Exome-wide association study to identify rare variants influencing COVID-19 outcomes : Results from the Host Genetics Initiative

Publisher Copyright: Copyright: © 2022 Butler-Laporte et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75–10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.Peer reviewe

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Anion-Dependent Cu(II) Coordination Polymers: Geometric, Magnetic and Luminescent Properties

A one-dimensional (1D) coordination polymer [Cu2(bpba)(CH3COO)4] (1) and a two-dimensional (2D) coordination polymer [Cu(bpba)2(H2O)(NO3)](NO3)∙2H2O∙MeOH (2) were synthesized by the reaction between Cu(CH3COO)2∙H2O/Cu(NO3)2∙3H2O and bis(4-pyridyl)benzylamine (bpba). The Cu(II) ions of 1 and 2 have distorted-square pyramidal coordination with a paddle-wheel structure and an octahedral geometry, respectively. By coordinating the Cu(II) ions and bpba ligands, 1 and 2 formed zigzag 1D and puckered 2D coordination polymers, respectively. Polymer 1 exhibits strong emissions at 355 and 466 nm, whereas polymer 2 exhibits strong emissions only at 464 nm. The emissions are strongly dependent on the geometry of the Cu(II) ions linked by the bpba and anionic ligands. Polymer 1 exhibits a very strong antiferromagnetic interaction within the paddle-wheel dimer, whereas polymer 2 exhibits a very weak antiferromagnetic interaction through the bpba linkers and/or space

Cooperative Spin-State Switching and Vapochromism of Mononuclear Ni(II) Complexes by Pyridine Coordination/Decoordination

International audienceTwo mononuclear Ni(II) complexes (1 and 2) have been found to display color changes upon coordination/decoordination of pyridine, resulting in their structural transformation between square-planar and octahedral geometries as well as a change in their spin state. Compound 1 changes between red (1r) and yellow (1y) upon exposure to or elimination of pyridine, while 2 undergoes a two-step transformation, changing orange 2o (S = 0) ⇄ gray 2g' (S = 1) → yellow 2y' (S = 1) depending on the reaction time. The first step (2o→2g') takes less than 45 minutes, which is significantly faster than the previously reported reaction time of one day for a Ni(II) complex/pyridine vapor system. The 2o reacting with pyridine can be easily prepared by dispersing 2g in methanol instead of annealing at high temperatures (130 °C), which can be applied to develop chemical sensors for pyridine utilizing color changes and/or magnetic switching

High-temperature spin crossover in FeIII N4O2 complexes incorporating an [R-sal2323] backbone

Of the multitude of [FeIII(R-sal2323)]X complexes reported in the literature, only four have demonstrated spin crossover (SCO). Herein, we report four additional examples of thermal spin crossover in [FeIII(R-sal2323)]X complexes (where R = Br, NEt2, and X = ClO4-, BF4-). Magnetic susceptibility measurements reveal gradual, high-temperature spin transitions in all four compounds with onsets near room temperature. To investigate the emergence of SCO behaviors being observed in these compounds, a range of intramolecular and intermolecular structural parameters were examined. The effect that ligand substituents may have on the electronic environment, as well as the effect of counterions and various intermolecular interactions on the crystal packing, were investigated and compared to the literature of [FeIII(R-sal2323)]X compounds for which magnetic measurements are reported. This comparison found that neither intramolecular subtleties nor intermolecular interactions have a large impact on whether or not these compounds are SCO active. Instead, it is shown and proposed that many compounds in the [FeIII(R-sal2323)]X family may demonstrate SCO activity if measured to higher temperatures (above 300 K). This would provide a wide range of FeIII compounds that are SCO active near or above room temperature to be explored in future work

Spin Crossover Induced by Changing the Identity of the Secondary Metal Ion from PdII to NiII in a Face-Centered FeII8MII6 Cubic Cage

The engineering of spin crossover (SCO) coordination cages is a complex endeavor with great potential in next generation multifunctional materials. Discrete metallosupramolecular cages exhibiting SCO are an exciting, though rare, class of porous polyhedral material. Incorporating the SCO property into these architectures is complicated, as there are many inter- and intramolecular factors which must be appropriately balanced. Previous investigations into the magnetic properties of a large cubic metallosupramolecular cage, [Fe8Pd6L8]28+, constructed using semi-rigid metalloligands, found that the Fe(II) centers that occupied the corners of the cubic structure did not undergo a spin transition. In this work, substitution of the linker metal on the face of the cage resulted in spin crossover behavior, as evidenced by magnetic susceptibility, Mӧssbauer and single crystal X-ray diffraction. Structural comparisons of these two cages were undertaken to shed light on the possible mechanism responsible for switching of the [Fe8MII6L8]28+ architecture from SCO inactive to active by simply changing the identity of M(II). This led to the suggestion that a possible interplay of intra- and intermolecular interactions may permit SCO in the Ni(II) analogue, 1. The distorted octahedral coordination environment of the secondary Ni(II) centers occupying the cage faces provided conformational flexibility for the eight metalloligands of the cubic architecture relative to the square planar Pd(II) environment. Meanwhile the occupation of axial coordination sites of the Ni(II) cations by CH3CN prevented the close packing of cages observed for the Pd(II) analogue, leading to a more offset, distant packing arrangement of cages in the lattice, whereby important areas of the cage that were shown to change most dramatically with SCO experienced a lesser degree of steric hindrance. Design via the effect of secondary metal centers on the flexibility of metalloligand structures and the effect of the axial donors on the packing arrangements may serve as new routes for engineering cage systems with desired magnetic properties

Spin crossover induced by changing the identity of the secondary metal ion from PdII­ to NiII in a face-centered FeII8MII6 cubic cage

Discrete spin crossover (SCO) heteronuclear cages are a rare class of material which have potential use in next-generation molecular transport and catalysis. Previous investigations of cubic cage [Fe8Pd6L8]28+ constructed using semi-rigid metalloligands, found that Fe(II) centers of the cage did not undergo spin transition. In this work, substitution of the secondary metal center at the face of the cage resulted in SCO behavior, evidenced by magnetic susceptibility, Mössbauer and single crystal X-ray diffraction. Structural comparisons of these two cages shed light on the possible interplay of inter- and intramolecular interactions associated with SCO in the Ni(II) analogue, 1. The distorted octahedral coordination environment, as well as the occupation of the CH3CN in the Ni(II) axial positions of 1, prevented close packing of cages observed in the Pd(II) analogue. This led to offset, distant packing arrangements whereby important areas within the cage underwent dramatic structural changes with the exhibition of SCO

Unique Spin Crossover Pathways Differentiated by Scan Rate in a New Dinuclear Fe(II) Triple Helicate: Mechanistic Deductions Enabled by Synchrotron Radiation Studies

The achievement of targeted properties in spin crossover (SCO) materials is complicated by often unpredictable cooperative interactions in the solid state. Herein, we report a dinuclear Fe(II) triple helicate 1, which is a rare example of a SCO material possessing two distinct magnetic behaviors that depend upon the thermal scan rate. Desolvated 1 was seen to undergo spin transition (ST) which was complete following slow cooling (1 K min-1), but incomplete ST (corresponding to 50% conversion) on fast cooling (10 K min-1). The incomplete ST observed in the latter case was accompanied by a higher temperature onset of ST, differing from TIESST (Temperature-Induced Excited Spin-State Trapping) materials. The two SCO pathways have been shown to arise from the interconversion between two structural phases (a and b), with both phases having associated high spin (HS) and low spin (LS) states. SCXRD (Single Crystal X-ray Diffraction) experiments using controlled cooling rates and a synchrotron light source enabled short collection times (2-3 minutes per dataset) which has enabled the identification of a mechanism by which the slow-cooled material may fully relax. In contrast, fast-cooled materials exhibit disordered arrangements of multiple structural phases, which has in turn revealed that the [HS-LS] ↔ [LS-HS] equilibria are controllable in the solid by varying the scan rate. Such behavior has been previously observed in solution studies, but its control in solids has not been reported up to now. This study demonstrates how intermolecular cooperativity can allow multiple distinct magnetic behaviors, and provides some insight into how [HS-LS] ↔ [LS-HS] equilibria can be controlled in the solid state, which may assist in the design of next-generation logic and signaling devices