår i: Frontiers in Psychiatry. - : Frontiers Media SA. - 1664-0640. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen) Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD associated miRNAs However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset (n = 2,563 patients) using a set-based testing approach adapted from the versatile gene based test for GWAS (VEGAS2). In the candidate approach, miR-499a showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with miR-633 showing the strongest association with the continuous trait (p = 9.80E-04) and miR-607 with the dichotomous phenotype (p = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted.
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- Wuttke, Matthias, et al.
(författare)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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- Akiyama, Kazunori, et al.
(författare)
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First M87 Event Horizon Telescope Results. I. the Shadow of the Supermassive Black Hole
- 2019
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Ingår i: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 875:1
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Tidskriftsartikel (refereegranskat)abstract
- When surrounded by a transparent emission region, black holes are expected to reveal a dark shadow caused by gravitational light bending and photon capture at the event horizon. To image and study this phenomenon, we have assembled the Event Horizon Telescope, a global very long baseline interferometry array observing at a wavelength of 1.3 mm. This allows us to reconstruct event-horizon-scale images of the supermassive black hole candidate in the center of the giant elliptical galaxy M87. We have resolved the central compact radio source as an asymmetric bright emission ring with a diameter of 42 ±3 μas, which is circular and encompasses a central depression in brightness with a flux ratio ≈10:1. The emission ring is recovered using different calibration and imaging schemes, with its diameter and width remaining stable over four different observations carried out in different days. Overall, the observed image is consistent with expectations for the shadow of a Kerr black hole as predicted by general relativity. The asymmetry in brightness in the ring can be explained in terms of relativistic beaming of the emission from a plasma rotating close to the speed of light around a black hole. We compare our images to an extensive library of ray-traced general-relativistic magnetohydrodynamic simulations of black holes and derive a central mass of M =(6.5 ±0.7) ×10 9 M o . Our radio-wave observations thus provide powerful evidence for the presence of supermassive black holes in centers of galaxies and as the central engines of active galactic nuclei. They also present a new tool to explore gravity in its most extreme limit and on a mass scale that was so far not accessible.
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- Akiyama, Kazunori, et al.
(författare)
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First M87 Event Horizon Telescope Results. II. Array and Instrumentation
- 2019
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Ingår i: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 875:1
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Tidskriftsartikel (refereegranskat)abstract
- The Event Horizon Telescope (EHT) is a very long baseline interferometry (VLBI) array that comprises millimeter- and submillimeter-wavelength telescopes separated by distances comparable to the diameter of the Earth. At a nominal operating wavelength of ∼1.3 mm, EHT angular resolution (λ/D) is ∼25 μas, which is sufficient to resolve nearby supermassive black hole candidates on spatial and temporal scales that correspond to their event horizons. With this capability, the EHT scientific goals are to probe general relativistic effects in the strong-field regime and to study accretion and relativistic jet formation near the black hole boundary. In this Letter we describe the system design of the EHT, detail the technology and instrumentation that enable observations, and provide measures of its performance. Meeting the EHT science objectives has required several key developments that have facilitated the robust extension of the VLBI technique to EHT observing wavelengths and the production of instrumentation that can be deployed on a heterogeneous array of existing telescopes and facilities. To meet sensitivity requirements, high-bandwidth digital systems were developed that process data at rates of 64 gigabit s -1 , exceeding those of currently operating cm-wavelength VLBI arrays by more than an order of magnitude. Associated improvements include the development of phasing systems at array facilities, new receiver installation at several sites, and the deployment of hydrogen maser frequency standards to ensure coherent data capture across the array. These efforts led to the coordination and execution of the first Global EHT observations in 2017 April, and to event-horizon-scale imaging of the supermassive black hole candidate in M87.
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| 10. |
- Akiyama, Kazunori, et al.
(författare)
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First M87 Event Horizon Telescope Results. III. Data Processing and Calibration
- 2019
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Ingår i: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 875:1
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Tidskriftsartikel (refereegranskat)abstract
- We present the calibration and reduction of Event Horizon Telescope (EHT) 1.3 mm radio wavelength observations of the supermassive black hole candidate at the center of the radio galaxy M87 and the quasar 3C 279, taken during the 2017 April 5-11 observing campaign. These global very long baseline interferometric observations include for the first time the highly sensitive Atacama Large Millimeter/submillimeter Array (ALMA); reaching an angular resolution of 25 μas, with characteristic sensitivity limits of ∼1 mJy on baselines to ALMA and ∼10 mJy on other baselines. The observations present challenges for existing data processing tools, arising from the rapid atmospheric phase fluctuations, wide recording bandwidth, and highly heterogeneous array. In response, we developed three independent pipelines for phase calibration and fringe detection, each tailored to the specific needs of the EHT. The final data products include calibrated total intensity amplitude and phase information. They are validated through a series of quality assurance tests that show consistency across pipelines and set limits on baseline systematic errors of 2% in amplitude and 1° in phase. The M87 data reveal the presence of two nulls in correlated flux density at ∼3.4 and ∼8.3 Gλ and temporal evolution in closure quantities, indicating intrinsic variability of compact structure on a timescale of days, or several light-crossing times for a few billion solar-mass black hole. These measurements provide the first opportunity to image horizon-scale structure in M87.
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