DeepPheWAS: an R package for phenotype generation and association analysis for phenome-wide association studies.

SUMMARY: DeepPheWAS is an R package for phenome-wide association studies that creates clinically curated composite phenotypes and integrates quantitative phenotypes from primary care data, longitudinal trajectories of quantitative measures, disease progression and drug response phenotypes. Tools are provided for efficient analysis of association with any genetic input, under any genetic model, with optional sex-stratified analysis, and for developing novel phenotypes. AVAILABILITY AND IMPLEMENTATION: The DeepPheWAS R package is freely available under GNU general public licence v3.0 from at https://github.com/Richard-Packer/DeepPheWAS. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Genome-wide association study of chronic sputum production implicates loci involved in mucus production and infection.

BACKGROUND: Chronic sputum production impacts on quality of life and is a feature of many respiratory diseases. Identification of the genetic variants associated with chronic sputum production in a disease agnostic sample could improve understanding of its causes and identify new molecular targets for treatment. METHODS: We conducted a genome-wide association study (GWAS) of chronic sputum production in UK Biobank. Signals meeting genome-wide significance (p<5×10-8) were investigated in additional independent studies, were fine-mapped and putative causal genes identified by gene expression analysis. GWASs of respiratory traits were interrogated to identify whether the signals were driven by existing respiratory disease among the cases and variants were further investigated for wider pleiotropic effects using phenome-wide association studies (PheWASs). RESULTS: From a GWAS of 9714 cases and 48 471 controls, we identified six novel genome-wide significant signals for chronic sputum production including signals in the human leukocyte antigen (HLA) locus, chromosome 11 mucin locus (containing MUC2, MUC5AC and MUC5B) and FUT2 locus. The four common variant associations were supported by independent studies with a combined sample size of up to 2203 cases and 17 627 controls. The mucin locus signal had previously been reported for association with moderate-to-severe asthma. The HLA signal was fine-mapped to an amino acid change of threonine to arginine (frequency 36.8%) in HLA-DRB1 (HLA-DRB1*03:147). The signal near FUT2 was associated with expression of several genes including FUT2, for which the direction of effect was tissue dependent. Our PheWAS identified a wide range of associations including blood cell traits, liver biomarkers, infections, gastrointestinal and thyroid-associated diseases, and respiratory disease. CONCLUSIONS: Novel signals at the FUT2 and mucin loci suggest that mucin fucosylation may be a driver of chronic sputum production even in the absence of diagnosed respiratory disease and provide genetic support for this pathway as a target for therapeutic intervention.

Does a change in end-tidal carbon dioxide level predict high altitude mountain sickness?

Background: It is postulated that lack of hypoxic ventilatory response is a predictor for AMS. End-tidal carbon dioxide (ETCO2) is an accurate, noninvasive surrogate measure of ventilation. Objectives: We sought to determine if changes in baseline ETCO2 predicts the development of AMS. Methods: This prospective cohort study took place in three separate high-altitude hiking treks. Subjects included a convenience sample of hikers. Predictor variable was change in ETCO2 levels and outcome variable was AMS. Measurements of ETCO2 levels were obtained at the base and repeated daily at various elevations and the summit of each hike. Concurrently, hikers were scored for AMS by a trained investigator. We utilized correlation coefficients and developed a linear regression model for analysis. Results: 21 subjects in 3 separate hikes participated: 10 ascended to 19,341 ft over 7 days, 6 ascended to 8900 ft in 1 day, and 4 ascended to 11,006 ft in 1 day. Mean age was 40 years, 67% were males, mean daily elevation gain was 2150 ft, and 5 hikers developed AMS. The correlation coefficients for ETCO2 and development of AMS were -0.46 (95%CI -0.33 to -0.57), and -0.77 (95%CI -0.71 to -0.83) for ETCO2 and altitude. ETCO2 predicted the development of symptoms better than the elevation with AUCs of 0.90 (95%CI 0.81-0.99) versus 0.64 (95%CI 0.45-0.83). An ETCO2 measurement of ≤22 mmHg was 100% sensitive and 60% specific for predicting AMS. Conclusions: ETCO2 was strongly correlated with altitude and moderately correlated with AMS and it was a better predictor than altitude.