Biology subjects

Bosse, Y.

Publications and source records attributed to Bosse, Y..

18 recordsLinked to original sources

bioRxiv2026

Decoding causal genes and programs from regulatory variants in aortic valve disease

Aortic valve disease is common, yet its regulatory mechanisms remain poorly understood. We performed multi-omic profiling of human aortic valve interstitial cells (HAVICs), identifying 11,891 allele-specific chromatin accessibility QTLs (as-caQTLs), 48% novel to this cell type. These variants were enriched in active enhancers, disrupted transcription factor (TF) motifs, particularly AP-1, TEAD and GATA families, and were validated by allele-specific TF binding assays. A fine-tuned deep DNA sequence model prioritized common and rare variants at risk loci predicted to impact chromatin accessibility. Single-cell CRISPRi perturbation of 247 variants identified cis-target genes at 55 as-caQTL elements, including loci without eQTLs. We demonstrate that common regulatory variants controlling elastin and fibrillin impact the development of the aortic valve apparatus. We provide genetic evidence and a mechanistic framework for the contribution of a reduced aortic root size to CAVD risk. Perturbations identified core cell programs led by upstream regulators AHNAK, PDIA6, and RNFT1 converging on extracellular matrix production and iron transport.

genetics↗

bioRxiv2026

Testosterone alleviates inflammation but increases the methacholine response in mice with allergic lung inflammation

Testosterone seems protective against asthma, but the underlying mechanisms are uncertain. Herein, the effect of testosterone was investigated on several features of experimental asthma. Systemic testosterone was first altered to subphysiological, physiological, or supraphysiological levels in male BALB/c mice through orchiectomy and testosterone supplementation. Testosterone (0.25 mg/day/30 g of body weight) was delivered continuously during 20 days using an implanted pump. At day 10, each group was exposed intranasally to either saline or house dust mite (HDM) once daily for 10 consecutive days to induce allergic lung inflammation. The day after the last exposure, respiratory mechanics was measured at baseline and in response to nebulized methacholine. Bronchoalveolar lavages (BAL) and lung tissues were also collected to quantify inflammation. Baseline respiratory mechanics were altered in mice with subphysiological levels of testosterone, with signs of small airway narrowing heterogeneity and closure. Testosterone drastically inhibited the HDM-induced inflammation. Yet, testosterone also increased the response to methacholine, as well as hysteresis, which are both indicators of enhanced airway smooth muscle activity. While it suggests that testosterone increases the contractility of the smooth muscle, it simultaneously and markedly inhibits inflammation. Explanations as to how these outcomes may lead to protection in asthma are discussed.

physiology↗

bioRxiv2025

Revealing the Drivers Underlying Distinct Evolutionary Trajectories in Lung Adenocarcinoma

Elucidating the evolution of cancers allows us to understand their key events, and the order in which they occur. To chart and interpret these evolutionary trajectories, we leverage whole-genome sequencing of lung tumours, including those from the largest cohort to date of lung cancers in subjects who have never smoked. Through ordering frequent genomic alterations, we discover three distinct evolutionary paths taken by lung adenocarcinomas; two dominated by tumours from people who have never smoked (NS-LUAD), and one followed by the vast majority of those who have smoked (S-LUAD). However, one in six NS-LUAD follow the smoking-dominant trajectory. These tumours, surprisingly, have fewer somatic alterations than the other NS-LUAD, and have shorter latency. They are strongly enriched for KRAS mutations. Our results suggest that gaining KRAS mutations allows these tumours to evolve more rapidly, acquiring a set of smoking-associated key alterations, with less need for genomic instability to progress. These tumours are three times more frequent in subjects of European vs. East Asian ancestry. These findings could shape clinical management strategies for lung adenocarcinoma patients, particularly for tumours driven by smoking-like evolutionary trajectories.

cancer biology↗

bioRxiv2025

A prognostic signature for lung adenocarcinoma in people who have never smoked

Knowledge of tumor cell dynamics can inform prognosis and treatment yet is largely lacking for lung adenocarcinoma in people who have never smoked (NS-LUAD). With RNA-seq data from 684 NS-LUAD and validation in an independent dataset, we identified three subtypes with distinct phenotypic traits and cell compositions. Additional genomic and histological data further characterized the subtypes. Steady, marked by low proliferation, high alveolar cell fraction, moderate-to-well differentiation, and fewer driver genes alterations, is linked to prolonged survival and low immune evasion. Proliferative shows high proliferation markers, TP53 mutations, and gene fusions. Chaotic, with high epithelial-to-mesenchymal transition markers, has the worst prognosis even within stage I tumors. Lacking known molecular or histological characteristics, this aggressive subtype is solely identified by transcriptomic data. A 60-gene signature recapitulates the overall classification and strongly predicts survival even within subgroups based on tumor stage or known genomic features, emphasizing its potential for improving NS-LUAD prognostication in clinical settings. SignificanceThe transcriptome of 684 lung adenocarcinomas in people who have never smoked (NS-LUAD) identifies three subtypes with different cellular dynamics, and genomic and morphologic features. A 60-gene signature accurately stratifies subjects for mortality risk, even in stage I, offering a clinically applicable tool for treatment decision making in NS-LUAD patients.

genomics↗

bioRxiv2025

Cell-Specific Transcriptomic and Mito-Nuclear Imbalance in Lungs Under Intermittent Hypoxia in Adult Male Mice.

Obstructive sleep apnea and its characteristic intermittent hypoxia (IH) are widely recognized as significant contributors to various pulmonary diseases, including asthma, pulmonary arterial hypertension, fibrosis, and chronic obstructive pulmonary disease. While single-cell RNA sequencing (scRNA-seq) has provided valuable insights into cell-type-specific responses to IH, previous studies have primarily focused on post-hypoxic recovery states, leaving immediate molecular responses during active IH exposure unexplored. To address this critical knowledge gap, we investigated real-time transcriptional responses to IH at single-cell resolution in lung tissue using male mice (n=3/group) exposed to either normoxia or IH (30 cycles/h, nadir 6% O2, 12 h/day) for 14 days, with tissue collection during active IH exposure. Our analysis revealed pronounced cell-type-specific transcriptional reprogramming, particularly in airway smooth muscle cells (ASMC), arterial endothelial cells (AEC), and lymphatic endothelial cells (LEC). These changes were characterized by enrichment in pathways related to epithelial-to-mesenchymal transition (ASMC, LEC), myogenesis (ASMC), and antioxidant defenses (AEC, LEC). Most cell types demonstrated substantial upregulation of genes encoding mitochondrial complex I-IV proteins and TCA cycle enzymes accompanied by a decreased expression of genes encoded by mitochondrial DNA that was markedly present in LEC, AEC, and cells of the alveolar-capillary unit, revealing a mito-nuclear imbalance. These findings provide novel insights into the immediate cellular responses to IH, showing previously uncharacterized metabolic reorganization that may underlie the development of IH-related pulmonary complications. This improved understanding of early molecular events during active IH exposure advances our knowledge of sleep apnea-related lung pathologies and may inform future therapeutic strategies.

physiology↗

bioRxiv2024

Airway smooth muscle tone curbs hyperresponsiveness in experimental asthma

Background & ObjectivesA sustained contraction of airway smooth muscle, hereinafter called tone, increases the response to methacholine in healthy mice and humans. However, the effect of tone in the context of an active inflammation remains to be investigated. The objective of the present study was to test the effect of tone on the in vivo response to methacholine in mice during an active inflammatory phase of experimental asthma. MethodsMale BALB/c mice were exposed once-daily to either intranasal saline or house dust mite for 10 consecutive days to induce experimental asthma. They then underwent one of two methacholine challenges 24 h after the last exposure. While the same cumulative dose was administered in both challenges, one was preceded by a 20-min period of tone induced by nebulizing low doses of methacholine at 5-min intervals. Respiratory mechanics were monitored before and throughout the methacholine challenge by oscillometry. Bronchoalveolar lavages (BAL) and histology were also performed. ResultsBAL inflammation and histological alterations were consistent with experimental asthma. In accordance with previous studies, tone potentiated the response to methacholine in control mice, mainly by stiffening the lung periphery. The lung was even stiffer upon methacholine challenge during an active phase of inflammation in mice with experimental asthma, but this was not further potentiated by tone. In fact, in mice with experimental asthma, tone mitigated hyperresponsiveness by preventing further airway narrowing and, more importantly, small airway narrowing heterogeneity and closure. ConclusionDuring an active inflammatory phase of experimental asthma, tone protects against hyperresponsiveness. Take-home messageThe effect of airway smooth muscle tone on the methacholine response was investigated in mice with or without experimental asthma. While tone potentiated the methacholine response in control mice, it mitigated hyperresponsiveness in experimental asthma. These results unveiled a protective role of the airway smooth muscle in experimental asthma.

physiology↗

bioRxiv2024

Single-cell and single-nucleus RNA-sequencing from paired normal-adenocarcinoma lung samples provides both common and discordant biological insights.

Whether single-cell RNA-sequencing (scRNA-seq) captures the same biological information as single-nucleus RNA-sequencing (snRNA-seq) remains uncertain and likely to be context-dependent. Herein, a head-to-head comparison was performed in matched normal-adenocarcinoma human lung samples to assess biological insights derived from scRNA-seq versus snRNA-seq and better understand the cellular transition that occurs from normal to tumoral tissue. Here, the transcriptome of 160,621 cells/nuclei was obtained. In non-tumor lung, cell type proportions varied widely between scRNA-seq and snRNA-seq with a predominance of immune cells in the former (81.5%) and epithelial cells (69.9%) in the later. Similar results were observed in adenocarcinomas, in addition to an overall increase in cell type heterogeneity and a greater prevalence of copy number variants in cells of epithelial origin, which suggests malignant assignment. The cell type transition that occurs from normal lung tissue to adenocarcinoma was not always concordant whether cells or nuclei were examined. As expected, large differential expression of the whole-cell and nuclear transcriptome was observed, but cell-type specific changes of paired normal and tumor lung samples revealed a set of common genes in the cells and nuclei involved in cancer-related pathways. In addition, we showed that the ligand-receptor interactome landscape of lung adenocarcinoma was largely different whether cells or nuclei were evaluated. Immune cell depletion in fresh specimens partly mitigated the difference in cell type composition observed between cells and nuclei. However, the extra manipulations affected cell viability and amplified the transcriptional signatures associated with stress responses. In conclusion, research applications focussing on mapping the immune landscape of lung adenocarcinoma benefit from scRNA-seq in fresh samples, whereas snRNA-seq of frozen samples provide a low-cost alternative to profile more epithelial and cancer cells, and yield cell type proportions that more closely match tissue content. Author SummarySingle-cell transcriptomic datasets provide unprecedented opportunities to disentangle the complex tissue microenvironment and cellular origin of cancer. Data are scarce regarding the pros and cons of single-cell RNA sequencing (scRNA-seq) of freshly explanted human tissues over single-nuclei sequencing (snRNA-seq) from the same archived frozen tissues. Lung adenocarcinoma represents a medically valuable case study to compare the biological signal recovered through cells and nuclei sequencing. Here, we sequenced the transcriptome of 160,621 cells/nuclei in paired normal-adenocarcinoma lung samples. Cell type proportions varied widely between scRNA-seq and snRNA-seq with a predominance of immune cells in the former and epithelial cells in the later. Adenocarcinomas were characterized by an increase in cell type heterogeneity and a greater prevalence of malignant epithelial cells in both scRNA-seq and snRNA-seq. The cellular and gene expression transition that occur from normal lung to adenocarcinoma showed common and discordant biological insights whether cells or nuclei were examined. Research applications focussing on mapping the immune landscape of lung cancer benefit from scRNA-seq in fresh samples, whereas snRNA-seq of the same frozen samples provide a low-cost and more flexible alternative to profile more epithelial and cancer cells, and yield cell type proportions that more closely match tissue content.

cancer biology↗

bioRxiv2019

The protective effect of club cell secretory protein (CC-16) on COPD risk and progression: a Mendelian randomisation study

BackgroundThere are currently no robust biomarkers of chronic obstructive pulmonary disease (COPD) risk or progression. Club cell secretory protein-16 (CC-16) is associated with the clinical expression of COPD. We aimed to determine if there is a causal effect of serum CC-16 level on COPD risk and/or progression using Mendelian randomisation (MR) analysis. MethodsWe performed a genome-wide association meta-analysis for serum CC-16 in two COPD cohorts (Lung Health Study [LHS], n=3,850 and ECLIPSE, n=1,702). We then used the CC-16-associated single-nucleotide polymorphisms (SNPs) in MR analysis to estimate the causal effect of serum CC-16 on COPD risk (International COPD Genetics Consortium/UK-Biobank dataset; n=35,735 cases, n=222,076 controls) and progression (change in forced expiratory volume in 1 s [FEV1] in LHS and ECLIPSE). We also determined the associations between SNPs associated with CC-16 and gene expression using n=1,111 lung tissue samples from the Lung eQTL Study. ResultsWe identified 7 SNPs independently associated (p<5x10-8) with serum CC-16 levels; 6 of these were novel. MR analysis suggested a protective causal effect of increased serum CC-16 on COPD risk (p=0.008) and progression (LHS only, p=0.02). Five of the SNPs were also associated with gene expression in lung tissue, including that of the CC-16-encoding gene SCGB1A1 (false discovery rate<0.1). ConclusionWe have identified several novel genetic variants associated with serum CC-16 level in COPD cohorts. These genetic associations suggest a potential causal effect of serum CC-16 on COPD risk and progression. Further investigation of CC-16 as a biomarker or therapeutic target in COPD is warranted. KEY MESSAGESWhat is the key question? Can genetics help uncover a causal effect of serum CC-16 level on COPD risk and/or progression? What is the bottom line? There is a protective effect of genetically-increased serum CC-16 on both COPD risk and progression (as measured by change in FEV1 over time), which may be due to increased expression of the CC-16-encoding gene SCGB1A1 in the lung. Why read on? This is the first study to demonstrate a possible causal effect of serum CC-16 in people with COPD, and highlights the potential for CC-16 as a biomarker or therapeutic target.

genomics↗

bioRxiv2019

Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis

RationaleIdiopathic pulmonary fibrosis (IPF) is a complex lung disease characterised by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. The mechanisms by which this arises are poorly understood and it is likely that multiple pathways are involved. The strongest genetic association with IPF is a variant in the promoter of MUC5B where each copy of the risk allele confers a five-fold risk of disease. However, genome-wide association studies have reported additional signals of association implicating multiple pathways including host defence, telomere maintenance, signalling and cell-cell adhesion.\n\nObjectivesTo improve our understanding of mechanisms that increase IPF susceptibility by identifying previously unreported genetic associations.\n\nMethods and measurementsWe performed the largest genome-wide association study undertaken for IPF susceptibility with a discovery stage comprising up to 2,668 IPF cases and 8,591 controls with replication in an additional 1,467 IPF cases and 11,874 controls. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF.\n\nMain resultsWe identified and replicated three new genome-wide significant (P<5x10-8) signals of association with IPF susceptibility (near KIF15, MAD1L1 and DEPTOR) and confirm associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as-yet unreported IPF risk variants contribute to IPF susceptibility.\n\nConclusionsNovel association signals support the importance of mTOR signalling in lung fibrosis and suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.

genomics↗

bioRxiv2019

Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility

Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV1: rg=0.098, p=2.3x10-8) and the ratio of FEV1 to forced vital capacity (FEV1/FVC: rg=0.137, p=2.0x10-12). Mendelian randomization analyses demonstrate that reduced FEV1 increases squamous cell carcinoma risk (odds ratio (OR)=1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV1/FVC increases the risk of adenocarcinoma (OR=1.17, 1.01-1.35) and lung cancer in never smokers (OR=1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis.

genetics↗

bioRxiv2019

Long-Term Exposure to Elevated Lipoprotein(a) Levels, Parental Lifespan and Risk of Mortality

BackgroundElevated Lipoprotein(a) (Lp[a]) levels are associated with a broad range of atherosclerotic cardiovascular diseases (CVD). The impact of high Lp(a) levels on human longevity is however controversial. Our objectives were to determine whether genetically-determined Lp(a) levels are associated with parental lifespan and to assess the association between measured and genetically-determined Lp(a) levels and long-term all-cause and cardiovascular mortality.\n\nMethodsWe determined the association between a genetic risk score of 26 single nucleotide polymorphisms weighted for their impact on Lp(a) levels (wGRS) and parental lifespan (at least one long-lived parent; father still alive and older than 90 or fathers age of death [≥]90 or mother still alive and older than 93 or mothers age of death [≥]93) in 139,362 participants from the UK Biobank. A total of 17,686 participants were considered as having high parental lifespan. We also investigated the association between Lp(a) levels and all-cause and cardiovascular mortality in 18,720 participants from the EPIC-Norfolk study.\n\nResultsIn the UK Biobank, increases in the wGRS (weighted for a 50 mg/dL increase in Lp(a) levels) were inversely associated with a high parental lifespan (odds ratio=0.92, 95% confidence interval [CI]=0.89-0.94, p=2.7x10-8). During the 20-year follow-up of the EPIC-Norfolk study, 5686 participants died (2412 from CVD-related causes). Compared to participants with Lp(a) levels <50 mg/dL, those with Lp(a) levels [≥]50 mg/dL had an increased hazard ratio (HR) for all-cause (HR=1.17, 95% CI=1.08-1.27) and cardiovascular (HR=1.54, 95% CI=1.37-1.72) mortality. Compared to individuals with Lp(a) levels below the 50th percentile of the Lp(a) distribution (in whom event rates were 29.8% and 11.3%, respectively for all-cause and cardiovascular mortality), those with Lp(a) levels equal or above the 95th percentile of the population distribution ([≥]70 mg/dL) had HRs of 1.22 (95% CI=1.09-1.37, event rate 37.5%) and 1.71 (95% CI=1.46-2.00, event rate 20.0%), for all-cause mortality and cardiovascular mortality, respectively.\n\nConclusionsResults of this study suggest a potentially causal effect of Lp(a) on human longevity, support the use of parental lifespan as a tool to study the genetic determinants of human longevity, and provide a rationale for a trial of Lp(a)-lowering therapy in individuals with high Lp(a) levels.

genetics↗

bioRxiv2019

SNPs associated with HHIP expression have differential effects on lung function in males and females

Adult lung function is highly heritable and 279 genetic loci were recently reported as associated with spirometry-based measures of lung function. Though lung development and function differ between males and females throughout life, there has been no genome-wide study to identify genetic variants with differential effects on lung function in males and females. Here, we present the first genome-wide genotype-by-sex interaction study on four lung function traits in 303,612 participants from the UK Biobank. We detected five SNPs showing genome-wide significant (P<5 x 10-8) interactions with sex on lung function, as well as 21 suggestively significant interactions (P<1 x 10-6). The strongest sex interaction signal came from rs7697189 at 4:145436894 on forced expiratory volume in 1 second (FEV1) (P = 3.15 x 10-15), and was replicated (P = 0.016) in 75,696 individuals in the SpiroMeta consortium. Sex-stratified analyses demonstrated that the minor (C) allele of rs7697189 increased lung function to a greater extent in males than females (untransformed FEV1 {beta} = 0.028 [SE 0.0022] litres in males vs {beta} = 0.009 [SE 0.0014] litres in females), and this effect was not accounted for by differential effects on height, smoking or age at puberty. This SNP resides upstream of the gene encoding hedgehog-interacting protein (HHIP) and has previously been reported for association with lung function and HHIP expression in lung tissue. In our analyses, while HHIP expression in lung tissue was significantly different between the sexes with females having higher expression (most significant probeset P=6.90 x 10-6) after adjusting for age and smoking, rs7697189 did not demonstrate sex differential effects on expression. Establishing the mechanism by which HHIP SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases, such as chronic obstructive pulmonary disease (COPD), in both sexes.

genetics↗

bioRxiv2019

Genetic inhibition of PCSK9, atherogenic lipoprotein concentrations, and calcific aortic valve stenosis

BackgroundProprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition reduces plasma concentrations of low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apoB) and lipoprotein(a) [Lp(a)]. Atherogenic lipoprotein levels have been linked with calcific aortic valve stenosis (CAVS). Our objectives were to determine the association between variants in PCSK9 and lipoprotein-lipid levels, coronary artery disease (CAD) and CAVS, and to evaluate if PCSK9 could be implicated in aortic valve interstitial cells (VICs) calcification. MethodsWe built a genetic risk score weight for LDL-C levels (wGRS) using 10 independent PCSK9 single nucleotide polymorphisms and determined its association with lipoprotein-lipid levels in 9692 participants of the EPIC-Norfolk study. We investigated the association between the wGRS and CAD and CAVS in the UK Biobank, as well as the association between the PCSK9 R46L variant and CAVS in a meta-analysis of published prospective, population-based studies (Copenhagen studies, 1463 cases/101,620 controls) and unpublished studies (UK Biobank, 1350 cases/349,043 controls, Malmo Diet and Cancer study, 682 cases/5963 controls and EPIC-Norfolk study, 508 cases/20,421 controls). We evaluated PCSK9 expression and localization in explanted aortic valves by capillary Western blot and immunohistochemistry in patients with and without CAVS. Von Kossa staining was used to visualize aortic leaflet calcium deposits. PCSK9 expression under oxidative stress conditions in VICs was assessed. ResultsThe wGRS was significantly associated with lower LDL-C and apoB (p<0.001), but not with Lp(a). In the UK Biobank, the association of PCSK9 variants with CAD were positively correlated with their effects on apoB levels. CAVS was less prevalent in carriers of the PCSK9 R46L variant [odds ratio=0.71 (95% confidence interval, 0.57-0.88), p<0.001]. PCSK9 expression was elevated in the aortic valves of patients with aortic sclerosis and CAVS compared to controls. In calcified leaflets, PCSK9 co-localized with calcium deposits. PCSK9 expression was induced by oxidative stress in VICs. ConclusionGenetic inhibition of PCSK9 is associated with lifelong reductions in the levels of non-Lp(a) apoB-containing lipoproteins as well as lower odds of CAD and CAVS. PCSK9 is abundant in fibrotic and calcified aortic leaflets. Oxidative stress increases PCSK9 expression in VICs. These results provide a rationale for performing randomized clinical trials of PCSK9 inhibition in CAVS.

genetics↗

bioRxiv2019

Genetic association analyses highlight IL6, ALPL, and NAV1 as three new susceptibility genes underlying calcific aortic valve stenosis

To date, only two replicated loci, LPA and PALMD, have been identified as causal genes for calcific aortic valve stenosis (CAVS) using genome-wide and transcriptome-wide association study (TWAS). To identify additional susceptibility genes for CAVS, we performed a GWAS meta-analysis totaling 5,115 cases and 354,072 controls of European descent. Four loci achieved genome-wide significance, including two new loci: IL6 (interleukin 6) on 7p15.3 and ALPL (alkaline phosphatase) on 1p36.12. A TWAS integrating an eQTL study of 233 human aortic valves identified NAV1 (neuron navigator 1) on 1q32.1 as a new candidate causal gene. The CAVS risk alleles were associated with higher mRNA expression of NAV1 in valve tissues. Association results at the genome-wide scale showed genetic correlation with coronary artery disease and cardiovascular risk factors. Our study highlights three new loci implicating inflammation, mineralization and blood vessel integrity in CAVS pathogenesis and supports shared genetic etiology with cardiovascular traits.

genomics↗

bioRxiv2018

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

Reduced lung function predicts mortality and is key to the diagnosis of COPD. In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, one-half of which are new. In combination these variants strongly predict COPD in deeply-phenotyped patient populations. Furthermore, the combined effect of these variants showed generalisability 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.

genomics↗

bioRxiv2017

Leveraging lung tissue transcriptome to uncover candidate causal genes in COPD genetic associations

We collated 129 non-overlapping risk loci for chronic obstructive pulmonary disease (COPD) from the GWAS literature. Using recent and complementary integrative genomics approaches, combining GWAS and lung eQTL results, we identified 12 novel COPD loci and corresponding causal genes. In addition, we mapped candidate causal genes for 60 out of the 129 GWAS-nominated loci as well as for four sub-genome-wide significant COPD risk loci derived from the largest GWAS on COPD. Mapping causal genes in lung tissue represents an important contribution on the genetics of COPD, enriches our biological interpretation of GWAS findings, and brings us closer to clinical translation of genetic associations.

genomics↗

bioRxiv2017

A transcriptome-wide association study identifies PALMD as a susceptibility gene for calcific aortic valve stenosis

Calcific aortic valve stenosis (CAVS) is a common and life-threatening heart disease with no drug that can stop or delay its progression. Elucidating the genetic factors underpinning CAVS is an urgent priority to find new therapeutic targets1. Major landmarks in genetics of CAVS include the discoveries of NOTCH12 and LPA3. However, genetic variants in these genes accounted for a small number of cases and low population-attributable risk. Here we mapped a new susceptibility locus for CAVS on chromosome 1p21.2 and identified PALMD (palmdelphin) as the causal gene. PALMD was revealed using a transcriptome-wide association study (TWAS)4, which combines a genome-wide association study (GWAS) of 1,009 cases and 1,017 ethnically-matched controls with the first large-scale expression quantitative trait loci (eQTL) mapping study on human aortic valve tissues (n=233). The CAVS risk alleles and increasing disease severity were both associated with lowered mRNA expression levels of PALMD in valve tissues. The top variant explained up to 12.5% of the population-attributable risk and showed similar effect and strong association with CAVS (P=1.53 x 10-10) in UK Biobank comparing 1,391 cases and 352,195 controls. The identification of PALMD as a susceptibility gene for CAVS provides new insights about the genetic nature of this disease and opens new avenues to investigate its etiology and develop much-needed therapeutic options.

genomics↗

bioRxiv2017

Meta-analysis of exome array data identifies six novel genetic loci for lung function

Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease (COPD). We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. We identified significant (P<2{middle dot}8x10-7) associations with six SNPs: a nonsynonymous variant in RPAP1, which is predicted to be damaging, three intronic SNPs (SEC24C, CASC17 and UQCC1) and two intergenic SNPs near to LY86 and FGF10. eQTL analyses found evidence for regulation of gene expression at three signals and implicated several genes including TYRO3 and PLAU. Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.

genetics↗