Publications by authors named "Louise V Wain"

92 Publications

Genetic correlation and causal relationships between cardio-metabolic traits and lung function impairment.

Genome Med 2021 Jun 21;13(1):104. Epub 2021 Jun 21.

Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, Norfolk Place, London, W2 1PG, UK.

Background: Associations of low lung function with features of poor cardio-metabolic health have been reported. It is, however, unclear whether these co-morbidities reflect causal associations, shared genetic heritability or are confounded by environmental factors.

Methods: We performed three analyses: (1) cardio-metabolic health to lung function association tests in Northern Finland Birth cohort 1966, (2) cross-trait linkage disequilibrium score regression (LDSC) to compare genetic backgrounds and (3) Mendelian randomisation (MR) analysis to assess the causal effect of cardio-metabolic traits and disease on lung function, and vice versa (bidirectional MR). Genetic associations were obtained from the UK Biobank data or published large-scale genome-wide association studies (N > 82,000).

Results: We observed a negative genetic correlation between lung function and cardio-metabolic traits and diseases. In Mendelian Randomisation analysis (MR), we found associations between type 2 diabetes (T2D) instruments and forced vital capacity (FVC) as well as FEV1/FVC. Body mass index (BMI) instruments were associated to all lung function traits and C-reactive protein (CRP) instruments to FVC. These genetic associations provide evidence for a causal effect of cardio-metabolic traits on lung function. Multivariable MR suggested independence of these causal effects from other tested cardio-metabolic traits and diseases. Analysis of lung function specific SNPs revealed a potential causal effect of FEV1/FVC on blood pressure.

Conclusions: The present study overcomes many limitations of observational studies by using Mendelian Randomisation. We provide evidence for an independent causal effect of T2D, CRP and BMI on lung function with some of the T2D effect on lung function being attributed to inflammatory mechanisms. Furthermore, this analysis suggests a potential causal effect of FEV1/FVC on blood pressure. Our detailed analysis of the interplay between cardio-metabolic traits and impaired lung function provides the opportunity to improve the quality of existing intervention strategies.
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http://dx.doi.org/10.1186/s13073-021-00914-xDOI Listing
June 2021

Variants associated with expression have sex-differential effects on lung function.

Wellcome Open Res 2020 24;5:111. Epub 2021 May 24.

Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, EH4 2XU, UK.

Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10 ) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10 ). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV ) (P=3.15x10 ), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV more in males (untransformed FEV β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein ( ) gene and was previously associated with lung function and lung expression. We found expression was significantly different between the sexes (P=6.90x10 ), but we could not detect sex differential effects of rs7697189 on expression. We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the gene. Establishing the mechanism by which SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.
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http://dx.doi.org/10.12688/wellcomeopenres.15846.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938335.2PMC
May 2021

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

Clin Exp Allergy 2021 May 28. Epub 2021 May 28.

Institute for Lung Health, Department of Respiratory Sciences, Leicester Respiratory Biomedical Research Centre, University of Leicester and National Institute for Health Research, Glenfield Hospital, University Hospitals of Leicester NHS Trust, Leicester, UK.

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http://dx.doi.org/10.1111/cea.13957DOI Listing
May 2021

Pleiotropic associations of heterozygosity for the Z allele in the UK Biobank.

ERJ Open Res 2021 Apr 10;7(2). Epub 2021 May 10.

Division of Respiratory Medicine, University of Nottingham, and NIHR Nottingham BRC, NUH NHS Trust, Nottingham, UK.

Homozygosity for the Z allele causes α-antitrypsin deficiency, a rare condition that can cause lung and liver disease. However, the effects of Z allele heterozygosity on nonrespiratory phenotypes, and on lung function in the general population, remain unclear. We conducted a large, population-based study to determine Z allele effects on >2400 phenotypes in the UK Biobank (N=303 353). Z allele heterozygosity was strongly associated with increased height (β=1.02 cm, p=3.91×10), and with other nonrespiratory phenotypes including increased risk of gall bladder disease, reduced risk of heart disease and lower blood pressure, reduced risk of osteoarthritis and reduced bone mineral density, increased risk of headache and enlarged prostate, as well as with blood biomarkers of liver function. Heterozygosity was associated with higher height-adjusted forced expiratory volume in 1 s (FEV) (β=19.36 mL, p=9.21×10) and FEV/forced vital capacity (β=0.0031, p=1.22×10) in nonsmokers, whereas in smokers, this protective effect was abolished. Furthermore, we show for the first time that sex modifies the association of the Z allele on lung function. We conclude that Z allele heterozygosity and homozygosity exhibit opposing effects on lung function in the UK population, and that these associations are modified by smoking and sex. In exploratory analyses, heterozygosity for the Z allele also showed pleiotropic associations with nonrespiratory health-related traits and disease risk.
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http://dx.doi.org/10.1183/23120541.00049-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107350PMC
April 2021

A Systematic Analysis of Protein-altering Exonic Variants in Chronic Obstructive Pulmonary Disease.

Am J Physiol Lung Cell Mol Physiol 2021 Apr 28. Epub 2021 Apr 28.

University of Leicester, United Kingdom.

Genome-wide association studies (GWASs) have identified regions associated with chronic obstructive pulmonary disease (COPD). GWASs of other diseases have shown an approximately 10-fold overrepresentation of nonsynonymous variants, despite limited exonic coverage on genotyping arrays. We hypothesized that a large-scale analysis of coding variants could discover novel genetic associations with COPD, including rare variants with large effect sizes. We performed a meta-analysis of exome arrays from 218,399 controls and 33,851 moderate-to-severe COPD cases. All exome-wide significant associations were present in regions previously identified by GWAS. We did not identify any novel rare coding variants with large effect sizes. Within GWAS regions on chromosomes 5q, 6p, and 15q, four coding variants were conditionally significant (p < 0.00015) when adjusting for lead GWAS SNPs. A common GSDMB splice variant (rs11078928) previously associated with decreased risk for asthma, was nominally associated with decreased risk for COPD (MAF = 0.46, p=1.8e-4). Two stop variants in CCHCR1, a gene involved in regulating cell proliferation, were associated with COPD (both p < 0.0001). The SERPINA1 Z allele was associated with a random effects odds ratio of 1.43 for COPD (95% CI: 1.17-1.74), though with marked heterogeneity across studies. Overall, COPD-associated exonic variants were identified in genes involved in DNA methylation, cell-matrix interactions, cell proliferation, and cell death. In conclusion, we performed the largest exome array meta-analysis of COPD to date and identified potential functional coding variants. Future studies are needed to identify rarer variants, and further define the role of coding variants in COPD pathogenesis.
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http://dx.doi.org/10.1152/ajplung.00009.2021DOI Listing
April 2021

Identification of a missense variant in SPDL1 associated with idiopathic pulmonary fibrosis.

Commun Biol 2021 Mar 23;4(1):392. Epub 2021 Mar 23.

Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.

Idiopathic pulmonary fibrosis (IPF) is a fatal disorder characterised by progressive, destructive lung scarring. Despite substantial progress, the genetic determinants of this disease remain incompletely defined. Using whole genome and whole exome sequencing data from 752 individuals with sporadic IPF and 119,055 UK Biobank controls, we performed a variant-level exome-wide association study (ExWAS) and gene-level collapsing analyses. Our variant-level analysis revealed a novel association between a rare missense variant in SPDL1 and IPF (NM_017785.5:g.169588475 G > A p.Arg20Gln; p = 2.4 × 10, odds ratio = 2.87, 95% confidence interval: 2.03-4.07). This signal was independently replicated in the FinnGen cohort, which contains 1028 cases and 196,986 controls (combined p = 2.2 × 10), firmly associating this variant as an IPF risk allele. SPDL1 encodes Spindly, a protein involved in mitotic checkpoint signalling during cell division that has not been previously described in fibrosis. To the best of our knowledge, these results highlight a novel mechanism underlying IPF, providing the potential for new therapeutic discoveries in a disease of great unmet need.
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http://dx.doi.org/10.1038/s42003-021-01910-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988141PMC
March 2021

Genetic and clinical characteristics of treatment-resistant depression using primary care records in two UK cohorts.

Mol Psychiatry 2021 Mar 22. Epub 2021 Mar 22.

Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Treatment-resistant depression (TRD) is a major contributor to the disability caused by major depressive disorder (MDD). Primary care electronic health records provide an easily accessible approach to investigate TRD clinical and genetic characteristics. MDD defined from primary care records in UK Biobank (UKB) and EXCEED studies was compared with other measures of depression and tested for association with MDD polygenic risk score (PRS). Using prescribing records, TRD was defined from at least two switches between antidepressant drugs, each prescribed for at least 6 weeks. Clinical-demographic characteristics, SNP-based heritability (h) and genetic overlap with psychiatric and non-psychiatric traits were compared in TRD and non-TRD MDD cases. In 230,096 and 8926 UKB and EXCEED participants with primary care data, respectively, the prevalence of MDD was 8.7% and 14.2%, of which 13.2% and 13.5% was TRD, respectively. In both cohorts, MDD defined from primary care records was strongly associated with MDD PRS, and in UKB it showed overlap of 71-88% with other MDD definitions. In UKB, TRD vs healthy controls and non-TRD vs healthy controls h was comparable (0.25 [SE = 0.04] and 0.19 [SE = 0.02], respectively). TRD vs non-TRD was positively associated with the PRS of attention deficit hyperactivity disorder, with lower socio-economic status, obesity, higher neuroticism and other unfavourable clinical characteristics. This study demonstrated that MDD and TRD can be reliably defined using primary care records and provides the first large scale population assessment of the genetic, clinical and demographic characteristics of TRD.
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http://dx.doi.org/10.1038/s41380-021-01062-9DOI Listing
March 2021

Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity.

EBioMedicine 2021 Mar 10;65:103277. Epub 2021 Mar 10.

Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.

Background: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease, characterized by progressive lung scarring. Severe COVID-19 is associated with substantial pneumonitis and has a number of shared major risk factors with IPF. This study aimed to determine the genetic correlation between IPF and severe COVID-19 and assess a potential causal role of genetically increased risk of IPF on COVID-19 severity.

Methods: The genetic correlation between IPF and COVID-19 severity was estimated with linkage disequilibrium (LD) score regression. We performed a Mendelian randomization (MR) study for IPF causality in COVID-19. Genetic variants associated with IPF susceptibility (P<5 × 10) in previous genome-wide association studies (GWAS) were used as instrumental variables (IVs). Effect estimates of those IVs on COVID-19 severity were gathered from the GWAS meta-analysis by the COVID-19 Host Genetics Initiative (4,336 cases & 623,902 controls).

Findings: We detected a positive genetic correlation of IPF with COVID-19 severity (rg=0·31 [95% CI 0·04-0·57], P = 0·023). The MR estimates for severe COVID-19 did not reveal any genetic association (OR 1·05, [95% CI 0·92-1·20], P = 0·43). However, outlier analysis revealed that the IPF risk allele rs35705950 at MUC5B had a different effect compared with the other variants. When rs35705950 was excluded, MR results provided evidence that genetically increased risk of IPF has a causal effect on COVID-19 severity (OR 1·21, [95% CI 1·06-1·38], P = 4·24 × 10). Furthermore, the IPF risk-allele at MUC5B showed an apparent protective effect against COVID-19 hospitalization only in older adults (OR 0·86, [95% CI 0·73-1·00], P = 2·99 × 10) .

Interpretation: The strongest genetic determinant of IPF, rs35705950 at MUC5B, seems to confer protection against COVID-19, whereas the combined effect of all other IPF risk loci seem to confer risk of COVID-19 severity. The observed effect of rs35705950 could either be due to protective effects of mucin over-production on the airways or a consequence of selection bias due to (1) a patient group that is heavily enriched for the rs35705950 T undertaking strict self-isolation and/or (2) due to survival bias of the rs35705950 non-IPF risk allele carriers. Due to the diverse impact of IPF causal variants on SARS-CoV-2 infection, with a possible selection bias as an explanation, further investigation is needed to address this apparent paradox between variance at MUC5B and other IPF genetic risk factors.

Funding: Novo Nordisk Foundation and Oak Foundation.
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http://dx.doi.org/10.1016/j.ebiom.2021.103277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946355PMC
March 2021

Call for Papers: "Morphology is the link between genetics and function": a tribute to Ewald R. Weibel.

Am J Physiol Lung Cell Mol Physiol 2021 02 25;320(2):L254-L256. Epub 2020 Nov 25.

Institute of Functional Anatomy, Charité - Universitätsmedizin Berlin, Berlin, Germany.

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http://dx.doi.org/10.1152/ajplung.00561.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948087PMC
February 2021

Telomere length and risk of idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease: a mendelian randomisation study.

Lancet Respir Med 2021 03 13;9(3):285-294. Epub 2020 Nov 13.

Institute of Biomedical & Clinical Science, College of Medicine & Health, University of Exeter, Exeter, UK; Exeter Patients in Collaboration for PF, Exeter, UK. Electronic address:

Background: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease accounting for 1% of UK deaths. In the familial form of pulmonary fibrosis, causal genes have been identified in about 30% of cases, and a majority of these causal genes are associated with telomere maintenance. Prematurely shortened leukocyte telomere length is associated with IPF and chronic obstructive pulmonary disease (COPD), a disease with similar demographics and shared risk factors. Using mendelian randomisation, we investigated evidence supporting a causal role for short telomeres in IPF and COPD.

Methods: Mendelian randomisation inference of telomere length causality was done for IPF (up to 1369 cases) and COPD (13 538 cases) against 435 866 controls of European ancestry in UK Biobank. Polygenic risk scores were calculated and two-sample mendelian randomisation analyses were done using seven genetic variants previously associated with telomere length, with replication analysis in an IPF cohort (2668 cases vs 8591 controls) and COPD cohort (15 256 cases vs 47 936 controls).

Findings: In the UK Biobank, a genetically instrumented one-SD shorter telomere length was associated with higher odds of IPF (odds ratio [OR] 4·19, 95% CI 2·33-7·55; p=0·0031) but not COPD (1·07, 0·88-1·30; p=0·51). Similarly, an association was found in the IPF replication cohort (12·3, 5·05-30·1; p=0·0015) and not in the COPD replication cohort (1·04, 0·71-1·53; p=0·83). Meta-analysis of the two-sample mendelian randomisation results provided evidence inferring that shorter telomeres cause IPF (5·81 higher odds of IPF, 95% CI 3·56-9·50; p=2·19 × 10). There was no evidence to infer that telomere length caused COPD (OR 1·07, 95% CI 0·90-1·27; p=0·46).

Interpretation: Cellular senescence is hypothesised as a major driving force in IPF and COPD; telomere shortening might be a contributory factor in IPF, suggesting divergent mechanisms in COPD. Defining a key role for telomere shortening enables greater focus in telomere-related diagnostics, treatments, and the search for a cure in IPF. Investigation of therapies that improve telomere length is warranted.

Funding: Medical Research Council.
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http://dx.doi.org/10.1016/S2213-2600(20)30364-7DOI Listing
March 2021

Genome-Wide Gene-by-Smoking Interaction Study of Chronic Obstructive Pulmonary Disease.

Am J Epidemiol 2021 05;190(5):875-885

Risk of chronic obstructive pulmonary disease (COPD) is determined by both cigarette smoking and genetic susceptibility, but little is known about gene-by-smoking interactions. We performed a genome-wide association analysis of 179,689 controls and 21,077 COPD cases from UK Biobank subjects of European ancestry recruited from 2006 to 2010, considering genetic main effects and gene-by-smoking interaction effects simultaneously (2-degrees-of-freedom (df) test) as well as interaction effects alone (1-df interaction test). We sought to replicate significant results in COPDGene (United States, 2008-2010) and SpiroMeta Consortium (multiple countries, 1947-2015) data. We considered 2 smoking variables: 1) ever/never and 2) current/noncurrent. In the 1-df test, we identified 1 genome-wide significant locus on 15q25.1 (cholinergic receptor nicotinic β4 subunit, or CHRNB4) for ever- and current smoking and identified PI*Z allele (rs28929474) of serpin family A member 1 (SERPINA1) for ever-smoking and 3q26.2 (MDS1 and EVI1 complex locus, or MECOM) for current smoking in an analysis of previously reported COPD loci. In the 2-df test, most of the significant signals were also significant for genetic marginal effects, aside from 16q22.1 (sphingomyelin phosphodiesterase 3, or SMPD3) and 19q13.2 (Egl-9 family hypoxia inducible factor 2, or EGLN2). The significant effects at 15q25.1 and 19q13.2 loci, both previously described in prior genome-wide association studies of COPD or smoking, were replicated in COPDGene and SpiroMeta. We identified interaction effects at previously reported COPD loci; however, we failed to identify novel susceptibility loci.
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http://dx.doi.org/10.1093/aje/kwaa227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096488PMC
May 2021

Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants.

Nat Commun 2020 10 14;11(1):5182. Epub 2020 Oct 14.

The Institute for Translational Genomics and Population Sciences, The Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.

Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.
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http://dx.doi.org/10.1038/s41467-020-18334-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598941PMC
October 2020

Krebs von den Lungen-6 (KL-6) is a pathophysiological biomarker of early-stage acute hypersensitivity pneumonitis among pigeon fanciers.

Clin Exp Allergy 2020 12 4;50(12):1391-1399. Epub 2020 Oct 4.

Institute of Infection, Immunity and Inflammation, Glasgow University, Glasgow, UK.

Background: Identifying early stages of hypersensitivity pneumonitis (HP) is hampered by variable presentation, heterogeneous or undetected causal antigens and lack of gold-standard biomarkers. Krebs von den Lungen (KL)-6 is pathophysiological biomarker of alveolar epithelial damage. Pigeon fanciers, susceptible to HP, provide a model to investigate early HP.

Objective: To test the hypothesis that plasma concentrations of KL-6 are increased in early-stage acute HP.

Methods: Clinical history, spirometry and blood samples were obtained from pigeon fanciers, 20 with intermittent acute symptoms indicative of developing HP, 27 with no symptoms and 10 healthy subjects with no avian exposure. Plasma KL-6 (units/mL) and pigeon antigen-specific IgG antibody were quantified by enzyme immunoassay. Blood lymphocytes were quantified by flow cytometry and antigen specificity by in vitro cytokine production.

Results: KL-6 was higher in fanciers than controls, median (IQR) 452 (244, 632) vs 274 (151, 377), P = .01. Although fanciers with symptoms had similar antigen exposure and lung function, they had higher KL-6 than those without, 632 (468, 1314) vs 320 (200, 480), P < .001. KL-6 correlated with IgG antibody titre in those with symptoms, r = .591, P = .006. High KL-6, irrespective of symptom category, was associated with higher antibody (P = .006) and lymphocyte proliferation (P = .041), and lower CD4+ T lymphocyte proportion (P = .032).

Conclusion And Clinical Relevance: Raised KL-6 is associated with acute symptoms of early-stage HP, and its correlation with antibody may support therapeutic strategies when HP is suspected. KL-6 may act as a mechanistic biomarker of early pathogenesis by linking lung pathophysiological changes with an endotype of immune hypersensitivity.
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http://dx.doi.org/10.1111/cea.13744DOI Listing
December 2020

Phenotypic and functional translation of IL33 genetics in asthma.

J Allergy Clin Immunol 2021 Jan 19;147(1):144-157. Epub 2020 May 19.

Department of Health Sciences, University of Leicester, Leicester, United Kingdom; National Institute for Health Research Leicester Respiratory Biomedical Research Centre, Leicester, United Kingdom.

Background: Asthma is a complex disease with multiple phenotypes that may differ in disease pathobiology and treatment response. IL33 single nucleotide polymorphisms (SNPs) have been reproducibly associated with asthma. IL33 levels are elevated in sputum and bronchial biopsies of patients with asthma. The functional consequences of IL33 asthma SNPs remain unknown.

Objective: This study sought to determine whether IL33 SNPs associate with asthma-related phenotypes and with IL33 expression in lung or bronchial epithelium. This study investigated the effect of increased IL33 expression on human bronchial epithelial cell (HBEC) function.

Methods: Association between IL33 SNPs (Chr9: 5,815,786-6,657,983) and asthma phenotypes (Lifelines/DAG [Dutch Asthma GWAS]/GASP [Genetics of Asthma Severity & Phenotypes] cohorts) and between SNPs and expression (lung tissue, bronchial brushes, HBECs) was done using regression modeling. Lentiviral overexpression was used to study IL33 effects on HBECs.

Results: We found that 161 SNPs spanning the IL33 region associated with 1 or more asthma phenotypes after correction for multiple testing. We report a main independent signal tagged by rs992969 associating with blood eosinophil levels, asthma, and eosinophilic asthma. A second, independent signal tagged by rs4008366 presented modest association with eosinophilic asthma. Neither signal associated with FEV, FEV/forced vital capacity, atopy, and age of asthma onset. The 2 IL33 signals are expression quantitative loci in bronchial brushes and cultured HBECs, but not in lung tissue. IL33 overexpression in vitro resulted in reduced viability and reactive oxygen species-capturing of HBECs, without influencing epithelial cell count, metabolic activity, or barrier function.

Conclusions: We identify IL33 as an epithelial susceptibility gene for eosinophilia and asthma, provide mechanistic insight, and implicate targeting of the IL33 pathway specifically in eosinophilic asthma.
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http://dx.doi.org/10.1016/j.jaci.2020.04.051DOI Listing
January 2021

Phenotypic and functional translation of IL1RL1 locus polymorphisms in lung tissue and asthmatic airway epithelium.

JCI Insight 2020 04 23;5(8). Epub 2020 Apr 23.

Department of Human Development and.

The IL1RL1 (ST2) gene locus is robustly associated with asthma; however, the contribution of single nucleotide polymorphisms (SNPs) in this locus to specific asthma subtypes and the functional mechanisms underlying these associations remain to be defined. We tested for association between IL1RL1 region SNPs and characteristics of asthma as defined by clinical and immunological measures and addressed functional effects of these genetic variants in lung tissue and airway epithelium. Utilizing 4 independent cohorts (Lifelines, Dutch Asthma GWAS [DAG], Genetics of Asthma Severity and Phenotypes [GASP], and Manchester Asthma and Allergy Study [MAAS]) and resequencing data, we identified 3 key signals associated with asthma features. Investigations in lung tissue and primary bronchial epithelial cells identified context-dependent relationships between the signals and IL1RL1 mRNA and soluble protein expression. This was also observed for asthma-associated IL1RL1 nonsynonymous coding TIR domain SNPs. Bronchial epithelial cell cultures from asthma patients, exposed to exacerbation-relevant stimulations, revealed modulatory effects for all 4 signals on IL1RL1 mRNA and/or protein expression, suggesting SNP-environment interactions. The IL1RL1 TIR signaling domain haplotype affected IL-33-driven NF-κB signaling, while not interfering with TLR signaling. In summary, we identify that IL1RL1 genetic signals potentially contribute to severe and eosinophilic phenotypes in asthma, as well as provide initial mechanistic insight, including genetic regulation of IL1RL1 isoform expression and receptor signaling.
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http://dx.doi.org/10.1172/jci.insight.132446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205441PMC
April 2020

Defining genetic risk factors for scleroderma-associated interstitial lung disease : IRF5 and STAT4 gene variants are associated with scleroderma while STAT4 is protective against scleroderma-associated interstitial lung disease.

Clin Rheumatol 2020 Apr 8;39(4):1173-1179. Epub 2020 Jan 8.

Interstitial Lung Disease Unit, National Heart and Lung Institute, Imperial College London, Royal Brompton and Harefield NHS Foundation Trust, Sydney Street, London, SW3 6NP, UK.

Although several genetic associations with scleroderma (SSc) are defined, very little is known on genetic susceptibility to SSc-associated interstitial lung disease (SSc-ILD). A number of common polymorphisms have been associated with SSc-ILD, but most have not been replicated in separate populations. Four SNPs in IRF5, and one in each of STAT4, CD226 and IRAK1, selected as having been previously the most consistently associated with SSc-ILD, were genotyped in 612 SSc patients, of European descent, of whom 394 had ILD. The control population (n = 503) comprised individuals of European descent from the 1000 Genomes Project. After Bonferroni correction, two of the IRF5 SNPs, rs2004640 (OR (95% CI)1.30 (1.10-1.54), p = 0.015) and rs10488631 (OR 1.48 (1.14-1.92), p = 0.022), and the STAT4 SNP rs7574865 (OR 1.43 (1.18-1.73), p = 0.0015) were significantly associated with SSc compared with controls. However, none of the SNPs were significantly different between patients with SSc-ILD and controls. Two SNPs in IRF5, rs10488631 (OR 1.72 (1.24-2.39), p = 0.0098), and rs2004640 (OR 1.39 (1.11-1.75), p = 0.03), showed a significant difference in allele frequency between controls and patients without ILD, as did STAT4 rs7574865 (OR 1.86 (1.45-2.38), p = 6.6 × 10). A significant difference between SSc with and without ILD was only observed for STAT4 rs7574865, being less frequent in patients with ILD (OR 0.66 (0.51-0.85), p = 0.0084). In conclusion, IRF5 rs2004640 and rs10488631, and STAT4 rs7574865 were significantly associated with SSc as a whole. Only STAT4 rs7574865 showed a significant difference in allele frequency in SSc-ILD, with the T allele being protective against ILD.Key points• We confirm the associations of the IRF5 SNPs rs2004640 and rs10488631, and the STAT4 SNP rs7574865, with SSc as a whole.• None of the tested SNPs were risk factors for SSc-ILD specifically.• The STAT4 rs7574865 T allele was protective against the development of lung fibrosis in SSc patients.• Further work is required to understand the genetic basis of lung fibrosis in association with scleroderma.
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http://dx.doi.org/10.1007/s10067-019-04922-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142048PMC
April 2020

Genome-Wide Association Study of Susceptibility to Idiopathic Pulmonary Fibrosis.

Am J Respir Crit Care Med 2020 03;201(5):564-574

Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut.

Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterized by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. Genome-wide association studies have reported signals of association implicating multiple pathways including host defense, telomere maintenance, signaling, and cell-cell adhesion. To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations. We conducted genome-wide analyses across three independent studies and meta-analyzed these results to generate the largest genome-wide association study of IPF to date (2,668 IPF cases and 8,591 controls). We performed replication in two independent studies (1,456 IPF cases and 11,874 controls) and functional analyses (including statistical fine-mapping, investigations into gene expression, and testing for enrichment of IPF susceptibility signals in regulatory regions) to determine putatively causal genes. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF. We identified and replicated three new genome-wide significant ( < 5 × 10) signals of association with IPF susceptibility (associated with altered gene expression of , , and ) and confirmed associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as yet unreported IPF susceptibility variants contribute to IPF susceptibility. The observation that decreased expression associates with increased susceptibility to IPF supports recent studies demonstrating the importance of mTOR signaling in lung fibrosis. New signals of association implicating and suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.
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http://dx.doi.org/10.1164/rccm.201905-1017OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047454PMC
March 2020

Uganda Genome Resource Enables Insights into Population History and Genomic Discovery in Africa.

Cell 2019 10;179(4):984-1002.e36

Wellcome Sanger Institute, Hinxton, Cambridge, UK.

Genomic studies in African populations provide unique opportunities to understand disease etiology, human diversity, and population history. In the largest study of its kind, comprising genome-wide data from 6,400 individuals and whole-genome sequences from 1,978 individuals from rural Uganda, we find evidence of geographically correlated fine-scale population substructure. Historically, the ancestry of modern Ugandans was best represented by a mixture of ancient East African pastoralists. We demonstrate the value of the largest sequence panel from Africa to date as an imputation resource. Examining 34 cardiometabolic traits, we show systematic differences in trait heritability between European and African populations, probably reflecting the differential impact of genes and environment. In a multi-trait pan-African GWAS of up to 14,126 individuals, we identify novel loci associated with anthropometric, hematological, lipid, and glycemic traits. We find that several functionally important signals are driven by Africa-specific variants, highlighting the value of studying diverse populations across the region.
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http://dx.doi.org/10.1016/j.cell.2019.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202134PMC
October 2019

Translational genomics and precision medicine: Moving from the lab to the clinic.

Science 2019 09;365(6460):1409-1413

Department of Health Sciences, University of Leicester, Leicester, UK.

Translational genomics aims to improve human health by building on discoveries made through genetics research and applying them in the clinical setting. This progress has been made possible by technological advances in genomics and analytics and by the digital revolution. Such advances should enable the development of prognostic markers, tailored interventions, and the design of prophylactic preventive approaches. We are at the cusp of predicting disease risk for some disorders by means of polygenic risk scores integrated with classical epidemiological risk factors. This should lead to better risk stratification and clinical decision-making. A deeper understanding of the link between genome-wide sequence and association with well-characterized phenotypes will empower the development of biomarkers to aid diagnosis, inform disease progression trajectories, and allow better targeting of treatments to those patients most likely to respond.
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http://dx.doi.org/10.1126/science.aax4588DOI Listing
September 2019

Overlap of Genetic Risk between Interstitial Lung Abnormalities and Idiopathic Pulmonary Fibrosis.

Am J Respir Crit Care Med 2019 12;200(11):1402-1413

Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, Virginia.

Interstitial lung abnormalities (ILAs) are associated with the highest genetic risk locus for idiopathic pulmonary fibrosis (IPF); however, the extent to which there are unique associations among individuals with ILAs or additional overlap with IPF is not known. To perform a genome-wide association study (GWAS) of ILAs. ILAs and a subpleural-predominant subtype were assessed on chest computed tomography (CT) scans in the AGES (Age Gene/Environment Susceptibility), COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]), Framingham Heart, ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points), MESA (Multi-Ethnic Study of Atherosclerosis), and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) studies. We performed a GWAS of ILAs in each cohort and combined the results using a meta-analysis. We assessed for overlapping associations in independent GWASs of IPF. Genome-wide genotyping data were available for 1,699 individuals with ILAs and 10,274 control subjects. The (mucin 5B) promoter variant rs35705950 was significantly associated with both ILAs ( = 2.6 × 10) and subpleural ILAs ( = 1.6 × 10). We discovered novel genome-wide associations near (rs6886640,  = 3.8 × 10) and (rs73199442,  = 4.8 × 10) with ILAs, and near (rs7744971,  = 4.2 × 10) with subpleural-predominant ILAs. These novel associations were not associated with IPF. Among 12 previously reported IPF GWAS loci, five (, , , , and ) were significantly associated ( < 0.05/12) with ILAs. In a GWAS of ILAs in six studies, we confirmed the association with a promoter variant and found strong evidence for an effect of previously described IPF loci; however, novel ILA associations were not associated with IPF. These findings highlight common genetically driven biologic pathways between ILAs and IPF, and also suggest distinct ones.
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http://dx.doi.org/10.1164/rccm.201903-0511OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884045PMC
December 2019

Novel idiopathic pulmonary fibrosis susceptibility variants revealed by deep sequencing.

ERJ Open Res 2019 Apr 10;5(2). Epub 2019 Jun 10.

Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER), Santa Cruz de Tenerife, Spain.

Background: Specific common and rare single nucleotide variants (SNVs) increase the likelihood of developing sporadic idiopathic pulmonary fibrosis (IPF). We performed target-enriched sequencing on three loci previously identified by a genome-wide association study to gain a deeper understanding of the full spectrum of IPF genetic risk and performed a two-stage case-control association study.

Methods: A total of 1.7 Mb of DNA from 181 IPF patients was deep sequenced (>100×) across 11p15.5, 14q21.3 and 17q21.31 loci. Comparisons were performed against 501 unrelated controls and replication studies were assessed in 3968 subjects.

Results: 36 SNVs were associated with IPF susceptibility in the discovery stage (p<5.0×10). After meta-analysis, the strongest association corresponded to rs35705950 (p=9.27×10) located upstream from the mucin 5B gene (). Additionally, a novel association was found for two co-inherited low-frequency SNVs (<5%) in , predicting a missense amino acid change in mucin 5AC (lowest p=2.27×10). Conditional and haplotype analyses in 11p15.5 supported the existence of an additional contribution of variants to IPF risk.

Conclusions: This study reinforces the significant IPF associations of these loci and implicates as another key player in IPF susceptibility.
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http://dx.doi.org/10.1183/23120541.00071-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556557PMC
April 2019

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

Nat Commun 2019 04 5;10(1):1561. Epub 2019 Apr 5.

Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, WC1E 6BT, UK.

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.
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http://dx.doi.org/10.1038/s41467-019-09381-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450903PMC
April 2019

Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations.

Nat Genet 2019 03 25;51(3):494-505. Epub 2019 Feb 25.

Department of Internal Medicine and Environmental Health Center, School of Medicine, Kangwon National University, Chuncheon, South Korea.

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 × 10; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.
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http://dx.doi.org/10.1038/s41588-018-0342-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546635PMC
March 2019

New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries.

Nat Genet 2019 03 25;51(3):481-493. Epub 2019 Feb 25.

Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function-associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.
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http://dx.doi.org/10.1038/s41588-018-0321-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397078PMC
March 2019

Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci.

Mol Psychiatry 2020 10 7;25(10):2392-2409. Epub 2019 Jan 7.

Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, Amsterdam, Netherlands.

Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.
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http://dx.doi.org/10.1038/s41380-018-0313-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515840PMC
October 2020

Trans-ethnic association study of blood pressure determinants in over 750,000 individuals.

Nat Genet 2019 01 21;51(1):51-62. Epub 2018 Dec 21.

MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK.

In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.
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http://dx.doi.org/10.1038/s41588-018-0303-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365102PMC
January 2019