Phenotypic complexity, measurement bias, and poor phenotypic resolution contribute to the missing heritability problem in genetic association studies

Background

The variance explained by genetic variants as identified in (genome-wide) genetic association studies is typically small compared to family-based heritability estimates. Explanations of this ‘missing heritability’ have been mainly genetic, such as genetic heterogeneity and complex (epi-)genetic mechanisms.

Methodology

We used comprehensive simulation studies to show that three phenotypic measurement issues also provide viable explanations of the missing heritability: phenotypic complexity, measurement bias, and phenotypic resolution. We identify the circumstances in which the use of phenotypic sum-scores and the presence of measurement bias lower the power to detect genetic variants. In addition, we show how the differential resolution of psychometric instruments (i.e., whether the instrument includes items that resolve individual differences in the normal range or in the clinical range of a phenotype) affects the power to detect genetic variants.

Conclusion

We conclude that careful phenotypic data modelling can improve the genetic signal, and thus the statistical power to identify genetic variants by 20–99%.     

Concerted changes in gene expression and cell physiology of the cyanobacterium Synechocystis sp. strain PCC 6803 during transitions between nitrogen and light-limited growth

Physiological adaptation and genome-wide expression profiles of the cyanobacterium Synechocystis sp. strain PCC 6803 in response to gradual transitions between nitrogen-limited and light-limited growth conditions were measured in continuous cultures. Transitions induced changes in pigment composition, light absorption coefficient, photosynthetic electron transport, and specific growth rate. Physiological changes were accompanied by reproducible changes in the expression of several hundred open reading frames, genes with functions in photosynthesis and respiration, carbon and nitrogen assimilation, protein synthesis, phosphorus metabolism, and overall regulation of cell function and proliferation. Cluster analysis of the nearly 1,600 regulated open reading frames identified eight clusters, each showing a different temporal response during the transitions. Two large clusters mirrored each other. One cluster included genes involved in photosynthesis, which were up-regulated during light-limited growth but down-regulated during nitrogen-limited growth. Conversely, genes in the other cluster were down-regulated during light-limited growth but up-regulated during nitrogen-limited growth; this cluster included several genes involved in nitrogen uptake and assimilation. These results demonstrate complementary regulation of gene expression for two major metabolic activities of cyanobacteria. Comparison with batch-culture experiments revealed interesting differences in gene expression between batch and continuous culture and illustrates that continuous-culture experiments can pick up subtle changes in cell physiology and gene expression.     

Natural variation of submergence tolerance among Arabidopsis thaliana accessions

? The exploitation of natural variation in Arabidopsis thaliana (Arabidopsis) provides a huge potential for the identification of the molecular mechanisms underlying this variation as a result of the availability of a vast array of genetic and genomic resources for this species. Eighty-six Arabidopsis accessions were screened for natural variation in flooding tolerance. This forms the first step towards the identification and characterization of the role of candidate genes contributing to flooding tolerance. ? Arabidopsis accessions at the 10-leaf stage were subjected to complete submergence in the dark. Survival curves were plotted to estimate median lethal times as a measure of tolerance. Flooding-associated survival parameters, such as root and shoot oxygen content, initial carbohydrate content and petiole elongation under water, were also measured. ? There was a significant variation in submergence tolerance among Arabidopsis accessions. However, the order of tolerance did not correlate with root and shoot oxygen content or initial amounts of shoot starch and total soluble sugars. A negative correlation was observed between submergence tolerance and underwater petiole elongation. ? Arabidopsis accessions show considerable variation in the ability to tolerate complete submergence, making it a good species in which to identify and characterize genes and to study mechanisms that contribute to survival under water.     

Patent pools and clearinghouses in the life sciences

The biopharmaceutical industry is slowly absorbing the idea of collaborative patent licensing models. Recently, two patent pools for developing countries have been launched: the Pool for Open Innovation against Neglected Tropical Diseases initiated by GlaxoSmithKline (GSK), which is referred to as the BIO Ventures for Global Health (BVGH) pool, and the Medicines Patent Pool (MPP) initiated by UNITAID. Various organizations have recommended using pools or clearinghouses beyond the humanitarian dimension where many patents are owned by many different actors. As a first attempt, MPEG LA, which administers patent pools in various technology fields, is now setting up a clearinghouse for patents related to molecular diagnostics. These examples as well as the results from an empirical study provide useful insights for the design and administration of future pools and clearinghouses in the life sciences.     

Repeated triggering of sporulation in Bacillus subtilis selects against a protein that affects the timing of cell division

Bacillus subtilis sporulation is a last-resort phenotypical adaptation in response to starvation. The regulatory network underlying this developmental pathway has been studied extensively. However, how sporulation initiation is concerted in relation to the environmental nutrient availability is poorly understood. In a fed-batch fermentation set-up, in which sporulation of ultraviolet (UV)-mutagenized B. subtilis is repeatedly triggered by periods of starvation, fitter strains with mutated tagE evolved. These mutants display altered timing of phenotypical differentiation. The substrate for the wall teichoic acid (WTA)-modifying enzyme TagE, UDP-glucose, has recently been shown to be an intracellular proxy for nutrient availability, and influences the timing of cell division. Here we suggest that UDP-glucose also influences timing of cellular differentiation.     

Urinating Standing versus Sitting: Position Is of Influence in Men with Prostate Enlargement. A Systematic Review and Meta-Analysis

Background

It is suggested that the body posture during urination can influence urodynamic parameters in patients with Lower Urinary Tract Symptoms (LUTS) to an extent approaching pharmacological interventions. In this article, the influence of body position during micturition on maximum urinary flow rate (Qmax), voiding time (TQ) and post-void residual volume (PVR) in healthy males and patients with LUTS is analyzed by means of a systematic review and meta-analysis.

Evidence Acquisition

A systematic search was conducted in 14 medical databases. Studies comparing urodynamic parameters in standing versus sitting position were eligible for inclusion. Studies were stratified according to health status of included male participants: healthy individuals and patients with LUTS. Standardized mean differences for Qmax, TQ and PVR were pooled in a random effects model.

Results

Eleven articles were included. In men with LUTS, a significantly lower PVR (−24.96 ml; 95%CI −48.70 to −1.23) was shown in sitting position compared to standing. In accordance, Qmax was increased (1.23 ml/s; 95%CI −1.02 to 3.48), and TQ was decreased (−0.62 s; 95%CI −1.66 to 0.42) in sitting position, although these differences did not reach statistical significance. In healthy men, Qmax (0.18 ml/s; 95% CI −1.67 to 2.02), TQ (0.49 s; 95%CI −3.30 to 4.27) and PVR (0.43 ml; 95%CI −0.79 to 1,65) were similar in sitting and standing position.

Conclusion

For healthy men, no difference is found in any of the urodynamic parameters. In patients with LUTS, the sitting position is linked with an improved urodynamic profile.     

Heated Relations: Temperature-Mediated Shifts in Consumption across Trophic Levels

A rise in temperature will intensify the feeding links involving ectotherms in food webs. However, it is unclear how the effects will quantitatively differ between the plant-herbivore and herbivore-carnivore interface. To test how warming could differentially affect rates of herbivory and carnivory, we studied trophic interaction strength in a food chain comprised of green algae, herbivorous rotifers and carnivorous rotifers at 10, 15, 20 and 25°C. We found significant warming-induced changes in feeding by both herbivorous and carnivorous rotifers, but these responses occurred at different parts of the entire temperature gradient. The strongest response of the per capita herbivore''s ingestion rate occurred due to an increase in temperature from 15 to 20°C (1.9 fold: from 834 to 1611 algal cells per h⁻¹) and of the per capita carnivore''s ingestion rate from 20 to 25°C (1.6 fold: from 1.5 to 2.5 prey h⁻¹). Handling time, an important component of a consumer''s functional response, significantly decreased from 15 to 20°C in herbivorous rotifers. In contrast, it decreased from 20 to 25°C in carnivorous rotifers. Attack rates significantly and strongly increased from 10 to 25°C in the herbivorous animals, but not at all in the carnivores. Our results exemplify how the relative forces of top-down control exerted by herbivores and carnivores may strongly shift under global warming. But warming, and its magnitude, are not the only issue: If our results would prove to be representative, shifts in ectotherm interactions will quantitatively differ when a 5°C increase starts out from a low, intermediate or high initial temperature. This would imply that warming could have different effects on the relative forces of carnivory and herbivory in habitats differing in average temperature, as would exist at different altitudes and latitudes.     

Predicting Cannabis Abuse Screening Test (CAST) Scores: A Recursive Partitioning Analysis Using Survey Data from Czech Republic,Italy, the Netherlands and Sweden

Introduction

Cannabis is Europe''s most commonly used illicit drug. Some users do not develop dependence or other problems, whereas others do. Many factors are associated with the occurrence of cannabis-related disorders. This makes it difficult to identify key risk factors and markers to profile at-risk cannabis users using traditional hypothesis-driven approaches. Therefore, the use of a data-mining technique called binary recursive partitioning is demonstrated in this study by creating a classification tree to profile at-risk users.

Methods

59 variables on cannabis use and drug market experiences were extracted from an internet-based survey dataset collected in four European countries (Czech Republic, Italy, Netherlands and Sweden), n = 2617. These 59 potential predictors of problematic cannabis use were used to partition individual respondents into subgroups with low and high risk of having a cannabis use disorder, based on their responses on the Cannabis Abuse Screening Test. Both a generic model for the four countries combined and four country-specific models were constructed.

Results

Of the 59 variables included in the first analysis step, only three variables were required to construct a generic partitioning model to classify high risk cannabis users with 65–73% accuracy. Based on the generic model for the four countries combined, the highest risk for cannabis use disorder is seen in participants reporting a cannabis use on more than 200 days in the last 12 months. In comparison to the generic model, the country-specific models led to modest, non-significant improvements in classification accuracy, with an exception for Italy (p = 0.01).

Conclusion

Using recursive partitioning, it is feasible to construct classification trees based on only a few variables with acceptable performance to classify cannabis users into groups with low or high risk of meeting criteria for cannabis use disorder. The number of cannabis use days in the last 12 months is the most relevant variable. The identified variables may be considered for use in future screeners for cannabis use disorders.     

Context coding in the mouse nucleus accumbens modulates motivationally relevant information

Neural activity in the nucleus accumbens (NAc) is thought to track fundamentally value-centric quantities linked to reward and effort. However, the NAc also contributes to flexible behavior in ways that are difficult to explain based on value signals alone, raising the question of if and how nonvalue signals are encoded in NAc. We recorded NAc neural ensembles while head-fixed mice performed an odor-based biconditional discrimination task where an initial discrete cue modulated the behavioral significance of a subsequently presented reward-predictive cue. We extracted single-unit and population-level correlates related to the cues and found value-independent coding for the initial, context-setting cue. This context signal occupied a population-level coding space orthogonal to outcome-related representations and was predictive of subsequent behaviorally relevant responses to the reward-predictive cues. Together, these findings support a gating model for how the NAc contributes to behavioral flexibility and provide a novel population-level perspective from which to view NAc computations.

Neural activity in the nucleus accumbens is thought to track value-centric quantities such as current or future expected reward, reward prediction errors, etc. This study shows that neural ensembles in nucleus accumbens encode a context signal that modulates subsequent stimulus-outcome associations, supporting a circuit-level gating model for behavioral flexibility.