Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Film conformality and extracted recombination probabilities of O atoms during plasma-assisted atomic layer deposition of SiO\u3csub\u3e2\u3c/sub\u3e, TiO\u3csub\u3e2\u3c/sub\u3e, Al2O\u3csub\u3e3\u3c/sub\u3e, and HfO\u3csub\u3e2\u3c/sub\u3e

Surface recombination of plasma radicals is generally considered to limit film conformality during plasma-assisted atomic layer deposition (ALD). Here, we experimentally studied film penetration into high-aspect-ratio structures and demonstrated that it can give direct information on the recombination probability r of plasma radicals on the growth surface. This is shown for recombination of oxygen (O) atoms on SiO2, TiO2, Al2O3, and HfO2 where a strong material dependence has been observed. Using extended plasma exposures, films of SiO2 and TiO2 penetrated extremely deep up to an aspect ratio (AR) of ∼900, and similar surface recombination probabilities of r = (6 ± 2) × 10–5 and (7 ± 4) × 10–5 were determined for these processes. Growth of Al2O3 and HfO2 was conformal up to depths corresponding to ARs of ∼80 and ∼40, with r estimated at (1–10) × 10–3 and (0.1–10) × 10–2, respectively. Such quantitative insight into surface recombination, as provided by our method, is essential for modeling radical-surface interaction and understanding for which materials and conditions conformal film growth is feasible by plasma-assisted ALD.\u3cbr/\u3

Sticking probabilities of H2O and Al(CH3)3 during atomic layer deposition of Al2O3 extracted from their impact on film conformality

The conformality of a film grown by atomic layer deposition (ALD) is strongly affected by the reactivities of the precursor and coreactant, which can be expressed in terms of their sticking probabilities toward the surface. We show that the leading front of the thickness profile in high-aspect-ratio structures gives direct information on the sticking probabilities of the reactants under most conditions. The slope of the front has been used to determine the sticking probabilities of Al(CH3)3 and H2O during ALD of Al2O3. The determined values are (0.5–2) × 10−3 for Al(CH3)3 and (0.8–2) × 10−4 for H2O at a set-point temperature of 275 °C, corresponding to an estimated substrate temperature of ∼220 °C. Additionally, the thickness profiles reveal soft-saturation behavior during the H2O step, most dominantly at reduced temperatures, which can limit the conformality of Al2O3 grown by ALD. This work thus provides insights regarding quantitative information on sticking probabilities and conformality during ALD, which is valuable for gaining a deeper understanding of ALD kinetics.\u3cbr/\u3