We present a method to identify approximately independent blocks of linkage disequilibrium in the human genome. These blocks enable automated analysis of multiple genome-wide association studies.
...code: http://bitbucket.org/nygcresearch/ldetect; data: http://bitbucket.org/nygcresearch/ldetect-data.
tberisa@nygenome.org
Supplementary data are available at Bioinformatics online.
We performed a scan for genetic variants associated with multiple phenotypes by comparing large genome-wide association studies (GWAS) of 42 traits or diseases. We identified 341 loci (at a false ...discovery rate of 10%) associated with multiple traits. Several loci are associated with multiple phenotypes; for example, a nonsynonymous variant in the zinc transporter SLC39A8 influences seven of the traits, including risk of schizophrenia (rs13107325: log-transformed odds ratio (log OR) = 0.15, P = 2 × 10(-12)) and Parkinson disease (log OR = -0.15, P = 1.6 × 10(-7)), among others. Second, we used these loci to identify traits that have multiple genetic causes in common. For example, variants associated with increased risk of schizophrenia also tended to be associated with increased risk of inflammatory bowel disease. Finally, we developed a method to identify pairs of traits that show evidence of a causal relationship. For example, we show evidence that increased body mass index causally increases triglyceride levels.
Low pass sequencing has been proposed as a cost-effective alternative to genotyping arrays to identify genetic variants that influence multifactorial traits in humans. For common diseases this ...typically has required both large sample sizes and comprehensive variant discovery. Genotyping arrays are also routinely used to perform pharmacogenetic (PGx) experiments where sample sizes are likely to be significantly smaller, but clinically relevant effect sizes likely to be larger.
To assess how low pass sequencing would compare to array based genotyping for PGx we compared a low-pass assay (in which 1x coverage or less of a target genome is sequenced) along with software for genotype imputation to standard approaches. We sequenced 79 individuals to 1x genome coverage and genotyped the same samples on the Affymetrix Axiom Biobank Precision Medicine Research Array (PMRA). We then down-sampled the sequencing data to 0.8x, 0.6x, and 0.4x coverage, and performed imputation. Both the genotype data and the sequencing data were further used to impute human leukocyte antigen (HLA) genotypes for all samples. We compared the sequencing data and the genotyping array data in terms of four metrics: overall concordance, concordance at single nucleotide polymorphisms in pharmacogenetics-related genes, concordance in imputed HLA genotypes, and imputation r
. Overall concordance between the two assays ranged from 98.2% (for 0.4x coverage sequencing) to 99.2% (for 1x coverage sequencing), with qualitatively similar numbers for the subsets of variants most important in pharmacogenetics. At common single nucleotide polymorphisms (SNPs), the mean imputation r
from the genotyping array was 0.90, which was comparable to the imputation r
from 0.4x coverage sequencing, while the mean imputation r
from 1x sequencing data was 0.96.
These results indicate that low-pass sequencing to a depth above 0.4x coverage attains higher power for association studies when compared to the PMRA and should be considered as a competitive alternative to genotyping arrays for trait mapping in pharmacogenetics.
A number of open questions in human evolutionary genetics would become tractable if we were able to directly measure evolutionary fitness. As a step towards this goal, we developed a method to ...examine whether individual genetic variants, or sets of genetic variants, currently influence viability. The approach consists in testing whether the frequency of an allele varies across ages, accounting for variation in ancestry. We applied it to the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort and to the parents of participants in the UK Biobank. Across the genome, we found only a few common variants with large effects on age-specific mortality: tagging the APOE ε4 allele and near CHRNA3. These results suggest that when large, even late-onset effects are kept at low frequency by purifying selection. Testing viability effects of sets of genetic variants that jointly influence 1 of 42 traits, we detected a number of strong signals. In participants of the UK Biobank of British ancestry, we found that variants that delay puberty timing are associated with a longer parental life span (P~6.2 × 10-6 for fathers and P~2.0 × 10-3 for mothers), consistent with epidemiological studies. Similarly, variants associated with later age at first birth are associated with a longer maternal life span (P~1.4 × 10-3). Signals are also observed for variants influencing cholesterol levels, risk of coronary artery disease (CAD), body mass index, as well as risk of asthma. These signals exhibit consistent effects in the GERA cohort and among participants of the UK Biobank of non-British ancestry. We also found marked differences between males and females, most notably at the CHRNA3 locus, and variants associated with risk of CAD and cholesterol levels. Beyond our findings, the analysis serves as a proof of principle for how upcoming biomedical data sets can be used to learn about selection effects in contemporary humans.
Low-pass sequencing (sequencing a genome to an average depth less than 1× coverage) combined with genotype imputation has been proposed as an alternative to genotyping arrays for trait mapping and ...calculation of polygenic scores. To empirically assess the relative performance of these technologies for different applications, we performed low-pass sequencing (targeting coverage levels of 0.5× and 1×) and array genotyping (using the Illumina Global Screening Array GSA) on 120 DNA samples derived from African- and European-ancestry individuals that are part of the 1000 Genomes Project. We then imputed both the sequencing data and the genotyping array data to the 1000 Genomes Phase 3 haplotype reference panel using a leave-one-out design. We evaluated overall imputation accuracy from these different assays as well as overall power for GWAS from imputed data and computed polygenic risk scores for coronary artery disease and breast cancer using previously derived weights. We conclude that low-pass sequencing plus imputation, in addition to providing a substantial increase in statistical power for genome-wide association studies, provides increased accuracy for polygenic risk prediction at effective coverages of ∼0.5× and higher compared to the Illumina GSA.
In this paper, we provide a comprehensive discussion focused on the motivation and benefits of providing real-time (RT) signaling mechanisms in multi-channel PONs, outlining several emerging ...low-latency applications such as Smart Grid, machine-to-machine (M2M) communication, and cloud computing. We expand this discussion to provide a straightforward definition for signaling delay and define that for a signaling mechanism to be considered RT in PONs the majority of the signaling delay should be attributed to the one-way propagation time. We propose backwards compatible mechanisms capable of realizing RT signaling without necessarily requiring additional PHY-layer cost and complexity. Based on frequent signaling data bursts (SDBs) scheduled by the Optical Line Terminal (OLT) for selected upgraded Optical Network Units (ONUs), our proposed mechanisms enable pay-as-you-grow migration from conventional TDM PONs to highly flexible RT signaling for multi-channel PONs capable of supporting emerging low-latency applications. We provide simulation results of system performance with relevant benchmarks showing up to 15% delay reductions with respect to previously proposed OC (Optical Coding) RT architectures, which have already demonstrated significant performance increases with respect to conventional PONs. Finally, we emphasize the flexibility of the proposed mechanisms provided to future RT Dynamic Bandwidth Allocation (DBA) algorithms aimed at achieving efficient Quality-of-Service (QoS) requirements.
In this letter, we present a passive optical network (PON) polling mechanism for services that require low-latency performance, which achieves delay performance gains reaching 57%. This is ...accomplished by decoupling the in-band report messages from the upstream data transmission time window and scheduling them separately in order to arrive immediately before a grant is to be transmitted from the optical line terminal (OLT). We analyze the details of this mechanism and provide discrete event simulation results to support the analysis. We emphasize that the proposed mechanisms maintain a statistical multiplexing approach (as opposed to a fixed window TDM approach), require only firmware upgrades at the OLT, can be rolled out on a per-ONU basis and come only at the cost of one extra guard time per ONU being polled in this manner.
This paper addresses the problem of providing absolute delay variation guarantees in passive optical networks and their optical coding enhanced counterparts. We analyze the components of frame delay ...variation in these settings and propose a dynamic bandwidth allocation algorithm that provides the optical line terminal with mechanisms to ensure that frame delay variation never breaches a predefined value. Furthermore, we provide simulation results and analyses to show that the proposed algorithm does not breach delay variation bounds. We also provide a lower bound analysis for providing absolute delay variation guarantees for both scenarios and show the duality between absolute delay and delay variation guarantees.
In this paper, optical pulse encoding and decoding technology is proposed to enable real-time signaling in a passive optical network (PON) setting. Unique optical codes are assigned to selected ...optical network units (ONUs) equipped with the corresponding encoders. An out-of-band pulse train is broadcast from the optical line terminal (OLT) and is modulated by ONU-based switches. The encoded reflections of pulses are thus used to update the status of the OC-enabled queues at the OLT in real time. We explore the enhanced PON architecture and define its major design parameters. Through extensive simulations, we investigate the design principles and limits of our system parameters. Through a performance comparison of native interleaved polling with adaptive cycle time with its OC-enhanced counterpart, we show that our OC enhancement breaks the fundamental delay lower bound associated to the polling cycle. We propose and investigate new dynamic bandwidth allocation (DBA) algorithms that exploit real-time queue updates enabled through OC-enhanced polling. We also explore the pay-as-you-grow implementation of OC-enhanced polling to realize quality-of-service (QoS) differentiation, elaborate on possible migration paths from conventional PONs, and investigate absolute QoS performance guarantee improvements achieved through OC-enabled real-time DBA algorithms.
We present a distributed mechanism termed Adaptive Grant Extension (AGE) for grant-size adjustment in Optical Coding (OC)-enhanced Passive Optical Networks (OC-PONs). AGE exploits the real-time queue ...updates of OC-PONs to allow the Optical Network Unit (ONU) to extend its transmission beyond the grant provided by the Optical Line Terminal (OLT), thus reducing average frame delay. We discuss the parameters and requirements of AGE in OC-enhanced Ethernet PONs (EPONs). Our simulations show delay gains reaching 9% over OC-PONs.
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