Bayesian test for colocalisation between pairs of genetic association studies using summary statistics.

Genetic association studies, in particular the genome-wide association study (GWAS) design, have provided a wealth of novel insights into the aetiology of a wide range of human diseases and traits, in particular cardiovascular diseases and lipid biomarkers. The next challenge consists of understanding the molecular basis of these associations. The integration of multiple association datasets, including gene expression datasets, can contribute to this goal. We have developed a novel statistical methodology to assess whether two association signals are consistent with a shared causal variant. An application is the integration of disease scans with expression quantitative trait locus (eQTL) studies, but any pair of GWAS datasets can be integrated in this framework. We demonstrate the value of the approach by re-analysing a gene expression dataset in 966 liver samples with a published meta-analysis of lipid traits including >100,000 individuals of European ancestry. Combining all lipid biomarkers, our re-analysis supported 26 out of 38 reported colocalisation results with eQTLs and identified 14 new colocalisation results, hence highlighting the value of a formal statistical test. In three cases of reported eQTL-lipid pairs (SYPL2, IFT172, TBKBP1) for which our analysis suggests that the eQTL pattern is not consistent with the lipid association, we identify alternative colocalisation results with SORT1, GCKR, and KPNB1, indicating that these genes are more likely to be causal in these genomic intervals. A key feature of the method is the ability to derive the output statistics from single SNP summary statistics, hence making it possible to perform systematic meta-analysis type comparisons across multiple GWAS datasets (implemented online at http://coloc.cs.ucl.ac.uk/coloc/). Our methodology provides information about candidate causal genes in associated intervals and has direct implications for the understanding of complex diseases as well as the design of drugs to target disease pathways

Data series subtraction with unknown and unmodeled background noise

LISA Pathfinder (LPF), ESA's precursor mission to a gravitational wave observatory, will measure the degree to which two test-masses can be put into free-fall, aiming to demonstrate a residual relative acceleration with a power spectral density (PSD) below 30 fm/s$^2$/Hz$^{1/2}$ around 1 mHz. In LPF data analysis, the measured relative acceleration data series must be fit to other various measured time series data. This fitting is required in different experiments, from system identification of the test mass and satellite dynamics to the subtraction of noise contributions from measured known disturbances. In all cases, the background noise, described by the PSD of the fit residuals, is expected to be coloured, requiring that we perform such fits in the frequency domain. This PSD is unknown {\it a priori}, and a high accuracy estimate of this residual acceleration noise is an essential output of our analysis. In this paper we present a fitting method based on Bayesian parameter estimation with an unknown frequency-dependent background noise. The method uses noise marginalisation in connection with averaged Welch's periodograms to achieve unbiased parameter estimation, together with a consistent, non-parametric estimate of the residual PSD. Additionally, we find that the method is equivalent to some implementations of iteratively re-weighted least-squares fitting. We have tested the method both on simulated data of known PSD, and to analyze differential acceleration from several experiments with the LISA Pathfinder end-to-end mission simulator.Comment: To appear Phys. Rev. D90 August 201

Mice with endogenous TDP-43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis

TDP-43 (encoded by the gene TARDBP) is an RNA binding protein central to the pathogenesis of amyotrophic lateral sclerosis (ALS). However, how TARDBP mutations trigger pathogenesis remains unknown. Here, we use novel mouse mutants carrying point mutations in endogenous Tardbp to dissect TDP-43 function at physiological levels both in vitro and in vivo Interestingly, we find that mutations within the C-terminal domain of TDP-43 lead to a gain of splicing function. Using two different strains, we are able to separate TDP-43 loss- and gain-of-function effects. TDP-43 gain-of-function effects in these mice reveal a novel category of splicing events controlled by TDP-43, referred to as "skiptic" exons, in which skipping of constitutive exons causes changes in gene expression. In vivo, this gain-of-function mutation in endogenous Tardbp causes an adult-onset neuromuscular phenotype accompanied by motor neuron loss and neurodegenerative changes. Furthermore, we have validated the splicing gain-of-function and skiptic exons in ALS patient-derived cells. Our findings provide a novel pathogenic mechanism and highlight how TDP-43 gain of function and loss of function affect RNA processing differently, suggesting they may act at different disease stages

Atlas of the clinical genetics of human dilated cardiomyopathy

[Abstract] Aim. Numerous genes are known to cause dilated cardiomyopathy (DCM). However, until now technological limitations have hindered elucidation of the contribution of all clinically relevant disease genes to DCM phenotypes in larger cohorts. We now utilized next-generation sequencing to overcome these limitations and screened all DCM disease genes in a large cohort. Methods and results. In this multi-centre, multi-national study, we have enrolled 639 patients with sporadic or familial DCM. To all samples, we applied a standardized protocol for ultra-high coverage next-generation sequencing of 84 genes, leading to 99.1% coverage of the target region with at least 50-fold and a mean read depth of 2415. In this well characterized cohort, we find the highest number of known cardiomyopathy mutations in plakophilin-2, myosin-binding protein C-3, and desmoplakin. When we include yet unknown but predicted disease variants, we find titin, plakophilin-2, myosin-binding protein-C 3, desmoplakin, ryanodine receptor 2, desmocollin-2, desmoglein-2, and SCN5A variants among the most commonly mutated genes. The overlap between DCM, hypertrophic cardiomyopathy (HCM), and channelopathy causing mutations is considerably high. Of note, we find that >38% of patients have compound or combined mutations and 12.8% have three or even more mutations. When comparing patients recruited in the eight participating European countries we find remarkably little differences in mutation frequencies and affected genes. Conclusion. This is to our knowledge, the first study that comprehensively investigated the genetics of DCM in a large-scale cohort and across a broad gene panel of the known DCM genes. Our results underline the high analytical quality and feasibility of Next-Generation Sequencing in clinical genetic diagnostics and provide a sound database of the genetic causes of DCM.Hôpitaux de Paris; PHRC AOM0414

The Mock LISA Data Challenges: from Challenge 1B to Challenge 3

The Mock LISA Data Challenges are a programme to demonstrate and encourage the development of LISA data-analysis capabilities, tools and techniques. At the time of this workshop, three rounds of challenges had been completed, and the next was about to start. In this article we provide a critical analysis of entries to the latest completed round, Challenge 1B. The entries confirm the consolidation of a range of data-analysis techniques for Galactic and massive--black-hole binaries, and they include the first convincing examples of detection and parameter estimation of extreme--mass-ratio inspiral sources. In this article we also introduce the next round, Challenge 3. Its data sets feature more realistic waveform models (e.g., Galactic binaries may now chirp, and massive--black-hole binaries may precess due to spin interactions), as well as new source classes (bursts from cosmic strings, isotropic stochastic backgrounds) and more complicated nonsymmetric instrument noise.Comment: 20 pages, 3 EPS figures. Proceedings of the 12th Gravitational Wave Data Analysis Workshop, Cambridge MA, 13--16 December 2007. Typos correcte

Laser Interferometer Space Antenna

Following the selection of The Gravitational Universe by ESA, and the successful flight of LISA Pathfinder, the LISA Consortium now proposes a 4 year mission in response to ESA's call for missions for L3. The observatory will be based on three arms with six active laser links, between three identical spacecraft in a triangular formation separated by 2.5 million km. LISA is an all-sky monitor and will offer a wide view of a dynamic cosmos using Gravitational Waves as new and unique messengers to unveil The Gravitational Universe. It provides the closest ever view of the infant Universe at TeV energy scales, has known sources in the form of verification binaries in the Milky Way, and can probe the entire Universe, from its smallest scales near the horizons of black holes, all the way to cosmological scales. The LISA mission will scan the entire sky as it follows behind the Earth in its orbit, obtaining both polarisations of the Gravitational Waves simultaneously, and will measure source parameters with astrophysically relevant sensitivity in a band from below $10^{-4}\,$Hz to above $10^{-1}\,$Hz.Comment: Submitted to ESA on January 13th in response to the call for missions for the L3 slot in the Cosmic Vision Programm