Fast Identification of Biological Pathways Associated with a Quantitative Trait Using Group Lasso with Overlaps

Where causal SNPs (single nucleotide polymorphisms) tend to accumulate within biological pathways, the incorporation of prior pathways information into a statistical model is expected to increase the power to detect true associations in a genetic association study. Most existing pathways-based methods rely on marginal SNP statistics and do not fully exploit the dependence patterns among SNPs within pathways. We use a sparse regression model, with SNPs grouped into pathways, to identify causal pathways associated with a quantitative trait. Notable features of our "pathways group lasso with adaptive weights" (P-GLAW) algorithm include the incorporation of all pathways in a single regression model, an adaptive pathway weighting procedure that accounts for factors biasing pathway selection, and the use of a bootstrap sampling procedure for the ranking of important pathways. P-GLAW takes account of the presence of overlapping pathways and uses a novel combination of techniques to optimise model estimation, making it fast to run, even on whole genome datasets. In a comparison study with an alternative pathways method based on univariate SNP statistics, our method demonstrates high sensitivity and specificity for the detection of important pathways, showing the greatest relative gains in performance where marginal SNP effect sizes are small.Comment: 29 page

Identification of gene pathways implicated in Alzheimer's disease using longitudinal imaging phenotypes with sparse regression

We present a new method for the detection of gene pathways associated with a multivariate quantitative trait, and use it to identify causal pathways associated with an imaging endophenotype characteristic of longitudinal structural change in the brains of patients with Alzheimer's disease (AD). Our method, known as pathways sparse reduced-rank regression (PsRRR), uses group lasso penalised regression to jointly model the effects of genome-wide single nucleotide polymorphisms (SNPs), grouped into functional pathways using prior knowledge of gene-gene interactions. Pathways are ranked in order of importance using a resampling strategy that exploits finite sample variability. Our application study uses whole genome scans and MR images from 464 subjects in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. 66,182 SNPs are mapped to 185 gene pathways from the KEGG pathways database. Voxel-wise imaging signatures characteristic of AD are obtained by analysing 3D patterns of structural change at 6, 12 and 24 months relative to baseline. High-ranking, AD endophenotype-associated pathways in our study include those describing chemokine, Jak-stat and insulin signalling pathways, and tight junction interactions. All of these have been previously implicated in AD biology. In a secondary analysis, we investigate SNPs and genes that may be driving pathway selection, and identify a number of previously validated AD genes including CR1, APOE and TOMM40

Intergenerational Influences on Child Development: An Epigenetic Perspective.

The link between poor maternal nutrition and suboptimal outcomes in offspring is well established, but underlying mechanisms are not well understood. Modifications to the offspring epigenome are a plausible mechanism for the transmission of intergenerational signals that could extend to effects of paternal nutrition mediated by epigenetic modifications in sperm. The epigenome is extensively remodeled in the early embryo. Attention has therefore focused on the periconceptional period as a time when differences in parental nutrition might influence the establishment of epigenetic marks in offspring. So-called "natural experiments" in The Gambia and elsewhere have highlighted loci that may be especially sensitive to periconceptional nutrition, and some are associated with health-related outcomes in later life. There is speculation that some epigenetic signals could be transmitted across multiple generations, although this would require epigenetic marks to evade epigenetic reprogramming events at conception and in primordial germ cells, and evidence for this is lacking in humans. Effects on child development spanning one or more generations could impose an intergenerational "brake" on a child's growth potential, limiting, for example, the rate at which populations can escape from stunting

Fetal programming and epigenetics

Accumulating evidence suggests that the intrauterine environment can have an impact on long-term offspring health, so-called �fetal programming�. A number of environmental stressors have been studied in humans including maternal nutrition, smoking, substance misuse and mental illness. Although various biological mechanisms are likely to underpin fetal programming effects, there has been a particular focus on epigenetic modifications as potential mediators of observed associations between early environmental exposures and later health outcomes. In this review, we give an overview of evidence supporting a role for epigenetics in fetal programming, highlighting key human and animal studies. We also discuss challenges for research in this area, along with recommendations for future work, and potential therapeutic applications

SPH Simulations of Direct Impact Accretion in the Ultracompact AM CVn Binaries

The ultracompact binary systems V407 Vul (RX J1914.4+2456) and HM Cnc (RX J0806.3+1527) - a two-member subclass of the AM CVn stars - continue to pique interest because they defy unambiguous classification. Three proposed models remain viable at this time, but none of the three is significantly more compelling than the remaining two, and all three can satisfy the observational constraints if parameters in the models are tuned. One of the three proposed models is the direct impact model of Marsh & Steeghs (2002), in which the accretion stream impacts the surface of a rapidly-rotating primary white dwarf directly but at a near-glancing angle. One requirement of this model is that the accretion stream have a high enough density to advect its specific kinetic energy below the photosphere for progressively more-thermalized emission downstream, a constraint that requires an accretion spot size of roughly 1.2x10^5 km^2 or smaller. Having at hand a smoothed particle hydrodynamics code optimized for cataclysmic variable accretion disk simulations, it was relatively straightforward for us to adapt it to calculate the footprint of the accretion stream at the nominal radius of the primary white dwarf, and thus to test this constraint of the direct impact model. We find that the mass flux at the impact spot can be approximated by a bivariate Gaussian with standard deviation \sigma_{\phi} = 164 km in the orbital plane and \sigma_{\theta} = 23 km in the perpendicular direction. The area of the the 2\sigma ellipse into which 86% of the mass flux occurs is roughly 47,400 km^2, or roughly half the size estimated by Marsh & Steeghs (2002). We discuss the necessary parameters of a simple model of the luminosity distribution in the post-impact emission region.Comment: 24 pages, 5 figures, Accepted for publication in Ap

Influence of intergenerational in utero parental energy and nutrient restriction on offspring growth in rural Gambia.

The prenatal environment can alter an individual's developmental trajectory with long-lasting effects on health. Animal models demonstrate that the impact of the early life environment extends to subsequent generations, but there is a paucity of data from human populations on intergenerational transmission of environmentally induced phenotypes. Here we investigated the association of parental exposure to energy and nutrient restriction in utero on their children's growth in rural Gambia. In a Gambian cohort with infants born between 1972 and 2011, we used multiple regression to test whether parental season of birth predicted offspring birth weight (n = 2097) or length (n = 1172), height-for-age z score (HAZ), weight-for-height z score (WHZ), and weight-for-age z score (WAZ) at 2 yr of age (n = 923). We found that maternal exposure to seasonal energy restriction in utero was associated with reduced offspring birth length (crude:-4.2 mm, P = 0.005; adjusted: -4.0 mm, P = 0.02). In contrast, paternal birth season predicted offspring HAZ at 24 mo (crude: -0.21, P = 0.005; adjusted: -0.22, P = 0.004) but had no discernible impact at birth. Our results indicate that periods of nutritional restriction in a parent's fetal life can have intergenerational consequences in human populations. Fetal growth appears to be under matriline influence, and postnatal growth appears to be under patriline intergenerational influences.-Eriksen, K. G., Radford, E. J., Silver, M. J., Fulford, A. J. C., Wegmüller, R., Prentice, A. M. Influence of intergenerational in utero parental energy and nutrient restriction on offspring growth in rural Gambia

Establishment of environmentally sensitive DNA methylation states in the very early human embryo.

The molecular mechanisms responsible for the developmental origins of later disease are currently unknown. We previously demonstrated that women's periconceptional nutrition predicts their offspring's DNA methylation at metastable epialleles (MEs). We present a genome-wide screen yielding 687 MEs and track their trajectories across nine developmental stages in human in vitro fertilization embryos. MEs exhibit highly unusual methylation dynamics across the implantation-gastrulation transition, producing a large excess of intermediate methylation states, suggesting the potential for differential programming in response to external signals. Using a natural experiment in rural Gambia, we show that genomic regions sensitive to season of conception are highly enriched for MEs and show similar atypical methylation patterns. MEs are enriched for proximal enhancers and transcription start sites and are influenced by genotype. Together, these observations position MEs as distinctive epigenomic features programmed in the early embryo, sensitive to genetic and periconceptional environment, and with the potential to influence phenotype

Periconceptional environment predicts leukocyte telomere length in a cross-sectional study of 7-9 year old rural Gambian children

Early life exposures are important predictors of adult disease risk. Although the underlying mechanisms are largely unknown, telomere maintenance may be involved. This study investigated the relationship between seasonal differences in parental exposures at time of conception and leukocyte telomere length (LTL) in their offspring. LTL was measured in two cohorts of children aged 2 yrs (N = 487) and 7–9 yrs (N = 218). The association between date of conception and LTL was examined using Fourier regression models, adjusted for age, sex, leukocyte cell composition, and other potential confounders. We observed an effect of season in the older children in all models [likelihood ratio test (LRT) χ²2 = 7.1, p = 0.03; fully adjusted model]. LTL was greatest in children conceived in September (in the rainy season), and smallest in those conceived in March (in the dry season), with an effect size (LTL peak–nadir) of 0.60 z-scores. No effect of season was evident in the younger children (LRT χ²2 = 0.87, p = 0.65). The different results obtained for the two cohorts may reflect a delayed effect of season of conception on postnatal telomere maintenance. Alternatively, they may be explained by unmeasured differences in early life exposures, or the increased telomere attrition rate during infancy