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Genome-wide association studies (GWAS) are not fully comprehensive, as current strategies typically test only the additive model, exclude the X chromosome, and use only one reference panel for genotype imputation. We implement an extensive GWAS strategy, GUIDANCE, which improves genotype imputation by using multiple reference panels and includes the analysis of the X chromosome and non-additive models to test for association. We apply this methodology to 62,281 subjects across 22 age-related diseases and identify 94 genome-wide associated loci, including 26 previously unreported. Moreover, we observe that 27.7% of the 94 loci are missed if we use standard imputation strategies with a single reference panel, such as HRC, and only test the additive model. Among the new findings, we identify three novel low-frequency recessive variants with odds ratios larger than 4, which need at least a three-fold larger sample size to be detected under the additive model. This study highlights the benefits of applying innovative strategies to better uncover the genetic architecture of complex diseases., Most genome-wide association studies assume an additive model, exclude the X chromosome, and use one reference panel. Here, the authors implement a strategy including non-additive models and find that the number of loci for age-related traits increases as compared to the additive model alone.

Birth weight (BW) variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. These associations have been proposed to reflect the lifelong consequences of an adverse intrauterine environment. In earlier work, we demonstrated that much of the negative correlation between BW and adult cardio-metabolic traits could instead be attributable to shared genetic effects. However, that work and other previous studies did not systematically distinguish the direct effects of an individual’s own genotype on BW and subsequent disease risk from indirect effects of their mother’s correlated genotype, mediated by the intrauterine environment. Here, we describe expanded genome-wide association analyses of own BW (n=321,223) and offspring BW (n=230,069 mothers), which identified 278 independent association signals influencing BW (214 novel). We used structural equation modelling to decompose the contributions of direct fetal and indirect maternal genetic influences on BW, implicating fetal- and maternal-specific mechanisms. We used Mendelian randomization to explore the causal relationships between factors influencing BW through fetal or maternal routes, for example, glycemic traits and blood pressure. Direct fetal genotype effects dominate the shared genetic contribution to the association between lower BW and higher type 2 diabetes risk, whereas the relationship between lower BW and higher later blood pressure (BP) is driven by a combination of indirect maternal and direct fetal genetic effects: indirect effects of maternal BP-raising genotypes act to reduce offspring BW, but only direct fetal genotype effects (once inherited) increase the offspring’s later BP. Instrumental variable analysis using maternal BW-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring BP. In successfully separating fetal from maternal genetic effects, this work represents an important advance in genetic studies of perinatal outcomes, and shows that the association between lower BW and higher adult BP is attributable to genetic effects, and not to intrauterine programming.

Background A prime objective in metagenomics is to classify DNA sequence fragments into taxonomic units. It usually requires several stages: read’s quality control, de novo assembly, contig annotation, gene prediction, etc. These stages need very efficient programs because of the number of reads from the projects. Furthermore, the complexity of metagenomes requires efficient and automatic tools that orchestrate the different stages. Method DATMA is a pipeline for fast metagenomic analysis that orchestrates the following: sequencing quality control, 16S rRNA-identification, reads binning, de novo assembly and evaluation, gene prediction, and taxonomic annotation. Its distributed computing model can use multiple computing resources to reduce the analysis time. Results We used a controlled experiment to show DATMA functionality. Two pre-annotated metagenomes to compare its accuracy and speed against other metagenomic frameworks. Then, with DATMA we recovered a draft genome of a novel Anaerolineaceae from a biosolid metagenome. Conclusions DATMA is a bioinformatics tool that automatically analyzes complex metagenomes. It is faster than similar tools and, in some cases, it can extract genomes that the other tools do not. DATMA is freely available at https://github.com/andvides/DATMA.

The reanalysis of existing GWAS data represents a powerful and cost-effective opportunity to gain insights into the genetics of complex diseases. By reanalyzing publicly available type 2 diabetes (T2D) genome-wide association studies (GWAS) data for 70,127 subjects, we identify seven novel associated regions, five driven by common variants (LYPLAL1, NEUROG3, CAMKK2, ABO, and GIP genes), one by a low-frequency (EHMT2), and one driven by a rare variant in chromosome Xq23, rs146662075, associated with a twofold increased risk for T2D in males. rs146662075 is located within an active enhancer associated with the expression of Angiotensin II Receptor type 2 gene (AGTR2), a modulator of insulin sensitivity, and exhibits allelic specific activity in muscle cells. Beyond providing insights into the genetics and pathophysiology of T2D, these results also underscore the value of reanalyzing publicly available data using novel genetic resources and analytical approaches., Genome-wide association studies have uncovered several loci associated with diabetes risk. Here, the authors reanalyse public type 2 diabetes GWAS data to fine map 50 known loci and identify seven new ones, including one near ATGR2 on the X-chromosome that doubles the risk of diabetes in men.

The reanalysis of existing GWAS data represents a powerful and cost-effective opportunity to gain insights into the genetics of complex diseases. By reanalyzing publicly available type 2 diabetes (T2D) genome-wide association studies (GWAS) data for 70,127 subjects, we identify seven novel associated regions, five driven by common variants (LYPLAL1, NEUROG3, CAMKK2, ABO, and GIP genes), one by a low-frequency (EHMT2), and one driven by a rare variant in chromosome Xq23, rs146662057, associated with a twofold increased risk for T2D in males. rs146662057 is located within an active enhancer associated with the expression of Angiotensin II Receptor type 2 gene (AGTR2), a modulator of insulin sensitivity, and exhibits allelic specific activity in muscle cells. Beyond providing insights into the genetics and pathophysiology of T2D, these results also underscore the value of reanalyzing publicly available data using novel genetic resources and analytical approaches., This work has been sponsored by the grant SEV-2011-00067 of Severo Ochoa Program, awarded by the Spanish Government. This work was supported by an EFSD/Lilly research fellowship. Josep M. Mercader was supported by Sara Borrell Fellowship from the Instituto Carlos III and Beatriu de Pinós fellowship from the Agency for Management of University and Research Grants (AGAUR). Sílvia Bonàs was FI-DGR Fellowship from FI-DGR 2013 from Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR, Generalitat de Catalunya). This study makes use of data generated by the WTCCC. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113. This study also makes use of data generated by the UK10K Consortium, derived from samples from UK10K COHORT IMPUTATION (EGAS00001000713). A full list of the investigators who contributed to the generation of the data is available in www.UK10K.org. Funding for UK10K was provided by the Wellcome Trust under award WT091310. We acknowledge PRACE for awarding us to access MareNostrum supercomputer, based in Spain at Barcelona. The technical support group, particularly Pablo Ródenas and Jorge Rodríguez, from the Barcelona Supercomputing Center is gratefully acknowledged. This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 667191. Mercè Planas-Fèlix is funded by the Obra Social Fundación la Caixa fellowship under the Severo Ochoa 2013 program. Work from Irene Miguel-Escalada, Ignasi Moran, Goutham Atla, and Jorge Ferrer was supported by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, the Wellcome Trust (WT101033), Ministerio de Economía y Competitividad (BFU2014-54284-R) and Horizon 2020 (667191). Irene Miguel-Escalada has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska–Curie grant agreement No 658145. We acknowledge Prof. Giulio Cossu (Institute of Inflammation and Repair, University of Manchester) for providing the muscle myoblast cell line. We also acknowledge the InterAct and SIGMA Type 2 Diabetes Consortia for access to the data to replicate the rs146662075 variant. A full list of the investigators of the SIGMA Type 2 Diabetes and the InterAct consortia is provided in Supplementary Notes 3 and 4. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk). This research has been conducted using the UK Biobank Resource (application number 16803). We also acknowledge Bianca C. Porneala, MS for his technical assistance in the collection and curation of the genotype and phenotype data from Partners Biobank. We also thank Marcin von Grotthuss for their support for uploading the summary statistics data to the Type 2 Diabetes Genetic Portal (AMP-T2D portal). Finally, we thank all the Computational Genomics group at the BSC for their helpful discussions and valuable comments on the manuscript.

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P&thinsp

Motivation: The prediction and annotation of the genomic regions involved in gene expression has been largely explored. Most of the energy has been devoted to the development of approaches that detect transcription start sites, leaving the identification of regulatory regions and their functional transcription factor binding sites (TFBSs) largely unexplored and with important quantitative and qualitative methodological gaps. Results: We have developed ReLA (for REgulatory region Local Alignment tool), a unique tool optimized with the Smith–Waterman algorithm that allows local searches of conserved TFBS clusters and the detection of regulatory regions proximal to genes and enhancer regions. ReLA's performance shows specificities of 81 and 50% when tested on experimentally validated proximal regulatory regions and enhancers, respectively. Availability: The source code of ReLA's is freely available and can be remotely used through our web server under http://www.bsc.es/cg/rela. Contact: david.torrents@bsc.es Supplementary information: Supplementary data are available at Bioinformatics online.

Biological sequence comparison is one of the most important tasks in Bioinformatics. Owing to the fast growth of databases that contain biological information, sequence comparison represents an important challenge for high-performance computing, especially when very long sequences are compared, i.e. the complete genome of several organisms. The Smith–Waterman (SW) algorithm is an exact method based on dynamic programming to quantify local similarity between sequences. The inherent large parallelism of the algorithm makes it ideal for architectures supporting multiple dimensions of parallelism (TLP, DLP and ILP). Concurrently, there is a paradigm shift towards chip multiprocessors in computer architecture, which offer a huge amount of potential performance that can only be exploited efficiently if applications are effectively mapped and parallelized. In this work, we analyze how large-scale biology sequence comparison takes advantage of the current and future multicore architectures. Our starting point is the performance analysis of the current multicore IBM Cell B.E. processor; we analyze two different SW implementations on the Cell B.E. Then, using simulation tools, we study the performance scalability when a many-core architecture is used for performing long DNA sequence comparison. We investigate the efficient memory organization that delivers the maximum bandwidth with the minimum cost. Our results show that a heterogeneous architecture can be an efficient alternative to execute challenging bioinformatic workloads. Copyright © 2011 John Wiley & Sons, Ltd.

In bioinformatics, protein sequence alignment is one of the fundamental tasks that scientists perform. Since the growth of biological data is exponential, there is an ever-increasing demand for computational power. While current processor technology is shifting towards the use of multicores, the mapping and parallelization of applications has become a critical issue. In order to keep up with the processing demands, applications' bottlenecks to performance need to be found and properly addressed. In this paper we study the parallelism and performance scalability of HMMER, a bioinformatics application to perform sequence alignment. After our study of the bottlenecks in a HMMER version ported to the Cell processor, we present two optimized versions to improve scalability in a larger multicore architecture. We use a simulator that allows us to model a system with up to 512 processors and study the performance of the three parallel versions of HMMER. Results show that removing the I/O bottleneck improves performance by 3X and 2.4X for a short and a long HMM query respectively. Additionally, by offloading the sequence pre-formatting to the worker cores, larger speedups of up to 27X and 7X are achieved. Compared to using a single worker processor, up to 156X speedup is obtained when using 256 cores.

Sequence alignment is a fundamental instrument in Bioinformatics. In recent years, numerous proposals have been addressing the problem of accelerating this class of applications. This, due to the rapid growth of sequence databases in combination with the high computational demands imposed by the algorithms. In this paper we focus on the analysis of the progressive alignment in ClustalW, a widely used program for performing multiple sequence alignment. We have parallelized ClustalW for the Cell processor architecture and have carefully analyzed the scalability of its different phases with both the number of cores used and the input size. Experimental results show that computing profile scores scales well up to 16 SPE cores. With the increase of the input size, profiles initialization in the PPE core becomes the predominant bottleneck.

Biological sequence comparison is one of the most important tasks in Bioinformatics. Due to the growth of biological databases, sequence comparison is becoming an important challenge for high performance computing, especially when very long sequences are compared. The Smith-Waterman (SW) algorithm is an exact method based on dynamic programming to quantify local similarity between sequences. The inherent large parallelism of the algorithm makes it ideal for architectures supporting multiple dimensions of parallelism (TLP, DLP and ILP). In this work, we show how long sequences comparison takes advantage of current and future multicore architectures. We analyze two different SW implementations on the CellBE and use simulation tools to study the performance scalability in a multicore architecture. We study the memory organization that delivers the maximum bandwidth with the minimum cost. Our results show that a heterogeneous architecture is an valid alternative to execute challenging bioinformatic workloads.

The exponential growth of databases that contains biological information (such as protein and DNA data) demands great efforts to improve the performance of computational platforms. In this work we investigate how bioinformatics applications benefit from parallel architectures that combine different alternatives to exploit coarse- and fine-grain parallelism. As a case of analysis we study the performance behavior of the Ssearch application that implements the Smith-Waterman algorithm, which is a dynamic programing approach that explores the similarity between a pair of sequences. The inherent large parallelism of the algorithm makes it ideal for architectures supporting multiple dimensions of parallelism (TLP, DLP and ILP). We study how this algorithm can take advantage of different parallel machines like the SGI Altix, IBM Power6, Cell BE machines and MareNostrum. Our results show that a share memory architecture like the PowerPC 970MP of Marenostrum can surpass a heterogeneous machine like the current Cell BE. Our quantitative analysis includes not only a study of scalability of the performance in terms of speedup, but also includes the analysis of bottlenecks in the execution of the application. This analysis is carried out through the study of the execution phases that the application presents.

The fast growth of bioinformatics field has attracted the attention of computer scientists in the last few years. At the same time the increasing database sizes require greater efforts to improve the computational performance. From a computer architecture point of view, we intend to investigate how bioinformatics applications can benefit from future multi-core processors. In this paper we present a preliminary study of the Cell BE processor limitations when executing two representative sequence alignment applications (Ssearch and ClustalW). The inherent large parallelism of the targeted algorithms makes them ideal for architectures supporting multiple dimensions of parallelism (TLP and DLP). However, in the case of Cell BE we identified several architectural limitations that need a careful study and quantification.

Advances in molecular biology have led to a continued growth in the biological information generated by the scientific community. Additionally, this area has become a multi-disciplinary field, including components of mathematics, biology, chemistry, and computer science, generating several challenges in the scientific community from different points of view. For this reason, bioinformatic applications represent an increasingly important workload. However, even though the importance of this field is clear, common bioinformatic applications and their implications on micro-architectural design have not received enough attention from the computer architecture community. This paper presents a micro-architecture performance analysis of recognized bioinformatic applications for the comparison and alignment of biological sequences, including BLAST, FASTA and some recognized parallel implementations of the Smith-Waterman algorithm that use the Altivec SIMD extension to speed-up the performance. We adopt a simulation-based methodology to perform a detailed workload characterization. We analyze architectural and micro-architectural aspects like pipeline configurations, issue widths, functional unit mixes, memory hierarchy and their implications on the performance behavior. We have found that the memory subsystem is the component with more impact in the performance of the BLAST heuristic, the branch predictor is responsible for the major performance loss for FASTA and SSEARCH34, and long dependency chains are the limiting factor in the SIMD implementations of Smith-Waterman.

The SARC architecture is composed of multiple processor types and a set of user-managed direct memory access (DMA) engines that let the runtime scheduler overlap data transfer and computation. The runtime system automatically allocates tasks on the heterogeneous cores and schedules the data transfers through the DMA engines. SARC's programming model supports various highly parallel applications, with matching support from specialized accelerator processors.