A computational method for genotype calling in family-based sequencing data

Background: As sequencing technologies can help researchers detect common and rare variants across the human genome in many individuals, it is known that jointly calling genotypes across multiple individuals based on linkage disequilibrium (LD) can facilitate the analysis of low to modest coverage sequence data. However, genotype-calling methods for family-based sequence data, particularly for complex families beyond parent-offspring trios, are still lacking. Results: In this study, first, we proposed an algorithm that considers both linkage disequilibrium (LD) patterns and familial transmission in nuclear and multi-generational families while retaining the computational efficiency. Second, we extended our method to incorporate external reference panels to analyze family-based sequence data with a small sample size. In simulation studies, we show that modeling multiple offspring can dramatically increase genotype calling accuracy and reduce phasing and Mendelian errors, especially at low to modest coverage. In addition, we show that using external panels can greatly facilitate genotype calling of sequencing data with a small number of individuals. We applied our method to a whole genome sequencing study of 1339 individuals at ~10X coverage from the Minnesota Center for Twin and Family Research. Conclusions: The aggregated results show that our methods significantly outperform existing ones that ignore family constraints or LD information. We anticipate that our method will be useful for many ongoing family-based sequencing projects. We have implemented our methods efficiently in a C++ program FamLDCaller, which is available from http://www.pitt.edu/~wec47/famldcaller.html

Temporal Stability and the Effects of Training on Saccade Latency in “Express Saccade Makers”

The temporal stability of saccade latency, and the effects of training, particularly in “express saccade makers” (ESMs), has received little attention. ESMs are healthy, naïve, adults, who persist in executing very many low latency “express saccades” (ES; saccades with latency of 80 ms to 130 ms), in conditions designed to suppress such responses. We investigated the stability of ES production (%ES) in 59 ESM and 54 non-ESM participants in overlap tasks. Within a single session, the intraclass correlation coefficient (ICC) for %ES in two runs of 200 trials was 0.97 (p30% of saccades over the two runs were ES, were classified as ESMs. For 60 participants tested over two sessions 12 weeks apart, and 30 participants tested in three sessions over approximately six months, the ICC for %ES was uniformly high (0.95, p<0.001 and 0.97, p<0.001 respectively) and participants behaved consistently with their initial classification. Fourteen participants (7 ESMs) were then exposed to training consisting of either gap or overlap tasks. Training increased %ES in both groups. However, when tested in overlap tasks, it was not sufficient to transform Normal participants into ESMs. We conclude that the pattern of saccade behaviour exhibited by ESMs constitutes a stable and distinct oculomotor phenotype

Large-scale collaboration in ENIGMA-EEG: A perspective on the meta-analytic approach to link neurological and psychiatric liability genes to electrophysiological brain activity

BACKGROUND AND PURPOSE: The ENIGMA-EEG working group was established to enable large-scale international collaborations among cohorts that investigate the genetics of brain function measured with electroencephalography (EEG). In this perspective, we will discuss why analyzing the genetics of functional brain activity may be crucial for understanding how neurological and psychiatric liability genes affect the brain. METHODS: We summarize how we have performed our currently largest genome-wide association study of oscillatory brain activity in EEG recordings by meta-analyzing the results across five participating cohorts, resulting in the first genome-wide significant hits for oscillatory brain function located in/near genes that were previously associated with psychiatric disorders. We describe how we have tackled methodological issues surrounding genetic meta-analysis of EEG features. We discuss the importance of harmonizing EEG signal processing, cleaning, and feature extraction. Finally, we explain our selection of EEG features currently being investigated, including the temporal dynamics of oscillations and the connectivity network based on synchronization of oscillations. RESULTS: We present data that show how to perform systematic quality control and evaluate how choices in reference electrode and montage affect individual differences in EEG parameters. CONCLUSION: The long list of potential challenges to our large-scale meta-analytic approach requires extensive effort and organization between participating cohorts; however, our perspective shows that these challenges are surmountable. Our perspective argues that elucidating the genetic of EEG oscillatory activity is a worthwhile effort in order to elucidate the pathway from gene to disease liability

Resource profile and user guide of the Polygenic Index Repository

Polygenic indexes (PGIs) are DNA-based predictors. Their value for research in many scientific disciplines is growing rapidly. As a resource for researchers, we used a consistent methodology to construct PGIs for 47 phenotypes in 11 datasets. To maximize the PGIs’ prediction accuracies, we constructed them using genome-wide association studies — some not previously published — from multiple data sources, including 23andMe and UK Biobank. We present a theoretical framework to help interpret analyses involving PGIs. A key insight is that a PGI can be understood as an unbiased but noisy measure of a latent variable we call the ‘additive SNP factor’. Regressions in which the true regressor is this factor but the PGI is used as its proxy therefore suffer from errors-in-variables bias. We derive an estimator that corrects for the bias, illustrate the correction, and make a Python tool for implementing it publicly available

A multi-modal network approach to model public transport accessibility impacts of bicycle-train integration policies

In the Netherlands, the bicycle plays an important in station access and, to a lesser extent, in station egress. There is however fairly little knowledge in the potential effects of bicycle-train integration policies. The aim of this paper is to examine the impacts of bicycle-train integration policies on train ridership and job accessibility for public transport users.MethodsWe extended the Dutch National Transport Model (NVM) by implementing a detailed bicycle network linked to the public transport network, access/egress mode combinations and station specific access and egress penalties by mode and station type derived from a stated choice survey. Furthermore, the effects of several bicycletrain integration policy scenarios were examined for a case study for Randstad South, in the Netherlands, comprising a dense train network with 54 train stations.ConclusionsOur analysis shows that improving the quality of bicycle routes and parking can substantially increase train ridership and potential job accessibility for train users. Large and medium stations are more sensitive to improvements in bicycle-train integration policies, while small stations are more sensitive to improvements in the train level of service

Electrical conductivity during incipient melting in the oceanic low-velocity zone

International audienceThe low-viscosity layer in the upper mantle, the asthenosphere, is a requirement for plate tectonics1. The seismic low velocities and the high electrical conductivities of the asthenosphere are attributed either to subsolidus, water-related defects in olivine minerals2, 3, 4 or to a few volume per cent of partial melt5, 6, 7, 8, but these two interpretations have two shortcomings. First, the amount of water stored in olivine is not expected to be higher than 50 parts per million owing to partitioning with other mantle phases9 (including pargasite amphibole at moderate temperatures10) and partial melting at high temperatures9. Second, elevated melt volume fractions are impeded by the temperatures prevailing in the asthenosphere, which are too low, and by the melt mobility, which is high and can lead to gravitational segregation11, 12. Here we determine the electrical conductivity of carbon-dioxide-rich and water-rich melts, typically produced at the onset of mantle melting. Electrical conductivity increases modestly with moderate amounts of water and carbon dioxide, but it increases drastically once the carbon dioxide content exceeds six weight per cent in the melt. Incipient melts, long-expected to prevail in the asthenosphere10, 13, 14, 15, can therefore produce high electrical conductivities there. Taking into account variable degrees of depletion of the mantle in water and carbon dioxide, and their effect on the petrology of incipient melting, we calculated conductivity profiles across the asthenosphere for various tectonic plate ages. Several electrical discontinuities are predicted and match geophysical observations in a consistent petrological and geochemical framework. In moderately aged plates (more than five million years old), incipient melts probably trigger both the seismic low velocities and the high electrical conductivities in the upper part of the asthenosphere, whereas in young plates4, where seamount volcanism occurs6, a higher degree of melting is expected

SPEM dysfunction and general schizotypy as measured by the SSQ: a controlled study

Abstract Background SPEM dysfunction is a well-known phenomenon in schizophrenia. The principal aim of the present study was to examine whether SPEM dysfunction is already observable in subjects scoring high on a specific measure of schizotypy (SSQ General Schizotypy) that was selected because of its intimate relationship with schizophrenic prodromal unfolding. Methods Applying ANOVAs, we determined the relationship of subjects' scores on SSQ General Schizotypy and eye movements elicited by targets of different speed. We also examined whether there exists an association between our schizotypy measure and pupil size. Results We found more SPEM dysfunction in subjects scoring high on SSQ General Schizotypy than in subjects scoring average on that factor, irrespective of the speed of the target. No relationship was found between baseline pupil size and General Schizotypy. Conclusion The present study provides additional evidence that SPEM dysfunction is associated with schizotypic features that precede the onset of schizophrenia and is already observable in general population subjects that show these features

Fluid Intelligence and Psychosocial Outcome: From Logical Problem Solving to Social Adaptation

While fluid intelligence has proved to be central to executive functioning, logical reasoning and other frontal functions, the role of this ability in psychosocial adaptation has not been well characterized.Lower fluid intelligence scores were associated with physical violence, both in the role of victim and victimizer. Drug intake, especially cannabis, cocaine and inhalants and lower self-esteem were also associated with lower fluid intelligence. Finally, scores on the perceived mental health assessment were better when fluid intelligence scores were higher.Our results show evidence of a strong association between psychosocial adaptation and fluid intelligence, suggesting that the latter is not only central to executive functioning but also forms part of a more general capacity for adaptation to social contexts