Author: "Roy, H." / Topic: biology - Searchworks@Jio Institute Digital Library Search Results

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1. Increased learning observed in redesigned introductory biology course that employed web-enhanced, interactive pedagogy.

Author: McDaniel CN, Lister BC, Hanna MH, and Roy H
Subjects: Curriculum, Humans, Universities, Biology education, Internet, Learning, Teaching methods
Abstract: Our Introduction to Biology course (BIOL 1010) changed in 2004 from a standard instructor-centered, lecture-homework-exam format to a student-centered format that used Web-enhanced, interactive pedagogy. To measure and compare conceptual learning gains in the traditional course in fall 2003 with a section of the interactive course in fall 2004, we created concept inventories for both evolution and ecology. Both classes were taught by the same instructor who had taught BIOL 1010 since 1976, and each had a similar student composition with comparable biological knowledge. A significant increase in learning gain was observed with the Web-enhanced, interactive pedagogy in evolution (traditional, 0.10; interactive, 0.19; p = 0.024) and ecology (traditional, -0.05; interactive, 0.14; p = 0.000009) when assessment was made unannounced and for no credit in the last week of classes. These results strengthen the case for augmenting or replacing instructor-centered teaching with Web-enhanced, interactive, student-centered teaching. When assessment was made using the final exam in the interactive course, for credit and after studying, significantly greater learning gains were made in evolution (95%, 0.37, p = 0.0001) and ecology (143%, 0.34, p = 0.000003) when compared with learning gains measured without credit or study in the last week of classes.
Published: 2007
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2. Artificial light at night disrupts species interactions and changes insect communities

Author: Roy H. A. van Grunsven and Maja Grubisic
Subjects: education.field_of_study, Insecta, Artificial light, Ecology, media_common.quotation_subject, Population, Biodiversity, Insect, Moths, Biology, Nocturnal, Insect Science, Animals, Ecosystem, Cascading effects, education, Ecology, Evolution, Behavior and Systematics, media_common, Trophic level
Abstract: Artificial light at night (ALAN) is globally increasing, posing a threat to biodiversity. The impact of nocturnal illumination on individual insects has been relatively well documented. Recent studies show that ALAN also impacts species interactions, including intra-specific communication, trophic interactions and plant-pollinator interactions, with cascading effects in the ecosystem and impacts on ecosystem functioning that extend beyond nocturnal communities and illuminated areas. Reduced population sizes and changes in community composition because of exposure to ALAN have been reported but the understanding of the impacts of ALAN on insect communities is currently limited to few groups and ecosystems. The theoretical framework on how ALAN impacts insect communities and populations is poorly developed, limiting our understanding and the formulation of relevant hypotheses.
Published: 2021

3. Calculating population reductions of invertebrate species for IUCN Red List assessments

Author: Sérgio Henriques, H. Resit Akçakaya, Geert De Knijf, John P. Simaika, Jason T. Bried, Axel Hochkirch, and Roy H. A. van Grunsven
Subjects: 0106 biological sciences, education.field_of_study, Extinction, Ecology, Population, Biodiversity, Biology, 010603 evolutionary biology, 01 natural sciences, 010602 entomology, Population decline, Animal ecology, Insect Science, Threatened species, IUCN Red List, Animal Science and Zoology, education, Nature and Landscape Conservation, Invertebrate
Abstract: Population reductions are often used to assess extinction risk of species in the IUCN Red List. Guidelines for Red List assessments describe specific methods for calculating the amount of reduction for species with strongly fluctuating populations. Recently, an alternative approach that involves expert opinion has been suggested for calculating population reduction in insect species. We argue that, while populations with high temporal variability do present challenges, the alternative suggestion is unnecessary, and inconsistent with the IUCN Red List Categories and Criteria. Consistent application of standardized methods for calculating population reductions allows robust and objective assessment of extinction risk faced by invertebrate species.
Published: 2021

4. Identifying the Common Genetic Basis of Antidepressant Response

Author: Sara A. Paciga, Richard M. Weinshilboum, Andrew M. McIntosh, Tim B. Bigdeli, Stephanie H. Witt, Sven Cichon, Glyn Lewis, Henning Teismann, Brenda W.J.H. Penninx, Gerome Breen, Roseann E. Peterson, Saira Saeed Mirza, Diego Albani, Lisa Jones, Andreas J. Forstner, Sara Mostafavi, Julien Bryois, Qingqin S. Li, Kenneth S. Kendler, Thomas Damm Als, Fernando S. Goes, Marie Bækvad-Hansen, Nancy L. Pedersen, Gianluigi Forloni, Per Qvist, Carsten Horn, Per Hoffmann, Steven P. Hamilton, Georg Homuth, Michael Gill, Julien Mendlewicz, Katharina Domschke, Volker Arolt, Adrian I. Campos, Christine Søholm Hansen, Scott D. Gordon, Hogni Oskarsson, Peter McGuffin, Oliver Pain, Eric Jorgenson, Victoria S. Marshe, Stacy Steinberg, Bertram Müller-Myhsok, Mark Adams, J. Raymond DePaulo, Rick Jansen, Katherine J. Aitchison, Vassily Trubetskoy, Henry Völzke, Manuel Mattheisen, Bernard Ng, James A. Knowles, Dorret I. Boomsma, Tracy Air, Elisabeth B. Binder, Ian B. Hickie, Christel M. Middeldorp, Tõnu Esko, David M. Hougaard, E.J.C. de Geus, Toni-Kim Clarke, Helena Gaspar, Bernhard T. Baune, Abdel Abdellaoui, Engilbert Sigurdsson, Andres Metspalu, Klaus Berger, Jorge A. Quiroz, Patrick F. Sullivan, Aartjan T.F. Beekman, Thomas Hansen, Panagiotis Ferentinos, Jürgen Wellmann, Miguel E. Rentería, Daniel Umbricht, Marcella Rietschel, Stanley I. Shyn, Chiara Fabbri, Hreinn Stefansson, Jerome C. Foo, Daniel Souery, Zoltán Kutalik, Yu-Li Liu, Paul F. O'Reilly, Michael John Owen, Nese Direk, Douglas F. Levinson, Stuart Montgomery, Hamdi Mbarek, David M. Howard, Guido Bondolfi, Lucía Colodro-Conde, Pippa A. Thomson, Merete Nordentoft, Stefan Kloiber, Yunpeng Wang, Michael Conlon O'Donovan, Grant C.B. Sinnamon, Alexander Viktorin, Hilary K. Finucane, Esben Agerbo, Stefan Herms, Markus M. Nöthen, Till F. M. Andlauer, Divya Mehta, Bradley T. Webb, Joanna M. Biernacka, David J. Porteous, Jordan W. Smoller, Jonathan R. I. Coleman, Dean F. MacKinnon, Farnush Farhadi Hassan Kiadeh, Baptiste Couvy-Duchesne, Evelin Mihailov, Eleanor M. Wigmore, Franziska Degenhardt, Jianxin Shi, Dale R. Nyholt, Enda M. Byrne, Stephan Ripke, Ole Mors, Patrik K. E. Magnusson, Eric J. Lenze, Warren W. Kretzschmar, Masaki Kato, Marcus Ising, Ian Jones, Lynsey S. Hall, Wouter J. Peyrot, Ling Shen, Nader Perroud, Na Cai, Maciej Trzaskowski, Matthias Nauck, Isaac S. Kohane, Enrico Domenici, Fabian Streit, James L. Kennedy, Peter M. Visscher, Valentina Escott-Price, Donald J. MacIntyre, Enrique Castelao, Margarita Rivera, Mojca Z. Dernovsek, John P. Rice, Joseph Zohar, Gail Davies, Andrew C. Heath, Josef Frank, Wesley K. Thompson, Caroline Hayward, Penelope A. Lind, Thorgeir E. Thorgeirsson, Rudolf Uher, Jana Strohmaier, Henriette N. Buttenschøn, Erin C. Dunn, Jonas Bybjerg-Grauholm, Alexander Teumer, Jakob Grove, Eske M. Derks, Nicholas G. Martin, Jodie N. Painter, Myrna M. Weissman, Preben Bo Mortensen, Michel G. Nivard, Catherine Schaefer, Yihan Li, Daniel J. Smith, Shih-Jen Tsai, Niamh Mullins, Jian Yang, Marianne Giørtz Pedersen, Dan Rujescu, Thomas G. Schulze, Lili Milani, Yuri Milaneschi, Giorgio Pistis, James B. Potash, Neven Henigsberg, Nicholas John Craddock, Karen Hodgson, Silviu-Alin Bacanu, Shantel Weinsheimer, Charles F. Reynolds, Johannes H. Smit, Gonneke Willemsen, Futao Zhang, Henning Tiemeier, Grant W. Montgomery, Martin Preisig, Udo Dannlowski, Thalia C. Eley, Thomas Werge, Katherine E. Tansey, Jane H. Christensen, Julia Kraft, Ian J. Deary, Cathryn M. Lewis, Sarah E. Medland, André G. Uitterlinden, Daniel J. Müller, Carsten Bøcker Pedersen, Gustavo Turecki, Hans J. Grabe, Matthew Traylor, Brien P. Riley, Roy H. Perlis, Patrick J. McGrath, Conor V. Dolan, Hualin S. Xi, Jonathan Marchini, Robert A. Schoevers, Albert M. van Hemert, Anders D. Børglum, Susanne Lucae, Jouke-Jan Hottenga, Kari Stefansson, Benoit H. Mulsant, Francis M. Mondimore, Naomi R. Wray, Yang Wu, Wolfgang Maier, Danielle Posthuma, Annamaria Cattaneo, Gregory E. Crawford, Siegfried Kasper, Alessandro Serretti, Tania Carrillo-Roa, Robert Maier, Pamela A. F. Madden, Eva C. Schulte, Jens Treutlein, Joanna Hauser, Sandra Van der Auwera, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Amsterdam Neuroscience - Complex Trait Genetics, APH - Methodology, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), Adult Psychiatry, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Epidemiology, Child and Adolescent Psychiatry / Psychology, and Internal Medicine
Subjects: Oncology, MDD, medicine.medical_specialty, Single-nucleotide polymorphism, Genome-wide association study, Biology, Antidepressant response, Depression, GWAS, Genetics, Polygenic score, SDG 3 - Good Health and Well-being, Internal medicine, Genetic variation, medicine, ddc:610, Genetic association, General Medicine, Heritability, medicine.disease, Schizophrenia, Sample size determination, Settore BIO/14 - Farmacologia, Major depressive disorder
Abstract: Background: Antidepressants are a first-line treatment for depression. However, only a third of individuals experience remission after the first treatment. Common genetic variation, in part, likely regulates antidepressant response, yet the success of previous genome-wide association studies has been limited by sample size. This study performs the largest genetic analysis of prospectively assessed antidepressant response in major depressive disorder to gain insight into the underlying biology and enable out-of-sample prediction.Methods: Genome-wide analysis of remission (nremit = 1852, nnonremit = 3299) and percentage improvement (n = 5218) was performed. Single nucleotide polymorphism–based heritability was estimated using genome-wide complex trait analysis. Genetic covariance with eight mental health phenotypes was estimated using polygenic scores/AVENGEME. Out-of-sample prediction of antidepressant response polygenic scores was assessed. Gene-level association analysis was performed using MAGMA and transcriptome-wide association study. Tissue, pathway, and drug binding enrichment were estimated using MAGMA.Results: Neither genome-wide association study identified genome-wide significant associations. Single nucleotide polymorphism–based heritability was significantly different from zero for remission (h2 = 0.132, SE = 0.056) but not for percentage improvement (h2 = −0.018, SE = 0.032). Better antidepressant response was negatively associated with genetic risk for schizophrenia and positively associated with genetic propensity for educational attainment. Leave-one-out validation of antidepressant response polygenic scores demonstrated significant evidence of out-of-sample prediction, though results varied in external cohorts. Gene-based analyses identified ETV4 and DHX8 as significantly associated with antidepressant response.Conclusions: This study demonstrates that antidepressant response is influenced by common genetic variation, has a genetic overlap schizophrenia and educational attainment, and provides a useful resource for future research. Larger sample sizes are required to attain the potential of genetics for understanding and predicting antidepressant response.
Published: 2022

5. Intrinsic resistance of Enterococcus faecalis strains to ΦEf11 phage endolysin is associated with the presence of ΦEf11 prophage

Author: Roy H. Stevens and Hongming Zhang
Subjects: chemistry.chemical_classification, 0303 health sciences, biology, Strain (chemistry), 030306 microbiology, viruses, Lysin, General Medicine, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, Antimicrobial, complex mixtures, Virology, Enterococcus faecalis, Microbiology, 03 medical and health sciences, Enzyme, chemistry, Lysogenic cycle, bacteria, Gene, Prophage, 030304 developmental biology
Abstract: The use of bacteriophage-encoded murein hydrolases (endolysins) is being actively explored as a means of controlling multidrug-resistant pathogens. Previously, we isolated and characterized one such enzyme, the phage ΦEf11 ORF28 lysin, which demonstrated profound antimicrobial activity against many strains of Enterococcus faecalis. Although the lysin is eminently active against many vancomycin-resistant enterococal (VRE) strains, and displays lower minimum inhibitory concentrations than vancomycin against vancomycin-sensitive strains, there is a subset of E. faecalis strains that is not affected by the lysin. Currently, there is no explanation for the disparate sensitivity to ORF28 lysin among E. faecalis strains. In the present investigation, we show that the intrinsic insensitivity of the insusceptible strains to the lysin is associated with the presence of a ΦEf11 prophage. Of the strains harboring phage ΦEf11 genes (N = 28), 68% were insensitive to the lysin, whereas 91% of the strains (N = 75) lacking detectable ΦEf11 genes demonstrated lysin sensitivity. Furthermore, curing a lysin-resistant, lysogenic E. faecalis strain resulted in a lysin-sensitive derivative, whereas lysogenizing a wild-type non-lysogenic strain converted it from lysin sensitivity to lysin resistance. Our results suggest that lysin resistance comes about through lysogenic conversion of non-lysogenic, lysin-sensitive strains.
Published: 2020

6. Towards Global Volunteer Monitoring of Odonate Abundance

Author: Leslie Ries, Adolfo Cordero-Rivera, Paulo De Marco, Vincent J. Kalkman, Göran Sahlén, Jason T. Bried, Albert G. Orr, Filip Harabiš, Robert A. Cannings, Colin D. Jones, Mary Ann C. Perron, Gabriella J. Kietzka, Aleš Dolný, Frank Suhling, Celeste Searles Mazzacano, Michael A. Patten, Alex Córdoba-Aguilar, Joan Ball-Damerow, Adam M. Siepielski, Roy H. A. van Grunsven, Michael J. Samways, David Halstead, Brenda J. Smith, John P. Simaika, Martin Jeanmougin, Klaas-Douwe B. Dijkstra, Les G. Underhill, Erin White, Maya Rocha-Ortega, Christopher Hassall, Leandro Juen, and John C. Abbott
Subjects: education.field_of_study, Data collection, biology, business.industry, Population, Environmental resource management, Odonata, biology.organism_classification, Geography, Anthropocene, Abundance (ecology), Butterfly, Citizen science, Organizational structure, General Agricultural and Biological Sciences, education, business
Abstract: Insects are reportedly experiencing widespread declines, but we generally have sparse data on their abundance. Correcting this shortfall will take more effort than professional entomologists alone can manage. Volunteer nature enthusiasts can greatly help to monitor the abundance of dragonflies and damselflies (Odonata), iconic freshwater sentinels and one of the few nonpollinator insect groups appreciated by the public and amenable to citizen science. Although counting individual odonates is common in some locations, current data will not enable a global perspective on odonate abundance patterns and trends. Borrowing insight from butterfly monitoring efforts, we outline basic plans for a global volunteer network to count odonates, including organizational structure, advertising and recruiting, and data collection, submission, and synthesis. We hope our proposal serves as a catalyst for richer coordinated efforts to understand population trends of odonates and other insects in the Anthropocene.
Published: 2020

7. Minimal phenotyping yields genome-wide association signals of low specificity for major depression

Author: Till F. M. Andlauer, Glyn Lewis, Brenda W.J.H. Penninx, Toni-Kim Clarke, Douglas F. Levinson, Alexander Viktorin, Kenneth S. Kendler, Yuri Milaneschi, Giorgio Pistis, Nicholas G. Martin, Jordan W. Smoller, Bertram Müller-Myhsok, Mark Adams, Myrna M. Weissman, Andreas J. Forstner, Enda M. Byrne, Hans J. Grabe, Roy H. Perlis, Ole Mors, James B. Potash, Jonathan Flint, Steven P. Hamilton, Jianxin Shi, Rudolf Uher, Joana A. Revez, Sandra Van der Auwera, Fabien Streit, Na Cai, Gerome Breen, Cathryn M. Lewis, Henning Tiemeier, Martin Preisig, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, Psychiatry, APH - Digital Health, Child and Adolescent Psychiatry / Psychology, and Epidemiology
Subjects: Adult, Male, Multifactorial Inheritance, Bipolar Disorder, Genotype, Genome-wide association study, Computational biology, Disease, Biology, Polymorphism, Single Nucleotide, Sensitivity and Specificity, behavioral disciplines and activities, Genome, Article, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, mental disorders, Genetics, medicine, Humans, Genetic Predisposition to Disease, Aged, 030304 developmental biology, Genetic association, Depressive Disorder, Major, 0303 health sciences, Middle Aged, Heritability, medicine.disease, Genetic architecture, Phenotype, Major depressive disorder, Female, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Minimal phenotyping refers to the reliance on the use of a small number of self-reported items for disease case identification, increasingly used in genome-wide association studies (GWAS). Here we report differences in genetic architecture between depression defined by minimal phenotyping and strictly defined major depressive disorder (MDD): the former has a lower genotype-derived heritability that cannot be explained by inclusion of milder cases and a higher proportion of the genome contributing to this shared genetic liability with other conditions than for strictly defined MDD. GWAS based on minimal phenotyping definitions preferentially identifies loci that are not specific to MDD, and, although it generates highly predictive polygenic risk scores, the predictive power can be explained entirely by large sample sizes rather than by specificity for MDD. Our results show that reliance on results from minimal phenotyping may bias views of the genetic architecture of MDD and impede the ability to identify pathways specific to MDD.Genetic analyses of depression based on minimal phenotyping identify nonspecific genetic risk factors shared between major depressive disorder (MDD) and other psychiatric conditions, suggesting that this approach may have limited ability to identify pathways specific to MDD.
Published: 2020

8. A psychiatric disease-related circular RNA controls synaptic gene expression and cognition

Author: Brian A. Rodriguez, Jason P. Weick, Michela Dell'Orco, Jasmin Lalonde, Nikolaos Mellios, Alexander Hafez, Begum Alural, Jonathan L. Brigman, Nora I. Perrone-Bizzozero, Brigham J. Hartley, Praveen Chander, Evelyn Lozano, Kristen J. Brennand, Amber Zimmerman, Stephen J. Haggarty, Maree J. Webster, Roy H. Perlis, and Stephen K. Amoah
Subjects: Adult, Male, 0301 basic medicine, Bipolar Disorder, HOMER1, Prefrontal Cortex, Biology, Mice, 03 medical and health sciences, Cellular and Molecular Neuroscience, Cognition, 0302 clinical medicine, Homer Scaffolding Proteins, medicine, Animals, Humans, Prefrontal cortex, Molecular Biology, Regulation of gene expression, Gene knockdown, Cognitive flexibility, RNA, Circular, Middle Aged, Mice, Inbred C57BL, Dorsolateral prefrontal cortex, Psychiatry and Mental health, 030104 developmental biology, medicine.anatomical_structure, Gene Expression Regulation, Synapses, Synaptic plasticity, Schizophrenia, Female, Orbitofrontal cortex, Immediate Communication, Neuroscience, 030217 neurology & neurosurgery
Abstract: Although circular RNAs (circRNAs) are enriched in the mammalian brain, very little is known about their potential involvement in brain function and psychiatric disease. Here, we show that circHomer1a, a neuronal-enriched circRNA abundantly expressed in the frontal cortex, derived from Homer protein homolog 1 (HOMER1), is significantly reduced in both the prefrontal cortex (PFC) and induced pluripotent stem cell-derived neuronal cultures from patients with schizophrenia (SCZ) and bipolar disorder (BD). Moreover, alterations in circHomer1a were positively associated with the age of onset of SCZ in both the dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC). No correlations between the age of onset of SCZ and linear HOMER1 mRNA were observed, whose expression was mostly unaltered in BD and SCZ postmortem brain. Using in vivo circRNA-specific knockdown of circHomer1a in mouse PFC, we show that it modulates the expression of numerous alternative mRNA transcripts from genes involved in synaptic plasticity and psychiatric disease. Intriguingly, in vivo circHomer1a knockdown in mouse OFC resulted in specific deficits in OFC-mediated cognitive flexibility. Lastly, we demonstrate that the neuronal RNA-binding protein HuD binds to circHomer1a and can influence its synaptic expression in the frontal cortex. Collectively, our data uncover a novel psychiatric disease-associated circRNA that regulates synaptic gene expression and cognitive flexibility.
Published: 2020

9. Mycoplasmal and Rickettsial Infections of the CNS

Author: Roy H. Rhodes
Subjects: biology, business.industry, Intracellular parasite, Meningoencephalitis, Mycoplasma, biology.organism_classification, medicine.disease_cause, medicine.disease, Orientia, Virology, Rickettsia, medicine, Vasculitis, business, Typhus, Encephalitis
Published: 2020

10. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

Author: Gabriëlla A.M. Blokland, Jakob Grove, Chia-Yen Chen, Chris Cotsapas, Stuart Tobet, Robert Handa, David St Clair, Todd Lencz, Bryan J. Mowry, Sathish Periyasamy, Murray J. Cairns, Paul A. Tooney, Jing Qin Wu, Brian Kelly, George Kirov, Patrick F. Sullivan, Aiden Corvin, Brien P. Riley, Tõnu Esko, Lili Milani, Erik G. Jönsson, Aarno Palotie, Hannelore Ehrenreich, Martin Begemann, Agnes Steixner-Kumar, Pak C. Sham, Nakao Iwata, Daniel R. Weinberger, Pablo V. Gejman, Alan R. Sanders, Joseph D. Buxbaum, Dan Rujescu, Ina Giegling, Bettina Konte, Annette M. Hartmann, Elvira Bramon, Robin M. Murray, Michele T. Pato, Jimmy Lee, Ingrid Melle, Espen Molden, Roel A. Ophoff, Andrew McQuillin, Nicholas J. Bass, Rolf Adolfsson, Anil K. Malhotra, Nicholas G. Martin, Janice M. Fullerton, Philip B. Mitchell, Peter R. Schofield, Andreas J. Forstner, Franziska Degenhardt, Sabrina Schaupp, Ashley L. Comes, Manolis Kogevinas, José Guzman-Parra, Andreas Reif, Fabian Streit, Lea Sirignano, Sven Cichon, Maria Grigoroiu-Serbanescu, Joanna Hauser, Jolanta Lissowska, Fermin Mayoral, Bertram Müller-Myhsok, Beata Świątkowska, Thomas G. Schulze, Markus M. Nöthen, Marcella Rietschel, John Kelsoe, Marion Leboyer, Stéphane Jamain, Bruno Etain, Frank Bellivier, John B. Vincent, Martin Alda, Claire O’Donovan, Pablo Cervantes, Joanna M. Biernacka, Mark Frye, Susan L. McElroy, Laura J. Scott, Eli A. Stahl, Mikael Landén, Marian L. Hamshere, Olav B. Smeland, Srdjan Djurovic, Arne E. Vaaler, Ole A. Andreassen, Bernhard T. Baune, Tracy Air, Martin Preisig, Rudolf Uher, Douglas F. Levinson, Myrna M. Weissman, James B. Potash, Jianxin Shi, James A. Knowles, Roy H. Perlis, Susanne Lucae, Dorret I. Boomsma, Brenda W.J.H. Penninx, Jouke-Jan Hottenga, Eco J.C. de Geus, Gonneke Willemsen, Yuri Milaneschi, Henning Tiemeier, Hans J. Grabe, Alexander Teumer, Sandra Van der Auwera, Uwe Völker, Steven P. Hamilton, Patrik K.E. Magnusson, Alexander Viktorin, Divya Mehta, Niamh Mullins, Mark J. Adams, Gerome Breen, Andrew M. McIntosh, Cathryn M. Lewis, David M. Hougaard, Merete Nordentoft, Ole Mors, Preben B. Mortensen, Thomas Werge, Thomas D. Als, Anders D. Børglum, Tracey L. Petryshen, Jordan W. Smoller, Jill M. Goldstein, Stephan Ripke, Benjamin M. Neale, James T.R. Walters, Kai-How Farh, Peter A. Holmans, Phil Lee, Brendan Bulik-Sullivan, David A. Collier, Hailiang Huang, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Richard A. Belliveau, Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberly D. Chambert, Raymond C.K. Chan, Ronald Y.L. Chen, Eric Y.H. Chen, Wei Cheng, Eric F.C. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, David Curtis, Michael Davidson, Kenneth L. Davis, Jurgen Del Favero, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H. Fanous, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Giulio Genovese, Lyudmila Georgieva, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, Masashi Ikeda, Inge Joa, Antonio Julià, René S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kähler, Claudine Laurent, Jimmy Lee Chee Keong, S. Hong Lee, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Carmel M. Loughland, Jan Lubinski, Jouko Lönnqvist, Milan Macek, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Sandra Meier, Carin J. Meijer, Bela Melegh, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Vihra Milanova, Younes Mokrab, Derek W. Morris, Kieran C. Murphy, Inez Myin-Germeys, Mari Nelis, Igor Nenadic, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Eadbhard O’Callaghan, Colm O’Dushlaine, F. Anthony O’Neill, Sang-Yun Oh, Ann Olincy, Line Olsen, Jim Van Os, Christos Pantelis, George N. Papadimitriou, Sergi Papiol, Elena Parkhomenko, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietiläinen, Jonathan Pimm, Andrew J. Pocklington, John Powell, Alkes Price, Ann E. Pulver, Shaun M. Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander L. Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Ulrich Schall, Christian R. Schubert, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Hon-Cheong So, Chris C.A. Spencer, Hreinn Stefansson, Stacy Steinberg, Elisabeth Stogmann, Richard E. Straub, Eric Strengman, Jana Strohmaier, T. Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Svrakic, Jin P. Szatkiewicz, Erik Söderman, Srinivas Thirumalai, Draga Toncheva, Sarah Tosato, Juha Veijola, John Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer, Nigel M. Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily H.M. Wong, Brandon K. Wormley, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Naomi R. Wray, Kari Stefansson, Peter M. Visscher, Douglas H.R. Blackwood, Ariel Darvasi, Enrico Domenici, Michael Gill, Hugh Gurling, Christina M. Hultman, Assen V. Jablensky, Kenneth S. Kendler, Jo Knight, Qingqin S. Li, Jianjun Liu, Steven A. McCarroll, Jennifer L. Moran, Michael J. Owen, Carlos N. Pato, Danielle Posthuma, Pamela Sklar, Jens R. Wendland, Mark J. Daly, Michael C. O’Donovan, Peter Donnelly, Ines Barroso, Jenefer M. Blackwell, Matthew A. Brown, Juan P. Casas, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh S. Markus, Christopher G. Mathew, Colin N.A. Palmer, Robert Plomin, Anna Rautanen, Stephen J. Sawcer, Richard C. Trembath, Ananth C. Viswanathan, Nicholas W. Wood, Gavin Band, Céline Bellenguez, Colin Freeman, Eleni Giannoulatou, Garrett Hellenthal, Richard Pearson, Matti Pirinen, Amy Strange, Zhan Su, Damjan Vukcevic, Cordelia Langford, Hannah Blackburn, Suzannah J. Bumpstead, Serge Dronov, Sarah Edkins, Matthew Gillman, Emma Gray, Rhian Gwilliam, Naomi Hammond, Sarah E. Hunt, Alagurevathi Jayakumar, Jennifer Liddle, Owen T. McCann, Simon C. Potter, Radhi Ravindrarajah, Michelle Ricketts, Avazeh Tashakkori-Ghanbaria, Matthew Waller, Paul Weston, Pamela Whittaker, Sara Widaa, Mark I. McCarthy, Maria J. Arranz, Steven Bakker, Stephan Bender, Benedicto Crespo-Facorro, Jeremy Hall, Conrad Iyegbe, Stephen Lawrie, Kuang Lin, Don H. Linszen, Ignacio Mata, Muriel Walshe, Matthias Weisbrod, Durk Wiersma, Vassily Trubetskoy, Yunpeng Wang, Jonathan R.I. Coleman, Héléna A. Gaspar, Christiaan A. de Leeuw, Jennifer M. Whitehead Pavlides, Maciej Trzaskowski, Enda M. Byrne, Liam Abbott, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Adebayo Anjorin, Verneri Antilla, Swapnil Awasthi, Judith A. Badner, Marie Bækvad-Hansen, Jack D. Barchas, Nicholas Bass, Michael Bauer, Richard Belliveau, Carsten Bøcker Pedersen, Erlend Bøen, Marco P. Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Jonas Bybjerg-Grauholm, Miquel Casas, Felecia Cerrato, Kimberly Chambert, Alexander W. Charney, Danfeng Chen, Claire Churchhouse, Toni-Kim Clarke, William Coryell, David W. Craig, Cristiana Cruceanu, Piotr M. Czerski, Anders M. Dale, Simone de Jong, Jurgen Del-Favero, J. Raymond DePaulo, Amanda L. Dobbyn, Ashley Dumont, Torbjørn Elvsåshagen, Chun Chieh Fan, Sascha B. Fischer, Matthew Flickinger, Tatiana M. Foroud, Liz Forty, Christine Fraser, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Marianne Giørtz Pedersen, Jaqueline Goldstein, Scott D. Gordon, Katherine Gordon-Smith, Elaine K. Green, Melissa J. Green, Tiffany A. Greenwood, Weihua Guan, Martin Hautzinger, Urs Heilbronner, Maria Hipolito, Dominic Holland, Laura Huckins, Jessica S. Johnson, Radhika Kandaswamy, Robert Karlsson, Sarah Kittel-Schneider, Anna C. Koller, Ralph Kupka, Catharina Lavebratt, Jacob Lawrence, William B. Lawson, Markus Leber, Phil H. Lee, Shawn E. Levy, Jun Z. Li, Chunyu Liu, Anna Maaser, Donald J. MacIntyre, Pamela B. Mahon, Lina Martinsson, Steve McCarroll, Peter McGuffin, Melvin G. McInnis, James D. McKay, Helena Medeiros, Sarah E. Medland, Fan Meng, Grant W. Montgomery, Thomas W. Mühleisen, Hoang Nguyen, Caroline M. Nievergelt, Annelie Nordin Adolfsson, Evaristus A. Nwulia, Claire O'Donovan, Loes M. Olde Loohuis, Anil P.S. Ori, Lilijana Oruc, Urban Ösby, Amy Perry, Andrea Pfennig, Eline J. Regeer, Céline S. Reinbold, John P. Rice, Fabio Rivas, Margarita Rivera, Euijung Ryu, Cristina Sánchez-Mora, Alan F. Schatzberg, William A. Scheftner, Nicholas J. Schork, Cynthia Shannon Weickert, Tatyana Shehktman, Paul D. Shilling, Claire Slaney, Janet L. Sobell, Christine Søholm Hansen, Anne T. Spijker, Michael Steffens, John S. Strauss, Szabolcs Szelinger, Robert C. Thompson, Thorgeir E. Thorgeirsson, Jens Treutlein, Helmut Vedder, Weiqing Wang, Stanley J. Watson, Thomas W. Weickert, Simon Xi, Wei Xu, Allan H. Young, Peter Zandi, Peng Zhang, Sebastian Zöllner, Abdel Abdellaoui, Tracy M. Air, Till F.M. Andlauer, Silviu-Alin Bacanu, Aartjan T.F. Beekman, Elisabeth B. Binder, Julien Bryois, Henriette N. Buttenschøn, Na Cai, Enrique Castelao, Jane Hvarregaard Christensen, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Gregory E. Crawford, Gail Davies, Ian J. Deary, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Jerome C. Foo, Fernando S. Goes, Lynsey S. Hall, Thomas F. Hansen, Ian B. Hickie, Georg Homuth, Carsten Horn, David M. Howard, Marcus Ising, Rick Jansen, Ian Jones, Lisa A. Jones, Eric Jorgenson, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Dean F. MacKinnon, Robert M. Maier, Jonathan Marchini, Hamdi Mbarek, Patrick McGrath, Christel M. Middeldorp, Evelin Mihailov, Francis M. Mondimore, Sara Mostafavi, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O'Reilly, Hogni Oskarsson, Jodie N. Painter, Roseann E. Peterson, Wouter J. Peyrot, Giorgio Pistis, Jorge A. Quiroz, Per Qvist, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Stanley I. Shyn, Grant C.B. Sinnamon, Johannes H. Smit, Daniel J. Smith, Katherine E. Tansey, Henning Teismann, Wesley Thompson, Pippa A. Thomson, Matthew Traylor, André G. Uitterlinden, Daniel Umbricht, Albert M. van Hemert, Shantel Marie Weinsheimer, Jürgen Wellmann, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Volker Arolt, Klaus Berger, Udo Dannlowski, Katharina Domschke, Caroline Hayward, Andrew C. Heath, Stefan Kloiber, Glyn Lewis, Pamela AF. Madden, Patrik K. Magnusson, Preben Bo Mortensen, Michael C. O'Donovan, Sara A. Paciga, Nancy L. Pedersen, David J. Porteous, Catherine Schaefer, Henry Völzke, Marco Bortolato, Janita Bralten, Cynthia M. Bulik, Christie L. Burton, Caitlin E. Carey, Lea K. Davis, Laramie E. Duncan, Howard J. Edenberg, Lauren Erdman, Stephen V. Faraone, Slavina B. Goleva, Wei Guo, Christopher Hübel, Laura M. Huckins, Ekaterina A. Khramtsova, Joanna Martin, Carol A. Mathews, Elise Robinson, Eli Stahl, Barbara E. Stranger, Michela Traglia, Raymond K. Walters, Lauren A. Weiss, Stacey J. Winham, Yin Yao, Kristjar Skajaa, Markus Nöthen, Michael Owen, Robert H. Yolken, Niels Plath, Jonathan Mill, Daniel Geschwind, Psychiatry 1, RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, Centre of Excellence in Complex Disease Genetics, Research Programme of Molecular Medicine, Research Programs Unit, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Functional Genomics, Biological Psychology, APH - Mental Health, APH - Methodology, Sociology and Social Gerontology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Blokland, Gabriella AM, Grove, Jakob, Chen, Chia Yen, Cotsapas, Chris, Tobet, Stuart, Handa, Robert, Lee, Sang Hong, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium, iPSYCH, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), Child and Adolescent Psychiatry / Psychology, Adult Psychiatry, ANS - Complex Trait Genetics, and ANS - Mood, Anxiety, Psychosis, Stress & Sleep
Subjects: 0301 basic medicine, Male, Bipolar Disorder, Schizophrenia/genetics, LD SCORE REGRESSION, Genome-wide association study, 0302 clinical medicine, Receptors, SCHIZOPHRENIA, Psychotic Disorders/genetics, KYNURENINE PATHWAY METABOLISM, Genetics, RISK, Sex Characteristics, Vascular Endothelial Growth Factor, Bipolar Disorder/genetics, Major/genetics, Single Nucleotide, AFFECTIVE STIMULI IMPACT, Schizophrenia, Sulfurtransferases, Major depressive disorder, Female, Depressive Disorder, Major/genetics, Bipolar disorder, Locus (genetics), Genomics, Biology, Polymorphism, Single Nucleotide, Article, DYSPHORIC MOOD, 03 medical and health sciences, Sex differences, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Polymorphism, GENOME-WIDE ASSOCIATION, Genotype-by-sex interaction, Biological Psychiatry, Depressive Disorder, Major, Depressive Disorder, GENDER-DIFFERENCES, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], PARAVENTRICULAR NUCLEUS, 3112 Neurosciences, Endothelial Cells, MAJOR DEPRESSION, medicine.disease, Genetic architecture, 030104 developmental biology, Mood, Receptors, Vascular Endothelial Growth Factor, Psychotic Disorders, 3111 Biomedicine, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Contains fulltext : 248656.pdf (Publisher’s version ) (Closed access) BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10(-8)), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10(-6)) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10(-7); rs73033497, p = 8.8 × 10(-7); rs7914279, p = 6.4 × 10(-7)), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10(-7)) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10(-7)), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10(-7)) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
Published: 2022

11. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

Author: Andreas J. Forstner, Martin Alda, Manolis Kogevinas, Pak C. Sham, Patrick F. Sullivan, Michele T. Pato, John R. Kelsoe, Paul A. Tooney, Steven P. Hamilton, Dorret I. Boomsma, Gerome Breen, Tracy Air, Hannelore Ehrenreich, Nakao Iwata, Jill M. Goldstein, Olav B. Smeland, Daniel R. Weinberger, Andrew McQuillin, Stuart A. Tobet, Elvira Bramon, Gabriëlla A.M. Blokland, Jing Qin Wu, Erik G. Jönsson, Peter R. Schofield, Fabian Streit, Nicholas Bass, Aarno Palotie, Brian Kelly, Cathryn M. Lewis, Srdjan Djurovic, Thomas Damm Als, Chia-Yen Chen, Bettina Konte, Joanna Hauser, Claire O'Donovan, Laura J. Scott, Hans J. Grabe, Murray J. Cairns, Rudolf Uher, Pablo Cervantes, Nicholas G. Martin, James A. Knowles, Aiden Corvin, Espen Molden, Lili Milani, Andreas Reif, Maria Grigoroiu-Serbanescu, George Kirov, Yuri Milaneschi, David St Clair, Eco J. C. de Geus, Robert Handa, Tõnu Esko, Alexander Teumer, Anders D. Børglum, Divya Mehta, Roel A. Ophoff, Susanne Lucae, Henning Tiemeier, Marion Leboyer, Ina Giegling, Alan R. Sanders, Jouke-Jan Hottenga, Pablo V. Gejman, Bernhard T. Baune, Brenda W.J.H. Penninx, Chris Cotsapas, Martin Preisig, Thomas Werge, Jakob Grove, Ingrid Melle, Jordan W. Smoller, Marcella Rietschel, Myrna M. Weissman, Preben Bo Mortensen, Philip B. Mitchell, Jolanta Lissowska, Andrew M. McIntosh, Annette M. Hartmann, Ole A. Andreassen, Lea Sirignano, John B. Vincent, Niamh Mullins, Jimmy Lee, Gonneke Willemsen, Marian L. Hamshere, Rolf Adolfsson, Mark A. Frye, Markus M. Nöthen, Jianxin Shi, Ashley L. Comes, Robin M. Murray, Patrik K. E. Magnusson, Frank Bellivier, Stéphane Jamain, Ole Mors, Sven Cichon, Uwe Völker, Fermín Mayoral, Bryan J. Mowry, Bruno Etain, James B. Potash, Beata Świątkowska, Bertram Müller-Myhsok, Mikael Landén, Tracey L. Petryshen, Franziska Degenhardt, Mark Adams, Dan Rujescu, Jose Guzman-Parra, Thomas G. Schulze, Merete Nordentoft, Joseph D. Buxbaum, Janice M. Fullerton, Brien P. Riley, Roy H. Perlis, Arne E. Vaaler, David M. Hougaard, Eli A. Stahl, Susan L. McElroy, Sabrina K. Schaupp, Martin Begemann, Sandra Van der Auwera, Todd Lencz, Joanna M. Biernacka, Agnes A. Steixner-Kumar, Douglas F. Levinson, Sathish Periyasamy, Alexander Viktorin, and Anil K. Malhotra
Subjects: Genetics, 0303 health sciences, Medizin, Locus (genetics), Genomics, Biology, medicine.disease, Genetic architecture, 03 medical and health sciences, 0302 clinical medicine, Mood, medicine, Major depressive disorder, Bipolar disorder, Gene, NKAIN2 Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: BACKGROUNDSex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.METHODSWe conducted the largest to date genome-wide genotype–by–sex (GxS) interaction of risk for these disorders, using 85,735 cases (33,403 SCZ, 19,924 BIP, 32,408 MDD) and 109,946 controls from the Psychiatric Genomics Consortium (PGC) and iPSYCH.RESULTSAcross disorders, genome-wide significant SNP-by-sex interaction was detected for a locus encompassingNKAIN2(rs117780815;p=3.2×10−8), that interacts with sodium/potassium-transporting ATPase enzymes implicating neuronal excitability. Three additional loci showed evidence (p−6) for cross-disorder GxS interaction (rs7302529,p=1.6×10−7; rs73033497,p=8.8×10−7; rs7914279,p=6.4×10−7) implicating various functions. Gene-based analyses identified GxS interaction across disorders (p=8.97×10−7) with transcriptional inhibitorSLTM. Most significant in SCZ was aMOCOSgene locus (rs11665282;p=1.5×10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509;p=1.1×10−7) in a locus containingIDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant GxS of genes regulating vascular endothelial growth factor (VEGF) receptor signaling in MDD (pFDRCONCLUSIONSIn the largest genome-wide GxS analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development, immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway enrichment levels.
Published: 2022

12. The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia

Author: Anne M. Bara, Dane Z. Hazelbaker, Ellen J. Guss, Roy H. Perlis, Mitja I. Kurki, Steven E. Hyman, Aarno Palotie, Ralda Nehme, Aditi Trehan, Rolf Adolfsson, Mykyta Artomov, Bruce M. Cohen, Christina Lilliehook, Amanda Beccard, Emanuela Zuccaro, Mark J. Daly, Rhea Malik, Joao A. Paulo, Wade Harper, Lindy E. Barrett, Danielle Manning, Christina Bell, Jon M. Madison, Neale Bm, Donna L. McPhie, Olli Pietilainen, Derek Hawes, Kevin Eggan, Anna Neumann, Matthew Tegtmeyer, John D. Sherwood, Emily Peirent, Andrea Ganna, Vera Valakh, Eija Hämäläinen, Christina M. Hultman, Anna K. Kähler, Alexander A. Loboda, Samouil L. Farhi, Tarjinder Singh, Steven A. McCarroll, Giulio Genovese, Ricardo E. Dolmetsch, and Outi Kuismin
Subjects: Genetics, 0303 health sciences, Biology, medicine.disease, Neural stem cell, 03 medical and health sciences, 0302 clinical medicine, Schizophrenia, Gene expression, medicine, CRISPR, Trans-acting, Induced pluripotent stem cell, Gene, 030217 neurology & neurosurgery, Loss function, 030304 developmental biology
Abstract: To study how the 22q11.2 deletion predisposes to psychiatric disease, we generated induced pluripotent stem cells from deletion carriers and controls, as well as utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Upon differentiation into neural progenitor cells, we found the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including Autism Spectrum Disorder. In more differentiated excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common (per-SNP heritability p (τc)= 4.2 x 10-6) and rare, loss of function variants (p = 1.29×10-12). These findings suggest a potential relationship between cellular states, developmental windows and susceptibility to psychiatric conditions with different ages of onset. To understand how the deletion contributed to these observed changes in gene expression, we developed and applied PPItools, which identifies the minimal protein-protein interaction network that best explains an observed set of gene expression alterations. We found that many of the genes in the 22q11.2 interval interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways that underlie the broader alterations in psychiatric risk gene expression we identified. Our findings suggest that the 22q11.2 deletion impacts genes and pathways that may converge with risk loci implicated by psychiatric genetic studies to influence disease manifestation in each deletion carrier.
Published: 2021

13. An astronomically dated record of Earth’s climate and its predictability over the last 66 million years

Author: Fabio Florindo, Paul A. Wilson, Ann Holbourn, Thomas Westerhold, Roy H Wilkens, David A. Hodell, Claudia Agnini, Eleni Anagnostou, Mitchell W Lyle, Heiko Pälike, Dick Kroon, Kate Littler, Lucas Joost Lourens, Steven M Bohaty, Anna Joy Drury, Diederik Liebrand, David De Vleeschouwer, Norbert Marwan, Vittoria Lauretano, James S K Barnet, James C Zachos, Ursula Röhl, Jun Tian, Thomas Frederichs, Stratigraphy and paleontology, Stratigraphy & paleontology, Westerhold, Thomas [0000-0001-8151-4684], Marwan, Norbert [0000-0003-1437-7039], Drury, Anna Joy [0000-0001-6206-7284], Liebrand, Diederik [0000-0002-6925-7889], Agnini, Claudia [0000-0001-9749-6003], Anagnostou, Eleni [0000-0002-7200-4794], Barnet, James SK [0000-0003-3885-5664], Bohaty, Steven M [0000-0002-1193-7398], De Vleeschouwer, David [0000-0002-3323-807X], Florindo, Fabio [0000-0002-6058-9748], Frederichs, Thomas [0000-0003-0976-0332], Hodell, David A [0000-0001-8537-1588], Holbourn, Ann E [0000-0002-3167-0862], Lauretano, Vittoria [0000-0002-7869-6074], Littler, Kate [0000-0002-4604-3634], Lourens, Lucas J [0000-0002-3815-7770], Lyle, Mitchell [0000-0002-0861-0511], Pälike, Heiko [0000-0003-3386-0923], Röhl, Ursula [0000-0001-9469-7053], Tian, Jun [0000-0002-4842-7076], Wilkens, Roy H [0000-0001-8149-3908], Zachos, James C [0000-0001-8439-1886], and Apollo - University of Cambridge Repository
Subjects: 13 Climate Action, Multidisciplinary, 010504 meteorology & atmospheric sciences, biology, General Science & Technology, Astronomical forcing, sub-01, 010502 geochemistry & geophysics, biology.organism_classification, 01 natural sciences, Foraminifera, 13. Climate action, Isotopes of carbon, Benthic zone, Greenhouse gas, Statistical analysis, Physical geography, Predictability, General, Cenozoic, Geology, 0105 earth and related environmental sciences
Abstract: Much of our understanding of Earth's past climate comes from the measurement of oxygen and carbon isotope variations in deep-sea benthic foraminifera. Yet, long intervals in existing records lack the temporal resolution and age control needed to thoroughly categorize climate states of the Cenozoic era and to study their dynamics. Here, we present a new, highly resolved, astronomically dated, continuous composite of benthic foraminifer isotope records developed in our laboratories. Four climate states-Hothouse, Warmhouse, Coolhouse, Icehouse-are identified on the basis of their distinctive response to astronomical forcing depending on greenhouse gas concentrations and polar ice sheet volume. Statistical analysis of the nonlinear behavior encoded in our record reveals the key role that polar ice volume plays in the predictability of Cenozoic climate dynamics.
Published: 2020
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14. Author response for 'Morphological alterations in tongue epithelial cells infected by SARS-CoV-2: A case-control study'

Author: Roy H. Stevens, Ricardo Guimarães Fischer, Fábio Ramôa Pires, Josué da Costa Lima Junior, Taísa Coelho Guimarães, Justine Monteiro Monnerat Tinoco, Barbara Bruno Fagundes Marques, and Eduardo Muniz Barretto Tinoco
Subjects: medicine.anatomical_structure, Tongue, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), medicine, Case-control study, Biology, Virology
Published: 2021

15. Chromosome‐level reference genome of the soursop ( Annona muricata ): A new resource for Magnoliid research and tropical pomology

Author: Mareike Roeder, Michael D. Pirie, Kun-Fang Cao, Hervé Sauquet, Lars W. Chatrou, Joeri S. Strijk, Thomas L. P. Couvreur, Roy H. J. Erkens, Daniel C. Thomas, Damien Daniel Hinsinger, Etude du Polymorphisme des Génomes Végétaux (EPGV), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Maastricht Science Programme, RS: FSE MSP, Universiti Brunei Darussalam, Pha Tad Ke Botanical Garden, Guangxi University [Nanning], Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Chinese Academy of Agricultural Sciences (CAAS), Karlsruhe Institute of Technology (KIT), Universiteit Gent = Ghent University (UGENT), Diversité, adaptation, développement des plantes (UMR DIADE), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM), Maastricht University [Maastricht], National Herbarium of New South Wales, Royal Botanic Gardens and Domain Trust, University of Bergen (UiB), and Singapore Botanic Gardens
Subjects: 0106 biological sciences, 0301 basic medicine, INFORMATION, Geography & travel, PREDICTION, Lineage (evolution), Sequence assembly, pomology, plant, 01 natural sciences, Genome, Annona, magnoliids, Permanent Genetic Resources, ComputingMilieux_MISCELLANEOUS, ddc:910, 2. Zero hunger, Ecology, biology, RESOURCE ARTICLES, nome, basal angiosperms, ALIGNMENT, Annonaceae, Genome, Plant, Biotechnology, Evolution, Genomics, high quality draft g&#233, 010603 evolutionary biology, SEQUENCE, Chromosomes, Plant, DNA sequencing, [SDV.GEN.GPL]Life Sciences [q-bio]/Genetics/Plants genetics, 03 medical and health sciences, Behavior and Systematics, Genetics, Resource Article, Annona muricata, genome, Ecology, Evolution, Behavior and Systematics, Biology and Life Sciences, Molecular Sequence Annotation, 15. Life on land, biology.organism_classification, GENE, crop improvement, Plant Breeding, 030104 developmental biology, DOMESTICATION, Evolutionary biology, BOTTLENECK, high quality draft génome, Reference genome
Abstract: International audience; The flowering plant family Annonaceae includes important commercially grown tropical crops, but development of promising species is hindered by a lack of genomic resources to build breeding programs. Annonaceae are part of the magnoliids, an ancient lineage of angiosperms for which evolutionary relationships with other major clades remain unclear. To provide resources to breeders and evolutionary researchers, we report a chromosome-level genome assembly of the soursop (Annona muricata). We assembled the genome using 444.32 Gb of DNA sequences (676x sequencing depth) from PacBio and Illumina short-reads, in combination with 10x Genomics and Bionano data (v1). A total of 949 scaffolds were assembled to a final size of 656.77 Mb, with a scaffold N50 of 3.43 Mb (v1), and then further improved to seven pseudo-chromosomes using Hi-C sequencing data (v2; scaffold N50: 93.2 Mb, total size in chromosomes: 639.6 Mb). Heterozygosity was very low (0.06%), while repeat sequences accounted for 54.87% of the genome, and 23,375 protein-coding genes with an average of 4.79 exons per gene were annotated using de novo, RNA-seq and homology-based approaches. Reconstruction of the historical population size showed a slow continuous contraction, probably related to Cenozoic climate changes. The soursop is the first genome assembled in Annonaceae, supporting further studies of floral evolution in magnoliids, providing an essential resource for delineating relationships of ancient angiosperm lineages. Both genome-assisted improvement and conservation efforts will be strengthened by the availability of the soursop genome. As a community resource, this assembly will further strengthen the role of Annonaceae as model species for research on the ecology, evolution and domestication potential of tropical species in pomology and agroforestry.
Published: 2021

16. Aberrant mitochondrial function in patient-derived neural cells from CDKL5 deficiency disorder and Rett syndrome

Author: Ariel Feiglin, Jennifer P. Wang, Thomas O Dial, Steven D. Sheridan, Smita Jagtap, Jeffrey Chen, Ting Fu, Jasmin Lalonde, Roy H. Perlis, Jeannie T. Lee, Isaac S. Kohane, and Jessica M. Thanos
Subjects: Adult, Bioenergetics, Mutant, CDKL5, Rett syndrome, Protein Serine-Threonine Kinases, Biology, Mitochondrion, medicine.disease_cause, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Neural Stem Cells, Rett Syndrome, Genetics, medicine, Humans, Progenitor cell, Molecular Biology, Cells, Cultured, Genetics (clinical), 030304 developmental biology, 0303 health sciences, General Medicine, medicine.disease, Mitochondria, Cell biology, Oxygen, Oxidative Stress, Child, Preschool, Female, General Article, Energy Metabolism, Epileptic Syndromes, Spasms, Infantile, 030217 neurology & neurosurgery, Oxidative stress
Abstract: The X-linked neurodevelopmental diseases CDKL5 deficiency disorder (CDD) and Rett syndrome (RTT) are associated with intellectual disability, infantile spasms and seizures. Although mitochondrial dysfunction has been suggested in RTT, less is understood about mitochondrial function in CDD. A comparison of bioenergetics and mitochondrial function between isogenic wild-type and mutant neural progenitor cell (NPC) lines revealed increased oxygen consumption in CDD mutant lines, which is associated with altered mitochondrial function and structure. Transcriptomic analysis revealed differential expression of genes related to mitochondrial and REDOX function in NPCs expressing the mutant CDKL5. Furthermore, a similar increase in oxygen consumption specific to RTT patient–derived isogenic mutant NPCs was observed, though the pattern of mitochondrial functional alterations was distinct from CDKL5 mutant–expressing NPCs. We propose that aberrant neural bioenergetics is a common feature between CDD and RTT disorders. The observed changes in oxidative stress and mitochondrial function may facilitate the development of therapeutic agents for CDD and related disorders.
Published: 2019

17. Twelve new and exciting Annonaceae from the Neotropics

Author: Nadja Verspagen, Lubbert Y.Th. Westra, Heimo Rainer, Lars W. Chatrou, Nelson Zamora, Paul J. M. Maas, Roy H. J. Erkens, Maastricht Science Programme, and RS: FSE MSP
Subjects: Rollinia, Guatteria, Zoology, Annonaceae, Plant Science, Annona, Tetrameranthus, taxonomy, Magnoliopsida, neotropics, Magnoliales, lcsh:Botany, ROLLINIA, Klarobelia, Plantae, Ecology, Evolution, Behavior and Systematics, Taxonomy, new species, biology, Cenozoic, Biology and Life Sciences, Species diversity, South America, biology.organism_classification, Xylopia, lcsh:QK1-989, Tracheophyta, Central America and the Caribbean, Research Article
Abstract: As a result of concerted efforts of the community of Annonaceae taxonomists, increasingly detailed knowledge of the diversity of the Neotropical genera has been documented. With the exception of just two large genera, Annona and Xylopia, all Neotropical Annonaceae have been revised within the last 25 years. Subsequent to these publications, many new specimens have been collected and sent to us in Leiden for identification. These included a number that, despite the advanced state of taxonomic knowledge, proved to represent rarely collected, undescribed species. Here we describe 12 new species of Annona, Guatteria, Klarobelia, Tetrameranthus, and Xylopia. These species serve to illustrate the still underestimated diversity of the Neotropical flora, even in well studied plant groups like Annonaceae.
Published: 2019

18. Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning

Author: Jessica M. Thanos, Jessica Gracias, Carl M. Sellgren, Roy H. Perlis, Ajamete Kaykas, Rakesh Karmacharya, Kathleen A. Worringer, Paul B. Whittredge, Carleton Goold, Steven D. Sheridan, Jonathan D. Biag, Hannah E. Brown, Bradley Watmuff, Ting Fu, and Jennifer P. Wang
Subjects: Adult, Male, 0301 basic medicine, Cortical tissue, Adolescent, Synaptic pruning, Induced Pluripotent Stem Cells, Minocycline, Health records, Biology, Article, In vitro model, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Neural Stem Cells, Risk Factors, medicine, Humans, Cells, Cultured, Aged, Complement component 4, Neuronal Plasticity, Microglia, General Neuroscience, Neurosciences, Middle Aged, In vitro, Anti-Bacterial Agents, 030104 developmental biology, medicine.anatomical_structure, Synapses, Schizophrenia, Neuroscience, 030217 neurology & neurosurgery, medicine.drug
Abstract: Synapse density is reduced in postmortem cortical tissue from schizophrenia patients, which is suggestive of increased synapse elimination. Using a reprogrammed in vitro model of microglia-mediated synapse engulfment, we demonstrate increased synapse elimination in patient-derived neural cultures and isolated synaptosomes. This excessive synaptic pruning reflects abnormalities in both microglia-like cells and synaptic structures. Further, we find that schizophrenia risk-associated variants within the human complement component 4 locus are associated with increased neuronal complement deposition and synapse uptake; however, they do not fully explain the observed increase in synapse uptake. Finally, we demonstrate that the antibiotic minocycline reduces microglia-mediated synapse uptake in vitro and its use is associated with a modest decrease in incident schizophrenia risk compared to other antibiotics in a cohort of young adults drawn from electronic health records. These findings point to excessive pruning as a potential target for delaying or preventing the onset of schizophrenia in high-risk individuals.
Published: 2019

19. Dysregulated protocadherin-pathway activity as an intrinsic defect in induced pluripotent stem cell–derived cortical interneurons from subjects with schizophrenia

Author: Roy H. Perlis, Hualin Simon Xi, Leonard M. Eisenberg, Sangmi Chung, Alexander A. Moghadam, Donna L. McPhie, Bruce M. Cohen, Weihua Huang, Woong Bin Kim, Patric K. Stanton, Changhong Yin, Sarah E. Cote, Teruyoshi Hirayama, Joyce Zhao, Judith L. Rapoport, Emi Fukuda, Takeshi Yagi, Kevin Eggan, Elizabeth Noyes, Sulagna Ghosh, Dost Öngür, James M. Park, Daniel R. Weinberger, Teagan Parsons, Kelvin Zheng, Joshua J. Park, Thomas A. Lanz, Karen F. Berman, Jun-Hyeong Cho, Christine T. O. Nguyen, Haneul Noh, Hae Young Kim, Joseph T. Coyle, Jose A. Apud, Peiyan Ni, Richard E. Straub, and Zhicheng Shao
Subjects: 0301 basic medicine, animal structures, Kinase, General Neuroscience, virus diseases, Protocadherin, Biology, medicine.disease, female genital diseases and pregnancy complications, Pathogenesis, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, nervous system, Schizophrenia, Excitatory postsynaptic potential, medicine, Protein kinase A, Induced pluripotent stem cell, Prefrontal cortex, neoplasms, Neuroscience, 030217 neurology & neurosurgery
Abstract: We generated cortical interneurons (cINs) from induced pluripotent stem cells derived from 14 healthy controls and 14 subjects with schizophrenia. Both healthy control cINs and schizophrenia cINs were authentic, fired spontaneously, received functional excitatory inputs from host neurons, and induced GABA-mediated inhibition in host neurons in vivo. However, schizophrenia cINs had dysregulated expression of protocadherin genes, which lie within documented schizophrenia loci. Mice lacking protocadherin-α showed defective arborization and synaptic density of prefrontal cortex cINs and behavioral abnormalities. Schizophrenia cINs similarly showed defects in synaptic density and arborization that were reversed by inhibitors of protein kinase C, a downstream kinase in the protocadherin pathway. These findings reveal an intrinsic abnormality in schizophrenia cINs in the absence of any circuit-driven pathology. They also demonstrate the utility of homogenous and functional populations of a relevant neuronal subtype for probing pathogenesis mechanisms during development.
Published: 2019

20. The State of the Biology Major

Author: Carter, Jack L., Heppner, Frank, Saigo, Roy H., Twitty, Geraldine, and Walker, Dan
Published: 1990

21. Mountains, Sea Lure Students across the West

Author: Saigo, Roy H.
Published: 1973
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22. Adaptor protein ShcD/SHC4 interacts with Tie2 receptor to synergistically promote glioma cell invasion

Author: Jasmin Lalonde, Manali Tilak, Steven D. Sheridan, Marc G. Coppolino, Sarah E. Wismer, Megan I. Brasher, Nina Jones, Begum Alural, Laura A. New, and Roy H. Perlis
Subjects: 0301 basic medicine, Cancer Research, Transfection, Receptor tyrosine kinase, Article, Focal adhesion, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Glioma, Cell Line, Tumor, medicine, Humans, Neoplasm Invasiveness, Amino Acid Sequence, neoplasms, Molecular Biology, biology, Chemistry, Brain Neoplasms, Mesenchymal stem cell, Signal transducing adaptor protein, medicine.disease, Angiopoietin receptor, Receptor, TIE-2, nervous system diseases, 030104 developmental biology, HEK293 Cells, Oncology, Shc Signaling Adaptor Proteins, 030220 oncology & carcinogenesis, embryonic structures, Invadopodia, Cancer research, biology.protein
Abstract: Gliomas are characterized by diffuse infiltration of tumor cells into surrounding brain tissue, and this highly invasive nature contributes to disease recurrence and poor patient outcomes. The molecular mechanisms underlying glioma cell invasion remain incompletely understood, limiting development of new targeted therapies. Here, we have identified phosphotyrosine adaptor protein ShcD as upregulated in malignant glioma and shown that it associates with receptor tyrosine kinase Tie2 to facilitate invasion. In human glioma cells, we find that expression of ShcD and Tie2 increases invasion, and this significant synergistic effect is disrupted with a ShcD mutant that cannot bind Tie2 or hyperphosphorylate the receptor. Expression of ShcD and/or Tie2 further increases invadopodia formation and matrix degradation in U87 glioma cells. In a coculture model, we show that U87-derived tumor spheroids expressing both ShcD and Tie2 display enhanced infiltration into cerebral organoids. Mechanistically, we identify changes in focal adhesion kinase phosphorylation in the presence of ShcD and/or Tie2 in U87 cells upon Tie2 activation. Finally, we identify a strong correlation between transcript levels of ShcD and Tie2 signaling components as well as N-cadherin in advanced gliomas and those with classical or mesenchymal subtypes, and we show that elevated expression of ShcD correlates with a significant reduction in patient survival in higher grade gliomas with mesenchymal signature. Altogether, our data highlight a novel Tie2–ShcD signaling axis in glioma cell invasion, which may be of clinical significance. Implications: ShcD cooperates with Tie2 to promote glioma cell invasion and its elevated expression correlates with poor patient outcome in advanced gliomas.
Published: 2021

23. Preclinical and Clinical Status of PSMA-Targeted Alpha Therapy for Metastatic Castration-Resistant Prostate Cancer

Author: Asta Juzeniene, Øyvind S. Bruland, Vilde Yuli Stenberg, and Roy H. Larsen
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Targeted radionuclide therapy, Alpha (ethology), Review, Castration resistant, urologic and male genital diseases, lcsh:RC254-282, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, Prostate cancer, prostate-specific membrane antigen, 0302 clinical medicine, Internal medicine, Glutamate carboxypeptidase II, medicine, Lymph node, targeted alpha therapy, biology, business.industry, medicine.disease, prostate cancer, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer cell, biology.protein, Antibody, business
Abstract: Simple Summary Currently, there is no treatment that can cure patients with late stage metastatic prostate cancer. Prostate-specific membrane antigen is a type of protein overexpressed on the membrane surface of most prostate cancer cells. The preclinical and clinical experiences in the rapidly evolving field of targeted alpha-particle radiation therapy for metastatic prostate cancer overexpressing prostate-specific membrane antigen are reviewed. Targeted alpha therapy employs radionuclides emitting highly energetic alpha-particles (cytotoxic payload) chelated to small molecules or monoclonal antibodies designed to target prostate-specific membrane antigen. In this review, we summarize the availability of therapeutic alpha-emitting radionuclides (terbium-149, astatine-211, bismuth-212 (lead-212), bismuth-213, radium-223, actinium-225, thorium-227), and the development of small molecules and antibodies targeting prostate-specific membrane antigen. The limitations in studies using animal models of human prostate cancer to accurately predict efficacy and toxicity in patients are addressed. We have attempted to also critically discuss hurdles related to logistical and supply aspects between different alpha-emitting prostate-specific membrane antigen-targeting radiopharmaceuticals. Lastly, we discuss the potentials, limitations, and future perspectives of prostate-specific membrane antigen-targeted alpha therapy. Abstract Bone, lymph node, and visceral metastases are frequent in castrate-resistant prostate cancer patients. Since such patients have only a few months’ survival benefit from standard therapies, there is an urgent need for new personalized therapies. The prostate-specific membrane antigen (PSMA) is overexpressed in prostate cancer and is a molecular target for imaging diagnostics and targeted radionuclide therapy (theragnostics). PSMA-targeted α therapies (PSMA-TAT) may deliver potent and local radiation more selectively to cancer cells than PSMA-targeted β− therapies. In this review, we summarize both the recent preclinical and clinical advances made in the development of PSMA-TAT, as well as the availability of therapeutic α-emitting radionuclides, the development of small molecules and antibodies targeting PSMA. Lastly, we discuss the potentials, limitations, and future perspectives of PSMA-TAT.
Published: 2021

24. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Author: James McKay, Frank Bellivier, Mark A. Frye, Bertram Müller-Myhsok, Fermín Mayoral, I. Nicol Ferrier, Marion Leboyer, Fabian Streit, Dan J. Stein, James L. Kennedy, Christine Søholm Hansen, Scott D. Gordon, Beata Świątkowska, Valentina Escott-Price, Michael Bauer, Lina Martinsson, Donald J. MacIntyre, Oleksandr Frei, Daniel J. Smith, Sara A. Paciga, Takeo Saito, Jennifer L. Moran, Verneri Antilla, C Pantelis, Tomas Olsson, Swapnil Awasthi, Lena Backlund, Eirini Maratou, Martin Schalling, John B. Vincent, Niamh Mullins, Sarah E. Bergen, Niamh L. O'Brien, Marco P. Boks, Carsten Bøcker Pedersen, Mikael Landén, Franziska Degenhardt, Hang Zhou, Margarita Rivera, Andrew M. McIntosh, Manuel Mattheisen, Shawn Levy, Roy H. Perlis, John P. Rice, Sigurdur H. Magnusson, Amanda Dobbyn, Michael Conlon O'Donovan, Julien Bryois, Wolfgang Maier, John-Anker Zwart, J. Raymond DePaulo, Martin Alda, Laura G. Sloofman, Friederike Sophie David, James A. Knowles, Aiden Corvin, Thomas G. Schulze, Markus M. Nöthen, Nolan Kamitaki, Nina Dalkner, Brandon J. Coombes, Gustavo Turecki, Allan H. Young, Caroline M. Nievergelt, Patricia T. Michie, Ingrid Agartz, Towfique Raj, Diego Albani, Maria Grigoroiu-Serbanescu, Bernhard T. Baune, Kyooseob Ha, Vincent Millischer, Engilbert Sigurdsson, Eva C. Beins, Nicholas G. Martin, Gulja Babadjanova, Josef Frank, Eva Z. Reininghaus, Patrick F. Sullivan, Ian R. Gizer, Guy A. Rouleau, Carmel M. Loughland, Christine Lochner, Thorsten M. Kranz, Amy Perry, Arne E. Vaaler, Mariam M. Al Eissa, Simon Xi, Claire O'Donovan, Josep Antoni Ramos-Quiroga, Ketil J. Oedegaard, Helmut Vedder, Carol A. Mathews, Panagiotis Ferentinos, Tim B. Bigdeli, Derek W. Morris, Per Hoffmann, Mark Hyman Rapaport, Peter P. Zandi, Michael John Owen, Douglas M. Ruderfer, Anders D. Børglum, Catharina Lavebratt, Thorgeir E. Thorgeirsson, Paul A. Tooney, Michiaki Kubo, Steven A. Kushner, Jan Hillert, Loes M. Olde Loohuis, Anastasia Antoniou, Murielle Brum, Chikashi Terao, Nathaniel W. McGregor, Fabio Rivas, James B. Potash, Kevin S. O’Connell, Susanne Lucae, Brian M. Schilder, Katrin Gade, Stephan Ripke, Kristina Adorjan, Kari Stefansson, Tiffany A. Greenwood, Panos Roussos, Sarah Kittel-Schneider, Steven A. McCarroll, Sergi Papiol, Heon Jeong Lee, Assen Jablensky, Liliya Abramova, Dennis Hellgren, Jonas Bybjerg-Grauholm, Martin Lundberg, Hong-Hee Won, William Byerley, Lars Alfredsson, Joel Gelernter, Andrew McQuillin, Claire Slaney, Marta Ribasés, Stephanie H. Witt, Yoichiro Kamatani, Kyung Sue Hong, Marie Bækvad-Hansen, María Soler Artigas, Julie M. Cunningham, Fanny Senner, Stacy Steinberg, Paul D. Shilling, Nakao Iwata, Eystein Stordal, Armin Birner, Sarah E. Medland, Miquel Casas, Ben Michael Brumpton, Erlend Bøen, Bryan J. Mowry, Jolanta Lissowska, Francis J. McMahon, Howard J. Edenberg, Grant W. Montgomery, John I. Nurnberger, Stéphane Jamain, Claudio Toma, Ney Alliey-Rodriguez, Ole Mors, Micha Gawlik, David Curtis, Catrin Lewis, Evangelia-Eirini Tsermpini, Georgia Panagiotaropoulou, Marcella Rietschel, Jessica Yang, Ian Jones, Eduard Vieta, Ole A. Andreassen, Richard M. Myers, Dimitris Dikeos, Melissa J. Green, Janet L. Sobell, Maria Koromina, Piotr M. Czerski, Lilijana Oruc, Sven Cichon, Udo Dannlowski, Bruno Etain, Monika Budde, Alessia Fiorentino, Naomi R. Wray, Qingqin S. Li, Murray J. Cairns, Jonathan R. I. Coleman, Jose Guzman-Parra, Andreas J. Forstner, Hannah Young, Alfredo B. Cuellar-Barboza, Julian Roth, Torbjørn Elvsåshagen, Zhen Qiao, Thomas Werge, Athanassios Douzenis, Cristiana Cruceanu, Rolf Adolfsson, Peter Holmans, Vaughan J. Carr, Thomas W. Weickert, Masashi Ikeda, Joanna M. Biernacka, Lea Sirignano, Adam X. Maihofer, Ralph W. Kupka, John Strauss, Anders M. Dale, Elliot S. Gershon, Jakob Grove, Arianna Di Florio, Helena Medeiros, Ingrid Melle, Preben Bo Mortensen, Kristi Krebs, Saskia P. Hagenaars, Liz Forty, Stanley V. Catts, David M. Hougaard, Marianne Giørtz Pedersen, Andreas Reif, Toni-Kim Clarke, Anne T. Spijker, Danielle Posthuma, Manolis Kogevinas, Michael Boehnke, Rosa Bosch, Gerome Breen, Benjamin M. Neale, Jessica S. Johnson, Katherine Gordon-Smith, Cristina Sánchez-Mora, Alexander W. Charney, Henry R. Kranzler, Digby Quested, René S. Kahn, Lili Milani, Merete Nordentoft, Nathalie Brunkhorst-Kanaan, Laura M. Huckins, James T.R. Walters, Sigrid Børte, Antonio F. Pardiñas, Kristian Hveem, Julie Garnham, Jacob Lawrence, Vassily Trubetskoy, Rodney J. Scott, Nicholas Bass, Carlos N. Pato, Andrea Pfennig, Wei Xu, Calwing Liao, Nicholas John Craddock, Thomas Damm Als, Christina M. Hultman, Fernando S. Goes, Adebayo Anjorin, Evgenia Porichi, Frans Henskens, Nelson B. Freimer, Janice M. Fullerton, Cathryn M. Lewis, Srdjan Djurovic, Roel A. Ophoff, Phil Lee, Peter McGuffin, Gunnar Morken, George P. Patrinos, Alessandro Serretti, Cynthia Shannon Weickert, Pablo Cervantes, Bendik S. Winsvold, Tatiana Foroud, Tõnu Esko, Ulrich Schall, Michele T. Pato, Ji Hyun Baek, John R. Kelsoe, Olav B. Smeland, Janos Kalman, Eva C. Schulte, Joanna Hauser, Urs Heilbronner, Magnús Haraldsson, Martin Hautzinger, Lea Zillich, Eline J. Regeer, Douglas Blackwood, Laura J. Scott, Jordan W. Smoller, Michael J. Gandal, Marquis P. Vawter, Philip B. Mitchell, Ole Kristian Drange, Peter R. Schofield, Susanne Bengesser, Stefan Herms, George Kirov, Markus Leber, Louise Frisén, Thomas W. Mühleisen, Susan L. McElroy, Irwin D. Waldman, Wade H. Berrettini, Sally I. Sharp, Minsoo Kim, Lisa Jones, Eli A. Stahl, Hreinn Stefansson, Esben Agerbo, Dolores Malaspina, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), APH - Digital Health, Mullins N., Forstner A.J., O'Connell K.S., Coombes B., Coleman J.R.I., Qiao Z., Als T.D., Bigdeli T.B., Borte S., Bryois J., Charney A.W., Drange O.K., Gandal M.J., Hagenaars S.P., Ikeda M., Kamitaki N., Kim M., Krebs K., Panagiotaropoulou G., Schilder B.M., Sloofman L.G., Steinberg S., Trubetskoy V., Winsvold B.S., Won H.-H., Abramova L., Adorjan K., Agerbo E., Al Eissa M., Albani D., Alliey-Rodriguez N., Anjorin A., Antilla V., Antoniou A., Awasthi S., Baek J.H., Baekvad-Hansen M., Bass N., Bauer M., Beins E.C., Bergen S.E., Birner A., Bocker Pedersen C., Boen E., Boks M.P., Bosch R., Brum M., Brumpton B.M., Brunkhorst-Kanaan N., Budde M., Bybjerg-Grauholm J., Byerley W., Cairns M., Casas M., Cervantes P., Clarke T.-K., Cruceanu C., Cuellar-Barboza A., Cunningham J., Curtis D., Czerski P.M., Dale A.M., Dalkner N., David F.S., Degenhardt F., Djurovic S., Dobbyn A.L., Douzenis A., Elvsashagen T., Escott-Price V., Ferrier I.N., Fiorentino A., Foroud T.M., Forty L., Frank J., Frei O., Freimer N.B., Frisen L., Gade K., Garnham J., Gelernter J., Giortz Pedersen M., Gizer I.R., Gordon S.D., Gordon-Smith K., Greenwood T.A., Grove J., Guzman-Parra J., Ha K., Haraldsson M., Hautzinger M., Heilbronner U., Hellgren D., Herms S., Hoffmann P., Holmans P.A., Huckins L., Jamain S., Johnson J.S., Kalman J.L., Kamatani Y., Kennedy J.L., Kittel-Schneider S., Knowles J.A., Kogevinas M., Koromina M., Kranz T.M., Kranzler H.R., Kubo M., Kupka R., Kushner S.A., Lavebratt C., Lawrence J., Leber M., Lee H.-J., Lee P.H., Levy S.E., Lewis C., Liao C., Lucae S., Lundberg M., MacIntyre D.J., Magnusson S.H., Maier W., Maihofer A., Malaspina D., Maratou E., Martinsson L., Mattheisen M., McCarroll S.A., McGregor N.W., McGuffin P., McKay J.D., Medeiros H., Medland S.E., Millischer V., Montgomery G.W., Moran J.L., Morris D.W., Muhleisen T.W., O'Brien N., O'Donovan C., Olde Loohuis L.M., Oruc L., Papiol S., Pardinas A.F., Perry A., Pfennig A., Porichi E., Potash J.B., Quested D., Raj T., Rapaport M.H., DePaulo J.R., Regeer E.J., Rice J.P., Rivas F., Rivera M., Roth J., Roussos P., Ruderfer D.M., Sanchez-Mora C., Schulte E.C., Senner F., Sharp S., Shilling P.D., Sigurdsson E., Sirignano L., Slaney C., Smeland O.B., Smith D.J., Sobell J.L., Soholm Hansen C., Soler Artigas M., Spijker A.T., Stein D.J., Strauss J.S., Swiatkowska B., Terao C., Thorgeirsson T.E., Toma C., Tooney P., Tsermpini E.-E., Vawter M.P., Vedder H., Walters J.T.R., Witt S.H., Xi S., Xu W., Yang J.M.K., Young A.H., Young H., Zandi P.P., Zhou H., Zillich L., Adolfsson R., Agartz I., Alda M., Alfredsson L., Babadjanova G., Backlund L., Baune B.T., Bellivier F., Bengesser S., Berrettini W.H., Blackwood D.H.R., Boehnke M., Borglum A.D., Breen G., Carr V.J., Catts S., Corvin A., Craddock N., Dannlowski U., Dikeos D., Esko T., Etain B., Ferentinos P., Frye M., Fullerton J.M., Gawlik M., Gershon E.S., Goes F.S., Green M.J., Grigoroiu-Serbanescu M., Hauser J., Henskens F., Hillert J., Hong K.S., Hougaard D.M., Hultman C.M., Hveem K., Iwata N., Jablensky A.V., Jones I., Jones L.A., Kahn R.S., Kelsoe J.R., Kirov G., Landen M., Leboyer M., Lewis C.M., Li Q.S., Lissowska J., Lochner C., Loughland C., Martin N.G., Mathews C.A., Mayoral F., McElroy S.L., McIntosh A.M., McMahon F.J., Melle I., Michie P., Milani L., Mitchell P.B., Morken G., Mors O., Mortensen P.B., Mowry B., Muller-Myhsok B., Myers R.M., Neale B.M., Nievergelt C.M., Nordentoft M., Nothen M.M., O'Donovan M.C., Oedegaard K.J., Olsson T., Owen M.J., Paciga S.A., Pantelis C., Pato C., Pato M.T., Patrinos G.P., Perlis R.H., Posthuma D., Ramos-Quiroga J.A., Reif A., Reininghaus E.Z., Ribases M., Rietschel M., Ripke S., Rouleau G.A., Saito T., Schall U., Schalling M., Schofield P.R., Schulze T.G., Scott L.J., Scott R.J., Serretti A., Shannon Weickert C., Smoller J.W., Stefansson H., Stefansson K., Stordal E., Streit F., Sullivan P.F., Turecki G., Vaaler A.E., Vieta E., Vincent J.B., Waldman I.D., Weickert T.W., Werge T., Wray N.R., Zwart J.-A., Biernacka J.M., Nurnberger J.I., Cichon S., Edenberg H.J., Stahl E.A., McQuillin A., Di Florio A., Ophoff R.A., Andreassen O.A., IMRB - 'Neuropsychiatrie translationnelle' [Créteil] (U955 Inserm - UPEC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Etain, Bruno
Subjects: Multifactorial Inheritance, Bipolar Disorder, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Medizin, Genome-wide association study, Major Histocompatibility Complex/genetics, Major Histocompatibility Complex, 0302 clinical medicine, Risk Factors, MESH: Risk Factors, MESH: Bipolar Disorder, Chromosomes, Human, Spectrum disorder, Genetics, 0303 health sciences, Bipolar Disorder/genetics, MESH: Genetic Predisposition to Disease, MESH: Case-Control Studies, Phenotype, Schizophrenia, Synaptic signaling, Case-Control Studie, Human, Quantitative Trait Loci, Biology, MESH: Phenotype, MESH: Chromosomes, Human, Article, 03 medical and health sciences, MESH: Major Histocompatibility Complex, SDG 3 - Good Health and Well-being, ddc:570, medicine, Humans, Genetic Predisposition to Disease, Bipolar disorder, Multifactorial Inheritance/genetics, MESH: Genome, Human, 030304 developmental biology, MESH: Humans, Genome, Human, Risk Factor, Chromosomes, Human/genetics, Mental illness, medicine.disease, MESH: Quantitative Trait Loci, Human genetics, Psychologie, Case-Control Studies, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, MESH: Genome-Wide Association Study, Expression quantitative trait loci, MESH: Multifactorial Inheritance, Quantitative Trait Loci/genetics, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: International audience; Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
Published: 2021

25. Genome-wide association study of over 40,000 bipolar disorder cases provides new insights into the underlying biology

Author: Niamh Mullins, Andreas J. Forstner, Kevin S. O’Connell, Brandon Coombes, Jonathan R. I. Coleman, Zhen Qiao, Thomas D. Als, Tim B. Bigdeli, Sigrid Børte, Julien Bryois, Alexander W. Charney, Ole Kristian Drange, Michael J. Gandal, Saskia P. Hagenaars, Masashi Ikeda, Nolan Kamitaki, Minsoo Kim, Kristi Krebs, Georgia Panagiotaropoulou, Brian M. Schilder, Laura G. Sloofman, Stacy Steinberg, Vassily Trubetskoy, Bendik S. Winsvold, Hong-Hee Won, Liliya Abramova, Kristina Adorjan, Esben Agerbo, Mariam Al Eissa, Diego Albani, Ney Alliey-Rodriguez, Adebayo Anjorin, Verneri Antilla, Anastasia Antoniou, Swapnil Awasthi, Ji Hyun Baek, Marie Bækvad-Hansen, Nicholas Bass, Michael Bauer, Eva C. Beins, Sarah E. Bergen, Armin Birner, Carsten Bøcker Pedersen, Erlend Bøen, Marco P. Boks, Rosa Bosch, Murielle Brum, Ben M. Brumpton, Nathalie Brunkhorst-Kanaan, Monika Budde, Jonas Bybjerg-Grauholm, William Byerley, Murray Cairns, Miquel Casas, Pablo Cervantes, Toni-Kim Clarke, Cristiana Cruceanu, Alfredo Cuellar-Barboza, Julie Cunningham, David Curtis, Piotr M. Czerski, Anders M. Dale, Nina Dalkner, Friederike S. David, Franziska Degenhardt, Srdjan Djurovic, Amanda L. Dobbyn, Athanassios Douzenis, Torbjørn Elvsåshagen, Valentina Escott-Price, I. Nicol Ferrier, Alessia Fiorentino, Tatiana M. Foroud, Liz Forty, Josef Frank, Oleksandr Frei, Nelson B. Freimer, Louise Frisén, Katrin Gade, Julie Garnham, Joel Gelernter, Marianne Giørtz Pedersen, Ian R. Gizer, Scott D. Gordon, Katherine Gordon-Smith, Tiffany A. Greenwood, Jakob Grove, José Guzman-Parra, Kyooseob Ha, Magnus Haraldsson, Martin Hautzinger, Urs Heilbronner, Dennis Hellgren, Stefan Herms, Per Hoffmann, Peter A. Holmans, Laura Huckins, Stéphane Jamain, Jessica S. Johnson, Janos L. Kalman, Yoichiro Kamatani, James L. Kennedy, Sarah Kittel-Schneider, James A. Knowles, Manolis Kogevinas, Maria Koromina, Thorsten M. Kranz, Henry R. Kranzler, Michiaki Kubo, Ralph Kupka, Steven A. Kushner, Catharina Lavebratt, Jacob Lawrence, Markus Leber, Heon-Jeong Lee, Phil H. Lee, Shawn E. Levy, Catrin Lewis, Calwing Liao, Susanne Lucae, Martin Lundberg, Donald J. MacIntyre, Sigurdur H. Magnusson, Wolfgang Maier, Adam Maihofer, Dolores Malaspina, Eirini Maratou, Lina Martinsson, Manuel Mattheisen, Steven A. McCarroll, Nathaniel W. McGregor, Peter McGuffin, James D. McKay, Helena Medeiros, Sarah E. Medland, Vincent Millischer, Grant W. Montgomery, Jennifer L. Moran, Derek W. Morris, Thomas W. Mühleisen, Niamh O’Brien, Claire O’Donovan, Loes M. Olde Loohuis, Lilijana Oruc, Sergi Papiol, Antonio F. Pardiñas, Amy Perry, Andrea Pfennig, Evgenia Porichi, James B. Potash, Digby Quested, Towfique Raj, Mark H. Rapaport, J. Raymond DePaulo, Eline J. Regeer, John P. Rice, Fabio Rivas, Margarita Rivera, Julian Roth, Panos Roussos, Douglas M. Ruderfer, Cristina Sánchez-Mora, Eva C. Schulte, Fanny Senner, Sally Sharp, Paul D. Shilling, Engilbert Sigurdsson, Lea Sirignano, Claire Slaney, Olav B. Smeland, Daniel J. Smith, Janet L. Sobell, Christine Søholm Hansen, Maria Soler Artigas, Anne T. Spijker, Dan J. Stein, John S. Strauss, Beata Świątkowska, Chikashi Terao, Thorgeir E. Thorgeirsson, Claudio Toma, Paul Tooney, Evangelia-Eirini Tsermpini, Marquis P. Vawter, Helmut Vedder, James T. R. Walters, Stephanie H. Witt, Simon Xi, Wei Xu, Jessica Mei Kay Yang, Allan H. Young, Hannah Young, Peter P. Zandi, Hang Zhou, Lea Zillich, HUNT All-In Psychiatry, Rolf Adolfsson, Ingrid Agartz, Martin Alda, Lars Alfredsson, Gulja Babadjanova, Lena Backlund, Bernhard T. Baune, Frank Bellivier, Susanne Bengesser, Wade H. Berrettini, Douglas H. R. Blackwood, Michael Boehnke, Anders D. Børglum, Gerome Breen, Vaughan J. Carr, Stanley Catts, Aiden Corvin, Nicholas Craddock, Udo Dannlowski, Dimitris Dikeos, Tõnu Esko, Bruno Etain, Panagiotis Ferentinos, Mark Frye, Janice M. Fullerton, Micha Gawlik, Elliot S. Gershon, Fernando S. Goes, Melissa J. Green, Maria Grigoroiu-Serbanescu, Joanna Hauser, Frans Henskens, Jan Hillert, Kyung Sue Hong, David M. Hougaard, Christina M. Hultman, Kristian Hveem, Nakao Iwata, Assen V. Jablensky, Ian Jones, Lisa A. Jones, René S. Kahn, John R. Kelsoe, George Kirov, Mikael Landén, Marion Leboyer, Cathryn M. Lewis, Qingqin S. Li, Jolanta Lissowska, Christine Lochner, Carmel Loughland, Nicholas G. Martin, Carol A. Mathews, Fermin Mayoral, Susan L. McElroy, Andrew M. McIntosh, Francis J. McMahon, Ingrid Melle, Patricia Michie, Lili Milani, Philip B. Mitchell, Gunnar Morken, Ole Mors, Preben Bo Mortensen, Bryan Mowry, Bertram Müller-Myhsok, Richard M. Myers, Benjamin M. Neale, Caroline M. Nievergelt, Merete Nordentoft, Markus M. Nöthen, Michael C. O’Donovan, Ketil J. Oedegaard, Tomas Olsson, Michael J. Owen, Sara A. Paciga, Chris Pantelis, Carlos Pato, Michele T. Pato, George P. Patrinos, Roy H. Perlis, Danielle Posthuma, Josep Antoni Ramos-Quiroga, Andreas Reif, Eva Z. Reininghaus, Marta Ribasés, Marcella Rietschel, Stephan Ripke, Guy A. Rouleau, Takeo Saito, Ulrich Schall, Martin Schalling, Peter R. Schofield, Thomas G. Schulze, Laura J. Scott, Rodney J. Scott, Alessandro Serretti, Cynthia Shannon Weickert, Jordan W. Smoller, Hreinn Stefansson, Kari Stefansson, Eystein Stordal, Fabian Streit, Patrick F. Sullivan, Gustavo Turecki, Arne E. Vaaler, Eduard Vieta, John B. Vincent, Irwin D. Waldman, Thomas W. Weickert, Thomas Werge, Naomi R. Wray, John-Anker Zwart, Joanna M. Biernacka, John I. Nurnberger, Sven Cichon, Howard J. Edenberg, Eli A. Stahl, Andrew McQuillin, Arianna Di Florio, Roel A. Ophoff, and Ole A. Andreassen
Subjects: Genetics, 0303 health sciences, Druggability, Genome-wide association study, Biology, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Gene expression, Expression quantitative trait loci, medicine, Bipolar disorder, Synaptic signaling, Prefrontal cortex, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Bipolar disorder (BD) is a heritable mental illness with complex etiology. We performed a genome-wide association study (GWAS) of 41,917 BD cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. BD risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating eQTL data implicated 15 genes robustly linked to BD via gene expression, including druggable genes such as HTR6, MCHR1, DCLK3 and FURIN. This GWAS provides the best-powered BD polygenic scores to date, when applied in both European and diverse ancestry samples. Analyses of BD subtypes indicated high but imperfect genetic correlation between BD type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of BD, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
Published: 2020

26. Phenotypic signatures in clinical data enable systematic identification of patients for genetic testing

Author: Roy H. Perlis, Douglas M. Ruderfer, Victor M. Castro, Nancy J. Cox, Lide Han, Theodore Morley, Lisa Bastarache, and Jonathan Morra
Subjects: 0301 basic medicine, Adult, Male, Adolescent, DNA Copy Number Variations, Population, Computational biology, Disease, Biology, General Biochemistry, Genetics and Molecular Biology, Article, Predictive medicine, 03 medical and health sciences, 0302 clinical medicine, Rare Diseases, medicine, Electronic Health Records, Humans, Copy-number variation, Genetic Testing, education, Child, Genetic testing, education.field_of_study, medicine.diagnostic_test, Receiver operating characteristic, Genetic Diseases, Inborn, Infant, General Medicine, Microarray Analysis, Identification (information), 030104 developmental biology, Phenotype, Feature (computer vision), 030220 oncology & carcinogenesis, Child, Preschool, Female
Abstract: Around 5% of the population is affected by a rare genetic disease, yet most endure years of uncertainty before receiving a genetic test. A common feature of genetic diseases is the presence of multiple rare phenotypes that often span organ systems. Here, we use diagnostic billing information from longitudinal clinical data in the electronic health records (EHRs) of 2,286 patients who received a chromosomal microarray test, and 9,144 matched controls, to build a model to predict who should receive a genetic test. The model achieved high prediction accuracies in a held-out test sample (area under the receiver operating characteristic curve (AUROC), 0.97; area under the precision–recall curve (AUPRC), 0.92), in an independent hospital system (AUROC, 0.95; AUPRC, 0.62), and in an independent set of 172,265 patients in which cases were broadly defined as having an interaction with a genetics provider (AUROC, 0.9; AUPRC, 0.63). Patients carrying a putative pathogenic copy number variant were also accurately identified by the model. Compared with current approaches for genetic test determination, our model could identify more patients for testing while also increasing the proportion of those tested who have a genetic disease. We demonstrate that phenotypic patterns representative of a wide range of genetic diseases can be captured from EHRs to systematize decision-making for genetic testing, with the potential to speed up diagnosis, improve care and reduce costs. Machine learning of electronic health records identifies individuals with a high suspicion of a wide range of genetic diseases and prioritizes those individuals for genetic testing.
Published: 2020

27. Experimental light at night has a negative long-term impact on macro-moth populations

Author: Roy H. A. van Grunsven, Maurice Donners, Frank Berendse, Kamiel Spoelstra, Jurriën R. van Deijk, Marcel E. Visser, Elmar Veenendaal, and Animal Ecology (AnE)
Subjects: 0301 basic medicine, Conservation of Natural Resources, Light, Population, Population Dynamics, Color, Plant Ecology and Nature Conservation, Animal Breeding and Genomics, Biology, Moths, General Biochemistry, Genetics and Molecular Biology, Light at night, 03 medical and health sciences, 0302 clinical medicine, Life Science, Animals, Fokkerij en Genomica, education, Lighting, Netherlands, education.field_of_study, Artificial light, Ecology, fungi, national, Plan_S-Compliant_NO, PE&RC, Term (time), 030104 developmental biology, WIAS, Plantenecologie en Natuurbeheer, sense organs, General Agricultural and Biological Sciences, 030217 neurology & neurosurgery
Abstract: Van Grunsven et al. experimentally test the long-term effects of artificial light on natural moth populations. In the initial two years there was no effect on populations, but in the latter three years population sizes were reduced compared with the dark controls. This shows that artificial light negatively affects moth populations.
Published: 2020

28. Chromosome-level reference genome of the Soursop (Annona muricata), a new resource for Magnoliid research and tropical pomology

Author: Michael D. Pirie, Roy H. J. Erkens, Daniel C. Thomas, Lars W. Chatrou, Thomas L. P. Couvreur, Damien Daniel Hinsinger, Mareike Roeder, Kun-Fang Cao, Hervé Sauquet, and Joeri S. Strijk
Subjects: 2. Zero hunger, 0106 biological sciences, 0303 health sciences, education.field_of_study, biology, Lineage (evolution), Population, Sequence assembly, 15. Life on land, biology.organism_classification, 010603 evolutionary biology, 01 natural sciences, Genome, DNA sequencing, 03 medical and health sciences, Annonaceae, Evolutionary biology, education, Annona muricata, 030304 developmental biology, Reference genome
Abstract: Annonaceae contain important commercially grown tropical crops, but development of other promising species is hindered by a lack of genomic resources to build breeding programs. In addition, Annonaceae are part of the Magnoliids, an ancient lineage of angiosperms for which evolutionary relationships with other major clades have remained unclear. To provide resources to both breeders and evolutionary researchers, we report the chromosome-level genome assembly of the soursop (Annona muricata). We assembled the soursop genome using a total of 444.32 Gb of DNA sequences that were generated using PacBio and Illumina short-reads, in combination with 10XGenomics, Bionano data and Hi-C sequencing. 949 scaffolds were assembled to a final size of 656.77Mb, with a scaffold N50 of 3.43 Mb. Repeat sequences accounted for 54.87% of the genome, and 23,375 protein-coding genes with an average of 4.79 exons per gene were annotated using de novo, RNA-seq and homology-based approaches. Reconstruction of the historical population size of A. muricata showed a slow but regular contraction of the population, likely related to Cenozoic climate changes. The soursop is the first genome assembled in Annonaceae, supporting further studies of floral evolution in Magnoliids, and providing an essential resource for delineating relationships of major lineages at the base of the angiosperms. Both genome-assisted improvement and conservation efforts will be strengthened by the availability of the soursop genome. The genome assembly as a community resource will further strengthen the role of Annonaceae as model species for research on the ecology, evolution and domestication potential of tropical species in pomology and agroforestry.
Published: 2020

29. Mouthguard use and attitudes regarding dental trauma among elite cross-country mountain biking and field hockey athletes

Author: Eduardo Muniz Barretto Tinoco, Justine Monteiro Monnerat Tinoco, Joao Alves Grangeiro Neto, Daniel Deluiz Martins, Luciana Moura Sassone, and Roy H. Stevens
Subjects: Facial trauma, Adult, Male, medicine.medical_specialty, business.product_category, Field hockey, Adolescent, Poison control, Suicide prevention, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Injury prevention, medicine, Humans, Mouthguard, Dental trauma, biology, Athletes, business.industry, Tooth Injuries, 030229 sport sciences, 030206 dentistry, biology.organism_classification, medicine.disease, Cross-Sectional Studies, Hockey, Athletic Injuries, Physical therapy, Mouth Protectors, Female, Oral Surgery, business, human activities, Brazil
Abstract: BACKGROUND/AIMS Cross-country mountain biking and field hockey are two Olympic sports that pose a potential risk for dentofacial trauma. However, mouthguard use is not mandatory in either of these sports and knowledge about tooth rescue among athletes is often neglected. The aim of this cross-sectional epidemiological survey was to evaluate the prevalence of sports-related dentofacial injuries, mouthguard use, and attitudes regarding tooth rescue among cross-country mountain biking and field hockey athletes participating at pre-Olympic competitions held in Rio de Janeiro, Brazil. MATERIALS AND METHODS A convenience sample of 217 athletes from 33 countries participating in cross-country mountain biking (n = 82; mean age = 30.96 ± 8.52 years) and field hockey (n = 135; mean age = 19.72 ± 2.46 years) pre-Olympic competitions were examined clinically, and they answered a questionnaire regarding previous history of sports-related dentofacial injuries, attitudes toward mouthguard use, and tooth rescue. RESULTS There were 120 (55.30%) males and 97 (44.70%) females who participated in the study. The prevalence of facial trauma was higher in mountain biking (54.88%) than in field hockey (26.66%, P
Published: 2020

30. Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression

Author: Glanville, Kylie P, Coleman, Jonathan R I, Binder, Elisabeth B, Hall, Lynsey S, Hansen, Christine Søholm, Hansen, Thomas F, Herms, Stefan, Hickie, Ian B, Hoffmann, Per, Homuth, Georg, Horn, Carsten, Hottenga, Jouke-Jan, Hougaard, David M, Blackwood, Douglas H R, Howard, David M, Ising, Marcus, Jansen, Rick, Jones, Ian, Jones, Lisa A, Jorgenson, Eric, Knowles, James A, Kohane, Isaac S, Kraft, Julia, Kretzschmar, Warren W, Boomsma, Dorret I, Kutalik, Zoltán, Li, Yihan, Lind, Penelope A, MacIntyre, Donald J, MacKinnon, Dean F, Maier, Robert M, Maier, Wolfgang, Marchini, Jonathan, Mbarek, Hamdi, McGrath, Patrick, Buttenschøn, Henriette N, McGuffin, Peter, Medland, Sarah E, Mehta, Divya, Middeldorp, Christel M, Mihailov, Evelin, Milaneschi, Yuri, Milani, Lili, Mondimore, Francis M, Montgomery, Grant W, Mostafavi, Sara, Colodro-Conde, Lucía, Mullins, Niamh, Nauck, Matthias, Ng, Bernard, Nivard, Michel G, Nyholt, Dale R, O'Reilly, Paul F, Oskarsson, Hogni, Owen, Michael J, Painter, Jodie N, Pedersen, Carsten Bøcker, Dannlowski, Udo, Pedersen, Marianne Giørtz, Peterson, Roseann E, Pettersson, Erik, Peyrot, Wouter J, Pistis, Giorgio, Posthuma, Danielle, Quiroz, Jorge A, Qvist, Per, Rice, John P, Riley, Brien P, Direk, Nese, Rivera, Margarita, Mirza, Saira Saeed, Schoevers, Robert, Schulte, Eva C, Shen, Ling, Shi, Jianxin, Shyn, Stanley I, Sigurdsson, Engilbert, Sinnamon, Grant C B, Smit, Johannes H, Dunn, Erin C, Smith, Daniel J, Stefansson, Hreinn, Steinberg, Stacy, Streit, Fabian, Strohmaier, Jana, Tansey, Katherine E, Teismann, Henning, Teumer, Alexander, Thompson, Wesley, Thomson, Pippa A, Forstner, Andreas J, Thorgeirsson, Thorgeir E, Traylor, Matthew, Treutlein, Jens, Trubetskoy, Vassily, Uitterlinden, Andrés G, Umbricht, Daniel, Van der Auwera, Sandra, van Hemert, Albert M, Viktorin, Alexander, Visscher, Peter M, de Geus, Eco J C, Wang, Yunpeng, Webb, Bradley T, Weinsheimer, Shantel Marie, Wellmann, Jürgen, Willemsen, Gonneke, Witt, Stephanie H, Wu, Yang, Xi, Hualin S, Yang, Jian, Zhang, Futao, Hanscombe, Ken B, Grabe, Hans J, Arolt, Volker, Baune, Bernhard T, Berger, Klaus, Cichon, Sven, de Geus, E. J. C., DePaulo, J Raymond, Domenici, Enrico, Domschke, Katharina, Hamilton, Steven P, Esko, Tõnu, Hayward, Caroline, Heath, Andrew C, Kendler, Kenneth S, Kloiber, Stefan, Lewis, Glyn, Li, Qingqin S, Lucae, Susanne, Madden, Pamela Af, Magnusson, Patrik K, Martin, Nicholas G, McIntosh, Andrew M, Metspalu, Andres, Mors, Ole, Mortensen, Preben Bo, Müller-Myhsok, Bertram, Nordentoft, Merete, Nöthen, Markus M, O'Donovan, Michael C, Paciga, Sara A, Pedersen, Nancy L, Penninx, Brenda W J H, Perlis, Roy H, Porteous, David J, Potash, James B, Preisig, Martin, Rietschel, Marcella, Schaefer, Catherine, Schulze, Thomas G, Smoller, Jordan W, Stefansson, Kari, Tiemeier, Henning, Uher, Rudolf, Völzke, Henry, Weissman, Myrna M, Werge, Thomas, Lewis, Cathryn M, Levinson, Douglas F, Breen, Gerome, Børglum, Anders D, Sullivan, Patrick F, Euesden, Jack, Choi, Shing Wan, Ripke, Stephan, Purves, Kirstin L, Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics, Wray, Naomi R, Mattheisen, Manuel, Trzaskowski, Maciej, Byrne, Enda M, Abdellaoui, Abdel, Adams, Mark J, Agerbo, Esben, Air, Tracy M, Andlauer, Till F M, Bacanu, Silviu-Alin, Bækvad-Hansen, Marie, Beekman, Aartjan T F, Bigdeli, Tim B, Bryois, Julien, Bybjerg-Grauholm, Jonas, Cai, Na, Castelao, Enrique, Christensen, Jane Hvarregaard, Clarke, Toni-Kim, Couvy-Duchesne, Baptiste, Craddock, Nick, Crawford, Gregory E, Davies, Gail, Deary, Ian J, Degenhardt, Franziska, Derks, Eske M, Dolan, Conor V, Eley, Thalia C, Escott-Price, Valentina, Hassan Kiadeh, Farnush Farhadi, Finucane, Hilary K, Foo, Jerome C, Frank, Josef, Gaspar, Héléna A, Gill, Michael, Goes, Fernando S, Gordon, Scott D, Grove, Jakob, Adult Psychiatry, APH - Mental Health, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Wray, N.R., Ripke, S., Mattheisen, M., Trzaskowski, M., Byrne, E.M., Abdellaoui, A., Adams, M.J., Agerbo, E., Air, T.M., Andlauer, TFM, Bacanu, S.A., Bækvad-Hansen, M., Beekman, ATF, Bigdeli, T.B., Binder, E.B., Bryois, J., Buttenschøn, H.N., Bybjerg-Grauholm, J., Cai, N., Castelao, E., Christensen, J.H., Clarke, T.K., Coleman, JRI, Colodro-Conde, L., Couvy-Duchesne, B., Craddock, N., Crawford, G.E., Davies, G., Deary, I.J., Degenhardt, F., Derks, E.M., Direk, N., Dolan, C.V., Dunn, E.C., Eley, T.C., Escott-Price, V., Hassan Kiadeh, F.F., Finucane, H.K., Foo, J.C., Forstner, A.J., Frank, J., Gaspar, H.A., Gill, M., Goes, F.S., Gordon, S.D., Grove, J., Hall, L.S., Hansen, C.S., Hansen, T.F., Herms, S., Hickie, I.B., Hoffmann, P., Homuth, G., Horn, C., Hottenga, J.J., Hougaard, D.M., Howard, D.M., Ising, M., Jansen, R., Jones, I., Jones, L.A., Jorgenson, E., Knowles, J.A., Kohane, I.S., Kraft, J., Kretzschmar, W.W., Kutalik, Z., Li, Y., Lind, P.A., MacIntyre, D.J., MacKinnon, D.F., Maier, R.M., Maier, W., Marchini, J., Mbarek, H., McGrath, P., McGuffin, P., Medland, S.E., Mehta, D., Middeldorp, C.M., Mihailov, E., Milaneschi, Y., Milani, L., Mondimore, F.M., Montgomery, G.W., Mostafavi, S., Mullins, N., Nauck, M., Ng, B., Nivard, M.G., Nyholt, D.R., O'Reilly, P.F., Oskarsson, H., Owen, M.J., Painter, J.N., Pedersen, C.B., Pedersen, M.G., Peterson, R.E., Pettersson, E., Peyrot, W.J., Pistis, G., Posthuma, D., Quiroz, J.A., Qvist, P., Rice, J.P., Riley, B.P., Rivera, M., Mirza, S.S., Schoevers, R., Schulte, E.C., Shen, L., Shi, J., Shyn, S.I., Sigurdsson, E., Sinnamon, GCB, Smit, J.H., Smith, D.J., Stefansson, H., Steinberg, S., Streit, F., Strohmaier, J., Tansey, K.E., Teismann, H., Teumer, A., Thompson, W., Thomson, P.A., Thorgeirsson, T.E., Traylor, M., Treutlein, J., Trubetskoy, V., Uitterlinden, A.G., Umbricht, D., Van der Auwera, S., van Hemert, A.M., Viktorin, A., Visscher, P.M., Wang, Y., Webb, B.T., Weinsheimer, S.M., Wellmann, J., Willemsen, G., Witt, S.H., Wu, Y., Xi, H.S., Yang, J., Zhang, F., Arolt, V., Baune, B.T., Berger, K., Boomsma, D.I., Cichon, S., Dannlowski, U., de Geus, E., DePaulo, J.R., Domenici, E., Domschke, K., Esko, T., Grabe, H.J., Hamilton, S.P., Hayward, C., Heath, A.C., Kendler, K.S., Kloiber, S., Lewis, G., Li, Q.S., Lucae, S., Madden, P.A., Magnusson, P.K., Martin, N.G., McIntosh, A.M., Metspalu, A., Mors, O., Mortensen, P.B., Müller-Myhsok, B., Nordentoft, M., Nöthen, M.M., O'Donovan, M.C., Paciga, S.A., Pedersen, N.L., Penninx, BWJH, Perlis, R.H., Porteous, D.J., Potash, J.B., Preisig, M., Rietschel, M., Schaefer, C., Schulze, T.G., Smoller, J.W., Stefansson, K., Tiemeier, H., Uher, R., Völzke, H., Weissman, M.M., Werge, T., Lewis, C.M., Levinson, D.F., Breen, G., Børglum, A.D., Sullivan, P.F., Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Biological Psychology, APH - Methodology, Functional Genomics, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Complex Trait Genetics, Epidemiology, Child and Adolescent Psychiatry / Psychology, Psychiatry, Internal Medicine, Human genetics, Amsterdam Reproduction & Development (AR&D), APH - Digital Health, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), and Perceptual and Cognitive Neuroscience (PCN)
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), Major histocompatibility complex, LOCI, Complement, Autoimmune disorder, Genome-wide association study, Human leukocyte antigen, Genetic association, Major depressive disorder, Article, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, HLA Antigens, Genetic predisposition, IMPUTATION, Humans, ANXIETY, Genetic Predisposition to Disease, ddc:610, GENOME-WIDE ASSOCIATION, AUTOIMMUNE-DISEASE, Biological Psychiatry, Alleles, Complement component 4, Depressive Disorder, Major, Major histoconnpatibility complex, COMPLEX, biology, Depression, Haplotype, Odds ratio, ddc, 3. Good health, 030104 developmental biology, Haplotypes, Immunology, biology.protein, RISK-FACTORS, INFERENCE, HEALTH, 030217 neurology & neurosurgery
Abstract: Background\ud \ud The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a plausible explanation for the overlap, and in this study we tested whether genetic variation in the major histocompatibility complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression.\ud \ud \ud Methods\ud \ud We fine-mapped the classical MHC (chr6: 29.6–33.1 Mb), imputing 216 human leukocyte antigen (HLA) alleles and 4 complement component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium Major Depressive Disorder Working Group and the UK Biobank. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants, applying both a region-wide significance threshold (3.9 × 10−6) and a candidate threshold (1.6 × 10−4).\ud \ud \ud Results\ud \ud No HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold for testing in HLA genes in the meta-analysis (odds ratio = 0.98, 95% confidence interval = 0.97–0.99).\ud \ud \ud Conclusions\ud \ud We found no evidence that an increased risk for depression was conferred by HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia. These results suggest that any HLA or C4 variants associated with depression either are rare or have very modest effect sizes.
Published: 2020

31. N-3 polyunsaturated fatty acids promote astrocyte differentiation and neurotrophin production independent of cAMP in patient-derived neural stem cells

Author: Jennifer T. Wang, Jiang-Zhou Yu, Roy H. Perlis, Steven D. Sheridan, and Mark M. Rasenick
Subjects: 0301 basic medicine, medicine.medical_specialty, Docosahexaenoic Acids, Neurogenesis, CREB, Article, Cellular and Molecular Neuroscience, 03 medical and health sciences, Astrocyte differentiation, 0302 clinical medicine, Neural Stem Cells, Neurotrophic factors, Internal medicine, Fatty Acids, Omega-3, medicine, Glial cell line-derived neurotrophic factor, Humans, Nerve Growth Factors, Molecular Biology, 030304 developmental biology, 0303 health sciences, Depressive Disorder, Major, biology, Chemistry, food and beverages, Eicosapentaenoic acid, Neural stem cell, 3. Good health, Psychiatry and Mental health, 030104 developmental biology, Endocrinology, Docosahexaenoic acid, Neurotrophin production, Astrocytes, biology.protein, lipids (amino acids, peptides, and proteins), Stem cell, 030217 neurology & neurosurgery
Abstract: Evidence from epidemiological and laboratory studies, as well as randomized placebo-controlled trials, suggests supplementation with n-3 polyunsaturated fatty acids (PUFAs) may be efficacious for treatment of major depressive disorder (MDD). The mechanisms underlying n-3 PUFAs potential therapeutic properties remain unknown. There are suggestions in the literature that glial hypofunction is associated with depressive symptoms and that antidepressants may normalize glial function. In this study, iPSC-derived neuronal stem cell lines were generated from individuals with MDD. Astrocytes differentiated from patient-derived neuronal stem cells (iNSCs) were verified by GFAP. Cells were treated with eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and stearic acid (SA). During astrocyte differentiation, we found that n-3 PUFAs increased GFAP expression and GFAP positive cell formation. BDNF and GDNF production were increased in the astrocytes derived from patients subsequent to n-3 PUFA treatment. Stearic Acid (SA) treatment did not have this effect. CREB activity (phosphorylated CREB) was also increased by DHA and EPA but not by SA. Furthermore, when these astrocytes were treated with n-3 PUFAs, the cAMP antagonist, RP-cAMPs did not block n- 3 PUFA CREB activation. However, the CREB specific inhibitor (666-15) diminished BDNF and GDNF production induced by n-3 PUFA, suggesting CREB dependence. Together, these results suggested that n-3 PUFAs facilitate astrocyte differentiation, and may mimic effects of some antidepressants by increasing production of neurotrophic factors. The CREB-dependence and cAMP independence of this process suggests a manner in which n-3 PUFA could augment antidepressant effects. These data also suggest a role for astrocytes in both MDD and antidepressant action.
Published: 2020
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32. A Bi-Directional Competitive Interaction between CircHomer1 and Homer1b within the Orbitofrontal Cortex Regulates Reversal Learning

Author: Grigorios Papageorgiou, Gustavo Turecki, Stephen J. Haggarty, Roy H. Perlis, Caterina Chillotti, Begum Alural, Kristen J. Brennand, Stephen K. Amoah, Rixing Lin, Jasmin Lalonde, Nora I. Perrone-Bizzozero, Jayapriya Chandrasekaran, John Matthew Esposito, Nikolaos Mellios, Evelyn Lozano, Sabina Berretta, Alexander Hafez, Michela Dell'Orco, Alessio Squassina, Brigham J. Hartley, Amber Zimmerman, Caroline E. Pierotti, and Jonathan L. Brigman
Subjects: Gene isoform, Messenger RNA, Gene knockdown, Downregulation and upregulation, In vivo, Gene expression, Cognitive flexibility, Orbitofrontal cortex, Biology, Neuroscience
Abstract: Although circular RNAs (circRNAs) are abundantly expressed in the mammalian brain and preferentially-derived from synaptic genes, their relevance for brain function and psychiatric disorders and their interactions with neuronal protein-coding gene expression still remain poorly understood. Here we show that alterations in the levels of circHomer1, a neuronal-enriched circRNA altered in psychiatric disease that has been shown to influence OFC-mediated cognitive flexibility, are inversely associated with the relative expression of the long linear HOMER1B mRNA isoform in both the orbitofrontal cortex (OFC) and stem cell-derived neuronal cultures of subjects with psychiatric disorders. Using in vivo mature circHomer1-specific knockdown (KD) in adult mouse OFC, we further demonstrate that downregulation of circHomer1 results in increased synaptic expression of Homer1b mRNA. Furthermore, we utilize circRNA antisense purification to show that circHomer1 directly binds to Homer1b mRNA. We then demonstrate that in vivo Homer1b-specific KD increases synaptic circHomer1 levels within the OFC and improves OFC-mediated behavioral flexibility. Importantly, we show that double circHomer1 and Homer1b in vivo co-KD results in a complete rescue in circHomer1-associated alterations in both chance reversal learning and synaptic gene expression. Lastly, we demonstrate that circHomer1 is an experience-dependent circRNA that is significantly altered during chance reversal learning and that variability in its baseline expression within the OFC is significantly inversely correlated to behavioral performance during chance reversal learning. Taken together our data provide novel mechanistic insights into the importance of circRNAs in brain function and disease.
Published: 2020

33. Combination of177Lu-lilotomab with rituximab significantly improves the therapeutic outcome in preclinical models of non-Hodgkin's lymphoma

Author: Ada H. V. Repetto-Llamazares, Adam O'Shea, Bergthora Eiriksdottir, Roy H. Larsen, Trond Stokke, Marion Masitsa Malenge, and Jostein Dahle
Subjects: 0301 basic medicine, Radioimmunoconjugate, medicine.medical_treatment, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, medicine, CD20, biology, business.industry, Hematology, General Medicine, Immunotherapy, medicine.disease, Non-Hodgkin's lymphoma, Lymphoma, 030104 developmental biology, 030220 oncology & carcinogenesis, Radioimmunotherapy, Cancer research, biology.protein, Rituximab, Mantle cell lymphoma, business, medicine.drug
Abstract: Objectives To investigate the therapeutic potential of the next-generation anti-CD37 radioimmunoconjugate 177 Lu-lilotomab satetraxetan (177 Lu-lilotomab) in combination with the anti-CD20 antibody rituximab for treatment of mice with non-Hodgkin's lymphoma (NHL) xenografts. Methods Nude mice with subcutaneous (s.c.) Burkitt's lymphoma Daudi xenografts and SCID mice intravenously (i.v.) injected with Mantle cell lymphoma Rec-1 cells were treated with either 177 Lu-lilotomab or rituximab alone or with the combination of both treatments. Tumour volume, body weight, blood counts and clinical status were monitored. CD20 expression was measured using flow cytometry with fluorescence-labelled rituximab. Results The combination of 177 Lu-lilotomab and rituximab was synergistic for treatment of nude mice with s.c. Daudi xenografts while it was additive for treatment of SCID mice with i.v. injected Rec-1 cells. Binding of rituximab to NHL cells in-vitro was increased by pretreatment with 177 Lu-lilotomab. Conclusions Treatment of mice with NHL xenografts with 177 Lu-lilotomab synergistically increased tumour suppression of subsequent anti-CD20 immunotherapy and improved survival. If the same effect is confirmed in a recently started clinical study, it could change the way radioimmunotherapy and CD20 immunotherapy would be used in the future.
Published: 2018

34. Merkel Cell Carcinoma, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology

Author: Karin G. Hoffmann, Manisha J. Loss, Roy H. Decker, Rachel C. Blitzblau, Sumaira Z. Aasi, Murad Alam, Karthik Ghosh, Yaohui G. Xu, Roy C. Grekin, Valencia Thomas, Ashok R. Shaha, Anita M. Engh, James S. Andersen, Kishwer S. Nehal, Thomas Olencki, Carlo M. Contreras, Kenneth Grossman, Glen M. Bowen, Gregory A. Daniels, Kris Fisher, Alan L. Ho, Jane L. Messina, Paul Nghiem, John A. Zic, Igor Puzanov, Karl D. Lewis, Daniel D. Lydiatt, Brian R. Gastman, Jeffrey M. Farma, Chrysalyne D. Schmults, and Christopher K. Bichakjian
Subjects: Oncology, medicine.medical_specialty, Skin Neoplasms, medicine.medical_treatment, Aftercare, Merkel cell polyomavirus, Medical Oncology, Systemic therapy, Article, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Carcinoma, Humans, Societies, Medical, biology, Merkel cell carcinoma, business.industry, Incidence, food and beverages, Chemoradiotherapy, biology.organism_classification, medicine.disease, Primary tumor, United States, Carcinoma, Merkel Cell, Clinical Practice, Radiation therapy, 030220 oncology & carcinogenesis, Biomarker (medicine), business
Abstract: This selection from the NCCN Guidelines for Merkel Cell Carcinoma (MCC) focuses on areas impacted by recently emerging data, including sections describing MCC risk factors, diagnosis, workup, follow-up, and management of advanced disease with radiation and systemic therapy. Included in these sections are discussion of the new recommendations for use of Merkel cell polyomavirus as a biomarker and new recommendations for use of checkpoint immunotherapies to treat metastatic or unresectable disease. The next update of the complete version of the NCCN Guidelines for MCC will include more detailed information about elements of pathology and addresses additional aspects of management of MCC, including surgical management of the primary tumor and draining nodal basin, radiation therapy as primary treatment, and management of recurrence.
Published: 2018

35. Slugs (Arionidae) benefit from nocturnal artificial illumination

Author: Roy H. A. van Grunsven, Maja Grubisic, David Jähnichen, and Franz Hölker
Subjects: 0106 biological sciences, 0301 basic medicine, ALAN, Arionidae, light pollution, gastropoda, phototaxis, Light, Physiology, Gastropoda, Light pollution, Nocturnal, 010603 evolutionary biology, 01 natural sciences, Predation, 03 medical and health sciences, Germany, ddc:570, Genetics, Animals, Ecosystem, Molecular Biology, Lighting, Institut für Biochemie und Biologie, Ecology, Evolution, Behavior and Systematics, Economic consequences, Artificial illumination, biology, Ecology, Environmental Exposure, biology.organism_classification, 030104 developmental biology, Animal Science and Zoology
Abstract: Artificial illumination increases around the globe and this has been found to affect many groups of organisms and ecosystems. By manipulating nocturnal illumination using one large experimental field site with 24 streetlights and one dark control, we assessed the impact of artificial illumination on slugs over a period of 4 years. The number of slugs, primarily Arionidae, increased strongly in the illuminated site but not on the dark site. There are several nonexclusive explanations for this effect, including reduced predation and increased food quality in the form of carcasses of insects attracted by the light. As slugs play an important role in ecosystems and are also important pest species, the increase of slugs under artificial illumination cannot only affect ecosystem functioning but also have important economic consequences.
Published: 2018

36. Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression

Author: Jens Treutlein, James B. Potash, Cheynna A. Crowley, Paul F. O'Reilly, Francis M. Mondimore, Nicholas G. Martin, Jodie N. Painter, Qingqin S. Li, Tõnu Esko, Michael Conlon O'Donovan, Markus M. Nöthen, Toni-Kim Clarke, Roseann E. Peterson, Shantel Weinsheimer, Naomi R. Wray, Marie Bækvad-Hansen, Pamela F.A. Madden, Johannes H. Smit, Gonneke Willemsen, Thomas Hansen, Andrew C. Heath, Carsten Horn, Udo Dannlowski, Fulai Jin, Robert A. Schoevers, Jian Yang, Nicholas Eriksson, Marianne Giørtz Pedersen, Patrik K. E. Magnusson, Hans J. Grabe, Michael Gill, Lili Milani, Caroline Hayward, Shaun Purcell, Stanley I. Shyn, Penelope A. Lind, Giorgio Pistis, Michel G. Nivard, Thorgeir E. Thorgeirsson, Abdel Abdellaoui, Andres Metspalu, David J. Porteous, Anders D. Børglum, Christine Søholm Hansen, Scott D. Gordon, Nicholas John Craddock, Susanne Lucae, Douglas Blackwood, Jürgen Wellmann, Till M.F. Andlauer, Wesley K. Thompson, Chao Tian, Rudolf Uher, Nese Direk, Yuri Milaneschi, Paola Giusti-Rodríguez, Rick Jansen, Marcus Ising, Yang Wu, Jesper Krogh, Merete Nordentoft, Jouke-Jan Hottenga, Robert Maier, Ming Hu, Kari Stefansson, Glyn Lewis, Peter McGuffin, Wolfgang Maier, Erin C. Dunn, Bradley T. Webb, Gerome Breen, Henning Teismann, Eric Jorgenson, Jorge A. Quiroz, Brenda W.J.H. Penninx, Jonas Bybjerg-Grauholm, Warren W. Kretzschmar, Dean F. MacKinnon, Craig A. Stockmeier, Wouter J. Peyrot, Enrico Domenici, E. C.J. De Geus, Alexander Teumer, Henry Völzke, Yihan Li, Michael John Owen, Manuel Mattheisen, Bernard Ng, Baptiste Couvy-Duchesne, Daniel J. Smith, Jana Strohmaier, Vassily Trubetskoy, Volker Arolt, Douglas F. Levinson, Futao Zhang, Daniel Umbricht, Aartjan F.T. Beekman, David A. Hinds, Bernhard T. Baune, Henning Tiemeier, Hualin S. Xi, Hamdi Mbarek, Steven P. Hamilton, Stefan Kloiber, Fernando S. Goes, Jianxin Shi, Marcella Rietschel, Dale R. Nyholt, Zoltán Kutalik, Niamh Mullins, Grant W. Montgomery, Henriette N. Buttenschøn, Georg Homuth, Katharina Domschke, Alexander Viktorin, Hilary K. Finucane, Ashley R. Winslow, Saira Saeed Mirza, Fabian Streit, Erik Pettersson, Martin Preisig, Danielle Posthuma, Stephan Ripke, Lucía Colodro-Conde, Thalia C. Eley, Pippa A. Thomson, Thomas Werge, Enrique Castelao, Klaus Berger, Yun Li, Stacy Steinberg, Dorret I. Boomsma, Matthias Nauck, Sara Mostafavi, Jacqueline M. Lane, Katherine E. Tansey, Divya Mehta, Gregory E. Crawford, Andreas J. Forstner, Jane H. Christensen, Silviu Alin Bacanu, Julia Kraft, David M. Hougaard, Peter M. Visscher, Valentina Escott-Price, Donald J. MacIntyre, Sarah E. Medland, Per Qvist, Kenneth S. Kendler, Jordan W. Smoller, J. Raymond DePaulo, Ian J. Deary, Thomas G. Schulze, Julien Bryois, Ian B. Hickie, Helena Gaspar, Jonathan Mill, James A. Knowles, Cathryn M. Lewis, Hassan S. Dashti, Stefan Herms, Margarita Rivera, John P. Rice, Lynsey S. Hall, Eilis Hannon, Nancy L. Pedersen, Eva C. Schulte, Hreinn Stefansson, Maciej Trzaskowski, André G. Uitterlinden, Bertram Müller-Myhsok, Gail Davies, Mark Adams, Jakob Grove, Eske M. Derks, Sven Cichon, Jonathan I.R. Coleman, Sandra Van der Auwera, Myrna M. Weissman, Preben Bo Mortensen, Josef Frank, Enda M. Byrne, Esben Agerbo, Engilbert Sigurdsson, Xiaoxiao Liu, Patrick F. Sullivan, Carsten Bøcker Pedersen, Ole Mors, Catherine Schaefer, Richa Saxena, Albert M. van Hemert, Jonathan Marchini, Hogni Oskarsson, Franziska Degenhardt, Tracy Air, Elisabeth B. Binder, Christel M. Middeldorp, Farnush Hassan Farhadi Kiadeh, Conor V. Dolan, Sara A. Paciga, Per Hoffmann, Leina Lu, Andrew M. McIntosh, Tim B. Bigdeli, Stephanie H. Witt, Matthew Traylor, Grant Sinnamon, Brien P. Riley, Roy H. Perlis, Patrick J. McGrath, Craig L. Hyde, Ling Shen, Na Cai, Yunpeng Wang, Evelin Mihailov, Isaac S. Kohane, APH - Mental Health, Adult Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Biological Psychology, APH - Methodology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Integrative Neurophysiology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Psychiatry, Amsterdam Reproduction & Development (AR&D), Human genetics, Epidemiology and Data Science, APH - Digital Health, Epidemiology, Child and Adolescent Psychiatry / Psychology, Internal Medicine, eQTLGen, 23andMe, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Perceptual and Cognitive Neuroscience (PCN), and Clinical Cognitive Neuropsychiatry Research Program (CCNP)
Subjects: 0301 basic medicine, Male, Netherlands Twin Register (NTR), Multifactorial Inheritance, Schizophrenia/genetics, LD SCORE REGRESSION, LOCI, Genome-wide association study, Bioinformatics, 0302 clinical medicine, Risk Factors, POLYGENIC RISK, Depression (differential diagnoses), 3. Good health, Phenotype, Schizophrenia, Meta-analysis, MENDELIAN RANDOMIZATION, Genome-Wide Association Study/methods, Major depressive disorder, Female, Depressive Disorder, Major/genetics, EUROPE 2010, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, ddc:570, MENTAL-DISORDERS, Mendelian randomization, SYSTEMATIC ANALYSIS, Genetics, medicine, Journal Article, Humans, Genetic Predisposition to Disease, METAANALYSIS, EDUCATIONAL-ATTAINMENT, Depressive Disorder, Major, Case-control study, Case-Control Studies, medicine.disease, Genetic architecture, BODY-MASS INDEX, 030104 developmental biology, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened\ud risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified\ud 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and\ud implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved\ud in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression\ud with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were\ud putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry\ud lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression\ud and imply that a continuous measure of risk underlies the clinical phenotype.
Published: 2018

37. Genetic validation of bipolar disorder identified by automated phenotyping using electronic health records

Author: Douglas M. Ruderfer, Eli A. Stahl, Carlos N. Pato, Phil H. Lee, Jordan W. Smoller, Ian Jones, Jessica Minnier, Chia-Yen Chen, Tianxi Cai, Victor M. Castro, Pamela Sklar, Shawn N. Murphy, Vivian S. Gainer, Michele T. Pato, Alexander W. Charney, Mikael Landén, and Roy H. Perlis
Subjects: 0301 basic medicine, medicine.medical_specialty, Bipolar Disorder, Medical Records Systems, Computerized, Genome-wide association study, Biology, Bioinformatics, Polymorphism, Single Nucleotide, Genetic correlation, White People, Article, lcsh:RC321-571, Cohort Studies, Cellular and Molecular Neuroscience, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Genotype, medicine, Electronic Health Records, Humans, SNP, Genetic Predisposition to Disease, Bipolar disorder, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, 030304 developmental biology, Genetics, 0303 health sciences, business.industry, Heritability, medicine.disease, 3. Good health, Psychiatry and Mental health, Phenotype, 030104 developmental biology, Sample size determination, medicine.symptom, business, Mania, Algorithms, 030217 neurology & neurosurgery
Abstract: Bipolar disorder (BD) is a heritable mood disorder characterized by episodes of mania and depression. Although genomewide association studies (GWAS) have successfully identified genetic loci contributing to BD risk, sample size has become a rate-limiting obstacle to genetic discovery. Electronic health records (EHRs) represent a vast but relatively untapped resource for high-throughput phenotyping. As part of the International Cohort Collection for Bipolar Disorder (ICCBD), we previously validated automated EHR-based phenotyping algorithms for BD against in-person diagnostic interviews (Castro et al. Am J Psychiatry 172:363–372, 2015). Here, we establish the genetic validity of these phenotypes by determining their genetic correlation with traditionally ascertained samples. Case and control algorithms were derived from structured and narrative text in the Partners Healthcare system comprising more than 4.6 million patients over 20 years. Genomewide genotype data for 3330 BD cases and 3952 controls of European ancestry were used to estimate SNP-based heritability (h2g) and genetic correlation (rg) between EHR-based phenotype definitions and traditionally ascertained BD cases in GWAS by the ICCBD and Psychiatric Genomics Consortium (PGC) using LD score regression. We evaluated BD cases identified using 4 EHR-based algorithms: an NLP-based algorithm (95-NLP) and three rule-based algorithms using codified EHR with decreasing levels of stringency—“coded-strict”, “coded-broad”, and “coded-broad based on a single clinical encounter” (coded-broad-SV). The analytic sample comprised 862 95-NLP, 1968 coded-strict, 2581 coded-broad, 408 coded-broad-SV BD cases, and 3 952 controls. The estimated h2g were 0.24 (p = 0.015), 0.09 (p = 0.064), 0.13 (p = 0.003), 0.00 (p = 0.591) for 95-NLP, coded-strict, coded-broad and coded-broad-SV BD, respectively. The h2g for all EHR-based cases combined except coded-broad-SV (excluded due to 0 h2g) was 0.12 (p = 0.004). These h2g were lower or similar to the h2g observed by the ICCBD + PGCBD (0.23, p = 3.17E−80, total N = 33,181). However, the rg between ICCBD + PGCBD and the EHR-based cases were high for 95-NLP (0.66, p = 3.69 × 10–5), coded-strict (1.00, p = 2.40 × 10−4), and coded-broad (0.74, p = 8.11 × 10–7). The rg between EHR-based BD definitions ranged from 0.90 to 0.98. These results provide the first genetic validation of automated EHR-based phenotyping for BD and suggest that this approach identifies cases that are highly genetically correlated with those ascertained through conventional methods. High throughput phenotyping using the large data resources available in EHRs represents a viable method for accelerating psychiatric genetic research.
Published: 2018

38. A pigment composition analysis reveals community changes in pre-established stream periphyton under low-level artificial light at night

Author: Gabriel Singer, Roy H. A. van Grunsven, Franz Hölker, Michael T. Monaghan, Maja Grubisic, Alessandro Manfrin, and M. Cristina Bruno
Subjects: 0106 biological sciences, Cyanobacteria, Algae, Nutritional quality, 010501 environmental sciences, Aquatic Science, 01 natural sciences, ALAN, Settore BIO/07 - ECOLOGIA, Spring (hydrology), Periphyton, 0105 earth and related environmental sciences, geography, geography.geographical_feature_category, Artificial light, Primary producers, biology, Ecology, Biofilm, 010604 marine biology & hydrobiology, LED, Pigment composition, biology.organism_classification, Light pollution, HPLC, Environmental science
Abstract: Freshwaters are increasingly exposed to artificial light at night (ALAN), yet the consequences for aquatic primary producers remain largely unknown. We used stream-side flumes to expose three-week-old periphyton to LED light. Pigment composition was used to infer community changes in LED-lit and control periphyton before and after three weeks of treatment. The proportion of diatoms/chrysophytes decreased (14%) and cyanobacteria increased (17%) in lit periphyton in spring. This may reduce periphyton nutritional quality in artificially-lit waters.
Published: 2018

39. Declines in moth populations stress the need for conserving dark nights

Author: Martinus E. Huigens, W.N. Ellis, Jurriën R. van Deijk, Michiel F. WallisDeVries, Rob Groendijk, Olivier Poitevin, Rutger A. Vos, Marijke Braamburg-Annegarn, Frank van Langevelde, Roy H. A. van Grunsven, Markus Franzén, and Rob de Vos
Subjects: 0106 biological sciences, Conservation of Natural Resources, Light, ecology of the night, Fauna, Population Dynamics, Population, Night sky, Light pollution, Plant Ecology and Nature Conservation, Moths, artificial light at night, Biology, 010603 evolutionary biology, 01 natural sciences, Lepidoptera genitalia, Phototaxis, Animals, Environmental Chemistry, Circadian rhythm, education, Lighting, Netherlands, General Environmental Science, Global and Planetary Change, education.field_of_study, Ecology, Artificial light, 010604 marine biology & hydrobiology, light pollution, fungi, Feeding Behavior, PE&RC, ecological traits, Circadian Rhythm, Lepidoptera, Wildlife Ecology and Conservation, phototaxis, Plantenecologie en Natuurbeheer, sense organs
Abstract: Given the global continuous rise, artificial light at night is often considered a driving force behind moth population declines. Although negative effects on individuals have been shown, there is no evidence for effects on population sizes to date. Therefore, we compared population trends of Dutch macromoth fauna over the period 1985–2015 between moth species that differ in phototaxis and adult circadian rhythm. We found that moth species that show positive phototaxis or are nocturnally active have stronger negative population trends than species that are not attracted to light or are diurnal species. Our results indicate that artificial light at night is an important factor in explaining declines in moth populations in regions with high artificial night sky brightness. Our study supports efforts to reduce the impacts of artificial light at night by promoting lamps that do not attract insects and reduce overall levels of illumination in rural areas to reverse declines of moth populations.
Published: 2018

40. Effects of experimental light at night on extra-pair paternity in a songbird

Author: Maaike de Jong, Kamiel Spoelstra, Koosje P. Lamers, Arnaud Da Silva, Mark Eugster, A. Christa Mateman, Marcel E. Visser, Jenny Q. Ouyang, Roy H. A. van Grunsven, and Animal Ecology (AnE)
Subjects: Male, 0106 biological sciences, 0301 basic medicine, Light, Physiology, Offspring, Light pollution, Color, Zoology, Plant Ecology and Nature Conservation, artificial light at night, 010603 evolutionary biology, 01 natural sciences, Sexual Behavior, Animal, 03 medical and health sciences, extra-pair paternity, biology.animal, Parus major, Genetics, Animals, light color, Passeriformes, Molecular Biology, Lighting, Ecology, Evolution, Behavior and Systematics, Morning, Parus, biology, light pollution, Environmental Exposure, biology.organism_classification, PE&RC, Passerine, Songbird, 030104 developmental biology, great tit, Sexual selection, international, Dawn chorus, Plantenecologie en Natuurbeheer, Female, Animal Science and Zoology
Abstract: Light pollution is increasing worldwide and significantly affects animal behavior. In birds, these effects include advancement of morning activity and onset of dawn song, which may affect extra-pair paternity. Advanced dawn song of males may stimulate females to engage in extra-pair copulations, and the earlier activity onset may affect the males? mate guarding behavior. Earlier work showed an effect of light at night on extra-pair behavior, but this was in an area with other anthropogenic disturbances. Here, we present a two-year experimental study on effects of light at night on extra-pair paternity of great tits (Parus major). Previously dark natural areas were illuminated with white, red, and green LED lamps and compared to a dark control. In 2014, the proportion of extra-pair young in broods increased with distance to the red and white lamps (i.e., at lower light intensities), but decreased with distance to the poles in the dark control. In 2013, we found no effects on the proportion of extra-pair young. The total number of offspring sired by a male was unaffected by artificial light at night in both years, suggesting that potential changes in female fidelity in pairs breeding close to white and red light did not translate into fitness benefits for the males of these pairs. Artificial light at night might disrupt the natural patterns of extra-pair paternity, possibly negates potential benefits of extra-pair copulations and thus could alter sexual selection processes in wild birds.
Published: 2018

41. Analysis of the Influence of microRNAs in Lithium Response in Bipolar Disorder

Author: Céline S. Reinbold, Andreas J. Forstner, Julian Hecker, Janice M. Fullerton, Per Hoffmann, Liping Hou, Urs Heilbronner, Franziska Degenhardt, Mazda Adli, Kazufumi Akiyama, Nirmala Akula, Raffaella Ardau, Bárbara Arias, Lena Backlund, Antonio Benabarre, Susanne Bengesser, Abesh K. Bhattacharjee, Joanna M. Biernacka, Armin Birner, Cynthia Marie-Claire, Pablo Cervantes, Guo-Bo Chen, Hsi-Chung Chen, Caterina Chillotti, Scott R. Clark, Francesc Colom, David A. Cousins, Cristiana Cruceanu, Piotr M. Czerski, Alexandre Dayer, Bruno Étain, Peter Falkai, Louise Frisén, Sébastien Gard, Julie S. Garnham, Fernando S. Goes, Paul Grof, Oliver Gruber, Ryota Hashimoto, Joanna Hauser, Stefan Herms, Stéphane Jamain, Esther Jiménez, Jean-Pierre Kahn, Layla Kassem, Sarah Kittel-Schneider, Sebastian Kliwicki, Barbara König, Ichiro Kusumi, Nina Lackner, Gonzalo Laje, Mikael Landén, Catharina Lavebratt, Marion Leboyer, Susan G. Leckband, Carlos A. López Jaramillo, Glenda MacQueen, Mirko Manchia, Lina Martinsson, Manuel Mattheisen, Michael J. McCarthy, Susan L. McElroy, Marina Mitjans, Francis M. Mondimore, Palmiero Monteleone, Caroline M. Nievergelt, Urban Ösby, Norio Ozaki, Roy H. Perlis, Andrea Pfennig, Daniela Reich-Erkelenz, Guy A. Rouleau, Peter R. Schofield, K. Oliver Schubert, Barbara W. Schweizer, Florian Seemüller, Giovanni Severino, Tatyana Shekhtman, Paul D. Shilling, Kazutaka Shimoda, Christian Simhandl, Claire M. Slaney, Jordan W. Smoller, Alessio Squassina, Thomas J. Stamm, Pavla Stopkova, Sarah K. Tighe, Alfonso Tortorella, Gustavo Turecki, Julia Volkert, Stephanie H. Witt, Adam J. Wright, L. Trevor Young, Peter P. Zandi, James B. Potash, J. Raymond DePaulo, Michael Bauer, Eva Reininghaus, Tomáš Novák, Jean-Michel Aubry, Mario Maj, Bernhard T. Baune, Philip B. Mitchell, Eduard Vieta, Mark A. Frye, Janusz K. Rybakowski, Po-Hsiu Kuo, Tadafumi Kato, Maria Grigoroiu-Serbanescu, Andreas Reif, Maria Del Zompo, Frank Bellivier, Martin Schalling, Naomi R. Wray, John R. Kelsoe, Martin Alda, Francis J. McMahon, Thomas G. Schulze, Marcella Rietschel, Markus M. Nöthen, Sven Cichon, University Hospital Basel [Basel], Universitätsklinikum Bonn (UKB), Neuroscience Research Australia (NeuRA), Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], Human Genetics Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH), Department of Psychiatry and Psychotherapy, Georg-August-University [Göttingen], Department of Genomics, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Unit of Clinical Pharmacology, University-Hospital of Cagliari, Department of Psychiatry, Trinity College Dublin-St. James's Hospital, Mayo Clinic, University of Adelaide, McGill University = Université McGill [Montréal, Canada], Psychiatric Genetic Unit, Poznan University of Medical Sciences, Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Sorbonne Paris Cité (USPC), Université Paris Diderot - Paris 7 (UPD7), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Homburg, Department of Molecular Medicine, Karolinska Institutet [Stockholm], Service de psychiatrie adulte, Université Bordeaux Segalen - Bordeaux 2-Hôpital Charles Perrens, Dalhousie University [Halifax], Johns Hopkins University (JHU), Mood Disorders Center of Ottawa (MDCO), University of Ottawa [Ottawa], Department of Psychiatry [Heidelberg], University of Heidelberg, Medical Faculty, Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University [Osaka], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), IrsiCaixa (Institut de Recerca de la Sida), Service de Psychiatrie et Psychologie Clinique, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Hôpital Jeanne-d'Arc, Mental Health Sciences Unit, University College of London [London] (UCL), Department of Adult Psychiatry, Abteilung Informatik und angewandte Kognitionswissenschaft [Duisburg] (INKO), Universität Duisburg-Essen [Essen], Hokkaido University Graduate School of Medicine, Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Molecular Medicine and Surgery department, University of California [San Diego] (UC San Diego), University of California-University of California, University of Antioquia, Università degli Studi di Salerno (UNISA), Department of Clinical Neuroscience, R&D Unit, Department of Psychiatry, Danderyd University Hospital–Karolinska Institutet, Fujita Health University School of Medicine, Center for Human Genetic Research, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Prince of Wales Medical Research Institute, University of New South Wales [Sydney] (UNSW), Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Massachusetts General Hospital [Boston], Prague Psychiatric Center, University of Prague, Università degli Studi di Perugia (UNIPG), Department of Psychiatry [Montréal], School of Psychiatry, Black Dog Institute-University of New South Wales [Sydney] (UNSW), Department of Mental Health, Johns Hopkins University and Hospital, Center for Sepsis Control & Care, Jena University Hospital, Medical University Graz, Department of Mental Health and Psychiatry, University Hospital of Geneva, Università degli studi della Campania 'Luigi Vanvitelli', Institute of Neuroscience, Hospital Clinic-IDIBAPS - CIBERSAM - ENBREC-University of Barcelona, Institute of Epidemiology and Preventive Medicine, National Taiwan University [Taiwan] (NTU), Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science [Wako] (RIKEN CBS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN)-RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Psychiatric Hospital, Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, King‘s College London, Univerity of Mannheim, Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, McGill University, Optimisation Thérapeutique en Neuropsychopharmacologie (VariaPsy - U1144), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), University of Ottawa [Ottawa] (uOttawa), Technische Universität Dresden (TUD), University of New South Wales [Sydney] (UNSW)-Black Dog Institute, RIKEN Brain Science Institute, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Friedrich Alexander University [Erlangen-Nürnberg], Universitat de Barcelona, Georg-August-University = Georg-August-Universität Göttingen, University of California (UC)-University of California (UC), Università degli Studi di Salerno = University of Salerno (UNISA), Danderyds sjukhus = Danderyd University Hospital, Università degli Studi di Perugia = University of Perugia (UNIPG), Università degli studi della Campania 'Luigi Vanvitelli' = University of the Study of Campania Luigi Vanvitelli, Reinbold, Céline S., Forstner, Andreas J., Hecker, Julian, Fullerton, Janice M., Hoffmann, Per, Hou, Liping, Heilbronner, Ur, Degenhardt, Franziska, Adli, Mazda, Akiyama, Kazufumi, Akula, Nirmala, Ardau, Raffaella, Arias, Bárbara, Backlund, Lena, Benabarre, Antonio, Bengesser, Susanne, Bhattacharjee, Abesh K., Biernacka, Joanna M., Birner, Armin, Marie-Claire, Cynthia, Cervantes, Pablo, Chen, Guo-Bo, Chen, Hsi-Chung, Chillotti, Caterina, Clark, Scott R., Colom, Francesc, Cousins, David A., Cruceanu, Cristiana, Czerski, Piotr M., Dayer, Alexandre, Étain, Bruno, Falkai, Peter, Frisén, Louise, Gard, Sébastien, Garnham, Julie S., Goes, Fernando S., Grof, Paul, Gruber, Oliver, Hashimoto, Ryota, Hauser, Joanna, Herms, Stefan, Jamain, Stéphane, Jiménez, Esther, Kahn, Jean-Pierre, Kassem, Layla, Kittel-Schneider, Sarah, Kliwicki, Sebastian, König, Barbara, Kusumi, Ichiro, Lackner, Nina, Laje, Gonzalo, Landén, Mikael, Lavebratt, Catharina, Leboyer, Marion, Leckband, Susan G., Jaramillo, Carlos A. López, Macqueen, Glenda, Manchia, Mirko, Martinsson, Lina, Mattheisen, Manuel, Mccarthy, Michael J., Mcelroy, Susan L., Mitjans, Marina, Mondimore, Francis M., Monteleone, Palmiero, Nievergelt, Caroline M., Ösby, Urban, Ozaki, Norio, Perlis, Roy H., Pfennig, Andrea, Reich-Erkelenz, Daniela, Rouleau, Guy A., Schofield, Peter R., Schubert, K. Oliver, Schweizer, Barbara W., Seemüller, Florian, Severino, Giovanni, Shekhtman, Tatyana, Shilling, Paul D., Shimoda, Kazutaka, Simhandl, Christian, Slaney, Claire M., Smoller, Jordan W., Squassina, Alessio, Stamm, Thomas J., Stopkova, Pavla, Tighe, Sarah K., Tortorella, Alfonso, Turecki, Gustavo, Volkert, Julia, Witt, Stephanie H., Wright, Adam J., Trevor Young, L., Zandi, Peter P., Potash, James B., Depaulo, J. Raymond, Bauer, Michael, Reininghaus, Eva, Novák, Tomáš, Aubry, Jean-Michel, Maj, Mario, Baune, Bernhard T., Mitchell, Philip B., Vieta, Eduard, Frye, Mark A., Rybakowski, Janusz K., Kuo, Po-Hsiu, Kato, Tadafumi, Grigoroiu-Serbanescu, Maria, Reif, Andrea, Zompo, Maria Del, Bellivier, Frank, Schalling, Martin, Wray, Naomi R., Kelsoe, John R., Alda, Martin, Mcmahon, Francis J., Schulze, Thomas G., Rietschel, Marcella, Nöthen, Markus M., and Cichon, Sven
Subjects: 0301 basic medicine, Genome-wide association study, Lithium (medication), lcsh:RC435-571, Bipolar disorder, Common variants, Lithium response, MicroRNA, Psychiatry and Mental Health, Common variant, Lithium, Biology, ddc:616.89, 03 medical and health sciences, lcsh:Psychiatry, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], common variants, medicine, Manic-depressive illness, ddc:610, Gene, ComputingMilieux_MISCELLANEOUS, Trastorno Bipolar, Original Research, Psychiatry, bipolar disorder, Genetics, MicroARNs, Trastorn bipolar, genome-wide association study, microRNA, medicine.disease, genome-wide association stud, Liti, Phenotype, 3. Good health, MicroRNAs, Psychiatry and Mental health, 030104 developmental biology, Schizophrenia, Multiple comparisons problem, Litio, medicine.symptom, Mania, lithium response, medicine.drug
Abstract: Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable. Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen). Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD-associated miRNAs. However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGenGWAS dataset (n = 2,563 patients) using a set-based testing approach adapted from the versatile gene-based test for GWAS (VEGAS2). In the candidate approach, miR-499a showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genomewide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with miR-633 showing the strongest association with the continuous trait (p = 9.80E-04) and miR-607 with the dichotomous phenotype (p = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted. COL0029147
Published: 2018

42. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Author: Aude Nicolas, Kevin P. Kenna, Alan E. Renton, Nicola Ticozzi, Faraz Faghri, Ruth Chia, Janice A. Dominov, Brendan J. Kenna, Mike A. Nalls, Pamela Keagle, Alberto M. Rivera, Wouter van Rheenen, Natalie A. Murphy, Joke J.F.A. van Vugt, Joshua T. Geiger, Rick A. Van der Spek, Hannah A. Pliner, null Shankaracharya, Bradley N. Smith, Giuseppe Marangi, Simon D. Topp, Yevgeniya Abramzon, Athina Soragia Gkazi, John D. Eicher, Aoife Kenna, Gabriele Mora, Andrea Calvo, Letizia Mazzini, Nilo Riva, Jessica Mandrioli, Claudia Caponnetto, Stefania Battistini, Paolo Volanti, Vincenzo La Bella, Francesca L. Conforti, Giuseppe Borghero, Sonia Messina, Isabella L. Simone, Francesca Trojsi, Fabrizio Salvi, Francesco O. Logullo, Sandra D’Alfonso, Lucia Corrado, Margherita Capasso, Luigi Ferrucci, Cristiane de Araujo Martins Moreno, Sitharthan Kamalakaran, David B. Goldstein, Aaron D. Gitler, Tim Harris, Richard M. Myers, Hemali Phatnani, Rajeeva Lochan Musunuri, Uday Shankar Evani, Avinash Abhyankar, Michael C. Zody, Julia Kaye, Steven Finkbeiner, Stacia K. Wyman, Alex LeNail, Leandro Lima, Ernest Fraenkel, Clive N. Svendsen, Leslie M. Thompson, Jennifer E. Van Eyk, James D. Berry, Timothy M. Miller, Stephen J. Kolb, Merit Cudkowicz, Emily Baxi, Michael Benatar, J. Paul Taylor, Evadnie Rampersaud, Gang Wu, Joanne Wuu, Giuseppe Lauria, Federico Verde, Isabella Fogh, Cinzia Tiloca, Giacomo P. Comi, Gianni Sorarù, Cristina Cereda, Philippe Corcia, Hannu Laaksovirta, Liisa Myllykangas, Lilja Jansson, Miko Valori, John Ealing, Hisham Hamdalla, Sara Rollinson, Stuart Pickering-Brown, Richard W. Orrell, Katie C. Sidle, Andrea Malaspina, John Hardy, Andrew B. Singleton, Janel O. Johnson, Sampath Arepalli, Peter C. Sapp, Diane McKenna-Yasek, Meraida Polak, Seneshaw Asress, Safa Al-Sarraj, Andrew King, Claire Troakes, Caroline Vance, Jacqueline de Belleroche, Frank Baas, Anneloor L.M.A. ten Asbroek, José Luis Muñoz-Blanco, Dena G. Hernandez, Jinhui Ding, J. Raphael Gibbs, Sonja W. Scholz, Mary Kay Floeter, Roy H. Campbell, Francesco Landi, Robert Bowser, Stefan M. Pulst, John M. Ravits, Daniel J.L. MacGowan, Janine Kirby, Erik P. Pioro, Roger Pamphlett, James Broach, Glenn Gerhard, Travis L. Dunckley, Christopher B. Brady, Neil W. Kowall, Juan C. Troncoso, Isabelle Le Ber, Kevin Mouzat, Serge Lumbroso, Terry D. Heiman-Patterson, Freya Kamel, Ludo Van Den Bosch, Robert H. Baloh, Tim M. Strom, Thomas Meitinger, Aleksey Shatunov, Kristel R. Van Eijk, Mamede de Carvalho, Maarten Kooyman, Bas Middelkoop, Matthieu Moisse, Russell L. McLaughlin, Michael A. Van Es, Markus Weber, Kevin B. Boylan, Marka Van Blitterswijk, Rosa Rademakers, Karen E. Morrison, A. Nazli Basak, Jesús S. Mora, Vivian E. Drory, Pamela J. Shaw, Martin R. Turner, Kevin Talbot, Orla Hardiman, Kelly L. Williams, Jennifer A. Fifita, Garth A. Nicholson, Ian P. Blair, Guy A. Rouleau, Jesús Esteban-Pérez, Alberto García-Redondo, Ammar Al-Chalabi, Ekaterina Rogaeva, Lorne Zinman, Lyle W. Ostrow, Nicholas J. Maragakis, Jeffrey D. Rothstein, Zachary Simmons, Johnathan Cooper-Knock, Alexis Brice, Stephen A. Goutman, Eva L. Feldman, Summer B. Gibson, Franco Taroni, Antonia Ratti, Cinzia Gellera, Philip Van Damme, Wim Robberecht, Pietro Fratta, Mario Sabatelli, Christian Lunetta, Albert C. Ludolph, Peter M. Andersen, Jochen H. Weishaupt, William Camu, John Q. Trojanowski, Vivianna M. Van Deerlin, Robert H. Brown, Leonard H. van den Berg, Jan H. Veldink, Matthew B. Harms, Jonathan D. Glass, David J. Stone, Pentti Tienari, Vincenzo Silani, Adriano Chiò, Christopher E. Shaw, Bryan J. Traynor, John E. Landers, Isabella Simone, Giancarlo Logroscino, Ilaria Bartolomei, Maria Rita Murru, Emanuela Costantino, Carla Pani, Roberta Puddu, Carla Caredda, Valeria Piras, Stefania Tranquilli, Stefania Cuccu, Daniela Corongiu, Maurizio Melis, Antonio Milia, Francesco Marrosu, Maria Giovanna Marrosu, Gianluca Floris, Antonino Cannas, Gianluigi Mancardi, Paola Origone, Paola Mandich, Sebastiano Cavallaro, Kalliopi Marinou, Riccardo Sideri, Silvana Penco, Lorena Mosca, Giuseppe Lauria Pinter, Massimo Corbo, Paola Carrera, Nicola Fini, Antonio Fasano, Lucio Tremolizzo, Alessandro Arosio, Carlo Ferrarese, Gioacchino Tedeschi, Maria Rosaria Monsurrò, Giovanni Piccirillo, Cinzia Femiano, Anna Ticca, Enzo Ortu, Rossella Spataro, Tiziana Colletti, Marcella Zollino, Amelia Conte, Marco Luigetti, Serena Lattante, Marialuisa Santarelli, Antonio Petrucci, Maura Pugliatti, Angelo Pirisi, Leslie D. Parish, Patrizia Occhineri, Fabio Giannini, Claudia Ricci, Michele Benigni, Tea B. Cau, Daniela Loi, Cristina Moglia, Maura Brunetti, Marco Barberis, Gabriella Restagno, Federico Casale, Giuseppe Marrali, Giuseppe Fuda, Irene Ossola, Stefania Cammarosano, Antonio Canosa, Antonio Ilardi, Umberto Manera, Maurizio Grassano, Raffaella Tanel, Fabrizio Pisano, Neil A. Shneider, Stephen Goutman, Siddharthan Chandran, Suvankar Pal, George Manousakis, Stanley H. Appel, Ericka Simpson, Leo Wang, Summer Gibson, Richard Bedlack, David Lacomis, Dhruv Sareen, Alexander Sherman, Lucie Bruijn, Michelle Penny, Andrew S. Allen, Stanley Appel, Richard S. Bedlack, Braden E. Boone, Robert Brown, John P. Carulli, Alessandra Chesi, Wendy K. Chung, Elizabeth T. Cirulli, Gregory M. Cooper, Julien Couthouis, Aaron G. Day-Williams, Patrick A. Dion, Yujun Han, Sebastian D. Hayes, Angela L. Jones, Jonathan Keebler, Brian J. Krueger, Brittany N. Lasseigne, Shawn E. Levy, Yi-Fan Lu, Tom Maniatis, Slavé Petrovski, Alya R. Raphael, Zhong Ren, Katherine B. Sims, John F. Staropoli, Lindsay L. Waite, Quanli Wang, Jack R. Wimbish, Winnie W. Xin, Justin Kwan, James R. Broach, Ximena Arcila-Londono, Edward B. Lee, Noah Zaitlen, Gregory A. Cox, Steve Finkbeiner, Efthimios Dardiotis, Eran Hornstein, Daniel J. MacGowan, Terry Heiman-Patterson, Molly G. Hammell, Nikolaos A. Patsopoulos, Joshua Dubnau, Avindra Nath, Stacia Wyman, Alexander LeNail, Jenny Van Eyk, Stephan Züchner, Rebecca Schule, Jacob McCauley, Sumaira Hussain, Anne Cooley, Marielle Wallace, Christine Clayman, Richard Barohn, Jeffrey Statland, John Ravits, Andrea Swenson, Carlayne Jackson, Jaya Trivedi, Shaida Khan, Jonathan Katz, Liberty Jenkins, Ted Burns, Kelly Gwathmey, James Caress, Corey McMillan, Lauren Elman, Erik Pioro, Jeannine Heckmann, Yuen So, David Walk, Samuel Maiser, Jinghui Zhang, Fabiola De Marchi, Stefania Corti, Mauro Ceroni, Gabriele Siciliano, Massimiliano Filosto, Maurizio Inghilleri, Silvia Peverelli, Claudia Colombrita, Barbara Poletti, Luca Maderna, Roberto Del Bo, Stella Gagliardi, Giorgia Querin, Cinzia Bertolin, Viviana Pensato, Barbara Castellotti, Vincent Meininger, Gérard Besson, Emmeline Lagrange, Pierre Clavelou, Nathalie Guy, Philippe Couratier, Patrick Vourch, Véronique Danel, Emilien Bernard, Gwendal Lemasson, Ahmad Al Kheifat, Peter Andersen, Adriano Chio, Jonathan Cooper-Knock, Annelot Dekker, Vivian Drory, Alberto Garcia Redondo, Marc Gotkine, Winston Hide, Alfredo Iacoangeli, Jonathan Glass, Kevin Kenna, Matthew Kiernan, John Landers, Russell McLaughlin, Jonathan Mill, Miguel Mitne Neto, Mattieu Moisse, Jesus Mora Pardina, Karen Morrison, Stephen Newhouse, Susana Pinto, Sara Pulit, Pamela Shaw, Chris Shaw, William Sproviero, Gijs Tazelaar, Philip van Damme, Leonard van den Berg, Rick van der Spek, Kristel van Eijk, Michael van Es, Joke van Vugt, Jan Veldink, Mayana Zatz, Denis C. Bauer, Natalie A. Twine, Department of Neurosciences, Pentti Tienari / Principal Investigator, Neurologian yksikkö, Research Programs Unit, Clinicum, Research Programme for Molecular Neurology, University of Helsinki, Medicum, Department of Pathology, HUS Neurocenter, Nicolas A., Kenna K.P., Renton A.E., Ticozzi N., Faghri F., Chia R., Dominov J.A., Kenna B.J., Nalls M.A., Keagle P., Rivera A.M., van Rheenen W., Murphy N.A., van Vugt J.J.F.A., Geiger J.T., Van der Spek R.A., Pliner H.A., Shankaracharya, Smith B.N., Marangi G., Topp S.D., Abramzon Y., Gkazi A.S., Eicher J.D., Kenna A., Logullo F.O., Simone I.L., Logroscino G., Salvi F., Bartolomei I., Borghero G., Murru M.R., Costantino E., Pani C., Puddu R., Caredda C., Piras V., Tranquilli S., Cuccu S., Corongiu D., Melis M., Milia A., Marrosu F., Marrosu M.G., Floris G., Cannas A., Capasso M., Caponnetto C., Mancardi G., Origone P., Mandich P., Conforti F.L., Cavallaro S., Mora G., Marinou K., Sideri R., Penco S., Mosca L., Lunetta C., Pinter G.L., Corbo M., Riva N., Carrera P., Volanti P., Mandrioli J., Fini N., Fasano A., Tremolizzo L., Arosio A., Ferrarese C., Trojsi F., Tedeschi G., Monsurro M.R., Piccirillo G., Femiano C., Ticca A., Ortu E., La Bella V., Spataro R., Colletti T., Sabatelli M., Zollino M., Conte A., Luigetti M., Lattante S., Santarelli M., Petrucci A., Pugliatti M., Pirisi A., Parish L.D., Occhineri P., Giannini F., Battistini S., Ricci C., Benigni M., Cau T.B., Loi D., Calvo A., Moglia C., Brunetti M., Barberis M., Restagno G., Casale F., Marrali G., Fuda G., Ossola I., Cammarosano S., Canosa A., Ilardi A., Manera U., Grassano M., Tanel R., Pisano F., Mazzini L., Messina S., D'Alfonso S., Corrado L., Ferrucci L., Harms M.B., Goldstein D.B., Shneider N.A., Goutman S.A., Simmons Z., Miller T.M., Chandran S., Pal S., Manousakis G., Appel S.H., Simpson E., Wang L., Baloh R.H., Gibson S.B., Bedlack R., Lacomis D., Sareen D., Sherman A., Bruijn L., Penny M., Moreno C.D.A.M., Kamalakaran S., Allen A.S., Boone B.E., Brown R.H., Carulli J.P., Chesi A., Chung W.K., Cirulli E.T., Cooper G.M., Couthouis J., Day-Williams A.G., Dion P.A., Gitler A.D., Glass J.D., Han Y., Harris T., Hayes S.D., Jones A.L., Keebler J., Krueger B.J., Lasseigne B.N., Levy S.E., Lu Y.-F., Maniatis T., McKenna-Yasek D., Myers R.M., Petrovski S., Pulst S.M., Raphael A.R., Ravits J.M., Ren Z., Rouleau G.A., Sapp P.C., Sims K.B., Staropoli J.F., Waite L.L., Wang Q., Wimbish J.R., Xin W.W., Phatnani H., Kwan J., Broach J., Arcila-Londono X., Lee E.B., Van Deerlin V.M., Fraenkel E., Ostrow L.W., Baas F., Zaitlen N., Berry J.D., Malaspina A., Fratta P., Cox G.A., Thompson L.M., Finkbeiner S., Dardiotis E., Hornstein E., MacGowan D.J.L., Heiman-Patterson T., Hammell M.G., Patsopoulos N.A., Dubnau J., Nath A., Musunuri R.L., Evani U.S., Abhyankar A., Zody M.C., Kaye J., Wyman S.K., LeNail A., Lima L., Rothstein J.D., Svendsen C.N., Van Eyk J.E., Maragakis N.J., Kolb S.J., Cudkowicz M., Baxi E., Benatar M., Taylor J.P., Wu G., Rampersaud E., Wuu J., Rademakers R., Zuchner S., Schule R., McCauley J., Hussain S., Cooley A., Wallace M., Clayman C., Barohn R., Statland J., Swenson A., Jackson C., Trivedi J., Khan S., Katz J., Jenkins L., Burns T., Gwathmey K., Caress J., McMillan C., Elman L., Pioro E.P., Heckmann J., So Y., Walk D., Maiser S., Zhang J., Silani V., Gellera C., Ratti A., Taroni F., Lauria G., Verde F., Fogh I., Tiloca C., Comi G.P., Soraru G., Cereda C., De Marchi F., Corti S., Ceroni M., Siciliano G., Filosto M., Inghilleri M., Peverelli S., Colombrita C., Poletti B., Maderna L., Del Bo R., Gagliardi S., Querin G., Bertolin C., Pensato V., Castellotti B., Camu W., Mouzat K., Lumbroso S., Corcia P., Meininger V., Besson G., Lagrange E., Clavelou P., Guy N., Couratier P., Vourch P., Danel V., Bernard E., Lemasson G., Laaksovirta H., Myllykangas L., Jansson L., Valori M., Ealing J., Hamdalla H., Rollinson S., Pickering-Brown S., Orrell R.W., Sidle K.C., Hardy J., Singleton A.B., Johnson J.O., Arepalli S., Polak M., Asress S., Al-Sarraj S., King A., Troakes C., Vance C., de Belleroche J., ten Asbroek A.L.M.A., Munoz-Blanco J.L., Hernandez D.G., Ding J., Gibbs J.R., Scholz S.W., Floeter M.K., Campbell R.H., Landi F., Bowser R., Kirby J., Pamphlett R., Gerhard G., Dunckley T.L., Brady C.B., Kowall N.W., Troncoso J.C., Le Ber I., Heiman-Patterson T.D., Kamel F., Van Den Bosch L., Strom T.M., Meitinger T., Shatunov A., Van Eijk K.R., de Carvalho M., Kooyman M., Middelkoop B., Moisse M., McLaughlin R.L., Van Es M.A., Weber M., Boylan K.B., Van Blitterswijk M., Morrison K.E., Basak A.N., Mora J.S., Drory V.E., Shaw P.J., Turner M.R., Talbot K., Hardiman O., Williams K.L., Fifita J.A., Nicholson G.A., Blair I.P., Esteban-Perez J., Garcia-Redondo A., Al-Chalabi A., Al Kheifat A., Andersen P.M., Chio A., Cooper-Knock J., Dekker A., Redondo A.G., Gotkine M., Hide W., Iacoangeli A., Kiernan M., Landers J.E., Mill J., Neto M.M., Pardina J.M., Newhouse S., Pinto S., Pulit S., Robberecht W., Shaw C., Sproviero W., Tazelaar G., Van Damme P., van den Berg L.H., van Vugt J., Veldink J.H., Zatz M., Bauer D.C., Twine N.A., Rogaeva E., Zinman L., Brice A., Feldman E.L., Ludolph A.C., Weishaupt J.H., Trojanowski J.Q., Stone D.J., Tienari P., Shaw C.E., Traynor B.J., ITALSGEN Consortium, Genomic Translation ALS Care GTAC, ALS Sequencing Consortium, NYGC ALS Consortium, Answer ALS Fdn, Clinical Res ALS Related Disorders, SLAGEN Consortium, French ALS Consortium, Project MinE ALS Sequencing Consor, Medical Research Council (MRC), ANS - Complex Trait Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Università cattolica del Sacro Cuore [Roma] (Unicatt), Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier] (SLA CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1), Lunar and Planetary Laboratory [Tucson] (LPL), University of Arizona, Università degli studi di Torino (UNITO), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), New York Genome Center [New York], New York Genome Center, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), St Jude Children's Research Hospital, Howard Hughes Medical Institute [Chevy Chase] (HHMI), Howard Hughes Medical Institute (HHMI), Centre de compétence de la Sclérose Latérale Amyotrophique [CHRU Tours] (SLA CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), University College of London [London] (UCL), Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), King‘s College London, University of New Haven [Connecticut], Princeton University, Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Helmholtz-Zentrum München (HZM), University Medical Center [Utrecht], Deutsches Forschungszentrum für Künstliche Intelligenz GmbH = German Research Center for Artificial Intelligence (DFKI), Mayo Clinic [Jacksonville], Trinity College Dublin, Maurice Wohl Clinical Neuroscience Institut, Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Repositório da Universidade de Lisboa, Nicolas, A, Kenna, K, Renton, A, Ticozzi, N, Faghri, F, Chia, R, Dominov, J, Kenna, B, Nalls, M, Keagle, P, Rivera, A, van Rheenen, W, Murphy, N, van Vugt, J, Geiger, J, van der Spek, R, Pliner, H, Shankaracharya, N, Smith, B, Marangi, G, Topp, S, Abramzon, Y, Gkazi, A, Eicher, J, Kenna, A, Logullo, F, Simone, I, Logroscino, G, Salvi, F, Bartolomei, I, Borghero, G, Murru, M, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Marrosu, F, Marrosu, M, Floris, G, Cannas, A, Capasso, M, Caponnetto, C, Mancardi, G, Origone, P, Mandich, P, Conforti, F, Cavallaro, S, Mora, G, Marinou, K, Sideri, R, Penco, S, Mosca, L, Lunetta, C, Pinter, G, Corbo, M, Riva, N, Carrera, P, Volanti, P, Mandrioli, J, Fini, N, Fasano, A, Tremolizzo, L, Arosio, A, Ferrarese, C, Trojsi, F, Tedeschi, G, Monsurrò, M, Piccirillo, G, Femiano, C, Ticca, A, Ortu, E, La Bella, V, Spataro, R, Colletti, T, Sabatelli, M, Zollino, M, Conte, A, Luigetti, M, Lattante, S, Santarelli, M, Petrucci, A, Pugliatti, M, Pirisi, A, Parish, L, Occhineri, P, Giannini, F, Battistini, S, Ricci, C, Benigni, M, Cau, T, Loi, D, Calvo, A, Moglia, C, Brunetti, M, Barberis, M, Restagno, G, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Canosa, A, Ilardi, A, Manera, U, Grassano, M, Tanel, R, Pisano, F, Mazzini, L, Messina, S, D'Alfonso, S, Corrado, L, Ferrucci, L, Harms, M, Goldstein, D, Shneider, N, Goutman, S, Simmons, Z, Miller, T, Chandran, S, Pal, S, Manousakis, G, Appel, S, Simpson, E, Wang, L, Baloh, R, Gibson, S, Bedlack, R, Lacomis, D, Sareen, D, Sherman, A, Bruijn, L, Penny, M, Moreno, C, Kamalakaran, S, Allen, A, Boone, B, Brown, R, Carulli, J, Chesi, A, Chung, W, Cirulli, E, Cooper, G, Couthouis, J, Day-Williams, A, Dion, P, Gitler, A, Glass, J, Han, Y, Harris, T, Hayes, S, Jones, A, Keebler, J, Krueger, B, Lasseigne, B, Levy, S, Lu, Y, Maniatis, T, McKenna-Yasek, D, Myers, R, Petrovski, S, Pulst, S, Raphael, A, Ravits, J, Ren, Z, Rouleau, G, Sapp, P, Sims, K, Staropoli, J, Waite, L, Wang, Q, Wimbish, J, Xin, W, Phatnani, H, Kwan, J, Broach, J, Arcila-Londono, X, Lee, E, Van Deerlin, V, Fraenkel, E, Ostrow, L, Baas, F, Zaitlen, N, Berry, J, Malaspina, A, Fratta, P, Cox, G, Thompson, L, Finkbeiner, S, Dardiotis, E, Hornstein, E, Macgowan, D, Heiman-Patterson, T, Hammell, M, Patsopoulos, N, Dubnau, J, Nath, A, Musunuri, R, Evani, U, Abhyankar, A, Zody, M, Kaye, J, Wyman, S, Lenail, A, Lima, L, Rothstein, J, Svendsen, C, Van Eyk, J, Maragakis, N, Kolb, S, Cudkowicz, M, Baxi, E, Benatar, M, Taylor, J, Wu, G, Rampersaud, E, Wuu, J, Rademakers, R, Züchner, S, Schule, R, Mccauley, J, Hussain, S, Cooley, A, Wallace, M, Clayman, C, Barohn, R, Statland, J, Swenson, A, Jackson, C, Trivedi, J, Khan, S, Katz, J, Jenkins, L, Burns, T, Gwathmey, K, Caress, J, Mcmillan, C, Elman, L, Pioro, E, Heckmann, J, So, Y, Walk, D, Maiser, S, Zhang, J, Silani, V, Gellera, C, Ratti, A, Taroni, F, Lauria, G, Verde, F, Fogh, I, Tiloca, C, Comi, G, Sorarù, G, Cereda, C, De Marchi, F, Corti, S, Ceroni, M, Siciliano, G, Filosto, M, Inghilleri, M, Peverelli, S, Colombrita, C, Poletti, B, Maderna, L, Del Bo, R, Gagliardi, S, Querin, G, Bertolin, C, Pensato, V, Castellotti, B, Camu, W, Mouzat, K, Lumbroso, S, Corcia, P, Meininger, V, Besson, G, Lagrange, E, Clavelou, P, Guy, N, Couratier, P, Vourch, P, Danel, V, Bernard, E, Lemasson, G, Laaksovirta, H, Myllykangas, L, Jansson, L, Valori, M, Ealing, J, Hamdalla, H, Rollinson, S, Pickering-Brown, S, Orrell, R, Sidle, K, Hardy, J, Singleton, A, Johnson, J, Arepalli, S, Polak, M, Asress, S, Al-Sarraj, S, King, A, Troakes, C, Vance, C, de Belleroche, J, ten Asbroek, A, Muñoz-Blanco, J, Hernandez, D, Ding, J, Gibbs, J, Scholz, S, Floeter, M, Campbell, R, Landi, F, Bowser, R, Kirby, J, Pamphlett, R, Gerhard, G, Dunckley, T, Brady, C, Kowall, N, Troncoso, J, Le Ber, I, Kamel, F, Van Den Bosch, L, Strom, T, Meitinger, T, Shatunov, A, Van Eijk, K, de Carvalho, M, Kooyman, M, Middelkoop, B, Moisse, M, Mclaughlin, R, Van Es, M, Weber, M, Boylan, K, Van Blitterswijk, M, Morrison, K, Basak, A, Mora, J, Drory, V, Shaw, P, Turner, M, Talbot, K, Hardiman, O, Williams, K, Fifita, J, Nicholson, G, Blair, I, Esteban-Pérez, J, García-Redondo, A, Al-Chalabi, A, Al Kheifat, A, Andersen, P, Chio, A, Cooper-Knock, J, Dekker, A, Redondo, A, Gotkine, M, Hide, W, Iacoangeli, A, Kiernan, M, Landers, J, Mill, J, Neto, M, Pardina, J, Newhouse, S, Pinto, S, Pulit, S, Robberecht, W, Shaw, C, Sproviero, W, Tazelaar, G, van Damme, P, van den Berg, L, van Eijk, K, van Es, M, Veldink, J, Zatz, M, Bauer, D, Twine, N, Rogaeva, E, Zinman, L, Brice, A, Feldman, E, Ludolph, A, Weishaupt, J, Trojanowski, J, Stone, D, Tienari, P, Chiò, A, Traynor, B, Nicolas, Aude, Kenna, Kevin P, Renton, Alan E, Ticozzi, Nicola, Faghri, Faraz, Chia, Ruth, Dominov, Janice A, Kenna, Brendan J, Nalls, Mike A, Keagle, Pamela, Rivera, Alberto M, van Rheenen, Wouter, Murphy, Natalie A, van Vugt, Joke J F A, Geiger, Joshua T, Van der Spek, Rick A, Pliner, Hannah A, Shankaracharya, Null, Smith, Bradley N, Marangi, Giuseppe, Topp, Simon D, Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D, Kenna, Aoife, Mora, Gabriele, Calvo, Andrea, Mazzini, Letizia, Riva, Nilo, Mandrioli, Jessica, Caponnetto, Claudia, Battistini, Stefania, Volanti, Paolo, La Bella, Vincenzo, Conforti, Francesca L, Borghero, Giuseppe, Messina, Sonia, Simone, Isabella L, Trojsi, Francesca, Salvi, Fabrizio, Logullo, Francesco O, D'Alfonso, Sandra, Corrado, Lucia, Capasso, Margherita, Ferrucci, Luigi, Logullo, Fo, Murru, Mr, Marrosu, Mg, Conforti, Fl, Pinter, Gl, Tedeschi, Gioacchino, Monsurrò, Maria Rosaria, Parish, Ld, Cau, Tb, Moreno, Cristiane de Araujo Martin, Kamalakaran, Sitharthan, Goldstein, David B, Gitler, Aaron D, Harris, Tim, Myers, Richard M, Phatnani, Hemali, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C, Kaye, Julia, Finkbeiner, Steven, Wyman, Stacia K, Lenail, Alex, Lima, Leandro, Fraenkel, Ernest, Svendsen, Clive N, Thompson, Leslie M, Van Eyk, Jennifer E, Berry, James D, Miller, Timothy M, Kolb, Stephen J, Cudkowicz, Merit, Baxi, Emily, Benatar, Michael, Taylor, J Paul, Rampersaud, Evadnie, Wu, Gang, Wuu, Joanne, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P, Sorarù, Gianni, Cereda, Cristina, Corcia, Philippe, Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W, Sidle, Katie C, Malaspina, Andrea, Hardy, John, Singleton, Andrew B, Johnson, Janel O, Arepalli, Sampath, Sapp, Peter C, McKenna-Yasek, Diane, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, Baas, Frank, Ten Asbroek, Anneloor L M A, Muñoz-Blanco, José Lui, Hernandez, Dena G, Ding, Jinhui, Gibbs, J Raphael, Scholz, Sonja W, Floeter, Mary Kay, Campbell, Roy H, Landi, Francesco, Bowser, Robert, Pulst, Stefan M, Ravits, John M, Macgowan, Daniel J L, Kirby, Janine, Pioro, Erik P, Pamphlett, Roger, Broach, Jame, Gerhard, Glenn, Dunckley, Travis L, Brady, Christopher B, Kowall, Neil W, Troncoso, Juan C, Le Ber, Isabelle, Mouzat, Kevin, Lumbroso, Serge, Heiman-Patterson, Terry D, Kamel, Freya, Van Den Bosch, Ludo, Baloh, Robert H, Strom, Tim M, Meitinger, Thoma, Shatunov, Aleksey, Van Eijk, Kristel R, de Carvalho, Mamede, Kooyman, Maarten, Middelkoop, Ba, Moisse, Matthieu, Mclaughlin, Russell L, Van Es, Michael A, Weber, Marku, Boylan, Kevin B, Van Blitterswijk, Marka, Rademakers, Rosa, Morrison, Karen E, Basak, A Nazli, Mora, Jesús S, Drory, Vivian E, Shaw, Pamela J, Turner, Martin R, Talbot, Kevin, Hardiman, Orla, Williams, Kelly L, Fifita, Jennifer A, Nicholson, Garth A, Blair, Ian P, Rouleau, Guy A, Esteban-Pérez, Jesú, García-Redondo, Alberto, Al-Chalabi, Ammar, Rogaeva, Ekaterina, Zinman, Lorne, Ostrow, Lyle W, Maragakis, Nicholas J, Rothstein, Jeffrey D, Simmons, Zachary, Cooper-Knock, Johnathan, Brice, Alexi, Goutman, Stephen A, Feldman, Eva L, Gibson, Summer B, Taroni, Franco, Ratti, Antonia, Gellera, Cinzia, Van Damme, Philip, Robberecht, Wim, Fratta, Pietro, Sabatelli, Mario, Lunetta, Christian, Ludolph, Albert C, Andersen, Peter M, Weishaupt, Jochen H, Camu, William, Trojanowski, John Q, Van Deerlin, Vivianna M, Brown, Robert H, van den Berg, Leonard H, Veldink, Jan H, Harms, Matthew B, Glass, Jonathan D, Stone, David J, Tienari, Pentti, Silani, Vincenzo, Chiò, Adriano, Shaw, Christopher E, Traynor, Bryan J, Landers, John E, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: Male, Als gene, Genome-wide association study, FAMILIAL ALS, ALS, axonal transport, cargo, GWAS, KIF5A, WES, WGS, 0302 clinical medicine, 80 and over, Psychology, Aetiology, Aged, 80 and over, 0303 health sciences, French ALS Consortium, Kinesin, KINESIN HEAVY-CHAIN, Cognitive Sciences, Human, Hereditary spastic paraplegia, Neuroscience(all), Single-nucleotide polymorphism, TARGETED DISRUPTION, Article, 03 medical and health sciences, Genetics, Humans, Amino Acid Sequence, Loss function, Aged, HEXANUCLEOTIDE REPEAT, Neuroscience (all), MUTATIONS, Amyotrophic Lateral Sclerosis, 3112 Neurosciences, 1702 Cognitive Science, medicine.disease, ITALSGEN Consortium, Answer ALS Foundation, 030104 developmental biology, ALS Sequencing Consortium, Human medicine, 1109 Neurosciences, 030217 neurology & neurosurgery, 0301 basic medicine, [SDV]Life Sciences [q-bio], Kinesins, Neurodegenerative, Genetic analysis, Genome, AMYOTROPHIC-LATERAL-SCLEROSIS, 3124 Neurology and psychiatry, Cohort Studies, Pathogenesis, Loss of Function Mutation, Missense mutation, 2.1 Biological and endogenous factors, Amyotrophic lateral sclerosis, NYGC ALS Consortium, General Neuroscience, ALS, axonal transport, cargo, GWAS, KIF5A, WES, WGS, Middle Aged, Phenotype, Settore MED/26 - NEUROLOGIA, Neurological, Project MinE ALS Sequencing Consortium, Female, Adult, Biology, GENOTYPE IMPUTATION, Genome-Wide Association Study, Young Adult, NO, Rare Diseases, medicine, SLAGEN Consortium, Gene, 030304 developmental biology, Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium, Neurology & Neurosurgery, Human Genome, Neurosciences, AXONAL-TRANSPORT, Brain Disorders, Family member, DNA-DAMAGE, MOTOR-NEURONS, 3111 Biomedicine, Cohort Studie, Genomic Translation for ALS Care (GTAC) Consortium, Amyotrophic Lateral Sclerosi
Abstract: © 2018 Elsevier Inc., To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
Published: 2018

43. Antibacterial effect of genetically-engineered bacteriophage ϕEf11/ϕFL1C(Δ36)P nisA on dentin infected with antibiotic-resistant Enterococcus faecalis

Author: Roy H. Stevens, Luciana Moura Sassone, Nadia Liss, R. Nissan, Eduardo Muniz Barretto Tinoco, Justine Monteiro Monnerat Tinoco, Wanda Gordon, and Hongming Zhang
Subjects: 0301 basic medicine, Endodontic therapy, medicine.drug_class, Fusidic acid, Root canal, 030106 microbiology, Antibiotics, Cell Biology, General Medicine, Biology, biology.organism_classification, Enterococcus faecalis, Microbiology, 03 medical and health sciences, medicine.anatomical_structure, Antibiotic resistance, stomatognathic system, Otorhinolaryngology, medicine, Dentin, Vancomycin, General Dentistry, medicine.drug
Abstract: Objective Enterococcus faecalis is a gram-positive facultative anaerobic bacterium, which is present in 30–89% of teeth with postendodontic treatment failures. E. faecalis is capable of penetrating dentinal tubules and surviving as a monoculture after conventional endodontic therapy, indicating that it is resistant to commonly used endodontic disinfection protocols. Different E. faecalis strains have shown resistance to several antibiotics, and have been associated with both dental pathology and systemic infections. The aim of this study was to evaluate the efficacy of a genetically engineered bacteriophage to disinfect dentin infected with antibiotic resistant strains of E. faecalis. Methods Extracted human dentin root segments were cemented into sealable two-chamber devices, fabricated from syringe needle caps to form in vitro infected-dentin models. The models were inoculated with an overnight suspension of either E. faecalis V583 (vancomycin resistant strain) or E. faecalis JH2-2 (fusidic acid and rifampin resistant, vancomycin sensitive strain). After 7 days of incubation at 37 °C, a suspension of a genetically engineered phage, ϕEf11/ϕFL1C(Δ36)PnisA, was added to the root canal of each infected dentin segment, and the incubation was continued for an additional 72-h. Dentin was harvested from the walls of each root canal and assayed for the residual titer of E. faecalis cells. Results The recovered E. faecalis titer was reduced by 18% for the JH2-2 infected models, and by 99% for the V583 infected models. Conclusion Treatment: of E. faecalis-infected dentin with bacteriophage ϕEf11/ϕFL1C(Δ36)PnisA consistently resulted in a decrease in the residual bacterial population of both vancomycin-sensitive and resistant strains.
Published: 2017

44. Efficient Genome-wide Association in Biobanks Using Topic Modeling Identifies Multiple Novel Disease Loci

Author: Kamber L. Hart, Victor M. Castro, Thomas H. McCoy, Roy H. Perlis, and Leslie A. Snapper
Subjects: 0301 basic medicine, Topic model, Genotype, Genome-wide association study, Disease, Computational biology, Biology, Health records, Bioinformatics, lcsh:Biochemistry, 03 medical and health sciences, Genetics, Humans, lcsh:QD415-436, Medical diagnosis, Molecular Biology, Genetics (clinical), Genetic association, Biological Specimen Banks, lcsh:RM1-950, Genetic Variation, Models, Theoretical, Biobank, 030104 developmental biology, lcsh:Therapeutics. Pharmacology, Molecular Medicine, Diagnosis code, Research Article, Genome-Wide Association Study
Abstract: Biobanks and national registries represent a powerful tool for genomic discovery, but rely on diagnostic codes that can be unreliable and fail to capture relationships between related diagnoses. We developed an efficient means of conducting genome-wide association studies using combinations of diagnostic codes from electronic health records for 10,845 participants in a biobanking program at two large academic medical centers. Specifically, we applied latent Dirichilet allocation to fit 50 disease topics based on diagnostic codes, then conducted a genome-wide common-variant association for each topic. In sensitivity analysis, these results were contrasted with those obtained from traditional single-diagnosis phenome-wide association analysis, as well as those in which only a subset of diagnostic codes were included per topic. In meta-analysis across three biobank cohorts, we identified 23 disease-associated loci with p < 1e-15, including previously associated autoimmune disease loci. In all cases, observed significant associations were of greater magnitude than single phenome-wide diagnostic codes, and incorporation of less strongly loading diagnostic codes enhanced association. This strategy provides a more efficient means of identifying phenome-wide associations in biobanks with coded clinical data.
Published: 2017

45. Correlated evolutionary rates across genomic compartments in Annonaceae

Author: Roy H. J. Erkens, Erik Smets, Lars W. Chatrou, Rita D. Brandão, Jan J. Wieringa, Jenifer de Carvalho Lopes, Paul H. Hoekstra, RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, RS: FSE MSP, and Maastricht Science Programme
Subjects: 0301 basic medicine, Chloroplasts, Genome, Substitution rates, PHYLOGENETIC ANALYSIS, Molecular clock, Phylogeny, Genetics, ENDOSYMBIOTIC BACTERIA, education.field_of_study, Base Composition, Phylogenetic tree, FLOWERING PLANTS, Nuclear ribosomal DNA, BIASED GENE CONVERSION, Biosystematiek, Phylogenetics, Plastid genome, GRASS CHLOROPLAST DNA, Sequence Analysis, DNA, Plant, Evolution, Population, Annonaceae, Biology, Genes, Plant, DNA, Ribosomal, Evolution, Molecular, 03 medical and health sciences, SPECIES-RICHNESS, Molecular evolution, Journal Article, Annonoideae, education, Molecular Biology, Ribosomal DNA, Ecology, Evolution, Behavior and Systematics, Ribosomal, Molecular, NUCLEOTIDE SUBSTITUTION RATES, Bayes Theorem, Sequence Analysis, DNA, DNA, Plant, MOLECULAR EVOLUTION, Malmeoideae, 030104 developmental biology, Genes, ARABIDOPSIS-THALIANA, Biosystematics, Rate of evolution, SEQUENCE EVOLUTION, EPS
Abstract: The molecular clock hypothesis is an important concept in biology. Deviations from a constant rate of nucleotide substitution have been found widely among lineages, genomes, genes and individual sites. Phylogenetic research can accommodate for these differences in applying specific models of evolution. Lineage-specific rate heterogeneity however can generate bi- or multimodal distributions of substitution rates across the branches of a tree and this may mislead phylogenetic inferences with currently available models. The plant family Annonaceae is an excellent case to study lineage-specific rate heterogeneity. The two major sister subfamilies, Annonoideae and Malmeoideae, have shown great discrepancies in branch lengths. We used high-throughput sequencing data of 72 genes, 99 spacers and 16 introns from 24 chloroplast genomes and nuclear ribosomal DNA of 23 species to study the molecular rate of evolution in Annonaceae. In all analyses, longer branch lengths and/or higher substitution rates were found for the Annonoideae compared to the Malmeoideae. The Annonaceae had wide variability in chloroplast length, ranging from minimal 175,684 by to 201,723 for Annonoideae and minimal 152,357 to 170,985 bp in Malmeoideae, mostly reflecting variation in inverted-repeat length. The Annonoideae showed a higher GC-content in the conserved parts of the chloroplast genome and higher omega (dN/c/s)-ratios than the Malmeoideae, which could indicate less stringent purifying selection, a pattern that has been found in groups with small population sizes. This study generates new insights into the processes causing lineage-specific rate heterogeneity, which could lead to improved phylogenetic methods. (C) 2017 Elsevier Inc. All rights reserved.
Published: 2017

46. Restless roosts : Light pollution affects behavior, sleep, and physiology in a free-living songbird

Author: Roy H. A. van Grunsven, Marcel E. Visser, Jenny Q. Ouyang, Kevin D. Matson, Kamiel Spoelstra, Peter Meerlo, Mark F. Haussmann, Maaike de Jong, Meerlo lab, and Animal Ecology (AnE)
Subjects: 0106 biological sciences, 0301 basic medicine, Great tit, Light pollution, Physiology, Plant Ecology and Nature Conservation, Artificial light, Animal Breeding and Genomics, ECOLOGY, PARUS-MAJOR, 010603 evolutionary biology, 01 natural sciences, 03 medical and health sciences, Sleep debt, NIGHT, Oxalic acid, Environmental Chemistry, Fokkerij en Genomica, Circadian rhythm, EXPOSURE, ARTIFICIAL-LIGHT, General Environmental Science, Sleep restriction, Parus, sleep disruption, Global and Planetary Change, ENVIRONMENT, biology, PHOTOPERIODIC CONTROL, biology.organism_classification, PE&RC, Sleep in non-human animals, Songbird, Activity, Malaria, 030104 developmental biology, Telomeres, Haptoglobin, international, Wildlife Ecology and Conservation, WIAS, biomarker, Plantenecologie en Natuurbeheer, GREAT TITS, RESPONSES
Abstract: The natural nighttime environment is increasingly polluted by artificial light. Several studies have linked artificial light at night to negative impacts on human health. In free-living animals, light pollution is associated with changes in circadian, reproductive, and social behavior, but whether these animals also suffer from physiologic costs remains unknown. To fill this gap, we made use of a unique network of field sites which are either completely unlit (control), or are artificially illuminated with white, green, or red light. We monitored nighttime activity of adult great tits, Parus major, and related this activity to within-individual changes in physiologic indices. Because altered nighttime activity as a result of light pollution may affect health and well-being, we measured oxalic acid concentrations as a biomarker for sleep restriction, acute phase protein concentrations and malaria infection as indices of immune function, and telomere lengths as an overall measure of metabolic costs. Compared to other treatments, individuals roosting in the white light were much more active at night. In these individuals, oxalic acid decreased over the course of the study. We also found that individuals roosting in the white light treatment had a higher probability of malaria infection. Our results indicate that white light at night increases nighttime activity levels and sleep debt and affects disease dynamics in a free-living songbird. Our study offers the first evidence of detrimental effects of light pollution on the health of free-ranging wild animals.
Published: 2017

47. Patient-specific models of microglia-mediated engulfment of synapses and neural progenitors

Author: Carl M. Sellgren, Ting Fu, Roy H. Perlis, D Xuan, Steven D. Sheridan, and Jessica Gracias
Subjects: Male, 0301 basic medicine, Synaptic pruning, Cell Culture Techniques, Biology, Models, Biological, Peripheral blood mononuclear cell, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Neural Stem Cells, medicine, Humans, Progenitor cell, Induced pluripotent stem cell, Molecular Biology, Aged, Aged, 80 and over, Neurons, Neuronal Plasticity, Microglia, Brain, Complement C4, Neurodegenerative Diseases, Neural stem cell, 3. Good health, Psychiatry and Mental health, 030104 developmental biology, medicine.anatomical_structure, Cell culture, Synapses, Leukocytes, Mononuclear, Female, Immediate Communication, Neuroscience, Reprogramming, 030217 neurology & neurosurgery
Abstract: Engulfment of synapses and neural progenitor cells (NPCs) by microglia is critical for the development and maintenance of proper brain circuitry, and has been implicated in neurodevelopmental as well as neurodegenerative disease etiology. We have developed and validated models of these mechanisms by reprogramming microglia-like cells from peripheral blood mononuclear cells, and combining them with NPCs and neurons derived from induced pluripotent stem cells to create patient-specific cellular models of complement-dependent synaptic pruning and elimination of NPCs. The resulting microglia-like cells express appropriate markers and function as primary human microglia, while patient-matched macrophages differ markedly. As a demonstration of disease-relevant application, we studied the role of C4, recently implicated in schizophrenia, in engulfment of synaptic structures by human microglia. The ability to create complete patient-specific cellular models of critical microglial functions utilizing samples taken during a single clinical visit will extend the ability to model central nervous system disease while facilitating high-throughput screening.
Published: 2016

48. Circulating interleukin-6 is not altered while γ-tocopherol is increased in subjects scheduled for knee surgery with low vitamin D

Author: Roy H. Trawick, Vanessa T. Henriksen, Tyler Barker, Victoria E. Rogers, Nathan G. Momberger, and G. Lynn Rasmussen
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Knee Joint, Anterior cruciate ligament, medicine.medical_treatment, Immunology, Knee Injuries, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, Vitamin D and neurology, Humans, Immunology and Allergy, Tocopherol, Interleukin 6, Molecular Biology, Aged, gamma-Tocopherol, biology, Interleukin-6, Cholesterol, business.industry, Vitamin E, Interleukin, Hematology, Middle Aged, Vitamin D Deficiency, Arthroplasty, Surgery, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, chemistry, 030220 oncology & carcinogenesis, biology.protein, Female, business
Abstract: The purpose of this study was to identify if circulating interleukin (IL)-6 and γ-tocopherol (γT) fluctuate with vitamin D status in subjects with an underlying knee joint injury or disease. We hypothesized that low vitamin D associates with an increase in plasma γT while serum IL-6 remains unchanged in subjects with an underlying knee joint trauma or disease. Fifty-four subjects scheduled to undergo primary, unilateral anterior cruciate ligament reconstructive surgery (ACL; n=27) or total knee arthroplasty (TKA; n=27) were studied. Circulating γT, α-tocopherol (αT), lipids (cholesterol and triglycerides), IL-6, and 25-hydroxyvitamin D (25(OH)D) were measured in fasting blood samples obtained prior to surgery. Subjects were classified as vitamin D deficient, insufficient, or sufficient if they had a serum 25(OH)D concentration50, 50-75, or75nM, respectively. The majority (57%) of the subjects possessed a serum 25(OH)D less than 50nM. Circulating cholesterol, triglycerides, and IL-6 were not significantly (all p0.05) different between vitamin D status groups. However, lipid corrected αT was significantly (p0.05) decreased and both lipid- and non-lipid-corrected plasma γT concentrations were significantly (both p0.05) increased with low serum 25(OH)D (i.e.,50nM). A significant (p0.05) multi-variate analysis revealed that an increase in plasma γT per lipids was significantly (p0.05) predicted by a decrease in serum 25(OH)D but not by a decrease in plasma αT per lipids. We conclude that low vitamin D associates with an increase in plasma γT but not IL-6 in subjects with an underlying joint injury or disease.
Published: 2016

49. Proceedings #64: BDNF Polymorphism Predicts Plasticity in Motor Cortex Following Continuous Theta Burst Stimulation

Author: Ahmed Ahmed, Abdou Thiam, Roy H. Hamilton, Rachel Wurzman, Daniela Sacchetti, Olufunsho Faseyitan, Falk W. Lohoff, Denise Y. Harvey, and Laura DeLoretta
Subjects: General Neuroscience, Biophysics, Stimulation, Biology, Plasticity, lcsh:RC321-571, Theta burst, medicine.anatomical_structure, medicine, Neurology (clinical), Bdnf polymorphism, Neuroscience, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Motor cortex
Published: 2019

50. Bacteriophage φEf11 ORF28 Endolysin, a Multifunctional Lytic Enzyme with Properties Distinct from All Other Identified Enterococcus faecalis Phage Endolysins

Author: Derrick E. Fouts, Hongming Zhang, Roy H. Stevens, Bettina A. Buttaro, Salar Sanjari, and Bradley S. Evans
Subjects: Lysis, Lysin, Siphoviridae, Applied Microbiology and Biotechnology, Enterococcus faecalis, Microbiology, Amidase, Bacteriophage, 03 medical and health sciences, chemistry.chemical_compound, Viral Proteins, Endopeptidases, Amino Acid Sequence, Enzymology and Protein Engineering, 030304 developmental biology, 0303 health sciences, Ecology, biology, Base Sequence, 030306 microbiology, Chemistry, biology.organism_classification, Lytic cycle, Peptidoglycan, Sequence Alignment, Food Science, Biotechnology
Abstract: ϕEf11 is a temperate Siphoviridae bacteriophage that infects strains of Enterococcus faecalis. The ϕEf11 genome, encompassing 65 open reading frames (ORFs), is contained within 42,822 bp of DNA. Within this genome, a module of six lysis-related genes was identified. Based upon sequence homology, one of these six genes, ORF28, was predicted to code for an N-acetylmuramoyl-l-alanine amidase endolysin of 46.133 kDa, composed of 421 amino acids. The PCR-amplified ORF28 was cloned and expressed, and the resulting gene product was affinity purified to homogeneity. The purified protein was obtained from a fusion protein that exhibited a molecular mass of 72.5 kDa, consistent with a 46.1-kDa protein combined with a fused 26.5-kDa glutathione S-transferase tag. It produced rapid, profound lysis in E. faecalis populations and was active against 73 of 103 (71%) E. faecalis strains tested. In addition, it caused substantial destruction of E. faecalis biofilms. The lysin was quite stable, retaining its activity for three years in refrigerated storage, was stable over a wide range of pHs, and was unaffected by the presence of a reducing agent; however, it was inhibited by increasing concentrations of Ca2+. Liquid chromatography-mass spectrometry analysis of E. faecalis cell wall digestion products produced by the ORF28 endolysin indicated that the lysin acted as an N-acetylmuramidase, an endo-β-N-acetylglucosaminidase, and an endopeptidase, rather than an N-acetylmuramoyl-l-alanine amidase. The ϕEf11 ORF28 lysin shared 10% to 37% amino acid identity with the lytic enzymes of all other characterized E. faecalis bacteriophages. IMPORTANCE The emergence of multidrug-resistant pathogenic microorganisms has brought increasing attention to the urgent need for the development of alternative antimicrobial strategies. One such alternative to conventional antibiotics employs lytic enzymes (endolysins) that are produced by bacteriophages in the course of lytic infection. During lytic infection by a bacteriophage, these enzymes hydrolyze the cell wall peptidoglycan, resulting in the lysis of the host cell. However, external endolysin application can result in lysis from without. In this study, we have cloned, expressed, purified, and characterized an endolysin produced by a bacteriophage infecting strains of Enterococcus faecalis. The lysin is broadly active against most of the tested E. faecalis strains and exhibits multifunctional enzymatic specificities that differ from all other characterized endolysins produced by E. faecalis bacteriophages.
Published: 2019

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