The genomic signature of trait-associated variants

BACKGROUND: Genome-wide association studies have identified thousands of SNP variants associated with hundreds of phenotypes. For most associations the causal variants and the molecular mechanisms underlying pathogenesis remain unknown. Exploration of the underlying functional annotations of trait-associated loci has thrown some light on their potential roles in pathogenesis. However, there are some shortcomings of the methods used to date, which may undermine efforts to prioritize variants for further analyses. Here, we introduce and apply novel methods to rigorously identify annotation classes showing enrichment or depletion of trait-associated variants taking into account the underlying associations due to co-location of different functional annotations and linkage disequilibrium. RESULTS: We assessed enrichment and depletion of variants in publicly available annotation classes such as genic regions, regulatory features, measures of conservation, and patterns of histone modifications. We used logistic regression to build a multivariate model that identified the most influential functional annotations for trait-association status of genome-wide significant variants. SNPs associated with all of the enriched annotations were 8 times more likely to be trait-associated variants than SNPs annotated with none of them. Annotations associated with chromatin state together with prior knowledge of the existence of a local expression QTL (eQTL) were the most important factors in the final logistic regression model. Surprisingly, despite the widespread use of evolutionary conservation to prioritize variants for study we find only modest enrichment of trait-associated SNPs in conserved regions. CONCLUSION: We established odds ratios of functional annotations that are more likely to contain significantly trait-associated SNPs, for the purpose of prioritizing GWAS hits for further studies. Additionally, we estimated the relative and combined influence of the different genomic annotations, which may facilitate future prioritization methods by adding substantial information

LGBTQ+ and dental education: Analyzing the present and recommendations for the future

LGBTQ+ populations constitute increasing proportions of children, adolescents, and adults in the United States. Compared to their heterosexual counterparts, this group suffers from health inequities, including oral health. The report “Oral Health: Advances and Challenges” identified the LGBTQ+ community as an underserved population which faces significant barriers in accessing oral health care. Coverage of LGBTQ+ topics in formal education settings in both dental schools and dental hygiene programs is scarce, which contributes to inequities within this group. Increasing curriculum content related to LGBTQ+ populations is of utmost importance to promote optimal patient-provider interactions while improving oral health outcomes. Ensuring equity in oral health care provision will require deliberate, consistent efforts on the part of all stakeholders. Dental and allied dental education programs have made important strides in enhancing equity and inclusion in their institutions by engaging campus groups that support LGBTQ+ populations, creating mentorship programs, and collaborating with non-profit advocacy groups. Such efforts have successfully empowered LGBTQ+ patients, providers, and allies who are committed to further closing the knowledge gap. Most of the research regarding LGBTQ+ inclusion efforts have been done in the medical arena and there is a void in the data available from the dental profession. To fill this void, recommendations are offered that institutions can easily implement to expand LGBTQ+ diversity and inclusion visibility

Social Constructivism and Case-Writing for an Integrated Curriculum

Case-writing within an integrated, systems-based health professions education curriculum presents many unique challenges. Specifically, case-writing in this context must consider integration of multidisciplinary learning objectives and synthesis of biomedical and clinical sciences. Establishing an effective process for content integration and determining who should be involved in the case-writing process can be a daunting task and this specific context requires a new model for effective casewriting. This paper provides a model for the cycle of case development, implementation, evaluation and modification in an integrated, systems-based health professions curriculum. We highlight how this collaborative case-writing model parallels the social constructivist approach promoted by the problem-based learning process in which our students engage

LGBTQ+ and dental education: Analyzing the present and recommendations for the future

LGBTQ+ populations constitute increasing proportions of children, adolescents, and adults in the United States. Compared to their heterosexual counterparts, this group suffers from health inequities, including oral health. The report “Oral Health: Advances and Challenges” identified the LGBTQ+ community as an underserved population which faces significant barriers in accessing oral health care. Coverage of LGBTQ+ topics in formal education settings in both dental schools and dental hygiene programs is scarce, which contributes to inequities within this group. Increasing curriculum content related to LGBTQ+ populations is of utmost importance to promote optimal patient-provider interactions while improving oral health outcomes. Ensuring equity in oral health care provision will require deliberate, consistent efforts on the part of all stakeholders. Dental and allied dental education programs have made important strides in enhancing equity and inclusion in their institutions by engaging campus groups that support LGBTQ+ populations, creating mentorship programs, and collaborating with non-profit advocacy groups. Such efforts have successfully empowered LGBTQ+ patients, providers, and allies who are committed to further closing the knowledge gap. Most of the research regarding LGBTQ+ inclusion efforts have been done in the medical arena and there is a void in the data available from the dental profession. To fill this void, recommendations are offered that institutions can easily implement to expand LGBTQ+ diversity and inclusion visibility

Mast Cells Are Required for Full Expression of Allergen/SEB-Induced Skin Inflammation

Atopic dermatitis (AD) is a chronic pruritic inflammatory skin disease. We recently described an animal model in which repeated epicutaneous applications of a house dust mite extract and Staphylococcal enterotoxin B induced eczematous skin lesions. In this study we showed that global gene expression patterns are very similar between human AD skin and allergen/staphylococcal enterotoxin B–induced mouse skin lesions, particularly in the expression of genes related to epidermal growth/differentiation, skin barrier, lipid/energy metabolism, immune response, or extracellular matrix. In this model, mast cells and T cells, but not B cells or eosinophils, were shown to be required for the full expression of dermatitis, as revealed by reduced skin inflammation and reduced serum IgE levels in mice lacking mast cells or T cells (TCRβ−/- or Rag1−/-). The clinical severity of dermatitis correlated with the numbers of mast cells, but not eosinophils. Consistent with the idea that T helper type 2 (Th2) cells play a predominant role in allergic diseases, the receptor for the Th2-promoting cytokine thymic stromal lymphopoietin and the high-affinity IgE receptor, FcεRI, were required to attain maximal clinical scores. Therefore, this clinically relevant model provides mechanistic insights into the pathogenic mechanism of human AD

Time-evolving acoustic propagation modeling in a complex ocean environment

During naval operations, sonar performance estimates often need to be computed in-situ with limited environmental information. This calls for the use of fast acoustic propagation models. Many naval operations are carried out in challenging and dynamic environments. This makes acoustic propagation and sonar performance behavior particularly complex and variable, and complicates prediction. Using data from a field experiment, we have investigated the accuracy with which acoustic propagation loss (PL) can be predicted, using only limited modeling capabilities. Environmental input parameters came from various sources that may be available in a typical naval operation. The outer continental shelf shallow-water experimental area featured internal tides, packets of nonlinear internal waves, and a meandering water mass front. For a moored source/receiver pair separated by 19.6 km, the acoustic propagation loss for 800 Hz pulses was computed using the peak amplitude. The variations in sound speed translated into considerable PL variability of order 15 dB. Acoustic loss modeling was carried out using a data-driven regional ocean model as well as measured sound speed profile data for comparison. The acoustic model used a two-dimensional parabolic approximation (vertical and radial outward wavenumbers only). The variance of modeled propagation loss was less than that measured. The effect of the internal tides and sub-tidal features was reasonably well modeled; these made use of measured sound speed data. The effects of nonlinear waves were not well modeled, consistent with their known three-dimensional effects but also with the lack of measurements to initialize and constrain them.Netherlands. Ministry of DefenceUnited States. Office of Naval Research (Grant N00014-12-1-0944 (ONR6.2))United States. Office of Naval Research (Grant N00014-08-1-1097 (ONR6.1))United States. Office of Naval Research (Grant N00014-08-1-0680 (PLUS-SEAS)

Increased ultra-rare variant load in an isolated Scottish population impacts exonic and regulatory regions

Human population isolates provide a snapshot of the impact of historical demographic processes on population genetics. Such data facilitate studies of the functional impact of rare sequence variants on biomedical phenotypes, as strong genetic drift can result in higher frequencies of variants that are otherwise rare. We present the first whole genome sequencing (WGS) study of the VIKING cohort, a representative collection of samples from the isolated Shetland population in northern Scotland, and explore how its genetic characteristics compare to a mainland Scottish population. Our analyses reveal the strong contributions played by the founder effect and genetic drift in shaping genomic variation in the VIKING cohort. About one tenth of all high-quality variants discovered are unique to the VIKING cohort or are seen at frequencies at least ten fold higher than in more cosmopolitan control populations. Multiple lines of evidence also suggest relaxation of purifying selection during the evolutionary history of the Shetland isolate. We demonstrate enrichment of ultra-rare VIKING variants in exonic regions and for the first time we also show that ultra-rare variants are enriched within regulatory regions, particularly promoters, suggesting that gene expression patterns may diverge relatively rapidly in human isolates

Abundant local interactions in the 4p16.1 region suggest functional mechanisms underlying SLC2A9 associations with human serum uric acid

Human serum uric acid concentration (SUA) is a complex trait. A recent meta-analysis of multiple genome-wide association studies (GWAS) identified 28 loci associated with SUA jointly explaining only 7.7% of the SUA variance, with 3.4% explained by two major loci (SLC2A9 and ABCG2). Here we examined whether gene–gene interactions had any roles in regulating SUA using two large GWAS cohorts included in the meta-analysis [the Atherosclerosis Risk in Communities study cohort (ARIC) and the Framingham Heart Study cohort (FHS)]. We found abundant genome-wide significant local interactions in ARIC in the 4p16.1 region located mostly in an intergenic area near SLC2A9 that were not driven by linkage disequilibrium and were replicated in FHS. Taking the forward selection approach, we constructed a model of five SNPs with marginal effects and three epistatic SNP pairs in ARIC—three marginal SNPs were located within SLC2A9 and the remaining SNPs were all located in the nearby intergenic area. The full model explained 1.5% more SUA variance than that explained by the lead SNP alone, but only 0.3% was contributed by the marginal and epistatic effects of the SNPs in the intergenic area. Functional analysis revealed strong evidence that the epistatically interacting SNPs in the intergenic area were unusually enriched at enhancers active in ENCODE hepatic (HepG2, P = 4.7E−05) and precursor red blood (K562, P = 5.0E−06) cells, putatively regulating transcription of WDR1 and SLC2A9. These results suggest that exploring epistatic interactions is valuable in uncovering the complex functional mechanisms underlying the 4p16.1 region