Biology subjects

Jones, I.

Publications and source records attributed to Jones, I..

At least 19 recordsLinked to original sources

bioRxiv2026

Dyrk1a gene dosage controls bipolar cell development and retinal connectivity.

Mammalian retina development is governed by a core set of eye-field transcription factors that orchestrate tissue lamination and neuronal connectivity through tightly regulated genetic hierarchies. The LIM homeodomain gene Lhx2 functions as a master eye-field regulator and this study identifies Dyrk1a as a previously unrecognised effector of Lhx2-dependent programs during mouse retinal development. Conditional deletion of Dyrk1a in retinal progenitor cells led to increased apoptosis within the inner retina demonstrating a requirement for Dyrk1a in cell survival and lineage maintenance. Adult heterozygous mice exhibited dorsoventral reductions in bipolar cell number and indicated a gene-dosage-sensitive control of interneuron survival. Bipolar cell loss disrupted their mosaic organisation and resulted in diminished activity across both scotopic and photopic retinal pathways. Dyrk1a haploinsufficient mice also displayed pronounced disruption of inner plexiform layer stratification consistent with defective laminar targeting and synaptic partner integration. This study defines a gene-dosage-dependent mechanism through which transcriptional hierarchies regulate neuronal connectivity and function during mammalian retinal development.

developmental biology↗

bioRxiv2026

Protozoan predation selects for key symbiotic traits in an environmentally transmitted beneficial symbiosis

AbstractBeneficial associations between bobtail squids (Cephalopoda: Sepiolidae) and Vibrio bacteria encompass a unique association where symbionts are obtained environmentally from the surrounding environment. Vibrio symbionts are susceptible to a number of ecological pressures such as protozoan grazing whilst in their free-living state. Impacts of grazing have several consequences for symbiosis characteristics such as biofilm formation, a trait crucial for survival both in and outside the squid. Therefore, in order to ascertain how biotic factors such as grazing in the environment effect symbiotic success, two V. fischeri strains, ES114 and ETBB1-C were experimentally evolved in separate biofilm grazing experiments with the amoeba, Acanthamoeba castellanii and ciliate Tetrahymena pyriformis. Both ES114 and ETBB1-C biofilms were evolved up to 50 generations through serial passaging. At 50 generations, ES114 biofilms displayed variability in response to predation by both predators, whereas ETBB1-C biofilms were more stable across generations of grazing. A. castellanii decreased in population numbers when co-inoculated with ETBB1-C, whereas T. pyriformis increased in numbers with biofilm growth. Growth of V. fischeri biofilms in the presence of grazers such as T. pyriformis has an important role in inducing biofilm growth by acting as a chaperone for recycling nutrients back into the environment. Additionally, V. fischeri colonization fitness in the host was dependent on which grazer was used to evolve the biofilms. Such variation in response by V. fischeri to different types of predation demonstrates the versatility of this symbiont in its free living state and has subsequent impacts on the eventual association with squids. ImportanceThis manuscript demonstrates the importance of biotic factors (such as protozoan grazing) in the environment that effect host colonization in a beneficial symbiosis. Using an experimental evolution approach, this work demonstrates how symbiotic biofilms can adapt to pressures such as grazing that subsequently influences the ability to colonize its invertebrate host.

microbiology↗

bioRxiv2024

Small mammals and their burrows shape the distribution of Coccidioides in soils: a long-term ecological experiment

BackgroundFor nearly all human fungal pathogens, the environmental constraints on their distributions remain poorly understood, hindering disease management. Here, we investigated the role of zoonotic host presence, soil conditions, and their interaction on the presence of Coccidioides immitis - an emerging fungal pathogen and causative agent of coccidioidomycosis. MethodsA long-term experimental study initiated in 2007 in the Carrizo Plain National Monument, California excluded rodents from certain areas (20 by 20-meter exclosures; n = 20) via the installation of submerged mesh fences, leaving emptied burrows intact. We collected 1,988 soil samples over four sampling periods spanning April 2021 to April 2022 using a factorial design that crossed burrows and surface soils (i.e., top 10 cm of soil) with exclosures (i.e., rodent absence) and non-exclosures (i.e., rodent presence). We measured in situ soil moisture, temperature, and vegetation, and analyzed soils for C. immitis DNA. ResultsThe proportion of samples containing C. immitis was significantly higher (p <0.0001) in burrow samples taken from outside rodent exclosures (i.e., rodents present; 28.5% positive) compared to burrow samples taken from within exclosures (i.e., rodents absent; 19.7%), surface soils outside of exclosures (3.6%) and surface soils within exclosures (0.5%). In generalized linear mixed models adjusting for soil conditions, rodent presence, and sample type (burrow vs. surface soil), we estimated that the odds of detecting C. immitis were 19.2 (95% CI: 11.3 - 36.7, p < 0.0001) times higher in soils taken from burrows compared to surface soils, and 2.6 (95% CI: 1.0 - 5.6, p = 0.049) times higher in soils where rodents were present compared to absent. Soil moisture was the only abiotic factor associated with C. immitis detection (odds ratio per 1% increase in water content: 0.83, 95% CI: 0.70 - 0.89, p = 0.0002). In mediation analyses, we estimated that 73.7% (95% CI: 68.9, 78.5) of the total association between rodents and Coccidioides detection effect was attributable to rodent creation of burrows. ConclusionsRodent creation and occupation of burrows substantially increases C. immitis detection. Synergy between reservoir host presence and environmental conditions may exist for other human fungal pathogens.

ecology↗

bioRxiv2023

Combinatorial transcription factor binding encodes cis-regulatory wiring of forebrain GABAergic neurogenesis

Transcription factors (TFs) bind combinatorially to genomic cis-regulatory elements (cREs), orchestrating transcription programs. While studies of chromatin state and chromosomal interactions have revealed dynamic neurodevelopmental cRE landscapes, parallel understanding of the underlying TF binding lags. To elucidate the combinatorial TF-cRE interactions driving mouse basal ganglia development, we integrated ChIP-seq for twelve TFs, H3K4me3-associated enhancer-promoter interactions, chromatin and transcriptional state, and transgenic enhancer assays. We identified TF-cREs modules with distinct chromatin features and enhancer activity that have complementary roles driving GABAergic neurogenesis and suppressing other developmental fates. While the majority of distal cREs were bound by one or two TFs, a small proportion were extensively bound, and these enhancers also exhibited exceptional evolutionary conservation, motif density, and complex chromosomal interactions. Our results provide new insights into how modules of combinatorial TF-cRE interactions activate and repress developmental expression programs and demonstrate the value of TF binding data in modeling gene regulatory wiring.

developmental biology↗

bioRxiv2023

Cell growth dilutes YAP/TAZ influencing its subcellular distribution and phenotypic heterogeneity

The concentration of many transcription factors exhibit high cell-to-cell variability due to differences in synthesis, degradation, and cell size. How these factors are robust to fluctuations in concentration is poorly understood. Here we quantified the single cell levels of the YAP/TAZ transcriptional co-activators in parallel with cell morphology for over 400,000 single cells across 17 cell lines. We show the whole cell concentration of YAP/TAZ sub-scales with respect to size as cells grow during proliferation. However, the mean nuclear concentration of YAP/TAZ remains constant during the cell cycle. Theoretical modelling demonstrates that the extent to which whole cell YAP/TAZ dilutes in single cells during proliferative growth dictates the variability of YAP/TAZ levels across the population. Integrative analysis of imaging and proteomic data show the average nuclear YAP/TAZ concentration is predicted by differences in RAS/MAPK signalling, focal adhesion maturation, and nuclear transport processes. We developed a statistical framework capable of discriminating between perturbations that affect YAP/TAZ directly, or via changes in morphology. Deployment of these models on genetic screening data or small-molecule treatments reveal that inhibition of MEK, CDK4/6, LATS and RhoGTPases decouple nuclear YAP/TAZ from cell morphology by regulating nuclear translocation. Thus signalling activity couples size changes to YAP/TAZ translocation; leading to a stable pool of nuclear YAP/TAZ during proliferation. Significance StatementMany proteins dilute/concentrate with changes in cell size. It is unclear how robustness in cell signalling emerges across differently sized cells, with varying intracellular protein concentrations, over generations. Here, we have shown that despite whole cell dilution of the transcriptional co activators YAP/TAZ with increasing size, a steady-state nuclear concentration distribution is maintained across the population. Thus nuclear transport promotes robustness of signal response in the face of a dwindling cytoplasmic YAP/TAZ levels. An integrative approach revealed that focal adhesions, RAS/MAPK and nuclear import contributes to the the maintenance of YAP/TAZ nuclear levels. Cells appear to have evolved systems to ensure robustness against alterations to cell size during the cell cycle.

cell biology↗

bioRxiv2023

Autofluorescence lifetime imaging classifies human lymphocyte activation and subtype

New non-destructive tools are needed to reliably assess lymphocyte function for immune profiling and adoptive cell therapy. Optical metabolic imaging (OMI) is a label-free method that measures the autofluorescence intensity and lifetime of metabolic cofactors NAD(P)H and FAD to quantify metabolism at a single-cell level. Here, we investigate whether OMI can resolve metabolic changes between human quiescent versus IL4/CD40 activated B cells and IL12/IL15/IL18 activated memory-like NK cells. We found that quiescent B and NK cells were more oxidized compared to activated cells. Additionally, the NAD(P)H mean fluorescence lifetime decreased and the fraction of unbound NAD(P)H increased in the activated B and NK cells compared to quiescent cells. Machine learning classified B cells and NK cells according to activation state (CD69+) based on OMI parameters with up to 93.4% and 92.6% accuracy, respectively. Leveraging our previously published OMI data from activated and quiescent T cells, we found that the NAD(P)H mean fluorescence lifetime increased in NK cells compared to T cells, and further increased in B cells compared to NK cells. Random forest models based on OMI classified lymphocytes according to subtype (B, NK, T cell) with 97.8% accuracy, and according to activation state (quiescent or activated) and subtype (B, NK, T cell) with 90.0% accuracy. Our results show that autofluorescence lifetime imaging can accurately assess lymphocyte activation and subtype in a label-free, non-destructive manner. TeaserLabel-free optical imaging can assess the metabolic state of lymphocytes on a single-cell level in a touch-free system.

bioengineering↗

bioRxiv2022

Sodium regulates PLC and IP3R-mediated calcium signalling in invasive breast cancer cells

Intracellular Ca2+ signalling and Na+ homeostasis are inextricably linked via ion channels and co-transporters, with alterations in the concentration of one ion having profound effects on the other. Evidence indicates that intracellular Na+ concentration ([Na+]i) is elevated in breast tumours, and that aberrant Ca2+ signalling regulates numerous key cancer hallmark processes. The present study therefore aimed to determine the effects of Na+ depletion on intracellular Ca2+ handling in metastatic breast cancer cell lines. The relationship between Na+ and Ca2+ was probed using fura-2 and SBFI fluorescence imaging and replacement of extracellular Na+ with equimolar N-methyl-D-glucamine (0Na+/NMDG) or choline chloride (0Na+/ChoCl). In triple-negative MDA-MB-231 and MDA-MB-468 cells and Her2+ SKBR3 cells, but not ER+ MCF-7 cells, 0Na+/NMDG and 0Na+/ChoCl resulted in a slow, sustained depletion in [Na+]i that was accompanied by a rapid and sustained increase in intracellular Ca2+ concentration ([Ca2+]i). Application of La3+ in nominal Ca2+-free conditions had no effect on this response, ruling out reverse-mode NCX activity and Ca2+ entry channels. Moreover, the Na+-linked [Ca2+]i increase was independent of membrane potential hyperpolarisation (NS-1619), but was inhibited by pharmacological blockade of IP3 receptors (2-APB), phospholipase C (PLC, U73122) or following depletion of endoplasmic reticulum Ca2+ stores (cyclopiazonic acid). Thus, Na+ is linked to PLC/IP3-mediated activation of endoplasmic reticulum Ca2+ release in metastatic breast cancer cells and this may have an important role in breast tumours where [Na+]i is perturbed.

cancer biology↗

bioRxiv2022

Characterization of proteome-size scaling by integrative omics reveals mechanisms of proliferation control in cancer

Almost all living cells maintain size uniformity through successive divisions. Proteins that sub- or super-scale with size act as rheostats which regulate cell progression. A comprehensive atlas of these proteins is lacking; particularly in cancer cells where both mitogen and growth signalling are dysregulated. Utilising a multi-omic strategy, that integrates quantitative single cell imaging, phosphoproteomic and transcriptomic datasets, we leverage the inherent size heterogeneity of melanoma cells to investigate how peptides, post-translational modifications, and mRNAs scale with cell size to regulate proliferation. We find melanoma cells have different mean sizes, but all retain uniformity. Across the proteome, we identify proteins and phosphorylation events that sub and super scale with cell size. In particular, G2/M, biosynthetic, and cytoskeletal regulators sub- and super-scale with size. In small cells growth and proliferation processes are tightly coupled by translation which promotes CCND1 accumulation and anabolic increases in mass. Counter intuitively, anabolic growth pathways and translational process are low in large cells, which throttles the expression of factors such as CCND1 and thereby coupling proliferation from anabolic growth. Strikingly, these cells exhibit increased growth and comparable proliferation rates. Mathematical modelling suggests that decoupling growth and proliferative signalling fosters proliferation under mitogenic inhibition. As factors which promote adhesion and actin reorganization super-scale with size or are enriched in large cells, we suggest that growth/proliferation in these cells may be decoupled by cell spreading and mechanics. This study provides one of the first demonstrations of size-scaling phenomena in cancer and how morphology determines the chemistry of the cell.

systems biology↗

bioRxiv2021

Aberrant glycosylation of anti-SARS-CoV-2 IgG is a pro-thrombotic stimulus for platelets

A subset of patients with COVID-19 become critically ill, suffering from severe respiratory problems and also increased rates of thrombosis. The causes of thrombosis in severely ill COVID-19 patients are still emerging, but the coincidence of critical illness with the timing of the onset of adaptive immunity could implicate an excessive immune response. We hypothesised that platelets might be susceptible to activation by anti-SARS-CoV-2 antibodies and contribute to thrombosis. We found that immune complexes containing recombinant SARS-CoV-2 spike protein and anti-spike IgG enhanced platelet-mediated thrombosis on von Willebrand Factor in vitro, but only when the glycosylation state of the Fc domain was modified to correspond with the aberrant glycosylation previously identified in patients with severe COVID-19. Furthermore, we found that activation was dependent on FcyRIIA and we provide in vitro evidence that this pathogenic platelet activation can be counteracted by therapeutic small molecules R406 (fostamatinib) and ibrutinib that inhibit tyrosine kinases syk and btk respectively or by the P2Y12 antagonist cangrelor.

immunology↗

bioRxiv2020

Transcriptional Network Orchestrating Regional Patterning of Cortical Progenitors

We uncovered a transcription factor (TF) network that regulates cortical regional patterning. Screening the expression of hundreds of TFs in the developing mouse cortex identified 38 TFs that are expressed in gradients in the ventricular zone (VZ). We tested whether their cortical expression was altered in mutant mice with known patterning defects (Emx2, Nr2f1 and Pax6), which enabled us to define a cortical regionalization TF network (CRTFN). To identify genomic programming underlying this network, we performed TF ChIP-seq and chromatin-looping conformation to identify enhancer-gene interactions. To map enhancers involved in regional patterning of cortical progenitors, we performed assays for epigenomic marks and DNA accessibility in VZ cells purified from wild-type and patterning mutant mice. This integrated approach has identified a CRTFN and VZ enhancers involved in cortical regional patterning.

neuroscience↗

bioRxiv2020

3D Epigenomic Characterization Reveals Insights Into Gene Regulation and Lineage Specification During Corticogenesis

Lineage-specific epigenomic changes during human corticogenesis have previously remained elusive due to challenges with tissue heterogeneity and sample availability. Here, we analyze cis-regulatory chromatin interactions, open chromatin regions, and transcriptomes for radial glia, intermediate progenitor cells, excitatory neurons, and interneurons isolated from mid-gestational human brain samples. We show that chromatin looping underlies transcriptional regulation for lineage-specific genes, with transcription factor motifs, families of transposable elements, and disease-associated variants enriched at distal interacting regions in a cell type-specific manner. A subset of promoters exhibit unusually high degrees of chromatin interactivity, which we term super interactive promoters. Super interactive promoters are enriched for critical lineage-specific genes, suggesting that interactions at these loci contribute to the fine-tuning of cell type-specific transcription. Finally, we present CRISPRview, a novel approach for validating distal interacting regions in primary cells. Our study presents the first characterization of cell type-specific 3D epigenomic landscapes during human corticogenesis, advancing our understanding of gene regulation and lineage specification during human brain development.

genomics↗

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

Differences in Genetic Liability for Insomnia and Hypersomnia in Bipolar Disorder Subtypes

BackgroundInsomnia and hypersomnia are common in bipolar disorder (BD) but it is unclear whether genetic factors influence this association. Stratifying by bipolar subtypes could elucidate the nature of this association and inform research on sleep and BD. We therefore aimed to determine whether polygenic risk scores (PRS) for insomnia, daytime sleepiness and sleep duration differ according to bipolar subtypes (bipolar I disorder, BD-I or bipolar II disorder, BD-II).\n\nMethodsIn this case-control study, we used multinomial regression to determine whether PRS for insomnia, daytime sleepiness, and sleep duration were associated with risk of BD-I or BD-II when compared to each other and to controls. Cases (n=4672) were recruited within the United Kingdom from the Bipolar Disorder Research Network. Controls (n=5714) were recruited from the 1958 British Birth Cohort and UK Blood Service. All participants were of European ancestry. Clinical subtypes of BD were determined by semi-structured psychiatric interview (the Schedules for Clinical Assessment in Neuropsychiatry) and case notes.\n\nResultsWithin cases, 3404 and 1268 met DSM-IV criteria for BD-I and BD-II, respectively. Insomnia PRS was associated with increased risk of BD-II (RR = 1.14, 95% CI = 1.07-1.21, P = 8.26 x 10-5) but not BD-I (RR = 0.98, 95% CI = 0.94-1.03, P = .409) relative to controls. In contrast, sleep duration PRS was associated with increased relative risk of BD-I (RR = 1.10, 95% CI = 1.06-1.15, P = 1.13 x 10-5), but not BD-II (RR = 0.99, 95% CI = 0.93-1.06, P = .818). Daytime sleepiness PRS was associated with an increased risk of BD-I (RR = 1.07, 95% CI = 1.02-1.11, P = .005) and BD-II (RR = 1.14, 95% CI = 1.07-1.22, P = 3.22 x 10-5) compared to controls, but did not distinguish subtypes from each other.\n\nConclusionsBipolar subtypes differ in genetic liability to insomnia and sleep duration. Our findings provide further evidence that the distinction between BD-I and BD-II has biological and genetic validity. This distinction will be critical in the selection of participants for future research on the role of sleep disturbance in BD.

genomics↗

bioRxiv2019

Label-free Method for Classification of T cell Activation

T cells have a range of cytotoxic and immune-modulating functions, depending on activation state and subtype. However, current methods to assess T cell function use exogenous labels that often require cell permeabilization, which is limiting for time-course studies of T cell activation and non-destructive quality control of immunotherapies. Label-free optical imaging is an attractive solution. Here, we use autofluorescence imaging of NAD(P)H and FAD, co-enzymes of metabolism, to quantify optical imaging endpoints in quiescent and activated T cells. Machine learning classification models were developed for label-free, non-destructive determination of T cell activation state. T cells were isolated from the peripheral blood of human donors, and a subset were activated with a tetrameric antibody against CD2/CD3/CD28 surface ligands. NAD(P)H and FAD autofluorescence intensity and lifetime of the T cells were imaged using a multiphoton fluorescence lifetime microscope. Significant differences in autofluorescence imaging end-points were observed between quiescent and activated T cells. Feature selection methods revealed that the contribution of the short NAD(P)H lifetime (1) is the most important feature for classification of activation state, across multiple donors and T cell subsets. Logistic regression models achieved 97-99% accuracy for classification of T cell activation from the autofluorescence imaging endpoints. Additionally, autofluorescence imaging revealed NAD(P)H and FAD autofluorescence differences between CD3+CD8+ and CD3+CD4+ T cells, and random forest models of the autofluorescence imaging endpoints achieved 97+% accuracy for four-group classification of quiescent and activated CD3+CD8+ and CD3+CD4+ T cells. Altogether these results indicate that autofluorescence imaging of NAD(P)H and FAD is a powerful method for label-free, non-destructive determination of T cell activation and subtype, which could have important applications for the treatment of cancer, autoimmune, infectious, and other diseases.

bioengineering↗

bioRxiv2018

cis-Regulatory Chromatin Contacts in Neural Cells Reveal Contributions of Genetic Variants to Complex Neurological Disorders

Mutations in gene regulatory elements have been associated with a wide range of complex neurological disorders. However, due to their inherent cell type-specificity and difficulties in characterizing their regulatory targets, our ability to identify causal genetic variants has remained limited. To address these constraints, we perform integrative analysis of chromatin interactions using promoter capture Hi-C (pcHi-C), open chromatin regions using ATAC-seq, and transcriptomes using RNA-seq in four functionally distinct neural cell types: iPSC-induced excitatory neurons and lower motor neurons, iPSC-derived hippocampal dentate gyrus (DG)-like neurons, and primary astrocytes. We identify hundreds of thousands of long-range cis interactions between promoters and distal promoter-interacting regions (PIRs), enabling us to link regulatory elements to their target genes and reveal putative pathways that are dysregulated in disease. We validate several novel PIRs using CRISPR techniques in human excitatory neurons, demonstrating that CDK5RAP3, STRAP, and DRD2 are transcriptionally regulated by physically linked enhancers. Finally, we show that physical chromatin interactions mediate genetic interactions in autism spectrum disorder (ASD). Our study illustrates how characterizing the 3D epigenome elucidates novel regulatory relationships in the central nervous system (CNS), shedding light on previously unknown functions for noncoding variants in complex neurological disorders.

genomics↗

bioRxiv2018

Genetic variation in the Major Histocompatibility Complex and association with depression

BackgroundThe prevalence of depression is higher in individuals suffering from autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Epidemiological findings point to a bi-directional relationship - that depression increases the risk of developing an autoimmune disease, and vice-versa. Shared genetic etiology is a plausible explanation for the overlap between depression and autoimmune diseases. In this study we tested whether genetic variation in the Major Histocompatibility Complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression.\n\nMethodWe fine-mapped the classical MHC (chr6: 29.6-33.1 Mb), imputing 216 Human Leukocyte Antigen (HLA) alleles and four Complement Component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium (PGC) Major Depressive Disorder (MDD) working group and the UK Biobank (UKB). In the 26 PGC-MDD studies, cases met a lifetime diagnosis of MDD, determined by a structured diagnostic interview. In the UKB, cases and controls were identified from an online mental health questionnaire. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants in each study and performed an inverse-variance weighted meta-analysis across the PGC-MDD and UKB samples, applying both a conservative region-wide significance threshold (3.9-e6) and a candidate threshold (1.6e-4).\n\nResultsNo HLA alleles or C4 haplotypes were associated with depression at the conservative threshold in the PGC, UKB or meta-analysis. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold in the meta-analysis. Under the conservative threshold, 70 SNPs were detected in the UKB and 143 SNPs were detected in the meta-analysis, mirroring previous findings from highly powered GWAS of depression.\n\nDiscussionWe found no evidence that HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia, confer risk for depression. These results indicate that autoimmune diseases and depression do not share common risk loci of moderate or large effect in the MHC.

genetics↗

bioRxiv2018

Prawn aquaculture as a method for schistosomiasis control and poverty alleviation: a win-win approach to address a critical infectious disease of poverty

Recent evidence suggests crustacean snail predators may aid schistosomiasis control programs by targeting the environmental component of the parasites life cycle through predation of the snail species that serve as intermediate hosts of the parasite. We evaluate costs, benefits, and potential synergies between schistosomiasis control and aquaculture of giant prawns using an integrated bio-economic-epidemiologic model. We identified combinations of stocking density and aquaculture cycle length that maximize profit and offer disease control benefits for sustainable schistosomiasis control. We consider two prawn species in sub-Saharan Africa: the endemic, non-domesticated Macrobrachium vollenhovenii, and the non-native, domesticated Macrobrachium rosenbergii. We find that, at profit-optimal densities, both M. rosenbergii and M. vollenhovenii can complement conventional control approaches (mass drug treatment of people) and lead to sustainable schistosomiasis control. We conclude that integrated aquaculture strategies can be a win-win strategy in terms of health and sustainable development in schistosomiasis endemic regions of the world.

epidemiology↗

bioRxiv2018

Contribution of rare copy number variants to bipolar disorder risk is limited to schizoaffective cases

BackgroundGenetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. BD subtypes schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I) and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania and depression. The factors contributing to the combination of symptoms within a given patient are poorly understood.\n\nMethodsRare, large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis], 1436 BD II, 579 SAB) and 8656 controls. Measures of CNV burden were integrated with polygenic risk scores (PRS) for schizophrenia (SCZ) to evaluate the relative contributions of rare and common variants to psychosis risk.\n\nResultsCNV burden did not differ in BD relative to controls when treated as a single diagnostic entity. Burden in SAB was increased compared to controls (p-value = 0.001), BD I (p-value = 0.0003) and BD II (p-value = 0.0007). Burden and SCZ PRS were higher in SAB compared to BD I with psychosis (CNV p-value = 0.0007, PRS p-value = 0.004) and BD I without psychosis (CNV p-value = 0.0004, PRS p-value = 3.9 x 10-5). Within BD I, psychosis was associated with higher SCZ PRS (p-value = 0.005) but not with CNV burden.\n\nConclusionsCNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.

genetics↗