Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps

We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci,135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency 2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).Peer reviewe

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

All-optical switching and two-photon absorption effects in long- period gratings in As2Se3 chalcogenide fibre

We show that two-photon absorption can actually improve the performance of a long-period grating switch in highly nonlinear As2Se3 chalcogenide fibre. We demonstrate numerically and experimentally low power switching behavior at pulse intensities around 65MW/cm2

Liquid crystal dynamics in a photonic crystal cavity created by selective microfluidic infiltration

A microfluidic double heterostructure cavity is created in a silicon planar photonic crystal waveguide by selective infiltration of a liquid crystal. The spectral evolution of the cavity resonances probed by evanescent coupling reveals that the liquid crystal evaporates, even at room temperature, despite its relatively low vapor pressure of 5 × 10-3 Pa. We explore the infiltration and evaporation dynamics of the liquid crystal within the cavity using a Fabry-Perot model that accounts for the joint effects of liquid volume reduction and cavity length variation due to liquid evaporation. While discussing how the pattern of the infiltrated liquid can be optimized to restrict evaporation, we find that the experimental behavior is consistent with basic microfluidic relations considering the small volumes of liquids and large surface areas present in our structure.© 2010 OS

All-optical high-speed signal processing with silicon-organic hybrid slot waveguidesx

Integrated optical circuits based on silicon-on-insulator technology are likely to become the mainstay of the photonics industry. Over recent years an impressive range of silicon-on-insulator devices has been realized, including waveguides(1,2), filters(3,4) and photonic-crystal devices(5). However, silicon-based all-optical switching is still challenging owing to the slow dynamics of two-photon generated free carriers. Here we show that silicon-organic hybrid integration overcomes such intrinsic limitations by combining the best of two worlds, using mature CMOS processing to fabricate the waveguide, and molecular beam deposition to cover it with organic molecules that efficiently mediate all-optical interaction without introducing significant absorption. We fabricate a 4-mm-long silicon-organic hybrid waveguide with a record nonlinearity coefficient of gamma approximate to 1 x 10(5) W-1 km(-1) and perform all-optical demultiplexing of 170.8 Gb s(-1) to 42.7 Gb s(-1). This is-to the best of our knowledge-the fastest silicon photonic optical signal processing demonstrated

Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps

We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency &lt;5%, 14 with estimated allelic odds ratio &gt;2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for &gt;80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA &gt;80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence). © 2018, The Author(s), under exclusive licence to Springer Nature America, Inc