CollapsABEL: An R library for detecting compound heterozygote alleles in genome-wide association studies

Background: Compound Heterozygosity (CH) in classical genetics is the presence of two different recessive mutations at a particular gene locus. A relaxed form of CH alleles may account for an essential proportion of the missing heritability, i.e. heritability of phenotypes so far not accounted for by single genetic variants. Methods to detect CH-like effects in genome-wide association studies (GWAS) may facilitate explaining the missing heritability, but to our knowledge no viable software tools for this purpose are currently available. Results: In this work we present the Generalized Compound Double Heterozygosity (GCDH) test and its implementation in the R package CollapsABEL. Time-consuming procedures are optimized for computational efficiency using Java or C++. Intermediate results are stored either in an SQL database or in a so-called big.matrix file to achieve reasonable memory footprint. Our large scale simulation studies show that GCDH is capable of discovering genetic associations due to CH-like interactions with much higher power than a conventional single-SNP approach under various settings, whether the causal genetic variations are available or not. CollapsABEL provides a user-friendly pipeline for genotype collapsing, statistical testing, power estimation, type I error control and graphics generation in the R language. Conclusions: CollapsABEL provides a computationally efficient solution for screening general forms of CH alleles in densely imputed microarray or whole genome sequencing datasets. The GCDH test provides an improved power over single-SNP based methods in detecting the prevalence of CH in human complex phenotypes, offering an opportunity for tackling the missing heritability problem. Binary and source packages of CollapsABEL are available on CRAN (https://cran.r-project.org/web/packages/CollapsABEL) and the website of the GenABEL project (http://www.genabel.org/packages)

GAGA: A New Algorithm for Genomic Inference of Geographic Ancestry Reveals Fine Level Population Substructure in Europeans

Attempts to detect genetic population substructure in humans are troubled by the fact that the vast majority of the total amount of observed genetic variation is present within populations rather than between populations. Here we introduce a new algorithm for transforming a genetic distance matrix that reduces the within-population variation considerably. Extensive computer simulations revealed that the transformed matrix captured the genetic population differentiation better than the original one which was based on the T1 statistic. In an empirical genomic data set comprising 2,457 individuals from 23 different European subpopulations, the proportion of individuals that were determined as a genetic neighbour to another individual from the same sampling location increased from 25% with the original matrix to 52% with the transformed matrix. Similarly, the percentage of genetic variation explained between populations by means of Analysis of Molecular Variance (AMOVA) increased from 1.62% to 7.98%. Furthermore, the first two dimensions of a classical multidimensional scaling (MDS) using the transformed matrix explained 15% of the variance, compared to 0.7% obtained with the original matrix. Application of MDS with Mclust, SPA with Mclust, and GemTools algorithms to the same dataset also showed that the transformed matrix gave a better association of the genetic clusters with the sampling locations, and particularly so when it was used in the AMOVA framework with a genetic algorithm. Overall, the new matrix transformation introduced here substantially reduces the within population genetic differentiation, and can be broadly applied to methods such as AMOVA to enhance their sensitivity to reveal population substructure. We herewith provide a publically available (http://www.erasmusmc.nl/fmb/resources/GAGA) model-free method for improved genetic population substructure detection that can be applied to human as well as any other species data in future studies relevant to evolutionary biology, behavioural ecology, medicine, and forensics

Predicting hair cortisol levels with hair pigmentation genes

Cortisol concentrations in hair are used to create hormone profiles spanning months. This method allows assessment of chronic cortisol exposure, but might be biased by hair pigmentation: dark hair was previously related to higher concentrations. It is unclear whether this association arises from local effects, such as increased hormone extractability, or whether the association represents systemic differences arising from population stratification. We tested the hypothesis that hair pigmentation gene variants are associated with varying cortisol levels independent of genetic ancestry. Hormone concentrations and genotype were measured in 1674 children from the Generation R cohort at age 6. We computed a polygenic score of hair color based on 9 single nucleotide polymorphisms. This score was used to predict hair cortisol concentrations, adjusted for genetic ancestry, sex, age and corticosteroid use. A 1-standard deviation (SD) higher polygenic score (darker hair) was associated with 0.08 SD higher cortisol levels (SE = 0.03, p = 0.002). This suggests that variation in hair cortisol concentrations is partly explained by local hair effects. In multi-ancestry studies this hair pigmentation bias can reduce power and confound results. Researchers should therefore consider adjusting analyses by reported hair color, by polygenic scores, or by both

Quantum phase properties of two-mode Jaynes-Cummings model for Schr\"odinger-cat states: interference and entanglement

In this paper we investigate the quantum phase properties for the coherent superposition states (Schr\"odinger-cat states) for two-mode multiphoton Jaynes-Cummings model in the framework of the Pegg-Barnett formalism. We also demonstrate the behavior of the Wigner ($W$) function at the phase space origin. We obtain many interesting results such as there is a clear relationship between the revival-collapse phenomenon occurring in the atomic inversion (as well as in the evolution of the $W$ function) and the behavior of the phase distribution of both the single-mode and two-mode cases. Furthermore, we find that the phase variances of the single-mode case can exhibit revival-collapse phenomenon about the long-time behavior. We show that such behavior occurs for interaction time several times smaller than that of the single-mode Jaynes-Cummings model.Comment: 23, 8 figure

Model-based prediction of human hair color using DNA variants

Predicting complex human phenotypes from genotypes is the central concept of widely advocated personalized medicine, but so far has rarely led to high accuracies limiting practical applications. One notable exception, although less relevant for medical but important for forensic purposes, is human eye color, for which it has been recently demonstrated that highly accurate prediction is feasible from a small number of DNA variants. Here, we demonstrate that human hair color is predictable from DNA variants with similarly high accuracies. We analyzed in Polish Europeans with single-observer hair color grading 45 single nucleotide polymorphisms (SNPs) from 12 genes previously associated with human hair color variation. We found that a model based on a subset of 13 single or compound genetic markers from 11 genes predicted red hair color with over 0.9, black hair color with almost 0.9, as well as blond, and brown hair color with over 0.8 prevalence-adjusted accuracy expressed by the area under the receiver characteristic operating curves (AUC). The identified genetic predictors also differentiate reasonably well between similar hair colors, such as between red and blond-red, as well as between blond and dark-blond, highlighting the value of the identified DNA variants for accurate hair color prediction

Polariton condensation and lasing in optical microcavities - the decoherence driven crossover

We explore the behaviour of a system which consists of a photon mode dipole coupled to a medium of two-level oscillators in a microcavity in the presence of decoherence. We consider two types of decoherence processes which are analogous to magnetic and non-magnetic impurities in superconductors. We study different phases of this system as the decoherence strength and the excitation density is changed. For a low decoherence we obtain a polariton condensate with comparable excitonic and photonic parts at low densities and a BCS-like state with bigger photon component due to the fermionic phase space filling effect at high densities. In both cases there is a large gap in the density of states. As the decoherence is increased the gap is broadened and suppressed, resulting in a gapless condensate and finally a suppression of the coherence in a low density regime and a laser at high density limit. A crossover between these regimes is studied in a self-consistent way analogous to the Abrikosov and Gor'kov theory of gapless superconductivity.Comment: 17 pages, 8 figures, submitted to PR

PHOX2B polyalanine repeat length is associated with sudden infant death syndrome and unclassified sudden infant death in the Dutch population

Unclassified sudden infant death (USID) is the sudden and unexpected death of an infant that remains unexplained after thorough case investigation including performance of a complete autopsy and review of the circumstances of death and the clinical history. When the infant is below 1 year of age and with onset of the fatal episode apparently occurring during sleep, this is referred to as sudden infant death syndrome (SIDS). USID and SIDS remain poorly understood despite the identification of several environmental and some genetic risk factors. In this study, we investigated genetic risk factors involved in the autonomous nervous system in 195 Dutch USID/SIDS cases and 846 Dutch, age-matched healthy controls. Twenty-five DNA variants from 11 genes previously implicated in the serotonin household or in the congenital central hypoventilation syndrome, of which some have been associated with SIDS before, were tested. Of all DNA variants considered, only the length variation of the polyalanine repeat in exon 3 of the PHOX2B gene was found to be statistically significantly associated with USID/SIDS in the Dutch population after multiple test correction. Interestingly, our data suggest that contraction of the PHOX2B exon 3 polyalanine repeat that we found in six of 160 SIDS and USID cases and in six of 814 controls serves as a probable genetic risk factor for USID/SIDS at least in the Dutch population. Future studies are needed to confirm this finding and to understand the functional effect of the polyalanine repeat length variation, in particular contraction, in exon 3 of the PHOX2B gene

Global skin colour prediction from DNA

Human skin colour is highly heritable and externally visible with relevance in medical, forensic, and anthropological genetics. Although eye and hair colour can already be predicted with high accuracies from small sets of carefully selected DNA markers, knowledge about the genetic predictability of skin colour is limited. Here, we investigate the skin colour predictive value of 77 single-nucleotide polymorphisms (SNPs) from 37 genetic loci previously associated with human pigmentation using 2025 individuals from 31 global populations. We identified a minimal set of 36 highly informative skin colour predictive SNPs and developed a statistical prediction model capable of skin colour prediction on a global scale. Average cross-validated prediction accuracies expressed as area under the receiver-operating characteristic curve (AUC) ± standard deviation were 0.97 ± 0.02 for Light, 0.83 ± 0.11 for Dark, and 0.96 ± 0.03 for Dark-Black. When using a 5-category, this resulted in 0.74 ± 0.05 for Very Pale, 0.72 ± 0.03 for Pale, 0.73 ± 0.03 for Intermediate, 0.87±0.1 for Dark, and 0.97 ± 0.03 for Dark-Black. A comparative analysis in 194 independent samples from 17 populations demonstrated that our model outperformed a previously proposed 10-SNP-classifier approach with AUCs rising from 0.79 to 0.82 for White, comparable at the intermediate level of 0.63 and 0.62, respectively, and a large increase from 0.64 to 0.92 for Black. Overall, this study demonstrates that the chosen DNA markers and prediction model, particularly the 5-category level; allow skin colour predictions within and between continental regions for the first time, which will serve as a valuable resource for future applications in forensic and anthropologic genetics

Opto-mechanical measurement of micro-trap via nonlinear cavity enhanced Raman scattering spectrum

High-gain resonant nonlinear Raman scattering on trapped cold atoms within a high-fineness ring optical cavity is simply explained under a nonlinear opto-mechanical mechanism, and a proposal using it to detect frequency of micro-trap on atom chip is presented. The enhancement of scattering spectrum is due to a coherent Raman conversion between two different cavity modes mediated by collective vibrations of atoms through nonlinear opto-mechanical couplings. The physical conditions of this technique are roughly estimated on Rubidium atoms, and a simple quantum analysis as well as a multi-body semiclassical simulation on this nonlinear Raman process is conducted.Comment: 7 pages, 2 figure

Genome-wide compound heterozygote analysis highlights alleles associated with adult height in Europeans

Adult height is the most widely genetically studied common trait in humans; however, the trait variance explainable by currently known height-associated single nucleotide polymorphisms (SNPs) identified from the previous genome-wide association studies (GWAS) is yet far from complete given the high heritability of this complex trait. To exam if compound heterozygotes (CH) may explain extra height variance, we conducted a genome-wide analysis to screen for CH in association with adult height in 10,631 Dutch Europeans enriched with extremely tall people, using our recently developed method implemented in the software package CollapsABEL. The analysis identified six regions (3q23, 5q35.1, 6p21.31, 6p21.33, 7q21.2, and 9p24.3), where multiple pairs of SNPs as CH showed genome-wide significant association with height (P < 1.67 × 10−10). Of those, 9p24.3 represents a novel region influencing adult height, whereas the others have been highlighted in the previous GWAS on height based on analysis of individual SNPs. A replication analysis in 4080 Australians of European ancestry confirmed the significant CH-like association at 9p24.3 (P < 0.05). Together, the collapsed genotypes at these six loci explained 2.51% of the height variance (after adjusting for sex and age), compared with 3.23% explained by the 14 top-associated SNPs at 14 loci identified by traditional GWAS in the same data set (P < 5 × 10−8). Overall, our study empirically demonstrates that CH plays an important role in adult height and may explain a proportion of its “missing heritability”. Moreover, our findings raise promising expectations for other highly polygenic complex traits to explain missing heritability identifiable through CH-like associations