Fine Mapping of Lung Function Association in the MHC Region by Haplotype Imputation Reveals an Amino Acid change Underlying SNP Associations

We performed a Genome-wide association study (GWAS) of lung function quantitative traits forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and their ratio (FEV1/FVC) in 48,493 samples of European Ancestry (UK BiLEVE study) which, in addition to confirming 4 previously identified lung function signals in the major histocompatibility complex (MHC) on chromosome 6, identified 2 new secondary independent signals.In order to fine map the MHC GWAS signals, we used a published reference panel to impute HLA classical alleles and amino acid changes and tested their association with lung function traits. The new second most significant signal across the MHC region for both FEV1 (P=5.7×10-13) and FEV1/FVC (P=1.2×10‑20) was an association with HLA-DQB1 amino acid 57 Alanine present/absent (Alanine frequency=36.6%). After conditioning on the amino acid variant, 1 of 2 genome-wide significant (P‑8) GWAS signals for FEV1 and 5 of 6 for FEV1/FVC were strongly attenuated (minimum P=2.1×10‑5). Stepwise conditional analyses showed that the majority of the MHC lung function association signal could be explained by just the lead independent GWAS SNP and the amino acid change for both traits.Using haplotype imputation allowed us to build upon lung function GWAS discovery to pinpoint a potential causal variant in the MHC (HLA-DQB1 amino acid change 57, previously linked to type 1 diabetes risk) that explains a substantial proportion of the variance previously attributed to GWAS SNPs in this region.</p

Krebs Von Den Lungen-6 Is a Molecular Biomarker of Early-Stage Acute Hypersensitivity Pneumonitis Among Pigeon Fanciers

Conference abstrac

Long COVID research: an update from the PHOSP-COVID Scientific Summit

Correspondence</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

Adjustment for index event bias in genome-wide association studies of subsequent events.

Following numerous genome-wide association studies of disease susceptibility, there is increasing interest in genetic associations with prognosis, survival or other subsequent events. Such associations are vulnerable to index event bias, by which selection of subjects according to disease status creates biased associations if common causes of incidence and prognosis are not accounted for. We propose an adjustment for index event bias using the residuals from the regression of genetic effects on prognosis on genetic effects on incidence. Our approach eliminates this bias when direct genetic effects on incidence and prognosis are independent, and otherwise reduces bias in realistic situations. In a study of idiopathic pulmonary fibrosis, we reverse a paradoxical association of the strong susceptibility gene MUC5B with increased survival, suggesting instead a significant association with decreased survival. In re-analysis of a study of Crohn's disease prognosis, four regions remain associated at genome-wide significance but with increased standard errors

Proportion of Idiopathic Pulmonary Fibrosis Risk Explained by Known Common Genetic Loci in European Populations

Understanding how genetic factors contribute to disease risk improves our understanding of pathogenesis, supports drug development, and aids risk prediction (1). Appropriate quantification and interpretation of this contribution is essential for measuring the impact of genetic variation and in motivating and informing future studies. </p

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

Familial hypereosinophilia associated with eosinophilic gastrointestinal symptoms in individuals with a missense mutation in CKLF-like MARVEL transmembrane domain containing 3

Key MessagesThe letter describes a rare familial form of peripheral blood eosinophilia with GI symptoms.A variant causing a Phe75Leu mutation in CMTM3 is associated with the family's symptoms.The mutation is predicted to cause destabilisation of the interaction of the protein with membrane lipids.</h3