Biology subjects

Mehta, D.

Publications and source records attributed to Mehta, D..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Matrimeres are systemic nanoscale mediators of tissue integrity and function

Tissue barriers must be rapidly restored after injury to promote regeneration. However, the mechanism behind this process is unclear, particularly in cases where the underlying extracellular matrix is still compromised. Here, we report the discovery of matrimeres as constitutive nanoscale mediators of tissue integrity and function. We define matrimeres as non-vesicular nanoparticles secreted by cells, distinguished by a primary composition comprising at least one matrix protein and DNA molecules serving as scaffolds. Mesenchymal stromal cells assemble matrimeres from fibronectin and DNA within acidic intracellular compartments. Drawing inspiration from this biological process, we have achieved the successful reconstitution of matrimeres without cells. This was accomplished by using purified matrix proteins, including fibronectin and vitronectin, and DNA molecules under optimal acidic pH conditions, guided by the heparin-binding domain and phosphate backbone, respectively. Plasma fibronectin matrimeres circulate in the blood at homeostasis but exhibit a 10-fold decrease during systemic inflammatory injury in vivo. Exogenous matrimeres rapidly restore vascular integrity by actively reannealing endothelial cells post-injury and remain persistent in the host tissue matrix. The scalable production of matrimeres holds promise as a biologically inspired platform for regenerative nanomedicine.

bioengineering↗

bioRxiv2023

RGS2 is an innate immune checkpoint for TLR4 and Gαq-mediated IFNγ generation and lung injury

IFN{gamma}, a type II interferon secreted by immune cells, augments tissue responses to injury following pathogenic infections leading to lethal acute lung injury (ALI). Alveolar macrophages (AM) abundantly express Toll-like receptor-4 and represent the primary cell type of the innate immune system in the lungs. A fundamental question remains whether AM generation of IFNg leads to uncontrolled innate response and perpetuated lung injury. LPS induced a sustained increase in IFNg levels and unresolvable inflammatory lung injury in the mice lacking RGS2 but not in RGS2 null chimeric mice receiving WT bone marrow or receiving the RGS2 gene in AM. Thus, indicating RGS2 serves as a gatekeeper of IFNg levels in AM and thereby lungs innate immune response. RGS2 functioned by forming a complex with TLR4 shielding Gaq from inducing IFNg generation and AM inflammatory signaling. Thus, inhibition of Gaq blocked IFNg generation and subverted AM transcriptome from being inflammatory to reparative type in RGS2 null mice, resolving lung injury. HighlightsO_LIRGS2 levels are inversely correlated with IFN{gamma} in ARDS patients AM. C_LIO_LIRGS2 in alveolar macrophages regulate the inflammatory lung injury. C_LIO_LIDuring pathogenic insult RGS2 functioned by forming a complex with TLR4 shielding Gq from inducing IFN{gamma} generation and AM inflammatory signaling. C_LI eToc BlurbAuthors demonstrate an essential role of RGS2 in macrophages in airspace to promoting anti-inflammatory function of alveolar macrophages in lung injury. The authors provided new insight into the dynamic control of innate immune response by Gq and RGS2 axis to prevent ALI.

immunology↗

bioRxiv2023

Identifying molecular targets of a colloidal nanosilver formulation (Silversol) in multidrug resistant Pseudomonas aeruginosa

P. aeruginosa is a notorious pathogen. A multi-drug resistant strain of this bacterium was challenged with a colloidal nano-silver formulation- Silversol(R). Its minimum inhibitory concentration against P. aeruginosa was found to be 1.5 ppm, and at sub-MIC of 1 ppm, it was able to alter quorum-sensing regulated pigmentation, exopolysaccharide synthesis and biofilm formation, antibiotic susceptibility, protein synthesis and export, nitrogen metabolism, and siderophore production in this pathogen. Transcriptome analysis of the silver-exposed P. aeruginosa indicated generation of nitrosative stress and disturbance of iron homeostasis to be the major mechanisms associated with anti-Pseudomonas activity of Silversol(R). Network analysis of the differentially expressed genes in silver-treated bacterium identified ten genes as the potential molecular targets: norB, norD, nirS, nirF, nirM, nirQ, nosZ, nosY, narK1, and norE (all associated with nitrogen metabolism or denitrification). Three of them (norB, narK1, and norE) were also validated through RT-PCR.

microbiology↗

bioRxiv2023

Twilight length alters growth, flowering time, and clock function in Arabidopsis via LHY/CCA1

The plant circadian clock governs growth and development by syncing biological processes to periodic environmental changes. Decades of research has shown how the clock enables plants to respond to two environmental variables that change at different latitudes and over different seasons: photoperiod and temperature. However, a third variable, twilight length, has so far gone unstudied. The duration of twilight changes across the planet, lengthening with latitude and changing across seasons, and yet most circadian experiments are performed in lab environments with no twilight. Here, using controlled growth setups, we show that twilight length impacts plant growth and changes flowering time via the LHY/CCA1 morning module of the Arabidopsis circadian clock. Using a series of progressively truncated no-twilight photoperiods, we also found that plants are more sensitive to twilight length compared to equivalent changes in solely photoperiod. Further, transcriptome and proteome analyses indicated that twilight length alters the regulation of proteins involved in reactive oxygen species metabolism, photosynthesis, and carbon metabolism. Genetic analyses also implicated a twilight sensing pathway from phytochromes D and E, the morning elements of the circadian clock and modulating flowering time through the GI-FT pathway. Overall, our findings call for more nuanced models of daylength perception in plants and posit that twilight length is an important determinant of plant growth, development, and circadian function.

plant biology↗

bioRxiv2023

Tension sensing by FAK governs nuclear mechanotransduction, endothelial transcriptome and fate

Vascular endothelium forms a restrictive barrier to defend the underlying tissue against uncontrolled influx of circulating protein and immune cells. Mechanisms that mediate the transition from restrictive to leaky endothelium, a hallmark of tissue injury exemplified by acute lung injury (ALI), remain elusive. Using endothelial cell (EC)-Fak-/-mice, we show that FAK sensing and transmission of mechanical tension to the EC nucleus governs cell fate. In FAK- deleted EC, increased EC tension induced by Rho kinase caused tyrosine phosphorylation of nuclear envelope protein, emerin at Y74/Y95, and its localization in a nuclear cap. Activated emerin stimulated DNMT3a activity and methylation of the KLF2 promoter, impairing the restrictive EC transcriptome, including S1PR1. Inhibiting emerin phosphorylation or DNMT3a activity enabled KLF2 transcription of S1PR1, rescuing the restrictive EC phenotype in EC-Fak-/- lungs. Thus, FAK sensing of tension transmission to the nucleus is crucial for maintaining a restrictive EC fate and lung homeostasis.

cell biology↗

bioRxiv2022

Integrated Systems-Level Proteomics and Metabolomics Reveals the Diel Molecular Landscape of Diverse Kale Cultivars

Kale are a group of diverse Brassicaceae species that are nutritious leafy greens consumed for their abundance of vitamins and micronutrients. Typified by their curly, serrated and/or wavy leaves, kale varieties have been primarily defined based on their leaf morphology and geographic origin, despite having complex genetic backgrounds. Kale is a very promising crop for vertical farming due to its high nutritional content; however, being a non-model organism, foundational, systems-level analyses of kale are lacking. Previous studies in kale have shown that time-of-day harvesting can affect its nutritional composition. Therefore, to gain a systems-level diel understanding of kale across its wide-ranging and diverse genetic landscape, we selected nine publicly available and commercially grown kale cultivars for growth under near-sunlight LED light conditions ideal for vertical farming. We then analyzed changes in morphology, growth and nutrition using a combination of phenomics, proteomics and metabolomics. As the diel molecular activities of plants drive their daily growth and development, ultimately determining their productivity as a crop, we harvested kale leaf tissue at both end-of-day (ED) and end-of-night (EN) time-points for all molecular analyses. Our results reveal that diel proteome and metabolome signatures divide the selected kale cultivars into two distinct groups, defined by their amino acid and sugar content, along with significant proteome differences involving carbon and nitrogen metabolism, mRNA splicing, protein translation and light harvesting. Together, our multi-cultivar, multi-omic analysis provides robust quantitative insights into the molecular underpinnings of the diel growth and development landscape of kale, significantly advancing our fundamental understanding of this nutritious leafy green super-food for next-generation horticulture / vertical farming applications.

plant biology↗

bioRxiv2021

Multi-omic analysis reveals the biochemical changes underpinning the varied phenotypes of the Arabidopsis long-period mutant rve 4 6 8

Plants are able to sense changes in their light environments, such as the onset of day and night, as well as anticipate these changes in order to adapt and survive. Central to this ability is the plant circadian clock, a molecular circuit that precisely orchestrates plant cell processes over the course of a day. REVEILLE proteins (RVEs) are recently discovered members of the plant circadian circuitry that activate the evening complex and PRR genes to maintain regular circadian oscillation. The RVE 8 protein and its two homologs, RVE 4 and 6, have been shown to limit the length of the circadian period, with rve 4 6 8 triple-knockout plants possessing an elongated period along with increased leaf surface area, biomass, cell size and delayed flowering relative to wild-type Col-0 plants. Here, using a multi-omics approach consisting of phenomics, transcriptomics, proteomics, and metabolomics we draw novel connections between RVE8-like proteins and a number of core plant cell processes. In particular, we reveal that loss of RVE8-like proteins results in altered carbohydrate, organic acid and lipid metabolism, including a starch excess phenotype at dawn. We further demonstrate that rve 4 6 8 plants have lower levels of 20S proteasome subunits and possess significantly reduced proteasome activity, potentially explaining the increase in cell-size observed in RVE8-like mutants. Overall, this robust, multi-omic dataset, provides substantial new insights into the far reaching impact RVE8-like proteins have on the diel plant cell environment.

plant biology↗

bioRxiv2021

Dimerization of SARS-CoV-2 nucleocapsid protein affects sensitivity of ELISA based diagnostics of COVID-19

Diagnostics has played a significant role in effective management of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Nucleocapsid protein (N protein) is the primary antigen of the virus for development of sensitive diagnostic assays. Thus far, limited knowledge exists about the antigenic properties of the N protein. In this paper, we demonstrate the significant impact of dimerization of SARS-CoV-2 nucleocapsid protein on sensitivity of enzyme-linked immunosorbent assay (ELISA) based diagnostics of COVID-19. The expressed purified protein from E.coli consists of two forms, dimeric and monomeric forms, which have been further characterized by biophysical and immunological means. Indirect ELISA indicated elevated susceptibility of the dimeric form of the nucleocapsid protein for identification of protein-specific monoclonal antibody as compared to the monomeric form of the protein. These findings have also been confirmed with the modelled structure of monomeric and dimeric nucleocapsid protein via HHPred software and its solvent accessible surface area, which indicates higher stability and antigenicity of the dimeric type as compared to the monomeric form. It is evident that use of the dimeric form will increase the sensitivity of the current nucleocapsid dependent ELISA for rapid COVID-19 diagnostic. Further, the results indicate that monitoring and maintaining of the monomerdimer composition is critical for accurate and robust diagnostics. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/445305v2_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@16bf153org.highwire.dtl.DTLVardef@1b0be6corg.highwire.dtl.DTLVardef@a5b3aeorg.highwire.dtl.DTLVardef@b784a3_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2021

Computer-Vision Stabilized Intravital Imaging Reveals Lung Capillary Neutrophil Dynamics Crucial for Lung Host-Defense Function

Polymorphonuclear neutrophils (PMN) are highly dynamic innate immune cells which are essential for lung host defense. However, in vivo intravital imaging in moving organs such as the lung remains challenging due to motion artifacts. Here we describe a novel intravital imaging method with high-throughput analytical capability based on a computer vision stabilization algorithm, Computer-vision-Assisted STabilized intravital imaging (CASTii). The sub-micron precision of this approach enables analysis of compartmentalized intravital PMN dynamics. We quantified in real-time a novel patrolling function of lung intracapillary circulating PMN. We also describe the dynamics of intracapillary PMN pooling (marginated PMN pool) using direct imaging of PMNs. The pool was formed by repeated catch-and-release kinetics involving PMN deformation inside microvessels during the passage of PMNs in vessels. We observed rapid PMN recruitment into the lung tissue compartments from pooled PMNs in response to alveolar chemoattract exposure. In contrast, endotoxemia-induced intracapillary sequestration of PMN impaired PMN transmigration into the alveolar space and defective phagocytosis of live bacteria. Intravital imaging of PMN dynamics with CASTii provides fundamental insights into host-defense functions of lung capillary PMN.

microbiology↗

bioRxiv2020

Quantitative proteome and PTMome analysis of Arabidopsis thaliana root responses to persistent osmotic and salinity stress.

Abiotic stresses such as drought result in large annual economic losses around the world. As sessile organisms, plants cannot escape the environmental stresses they encounter, but instead must adapt to survive. Studies investigating plant responses to osmotic and/or salt stress have largely focused on short-term systemic responses, leaving our understanding of intermediate to longer-term adaptation (24 h - days) lacking. In addition to protein abundance and phosphorylation changes, evidence suggests reversible lysine acetylation may also be important for abiotic stress responses. Therefore, to characterize the protein-level effects of osmotic and salt stress, we undertook a label-free proteomic analysis of Arabidopsis thaliana roots exposed to 300 mM Mannitol and 150 mM NaCl for 24 h. We assessed protein phosphorylation, lysine acetylation and changes in protein abundance, detecting significant changes in 245, 35 and 107 total proteins, respectively. Comparison with available transcriptome data indicates that transcriptome- and proteome-level changes occur in parallel, while PTMs do not. Further, we find significant changes in PTMs and protein abundance involve different proteins from the same networks, indicating a multifaceted regulatory approach to prolonged osmotic and salt stress. In particular, we find extensive protein-level changes involving sulphur metabolism under both osmotic and salt conditions as well as changes in protein kinases and transcription factors that may represent new targets for drought stress signaling. Collectively, we find that protein-level changes continue to occur in plant roots 24 h from the onset of osmotic and salt stress and that these changes differ across multiple proteome levels.

plant biology↗

bioRxiv2020

Direct data-independent acquisition (direct DIA) enables substantially improved label-free quantitative proteomics in Arabidopsis

The last decade has seen significant advances in the application of quantitative mass spectrometry-based proteomics technologies to tackle important questions in plant biology. The current standard for quantitative proteomics in plants is the use of data-dependent acquisition (DDA) analysis with or without the use of chemical labels. However, the DDA approach preferentially measures higher abundant proteins, and often requires data imputation due to quantification inconsistency between samples. In this study we systematically benchmarked a recently developed library-free data-independent acquisition (directDIA) method against a state-of-the-art DDA label-free quantitative proteomics workflow for plants. We next developed a novel acquisition approach combining MS1-level BoxCar acquisition with MS2-level directDIA analysis that we call BoxCarDIA. DirectDIA achieves a 33% increase in protein quantification over traditional DDA, and BoxCarDIA a further 8%, without any changes in instrumentation, offline fractionation, or increases in mass-spectrometer acquisition time. BoxCarDIA, especially, offers wholly reproducible quantification of proteins between replicate injections, thereby addressing the long-standing missing-value problem in label-free quantitative proteomics. Further, we find that the gains in dynamic range sampling by directDIA and BoxCarDIA translate to deeper quantification of key, low abundant, functional protein classes (e.g., protein kinases and transcription factors) that are underrepresented in data acquired using DDA. We applied these methods to perform a quantitative proteomic comparison of dark and light grown Arabidopsis cell cultures, providing a critical resource for future plant interactome studies. Our results establish BoxCarDIA as the new method of choice in quantitative proteomics using Orbitrap-type mass-spectrometers, particularly for proteomes with large dynamic range such as that of plants.

plant biology↗

bioRxiv2020

Diversity and prevalence of ANTAR RNAs across actinobacteria

Computational approaches are often used to predict regulatory RNAs in bacteria, but their success is limited to RNAs that are highly conserved across phyla, in sequence and structure. The ANTAR regulatory system consists of a family of RNAs (the ANTAR-target RNAs) that selectively recruit ANTAR proteins. This protein-RNA complex together regulates genes at the level of translation or transcriptional elongation. Despite the widespread distribution of ANTAR proteins in bacteria, their targets RNAs havent been identified in certain bacterial phyla such as actinobacteria. Here, by using a computational search model that is tuned to actinobacterial genomes, we comprehensively identify ANTAR-target RNAs in actinobacteria. These RNA motifs lie in select transcripts, often overlapping with the ribosome binding site or start codon, to regulate translation. Transcripts harboring ANTAR-target RNAs majorly encode proteins involved in the transport and metabolism of cellular metabolites like sugars, amino acids and ions; or encode transcription factors that in turn regulate diverse genes. In this report, we substantially diversify and expand the family of ANTAR RNAs across bacteria.

bioinformatics↗

bioRxiv2020

Phosphate and phosphite differentially impact the proteome and phosphoproteome of Arabidopsis suspension cell cultures

Phosphorus absorbed in the form of phosphate (H2PO4-) is an essential but limiting macronutrient for plant growth and agricultural productivity. A comprehensive understanding of how plants respond to phosphate starvation is essential to develop more phosphate-efficient crops. Here we employed label-free proteomics and phosphoproteomics to quantify protein-level responses to 48 h of phosphate versus phosphite (H2PO3-) resupply to phosphate-deprived Arabidopsis thaliana suspension cells. Phosphite is similarly sensed, taken up, and transported by plant cells as phosphate, but cannot be metabolized or used as a nutrient. Phosphite is thus a useful tool to delineate between non-specific processes related to phosphate sensing and transport, and specific responses to phosphorus nutrition. We found that responses to phosphate versus phosphite resupply occurred mainly at the level of protein phosphorylation, complemented by limited changes in protein abundance, primarily in protein translation, phosphate transport and scavenging, and central metabolism proteins. Altered phosphorylation of proteins involved in core processes such as translation, RNA splicing, and kinase signalling were especially important. We also found differential phosphorylation in response to phosphate and phosphite in 69 proteins, including splicing factors, translation factors, the PHT1;4 phosphate transporter and the HAT1 histone acetyltransferase--potential phospho-switches signalling changes in phosphorus nutrition. Our study illuminates several new aspects of the phosphate-starvation response and identifies important targets for further investigation and potential crop improvement.

plant biology↗

bioRxiv2020

Explosive sensing with insect-based biorobots

Stand-off chemical sensing is an important capability with applications in several domains including homeland security. Engineered devices for this task, popularly referred to as electronic noses, have limited capacity compared to the broad-spectrum abilities of the biological olfactory system. Therefore, we propose a hybrid bio-electronic solution that directly takes advantage of the rich repertoire of olfactory sensors and sophisticated neural computational framework available in an insect olfactory system. We show that select subsets of neurons in the locust (Schistocerca americana) brain were activated upon exposure to various explosive chemical species (such as DNT and TNT). Responses from an ensemble of neurons provided a unique, multivariate fingerprint that allowed discrimination of explosive vapors from non-explosive chemical species and from each other. Notably, target chemical recognition could be achieved within a few hundred milliseconds of exposure. Finally, we developed a minimally-invasive surgical approach and mobile multi-unit electrophysiological recording system to tap into the neural signals in a locust brain and realize a biorobotic explosive sensing system. In sum, our study provides the first demonstration of how biological olfactory systems (sensors and computations) can be hijacked to develop a cyborg chemical sensing approach. SUMMARYWe demonstrate a bio-robotic chemical sensing approach where signals from an insect brain are directly utilized to detect and distinguish various explosive chemical vapors.

bioengineering↗

bioRxiv2019

Cooperation only for high rewards - a solvable task-based study on free-ranging dogs

The benefits of group living mostly surpass the disadvantages like sharing of resources and competition over food, space and mates, driving the evolution of social organization. Group living can be facilitated by social tolerance and cooperation among the group members. Social canids (e.g. wolves) display cooperative breeding, hunting, and prosocial activities in different contexts. Unlike cooperative pack-living wolves (Canis lupus lupus), their descendants, domesticated dogs (Canis lupus familiaris), show varying levels of associations from solitary to stable social groups. Free-ranging dogs are group-living but prefer to forage solitarily, hence providing an excellent opportunity for investigating social tolerance and coordinated task performance among the members in various situations. We tested 113 adult-only groups of free-ranging dogs in three different tasks to investigate group responses and performance in problem-solving situations in the presence of an unfamiliar human. Task 1 (unfamiliar, single food reward) and 2 (familiar, single food reward) examined group responses and cooperation from the perspective of familiarity, while Task 3 (familiar, multiple food rewards) enabled us to test whether increased food rewards promote social tolerance and food sharing among the group members. Regardless of significantly higher performance in Task 2 compared to Task 1, cooperation and food sharing were significantly lower in both. Task 3 revealed a strong positive correlation between food sharing and social tolerance, but not between success and social tolerance, suggesting a tendency for cooperation. We conclude that context-dependent cooperation and tolerance among group members facilitate group-living in free-ranging dogs.\n\nSignificance statementGroup living is a common phenomenon in the animal world where the members of a group show social tolerance and co-operative behaviours towards each other. This need for cooperative intents increases manifolds while groups face different problem-solving situations in their day to day lives. Here, we tested a large number of free-ranging dog groups to understand general cooperative intents such as social tolerance and food sharing in different problem-solving conditions. We found shreds of evidence of context-dependent cooperation and social tolerance among group members with minimal display of aggression. It is not adaptive for the dogs to fight or display aggression over resources. Alternatively, use of subtle cues such as display of dominance and subordination seem to be more plausible mechanisms for the development of efficient scavenging strategies and maintaining hierarchy.

animal behavior and cognition↗

bioRxiv2019

Non-coding RNAs control metabolic state in mycobacteria

Non-coding RNAs play pivotal roles in bacterial signaling. However, RNAs from certain phyla (specially high-GC actinobacteria) remain elusive. Here, by revamping existing approaches we discover a family of structurally conserved RNAs in actinobacteria. These RNAs function by the recruiting ANTAR proteins to select transcripts; regulating them via translational repression. By overlapping with ORF start sites, these RNAs provide mechanisms by which even leader-less transcripts are regulated. In mycobacteria, transcripts marked by ANTAR-target RNAs are few but encode important redox enzymes especially involved in lipid metabolism. Notably, the cellular response to ANTAR-regulation is hierarchical, wherein immediate metabolic changes induced by ANTAR-RNA binding are amplified through a global transcriptomic response. This includes several genes from oxidative/reductive pathways; ultimately switching cells towards reductive metabolism. This discovery of ANTAR-target RNAs and associated regulation places RNAs as crucial players in controlling metabolic flexibility of mycobacteria, proposing a prominent role for ANTAR regulation across actinobacteria.

biochemistry↗

bioRxiv2019

A Spiking Neuron and Population Model based on the Growth Transform Dynamical System

In neuromorphic engineering, neural populations are generally modeled in a bottom-up manner, where individual neuron models are connected through synapses to form large-scale spiking networks. Alternatively, a top-down approach treats the process of spike generation and neural representation of excitation in the context of minimizing some measure of network energy. However, these approaches usually define the energy functional in terms of some statistical measure of spiking activity (ex. firing rates), which does not allow independent control and optimization of neurodynamical parameters. In this paper, we introduce a new spiking neuron and population model where the dynamical and spiking responses of neurons can be derived directly from a network objective or energy functional of continuous-valued neural variables like the membrane potential. The key advantage of the model is that it allows for independent control over three neuro-dynamical properties: (a) control over the steady-state population dynamics that encodes the minimum of an exact network energy functional; (b) control over the shape of the action potentials generated by individual neurons in the network without affecting the network minimum; and (c) control over spiking statistics and transient population dynamics without affecting the network minimum or the shape of action potentials. At the core of the proposed model are different variants of Growth Transform dynamical systems that produce stable and interpretable population dynamics, irrespective of the network size and the type of neuronal connectivity (inhibitory or excitatory). In this paper, we present several examples where the proposed model has been configured to produce different types of single-neuron dynamics as well as population dynamics. In one such example, the network is shown to adapt such that it encodes the steady-state solution using a reduced number of spikes upon convergence to the optimal solution. In this paper we use this network to construct a spiking associative memory that uses fewer spikes compared to conventional architectures, while maintaining high recall accuracy at high memory loads.

neuroscience↗

bioRxiv2018

Genome-wide association study of suicide attempt in psychiatric disorders identifies association with major depression polygenic risk scores

ObjectiveOver 90% of suicide attempters have a psychiatric diagnosis, however twin and family studies suggest that the genetic etiology of suicide attempt (SA) is partially distinct from that of the psychiatric disorders themselves. Here, we present the largest genome-wide association study (GWAS) on suicide attempt using major depressive disorder (MDD), bipolar disorder (BIP) and schizophrenia (SCZ) cohorts from the Psychiatric Genomics Consortium.\n\nMethodSamples comprise 1622 suicide attempters and 8786 non-attempters with MDD, 3264 attempters and 5500 non-attempters with BIP and 1683 attempters and 2946 non-attempters with SCZ. SA GWAS were performed comparing attempters to non-attempters in each disorder followed by meta-analysis across disorders. Polygenic risk scoring investigated the genetic relationship between SA and the psychiatric disorders.\n\nResultsThree genome-wide significant loci for SA were found: one associated with SA in MDD, one in BIP, and one in the meta-analysis of SA in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. Polygenic risk scores for major depression were significantly associated with SA in MDD (P=0.0002), BIP (P=0.0006) and SCZ (P=0.0006).\n\nConclusionsThis study provides new information on genetic associations and the genetic etiology of SA across psychiatric disorders. The finding that polygenic risk scores for major depression predict suicide attempt across disorders provides a possible starting point for predictive modelling and preventative strategies. Further collaborative efforts to increase sample size hold potential to robustly identify genetic associations and gain biological insights into the etiology of suicide attempt.

genetics↗