Genome-Wide Analyses of Survival Time in the Rare Disease, Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a rare lung disease with poor prognosis (median survival time of 3 years) characterised by scarring of lung tissue. IPF has been linked with a number of environmental and genetic factors; the strongest genetic association being in the MUC5B gene. Despite this the pathogenesis of IPF is still unclear and more needs to be done to understand the genetic basis of IPF. We are conducting analyses genome-wide to investigate survival time in 565 IPF cases. Previous evidence suggests variants associated with susceptibility to IPF may not be associated with survival time or may even have effects in the opposite direction. A genome-wide association case-control study was also conducted allowing variants associated with susceptibility to IPF and survival time to be directly compared. This analysis has raised a number of methodological issues such as which survival models to fit, how well survival models fit variants of different allele frequencies, and how these influence power. The statistical power relates not only to the allele frequency but also to the number of events in each genotype group. In this study, we fitted a Cox proportional hazards model, which makes no assumption about the distribution of the underlying baseline hazard function, and compared findings with those from alternative models. </p

Genome-wide Association Study Combining UK Biobank and GASP Consortium Highlights Novel Loci Associated with Moderate-Severe Asthma

The genetic architecture of asthma to date has been described by the discovery of around 20 loci from genome-wide association studies (GWAS), primarily with cases covering mild-to-moderate asthma. We hypothesised that moderate-to-severe asthma, which is currently difficult to treat, may have a specific genetic architecture, however there have not been large GWAS of moderate-to-severe asthma.Accordingly, we selected 5,135 European ancestry moderate-severe asthma cases (British Thoracic Society criteria 3 or above) and 25,675 controls free from lung disease, allergic rhinitis and atopic dermatitis, from UK Biobank and the Genetics of Asthma Severity & Phenotypes (GASP) cohort (cases only). We tested 33,771,858 SNPs and indels genome-wide (imputation against combined UK10K and 1000 genomes phase 3 panels) for association with moderate-severe asthma.We identified 23 independent signals associated with moderate-to-severe asthma (P -8), including novels signals in or near GATA3, RIC1, ZNF652, RPAP3 and MUC5AC, highlighting regions that harbour variants that effect gene expression or genes that play a role in respiratory disease and immune response. Previously described asthma loci where replicated including signals in or near D2HGDH, CD247, HLA-DQB1, HLA-DQA1, TSLP/WDR36, IL1RL1/IL18R1, CLEC16A, GATA3, IL33, SMAD3, SLC22A5/IL13, C11orf30, ZBTB10, IKZF3-ORMDL3 and IKZF4.This largest GWAS of moderate-severe asthma to date and highlights novel loci that may provide new biological insights relevant to treatment of severe asthma.</p

Exome-wide analysis of copy number variation shows association of the human leukocyte antigen region with asthma in UK Biobank

Background: The role of copy number variants (CNVs) in susceptibility to asthma is not well understood. This is, in part, due to the difficulty of accurately measuring CNVs in large enough sample sizes to detect associations. The recent availability of whole-exome sequencing (WES) in large biobank studies provides an unprecedented opportunity to study the role of CNVs in asthma. Methods: We called common CNVs in 49,953 individuals in the first release of UK Biobank WES using ClinCNV software. CNVs were tested for association with asthma in a stage 1 analysis comprising 7098 asthma cases and 36,578 controls from the first release of sequencing data. Nominally-associated CNVs were then meta-analysed in stage 2 with an additional 17,280 asthma cases and 115,562 controls from the second release of UK Biobank exome sequencing, followed by validation and fine-mapping. Results: Five of 189 CNVs were associated with asthma in stage 2, including a deletion overlapping the HLA-DQA1 and HLA-DQB1 genes, a duplication of CHROMR/PRKRA, deletions within MUC22 and TAP2, and a duplication in FBRSL1. The HLA-DQA1, HLA-DQB1, MUC22 and TAP2 genes all reside within the human leukocyte antigen (HLA) region on chromosome 6. In silico analyses demonstrated that the deletion overlapping HLA-DQA1 and HLA-DQB1 is likely to be an artefact arising from under-mapping of reads from non-reference HLA haplotypes, and that the CHROMR/PRKRA and FBRSL1 duplications represent presence/absence of pseudogenes within the HLA region. Bayesian fine-mapping of the HLA region suggested that there are two independent asthma association signals. The variants with the largest posterior inclusion probability in the two credible sets were an amino acid change in HLA-DQB1 (glutamine to histidine at residue 253) and a multi-allelic amino acid change in HLA-DRB1 (presence/absence of serine, glycine or leucine at residue 11). Conclusions: At least two independent loci characterised by amino acid changes in the HLA-DQA1, HLA-DQB1 and HLA-DRB1 genes are likely to account for association of SNPs and CNVs in this region with asthma. The high divergence of haplotypes in the HLA can give rise to spurious CNVs, providing an important, cautionary tale for future large-scale analyses of sequencing data

Preliminary Results from Genome-wide Meta-analysis of Survival Time in Idiopathic Pulmonary Fibrosis

Introduction: Idiopathic pulmonary fibrosis (IPF) is a rare lung disease of unknown cause, with few effective treatments available and poor prognosis (median survival time of 3 years). Genome-wide studies have identified variants associated with susceptibility to IPF. Although the effects of those variants on survival time have been investigated, no study has investigated survival time genome-wide for IPF. We set out to identify novel signals of association with IPF survival time and to replicate previous reports that variants in MUC5B that are associated with increased susceptibility to IPF, are paradoxically associated with an increase in survival time. Methods: We performed genome-wide analyses investigating survival time in a UK IPF study and a USA IPF study and meta-analysed the results. Survival analyses were performed on variants with minor allele frequency (MAF)>0.5% in both studies using a Cox Proportional Hazards model. Independent variants meeting meta-analysis P−6 and P Results: A total of 963 individuals and 7,730,466 variants were included in the final meta-analysis with maximum follow-up of 16.5 years. A total of 79 independent signals (11 with MAF>5%) reached the criteria described above. Consistent with previous reports, the allele in rs35705950 in MUC5B that is associated with increased susceptibility to IPF, shows some association with increased survival time (HR=0.73, 95% CI: [0.61, 0.87], P=5.08×10−4). Conclusions: This details the first analysis to investigate survival time genome-wide in IPF.</p

Mendelian randomization of eosinophils and other cell types in relation to lung function and disease

Rationale Eosinophils are associated with airway inflammation in respiratory disease. Eosinophil production and survival is controlled partly by interleukin-5: anti-interleukin-5 agents reduce asthma and response correlates with baseline eosinophil counts. However, whether raised eosinophils are causally related to chronic obstructive pulmonary disease (COPD) and other respiratory phenotypes is not well understood. Objectives We investigated causality between eosinophils and: lung function, acute exacerbations of COPD, asthma-COPD overlap (ACO), moderate-to-severe asthma and respiratory infections. Methods We performed Mendelian randomisation (MR) using 151 variants from genome-wide association studies of blood eosinophils in UK Biobank/INTERVAL, and respiratory traits in UK Biobank/SpiroMeta, using methods relying on different assumptions for validity. We performed multivariable analyses using eight cell types where there was possible evidence of causation by eosinophils. Measurements and main results Causal estimates derived from individual variants were highly heterogeneous, which may arise from pleiotropy. The average effect of raising eosinophils was to increase risk of ACO (weighted median OR per SD eosinophils, 1.44 (95%CI 1.19 to 1.74)), and moderate-severe asthma (weighted median OR 1.50 (95%CI 1.23 to 1.83)), and to reduce forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) and FEV1 (weighted median estimator, SD FEV1/FVC: −0.054 (95% CI −0.078 to −0.029), effect only prominent in individuals with asthma). Conclusions Broad consistency across MR methods may suggest causation by eosinophils (although of uncertain magnitude), yet heterogeneity necessitates caution: other important mechanisms may be responsible for the impairment of respiratory health by these eosinophil-raising variants. These results could suggest that anti-IL5 agents (designed to lower eosinophils) may be valuable in treating other respiratory conditions, including people with overlapping features of asthma and COPD.</p