Genetic associations of protein-coding variants in human disease

Genome-wide association studies (GWAS) have identified thousands of genetic variants linked to the risk of human disease. However, GWAS have so far remained largely underpowered in relation to identifying associations in the rare and low-frequency allelic spectrum and have lacked the resolution to trace causal mechanisms to underlying genes(1). Here we combined whole-exome sequencing in 392,814 UK Biobank participants with imputed genotypes from 260,405 FinnGen participants (653,219 total individuals) to conduct association meta-analyses for 744 disease endpoints across the protein-coding allelic frequency spectrum, bridging the gap between common and rare variant studies. We identified 975 associations, with more than one-third being previously unreported. We demonstrate population-level relevance for mutations previously ascribed to causing single-gene disorders, map GWAS associations to likely causal genes, explain disease mechanisms, and systematically relate disease associations to levels of 117 biomarkers and clinical-stage drug targets. Combining sequencing and genotyping in two population biobanks enabled us to benefit from increased power to detect and explain disease associations, validate findings through replication and propose medical actionability for rare genetic variants. Our study provides a compendium of protein-coding variant associations for future insights into disease biology and drug discovery. A meta-analysis combining whole-exome sequencing data from UK Biobank participants and imputed genotypes from FinnGen participants enables identification of genetic associations with human disease in the rare and low-frequency allelic spectrumPeer reviewe

Poly[[tetra­kis­(μ2-pyrazine N,N′-dioxide-κ2 O:O′)holmium(III)] tris­(perchlorate)]

The title three-dimensional coordination network, {[Ho(C4H4N2O2)4](ClO4)3}n, is isostructural to that of other lanthanides. The Ho+3 cation lies on a fourfold roto-inversion axis. It is coordinated in a distorted square anti-prismatic fashion by eight O atoms from bridging pyrazine N,N′-dioxide ligands. There are two unique pyrazine N,N′-dioxide ligands. One ring is located around an inversion center, and there is a a twofold rotation axis at the center of the other ring. There are also two unique perchlorate anions. One is centered on a twofold rotation axis and the other on a fourfold roto-inversion axis. The perchlorate anions are located in channels that run perpendicular to (001) (110) and inter­act with the coordination network through C—H⋯O hydrogen bonds

Existence and conditional energetic stability of three-dimensional fully localised solitary gravity-capillary water waves

In this paper we show that the hydrodynamic problem for three-dimensional water waves with strong surface-tension effects admits a fully localised solitary wave which decays to the undisturbed state of the water in every horizontal direction. The proof is based upon the classical variational principle that a solitary wave of this type is a critical point of the energy subject to the constraint that the momentum is fixed. We prove the existence of a minimiser of the energy subject to the constraint that the momentum is fixed and small. The existence of a small-amplitude solitary wave is thus assured, and since the energy and momentum are both conserved quantities a standard argument may be used to establish the stability of the set of minimisers as a whole. `Stability' is however understood in a qualified sense due to the lack of a global well-posedness theory for three-dimensional water waves.Comment: 83 pages, 1 figur

Poly[[tetra­kis­(μ2-pyrazine N,N′-dioxide-κ2 O:O′)erbium(III)] tris­(perchlorate)]

The title three-dimensional coordination network, {[Er(C4H4N2O2)4](ClO4)3}n, is isostructural to that of other lanthanides. The Er+3 cation lies on a fourfold roto-inversion axis. It is coordinated in a distorted square-anti­prismatic fashion by eight O atoms from bridging pyrazine N,N′-dioxide ligands. There are two unique pyrazine N,N′-dioxide ligands. One ring is located around an inversion center, and there is a a twofold rotation axis at the center of the other ring. There are also two unique perchlorate anions. One is centered on a twofold rotation axis and the other on a fourfold roto-inversion axis. The perchlorate anions are located in channels that run perpendicular to (001) and (110) and inter­act with the coordination network through C—H⋯O hydrogen bonds

Surface acoustic wave devices on bulk ZnO at low temperature

Surface acoustic wave (SAW) devices based on thin films of ZnO are a well established technology. However, SAW devices on bulk ZnO crystals are not practical at room temperature due to the significant damping caused by finite electrical conductivity of the crystal. Here, by operating at low temperatures, we demonstrate effective SAW devices on the (0001) surface of bulk ZnO crystals, including a delay line operating at SAW wavelengths of {\lambda} = 4 and 6 {\mu}m and a one-port resonator at a wavelength of {\lambda} = 1.6 {\mu}m. We find that the SAW velocity is temperature dependent, reaching $v \simeq 2.68$ km/s at 10mK. Our resonator reaches a maximum quality factor of $Q_i \simeq 1.5\times 10^5$, demonstrating that bulk ZnO is highly viable for low temperature SAW applications. The performance of the devices is strongly correlated with the bulk conductivity, which quenches SAW transmission above about 200 K.Comment: 4 pages, 3 figure

Understanding the agglomerate crystallisation of hexamine through X-ray microscopy and crystallographic modelling

© 2022 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/The detailed molecular-scale mechanism of the growth of organic crystals underpins a diversity of phenomena, such as the isolation and purification of high-quality materials for the pharmaceutical and fine chemical sectors. Recent advances in X-ray Microscopy (XRM) and complementary diffraction contrast tomography (DCT) have enabled the detailed characterisation of the micro-structure of hexamine agglomerates. Detailed XRM analysis of the growth history and micro-structure of such agglomerates reveals a highly orientated epitaxial inter-relationship between their constituent micro-crystallites. This is found to be consistent with a secondary nucleation growth mechanism associated with re-growth at the 3-fold corner sites within the crystals’ dominant {1 1 0} dodecahedral morphology. The agglomeration appears to heal upon further growth as the aligned agglomerated micro-crystals connect and fuse together but, in doing so, pockets of inter-crystallite mother liquor become trapped forming a symmetric pattern of solvent inclusions. The mechanistic origin of this phenomenon is rationalised with respect to historical data together with an analysis of the solid-state chemistry of the compound through the development of a ‘snow flake’ model. The latter draws upon hexamine's propensity for edge growth instabilities with increasing crystal size as well as its tendency for unstable growth at the facet corners along the 〈1 1 1〉 directions, a situation compounded by the lack of growth-promoting dislocations at the centers of the {1 1 0} habit surfaces. The agglomerative mechanism presented here could apply to other high symmetry crystal systems, particularly those whose crystal structures involve centred Bravais lattices and where the dominant inter-molecular interactions are angled towards the facet edges.Peer reviewe