Improving polygenic prediction with genetically inferred ancestry.

Genome-wide association studies (GWASs) have demonstrated that most common diseases have a strong genetic component from many genetic variants each with a small effect size. GWAS summary statistics have allowed the construction of polygenic scores (PGSs) estimating part of the individual risk for common diseases. Here, we propose to improve PGS-based risk estimation by incorporating genetic ancestry derived from genome-wide genotyping data. Our method involves three cohorts: a base (or discovery) for association studies, a target for phenotype/risk prediction, and a map for ancestry mapping; successively, (1) it generates for each individual in the base and target cohorts a set of principal components based on the map cohort-called mapped PCs, (2) it associates in the base cohort the phenotype with the mapped-PCs, and (3) it uses the mapped PCs in the target cohort to generate a phenotypic predictor called the ancestry score. We evaluated the ancestry score by comparing a predictive model using a PGS with one combining a PGS and an ancestry score. First, we performed simulations and found that the ancestry score has a greater impact on traits that correlate with ancestry-specific variants. Second, we showed, using UK Biobank data, that the ancestry score improves genetic prediction for our nine phenotypes to very different degrees. Third, we performed simulations and found that the more heterogeneous the base and target cohorts, the more beneficial the ancestry score is. Finally, we validated our approach under realistic conditions with UK Biobank as the base cohort and Swiss individuals from the CoLaus|PsyCoLaus study as the target cohort

Recurrence quantification analysis as a tool for the characterization of molecular dynamics simulations

A molecular dynamics simulation of a Lennard-Jones fluid, and a trajectory of the B1 immunoglobulin G-binding domain of streptococcal protein G (B1-IgG) simulated in water are analyzed by recurrence quantification, which is noteworthy for its independence from stationarity constraints, as well as its ability to detect transients, and both linear and nonlinear state changes. The results demonstrate the sensitivity of the technique for the discrimination of phase sensitive dynamics. Physical interpretation of the recurrence measures is also discussed.Comment: 7 pages, 8 figures, revtex; revised for review for Phys. Rev. E (clarifications and expansion of discussion)-- addition of the 8 postscript figures previously omitted, but unchanged from version

Human genomics of the humoral immune response against polyomaviruses

Publisher Copyright: © The Author(s) 2021. Published by Oxford University Press.Human polyomaviruses are widespread in humans and can cause severe disease in immunocompromised individuals. To identify human genetic determinants of the humoral immune response against polyomaviruses, we performed genome-wide association studies and meta-analyses of qualitative and quantitative immunoglobulin G responses against BK polyomavirus (BKPyV), JC polyomavirus (JCPyV), Merkel cellpolyomavirus (MCPyV), WU polyomavirus (WUPyV), and human polyomavirus 6 (HPyV6) in 15,660 individuals of European ancestry from three independent studies. We observed significant associations for all tested viruses: JCPyV, HPyV6, and MCPyV associated with human leukocyte antigen class II variation, BKPyV and JCPyV with variants in FUT2, responsible for secretor status, MCPyV with variants in STING1, involved in interferon induction, and WUPyV with a functional variant in MUC1, previously associated with risk for gastric cancer. These results provide insights into the genetic control of a family of very prevalent human viruses, highlighting genes and pathways that play a modulating role in human humoral immunity.Peer reviewe

Solving Large Sparse Lyapunov Equations on Parallel Computers

Abstract. This paper describes the parallelization of the low-rank ADI iteration for the solution of large-scale, sparse Lyapunov equations. The only relevant operations involved in the method are matrix-vector prod-ucts and the solution of linear systems. Experimental results on a cluster, using the SuperLU library, show the performance of this approach

A common NFKB1 variant detected through antibody analysis in UK Biobank predicts risk of infection and allergy

Infectious agents contribute significantly to the global burden of diseases through both acute infection and their chronic sequelae. We leveraged the UK Biobank to identify genetic loci that influence humoral immune response to multiple infections. From 45 genome-wide association studies in 9,611 participants from UK Biobank, we identified NFKB1 as a locus associated with quantitative antibody responses to multiple pathogens, including those from the herpes, retro-, and polyoma-virus families. An insertion-deletion variant thought to affect NFKB1 expression (rs28362491), was mapped as the likely causal variant and could play a key role in regulation of the immune response. Using 121 infection- and inflammation-related traits in 487,297 UK Biobank participants, we show that the deletion allele was associated with an increased risk of infection from diverse pathogens but had a protective effect against allergic disease. We propose that altered expression of NFKB1, as a result of the deletion, modulates hematopoietic pathways and likely impacts cell survival, antibody production, and inflammation. Taken together, we show that disruptions to the tightly regulated immune processes may tip the balance between exacerbated immune responses and allergy, or increased risk of infection and impaired resolution of inflammation

Nucleocytoplasmic transport: a thermodynamic mechanism

The nuclear pore supports molecular communication between cytoplasm and nucleus in eukaryotic cells. Selective transport of proteins is mediated by soluble receptors, whose regulation by the small GTPase Ran leads to cargo accumulation in, or depletion from the nucleus, i.e., nuclear import or nuclear export. We consider the operation of this transport system by a combined analytical and experimental approach. Provocative predictions of a simple model were tested using cell-free nuclei reconstituted in Xenopus egg extract, a system well suited to quantitative studies. We found that accumulation capacity is limited, so that introduction of one import cargo leads to egress of another. Clearly, the pore per se does not determine transport directionality. Moreover, different cargo reach a similar ratio of nuclear to cytoplasmic concentration in steady-state. The model shows that this ratio should in fact be independent of the receptor-cargo affinity, though kinetics may be strongly influenced. Numerical conservation of the system components highlights a conflict between the observations and the popular concept of transport cycles. We suggest that chemical partitioning provides a framework to understand the capacity to generate concentration gradients by equilibration of the receptor-cargo intermediary.Comment: in press at HFSP Journal, vol 3 16 text pages, 1 table, 4 figures, plus Supplementary Material include

Insights into the molecular determinants involved in cap recognition by the vaccinia virus D10 decapping enzyme

Decapping enzymes are required for the removal of the 5′-end m7GpppN cap of mRNAs to allow their decay in cells. While many cap-binding proteins recognize the cap structure via the stacking of the methylated guanosine ring between two aromatic residues, the precise mechanism of cap recognition by decapping enzymes has yet to be determined. In order to get insights into the interaction of decapping enzymes with the cap structure, we studied the vaccinia virus D10 decapping enzyme as a model to investigate the important features for substrate recognition by the enzyme. We demonstrate that a number of chemically modified purines can competitively inhibit the decapping reaction, highlighting the molecular features of the cap structure that are required for recognition by the enzyme, such as the nature of the moiety at positions 2 and 6 of the guanine base. A 3D structural model of the D10 protein was generated which suggests amino acids implicated in cap binding. Consequently, we expressed 17 mutant proteins with amino acid substitutions in the active site of D10 and found that eight are critical for the decapping activity. These data underscore the functional features involved in the non-canonical cap-recognition by the vaccinia virus D10 decapping enzyme