Genome-wide data from medieval German Jews show that the Ashkenazi founder event pre-dated the 14th century

We report genome-wide data for 33 Ashkenazi Jews (AJ), dated to the 14th century, following a salvageexcavation at the medieval Jewish cemetery of Erfurt, Germany. The Erfurt individuals are geneticallysimilar to modern AJ and have substantial Southern European ancestry, but they show more variabilityin Eastern European-related ancestry than modern AJ. A third of the Erfurt individuals carried the samenearly-AJ-specific mitochondrial haplogroup and eight carried pathogenic variants known to affect AJtoday. These observations, together with high levels of runs of homozygosity, suggest that the Erfurtcommunity had already experienced the major reduction in size that affected modern AJ. However, theErfurt bottleneck was more severe, implying substructure in medieval AJ. Together, our results suggestthat the AJ founder event and the acquisition of the main sources of ancestry pre-dated the 14th centuryand highlight late medieval genetic heterogeneity no longer present in modern AJ

Matrix and Tensor Factorization Methods for Toxicogenomic Modeling and Prediction

Peer reviewe

Sympathetic Activation and Baroreflex Function during Intradialytic Hypertensive Episodes

BACKGROUND: The mechanisms of intradialytic increases in blood pressure are not well defined. The present study was undertaken to assess the role of autonomic nervous system activation during intradialytic hypertensive episodes. METHODOLOGY/PRINCIPAL FINDINGS: Continuous interbeat intervals (IBI) and systolic blood pressure (SBP) were monitored during hemodialysis in 108 chronic patients. Intradialytic hypertensive episodes defined as a period of at least 10 mmHg increase in SBP between the beginning and the end of a dialysis session or hypertension resistant to ultrafiltration occurring during or immediately after the dialysis procedure, were detected in 62 out of 113 hemodialysis sessions. SBP variability, IBI variability and baroreceptor sensitivity (BRS) in the low (LF) and high (HF) frequency ranges were assessed using the complex demodulation technique (CDM). Intradialytic hypertensive episodes were associated with an increased (n = 45) or decreased (n = 17) heart rate. The maximal blood pressure was similar in both groups. In patients with increased heart rate the increase in blood pressure was associated with marked increases in SBP and IBI variability, with suppressed BRS indices and enhanced sympatho-vagal balance. In contrast, in those with decreased heart rate, there were no significant changes in the above parameters. End-of-dialysis blood pressure in all sessions associated with hypertensive episode was significantly higher than in those without such episodes. In logistic regression analysis, predialysis BRS in the low frequency range was found to be the main predictor of intradialytic hypertension. CONCLUSION/SIGNIFICANCE: Our data point to sympathetic overactivity with feed-forward blood pressure enhancement as an important mechanism of intradialytic hypertension in a significant proportion of patients. The triggers of increased sympathetic activity during hemodialysis remain to be determined. Intradialytic hypertensive episodes are associated with higher end-of-dialysis blood pressure, suggesting that intradialytic hypertension may play a role in generation of interdialytic hypertension

O-056 Evaluating the utility of screening human IVF embryos with polygenic risk scores for complex diseases

Abstract Study question It is now feasible to screen human IVF embryos with “polygenic risk scores” for predicting complex disease risk. What is the expected risk reduction? Summary answer Under some conditions, prioritizing embryos based on polygenic risk scores can lead to substantial disease risk reductions. However, only excluding high-risk embryos is less effective. What is known already Recent genetic studies have identified numerous mutations associated with complex diseases, leading to the development of accurate polygenic risk scores (PRSs) for disease risk prediction. Given that genomes of human IVF embryos can now be sequenced with relative ease, it has become technically feasible to use PRSs for prioritization of embryos for transfer. Clearly, such use is associated with ethical and social concerns, from inequality to eugenics. Nevertheless, polygenic embryo screening is already offered to consumers, with little research so far on expected outcomes. Our previous evaluation of screening IVF embryos for polygenic traits showed little current utility. Study design, size, duration This is a theoretical/computational study based on statistical genetics theory and simulations. Participants/materials, setting, methods We used the liability threshold model to estimate the disease risk given the PRS. We considered screening for a single disease (with known prevalence and PRS accuracy), and assumed that n viable embryos are available. We calculated the risk of the child given these parameters and the prioritization strategy, either when parents are random or when their disease status is known. We also used simulations based on genomic data from a schizophrenia case-control study. Main results and the role of chance We modeled the disease risk of a hypothetical future child when the PRSs of embryos are used for prioritization, relative to random selection. When selecting an embryo at random among those who do not have an extremely high risk (typically, top 2% of the PRS distribution), the relative risk reduction (RRR) is limited, and is under 10% for currently realistic scenarios. In contrast, selecting the lowest risk embryo for implantation results in substantial RRRs of ∼20-50% already with n = 5 embryos and realistic disease parameters. For example, the RRR for schizophrenia is &amp;gt; 40% with current PRSs, a result we validated with simulated genomes of parents and children based on genotypes from a schizophrenia study. When one of the parents is known to be affected, selecting the lowest risk embryo out of n = 5 may restore the risk of the future child to nearly normal levels. Limitations, reasons for caution Our analytical modeling is based on several simplifying assumptions regarding the dependence of the risk on the PRS and the accuracy of the PRS. Further, the estimated risk reductions depend on the availability of n = 5 embryos that could lead to a live birth. Wider implications of the findings Under some conditions, prioritizing embryos for transfer based on polygenic risk scores could lead to substantial disease risk reductions. However, predicted outcomes vary considerably with prioritization strategies and disease and PRS parameters. The emerging ethical and social concerns and the challenges in communicating these results need to be urgently discussed. Trial registration number Not applicable </jats:sec

FUN-LDA: A LATENT DIRICHLET ALLOCATION MODEL FOR PREDICTING TISSUE-SPECIFIC FUNCTIONAL EFFECTS OF NONCODING VARIATION

ABSTRACTWe describe here a new method based on a latent Dirichlet allocation model for predicting functional effects of noncoding genetic variants in a cell type and tissue specific way (FUN-LDA) by integrating diverse epigenetic annotations for specific cell types and tissues from large scale epige-nomics projects such as ENCODE and Roadmap Epigenomics. Using this unsupervised approach we predict tissue-specific functional effects for every position in the human genome. We demonstrate the usefulness of our predictions using several validation experiments. Using eQTL data from several sources, including the Genotype-Tissue Expression project, the Geuvadis project and Twin-sUK cohort, we show that eQTLs in specific tissues tend to be most enriched among the predicted functional variants in relevant tissues in Roadmap. We further show how these integrated functional scores can be used to derive the most likely cell/tissue type causally implicated for a complex trait using summary statistics from genome-wide association studies, and estimate a tissue-based correlation matrix of various complex traits. We find large enrichment of heritability in functional components of relevant tissues for various complex traits, with FUN-LDA yielding the highest enrichment estimates relative to existing methods. Finally, using experimentally validated functional variants from the literature and variants possibly implicated in disease by previous studies, we rigorously compare FUN-LDA to state-of-the-art functional annotation methods such as GenoSky-line, ChromHMM, Segway, and IDEAS, and show that FUN-LDA has better prediction accuracy and higher resolution compared to these methods. In summary, we describe a new approach and perform rigorous comparisons with the most commonly used functional annotation methods, providing a valuable resource for the community interested in the functional annotation of noncoding variants. Scores for each position in the human genome and for each ENCODE/Roadmap tissue are available from http://www.columbia.edu/~ii2135/funlda.html.</jats:p