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52. Collection Analysis: Powerful Ways To Collect, Analyze, and Present Your Data.

Author

Hart, Amy

Abstract

Discussion of collection analysis in school libraries focuses on the kinds of data used and how to use library automation software to collect the data. Describes the use of Microsoft Excel and its chart-making capabilities to enhance the presentation of the analysis and suggests ways to use collection analysis output. (LRW)

Published
2003

53. Su1743 GUSELKUMAB BINDING TO CD64+ IL-23–PRODUCING MYELOID CELLS ENHANCES POTENCY FOR NEUTRALIZING IL-23 SIGNALING

Author

Abreu, Maria T., Atreya, Raja, Krueger, James G., Eyerich, Kilian, Greving, Carrie, Hammaker, Deepa, Stoveken, Brian, Hartman, John, Leppard, Kristin L., Sarabia, Indra, Wertheimer, Joshua, Deming, Janise, Kohler, Kristen, Li, He (., Freeman, Tom C., Hart, Amy, Keyes, Brice, Ritchlin, Christopher, McInnes, Iain B., Allez, Matthieu, Fourie, Anne M., and Sachen, Kacey

Published
2024
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54. Su1732 GUSELKUMAB INDUCTION RESTORES INTESTINAL IMMUNE HOMEOSTASIS AND PROMOTES EPITHELIAL REPAIR IN MODERATELY TO SEVERELY ACTIVE ULCERATIVE COLITIS

Author

Sridhar, Sunan, Hart, Amy, Venkat, Swati, Ruane, Darren, Horowitz, Dan, Lee, Tae, Waterworth, Dawn M., Huang, Kuan-Hsiang G., Germinaro, Matthew, Vetter, Marion, Cua, Daniel, Freeman, Tom C., Sisk, Christopher, Mcrae, Bradford, Verstockt, Bram, Rubin, David T., Sands, Bruce E., and Branigan, Patrick

Published
2024
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56. Identification of RIPK3 Type II Inhibitors Using High-Throughput Mechanistic Studies in Hit Triage

Author

Charu Chaudhry, Ping Zhang, Kyoung S. Kim, William J. Pitts, Cornelius Lyndon A M, Lynn M. Abell, Hart Amy C, Kevin O’Malley, Junqing Guo, Brian Carpenter, Hao Lu, Ramesh Padmanabha, Patrick J. Shaw, Mertzman Michael E, Kevin Kish, Andrew E Douglas, Matthew Pokross, John E. Macor, Deepa Calambur, and Carolyn A. Weigelt

Subjects
010405 organic chemistry, Kinase, Chemistry, Necroptosis, Organic Chemistry, Computational biology, 01 natural sciences, Biochemistry, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, Drug Discovery, Transferase, Identification (biology), Signal transduction
Abstract

[Image: see text] Necroptosis has been implicated in a variety of disease states, and RIPK3 is one of the kinases identified to play a critical role in this signaling pathway. In an effort to identify RIPK3 kinase inhibitors with a novel profile, mechanistic studies were incorporated at the hit triage stage. Utilization of these assays enabled identification of a Type II DFG-out inhibitor for RIPK3, which was confirmed by protein crystallography. Structure-based drug design on the inhibitors targeting this previously unreported conformation enabled an enhancement in selectivity against key off-target kinases.

Published
2019
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60. Getting Ready for RDA: What You Need to Know

Author

Hart, Amy

Abstract

Resource Description and Access (RDA) represents both a revised set of cataloging rules and a completely new framework in which to catalog. It aims for backward compatibility with AACR2 at the same time that it seeks to facilitate moving library data to the Semantic Web. Given these competing goals, it's not surprising that RDA's implementation will be an ongoing process. In some ways, this will make initial implementation simpler. The good news is that RDA records will be compatible with AACR2 records, can be expressed in MARC format, and will not require major changes to existing library systems. Nonetheless, it should be recognized that because RDA is built on the conceptual models Functional Requirements for Bibliographic Records (FRBR) and Functional Requirements for Authority Data (FRAD), its structure and vocabulary are very different from AACR2 and will take some getting used to. Finally, RDA is poised to move library data into the future and onto the Semantic Web. The path from here to there is not fully charted, but the first steps are underway. (Contains 1 figure, 1 resource and 7 online resources.)

Published
2010

62. Biopsy and blood-based molecular biomarker of inflammation in IBD

Author

Argmann, Carmen, Hou, Ruixue, Ungaro, Ryan C, Irizar, Haritz, Al-Taie, Zainab, Huang, Ruiqi, Kosoy, Roman, Venkat, Swati, Song, Won-Min, Di'Narzo, Antonio F, Losic, Bojan, Hao, Ke, Peters, Lauren, Comella, Phillip H, Wei, Gabrielle, Atreja, Ashish, Mahajan, Milind, Iuga, Alina, Desai, Prerak T, Branigan, Patrick, Stojmirovic, Aleksandar, Perrigoue, Jacqueline, Brodmerkel, Carrie, Curran, Mark, Friedman, Joshua R, Hart, Amy, Lamousé-Smith, Esi, Wehkamp, Jan, Mehandru, Saurabh, Schadt, Eric E, Sands, Bruce E, Dubinsky, Marla C, Colombel, Jean-Frederic, Kasarskis, Andrew, and Suárez-Fariñas, Mayte

Abstract

ObjectiveIBD therapies and treatments are evolving to deeper levels of remission. Molecular measures of disease may augment current endpoints including the potential for less invasive assessments.DesignTranscriptome analysis on 712 endoscopically defined inflamed (Inf) and 1778 non-inflamed (Non-Inf) intestinal biopsies (n=498 Crohn’s disease, n=421 UC and 243 controls) in the Mount Sinai Crohn’s and Colitis Registry were used to identify genes differentially expressed between Inf and Non-Inf biopsies and to generate a molecular inflammation score (bMIS) via gene set variance analysis. A circulating MIS (cirMIS) score, reflecting intestinal molecular inflammation, was generated using blood transcriptome data. bMIS/cirMIS was validated as indicators of intestinal inflammation in four independent IBD cohorts.ResultsbMIS/cirMIS was strongly associated with clinical, endoscopic and histological disease activity indices. Patients with the same histologic score of inflammation had variable bMIS scores, indicating that bMIS describes a deeper range of inflammation. In available clinical trial data sets, both scores were responsive to IBD treatment. Despite similar baseline endoscopic and histologic activity, UC patients with lower baseline bMIS levels were more likely treatment responders compared with those with higher levels. Finally, among patients with UC in endoscopic and histologic remission, those with lower bMIS levels were less likely to have a disease flare over time.ConclusionTranscriptionally based scores provide an alternative objective and deeper quantification of intestinal inflammation, which could augment current clinical assessments used for disease monitoring and have potential for predicting therapeutic response and patients at higher risk of disease flares.

Published
2023
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63. FRBR and School Libraries

Author

Hart, Amy

Abstract

This article discusses the Functional Requirements for Bibliographic Records (FRBR), a plan that is quickly gaining the support of library organizations around the globe. The FRBR Study Group was appointed by International Federation of Library Associations (IFLA) and issued its final report in 1998. The report redefines the basic unit of cataloging. In current practice, the MARC record represents a physical bibliographic entity. In contrast, FRBR recommends cataloging over four primary levels of bibliographic existence (or entities), and it parses out the elements of today's records across them. These four primary entities are: Works; Expressions; Manifestations; and Items. Although FRBR is a complex theoretical model, library media specialists will recognize the basic components of a catalog record (author, title, and subject) in its three entity groups.

Published
2006

64. 603 IBD-ASSOCIATED DYSBIOSIS IN UNAFFECTED RELATIVES OF IBD PATIENTS EMERGES IN LATE ADOLESCENCE AND INCREASES WITH AGE

Author

Jacobs, Jonathan P., primary, Yang, Julianne C., additional, Spencer, Elizabeth A., additional, Gettler, Kyle, additional, Cho, Judy H., additional, Colombel, Jean Frederic, additional, Helmus, Drew, additional, Mercedes, Pamela Reyes, additional, Hart, Amy, additional, Lamouse-Smith, Esi, additional, Wehkamp, Jan, additional, Landers, Carol, additional, Debbas, Philip, additional, Bongers, Gerold, additional, Dubinsky, Marla, additional, Faith, Jeremiah, additional, and Braun, Jonathan G., additional

Published
2021
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65. Sa473 RISK PROFILING OF UNAFFECTED MEMBERS OF FAMILIES WITH A HISTORY OF IBD USING SEROLOGY SCORE, DYSBIOSIS SCORE, POLYGENIC RISK SCORE, AND FECAL CALPROTECTIN

Author

Jacobs, Jonathan P., primary, Spencer, Elizabeth A., additional, Gettler, Kyle, additional, Cho, Judy H., additional, Colombel, Jean Frederic, additional, Helmus, Drew, additional, Mercedes, Pamela Reyes, additional, Hart, Amy, additional, Lamouse-Smith, Esi, additional, Wehkamp, Jan, additional, Landers, Carol, additional, Debbas, Philip, additional, Bongers, Gerold, additional, Faith, Jeremiah, additional, Braun, Jonathan G., additional, and Dubinsky, Marla, additional

Published
2021
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67. Phenotypic and transcriptomic changes associated with potato autopolyploidization

Author

Stupar, Robert M., Bhaskar, Pudota B., Yandell, Brian S., Rensink, Willem A., Hart, Amy L., Ouyang, Shu, Veilleux, Richard E., Busse, James S., Erhardt, Robert J., Buell, C. Robin, and Jiang, Jiming

Subjects
Genetic transcription -- Evaluation, Phenotype -- Properties, Autopolyploidy -- Research, Potatoes -- Genetic aspects, Biological sciences
Abstract

Polyploidy is remarkably common in the plant kingdom and polyploidization is a major driving force for plant genome evolution. Polyploids may contain genomes from different parental species (allopolyploidy) or include multiple sets of the same genome (autopolyploidy). Genetic and epigenetic changes associated with allopolyploidization have been a major research subject in recent years. However, we know little about the genetic impact imposed by autopolyploidization. We developed a synthetic autopolyploid series in potato (Solanum phureja) that includes one monoploid (1x) clone, two diploid (2x) clones, and one tetraploid (4x) clone. Cell size and organ thickness were positively correlated with the ploidy level. However, the 2x plants were generally the most vigorous and the lx plants exhibited less vigor compared to the 2x and 4x individuals. We analyzed the transcriptomic variation associated with this autopolyploid series using a potato cDNA microarray containing ~9000 genes. Statistically significant expression changes were observed among the ploidies for ~10% of the genes in both leaflet and root tip tissues. However, most changes were associated with the monoploid and were within the twofold level. Thus, alteration of pioidy caused subtle expression changes of a substantial percentage of genes in the potato genome. We demonstrated that there are few genes, if any, whose expression is linearly correlated with the ploidy and can be dramatically changed because of ploidy alteration.

Published
2007

68. Development of a series of novel o-phenylenediamine-based indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors

Author

M. Jure-Kunkel, Jay A. Markwalder, Weifang Shan, Bin Chen, Steven P. Seitz, Andrew Nation, John T. Hunt, Lauren Haque, Gregory D. Vite, Jennifer Donnell, David K. Williams, Kelly L. Covello, Aaron Balog, Hart Amy C, Sunil Kumar Mandal, and Libing Chen

Subjects
0301 basic medicine, Clinical Biochemistry, Pharmaceutical Science, Phenylenediamines, Biochemistry, HeLa, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Immune system, o-Phenylenediamine, Drug Discovery, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase, Potency, Enzyme Inhibitors, Indoleamine 2,3-dioxygenase, Molecular Biology, chemistry.chemical_classification, Tumor microenvironment, biology, Organic Chemistry, biology.organism_classification, 030104 developmental biology, Enzyme, chemistry, 030220 oncology & carcinogenesis, Microsomes, Liver, Cancer research, Molecular Medicine, Kynurenine, HeLa Cells
Abstract

A novel series of o-phenylenediamine-based inhibitors of indoleamine 2,3-dioxygenase (IDO) has been identified. IDO is a heme-containing enzyme, overexpressed in the tumor microenvironment of many cancers, which can contribute to the suppression of the host immune system. Synthetic modifications to a previously described diarylether series resulted in an additional degree of molecular diversity which was exploited to afford compounds that demonstrated significant potency in the HeLa human cervical cancer IDO1 assay. .

Published
2018
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70. Polygenic risk score for alcohol drinking behavior improves prediction of inflammatory bowel disease risk

Author

Di Narzo, Antonio F, primary, Hart, Amy, additional, Kosoy, Roman, additional, Peters, Lauren, additional, Stojmirovic, Aleksandar, additional, Cheng, Haoxiang, additional, Zhang, Zhongyang, additional, Shan, Mingxu, additional, Cho, Judy, additional, Kasarskis, Andrew, additional, Argmann, Carmen, additional, Peter, Inga, additional, Schadt, Eric E, additional, and Hao, Ke, additional

Published
2021
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72. Comparative analyses of potato expressed sequence tag libraries (1)

Author

Ronning, Catherine M., Stegalkina, Svetlana S., Ascenzi, Robert A., Bougri, Oleg, Hart, Amy L., Utterbach, Teresa R., Vanaken, Susan E., Riedmuller, Steve B., White, Joseph A., Cho, Jennifer, Pertea, Geo M., Lee, Yuandan, Karamycheva, Svetlana, Sultana, Razvan, Tsai, Jennifer, Quackenbush, John, Griffiths, Helen M., Restrepo, Silvia, Smart, Christine D., Fry, William E., van der Hoeven, Rutger, Tanksley, Steve, Zhang, Peifen, Jin, Hailing, Yamamoto, Miki L., Baker, Barbara J., and Buell, C. Robin

Subjects
Potatoes -- Research, Potatoes -- Properties, Potatoes -- Comparative analysis, Solanaceae -- Properties, Solanaceae -- Genetic aspects, Solanaceae -- Comparative analysis, Tomatoes -- Properties, Tomatoes -- Genetic aspects, Tomatoes -- Comparative analysis, Biological sciences, Science and technology
Published
2003

74. Pathogenic Activation of Mesenchymal Stem Cells Is Induced by the Disease Microenvironment in Systemic Sclerosis

Author

Taki, Zeinab, primary, Gostjeva, Elena, additional, Thilly, William, additional, Yaseen, Bodoor, additional, Lopez, Henry, additional, Mirza, Maria, additional, Hassuji, Zainab, additional, Vigneswaran, Shivanee, additional, Ahmed Abdi, Bahja, additional, Hart, Amy, additional, Arumalla, Nikita, additional, Thomas, Gemma, additional, Denton, Christopher P., additional, Suleman, Yasir, additional, Liu, Huan, additional, Venturini, Cristina, additional, O'Reilly, Steven, additional, Xu, Shiwen, additional, and Stratton, Richard, additional

Published
2020
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81. Identification of RIPK3 Type II Inhibitors Using High-Throughput Mechanistic Studies in Hit Triage

Author

Hart, Amy C., primary, Abell, Lynn, additional, Guo, Junqing, additional, Mertzman, Michael E., additional, Padmanabha, Ramesh, additional, Macor, John E., additional, Chaudhry, Charu, additional, Lu, Hao, additional, O’Malley, Kevin, additional, Shaw, Patrick J., additional, Weigelt, Carolyn, additional, Pokross, Matthew, additional, Kish, Kevin, additional, Kim, Kyoung S., additional, Cornelius, Lyndon, additional, Douglas, Andrew E., additional, Calambur, Deepa, additional, Zhang, Ping, additional, Carpenter, Brian, additional, and Pitts, William J., additional

Published
2019
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87. Structure-Based Design of Selective Janus Kinase 2 Imidazo[4,5-d]pyrrolo[2,3-b]pyridine Inhibitors

Author

Hart Amy C, Javed Khan, Grebinski James W, James Kempson, Jonathan Lippy, Gretchen M. Schroeder, Theresa M. McDevitt, Ashok V. Purandare, Ragini Vuppugalla, John S. Tokarski, George L. Trainor, Junqing Guo, Jennifer Inghrim, Matthew V. Lorenzi, Dan You, Honghe Wan, John S. Sack, William J. Pitts, Yueping Zhang, and Louis J. Lombardo

Subjects
Janus kinase 2, biology, Kinase, Organic Chemistry, Hit to lead, Biochemistry, Combinatorial chemistry, chemistry.chemical_compound, chemistry, Drug Discovery, Pyridine, biology.protein, Side chain, Structure based, Selectivity, Thiazole
Abstract

Early hit to lead work on a pyrrolopyridine chemotype provided access to compounds with biochemical and cellular potency against Janus kinase 2 (JAK2). Structure-based drug design along the extended hinge region of JAK2 led to the identification of an important H-bond interaction with the side chain of Tyr 931, which improved JAK family selectivity. The 4,5-dimethyl thiazole analogue 18 demonstrated high levels of JAK family selectivity and was identified as a promising lead for the program.

Published
2015
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88. Prospective Countywide Surveillance and Autopsy Characterization of Sudden Cardiac Death: POST SCD Study.

Author

Tseng, Zian H, Tseng, Zian H, Olgin, Jeffrey E, Vittinghoff, Eric, Ursell, Philip C, Kim, Anthony S, Sporer, Karl, Yeh, Clement, Colburn, Benjamin, Clark, Nina M, Khan, Rana, Hart, Amy P, Moffatt, Ellen, Tseng, Zian H, Tseng, Zian H, Olgin, Jeffrey E, Vittinghoff, Eric, Ursell, Philip C, Kim, Anthony S, Sporer, Karl, Yeh, Clement, Colburn, Benjamin, Clark, Nina M, Khan, Rana, Hart, Amy P, and Moffatt, Ellen

Abstract

BackgroundStudies of out-of-hospital cardiac arrest and sudden cardiac death (SCD) use emergency medical services records, death certificates, or definitions that infer cause of death; thus, the true incidence of SCD is unknown. Over 90% of SCDs occur out-of-hospital; nonforensic autopsies are rarely performed, and therefore causes of death are presumed. We conducted a medical examiner-based investigation to determine the precise incidence and autopsy-defined causes of all SCDs in an entire metropolitan area. We hypothesized that postmortem investigation would identify actual sudden arrhythmic deaths among presumed SCDs.MethodsBetween February 1, 2011, and March 1, 2014, we prospectively identified all incident deaths attributed to out-of-hospital cardiac arrest (emergency medical services primary impression, cardiac arrest) between 18 to 90 years of age in San Francisco County for autopsy, toxicology, and histology via medical examiner surveillance of consecutive out-of-hospital deaths, all reported by law. We obtained comprehensive records to determine whether out-of-hospital cardiac arrest deaths met World Health Organization (WHO) criteria for SCD. We reviewed death certificates filed quarterly for missed SCDs. Autopsy-defined sudden arrhythmic deaths had no extracardiac cause of death or acute heart failure. A multidisciplinary committee adjudicated final cause.ResultsAll 20 440 deaths were reviewed; 12 671 were unattended and reported to the medical examiner. From these, we identified 912 out-of-hospital cardiac arrest deaths; 541 (59%) met WHO SCD criteria (mean 62.8 years, 69% male) and 525 (97%) were autopsied. Eighty-nine additional WHO-defined SCDs occurred within 3 weeks of active medical care with the death certificate signed by the attending physician, ineligible for autopsy but included in the countywide WHO-defined SCD incidence of 29.6/100 000 person-years, highest in black men (P<0.0001). Of 525 WHO-defined SCDs, 301 (57%) had no cardiac history

Published
2018

90. Collision of transitional cell carcinoma and renal cell carcinoma: an immunohistochemical study and review of the literature

Author

Hart, Amy P., Brown, Richard, Lechago, Juan, and Truong, Luan D.

Subjects
Carcinoma, Renal cell -- Diagnosis, Kidney cancer -- Diagnosis, Health
Abstract

A case characterized by a rare synchronous occurrence of transitional cell carcinoma (TCC) of the renal pelvis and renal cell carcinoma (RCC) in the same kidney is presented. A retrospective analysis of 23 similar cases reported in the English literature over the last 71 years demonstrated a male-to-female ratio of 2:1, an average age of 64.5 years, and a left-to-right-side ratio of 3.2:1. The three most common findings at initial examination were hematuria (90%), flank pain (19%), and flank mass (14%). Moreover, 24% of patients had tumor metastases even at initial examination. Thirty-four percent of patients had bladder neoplasms, and 24% of them had a history of cigarette smoking. There is no tendency toward higher grade of malignancy or specific histologic pattern for TCC and RCC when they occur together in the same kidney. Immunohistochemical studies were used to examine TCC and RCC, with special attention paid to the site of their collision, which displayed multifocal lymphatic permeation. Both TCC and RCC were positive for epithelial membrane antigen (EMA) and cytokeratins identified by monoclonal antibodies CAM-5.2, AE1/AE3, and MAK-6. TCC was focally positive for keratin, detectable by antibody 34[beta]E12, but RCC was not. The tumor tissue infiltrating the lymphatics, which seemed to be RCC, demonstrated positive staining for EMA and keratins CAM-5.2, AE1/AE3, and MAK-6 and negative staining for keratin 34[beta]E12. Interestingly, the tumor in lymphatics displayed strong staining for carcinoembryonic antigen (CEA) but both TCC and RCC in the vicinity were negative. These findings suggest that keratin 34[beta]E12 may play a role in the differential diagnosis between TCC and RCC and that tumor-invading lymphatics may change phenotype, including the neoexpression of CEA.

Published
1994

91. TRENDS IN APPLICATION OF GREEN STAR SA CREDITS IN SOUTH AFRICAN GREEN BUILDING.

Author

Hoffman, Danie, Ling-Yi Huang, van Rensburg, Jean, and Yorke-Hart, Amy

Subjects
CREDIT, EDUCATIONAL attainment, OFFICE buildings, CONSTRUCTION industry
Abstract

Copyright of Acta Structilia is the property of University of the Free State and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Published
2020
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92. Operation Cleanup: The Problem Resolution Phase of a Retrospective Conversion Project.

Author

Hart, Amy

Abstract

Examines the problem resolution phase of a retrospective conversion project of monographic records at the University of Massachusetts-Amherst (UMass). The kinds of problems encountered are categorized and discussed. Suggestions for developing editing guidelines are offered, and the guidelines developed for standardization of problem resolution at UMass are presented. (four references) (Author/MES)

Published
1988

95. Diosphenol-based approach to the A-ring functionalization of advanced taxol precursors

Author

Hart, Amy C., Kreilein, Matthew M., Hofferberth, John E., and Paquette, Leo A.

Subjects
Carbon compounds -- Chemical properties, Biological sciences, Chemistry
Abstract

Many different approaches to the A ring functionalization of an advanced, highly functionalized diosphenol precursor to Taxol are described. Sodium borohydride reduction operates from the beta-face of C-14 as long as the C-1 hydroxyl is not protected so as to offer steric exclusion.

Published
2006

96. Total synthesis of (+)-cylindramide A

Author

Hart, Amy C. and Phillips, Andrew J.

Subjects
Ring-opening polymerization -- Analysis, Polyenes -- Structure, Polyenes -- Chemical properties, Nuclear magnetic resonance -- Analysis, Chemistry
Abstract

A study is conducted on the structure of cylindramide A, a macrocyclic tetramic and isolated from the sponge Halichondria cylindrata that is cytotoxic to B16 melanoma cells with an IC(sub 50) of 0.8 mug mL(super -1). It is concluded that a synthesis of cylindramide A is delineated that proceeds in 19 steps which is the longest linear sequence and highlights the utility of the tandem ring-opening-ring-closing-cross metathesis of simple norbornenes in the context of complex natural products synthesis.

Published
2006

97. 1,3-Dicyclohexylcarbodiimide

Author

Albert, Jeffrey S., primary, Hamilton, Andrew D., additional, Hart, Amy C., additional, Feng, Xiaoming, additional, Lin, Lili, additional, and Wang, Zhen, additional

Published
2017
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99. Genome-wide association study identifies novel locus for neuroticism and shows polygenic association with Major Depressive Disorder

Author

de Moor, Marleen H.M., van den Berg, Stéphanie M., Verweij, Karin J.H., Krueger, Robert F., Luciano, Michelle, Vasquez, Alejandro Arias, Matteson, Lindsay K., Derringer, Jaime, Esko, Tõnu, Amin, Najaf, Gordon, Scott D., Hansell, Narelle K., Hart, Amy B., Seppälä, Ilkka, Huffman, Jennifer E., Konte, Bettina, Lahti, Jari, Lee, Minyoung, Miller, Mike, Nutile, Teresa, Tanaka, Toshiko, Teumer, Alexander, Viktorin, Alexander, Wedenoja, Juho, Abecasis, Goncalo R., Adkins, Daniel E., Agrawal, Arpana, Allik, Jüri, Appel, Katja, Bigdeli, Timothy B., Busonero, Fabio, Campbell, Harry, Costa, Paul T., Smith, George Davey, Davies, Gail, de Wit, Harriet, Ding, Jun, Engelhardt, Barbara E., Eriksson, Johan G., Fedko, Iryna O., Ferrucci, Luigi, Franke, Barbara, Giegling, Ina, Grucza, Richard, Hartmann, Annette M., Heath, Andrew C., Heinonen, Kati, Henders, Anjali K., Homuth, Georg, Hottenga, Jouke-Jan, Janzing, Joost, Jokela, Markus, Karlsson, Robert, Kemp, John P., Kirkpatrick, Matthew G., Latvala, Antti, Lehtimäki, Terho, Liewald, David C., Madden, Pamela A.F., Magri, Chiara, Magnusson, Patrik K.E., Marten, Jonathan, Maschio, Andrea, Medland, Sarah E., Mihailov, Evelin, Milaneschi, Yuri, Montgomery, Grant W., Nauck, Matthias, Ouwens, Klaasjan G., Palotie, Aarno, Pettersson, Erik, Polasek, Ozren, Qian, Yong, Pulkki-Råback, Laura, Raitakari, Olli T., Realo, Anu, Rose, Richard J., Ruggiero, Daniela, Schmidt, Carsten O., Slutske, Wendy S., Sorice, Rossella, Starr, John M., Pourcain, Beate St, Sutin, Angelina R., Timpson, Nicholas J., Trochet, Holly, Vermeulen, Sita, Vuoksimaa, Eero, Widen, Elisabeth, Wouda, Jasper, Wright, Margaret J., Zgaga, Lina, Scotland, Generation, Porteous, David, Minelli, Alessandra, Palmer, Abraham A., Rujescu, Dan, Ciullo, Marina, Hayward, Caroline, Rudan, Igor, Metspalu, Andres, Kaprio, Jaakko, Deary, Ian J., Räikkönen, Katri, Wilson, James F., Keltikangas-Järvinen, Liisa, Bierut, Laura J., Hettema, John M., Grabe, Hans J., van Duijn, Cornelia M., Evans, David M., Schlessinger, David, Pedersen, Nancy L., Terracciano, Antonio, McGue, Matt, Penninx, Brenda W.J.H., Martin, Nicholas G., and Boomsma, Dorret I.

Subjects
Neuroticism, Depressive Disorder, Major, Multifactorial Inheritance, Cell Adhesion Molecules, Neuronal, Anxiety Disorders, Polymorphism, Single Nucleotide, Article, Risk Factors, Humans, Genetic Predisposition to Disease, Cell Adhesion Molecules, Guanylate Kinases, Adaptor Proteins, Signal Transducing, Genome-Wide Association Study, Personality
Abstract

Neuroticism is a pervasive risk factor for psychiatric conditions. It genetically overlaps with major depressive disorder (MDD) and is therefore an important phenotype for psychiatric genetics. The Genetics of Personality Consortium has created a resource for genome-wide association analyses of personality traits in more than 63,000 participants (including MDD cases).To identify genetic variants associated with neuroticism by performing a meta-analysis of genome-wide association results based on 1000 Genomes imputation; to evaluate whether common genetic variants as assessed by single-nucleotide polymorphisms (SNPs) explain variation in neuroticism by estimating SNP-based heritability; and to examine whether SNPs that predict neuroticism also predict MDD.Genome-wide association meta-analysis of 30 cohorts with genome-wide genotype, personality, and MDD data from the Genetics of Personality Consortium. The study included 63,661 participants from 29 discovery cohorts and 9786 participants from a replication cohort. Participants came from Europe, the United States, or Australia. Analyses were conducted between 2012 and 2014.Neuroticism scores harmonized across all 29 discovery cohorts by item response theory analysis, and clinical MDD case-control status in 2 of the cohorts.A genome-wide significant SNP was found on 3p14 in MAGI1 (rs35855737; P = 9.26 × 10-9 in the discovery meta-analysis). This association was not replicated (P = .32), but the SNP was still genome-wide significant in the meta-analysis of all 30 cohorts (P = 2.38 × 10-8). Common genetic variants explain 15% of the variance in neuroticism. Polygenic scores based on the meta-analysis of neuroticism in 27 cohorts significantly predicted neuroticism (1.09 × 10-12 P .05) and MDD (4.02 × 10-9 P .05) in the 2 other cohorts.This study identifies a novel locus for neuroticism. The variant is located in a known gene that has been associated with bipolar disorder and schizophrenia in previous studies. In addition, the study shows that neuroticism is influenced by many genetic variants of small effect that are either common or tagged by common variants. These genetic variants also influence MDD. Future studies should confirm the role of the MAGI1 locus for neuroticism and further investigate the association of MAGI1 and the polygenic association to a range of other psychiatric disorders that are phenotypically correlated with neuroticism.

Published
2015

100. High-Resolution Genotyping of Formalin-Fixed Tissue Accurately Estimates Polygenic Risk Scores in Human Diseases

Author

Youssef, Omar, Loukola, Anu, Zidi-Mouaffak, Yossra H.S., Tamlander, Max, Ruotsalainen, Sanni, Kilpeläinen, Elina, Mars, Nina, Ripatti, Samuli, Palotie, Aarno, Daly, Mark, Riley-Gills, Bridget, Jacob, Howard, Paul, Dirk, Petrovski, Slavé, Runz, Heiko, John, Sally, Okafo, George, Lawless, Nathan, Salminen-Mankonen, Heli, Plenge, Robert, Maranville, Joseph, McCarthy, Mark, Ehm, Margaret G., Auro, Kirsi, Longerich, Simonne, Mälarstig, Anders, Klinger, Katherine, Chatelain, Clement, Gossel, Matthias, Estrada, Karol, Graham, Robert, Yang, Robert, ODonnell, Chris, Mäkelä, Tomi P., Kaprio, Jaakko, Virolainen, Petri, Hakanen, Antti, Kilpi, Terhi, Perola, Markus, Partanen, Jukka, Pitkäranta, Anne, Raivio, Taneli, Tikkanen, Jani, Serpi, Raisa, Laitinen, Tarja, Kosma, Veli-Matti, Laukkanen, Jari, Hautalahti, Marco, Tuovila, Outi, Pakkanen, Raimo, Waring, Jeffrey, Riley-Gillis, Bridget, Rahimov, Fedik, Tachmazidou, Ioanna, Chen, Chia-Yen, Runz, Heiko, Ding, Zhihao, Jung, Marc, Biswas, Shameek, Pendergrass, Rion, Ehm, Margaret G., Pulford, David, Raghavan, Neha, Huertas-Vazquez, Adriana, Sul, Jae-Hoon, Mälarstig, Anders, Hu, Xinli, Hedman, Åsa, Klinger, Katherine, Graham, Robert, Rivas, Manuel, Waterworth, Dawn, Renaud, Nicole, Obeidat, Maen, Ripatti, Samuli, Schleutker, Johanna, Perola, Markus, Arvas, Mikko, Carpén, Olli, Hinttala, Reetta, Kettunen, Johannes, Mannermaa, Arto, Aalto-Setälä, Katriina, Kähönen, Mika, Laukkanen, Jari, Mäkelä, Johanna, Kälviäinen, Reetta, Julkunen, Valtteri, Soininen, Hilkka, Remes, Anne, Hiltunen, Mikko, Peltola, Jukka, Raivio, Minna, Tienari, Pentti, Rinne, Juha, Kallionpää, Roosa, Partanen, Juulia, Abbasi, Ali, Ziemann, Adam, Smaoui, Nizar, Lehtonen, Anne, Eaton, Susan, Runz, Heiko, Lahdenperä, Sanni, Biswas, Shameek, Bowers, Natalie, Teng, Edmond, Pendergrass, Rion, Xu, Fanli, Pulford, David, Auro, Kirsi, Addis, Laura, Eicher, John, Li, Qingqin S., He, Karen, Khramtsova, Ekaterina, Raghavan, Neha, Färkkilä, Martti, Koskela, Jukka, Pikkarainen, Sampsa, Jussila, Airi, Kaukinen, Katri, Blomster, Timo, Kiviniemi, Mikko, Voutilainen, Markku, Daly, Mark, Abbasi, Ali, Waring, Jeffrey, Smaoui, Nizar, Rahimov, Fedik, Lehtonen, Anne, Lu, Tim, Bowers, Natalie, Pendergrass, Rion, McCarthy, Linda, Hart, Amy, Guan, Meijian, Miller, Jason, Kalpala, Kirsi, Miller, Melissa, Hu, Xinli, Eklund, Kari, Palomäki, Antti, Isomäki, Pia, Pirilä, Laura, Kaipiainen-Seppänen, Oili, Huhtakangas, Johanna, Mars, Nina, Abbasi, Ali, Waring, Jeffrey, Rahimov, Fedik, Lertratanakul, Apinya, Smaoui, Nizar, Lehtonen, Anne, Viollet, Coralie, Hochfeld, Marla, Bowers, Natalie, Pendergrass, Rion, Gordillo, Jorge Esparza, Auro, Kirsi, Waterworth, Dawn, Farias, Fabiana, Kalpala, Kirsi, Bing, Nan, Hu, Xinli, Laitinen, Tarja, Pelkonen, Margit, Kauppi, Paula, Kankaanranta, Hannu, Harju, Terttu, Lahesmaa, Riitta, Smaoui, Nizar, Viollet, Coralie, Eaton, Susan, Chen, Hubert, Pendergrass, Rion, Bowers, Natalie, Betts, Joanna, Auro, Kirsi, Mishra, Rajashree, Mouded, Majd, Ngo, Debby, Niiranen, Teemu, Vaura, Felix, Salomaa, Veikko, Metsärinne, Kaj, Aittokallio, Jenni, Kähönen, Mika, Hernesniemi, Jussi, Gordin, Daniel, Sinisalo, Juha, Taskinen, Marja-Riitta, Tuomi, Tiinamaija, Hiltunen, Timo, Laukkanen, Jari, Elliott, Amanda, Reeve, Mary Pat, Ruotsalainen, Sanni, Paul, Dirk, Bowers, Natalie, Pendergrass, Rion, Chu, Audrey, Auro, Kirsi, Reilly, Dermot, Mendelson, Mike, Parkkinen, Jaakko, Miller, Melissa, Meretoja, Tuomo, Joensuu, Heikki, Carpén, Olli, Mattson, Johanna, Salminen, Eveliina, Auranen, Annika, Karihtala, Peeter, Auvinen, Päivi, Elenius, Klaus, Schleutker, Johanna, Pitkänen, Esa, Mars, Nina, Daly, Mark, Popovic, Relja, Waring, Jeffrey, Riley-Gillis, Bridget, Lehtonen, Anne, Fabre, Margarete, Schutzman, Jennifer, Bowers, Natalie, Pendergrass, Rion, Kulkarni, Diptee, Auro, Kirsi, Porello, Alessandro, Loboda, Andrey, Lehtonen, Heli, McDonough, Stefan, Vuoti, Sauli, Kaarniranta, Kai, Turunen, Joni A., Ollila, Terhi, Uusitalo, Hannu, Karjalainen, Juha, Pitkänen, Esa, Liu, Mengzhen, Runz, Heiko, Loomis, Stephanie, Strauss, Erich, Bowers, Natalie, Chen, Hao, Pendergrass, Rion, Tasanen, Kaisa, Huilaja, Laura, Hannula-Jouppi, Katariina, Salmi, Teea, Peltonen, Sirkku, Koulu, Leena, Smaoui, Nizar, Rahimov, Fedik, Lehtonen, Anne, Choy, David, Pendergrass, Rion, Waterworth, Dawn, Kalpala, Kirsi, Wu, Ying, Pussinen, Pirkko, Salminen, Aino, Salo, Tuula, Rice, David, Nieminen, Pekka, Palotie, Ulla, Siponen, Maria, Suominen, Liisa, Mäntylä, Päivi, Gursoy, Ulvi, Anttonen, Vuokko, Sipilä, Kirsi, Pendergrass, Rion, Laivuori, Hannele, Kurra, Venla, Kotaniemi-Talonen, Laura, Heikinheimo, Oskari, Kalliala, Ilkka, Aaltonen, Lauri, Jokimaa, Varpu, Kettunen, Johannes, Vääräsmäki, Marja, Uimari, Outi, Morin-Papunen, Laure, Niinimäki, Maarit, Piltonen, Terhi, Kivinen, Katja, Widen, Elisabeth, Tukiainen, Taru, Reeve, Mary Pat, Daly, Mark, Välimäki, Niko, Laakkonen, Eija, Tyrmi, Jaakko, Silven, Heidi, Sliz, Eeva, Arffman, Riikka, Savukoski, Susanna, Laisk, Triin, Pujol, Natalia, Liu, Mengzhen, Riley-Gillis, Bridget, Pendergrass, Rion, Kumar, Janet, Auro, Kirsi, Hovatta, Iiris, Chen, Chia-Yen, Isometsä, Erkki, Ollila, Hanna, Suvisaari, Jaana, Als, Thomas Damm, Mäkitie, Antti, Bizaki-Vallaskangas, Argyro, Toppila-Salmi, Sanna, Willberg, Tytti, Saarentaus, Elmo, Aarnisalo, Antti, Salminen, Eveliina, Rahikkala, Elisa, Kettunen, Johannes, Aittomäki, Kristiina, Åberg, Fredrik, Kurki, Mitja, Ripatti, Samuli, Daly, Mark, Karjalainen, Juha, Havulinna, Aki, Mehtonen, Juha, Palta, Priit, Hassan, Shabbeer, Della Briotta Parolo, Pietro, Zhou, Wei, Maasha, Mutaamba, Hassan, Shabbeer, Lemmelä, Susanna, Rivas, Manuel, Palotie, Aarno, Liu, Aoxing, Lehisto, Arto, Ganna, Andrea, Llorens, Vincent, Laivuori, Hannele, Tukiainen, Taru, Reeve, Mary Pat, Heyne, Henrike, Mars, Nina, Rämö, Joel, Saarentaus, Elmo, Ollila, Hanna, Rodosthenous, Rodos, Strausz, Satu, Palotie, Tuula, Palin, Kimmo, Garcia-Tabuenca, Javier, Siirtola, Harri, Kiiskinen, Tuomo, Lee, Jiwoo, Tsuo, Kristin, Elliott, Amanda, Kristiansson, Kati, Arvas, Mikko, Hyvärinen, Kati, Ritari, Jarmo, Carpén, Olli, Kettunen, Johannes, Pylkäs, Katri, Sliz, Eeva, Karjalainen, Minna, Mantere, Tuomo, Kangasniemi, Eeva, Heikkinen, Sami, Mannermaa, Arto, Laakkonen, Eija, Pitkänen, Nina, Lessard, Samuel, Chatelain, Clément, Kallio, Lila, Wahlfors, Tiina, Partanen, Jukka, Punkka, Eero, Serpi, Raisa, Siltanen, Sanna, Kosma, Veli-Matti, Kuopio, Teijo, Jalanko, Anu, Shen, Huei-Yi, Kajanne, Risto, Aavikko, Mervi, Cooper, Helen, Öller, Denise, Leinonen, Rasko, Palin, Henna, Linna, Malla-Maria, Kurki, Mitja, Karjalainen, Juha, Della Briotta Parolo, Pietro, Lehisto, Arto, Mehtonen, Juha, Zhou, Wei, Kanai, Masahiro, Maasha, Mutaamba, Zheng, Zhili, Laivuori, Hannele, Havulinna, Aki, Lemmelä, Susanna, Kiiskinen, Tuomo, Lahtela, L. Elisa, Kaunisto, Mari, Kilpeläinen, Elina, Sipilä, Timo P., Dada, Oluwaseun Alexander, Ghazal, Awaisa, Kytölä, Anastasia, Weldatsadik, Rigbe, Ruotsalainen, Sanni, Donner, Kati, Sipilä, Timo P., Loukola, Anu, Laiho, Päivi, Sistonen, Tuuli, Kaiharju, Essi, Laukkanen, Markku, Järvensivu, Elina, Lähteenmäki, Sini, Männikkö, Lotta, Wong, Regis, Toivola, Auli, Brunfeldt, Minna, Mattsson, Hannele, Kristiansson, Kati, Lemmelä, Susanna, Koskelainen, Sami, Hiekkalinna, Tero, Paajanen, Teemu, Palta, Priit, Pärn, Kalle, Kals, Mart, Luo, Shuang, Laitinen, Tarja, Reeve, Mary Pat, Padmanabhuni, Shanmukha Sampath, Niemi, Marianna, Siirtola, Harri, Gracia-Tabuenca, Javier, Helminen, Mika, Luukkaala, Tiina, Vähätalo, Iida, Tammerluoto, Jyrki, Hautalahti, Marco, Mäkelä, Johanna, Smith, Sarah, Southerington, Tom, Lehto, Petri, Palotie, Aarno, Donner, Kati, and Carpén, Olli

Abstract

Formalin-fixed paraffin-embedded (FFPE) tissues stored in biobanks and pathology archives are a vast but underutilized source for molecular studies on different diseases. Beyond being the “gold standard” for preservation of diagnostic human tissues, FFPE samples retain similar genetic information as matching blood samples, which could make FFPE samples an ideal resource for genomic analysis. However, research on this resource has been hindered by the perception that DNA extracted from FFPE samples is of poor quality. Here, we show that germline disease-predisposing variants and polygenic risk scores (PRS) can be identified from FFPE normal tissue (FFPE-NT) DNA with high accuracy. We optimized the performance of FFPE-NT DNA on a genome-wide array containing 657,675 variants. Via a series of testing and validation phases, we established a protocol for FFPE-NT genotyping with results comparable with blood genotyping. The median call rate of FFPE-NT samples in the validation phase was 99.85% (range 98.26%-99.94%) and median concordance with matching blood samples was 99.79% (range 98.85%-99.9%). We also demonstrated that a rare pathogenic PALB2variant predisposing to cancer can be correctly identified in FFPE-NT samples. We further imputed the FFPE-NT genotype data and calculated the FFPE-NT genome-wide PRS in 3 diseases and 4 disease risk variables. In all cases, FFPE-NT and matching blood PRS were highly concordant (all Pearson’s r> 0.95). The ability to precisely genotype FFPE-NT on a genome-wide array enables translational genomics applications of archived FFPE-NT samples with the possibility to link to corresponding phenotypes and longitudinal health data.

Published
2024
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