Biology subjects

Padmanabhan, S.

Publications and source records attributed to Padmanabhan, S..

At least 19 recordsLinked to original sources

bioRxiv2025

Origin of Eukaryotic Plasmalogen Biosynthesis by Horizontal Gene Transfer from Myxobacteria

Plasmalogens, a unique class of membrane lipids defined by a distinctive vinyl ether bond, are critical for human health, with their altered levels linked to various diseases. Despite their importance, their origin and evolutionary history remain enigmatic. Here, we uncover the evolutionary history of the aerobic plasmalogen biosynthesis pathway in eukaryotes, focusing on the four essential enzymes responsible for their formation. Through comprehensive phylogenetic analyses and experimental validation, we demonstrate a significant divide in plasmalogen synthesis capabilities across major eukaryotic lineages. Our study also suggests that the acquisition of these plasmalogen biosynthesis genes by an early eukaryotic ancestor was through horizontal gene transfer (HGT) from Myxobacteria. The findings yield insights into how HGT shapes metabolic pathways and illuminate a critical step in the genesis of eukaryotic cell complexity.

evolutionary biology↗

bioRxiv2025

Minimal Impact of Low Vision on Explicit Sensorimotor Adaptation

Rehabilitation from motor system dysfunction relies on learning deliberate motor corrections through practice and feedback. This is called explicit motor adaptation. One key source of feedback for this adaptation is the visual error signal between the intended movement and the achieved movement. As people age, both motor dysfunction and visual impairment become more common, potentially compromising the visual feedback signal. Previous work has shown that visual impairment can disrupt the implicit, automatic adjustments made by the sensorimotor system. But how visual impairment influences the explicit motor adaptation, a cornerstone of rehabilitation, remains unknown. To address this gap, we recruited individuals with low vision--defined as uncorrectable visual impairment resulting in functional vision loss--and age-matched controls to complete a visuomotor task designed to isolate two components of explicit motor adaptation: discovering a new deliberate sensorimotor strategy and recalling a previously learned one. Surprisingly, low vision had no measurable impact on either component. Despite reduced visual fidelity, individuals with low vision were as effective as controls in both discovering and retrieving successful explicit sensorimotor strategies. These results highlight potential mechanisms that can be leveraged in rehabilitation.

neuroscience↗

bioRxiv2025

Goal Uncertainty Attenuates Sensorimotor Adaptation

Implicit sensorimotor adaptation--the automatic correction of movement errors through feedback and practice--is driven by a perceptual prediction error, the mismatch between the perceived movement outcome and its intended goal. While perceptual uncertainty is known to attenuate adaptation, the impact of goal uncertainty on adaptation remains unknown. We employed a visuomotor adaptation task that isolates implicit adaptation (N = 180), manipulating goal uncertainty by varying how precisely the goals midpoint could be identified. Display format was varied independently to control for the objective size of visual features, and targets were hidden at movement onset, ensuring identical visual input at the moment the error was experienced. We found that goal uncertainty significantly attenuated implicit adaptation, independent of low-level visual and kinematic features. Together, these results demonstrate that a precise internal representation of the goal is essential for supporting implicit sensorimotor adaptation.

neuroscience↗

bioRxiv2025

Data-driven feedback augments ultrasound nanotheranostics in brain tumors

The blood-brain barrier (BBB) renders the delivery of nanomedicine in the brain ineffective and the detection of circulating disease-related DNA from the brain unreliable. Here, we show that the acoustic emission content of focused ultrasound-controlled microbubble dynamics (MB-FUS) incorporates precursor signals that allow large-data models to predict sonication regimens for safe and effective BBB opening. Crucially, closed-loop MB-FUS controller augmented by machine learning (ML-CL) expands the treatment window (4-fold), as compared to conventional controllers, by persistently and proactively maximizing the BBB permeability while preventing tissue damage. By successfully scaling up from mice to rats and from healthy to diseased brains (glioma), ML-CL rendered the BBB permeable to large nanoparticles and markedly improved the release and detection of tumor DNA in plasma. Together, our findings reveal the potential of data-driven feedback to support the development of next-generation AI-powered ultrasound systems for safe, robust, and efficient nanotheranostic targeting of brain diseases.

bioengineering↗

bioRxiv2025

Cryo-EM reveals the structural heterogeneity and conformational flexibility of multidrug efflux pumps MdtB and MdtF

RND efflux pumps are a major cause of multidrug resistance in bacteria, particularly in Gram-negative bacteria. They are complex molecular machines forming tripartite assemblies that actively pump out a wide range of antimicrobial agents, including antibiotics, biocides and host defence molecules. However, the presence of multiple RND pumps with overlapping functions in a single bacterium raises questions about their individual functional relevance. In this study, we determined the Cryo-EM structures of two distinct HAE-RND pumps from E.coli., MdtB and MdtF. MdtF is a unique class of RND pump whose expression is regulated by oxygen availability and is crucial for the survival of E.coli in anaerobic growth conditions. Surprisingly, homotrimeric MdtB, previously reported to be inactive, exhibited activity in our experiments. Cryo-EM structure determination of MdtF at 2.8 [A] resolution revealed the flexible transmembrane domain with significant conformational changes in the core helixes, leading to the closure of the central pore. While the MdtB structure adopts a resting state, MdtF displays structural dynamics in the presence of DDM. The apo structures of both pumps unveil novel conformational states of HAE-RND efflux transporters. Our findings highlight significant structural and functional divergence among closely related HAE-RND proteins. Despite 71% sequence similarity and phylogenetic proximity to AcrB, the structure of MdtF differs from the solved AcrB structures. In contrast, the MdtB structure exhibits greater resemblance to AcrB, regardless of 32% sequence similarity. Furthermore, our structural analysis provides insights into drug-binding sites and the transport mechanism of these important transporters.

biophysics↗

bioRxiv2025

SB 11285, a Novel Canonical Purine-Pyrimidine Cyclic Dinucleotide, is a Systemically Bioavailable STING Agonist for Cancer Immunotherapy

SummarySB 11285, a novel cell-permeable, canonical 3,5, purine-pyrimidine cyclic dinucleotide has been developed as a potent systemically bioavailable STING agonist currently in clinical trials. The stimulator of Interferon genes (STING) pathway, crucial for cytosolic DNA sensing and innate immunity, presents a promising avenue for novel cancer immunotherapies. Discussed here is the discovery and development of SB11285, a potent activator of the STING pathway, belonging to the canonical class of 3,5 purine-pyrimidine (PuPy) cyclic dinucleotides (CDNs). SB11285 exhibits superior potency and cell permeability compared to non-canonical 2,3-CDNs and demonstrates robust antitumor activity in in vivo syngeneic mouse tumor models, resulting in complete tumor regression, and durable immunological memory. Combination with checkpoint inhibitors and cytotoxic agents further enhances its efficacy. The anti-tumor effects of SB 11285 rely on the induction of CD8+ T cells, activated macrophages, and NK cells in the tumor microenvironment (TME), for efficient tumor killing and fostering profound and durable anti-tumor response. Our findings underscore the potential of functionalized canonical 3,5-Pu-Py CDNs, exemplified by SB11285, as safe and potent STING agonists for multiple routes of administration in cancer therapy. Currently, SB11285 administered intravenously (IV), is undergoing evaluation as the first systemically administered CDN analog in human clinical trials across various tumor types.

immunology↗

bioRxiv2024

Characterizing the dual regulation of Neisseria gonorrhoeae tdfJ in response to zinc and iron

Gonorrhea is a sexually transmitted infection, caused by the bacterial pathogen Neisseria gonorrhea (Ngo) and affects millions of individuals of all age groups across the globe every year. Infection with Ngo does not result in protection and no effective vaccine has been developed, leaving antibiotics as the only treatment option. With the emergence of strains showing high levels of antibiotic resistance, there is an urgent need for development of novel therapeutics for disease prevention. During pathogenesis the host employs nutritional immunity, to restrict important transition metals such as zinc away from Ngo. This process is counteracted in Ngo by the production of highly efficient zinc import TonB-dependent Transporters (TDTs) which are promising vaccine antigens and zinc shuttle ABC transporters found to be important for intracellular survival. In Ngo zinc homeostasis and transport proteins are regulated by the Zinc uptake regulator (Zur) which represses transcription in the presence of zinc and activates transcription in the absence of zinc. In this study, characterize the promoter elements of the zinc import TDT, tdfJ, which results in dual regulation by zinc and iron. We characterize specificity and binding affinities for regulation of tdfJ by a second regulator, Ferric uptake regulator (Fur) in response to iron. The response of tdfJ to both iron and zinc and its potential to be an important invasin, makes it an attractive candidate to investigate female genital tract infections. The female genital tract is a conglomerate of these conditions and infections here are often asymptomatic. Taken together, this research provides important knowledge on the regulation of virulence mechanisms in response to zinc, which will aid in the development of therapeutics and an efficacious vaccine against a gonococcal infection.

molecular biology↗

bioRxiv2024

Scrutinizing science to save lives: uncovering flaws in the data linking L-type calcium channels blockers to CRAC channels and heart failure.

Hypertension is estimated to affect almost 1 billion people globally and significantly increases risk of myocardial infarction, heart failure, stroke, retinopathy and kidney disease. One major front line therapy that has been used for over 50 years involves L-type Ca2+ channel blockers (LCCBs). One class of LCCBs is the dihydropyridine family, with amlodipine being widely prescribed regardless of gender, race, ethnicity or age. In 2020, Johnson et al.7 reported that all LCCBs significantly increased the risk of heart failure, and attributed this effect to non-canonical activation of store-operated Ca2+ entry. A major approach on which they based many of their arguments was to measure cytosolic Ca2+ using the fluorescent Ca2+ indicator dye fura-2. We recently demonstrated that amlodipine is highly fluorescent within cells and overwhelms the fura-2 signal, precluding the use of the indicator dye with amlodipine24. Our meta-analyses and prospective real world study showed that dihydropyridines were not associated with an increase in heart failure, likely explained by the lack of consideration by Johnson et al.7 of well-known confounding factors such as age, race, obesity, prior anti-hypertensive treatment or diabetes24. Trebak and colleagues have responded to our paper with a forthright and unwavering defence of their work27. In this paper, we carry out a forensic dissection of Johnson et al.,7 and conduct new experiments that address directly points raised by Trebak et al. 27. We show that there are major flaws in the design and interpretation of their key experiments, that fura-2 cannot be used with amlodipine, that there are fundamental mathematical misunderstandings and mistakes throughout their study leading to critical calculations on heart failure that are demonstrably wrong, and several of their own results are inconsistent with their interpretation. We therefore believe the study by Johnson et al. 7 is flawed at many levels and we stand by our conclusions.

physiology↗

bioRxiv2023

A potential patient stratification biomarker for Parkinson's disease based on LRRK2 kinase-mediated centrosomal alterations in peripheral blood-derived cells

Parkinsos disease (PD) is a common neurodegenerative movement disorder and leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for disease intervention. However, the ability to stratify patients who will benefit from such treatment modalities based on shared etiology is critical for the success of disease-modifying therapies. Ciliary and centrosomal alterations are commonly associated with pathogenic LRRK2 kinase activity and can be detected in many cell types. We previously found centrosomal deficits in immortalized lymphocytes from G2019S-LRRK2 PD patients. Here, to investigate whether such deficits may serve as a potential blood biomarker for PD which is susceptible to LRKK2 inhibitor treatment, we characterized patient-derived cells from distinct PD cohorts. We report centrosomal alterations in peripheral cells from a subset of early-stage idiopathic PD patients which is mitigated by LRRK2 kinase inhibition, supporting a role for aberrant LRRK2 activity in idiopathic PD. Centrosomal defects are detected in R1441G-LRRK2 and G2019S-LRRK2 PD patients and in non-manifesting LRRK2 mutation carriers, indicating that they acumulate prior to a clinical PD diagnosis. They are present in immortalized cells as well as in primary lymphocytes from peripheral blood. These findings indicate that analysis of centrosomal defects as a blood-based patient stratification biomarker may help nominate PD patients who will benefit from LRRK2-related therapeutics. One-sentence summaryPeripheral blood-derived cells can be employed to stratify Parkinsos disease patients most likely to respond to LRRK2-related therapeutics.

neuroscience↗

bioRxiv2022

Treatment with Tumor-Treating Fields (TTFields) Suppresses Intercellular Tunneling Nanotube Formation In Vitro and Upregulates Immuno-Oncologic Biomarkers In Vivo in Malignant Mesothelioma

Intercellular communication is critical for the development of invasive cancers. Multiple forms of intercellular communication have been well characterized, involving diffusible soluble factors or contact-dependent channels for immediately adjacent cells. Over the past 1-2 decades, the emergence of a unique form of F-actin-based cellular protrusion known as tunneling nanotubes (TNTs) has filled the niche of long-range cell-contact dependent intercellular communication that facilitates cell growth, differentiation, and in the case of invasive cancer phenotypes, a more chemoresistant phenotype. The cellular machinery of TNT-mediated transport is an area of active investigation, and microtubules have been implicated in this process as they are in other membranous protrusions. Tumor-Treating Fields (TTFields) therapy is a novel therapeutic strategy in clinical use for patients with advanced cancers, based on the principle of using low-intensity alternating electric fields to disrupt microtubules in cancer cells undergoing mitosis. Other mechanisms of action have also been demonstrated. In this study, we investigated the effects of TTFields on TNTs in malignant pleural mesothelioma (MPM) in vitro and also on the spatial transcriptomic landscape in vivo. We found that applying TTFields at 1.0 V/cm significantly suppressed TNT formation in a biphasic MPM cell line (MSTO-211H), but not in sarcomatoid MPM (VAMT). At these parameters, TTFields significantly reduced cell count in MSTO-211H, but did not significantly alter intercellular transport of mitochondria via intact TNTs. To understand how TTFields may impact expression of genes with known involvement to TNT formation and overall tumor growth, we performed spatial genomic assessment of TTFields-treated tumors from an in vivo animal model of MPM, and detected upregulation of immuno-oncologic biomarkers with simultaneous downregulation of pathways associated with cell hyperproliferation, invasion, and other critical regulators of oncogenic growth. Several molecular classes and pathways coincide with markers that we and others have found to be differentially expressed in cancer cell TNTs, including MPM specifically. In this study, we report novel cellular and molecular effects of TTFields in relation to tumor communication networks enabled by TNTs and related molecular pathways. These results position TNTs as potential therapeutic targets for TTFields-directed cancer treatment strategies; and also identify the ability of TTFields to potentially remodel the tumor microenvironment, thus enhancing response to immunotherapeutic drugs.

cancer biology↗

bioRxiv2022

Impact of 98 LRRK2 variants linked to Parkinson's Disease on kinase activity and microtubule binding

Mutations enhancing the kinase activity of LRRK2 cause Parkinsons disease (PD) and therapies that reduce LRRK2 kinase activity are being tested in clinical trials. Numerous rare variants of unknown clinical significance have been reported, but how the vast majority impact on LRRK2 function is unknown. Here, we investigate 100 LRRK2 variants linked to PD, including previously described pathogenic mutations. We identify 23 LRRK2 variants that robustly stimulate kinase activity, including variants within the N-terminal non-catalytic regions [ARM (E334K, A419V), ANK(R767H), LRR (R1067Q, R1325Q)], as well as variants predicted to destabilise the ROC:CORB interface [ROC (A1442P, V1447M), CORA (R1628P) CORB (S1761R, L1795F)] and COR:COR dimer interface [CORB (R1728H/L)]. Most activating variants decrease LRRK2 biomarker site phosphorylation (pSer935/pSer955/pSer973), consistent with the notion that the active kinase conformation blocks their phosphorylation. We conclude that the impact of variants on kinase activity is best evaluated by deploying a cellular assay of LRRK2-dependent Rab10 substrate phosphorylation, compared to a biochemical kinase assay, as only a minority of activating variants [CORB (Y1699C, R1728H/L, S1761R) and kinase (G2019S, I2020T, T2031S)], enhance in vitro kinase activity of immunoprecipitated LRRK2. Twelve variants including several that activate LRRK2 and have been linked to PD, suppressed microtubule association in the presence of a Type I kinase inhibitor [ARM(M712V), LRR(R1320S), ROC (A1442P, K1468E, S1508R), CORA(A1589S), CORB (Y1699C, R1728H/L) and WD40(R2143M, S2350I, G2385R)]. Our findings will stimulate work to better understand the mechanisms by which variants impact biology and provide rationale for variant carrier inclusion or exclusion in ongoing and future LRRK2 inhibitor clinical trials.

neuroscience↗

bioRxiv2022

A mitochondrial blood-based patient stratification candidate biomarker for Parkinson's disease

Parkinsons disease (PD) is the most common neurodegenerative movement disorder and neuroprotective interventions remain elusive. High throughput biomarkers aimed to stratify patients based on shared etiology is one critical path to the success of disease-modifying therapies in clinical trials. Mitochondrial dysfunction plays a prominent role in the pathogenesis of PD. Previously, we found brain region-specific mitochondrial DNA (mtDNA) damage accumulation in neuronal and in vivo PD models, as well as human PD postmortem brain tissue. In this study, to investigate mtDNA damage as a potential blood biomarker for PD, we describe a novel Mito DNADX assay that allows for the accurate real-time quantification of mtDNA damage in a 96-well platform, compatible with assessing large cohorts of patient samples. We found that levels of mtDNA damage were increased in blood derived from early-stage idiopathic PD patients or those harboring the pathogenic LRRK2 G2019S mutation compared to age-matched healthy controls. Given that increased mtDNA damage was also found in non-manifesting LRRK2 mutation carriers, mtDNA damage may begin to accumulate prior to a clinical PD diagnosis. LRRK2 kinase inhibition mitigated mtDNA damage in idiopathic PD models and patient-derived cells. The latter observations further substantiate a mechanistic role for wild-type LRRK2 kinase activity in idiopathic PD and support mtDNA damage reversal as a suitable approach to slow PD-related pathology. In light of recent advances in the field of precision medicine, the analysis of mtDNA damage as a blood-based patient stratification biomarker should be included in future clinical trials. One Sentence SummaryBlood test identifies Parkinsons patients most likely to respond to mitochondria-targeted therapeutics facilitating a precision medicine approach.

neuroscience↗

bioRxiv2021

Proteome Profiling of Cerebrospinal Fluid Reveals Novel Biomarker Candidates for Parkinson's Disease

Parkinsons disease (PD) is a growing burden worldwide, and despite ongoing efforts to find reliable biomarkers for early and differential diagnosis, prognosis and disease monitoring, there is no biofluid biomarker used in clinical routine to date. Cerebrospinal fluid (CSF) is collected often and should closely reflect structural and functional alterations in PD patients brains. Here we describe a scalable and sensitive mass spectrometry (MS)-based proteomics workflow for CSF proteome profiling to find specific biomarkers and identify disease-related changes in CSF protein levels in PD. From two independent cohorts consisting of more than 200 individuals, our workflow reproducibly quantified over 1,700 proteins from minimal sample amounts. Combined with machine learning, this identified a group of several proteins, including OMD, CD44, VGF, PRL, and MAN2B1 that were altered in PD patients or significantly correlate with clinical scores, indicative of disease progression. Interestingly, we uncovered signatures of enhanced neuroinflammation in patients with familial PD (LRRK2 G2019S carriers) as indicated by increased levels of CTSS, PLD4, HLA-DRA, HLA-DRB1, and HLA-DPA1. A comparison with urinary proteome changes in PD patients revealed a large overlap in protein composition PD-associated changes in these body fluids, including lysosomal factors like CTSS. Our results validate MS-based proteomics of CSF as a valuable strategy for biomarker discovery and patient stratification in a neurodegenerative disease like PD. Consistent proteomic signatures across two independent CSF cohorts and previously acquired urinary proteome profiles open up new avenues to improve our understanding of PD pathogenesis.

systems biology↗

bioRxiv2020

Urinary proteome profiling for stratifying patients with familial Parkinsons disease

The prevalence of Parkinsons disease (PD) is increasing but the development of novel treatment strategies and therapeutics altering the course of the disease would benefit from specific, sensitive and non-invasive biomarkers to detect PD early. Here, we describe a scalable and sensitive mass spectrometry (MS)-based proteomic workflow for urinary proteome profiling. Our workflow enabled the reproducible quantification of more than 2,000 proteins in more than 200 urine samples using minimal volumes from two independent patient cohorts. The urinary proteome was significantly different between PD patients and healthy controls, as well as between LRRK2 G2019S carriers and non-carriers in both cohorts. Interestingly, our data revealed lysosomal dysregulation in individuals with the LRRK2 G2019S mutation. When combined with machine learning, the urinary proteome data alone was sufficient to classify mutation status and disease manifestation in mutation carriers remarkably well, identifying VGF, ENPEP and other PD-associated proteins as the most discriminating features. Taken together, our results validate urinary proteomics as a valuable strategy for biomarker discovery and patient stratification in PD.

systems biology↗

bioRxiv2019

An assessment of LRRK2 serine 935 phosphorylation in human peripheral blood mononuclear cells in idiopathic Parkinson’s disease and G2019S LRRK2 cohorts

The phosphorylated form of LRRK2, pS935 LRRK2, has been proposed as a target modulation biomarker for LRRK2 inhibitors. To qualify the biomarker for therapeutic trials, we assessed pS935 LRRK2 levels in Peripheral Blood Mononuclear Cells (PBMCs). Analyses of PBMCs from healthy controls, idiopathic Parkinsons disease (iPD), and G2019S carriers with and without PD showed significant reductions in pS935 LRRK2 levels normalized to total LRRK2 levels in G2019S carriers with PD compared to those without PD or iPD. Neither analyte correlated with age, gender, or disease severity. Thus, pS935 LRRK2 in PBMCs may reflect a state marker for G2019S LRRK2-driven PD.

neuroscience↗

bioRxiv2019

KCND3 is a novel susceptibility locus for early repolarization

The presence of an early repolarization pattern (ERP) on the surface electrocardiogram (ECG) is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait but molecular genetic determinants are unknown. We assessed the ERP in 12-lead ECGs of 39,456 individuals and conducted a two-stage meta-analysis of genome-wide association studies (GWAS). In the discovery phase, we included 2,181 cases and 23,641 controls from eight European ancestry studies and identified 19 genome-wide significant (p<5E-8) variants in the KCND3 (potassium voltage gated channel subfamily D member 3) gene with a p-value of 4.6E-10. Replication of two loci in four additional studies including 1,124 cases and 12,510 controls confirmed the association at the KCND3 gene locus with a pooled odds ratio of 0.82, p=7.7E-12 (rs1545300 minor allele T). A subsequent GWAS meta-analysis combining all samples did not reveal additional loci. The lead SNP of the discovery stage (rs12090194) was in strong linkage disequilibrium with rs1545300 (r2=0.96, D=1). Summary statistics based conditional analysis did not reveal any secondary signals. Co-localization analyses indicate causal effects of KCND3 gene expression levels on ERP in both the left ventricle of the heart and in tibial artery.\n\nIn this study we identified for the first time a genome-wide significant association of a genetic variant with ERP. Our findings of a locus in the KCND3 gene not only provide insights into the genetic determinants but also into the pathophysiological mechanism of ERP, revealing a promising candidate for functional studies.

genetics↗

bioRxiv2019

Genetic comorbidity between major depression and cardio-metabolic disease, stratified by age at onset of major depression.

IntroductionIts imperative to understand the specific and shared aetiologies of major depression and cardio-metabolic disease, as both traits are frequently comorbid and each represents a major burden to society. This study examined whether there is a genetic association between major depression and cardio-metabolic traits and if this association is stratified by age at onset for major depression.\n\nMethodsPolygenic risk scores analysis and linkage disequilibrium score regression was performed to examine whether differences in shared genetic aetiology exist between depression case control status (N cases = 40,940, N controls = 67,532), earlier (N = 15,844), and later onset depression (N = 15,800) with body mass index, coronary artery disease, stroke, and type 2 diabetes in eleven data sets from the Psychiatric Genomics Consortium, Generation Scotland, and UK Biobank.\n\nResultsAll cardio-metabolic polygenic risk scores were associated with depression status. Significant genetic correlations were found between depression and body mass index, coronary artery disease, and type 2 diabetes. Higher polygenic risk for body mass index, coronary artery disease and type 2 diabetes was associated with both early and later onset depression, while higher polygenic risk for stroke was associated with later onset depression only. Significant genetic correlations were found between body mass index and later onset depression, and between coronary artery disease and both early and late onset depression.\n\nConclusionsThe phenotypic associations between major depression and cardio-metabolic traits may partly reflect their overlapping genetic aetiology irrespective of the age depression first presents.

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↗