Follow-up of loci from the International Genomics of Alzheimer's Disease Project identifies TRIP4 as a novel susceptibility gene

To follow-up loci discovered by the International Genomics of Alzheimer's Disease Project, we attempted independent replication of 19 single nucleotide polymorphisms (SNPs) in a large Spanish sample (Fundació ACE data set; 1808 patients and 2564 controls). Our results corroborate association with four SNPs located in the genes INPP5D, MEF2C, ZCWPW1 and FERMT2, respectively. Of these, ZCWPW1 was the only SNP to withstand correction for multiple testing (P=0.000655). Furthermore, we identify TRIP4 (rs74615166) as a novel genome-wide significant locus for Alzheimer's disease risk (odds ratio=1.31; confidence interval 95% (1.19-1.44); P=9.74 × 10 - 9)

Shared genetic contribution to ischemic stroke and Alzheimer's disease

Objective Increasing evidence suggests epidemiological and pathological links between Alzheimer's disease (AD) and ischemic stroke (IS). We investigated the evidence that shared genetic factors underpin the two diseases. Methods Using genome-wide association study (GWAS) data from METASTROKE + (15,916 IS cases and 68,826 controls) and the International Genomics of Alzheimer's Project (IGAP; 17,008 AD cases and 37,154 controls), we evaluated known associations with AD and IS. On the subset of data for which we could obtain compatible genotype-level data (4,610 IS cases, 1,281 AD cases, and 14,320 controls), we estimated the genome-wide genetic correlation (rG) between AD and IS, and the three subtypes (cardioembolic, small vessel, and large vessel), using genome-wide single-nucleotide polymorphism (SNP) data. We then performed a meta-analysis and pathway analysis in the combined AD and small vessel stroke data sets to identify the SNPs and molecular pathways through which disease risk may be conferred. Results We found evidence of a shared genetic contribution between AD and small vessel stroke (rG [standard error] = 0.37 [0.17]; p = 0.011). Conversely, there was no evidence to support shared genetic factors in AD and IS overall or with the other stroke subtypes. Of the known GWAS associations with IS or AD, none reached significance for association with the other trait (or stroke subtypes). A meta-analysis of AD IGAP and METASTROKE + small vessel stroke GWAS data highlighted a region (ATP5H/KCTD2/ICT1) associated with both diseases (p = 1.8 × 10-8). A pathway analysis identified four associated pathways involving cholesterol transport and immune response. Interpretation Our findings indicate shared genetic susceptibility to AD and small vessel stroke and highlight potential causal pathways and loci. Ann Neurol 2016;79:739-74

What does an interferometer really measure? Including instrument and data characteristics in the reconstruction of the 21cm power spectrum

Combining the visibilities measured by an interferometer to form a cosmological power spectrum is a complicated process in which the window functions play a crucial role. In a delay-based analysis, the mapping between instrumental space, made of per-baseline delay spectra, and cosmological space is not a one-to-one relation. Instead, neighbouring modes contribute to the power measured at one point, with their respective contributions encoded in the window functions. To better understand the power spectrum measured by an interferometer, we assess the impact of instrument characteristics and analysis choices on the estimator by deriving its exact window functions, outside of the delay approximation. Focusing on HERA as a case study, we find that observations made with long baselines tend to correspond to enhanced low-k tails of the window functions, which facilitate foreground leakage outside the wedge, whilst the choice of bandwidth and frequency taper can help narrow them down. With the help of simple test cases and more realistic visibility simulations, we show that, apart from tracing mode mixing, the window functions can accurately reconstruct the power spectrum estimator of simulated visibilities. We note that the window functions depend strongly on the chromaticity of the beam, and less on its spatial structure - a Gaussian approximation, ignoring side lobes, is sufficient. Finally, we investigate the potential of asymmetric window functions, down-weighting the contribution of low-k power to avoid foreground leakage. The window functions presented in this work correspond to the latest HERA upper limits for the full Phase I data. They allow an accurate reconstruction of the power spectrum measured by the instrument and can be used in future analyses to confront theoretical models and data directly in cylindrical space.Comment: 18 pages, 18 figures, submitted to MNRAS. Comments welcome

Characterization Of Inpaint Residuals In Interferometric Measurements of the Epoch Of Reionization

Radio Frequency Interference (RFI) is one of the systematic challenges preventing 21cm interferometric instruments from detecting the Epoch of Reionization. To mitigate the effects of RFI on data analysis pipelines, numerous inpaint techniques have been developed to restore RFI corrupted data. We examine the qualitative and quantitative errors introduced into the visibilities and power spectrum due to inpainting. We perform our analysis on simulated data as well as real data from the Hydrogen Epoch of Reionization Array (HERA) Phase 1 upper limits. We also introduce a convolutional neural network that capable of inpainting RFI corrupted data in interferometric instruments. We train our network on simulated data and show that our network is capable at inpainting real data without requiring to be retrained. We find that techniques that incorporate high wavenumbers in delay space in their modeling are best suited for inpainting over narrowband RFI. We also show that with our fiducial parameters Discrete Prolate Spheroidal Sequences (DPSS) and CLEAN provide the best performance for intermittent ``narrowband'' RFI while Gaussian Progress Regression (GPR) and Least Squares Spectral Analysis (LSSA) provide the best performance for larger RFI gaps. However we caution that these qualitative conclusions are sensitive to the chosen hyperparameters of each inpainting technique. We find these results to be consistent in both simulated and real visibilities. We show that all inpainting techniques reliably reproduce foreground dominated modes in the power spectrum. Since the inpainting techniques should not be capable of reproducing noise realizations, we find that the largest errors occur in the noise dominated delay modes. We show that in the future, as the noise level of the data comes down, CLEAN and DPSS are most capable of reproducing the fine frequency structure in the visibilities of HERA data.Comment: 26 pages, 18 figure

Direct Optimal Mapping Image Power Spectrum and its Window Functions

The key to detecting neutral hydrogen during the epoch of reionization (EoR) is to separate the cosmological signal from the dominating foreground radiation. We developed direct optimal mapping (Xu et al. 2022) to map interferometric visibilities; it contains only linear operations, with full knowledge of point spread functions from visibilities to images. Here we present an FFT-based image power spectrum and its window functions based on direct optimal mapping. We use noiseless simulation, based on the Hydrogen Epoch of Reionization Array (HERA) Phase I configuration, to study the image power spectrum properties. The window functions show $<10^{-11}$ power leakage from the foreground-dominated region into the EoR window; the 2D and 1D power spectra also verify the separation between the foregrounds and the EoR. Furthermore, we simulated visibilities from a $uv$-complete array and calculated its image power spectrum. The result shows that the foreground--EoR leakage is further suppressed below $10^{-12}$, dominated by the tapering function sidelobes; the 2D power spectrum does not show signs of the horizon wedge. The $uv$-complete result provides a reference case for future 21cm cosmology array designs.Comment: Submitted to Ap

Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease.

International audienceRecently, several genome wide association studies (GWAS) have led to the discovery of 9 new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches.. We performed a genome wide haplotype association (GWHA) study in the EADI1 study (n=2,025 AD cases and 5,328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2,820 AD cases and 6,356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case-control studies (5,093 AD cases and 4,061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analysed (OR=1.68, 95% CI 1.43- 1.96; p=1.1x10-10). We finally searched for association between SNPs within the FRMD4A locus and Ab plasma concentrations in three independent non demented populations (n=2,579). We reported that polymorphisms were associated with plasma Ab42/Ab40 ratio (best signal, p=5.4x10-7). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD

Direct Optimal Mapping for 21cm Cosmology: A Demonstration with the Hydrogen Epoch of Reionization Array

Motivated by the desire for wide-field images with well-defined statistical properties for 21cm cosmology, we implement an optimal mapping pipeline that computes a maximum likelihood estimator for the sky using the interferometric measurement equation. We demonstrate this direct optimal mapping with data from the Hydrogen Epoch of Reionization (HERA) Phase I observations. After validating the pipeline with simulated data, we develop a maximum likelihood figure-of-merit for comparing four sky models at 166MHz with a bandwidth of 100kHz. The HERA data agree with the GLEAM catalogs to <10%. After subtracting the GLEAM point sources, the HERA data discriminate between the different continuum sky models, providing most support for the model of Byrne et al. 2021. We report the computation cost for mapping the HERA Phase I data and project the computation for the HERA 320-antenna data; both are feasible with a modern server. The algorithm is broadly applicable to other interferometers and is valid for wide-field and non-coplanar arrays.Comment: 16 pages, 10 figures, 2 tables, published on Ap