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Chauhan, G.

Publications and source records attributed to Chauhan, G..

18 recordsLinked to original sources
bioRxiv2026

Phase Separation of Intracellular Proteins Influences Synaptic Bistability

Synaptic bistability at the post synaptic density has been proposed to be the result of the nucleation and evaporation of receptor clusters. The exact biophysical mechanism underlying these inter-receptor attractions that can trigger nucleation remains to be elucidated. Emerging evidence demonstrates that numerous postsynaptic density submembrane proteins, that interact with various membrane receptors, can undergo phase separation, necessitating a revised conceptual model. By employing Langevin dynamics simulations of coarse-grained scaffold proteins and interacting membrane receptors, we study how phase transitions of scaffold proteins alter receptor clustering at the membrane. In our model, scaffold macromolecules can undergo phase separation and interact with receptor molecules at the model membranes. We observed that the presence of scaffold polymers across the membrane creates an attractive interaction between otherwise purely repulsive receptors. By systematically varying the number of receptors at the membrane, we dissected the coupling between receptor clustering and the phase behavior of scaffold macromolecules. We show that the propensity for receptor clustering is enhanced by the condensation of scaffold proteins. We then used two different scaffolds and systematically varied the interaction between them, to change the spatial organization of two condensed phases w.r.t. one another. Interestingly, we observed that receptor clustering can be reduced by co-phase separation of scaffold macromolecules, indicating the role of competing interactions in receptor clustering. Our work advances understanding of receptor-mediated signaling and phase separation, providing insights into cellular compartmentalization and biochemical regulation at the synapse.

biophysics↗
bioRxiv2026

Building synthetic cell-cell synapses using engineered scaffold protein condensates

Synaptic assemblies that form at cell-cell junctions are often organized by multivalent scaffold proteins with condensate forming properties. An emerging hypothesis is that these scaffolds provide a thresholding mechanism whereby small increases in the density of cell-cell recognition receptors can trigger all-or-none assembly selectively at the correct partner cell interface. We test this hypothesis by engineering synthetic scaffolded synapses. Coarse-grained simulations suggest that properly-tuned scaffold interactions can yield a sharp condensation threshold. Guided by these simulations, we designed modular scaffold proteins consisting of PDZ domains and intrinsically disordered regions (IDRs) of different molecular grammars. Within a specific region of parameter space, controlled by valency, receptor binding affinity and IDR-driven condensation, the synthetic scaffold proteins exhibit switch-like condensation behaviors, where co-condensates of receptor and scaffold selectively form only at interfaces with the proper partner cell. Notably, orthogonal receptor-scaffold pairs enable a single receiver cell to form multiple distinct interfaces, each associated with a different partner cell. We demonstrate that these synthetic synapse assemblies can recruit different client proteins to enhance intercellular signaling, orient cell division, or sculpt complex synaptic morphologies. Our results illustrate how the ultrasensitive condensation properties of modular scaffold proteins can be harnessed to create novel and highly specific cell-cell interfaces.

synthetic biology↗
bioRxiv2026

State-dependent aperiodic EEG dynamics track cortical network reorganization in chronic epilepsy

Aperiodic (1/f-like) EEG activity has rapidly become a popular noninvasive marker of cortical network state, proposed to index excitation-inhibition (E/I) balance and increasingly applied across neurological and psychiatric disorders. However, whether this approach remains reliable in the pathological brain, where disease progressively reorganizes neural networks, alters signal morphology, and drives continuous transitions between cortical states has yet to be systematically established.Using a medication-free genetic model of chronic epilepsy (Lafora disease; Epm2a-- mice), we tracked the aperiodic component of the cortical EEG across resting wakefulness, isoflurane anesthesia, and PTZ-induced seizures of graded severity, asking how a single spectral marker behaves as the brain moves between states. Epileptic mice exhibited systematically steeper aperiodic exponents than controls, an effect that persisted after removal of interictal epileptiform discharges and was replicated using independent time-resolved spectral parameterization. Slopes steepened predictably under GABAergic anesthesia, supporting the interpretation that aperiodic activity captures biologically meaningful state transitions beyond simple contamination by pathological waveforms. Across seizure phases, the aperiodic exponent varied systematically, however, the exponent flattened during ictal activity in step with the dominant discharge morphology, revealing that pathological waveform shape itself is a substantial contributor to seizure-state exponent changes. Together, these findings indicate that aperiodic EEG dynamics reflect a combination of chronic network-state reorganization and waveform-shape-driven spectral distortion, with their relative contributions varying across brain states. These results support spectral parameterization as a sensitive approach for tracking pathological neural activity in chronic epilepsy while delineating its interpretive boundaries in the presence of pathological waveforms.

neuroscience↗
bioRxiv2026

Cdc42 small GTPase is a novel regulator of the fibrogenic activation of human intestinal myofibroblasts

Cell division cycle 42 (Cdc42) is a member of the Rho family of small GTPases, which plays crucial roles in regulating cytoskeletal remodeling, and membrane trafficking. While previous studies implicated Cdc42 in controlling intestinal epithelial homeostasis, the involvement of this small GTPase in the process of intestinal fibrogenesis remains unexplored. Our study was designed to determine whether Cdc42 regulates the fibrogenic activation of intestinal myofibroblasts in vitro. The study was conducted using a CCD-18Co normal human colonic fibroblast cell line, and primary human intestinal myofibroblasts (HIMF) isolated from Crohns disease (CD) patients. CCD-18Co and HIMF cells were stimulated by transforming growth factor-{beta}1 (TGF-{beta}1). Cdc42 was inhibited either genetically, using siRNA-mediated knockdown, or pharmacologically using specific Cdc42 inhibitors, ML141 and CASIN. Genetic and pharmacologic inhibition of Cdc42 markedly reduced TGF-{beta}1 induced expression of the major contractile cytoskeletal proteins, -smooth muscle actin, calponin 1 and L-caldesmon. Furthermore, Cdc42 inhibition significantly attenuated expression of key extracellular matrix (ECM) proteins, fibronectin and collagen I, in activated CCD-18Co cells and HIMF. Interestingly, decreased expression of contractile and ECM proteins in Cdc42-depleted myofibroblasts was not due to downregulation of the TGF-{beta}1 signaling, decreased mRNA transcription or increased lysosomal or proteasomal degradation of these proteins. Such suppressed pro-fibrotic activation of Cdc42-deficient CCD-18Co cells and HIMF involved a selective inhibition of protein translation due to inactivation of the AKT-mammalian target of rapamycin (mTOR) signaling module. These findings highlight Cdc42 as a key regulator of intestinal fibrosis that controls mTOR activation to enhance ECM production and contractile actomyosin cytoskeleton in intestinal myofibroblasts. In briefZafar et al. unravel a novel role of Cdc42 small GTPase in fibrogenic activation of human intestinal myofibroblasts. Genetic and pharmacologic inhibition of Cdc42 markedly reduced TGF-{beta} induced expression of contractile cytoskeletal proteins and extracellular matrix proteins in activated myofibroblasts. The mechanisms underlying such profibrotic activity of Cdc42 involve regulation of de novo protein translation via activation of the AKT-mTOR signaling module. HighlightsO_LICdc42 regulates TGF-{beta} dependent activation of human intestinal myofibroblasts C_LIO_LIProfibrotic activity of Cdc42 involves regulation of de novo protein translation C_LIO_LICdc42 regulates myofibroblast activation via AKT-mTOR signaling pathway C_LIO_LITargeting Cdc42-Akt-mTOR signaling may facilitate the development of novel antifibrotic therapies C_LI

cell biology↗
bioRxiv2026

Trait anxiety drives premature disengagement despite intact opportunity-cost sensitivity

Anxiety has been linked to difficulty sustaining engagement with ongoing tasks, even when continued engagement would yield greater rewards, yet the underlying mechanisms remain unclear. Here we examined how trait anxiety shapes sequential foraging decisions using a patch-leaving task grounded in the Marginal Value Theorem (MVT), a normative framework for explore-exploit decisions previously used to reveal altered computations in conditions such as problem gambling and attention-deficit hyperactivity disorder. Across two independent cohorts, participants adjusted patch residence times according to environmental opportunity costs, indicating preserved sensitivity to task structure irrespective of anxiety levels. Despite this, individuals with higher trait anxiety consistently left patches earlier and accrued fewer rewards. Drift diffusion modeling revealed that these deviations arose from reduced reward-driven evidence accumulation, rather than impaired environmental sensitivity or altered learning: trait anxiety reliably reduced the drift rate governing continued exploitation, providing a computational account of premature disengagement. This effect remained robust after accounting for pupil-linked arousal and baseline stress biomarkers, including salivary -amylase and cortisol, which independently constrained decision dynamics. Together, these findings identify reduced reward-evidence accumulation as a core mechanism through which anxiety promotes premature disengagement from rewarding environments.

neuroscience↗
bioRxiv2026

Spontaneous Phase Separation Enables Rapid, Polymerization-Free Fabrication of Dissolvable Hydrogels

Hydrogels are cross-linked polymeric networks with wide applications in drug delivery, tissue engineering, biosensing, and environmental remediation. These hydrogels additionally host living cells, small molecules and biological propagules, which further expand the applications of these materials. However, most if not all fabrication methods require covalent modifications. In this work, for the first time, we demonstrate that polymer mixtures can access an additional material state beyond the conventionally described homogeneous and two-phase regimes. By deliberately selecting polymers with a known propensity to phase separate and formulating compositions far from the binodal boundary, the system transitions directly into a mechanically stable hydrogel. We demonstrate this technique using a model system of poly (ethylene glycol) (PEG) and dextran (DEX). We have systematically characterized the hydrogels through FTIR, MALDI-TOF to discern the molecular compositions of the hydrogels. We also modulate the optical transparency of these hydrogels by varying the molecular weight of the polymers. These experimental findings are supplemented with coarse grained (CG) simulation insights to investigate the mechanistic origins of phase separation propensity with varying molecular weights of dextran. We utilized coexisting densities in the two phases using CG simulations to predict the role of dextran molecular weight on the partitioning of PEG and DEX in the two phases. Finally, we exploit the fabricated hydrogels ability to encapsulate live cells, antibiotics and plant seeds. We anticipate that this ATPS-based fabrication technique will provides a scalable, crosslinker-free route to multifunctional hydrogels enabling advanced applications in drug delivery and responsive materials.

bioengineering↗
bioRxiv2025

Distinguishing near- versus off-critical phase behaviors of intrinsically disordered proteins

Intrinsically disordered prion-like low complexity domains (PLCDs) drive phase transitions that underlie the biogenesis of different biomolecular condensates. The mapping of critical points is essential for generating quantitative assessments of driving forces and for distinguishing phase behaviors in the critical versus off-critical regimes. Computations play an important role in connecting the molecular-scale interactions to mesoscale phase behaviors of PLCDs and other intrinsically disordered proteins. We report results from accurate mapping of the critical regime for an archetypal PLCD. This is achieved by combining large-scale simulations with computations of Binder cumulants and the use of rigorous finite-size scaling approaches. The computed binodal, defined by knowledge of the critical point and intersection of the left arm of the binodal by the overlap and percolation lines, can be demarcated into three distinct regimes. Regime I is farthest from the critical point, with the coexisting dilute phase being akin to a gas of dispersed polymers. Regime II lies above the intersection of the overlap line and the dilute arm of the binodal. Here, coexisting dilute phases are characterized by heterogeneous cluster-size distributions with heavy tails. In Regimes I and II, dense phases are confined percolated networks. Regime III is closest to the critical point. Here, the dense phase becomes unconfined and the percolated network swells to become system-spanning. Thus, Regime III comprises two interconnected, system-spanning networks. In addition to accurately mapping the critical point, we also evaluated methods for identifying the theta temperature. We find that conventional scaling approaches lead to erroneously low estimates of the theta temperature. Instead, accurate estimation of the theta temperature requires direct calculation of the temperature dependence of the two-body interaction coefficient. We discuss the broader implications of these findings for inferring solvent quality from scaling analyses.

biophysics↗
bioRxiv2025

Crowding-induced collapse and adsorption of polymers with nonuniform bending stiffness

Macromolecular crowding can significantly impact the behavior of biopolymers, with crowding-induced depletion interactions influencing both the conformations and surface adsorption of individual polymers. Although previous studies have explored the influence of homogeneous polymer stiffness in crowded conditions, biomolecules such as DNA can exhibit sequence-dependent stiffness, and DNA origami nanoparticles can be designed with alternating stiff and flexible domains. In this work, we use Langevin dynamics simulations to characterize how nonuniform bending stiffness modulates the conformations and adsorption of polymers in crowded environments. By systematically varying the relative length and arrangement of flexible and semiflexible domains along a linear chain, we show that increasing osmotic pressure leads to a pattern-dependent collapse of the polymer, as revealed by a decrease in the radius of gyration. In general, large flexible regions promote polymer collapse, although flexible domains separating extended semi-flexible regions can facilitate their contact, leading to stable folded conformations. When a surface is present, large semiflexible domains promote adsorption, and the pattern of stiffness can be used to control the adsorption threshold. Our findings provide insight into the impact of spatially varying stiffness on the behavior of polymers in crowded environments, highlighting mechanisms relevant to biopolymers and deformable nanoparticles in both cellular and cell-free contexts.

biophysics↗
bioRxiv2023

Polyimide-Based Flexible Multi-Electrode Arrays: Synthesis, Microfabrication, and in-vivo Validation

Neurological disorders such as epilepsy, Parkinsons disease, are rising globally, with conditions like drug-resistant epilepsy affecting millions of patients for whom traditional pharmacological treatments are ineffective. Implantable neural devices have shown great promise in managing these conditions, but their accessibility is limited due to high costs and the availability of suitable biocompatible materials.Thin film implantable neural interfaces hold immense promise over conventional clinical electrodes, offering higher resolution, flexibility, and improved integration with neural tissue. However, their widespread use, especially for flexible interfaces, is limited by the lack of customizable and medical grade materials. We report a novel synthesis method for ISO 10993-11 compliant polyamic acid that enables the fabrication of biocompatible polyimide films tailored for neural implants. Using this material, we developed 4 and 32 channel depth and surface electrodes, including custom whole brain ECoG arrays. These were implanted in the laforin knockout mice, a validated model of drug-resistant epilepsy, to monitor spontaneous seizures. Both acute and 12 day recordings demonstrated mechanical flexibility, long term stability, and excellent biocompatibility. This study presents a clinically safe material platform and a complete fabrication pathway for building thin film neural interfaces, paving the way for broader clinical use in applications such as epilepsy monitoring and stereo EEG.

bioengineering↗
bioRxiv2023

Glutamate helps unmask the differences in driving forces for phase separation versus clustering of FET family proteins in sub-saturated solutions

Multivalent proteins undergo coupled segregative and associative phase transitions. Phase separation, a segregative transition, is driven by macromolecular solubility, and this leads to coexisting phases above system-specific saturation concentrations. Percolation is a continuous transition that is driven by multivalent associations among cohesive motifs. Contributions from percolation are highlighted by the formation of heterogeneous distributions of clusters in sub-saturated solutions, as was recently reported for Fused in sarcoma (FUS) and FET family proteins. Here, we show that clustering and phase separation are defined by a separation of length- and energy-scales. This is unmasked when glutamate is the primary solution anion. Glutamate is preferentially excluded from protein sites, and this enhances molecular associations. Differences between glutamate and chloride are manifest at ultra-low protein concentrations. These differences are amplified as concentrations increase, and they saturate as the micron-scale is approached. Therefore, condensate formation in supersaturated solutions and clustering in sub-saturated are governed by distinct energy and length scales. Glutamate, unlike chloride, is the dominant intracellular anion, and the separation of scales, which is masked in chloride, is unmasked in glutamate. Our work highlights how components of cellular milieus and sequence-encoded interactions contribute to amplifying distinct contributions from associative versus segregative phase transitions.

biophysics↗
bioRxiv2023

Crowder titrations enable the quantification of driving forces for macromolecular phase separation

Macromolecular solubility is an important contributor to the driving forces for phase separation. Formally, the driving forces in a binary mixture comprising a macromolecule dissolved in a solvent can be quantified in terms of the saturation concentration, which is the threshold macromolecular concentration above which the mixture separates into coexisting dense and dilute phases. Additionally, the second virial coefficient, which measures the effective strength of solvent-mediated intermolecular interactions provides direct assessments of solvent quality. The sign and magnitude of second virial coefficients will be governed by a combination of solution conditions and the nature of the macromolecule of interest. Here, we show, using a combination of theory, simulation, and in vitro experiments, that titrations of crowders, providing they are true depletants, can be used to extract the intrinsic driving forces for macromolecular phase separation. This refers to saturation concentrations in the absence of crowders and the second virial coefficients that quantify the magnitude of the incompatibility between macromolecules and the solvent. Our results show how the depletion-mediated attractions afforded by crowders can be leveraged to obtain comparative assessments of macromolecule-specific, intrinsic driving forces for phase separation. SIGNIFICANCEPhase separation has emerged as a process of significant relevance to sorting macromolecules into distinct compartments, thereby enabling spatial and temporal control over cellular matter. Considerable effort is being invested into uncovering the driving forces that enable the separation of macromolecular solutions into coexisting phases. At its heart, this process is governed by the balance of macromolecule-solvent, inter-macromolecule, and solvent-solvent interactions. We show that the driving forces for phase separation, including the coefficients that measure interaction strengths between macromolecules, can be extracted by titrating the concentrations of crowders that enable macromolecules to phase separate at lower concentrations. Our work paves the way to leverage specific categories of measurements for quantitative characterizations of driving forces for phase separation.

biophysics↗
bioRxiv2021

An Issue of Concern: Unique Truncated ORF8 Protein Variants of SARS-CoV-2

Open reading frame 8 (ORF8) protein is one of the most evolving accessory proteins in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19). It was previously reported that the ORF8 protein inhibits presentation of viral antigens by the major histocompatibility complex class I (MHC-I) and interacts with host factors involved in pulmonary inflammation. The ORF8 protein assists SARS-CoV-2 to evade immunity and replication. Among many contributing mutations, Q27STOP, a mutation in the ORF8 protein defines the B.1.1.7 lineage of SARS-CoV-2, which is engendering the second wave of COVID-19. In the present study, 47 unique truncated ORF8 proteins (T-ORF8) due to the Q27STOP mutations were identified among 49055 available B.1.1.7 SARS-CoV-2 sequences. The results show that only one of the 47 T-ORF8 variants spread to over 57 geo-locations in North America, and other continents which includes Africa, Asia, Europe and South America. Based on various quantitative features such as amino acid homology, polar/non-polar sequence homology, Shannon entropy conservation, and other physicochemical properties of all specific 47 T-ORF8 protein variants, a collection of nine possible T-ORF8 unique variants were defined. The question of whether T-ORF8 variants work similarly to ORF8 has yet to be investigated. A positive response to the question could exacerbate future COVID-19 waves, necessitating severe containment measures.

bioinformatics↗
bioRxiv2021

Adsorption of semiflexible polymers in crowded environments

Macromolecular crowding is a feature of cellular and cell-free systems that, through depletion effects, can impact the interactions of semiflexible biopolymers with surfaces. In this work, we use computer simulations to study crowding-induced adsorption of semiflexible polymers on otherwise repulsive surfaces. Crowding particles are modeled explicitly, and we investigate the interplay between the bending stiffness of the polymer and the volume fraction and size of crowding particles. Adsorption is promoted by stiffer polymers, smaller crowding particles, and larger volume fractions of crowders. We characterize transitions from non-adsorbed to partially and strongly adsorbed states as a function of the bending stiffness. The crowding-induced transitions occur at smaller values of the bending stiffness as the volume fraction of crowders increases. Concomitant effects on the size and shape of the polymer are reflected by crowding- and stiffness-dependent changes to the radius of gyration. We also demonstrate that curvature of the confining surface can induce desorption when the bending stiffness is sufficiently large. The results of our simulations shed light on the interplay of crowding and bending stiffness on the spatial organization of biopolymers in encapsulated cellular and cell-free systems.

biophysics↗
bioRxiv2020

Variability of Accessory Proteins Rules the SARS-CoV-2 Pathogenicity

The coronavirus disease 2019 (COVID-19) is caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) which is pandemic with an estimated fatality rate less than 1% is ongoing. SARS-CoV-2 accessory proteins ORF3a, ORF6, ORF7a, ORF7b, ORF8, and ORF10 with putative functions to manipulate host immune mechanisms such as interferons, immune signaling receptor NLRP3 (NOD-, LRR-, and pyrin domain-containing 3) inflammasome, inflammatory cytokines such as interleukin 1{beta} (IL-1{beta}) are critical in COVID-19 pathology. Outspread variations of each of the six accessory proteins of all complete proteomes (available as of October 26, 2020, in the National Center for Biotechnology Information depository) of SARS-CoV-2, were observed across six continents. Across all continents, the decreasing order of percentage of unique variations in the accessory proteins was found to be ORF3a>ORF8>ORF7a>ORF6>ORF10>ORF7b. The highest and lowest unique variations of ORF3a were observed in South America and Oceania, respectively. This finding suggests that the wide variations of accessory proteins seem to govern the pathogenicity of SARS-CoV-2, and consequently, certain propositions and recommendations can be made in the public interest.

bioinformatics↗
bioRxiv2020

Possible transmission flow of SARS-CoV-2 based on ACE2 features

Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) that is engendering the severe coronavirus disease 2019 (COVID-19) pandemic. The spike (S) protein receptor-binding domain (RBD) of SARS-CoV-2 binds to the three sub-domains viz. amino acids (aa) 22-42, aa 79-84, and aa 330-393 of ACE2 on human cells to initiate entry. It was reported earlier that the receptor utilization capacity of ACE2 proteins from different species, such as cats, chimpanzees, dogs, and cattle, are different. A comprehensive analysis of ACE2 receptors of nineteen species was carried out in this study, and the findings propose a possible SARS-CoV-2 transmission flow across these nineteen species.

bioinformatics↗
bioRxiv2018

Synergistic interactions between confinement and macromolecular crowding spatially order transcription and translation in cell-free expression

Synergistic interactions between macromolecular crowding and confinement spatially organize transcription and translation in cells. Yet, reproducing such spatial ordering in cell-free expression platforms has proven to be elusive. Here we report crowding- and confinement-driven spatial self-organization of cell-free expression that mimics expression behavior within and around the nucleoid of prokaryotes. These experiments use Ficoll-70 to approximate cellular macromolecular crowding conditions within cell-size lipid vesicles. Intriguingly, there was an abrupt change in transcriptional dynamics when crowding reached physiologically relevant levels. Imaging experiments revealed that this change in transcriptional dynamics was coincident with localization of plasmid DNA and mRNA at the vesicle wall. Computer simulations demonstrated that crowding leads to an entropically induced attraction between plasmid DNA and the wall, causing localization of DNA near the wall at sufficiently high crowding levels. The experiments demonstrate cell-like spatial organization of translation, where translational activity is controlled by chromosomally-templated positioning of mRNA. This cell-free system provides a flexible experimental platform to probe the underlying mechanisms of self-organization of membrane-less structures in cells and the spatial control of gene expression.

synthetic biology↗
bioRxiv2018

Self-organization controls expression more than abundance of molecular components of transcription and translation in confined cell-free gene expression

Cell-free gene expression using purified components or cell extracts has become an important platform for synthetic biology that is finding a growing numBer of practical applications. Unfortunately, at cell-relevant reactor volumes, cell-free expression suffers from excessive variability (noise) such that protein concentrations may vary by more than an order of magnitude across a population of identically constructed reaction chambers. Consensus opinion holds that variability in expression is due to the stochastic distribution of expression resources (DNA, RNAP, ribosomes, etc.) across the population of reaction chambers. In contrast, here we find that chamber-to-chamber variation in the expression efficiency generates the large variability in protein production. Through analysis and modeling, we show that chambers self-organize into expression centers that control expression efficiency. Chambers that organize into many centers, each having relatively few expression resources, exhibit high expression efficiency. Conversely, chambers that organize into just a few centers where each center has an abundance of resources, exhibit low expression efficiency. A particularly surprising finding is that diluting expression resources reduces the chamber-to-chamber variation in protein production. Chambers with dilute pools of expression resources exhibit higher expression efficiency and lower expression noise than those with more concentrated expression resources. In addition to demonstrating the means to tune expression noise, these results demonstrate that in cell-free systems, self-organization may exert even more influence over expression than the abundance of the molecular components of transcription and translation. These observations in cell-free platform may elucidate how self-organized, membrane-less structures emerge and function in cells.

biophysics↗
bioRxiv2017

Genetic Architecture of Subcortical Brain Structures in Over 40,000 Individuals Worldwide

Subcortical brain structures are integral to motion, consciousness, emotions, and learning. We identified common genetic variation related to the volumes of nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen, and thalamus, using genome-wide association analyses in over 40,000 individuals from CHARGE, ENIGMA and the UK-Biobank. We show that variability in subcortical volumes is heritable, and identify 25 significantly associated loci (20 novel). Annotation of these loci utilizing gene expression, methylation, and neuropathological data identified 62 candidate genes implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

genetics↗