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

Packer, Richard; Williams, Alexander T.; Hennah, William; Eisenberg, MT; Fawcett, Katherine A.; Pearson, Willow; Guyatt, Anna L; Edris, Ahmed; Hollox, Edward J.; Rao, B.S. Shankaranarayana; Bratty, J R; Wain, Louise V.; Dudbridge, Frank; Tobin, Martin D.

doi:10.1101/2022.05.05.22274419

Cited by 6 publications

(12 citation statements)

References 19 publications

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“…For each variant with the highest PIP per credible set, we performed a PheWAS of up to 1,913 UK Biobank-derived phenotypes using Deep-PheWAS 44 . Three out of the 8 variants were associated (false discovery rate [FDR] ≤0.01) with at least one trait ( Supplementary Table 10 ).…”

Section: Resultsmentioning

confidence: 99%

“…Phenome-wide association study. The Deep-PheWAS 44 pipeline was used to perform single-variant association testing with up to 1,913 phenotypes defined in UK Biobank individuals of European ancestry. These phenotypes included: (i) composite phenotypes defined using linked hospital data, primary care data and field-IDs, (ii) Phecode-based phenotypes, (iii) field-ID phenotypes, (iv) combined field-ID phenotypes (more than two quantitative field-ID phenotypes into a single measure), all generated using the phenotype matrix generation pipeline, and (v) formula phenotypes developed within the group.…”

Section: Exploring Pleiotropic Effects Of Associated Variantsmentioning

confidence: 99%

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Genome-wide association study of ACE inhibitor-induced cough implicates neuropeptides and shows genetic overlap with chronic dry cough

Coley

Shepherd

Packer

et al. 2022

Preprint

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ACE inhibitors (ACEIs) are commonly prescribed for hypertension, a global risk factor for cardiovascular disease. Their primary side effect is a dry cough which affects 5-35% of users. As clinical guidelines recommend switching those experiencing cough to an angiotensin-II receptor blocker, we have used this switch as a proxy for ACEI-induced cough. Through a two-stage multi-ancestry genome-wide association study, including up to 7,030 cases and 39,921 controls, we identify five independent genome-wide significant associations implicating six protein-coding genes, including INHBC, KCNIP4, NTSR1 and PREP which encode proteins involved in the nervous system. We also observe genetic overlap between ACEI-induced cough and chronic dry cough through genetic correlation and phenome-wide association studies. In line with existing hypotheses, our findings suggest a neurological basis for the pathology of ACEI-induced cough, particularly the role of proinflammatory mediators in sensory airway sensitivity and cough reflex modulation, and shared biological mechanisms with chronic dry cough.

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Section: Resultsmentioning

confidence: 99%

Section: Exploring Pleiotropic Effects Of Associated Variantsmentioning

confidence: 99%

Genome-wide association study of ACE inhibitor-induced cough implicates neuropeptides and shows genetic overlap with chronic dry cough

Coley

Shepherd

Packer

et al. 2022

Preprint

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“…This GRS more strongly predicted FEV 1 /FVC and COPD across all ancestries than a previously constructed risk score 5 . Partitioning this lung function GRS by the pathways defined by specific variants, informed by detailed, systematic variant-to-gene mapping and pathway analyses and using our new Deep-PheWAS platform 42 , illustrated unique patterns of phenotype associations for each pathway GRS. These patterns of PheWAS findings are relevant to the potential efficacy and potential side-effects of intervening in these pathways.…”

Section: Discussionmentioning

confidence: 99%

Multi-ancestry genome-wide association study improves resolution of genes, pathways and pleiotropy for lung function and chronic obstructive pulmonary disease

Shrine

Izquierdo

Chen

et al. 2022

Preprint

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Lung function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry GWAS meta-analysis of lung function to date, comprising 580,869 participants, 1020 independent association signals identified 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score (GRS) showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies (PheWAS) for selected associated variants, and trait and pathway-specific GRS to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.

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“…To investigate associations of the chronic sputum-associated variants with a wider range of phenotypes, we performed PheWAS for 2,172 traits in UK Biobank (FDR<0.01, Supplementary Text) and searched the Open Targets Genetics Portal (P<5×10 −8 , version 0.4.0 (bd664ca) - accessed 16 th April 2021[38]). PheWAS for imputed HLA alleles was performed using DeepPheWAS [39] (see Supplementary text).…”

Section: Methodsmentioning

confidence: 99%

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

Packer

Shrine

Hall

et al. 2022

Preprint

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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<5x10-8) were fine-mapped and putative causal genes identified by gene expression analysis. GWAS of respiratory traits were interrogated to identify whether the signals were driven by existing respiratory disease amongst the cases and variants were further investigated for wider pleiotropic effects using phenome-wide association studies (PheWAS). Findings From a GWAS of 9,714 cases and 48,471 controls, we identified six novel genome-wide significant signals for chronic sputum production including the Human Leukocyte Antigen (HLA) locus, chromosome 11 mucin locus (containing MUC2, MUC5AC and MUC5B) and the FUT2 locus. 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. Interpretation Novel signals at the FUT2 and mucin loci highlight mucin flucosylation as 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.

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

Cited by 6 publications

References 19 publications

Genome-wide association study of ACE inhibitor-induced cough implicates neuropeptides and shows genetic overlap with chronic dry cough

Genome-wide association study of ACE inhibitor-induced cough implicates neuropeptides and shows genetic overlap with chronic dry cough

Multi-ancestry genome-wide association study improves resolution of genes, pathways and pleiotropy for lung function and chronic obstructive pulmonary disease

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

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