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Sullivan, P.

Publications and source records attributed to Sullivan, P..

17 recordsLinked to original sources

MOSAIC: Learning Graph Node Embeddings from Spectrally Isolated Dominant Subspaces of Accumulated Diffusion Operators

Graph embedding transforms complex networks into low-dimensional representations for analysis and downstream machine learning. Existing methods often rely on eigenvalue ordering, random-walk sampling, or neural optimization. We introduce MOSAIC, Multistep Operator Spectral Accumulation with Isolated Components, an unsupervised framework that constructs an accumulated diffusion operator from successive powers of a graph transition matrix. MOSAIC uses Krylov subspace analysis to identify dominant spectral components according to their convergence behavior. This approach emphasizes persistent and spectrally separated diffusion modes rather than selecting embedding coordinates solely by eigenvalue magnitude. We evaluated MOSAIC using a biomedical graph projection derived from the Data Distillery Knowledge Graph that contained 5,171 human genes and 10,147 phenotypes. Across embedding dimensions from 16 to 128, MOSAIC achieved node-type classification AUROCs from 0.9863 to 0.9926 and exceeded FastRP, Node2Vec, HashGNN, and GraphSAGE. For gene-phenotype link prediction, validation and test associations were withheld before embedding generation. Under progressive removal of all edges or specific edge classes, MOSAIC retained more node-label information than FastRP, including after extreme graph sparsification. In a focused DICER1 analysis, 106 of 137 documented phenotype associations received scores above 0.90, demonstrating concordance with known pleiotropic biology and prioritizing additional relationships for independent evaluation. These results support MOSAIC as a fully unsupervised framework for learning informative graph representations. Although demonstrated using a biomedical graph projection, MOSAIC is domain independent and can be applied to other complex networks

bioinformatics↗

Unveiling the taxonomic diversity and unprecedented biosynthetic treasure of the phylum Myxococcota

Natural products remain vital sources of therapeutics, particularly anti-infectives, and members of the phylum Myxococcota constitute an especially rich reservoir for their discovery. Based on decades of microbiological efforts, we present 154 new Myxococcota genomes and propose a revised taxonomy expanding the number of described families from 11 to 28 and genera from 32 to 90. Comparison with an equivalent set from the prime source Actinomycetota shows that Myxococcota possess a comparable biosynthetic diversity, underscoring their promise for large-scale isolation and sequencing efforts. The vast untapped potential reflected in 2,387 uncharacterized gene cluster families is highlighted by genome mining efforts, yielding four validated compounds exhibiting novel chemistry, including myxolutamids and myxopentacins. We show that many Myxococcota-derived natural products, such as myxolutamid A and two new sorangicin derivatives, are conserved within taxonomic lineages. New described families thus bear high biosynthetic potential underpinning the importance of precise taxonomic classification guiding targeted drug discovery.

microbiology↗

CBL mutations in pediatric solid and CNS tumors are a marker of receptor tyrosine kinase activation and a potential therapeutic target

Mutations in CBL, an E3 ubiquitin ligase that negatively regulates receptor tyrosine kinases (RTKs) and potentiates intracellular signaling, have been extensively characterized in hematological malignancies. However, the impacts are unknown in other cancer types. We have identified established and novel aberrations in CBL in molecularly diverse pediatric CNS and solid tumors. Additionally, we present novel CBL splice mutations, including in the germline of a high-grade glioma patient, and alternative CBL splicing without corresponding genomic alterations. Functionally, we demonstrate that CBL exon 8/9{Delta}, typically associated with acute myeloid leukemia, is RTK activating in neuroblastoma and that novel CBL variants, CBL E366_E373del and CBL C384G, can cooperate with overexpression of EGFR to transform Ba/F3 cells. Collectively, these data represent a novel form of RTK activation in pediatric patients with solid and CNS tumors who might benefit from RTK-targeted therapies. Statement of significanceMolecularly targeted therapies improve childhood cancer outcomes. Therapies targeting genes called receptor tyrosine kinases are particularly effective. We have identified new genetic alterations that may be a marker for receptor tyrosine kinase activation and drug sensitivity, enabling more patients to benefit from targeted treatments.

cancer biology↗

Expanding the utility of transcriptome analysis for mutation detection in high-risk childhood precision oncology

In precision oncology, whole transcriptome sequencing (RNA-seq) excels at identifying oncogenic fusions. Here, using a cohort of 477 high-risk paediatric tumours, we demonstrate that RNA-seq can identify all mutation classes found previously using whole genome sequencing (WGS) and provides additional functional insights into their pathogenicity. By incorporating reference-guided fusion, and reference-free structural variant (SV) detection algorithms with RNA abundance assessment, RNA-seq identified 96% of SVs and resolved 33 complex SVs that WGS failed to identify. Furthermore, RNA-seq identified 92% of all single nucleotide variants and small insertions and deletions. Importantly RNA-seq informed the pathogenicity assessment in 22% of variants through identification of allele specific expression or the functional consequence of splice-altering variants. The utility of RNA-seq extends beyond fusion identification to the interpretation of mutation pathogenicity and the discovery of important mutations that would otherwise go undetected. We propose that RNA-seq is an indispensable companion to WGS in precision medicine.

genomics↗

Pan-cancer Analysis of Homologous Recombination Deficiency in Cell Lines

Homologous Recombination Deficiency (HRD) drives genomic instability in multiple cancer types and renders tumors vulnerable to certain DNA damaging agents such as PARP inhibitors. Thus, HRD is emerging as an attractive biomarker in oncology. A variety of in silico methods are available for predicting HRD; however, few of these methods have been applied to cell lines in a comprehensive manner. Here we utilized two of these methods, "CHORD" and "HRDsum" scores, to predict HRD for 1,332 cancer cell lines and 84 non-cancerous cell lines. Cell lines with biallelic mutations in BRCA1 or BRCA2, which encode key components of the homologous recombination pathway, showed the strongest HRD predictions, validating the two methods in cell lines. A small subset of BRCA1/2-wildtype cell lines were also classified as HRD, several of which showed evidence of epigenetic BRCA1 silencing. Similar to HRD in patient samples, HRD in cell lines was associated with p53 loss, was mutually exclusive with microsatellite instability and occurred most frequently in breast and ovarian cancer types. In addition to validating previously identified associations with HRD, we leveraged cell line-specific datasets to gain new insights into HRD and its relation to various genetic dependency and drug sensitivity profiles. We found that in cell lines, HRD was associated with sensitivity to PARP inhibition in breast cancer, but not at a pan-cancer level. By generating large-scale, pan-cancer datasets on HRD predictions in cell lines, we aim to facilitate efforts to improve our understanding of HRD and its utility as a biomarker. SIGNIFICANCE STATEMENTHomologous Recombination Deficiency (HRD) is common in cancer and can be exploited therapeutically, as it sensitizes cells to DNA damaging agents. Here we scored over 1,300 cancer cell lines for HRD using two different bioinformatic approaches, thereby enabling large-scale analyses that provide insight into the etiology and features of HRD.

cancer biology↗

Genome-wide annotation of gene regulatory elements linked to cell fitness

Noncoding regulatory elements control gene expression and thus govern nearly all biological processes. Epigenomic profiling assays have identified millions of putative regulatory elements, but systematically determining the function of those regulatory elements remains a substantial challenge. Here we adapt CRISPR screening by epigenetic repression to screen all 111,619 putative non-coding regulatory elements defined by open chromatin sites in human K562 leukemia cells for their role in regulating essential cellular processes and proliferation. In an initial screen containing 1,084,704 gRNAs, we implemented an analysis framework to quantify perturbation effects, and nominate 1,108 regulatory elements that strongly impact cell fitness. We tested 8,845 of the primary screen elements in a secondary screen, evaluated their cell-type specificity in a second cancer cell line, and then used a single-cell RNA-seq CRISPR screen to discover 63 connections between distal regulatory elements and target genes. This comprehensive and quantitative genome-wide map of essential gene regulatory elements presents a framework for extensive characterization of noncoding regulatory elements that drive complex cell phenotypes and for prioritizing non-coding genetic variants that may contribute to common traits and disease risk.

genomics↗

APOE2 promotes longevity independent of Alzheimer's disease

ObjectiveAlthough apolipoprotein E (APOE) allele associates with longevity, its mechanism is not understood. The protective effects of APOE2 and the deleterious effects of APOE4 on Alzheimers disease (AD) risk may confound APOE effects on longevity. MethodsWe analyzed a large number of subjects from the National Alzheimers Coordinating Center (NACC), and animal models expressing human apoE isoforms in the absence of AD. ResultsClinically, the APOE2 allele was associated with longer lifespan, while APOE4 associated with shorter lifespan, compared to the common APOE3 allele. This effect was also seen irrespective of clinical AD status, and in subjects with little amyloid pathology or after adjustment for AD-related pathologies. In animal studies, apoE2-TR mice also exhibited longer lifespan, while apoE4 showed some trends of shorter lifespan. Notably, old apoE2-TR mice kept activity measured by open field assay, associated with longer lifespan. Evidence of preserved activity in APOE2 carrier was also obtained in clinical records. In animal studies, higher levels of apoE2 in brain and plasma were correlated with activity. Moreover, lower levels of total cholesterol in the brain and higher levels of high-density lipoprotein cholesterol and triglycerides in the plasma of apoE2-TR mice were associated with apoE levels and more activity. InterpretationAPOE2 can contribute to longevity independent of AD. Preserved activity would be an early-observable feature of apoE2-mediated longevity, where higher levels of apoE2 and its-associated lipid metabolism might be involved.

neuroscience↗

Large-scale analysis of DNA methylation identifies cellular alterations in blood from psychosis patients and molecular biomarkers of treatment-resistant schizophrenia.

ObjectivePsychosis - a complex and heterogeneous neuropsychiatric condition characterized by hallucinations and delusions - is a common feature of schizophrenia. There is evidence for altered DNA methylation (DNAm) associated with schizophrenia in both brain and peripheral tissues. We aimed to undertake a systematic analysis of variable DNAm associated with psychosis, schizophrenia, and treatment-resistant schizophrenia, also exploring measures of biological ageing, smoking, and blood cell composition derived from DNAm data to identify molecular biomarkers of disease. MethodsWe quantified DNAm across the genome in blood samples from 4,483 participants from seven case-control cohorts including patients with schizophrenia or first-episode psychosis. Measures of biological age, cellular composition and smoking status were derived from DNAm data using established algorithms. DNAm and derived measures were analyzed within each cohort and the results combined by meta-analysis. ResultsPsychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNAm data, with the largest differences seen in treatment-resistant schizophrenia patients. DNAm at 95 CpG sites was significantly different between psychosis cases and controls, with 1,048 differentially methylated positions (DMPs) identified between schizophrenia cases and controls. Schizophrenia-associated DMPs colocalize to regions identified in genetic association studies, with genes annotated to these sites enriched for pathways relevant to disease. Finally, a number of the schizophrenia associated differences were only present in the treatment-resistant schizophrenia subgroup. ConclusionsWe show that DNAm data can be leveraged to derive measures of blood cell counts and smoking that are strongly associated with psychosis. Our DNAm meta-analysis identified multiple DMPs associated with both psychosis and a more refined diagnosis of schizophrenia, with evidence for differential methylation associated with treatment-resistant schizophrenia that potentially reflects exposure to clozapine.

genomics↗

25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner

Genome-wide association studies associated with Alzheimers disease (AD) have implicated pathways related to both lipid homeostasis and innate immunity in the pathophysiology of AD. However, the exact cellular and chemical mediators of neuroinflammation in AD remain poorly understood. The oxysterol 25-hydroxycholesterol (25-HC) is an important immunomodulator produced by peripheral macrophages with wide-ranging effects on cell signaling and innate immunity. Genetic variants of the enzyme responsible for 25-HC production, cholesterol 25-hydroxylase (CH25H), have been found to be associated with AD. In the present study, we found that the CH25H expression is upregulated in human AD brain tissue and in transgenic mouse brain tissue bearing amyloid-{beta} (A{beta}) plaques or tau pathology. Treatment with the toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS) markedly upregulates CH25H expression in the mouse brain in vivo. LPS also stimulates CH25H expression and 25-HC secretion in cultured mouse primary microglia. We also found that LPS-induced microglial production of the pro-inflammatory cytokine IL1{beta} is markedly potentiated by 25-HC and attenuated by genetic deletion of CH25H. Microglia expressing apolipoprotein E4 (apoE4), a genetic risk factor for AD, produce greater amounts of 25-HC than apoE3-expressing microglia following treatment with LPS. Remarkably, treatment of microglia with 25-HC results in a much greater level of IL1{beta} secretion in LPS-activated apoE4-expressing microglia than in apoE2- or apoE3-expressing microglia. Blocking potassium efflux or inhibiting caspase-1 prevents 25-HC-potentiated IL1{beta} release in apoE4-expressing microglia, indicating the involvement of caspase-1/NLRP3 inflammasome activity. 25-HC may function as a microglial secreted inflammatory mediator in brain, promoting IL1{beta}-mediated neuroinflammation in an apoE isoform-dependent manner (E4>>E2/E3) and thus may be an important mediator of neuroinflammation in AD.

neuroscience↗

Antipsychotic behavioral phenotypes in the mouse Collaborative Cross recombinant inbred inter-crosses (RIX)

Schizophrenia is an idiopathic disorder that affects approximately 1% of the human population, and presents with persistent delusions, hallucinations, and disorganized behaviors. Antipsychotics are the standard pharmacological treatment for schizophrenia, but are frequently discontinued by patients due to inefficacy and/or side effects. Chronic treatment with the typical antipsychotic haloperidol causes tardive dyskinesia (TD), which manifests as involuntary and often irreversible orofacial movements in around 30% of patients. Mice treated with haloperidol develop many of the features of TD, including jaw tremors, tongue protrusions, and vacuous chewing movements (VCMs). In this study, we used genetically diverse Collaborative Cross (CC) recombinant inbred inter-cross (RIX) mice to elucidate the genetic basis of antipsychotic-induced adverse drug reactions (ADRs). We performed a battery of behavioral tests in 840 mice from 73 RIX lines (derived from 62 CC strains) treated with haloperidol or placebo in order to monitor the development of ADRs. We used linear mixed models to test for strain and treatment effects. We observed highly significant strain effects for almost all behavioral measurements investigated (p<0.001). Further, we observed strong strain-by-treatment interactions for most phenotypes, particularly for changes in distance traveled, vertical activity, and extrapyramidal symptoms (EPS). Estimates of overall heritability ranged from 0.21 (change in body weight) to 0.4 (VCMs and change in distance traveled) while the portion attributable to the interactions of treatment and strain ranged from 0.01 (for change in body weight) to 0.15 (for change in EPS). Interestingly, close to 30% of RIX mice exhibited VCMs, a sensitivity to haloperidol exposure, approximately similar to the rate of TD in humans chronically exposed to haloperidol. Understanding the genetic basis for the susceptibility to antipsychotic ADRs may be possible in mouse, and extrapolation to humans could lead to safer therapeutic approaches for schizophrenia.

systems biology↗

Conditional GWAS analysis identifies putative disorder-specific SNPs for psychiatric disorders

Substantial genetic liability is shared across psychiatric disorders but less is known about risk variants that are specific to a given disorder. We used multi-trait conditional and joint analysis (mtCOJO) to adjust GWAS summary statistics of one disorder for the effects of genetically correlated traits to identify putative disorder-specific SNP associations. We applied mtCOJO to summary statistics for five psychiatric disorders from the Psychiatric Genomics Consortium - schizophrenia (SCZ), bipolar disorder (BIP), major depression (MD), attention-deficit hyperactivity disorder (ADHD) and autism (AUT). Most genom-wide significant variants for these disorders had evidence of pleiotropy (i.e., impact on multiple psychiatric disorders) and hence have reduced mtCOJO conditional effect sizes. However, subsets of genome-wide significant variants had larger conditional effect sizes consistent with disorder-specific effects: 15 of 130 genome-wide significant variants for schizophrenia, 5 of 40 for major depression, 3 of 11 for ADHD and 1 of 2 for autism. In addition, we identified a number of variants that approached genome-wide significance in the original GWAS and have larger conditional effect sizes after conditioning on the other disorders. We show that decreased expression of VPS29 in the brain may increase risk to SCZ only and increased expression of CSE1L is associated with SCZ and MD, but not with BIP. Likewise, decreased expression of PCDHA7 in the brain is linked to increased risk of MD but decreased risk of SCZ and BIP.

genetics↗

Characterization of single gene copy number variants in schizophrenia

Genetic studies of schizophrenia (SCZ) have now implicated numerous genomic loci that contribute to risk including several copy number variants (CNV) of large effect and hundreds of associated loci of small effect. However, in only a few cases has a specific gene been clearly identified. Rare CNV that affect only a single gene offer a potential avenue to discovering specific SCZ risk genes. Here, we use CNV generated from exome-sequencing of 4,913 SCZ cases and 6,188 controls in a homogenous Swedish cohort to assess the contribution of single-gene deletions and duplications to SCZ risk. As previously seen, we found an excess of rare deletions (p = 0.0004) and duplications (p = 0.0006) in SCZ cases compared to controls. When limiting to only single-gene CNV we identified nominally significant excess of deletions (p = 0.04) and duplications (p = 0.03). In an effort to increase the number of single-gene CNV, we reduced strict filtering criteria but required support from two independent CNV calling methods to create an expanded set that showed a significant burden of deletions in 11 out of 22 gene sets previously implicated in SCZ and in the combined set of genes across those sets (p = 0.008). Finally, for the significantly enriched set of voltage-gated calcium channels, we performed an extensive validation of all deletions generated from exome-sequencing as well as any deletion with evidence from previously analyzed genotyping arrays. In total, 4 exonic, single-gene deletions validated in cases and none in controls (p = 0.039), of which all were identified by exome-sequencing. Broadly, these results point to the potential contribution of single-gene CNV to SCZ and the added value of a deeper dive into CNV calls from exome-sequencing.

genetics↗

Genetic meta-analysis identifies 10 novel loci and functional pathways for Alzheimer’s disease risk

Late onset Alzheimers disease (AD) is the most common form of dementia with more than 35 million people affected worldwide, and no curative treatment available. AD is highly heritable and recent genome-wide meta-analyses have identified over 20 genomic loci associated with AD, yet only explaining a small proportion of the genetic variance indicating that undiscovered loci exist. Here, we performed the largest genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 AD cases, 383,378 controls). AD-by-proxy status is based on parental AD diagnosis, and showed strong genetic correlation with AD (rg=0.81). Genetic meta analysis identified 29 risk loci, of which 9 are novel, and implicating 215 potential causative genes. Independent replication further supports these novel loci in AD. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver and microglia). Furthermore, gene-set analyses indicate the genetic contribution of biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomisation results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying more of the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD to guide new drug development.

genetics↗

Functional consequences of genetic loci associated with intelligence in a meta-analysis of 87,740 individuals

Variance in IQ is associated with a wide range of health outcomes, and 1% of the population are affected by intellectual disability. Despite a century of research, the fundamental neural underpinnings of intelligence remain unclear. We integrate results from genome-wide association studies (GWAS) of intelligence with brain tissue and single cell gene expression data to identify tissues and cell types associated with intelligence. GWAS data for IQ (N = 78,308) were meta-analyzed with an extreme-trait cohort of 1,247 individuals with mean IQ [~]170 and 8,185 controls. Genes associated with intelligence implicate pyramidal neurons of the somatosensory cortex and CA1 region of the hippocampus, and midbrain embryonic GABAergic neurons. Tissue-specific analyses find the most significant enrichment for frontal cortex brain expressed genes. These results suggest specific neuronal cell types and genes may be involved in intelligence and provide new hypotheses for neuroscience experiments using model systems.

genomics↗

Genome-wide Association Study of Clinical Features in the Schizophrenia Psychiatric Genomics Consortium: Confirmation of Polygenic Effect on Negative Symptoms

Schizophrenia is a clinically heterogeneous disorder. Proposed revisions in DSM - 5 included dimensional measurement of different symptom domains. We sought to identify common genetic variants influencing these dimensions, and confirm a previous association between polygenic risk of schizophrenia and the severity of negative symptoms. The Psychiatric Genomics Consortium study of schizophrenia comprised 8,432 cases of European ancestry with available clinical phenotype data. Symptoms averaged over the course of illness were assessed using the OPCRIT, PANSS, LDPS, SCAN, SCID, and CASH. Factor analyses of each constituent PGC study identified positive, negative, manic, and depressive symptom dimensions. We examined the relationship between the resultant symptom dimensions and aggregate polygenic risk scores indexing risk of schizophrenia. We performed genome - wide association study (GWAS) of each quantitative traits using linear regression and adjusting for significant effects of sex and ancestry. The negative symptom factor was significantly associated with polygene risk scores for schizophrenia, confirming a previous, suggestive finding by our group in a smaller sample, though explaining only a small fraction of the variance. In subsequent GWAS, we observed the strongest evidence of association for the positive and negative symptom factors, with SNPs in RFX8 on 2q11.2 (P = 6.27x10-8) and upstream of WDR72 / UNC13C on 15q21.3 (P = 7.59x10-8), respectively. We report evidence of association of novel modifier loci for schizophrenia, though no single locus attained established genome - wide significance criteria. As this may have been due to insufficient statistical power, follow - up in additional samples is warranted. Importantly, we replicated our previous finding that polygenic risk explains at least some of the variance in negative symptoms, a core illness dimension.

genetics↗

Quantifying the impact of rare and ultra-rare coding variation across the phenotypic spectrum

There is a limited understanding about the impact of rare protein truncating variants across multiple phenotypes. We explore the impact of this class of variants on 13 quantitative traits and 10 diseases using whole-exome sequencing data from 100,296 individuals. Protein truncating variants in genes intolerant to this class of mutations increased risk of autism, schizophrenia, bipolar disorder, intellectual disability, ADHD. In individuals without these disorders, there was an association with shorter height, lower education, increased hospitalization and reduced age. Gene sets implicated from GWAS did not show a significant protein truncating variants-burden beyond what captured by established Mendelian genes. In conclusion, we provide the most thorough investigation to date of the impact of rare deleterious coding variants on complex traits, suggesting widespread pleiotropic risk.\n\nMain abbreviations

genetics↗

HUGIn: Hi-C Unifying Genomic Interrogator

MotivationHigh throughput chromatin conformation capture (3C) technologies, such as Hi-C and ChlA-PET, have the potential to elucidate the functional roles of non-coding variants. However, most of published genome-wide unbiased chromatin organization studies have used cultured cell lines, limiting their generalizability.\n\nResultsWe developed a web browser, HUGIn, to visualize Hi-C data generated from 21 human primary tissues and cell liens. HUGIn enables assessment of chromatin contacts both constitutive across and specific to tissue(s) and/or cell line(s) at any genomic loci, including GWAS SNPs, eQTLs and cis-regulatory elements, facilitating the understanding of both GWAS and eQTLs results and functional genomics data.\n\nAvailabilityHUGIn is available at http://yunliweb.its.unc.edu/HUGIn.\n\nContactyunli@med.unc.edu and hum@ccf.org\n\nSupplementary information:

genetics↗