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1. Socioeconomic deprivation and illness trajectory in the Scottish population after COVID-19 hospitalization

Author

Morrow, Andrew J., Sykes, Robert, Saleh, Merna, Zahra, Baryab, MacIntosh, Alasdair, Kamdar, Anna, Bagot, Catherine, Bayes, Hannah K., Blyth, Kevin G., Bulluck, Heerajnarain, Carrick, David, Church, Colin, Corcoran, David, Findlay, Iain, Gibson, Vivienne B., Gillespie, Lynsey, Grieve, Douglas, Barrientos, Pauline Hall, Ho, Antonia, Lang, Ninian N., Lowe, David J., Lennie, Vera, Macfarlane, Peter W., Mayne, Kaitlin J., Mark, Patrick B., McConnachie, Alex, McGeoch, Ross, Nordin, Sabrina, Payne, Alexander, Rankin, Alastair J., Robertson, Keith, Ryan, Nicola, Roditi, Giles, Sattar, Naveed, Stobo, David, Allwood-Spiers, Sarah, Touyz, Rhian M., Veldtman, Gruschen, Weeden, Sarah, Weir, Robin, Watkins, Stuart, Welsh, Paul, Mangion, Kenneth, and Berry, Colin

Published
2024
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6. A blood biomarker of the pace of aging is associated with brain structure: replication across three cohorts

Author

Whitman, Ethan T., Ryan, Calen P., Abraham, Wickliffe C., Addae, Angela, Corcoran, David L., Elliott, Maxwell L., Hogan, Sean, Ireland, David, Keenan, Ross, Knodt, Annchen R., Melzer, Tracy R., Poulton, Richie, Ramrakha, Sandhya, Sugden, Karen, Williams, Benjamin S., Zhou, Jiayi, Hariri, Ahmad R., Belsky, Daniel W., Moffitt, Terrie E., and Caspi, Avshalom

Published
2024
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7. Resource profile and user guide of the Polygenic Index Repository

Author

Becker, Joel, Burik, Casper AP, Goldman, Grant, Wang, Nancy, Jayashankar, Hariharan, Bennett, Michael, Belsky, Daniel W, Karlsson Linnér, Richard, Ahlskog, Rafael, Kleinman, Aaron, Hinds, David A, Caspi, Avshalom, Corcoran, David L, Moffitt, Terrie E, Poulton, Richie, Sugden, Karen, Williams, Benjamin S, Harris, Kathleen Mullan, Steptoe, Andrew, Ajnakina, Olesya, Milani, Lili, Esko, Tõnu, Iacono, William G, McGue, Matt, Magnusson, Patrik KE, Mallard, Travis T, Harden, K Paige, Tucker-Drob, Elliot M, Herd, Pamela, Freese, Jeremy, Young, Alexander, Beauchamp, Jonathan P, Koellinger, Philipp D, Oskarsson, Sven, Johannesson, Magnus, Visscher, Peter M, Meyer, Michelle N, Laibson, David, Cesarini, David, Benjamin, Daniel J, Turley, Patrick, and Okbay, Aysu

Subjects
Epidemiology, Health Sciences, 2.6 Resources and infrastructure (aetiology), Aetiology, Data Analysis, Databases, Genetic, Genome-Wide Association Study, Humans, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Polygenic score, Polygenic index, Repository, Measurement error, 23andMe Research Group, Biomedical and clinical sciences, Health sciences, Psychology
Abstract

Polygenic indexes (PGIs) are DNA-based predictors. Their value for research in many scientific disciplines is growing rapidly. As a resource for researchers, we used a consistent methodology to construct PGIs for 47 phenotypes in 11 datasets. To maximize the PGIs' prediction accuracies, we constructed them using genome-wide association studies-some not previously published-from multiple data sources, including 23andMe and UK Biobank. We present a theoretical framework to help interpret analyses involving PGIs. A key insight is that a PGI can be understood as an unbiased but noisy measure of a latent variable we call the 'additive SNP factor'. Regressions in which the true regressor is this factor but the PGI is used as its proxy therefore suffer from errors-in-variables bias. We derive an estimator that corrects for the bias, illustrate the correction, and make a Python tool for implementing it publicly available.

Published
2021

9. Invasive Endotyping in Patients With Angina and No Obstructive Coronary Artery Disease: A Randomized Controlled Trial

Author

Sidik, Novalia P., Stanley, Bethany, Sykes, Robert, Morrow, Andrew J., Bradley, Conor P., McDermott, Michael, Ford, Thomas J., Roditi, Giles, Hargreaves, Allister, Stobo, David, Adams, Jacqueline, Byrne, John, Mahrous, Ahmed, Young, Robin, Carrick, David, McGeoch, Ross, Corcoran, David, Lang, Ninian N., Heggie, Robert, Wu, Olivia, McEntegart, Margaret B., McConnachie, Alex, and Berry, Colin

Published
2024
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11. A living ex vivo platform for functional, personalized brain cancer diagnosis

Author

Mann, Breanna, Zhang, Xiaopei, Bell, Noah, Adefolaju, Adebimpe, Thang, Morrent, Dasari, Rajaneekar, Kanchi, Krishna, Valdivia, Alain, Yang, Yang, Buckley, Andrew, Lettry, Vivien, Quinsey, Carolyn, Rauf, Yasmeen, Kram, David, Cassidy, Noah, Vaziri, Cyrus, Corcoran, David L., Rego, Stephen, Jiang, Yuchao, Graves, Lee M., Dunn, Denise, Floyd, Scott, Baldwin, Albert, Hingtgen, Shawn, and Satterlee, Andrew B.

Published
2023
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13. Coronary vascular dysfunction : diagnostic evaluation and therapeutic modification

Author

Corcoran, David

Subjects
616.1, R Medicine (General)
Abstract

Introduction: There is a stenosis-centred concept of myocardial ischaemia, whereby angina pectoris is the consequence of obstructive epicardial coronary artery disease (CAD) that reduces myocardial blood flow (MBF) due to supply-demand mismatch. In clinical practice, the diagnostic management of patients with angina focusses on testing for epicardial CAD. This clinical paradigm fails to account for the approximately one-third of patients who suffer from angina and non-obstructive coronary artery disease (ANOCA). Similarly, patients with obstructive epicardial CAD may have recurrent symptoms following myocardial revascularisation. The management of this cohort of patients in heterogeneous. Patients may fail to have a diagnosis made for the aetiology of their symptoms, receive no further diagnostic work-up, and have no therapeutic intervention. Microvascular angina and vasospastic angina secondary to coronary vascular dysfunction may be relevant. I aimed to investigate the diagnostic role of invasive and non-invasive vascular function testing in patients presenting with stable angina, and the role of therapeutic interventions which may modulate coronary vascular function: 1. The proportion of abnormal invasive parameters of coronary vascular function in patients with both ANOCA and obstructive epicardial CAD. 2. The proportion of abnormal myocardial perfusion (as revealed by perfusion cardiac magnetic resonance (CMR) imaging) in patients with ANOCA. 3. The associations between baseline characteristics and coronary vascular dysfunction. 4. To determine whether remote ischaemic preconditioning (RIPC) might enhance endothelium-dependent and -independent coronary vascular function in patients with stable angina. 5. To evaluate the effects of recombinant relaxin-2 (serelaxin) on coronary microvascular and systemic macrovascular function in patients with stable angina. Methods: I performed two studies of diagnostic testing of vascular function, and two mechanistic trials of novel therapeutic modifications of coronary vascular function: 1. Clinical evaluation of magnetic resonance imaging in coronary heart disease 2 (CE-MARC 2) Coronary Physiology sub-study (NCT01664858): a pre-specified sub-study of a UK prospective multicentre randomised controlled trial of patients presenting with stable angina undergoing invasive coronary angiography (n=67). All patients undergoing invasive diagnostic coronary angiography had invasive parameters of coronary microvascular function measured. The primary outcome was the proportion of patients with coronary vascular dysfunction as defined by abnormal invasive tests (reduced coronary flow reserve (CFR, < 2.0), increased index of microcirculatory resistance (IMR, ≥25 U), and reduced resistance reserve ratio (RRR, <2.0). 2. The Coronary Microvascular Angina Cardiac Magnetic Resonance imaging (CorCMR) study: an observational study of multiparametric CMR imaging in the diagnostic pathway of a contemporary UK cohort of patients with ANOCA (n=143). Consecutive patients undergoing clinically-indicated invasive coronary angiography for the investigation angina found to have no obstructive epicardial CAD were invited to undergo multiparametric CMR imaging. The primary outcome was the proportion of patients with coronary vascular dysfunction (defined by reduced global myocardial perfusion reserve (MPR <2.0)). 3. The Effects of Remote Ischaemic Preconditioning on Coronary Artery Function in Patients with Stable Coronary Artery Disease (RIC-COR) (NCT02666235): a mechanistic, randomised, sham-controlled, blinded clinical trial of the effect of remote ischaemic preconditioning (RIPC) on coronary vascular function in patients with stable CAD (n=60). Consecutive patients undergoing clinically-indicated invasive management were prospectively enrolled, and randomised to RIPC or sham (1:1) prior to angiography. Coronary endothelial-dependent vasodilator function was assessed in a non-target coronary artery with intracoronary infusion of incremental acetylcholine doses. The primary outcome was the mean percentage change in coronary artery luminal diameter from baseline to the maximum administered acetylcholine infusion. 4. The Effects of Intravenous Serelaxin on Myocardial Blood Flow and Vascular Function in Patients with Stable Coronary Artery Disease (RELAXCAD) trial (NCT01979614): a mechanistic, randomised, double-blind, placebo controlled trial of recombinant relaxin-2 (serelaxin) on coronary microvascular and macrovascular function in patients with stable CAD (n=51). Consecutive patients referred for the invasive assessment of stable CAD were randomised (1:1) to 48 h intravenous serelaxin (30 μg/kg/day) or matching placebo. Patients underwent assessment of coronary microvascular (myocardial blood flow by stress perfusion CMR) and systemic (aortic) macrovascular function (augmentation index by applanation tonometry) at baseline and 47 h post-serelaxin or placebo. The co-primary outcome was the between-group difference in change from baseline to 47 h in MPR and augmentation index. Results: In summary, the main findings of this thesis are: 1. Abnormal invasive parameters of coronary vascular function are prevalent in patients with both ANOCA and obstructive epicardial CAD: In the CEMARC 2 Coronary Physiology sub-study, 25/67 (40%) patients were classified as having ANOCA. Of these patients, 17/25 (68%) had an abnormality in at least one measurement of microvascular function. There were 38/67 (60%) classified as having obstructive epicardial CAD. Of these patients, 15/38 (39%) had an abnormal IMR, 12/38 (32%) had an abnormal RRR, and a reduced CFR concordant with the abnormal FFR, was present in 20/38 (53%). 3. In patients with ANOCA, abnormalities in CMR-derived myocardial perfusion are a frequent finding: Using MPR thresholds of <2.0 and <1.5, there were 101 (71%) and 39 (27%) patients with reduced global MPR. 4. RIPC results in enhanced coronary endothelial function: The mean percentage change in coronary luminal diameter from baseline to the maximum administered acetylcholine dose was -13.3±22.3% and - 2.0±17.2% in the sham and RIPC groups (mean difference 11.32%, 95% CI: 1.2 to 21.4, p=0.032). That is, RIPC performed prior to invasive management results in a lower reduction in mean percentage coronary artery luminal diameter in patients with stable CAD. 4. Recombinant relaxin-2 had no effect of on coronary microvascular or macrovascular function. Compared to placebo, serelaxin did not result in a significant change in MPR from baseline to 47 h (serelaxin vs. placebo adjusted mean difference: -0.112, 95% CI: -0.4-0.18, p=0.44), or augmentation index (serelaxin vs. placebo adjusted mean difference 3.45, 95% CI: −2.04-8.95, p=0.21). Conclusions: Coronary vascular dysfunction is relevant in patients with both ANOCA and obstructive epicardial CAD, and the findings of this PhD have clinical implications. Invasive coronary vascular function testing provides an insight into the underlying disease endotypes in these patients, but routine use of the tests is limited by their invasive nature and cost. Multiparametric perfusion CMR is promising as a non-invasive alternative to reference invasive tests of coronary vascular function. I present novel insights into the mechanistic effects of RIPC and recombinant relaxin-2 on coronary vascular function in patients with stable CAD, and these studies inform the limited evidence base for disease-modifying agents. Current ongoing clinical trials in our research group will inform these uncertainties and define comprehensively endotyped patients in whom novel disease-modifying agents may be investigated.

Published
2019
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14. A multisystem, cardio-renal investigation of post-COVID-19 illness

Author

Morrow, Andrew J., Sykes, Robert, McIntosh, Alasdair, Kamdar, Anna, Bagot, Catherine, Bayes, Hannah K., Blyth, Kevin G., Briscoe, Michael, Bulluck, Heerajnarain, Carrick, David, Church, Colin, Corcoran, David, Findlay, Iain, Gibson, Vivienne B., Gillespie, Lynsey, Grieve, Douglas, Hall Barrientos, Pauline, Ho, Antonia, Lang, Ninian N., Lennie, Vera, Lowe, David J., Macfarlane, Peter W., Mark, Patrick B., Mayne, Kaitlin J., McConnachie, Alex, McGeoch, Ross, McGinley, Christopher, McKee, Connor, Nordin, Sabrina, Payne, Alexander, Rankin, Alastair J., Robertson, Keith E., Roditi, Giles, Ryan, Nicola, Sattar, Naveed, Allwood-Spiers, Sarah, Stobo, David, Touyz, Rhian M., Veldtman, Gruschen, Watkins, Stuart, Weeden, Sarah, Weir, Robin A., Welsh, Paul, Wereski, Ryan, Mangion, Kenneth, and Berry, Colin

Published
2022
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15. Genetics and the geography of health, behaviour and attainment

Author

Belsky, Daniel W, Caspi, Avshalom, Arseneault, Louise, Corcoran, David L, Domingue, Benjamin W, Harris, Kathleen Mullan, Houts, Renate M, Mill, Jonathan S, Moffitt, Terrie E, Prinz, Joseph, Sugden, Karen, Wertz, Jasmin, Williams, Benjamin, and Odgers, Candice L

Subjects
Public Health, Health Sciences, Pediatric, Mental Health, Aetiology, 2.3 Psychological, social and economic factors, Mental health, Generic health relevance, Good Health and Well Being, Adolescent, Adult, Child, Child, Preschool, Educational Status, England, Female, Genetic Predisposition to Disease, Health Surveys, Humans, Infant, Longitudinal Studies, Male, Obesity, Pregnancy, Pregnancy in Adolescence, Residence Characteristics, Risk Assessment, Schizophrenia, Socioeconomic Factors, United States, Wales, Young Adult, Biomedical and clinical sciences, Health sciences, Psychology
Abstract

Young people's life chances can be predicted by characteristics of their neighbourhood1. Children growing up in disadvantaged neighbourhoods exhibit worse physical and mental health and suffer poorer educational and economic outcomes than children growing up in advantaged neighbourhoods. Increasing recognition that aspects of social inequalities tend, in fact, to be geographical inequalities2-5 is stimulating research and focusing policy interest on the role of place in shaping health, behaviour and social outcomes. Where neighbourhood effects are causal, neighbourhood-level interventions can be effective. Where neighbourhood effects reflect selection of families with different characteristics into different neighbourhoods, interventions should instead target families or individuals directly. To test how selection may affect different neighbourhood-linked problems, we linked neighbourhood data with genetic, health and social outcome data for >7,000 European-descent UK and US young people in the E-Risk and Add Health studies. We tested selection/concentration of genetic risks for obesity, schizophrenia, teen pregnancy and poor educational outcomes in high-risk neighbourhoods, including genetic analysis of neighbourhood mobility. Findings argue against genetic selection/concentration as an explanation for neighbourhood gradients in obesity and mental health problems. By contrast, modest genetic selection/concentration was evident for teen pregnancy and poor educational outcomes, suggesting that neighbourhood effects for these outcomes should be interpreted with care.

Published
2019

19. Investigating the activation mechanism of discoidin domain receptor 1 using advanced microscopy techniques

Author

Corcoran, David Stephen, Leitinger, Birgit, and Ying, Liming

Subjects
610
Abstract

The discoidin domain receptors (DDR1 and DDR2) are unusual receptor tyrosine kinases (RTKs) that function as collagen receptors and regulate cell migration, adhesion, and differentiation. Ligand binding to the extracellular region of RTKs results in kinase activity and autophosphorylation of tyrosine residues on the intracellular side. For most RTKs, the molecular mechanism of receptor activation involves ligand-induced dimerisation. However, the DDRs exist as constitutive dimers in the absence of collagen. In addition, it is thought ligand-induced conformational changes within the DDR dimer cannot be transferred to the intracellular side. The DDRs also activate very slowly, over hours rather than seconds to minutes as is typical for other RTKs. As such, the DDRs employ a unique activation mechanism that is currently poorly understood. In this thesis, I investigate the activation mechanism of DDR1 using various microscopy techniques. DDR1 was found to be distributed on the cell surface in distinct puncta that are dependent on specific transmembrane interactions. Collagen is known to bind to a binding trench on the extracellular discoidin domain of DDR1, and here the data show collagen binding requires another site, the conserved "signalling patch" residues, which may be a secondary collagen binding site or a site for DDR1-protein interactions essential for collagen binding. Within 5 minutes of collagen binding, DDR1 redistributes on the cell surface, and over 60 minutes of stimulation DDR1 increasingly aggregates. DDR1 phosphorylation correlates with the increasing aggregation. In addition, the aggregation results in DDR1 molecules moving within 10 nm of each other, and preliminary experiments suggest this occurs between DDR1 dimers. Ligand-independent aggregation of DDR1, through incubation with a pentameric IgM antibody, also results in DDR1 phosphorylation. This thesis supports an activation mechanism where collagen binding promotes DDR1 aggregation between DDR1 dimers, which may be required for phosphorylation to occur.

Published
2018
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21. Atrx deletion impairs CGAS/STING signaling and increases sarcoma response to radiation and oncolytic herpesvirus

Author

Floyd, Warren, Pierpoint, Matthew, Su, Chang, Patel, Rutulkumar, Luo, Lixia, Deland, Katherine, Wisdom, Amy J., Zhu, Daniel, Ma, Yan, DeWitt, Suzanne Bartholf, Williams, Nerissa T., Lazarides, Alexander L., Somarelli, Jason A., Corcoran, David L., Eward, William C., Cardona, Diana M., and Kirsch, David G.

Subjects
Sarcoma -- Genetic aspects -- Care and treatment -- Development and progression, Cyclic guanylic acid -- Physiological aspects -- Health aspects, Radiotherapy -- Usage, Health care industry
Abstract

ATRX is one of the most frequently altered genes in solid tumors, and mutation is especially frequent in soft tissue sarcomas. However, the role of ATRX in tumor development and response to cancer therapies remains poorly understood. Here, we developed a primary mouse model of soft tissue sarcoma and showed that Atrx-deleted tumors were more sensitive to radiation therapy and to oncolytic herpesvirus. In the absence of Atrx, irradiated sarcomas had increased persistent DNA damage, telomere dysfunction, and mitotic catastrophe. Our work also showed that Atrx deletion resulted in downregulation of the CGAS/STING signaling pathway at multiple points in the pathway and was not driven by mutations or transcriptional downregulation of the CGAS/STING pathway components. We found that both human and mouse models of Atrx-deleted sarcoma had a reduced adaptive immune response, markedly impaired CGAS/STING signaling, and increased sensitivity to TVEC, an oncolytic herpesvirus that is currently FDA approved for the treatment of aggressive melanomas. Translation of these results to patients with ATRX-mutant cancers could enable genomically guided cancer therapy approaches to improve patient outcomes., Introduction ATRX, or [alpha]-thalassemia/mental retardation, X-linked, is a chromatin remodeling protein and tumor suppressor, with mutations or copy number alterations occurring in approximately 6% of the more than 65,163 tumors [...]

Published
2023
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22. Using DNA from Mothers and Children to Study Parental Investment in Children's Educational Attainment

Author

Wertz, Jasmin, Moffitt, Terrie E., Agnew-Blais, Jessica, Arseneault, Louise, Belsky, Daniel W., Corcoran, David L., Houts, Renate, Matthews, Timothy, Prinz, Joseph A., Richmond-Rakerd, Leah S., Sugden, Karen, Williams, Benjamin, and Caspi, Avshalom

Abstract

This study tested implications of new genetic discoveries for understanding the association between parental investment and children's educational attainment. A novel design matched genetic data from 860 British mothers and their children with home-visit measures of parenting: the E-Risk Study. Three findings emerged. First, both mothers' and children's education-associated genetics, summarized in a genome-wide polygenic score, were associated with parenting--a gene-environment correlation. Second, accounting for genetic influences slightly reduced associations between parenting and children's attainment--indicating some genetic confounding. Third, mothers' genetics were associated with children's attainment over and above children's own genetics, via cognitively stimulating parenting--an environmentally mediated effect. Findings imply that, when interpreting parents' effects on children, environmentalists must consider genetic transmission, but geneticists must also consider environmental transmission.

Published
2020
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23. Analysis of DNA Methylation in Young People: Limited Evidence for an Association Between Victimization Stress and Epigenetic Variation in Blood

Author

Marzi, Sarah J, Sugden, Karen, Arseneault, Louise, Belsky, Daniel W, Burrage, Joe, Corcoran, David L, Danese, Andrea, Fisher, Helen L, Hannon, Eilis, Moffitt, Terrie E, Odgers, Candice L, Pariante, Carmine, Poulton, Richie, Williams, Benjamin S, Wong, Chloe CY, Mill, Jonathan, and Caspi, Avshalom

Subjects
Mental Health, Pediatric, Basic Behavioral and Social Science, Genetics, Violence Research, Prevention, Behavioral and Social Science, Violence Against Women, Youth Violence, Human Genome, 2.3 Psychological, social and economic factors, Aetiology, 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, Mental health, Peace, Justice and Strong Institutions, Adolescent, Age Factors, Child, Child Abuse, Child, Preschool, Crime Victims, DNA Methylation, Epigenesis, Genetic, Genes, Humans, Longitudinal Studies, Stress, Psychological, Epigenetics, Maltreatment, Stress, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

ObjectiveDNA methylation has been proposed as an epigenetic mechanism by which early-life experiences become "embedded" in the genome and alter transcriptional processes to compromise health. The authors sought to investigate whether early-life victimization stress is associated with genome-wide DNA methylation.MethodThe authors tested the hypothesis that victimization is associated with DNA methylation in the Environmental Risk (E-Risk) Longitudinal Study, a nationally representative 1994-1995 birth cohort of 2,232 twins born in England and Wales and assessed at ages 5, 7, 10, 12, and 18 years. Multiple forms of victimization were ascertained in childhood and adolescence (including physical, sexual, and emotional abuse; neglect; exposure to intimate-partner violence; bullying; cyber-victimization; and crime).ResultsEpigenome-wide analyses of polyvictimization across childhood and adolescence revealed few significant associations with DNA methylation in peripheral blood at age 18, but these analyses were confounded by tobacco smoking and/or did not survive co-twin control tests. Secondary analyses of specific forms of victimization revealed sparse associations with DNA methylation that did not replicate across different operationalizations of the same putative victimization experience. Hypothesis-driven analyses of six candidate genes in the stress response (NR3C1, FKBP5, BDNF, AVP, CRHR1, SLC6A4) did not reveal predicted associations with DNA methylation in probes annotated to these genes.ConclusionsFindings from this epidemiological analysis of the epigenetic effects of early-life stress do not support the hypothesis of robust changes in DNA methylation in victimized young people. We need to come to terms with the possibility that epigenetic epidemiology is not yet well matched to experimental, nonhuman models in uncovering the biological embedding of stress.

Published
2018

24. Transcriptional profiling reveals distinct classes of parathyroid tumors in PHPT

Author

Koh, James, Hogue, Joyce A, Roman, Sanziana A, Scheri, Randall P, Fradin, Hèléne, Corcoran, David L, and Sosa, Julie A

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Genetics, Cancer, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Adenoma, Adult, Aged, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Hyperparathyroidism, Primary, Male, Middle Aged, Parathyroid Neoplasms, primary hyperparathyroidism, parathyroid adenoma, tumor profiling, gene expression, Biological Sciences, Medical and Health Sciences, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract

The clinical presentation of primary hyperparathyroidism (PHPT) varies widely, although the underlying mechanistic reasons for this disparity remain unknown. We recently reported that parathyroid tumors can be functionally segregated into two distinct groups on the basis of their relative responsiveness to ambient calcium, and that patients in these groups differ significantly in their likelihood of manifesting bone disability. To examine the molecular basis for this phenotypic variation in PHPT, we compared the global gene expression profiles of calcium-sensitive and calcium-resistant parathyroid tumors. RNAseq and proteomic analysis identified a candidate set of differentially expressed genes highly correlated with calcium-sensing capacity. Subsequent quantitative assessment of the expression levels of these genes in an independent cohort of parathyroid tumors confirmed that calcium-sensitive tumors cluster in a discrete transcriptional profile group. These data indicate that PHPT is not an etiologically monolithic disorder and suggest that divergent molecular mechanisms could drive the observed phenotypic differences in PHPT disease course, provenance, and outcome.

Published
2018

25. Auto-loaded TRAIL-exosomes derived from induced neural stem cells for brain cancer therapy

Author

Zhang, Xiaopei, primary, Taylor, Hannah, additional, Valdivia, Alain, additional, Dasari, Rajaneekar, additional, Buckley, Andrew, additional, Bonacquisti, Emily, additional, Nguyen, Juliane, additional, Kanchi, Krishna, additional, Corcoran, David L., additional, Herring, Laura E., additional, Steindler, Dennis A., additional, Baldwin, Albert, additional, Hingtgen, Shawn, additional, and Satterlee, Andrew Benson, additional

Published
2024
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26. Association between the FTO rs9939609 single nucleotide polymorphism and dietary adherence during a 2-year caloric restriction intervention: Exploratory analyses from CALERIE™ phase 2

Author

Dorling, James L., Belsky, Daniel W., Racette, Susan B., Das, Sai Krupa, Ravussin, Eric, Redman, Leanne M., Höchsmann, Christoph, Huffman, Kim M., Kraus, William E., Kobor, Michael S., MacIsaac, Julia L., Lin, David T.S., Corcoran, David L., and Martin, Corby K.

Published
2021
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27. ENTPD1 (CD39) Expression Inhibits UVR-Induced DNA Damage Repair through Purinergic Signaling and Is Associated with Metastasis in Human Cutaneous Squamous Cell Carcinoma

Author

Whitley, Melodi Javid, Suwanpradid, Jutamas, Lai, Chester, Jiang, Simon W., Cook, Jonathan L., Zelac, Daniel E., Rudolph, Ross, Corcoran, David L., Degan, Simone, Spasojevic, Ivan, Levinson, Howard, Erdmann, Detlev, Reid, Claire, Zhang, Jennifer Y., Robson, Simon C., Healy, Eugene, Havran, Wendy L., and MacLeod, Amanda S.

Published
2021
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28. Prurigo Nodularis Is Characterized by Systemic and Cutaneous T Helper 22 Immune Polarization

Author

Belzberg, Micah, Alphonse, Martin Prince, Brown, Isabelle, Williams, Kyle A., Khanna, Raveena, Ho, Byron, Wongvibulsin, Shannon, Pritchard, Thomas, Roh, Youkyung Sophie, Sutaria, Nishadh, Choi, Justin, Jedrych, Jaroslaw, Johnston, Andrew D., Sarkar, Kakali, Vasavda, Chirag, Meixiong, Jimmy, Dillen, Carly, Bondesgaard, Kent, Paolini, John F., Chen, Wei, Corcoran, David, Devos, Nicolas, Kwatra, Madan M., Chien, Anna L., Archer, Nathan K., Garza, Luis A., Dong, Xinzhong, Kang, Sewon, and Kwatra, Shawn G.

Published
2021
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31. A Multidimensional Bioinformatic Platform for the Study of Human Response to Surgery

Author

Eckhoff, Austin M., Connor, Ashton A., Thacker, Julie K. M., Blazer, Dan G., Moore, Harvey G., Scheri, Randall P., Lagoo-Deenadayalan, Sandhya A., Harpole, David H., Seymour, Keri A., Purves, J. Todd, Ravindra, Kadiyala V., Southerland, Kevin W., Rocke, Daniel J., Gilner, Jennifer B., Parker, Daniel C., Bain, James R., Muehlbauer, Michael J., Ilkayeva, Olga R., Corcoran, David L., Modliszewski, Jennifer L., Devos, Nicolas, Foster, Matthew W., Moseley, M. Arthur, Dressman, Holly K., Chan, Cliburn, Huebner, Janet L., Chasse, Scott, Stempora, Linda, Aschenbrenner, Mary E., Joshi, Mary-Beth, Hollister, Beth, Henao, Ricardo, Barfield, Richard T., Ellison, Mark A., Bailey, Sean, Woody, Stephen, Huang, Erich S., Kirk, Allan, and Hwang, E. Shelley

Published
2022
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35. 1-Year Outcomes of Angina Management Guided by Invasive Coronary Function Testing (CorMicA)

Author

Ford, Thomas J., Stanley, Bethany, Sidik, Novalia, Good, Richard, Rocchiccioli, Paul, McEntegart, Margaret, Watkins, Stuart, Eteiba, Hany, Shaukat, Aadil, Lindsay, Mitchell, Robertson, Keith, Hood, Stuart, McGeoch, Ross, McDade, Robert, Yii, Eric, McCartney, Peter, Corcoran, David, Collison, Damien, Rush, Christopher, Sattar, Naveed, McConnachie, Alex, Touyz, Rhian M., Oldroyd, Keith G., and Berry, Colin

Published
2020
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36. Investigating the genetic architecture of noncognitive skills using GWAS-by-subtraction

Author

Demange, Perline A., Malanchini, Margherita, Mallard, Travis T., Biroli, Pietro, Cox, Simon R., Grotzinger, Andrew D., Tucker-Drob, Elliot M., Abdellaoui, Abdel, Arseneault, Louise, van Bergen, Elsje, Boomsma, Dorret I., Caspi, Avshalom, Corcoran, David L., Domingue, Benjamin W., Harris, Kathleen Mullan, Ip, Hill F., Mitchell, Colter, Moffitt, Terrie E., Poulton, Richie, Prinz, Joseph A., Sugden, Karen, Wertz, Jasmin, Williams, Benjamin S., de Zeeuw, Eveline L., Belsky, Daniel W., Harden, K. Paige, and Nivard, Michel G.

Published
2021
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38. Perspectives on Unidirectional versus Divergent Transcription.

Author

Duttke, Sascha HC, Lacadie, Scott A, Ibrahim, Mahmoud M, Glass, Christopher K, Corcoran, David L, Benner, Christopher, Heinz, Sven, Kadonaga, James T, and Ohler, Uwe

Subjects
Humans, RNA Polymerase II, Models, Genetic, Promoter Regions, Genetic, Biological Sciences, Medical and Health Sciences, Developmental Biology
Published
2015

39. Human promoters are intrinsically directional.

Author

Duttke, Sascha HC, Lacadie, Scott A, Ibrahim, Mahmoud M, Glass, Christopher K, Corcoran, David L, Benner, Christopher, Heinz, Sven, Kadonaga, James T, and Ohler, Uwe

Subjects
Hela Cells, Humans, RNA Polymerase II, Sequence Analysis, DNA, Transcription, Genetic, Transcription Initiation Site, Models, Genetic, Promoter Regions, Genetic, HeLa Cells, Genetics, Underpinning research, 1.1 Normal biological development and functioning, Generic health relevance, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Divergent transcription, in which reverse-oriented transcripts occur upstream of eukaryotic promoters in regions devoid of annotated genes, has been suggested to be a general property of active promoters. Here we show that the human basal RNA polymerase II transcriptional machinery and core promoter are inherently unidirectional and that reverse-oriented transcripts originate from their own cognate reverse-directed core promoters. In vitro transcription analysis and mapping of nascent transcripts in HeLa cells revealed that sequences at reverse start sites are similar to those of their forward counterparts. The use of DNase I accessibility to define proximal promoter borders revealed that about half of promoters are unidirectional and that unidirectional promoters are depleted at their upstream edges of reverse core promoter sequences and their associated chromatin features. Divergent transcription is thus not an inherent property of the transcription process but rather the consequence of the presence of both forward- and reverse-directed core promoters.

Published
2015

41. Epigenome-wide Association Study of Attention-Deficit/Hyperactivity Disorder Symptoms in Adults

Author

Heijmans, Bastiaan T., ’t Hoen, Peter A.C., van Meurs, Joyce, Isaacs, Aaron, Jansen, Rick, Franke, Lude, Boomsma, Dorret I., Pool, René, van Dongen, Jenny, Hottenga, Jouke J., van Greevenbroek, Marleen M.J., Stehouwer, Coen D.A., van der Kallen, Carla J.H., Schalkwijk, Casper G., Wijmenga, Cisca, Zhernakova, Sasha, Tigchelaar, Ettje F., Slagboom, P. Eline, Beekman, Marian, Deelen, Joris, van Heemst, Diana, Veldink, Jan H., van den Berg, Leonard H., van Duijn, Cornelia M., Hofman, Bert A., Uitterlinden, André G., Jhamai, P. Mila, Verbiest, Michael, Suchiman, H. Eka D., Verkerk, Marijn, van der Breggen, Ruud, van Rooij, Jeroen, Lakenberg, Nico, Mei, Hailiang, van Iterson, Maarten, van Galen, Michiel, Bot, Jan, Zhernakova, Dasha V., Hof, Peter van ’t, Deelen, Patrick, Nooren, Irene, Moed, Matthijs, Vermaat, Martijn, Luijk, René, Bonder, Marc Jan, van Dijk, Freerk, Arindrarto, Wibowo, Kielbasa, Szymon M., Swertz, Morris A., van Zwet, Erik. W., Hoen, Peter-Bram ’t, Zilhão, Nuno R., Sugden, Karen, Hannon, Eilis J., Mill, Jonathan, Caspi, Avshalom, Agnew-Blais, Jessica, Arseneault, Louise, Corcoran, David L., Moffitt, Terrie E., Poulton, Richie, and Franke, Barbara

Published
2019
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43. Stratified Medical Therapy Using Invasive Coronary Function Testing in Angina: The CorMicA Trial

Author

Ford, Thomas J., Stanley, Bethany, Good, Richard, Rocchiccioli, Paul, McEntegart, Margaret, Watkins, Stuart, Eteiba, Hany, Shaukat, Aadil, Lindsay, Mitchell, Robertson, Keith, Hood, Stuart, McGeoch, Ross, McDade, Robert, Yii, Eric, Sidik, Novalia, McCartney, Peter, Corcoran, David, Collison, Damien, Rush, Christopher, McConnachie, Alex, Touyz, Rhian M., Oldroyd, Keith G., and Berry, Colin

Published
2018
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44. MODL-44. DEVELOPMENT OF A NOVEL, PERSONALIZED DRUG SENSITIVITY SCORE TO ASSESS TUMOR KILLING AND TOXICITY WITHIN AN ORGANOTYPIC BRAIN SLICE CULTURE PLATFORM

Author

Mann, Breanna, primary, Zhang, Xiaopei, additional, Bell, Noah, additional, Adefolaju, Adebimpe, additional, Thang, Morrent, additional, Dasari, Rajaneekar, additional, Kanchi, Krishna, additional, Valdivia, Alain, additional, Yang, Yang, additional, Buckley, Andrew, additional, Lettry, Vivien, additional, Quinsey, Carolyn, additional, Rauf, Yasmeen, additional, Kram, David, additional, Cassidy, Noah, additional, Vaziri, Cyrus, additional, Corcoran, David L, additional, Rego, Stephen, additional, Jiang, Yuchao, additional, Graves, Lee M, additional, Dunn, Denise, additional, Floyd, Scott, additional, Baldwin, Albert, additional, Hingtgen, Shawn, additional, and Satterlee, Andrew B, additional

Published
2023
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45. MODL-28. LIVING EX VIVO ORGANOTYPIC BRAIN SLICE CULTURES AS A COMPREHENSIVE SUBSTRATE FOR TUMOR ENGRAFTMENT AND ANALYSIS

Author

Adefolaju, Adebimpe, primary, Mann, Breanna, additional, Zhang, Xiaopei, additional, Bell, Noah, additional, Thang, Morrent, additional, Dasari, Rajaneekar, additional, Kanchi, Krishna, additional, Valdivia, Alain, additional, Yang, Yang, additional, Buckley, Andrew, additional, Lettry, Vivien, additional, Quinsey, Carolyn, additional, Rauf, Yasmeen, additional, Kram, David, additional, Cassidy, Noah, additional, Vaziri, Cyrus, additional, Corcoran, David L, additional, Rego, Stephen, additional, Jiang, Yuchao, additional, Graves, Lee M, additional, Dunn, Denise, additional, Floyd, Scott, additional, Baldwin, Albert, additional, Hingtgen, Shawn, additional, and Satterlee, Andrew B, additional

Published
2023
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46. CNSC-39. GENERATION AND CHARACTERIZATION OF LIVING ORGANOTYPIC BRAIN SLICE CULTURES AS A NOVEL PRE-CLINICAL MODEL FOR BRAIN CANCER

Author

Dasari, Rajaneekar, primary, Mann, Breanna, additional, Zhang, Xiaopei, additional, Bell, Noah, additional, Adefolaju, Adebimpe, additional, Thang, Morrent, additional, Kanchi, Krishna, additional, Valdivia, Alain, additional, Yang, Yang, additional, Buckley, Andrew, additional, Lettry, Vivien, additional, Quinsey, Carolyn, additional, Rauf, Yasmeen, additional, Kram, David, additional, Cassidy, Noah, additional, Vaziri, Cyrus, additional, Corcoran, David L, additional, Rego, Stephen, additional, Jiang, Yuchao, additional, Graves, Lee M, additional, Dunn, Denise, additional, Floyd, Scott, additional, Baldwin, Albert, additional, Hingtgen, Shawn, additional, and Satterlee, Andrew B, additional

Published
2023
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47. MODL-03. AN EX VIVO PLATFORM BASED ON ORGANOTYPIC BRAIN SLICE CULTURE FOR INFORMING PERSONALIZED BRAIN CANCER THERAPY

Author

Zhang, Xiaopei, primary, Mann, Breanna, additional, Bell, Noah, additional, Adefolaju, Adebimpe, additional, Thang, Morrent, additional, Dasari, Rajaneekar, additional, Kanchi, Krishna, additional, Valdivia, Alain, additional, Yang, Yang, additional, Buckley, Andrew, additional, Lettry, Vivien, additional, Quinsey, Carolyn, additional, Rauf, Yasmeen, additional, Kram, David, additional, Cassidy, Noah, additional, Vaziri, Cyrus, additional, Corcoran, David L, additional, Rego, Stephen, additional, Jiang, Yuchao, additional, Graves, Lee M, additional, Dunn, Denise, additional, Floyd, Scott, additional, Baldwin, Albert, additional, Hingtgen, Shawn, additional, and Satterlee, Andrew B, additional

Published
2023
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49. Calorie restriction modulates the transcription of genes related to stress response and longevity in human muscle: The CALERIE study

Author

Das, Jayanta Kumar, primary, Banskota, Nirad, additional, Candia, Julián, additional, Griswold, Michael E., additional, Orenduff, Melissa, additional, de Cabo, Rafael, additional, Corcoran, David L., additional, Das, Sai Krupa, additional, De, Supriyo, additional, Huffman, Kim Marie, additional, Kraus, Virginia B., additional, Kraus, William E., additional, Martin, Corby K., additional, Racette, Susan B., additional, Redman, Leanne M., additional, Schilling, Birgit, additional, Belsky, Daniel W., additional, and Ferrucci, Luigi, additional

Published
2023
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50. Invasive Endotyping in Patients With Angina and No Obstructive Coronary Artery Disease: A Randomized Controlled Trial

Author

Sidik, Novalia P., primary, Stanley, Bethany, additional, Sykes, Robert, additional, Morrow, Andrew J., additional, Bradley, Conor P., additional, McDermott, Michael, additional, Ford, Thomas J., additional, Roditi, Giles, additional, Hargreaves, Allister, additional, Stobo, David, additional, Adams, Jacqueline, additional, Byrne, John, additional, Mahrous, Ahmed, additional, Young, Robin, additional, Carrick, David, additional, McGeoch, Ross, additional, Corcoran, David, additional, Lang, Ninian N., additional, Heggie, Robert, additional, Wu, Olivia, additional, McEntegart, Margaret B., additional, McConnachie, Alex, additional, and Berry, Colin, additional

Published
2023
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