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1. Cyclic neutropenia and severe congenital neutropenia in patients with a shared ELANE mutation and paternal haplotype: Evidence for phenotype determination by modifying genes Conflict of interest: Nothing to declare.

Author: Departments of Obstetrics and Gynecology and Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan, Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts ; Department of Pediatrics, University of Massachusetts Medical School, Lake Avenue North, Worcester, MA 01655., Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, Department of Medicine, University of Washington Medical School, Seattle, Washington, Newburger, Peter E., Pindyck, Talia N., Zhu, Zhiqing, Bolyard, Audrey Anna, Aprikyan, Andrew A. G., Dale, David C., Smith, Gary D., Boxer, Laurence A., Departments of Obstetrics and Gynecology and Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan, Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts ; Department of Pediatrics, University of Massachusetts Medical School, Lake Avenue North, Worcester, MA 01655., Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, Department of Medicine, University of Washington Medical School, Seattle, Washington, Newburger, Peter E., Pindyck, Talia N., Zhu, Zhiqing, Bolyard, Audrey Anna, Aprikyan, Andrew A. G., Dale, David C., Smith, Gary D., and Boxer, Laurence A.
Abstract: Background Cyclic neutropenia (CN) and severe congenital neutropenia (SCN) are disorders of neutrophil production that differ markedly in disease severity. Mutations of the ELANE gene (the symbol recently replacing ELA2 ) are considered largely responsible for most cases of CN and SCN, but specific mutations are typically associated with one or the other. Procedure We performed ELANE genotyping on all individuals and paternal sperm in an SCN kindred with eight SCN progeny of a sperm donor and six different mothers. Results One patient with CN had the same S97L ELANE mutation as seven patients with the SCN phenotype. The mutant allele was detected in the donor's spermatozoa, representing 18% of the ELANE gene pool, but not in DNA from his lymphocytes, neutrophils, or buccal mucosa, indicating gonadal mosaicism. Conclusions The coexistence of CN and SCN phenotypes in this kindred with a shared paternal haplotype strongly suggests both a role for modifying genes in determination of congenital neutropenia disease phenotypes, and the classification of CN and SCN within a spectrum of phenotypes expressing varying degrees of the same disease process. Pediatr Blood Cancer. 2010;55:314???317. ?? 2010 Wiley???Liss, Inc.
Published: 2010

2. Report of the first international liver transplantation society expert panel consensus conference on renal insufficiency in liver transplantation

Author: Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, Mayo Clinic, Rochester MN, Department of General Surgery, London Health Science Center, London, Ontario, Canada, Liver Unit, Hospital Clinic, University of Barcelona School of Medicine, Barcelona, Spain, Department of Nephrology, University of Utah School of Medicine, Salt Lake City, UT, Medical School, University of Western Ontario, London, Ontario, Canada, Department of Medicine, McGill University Health Center, Montreal, Quebec, Canada, Transplant Institute, University of Tennessee, Memphis, TN, Baylor University Medical Center, Dallas, TX, Hospital Clinic I Provincial, Barcelona, Spain, Queen Elizabeth Hospital, Birmingham, England, Department of Transplant Surgery, University of California San Francisco Medical Center, San Francisco, CA, Department of Medicine, University of Washington Medical Center, Seattle, WA, Mayo Clinic, Jacksonville, FL, Charlton, Michael R., Wall, William J., Ojo, Akinlolu O., Ginés, Pere, Textor, Stephen, Shihab, Fuad S., Marotta, Paul, Cantarovich, Marcelo, Eason, James D., Wiesner, Russell H., Ramsay, Michael A., Garcia-Valdecasas, Juan C., Neuberger, James M., Feng, Sandy, Davis, Connie L., Gonwa, Thomas A., Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, Mayo Clinic, Rochester MN, Department of General Surgery, London Health Science Center, London, Ontario, Canada, Liver Unit, Hospital Clinic, University of Barcelona School of Medicine, Barcelona, Spain, Department of Nephrology, University of Utah School of Medicine, Salt Lake City, UT, Medical School, University of Western Ontario, London, Ontario, Canada, Department of Medicine, McGill University Health Center, Montreal, Quebec, Canada, Transplant Institute, University of Tennessee, Memphis, TN, Baylor University Medical Center, Dallas, TX, Hospital Clinic I Provincial, Barcelona, Spain, Queen Elizabeth Hospital, Birmingham, England, Department of Transplant Surgery, University of California San Francisco Medical Center, San Francisco, CA, Department of Medicine, University of Washington Medical Center, Seattle, WA, Mayo Clinic, Jacksonville, FL, Charlton, Michael R., Wall, William J., Ojo, Akinlolu O., Ginés, Pere, Textor, Stephen, Shihab, Fuad S., Marotta, Paul, Cantarovich, Marcelo, Eason, James D., Wiesner, Russell H., Ramsay, Michael A., Garcia-Valdecasas, Juan C., Neuberger, James M., Feng, Sandy, Davis, Connie L., and Gonwa, Thomas A.
Abstract: No abstract.
Published: 2009

3. The gene for a novel epidermal antigen maps near the neurofibromatosis 1 gene

Author: Departments of Human Genetics and Internal Medicine and the Howard Hughes Medical Institute, The University of Michigan Medical Center, Ann Arbor, Michigan, USA, Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA, Department of Dermatology, the University of Texas Medical School, USA; Department of Pharmacology, the University of Texas Medical School, USA., The Neurofibromatosis Institute Inc., Pasadena, California, USA., Department of Dermatology, the University of Texas Medical School, USA; M.D. Anderson Cancer Center, Houston, Texas, USA., Kayes, Lucille M., Schroeder, Wanda T., Marchuk, Douglas A., Collins, Francis S., Riccardi, Vincent M., Duvic, Madeleine, Stephens, Karen, Departments of Human Genetics and Internal Medicine and the Howard Hughes Medical Institute, The University of Michigan Medical Center, Ann Arbor, Michigan, USA, Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA, Department of Dermatology, the University of Texas Medical School, USA; Department of Pharmacology, the University of Texas Medical School, USA., The Neurofibromatosis Institute Inc., Pasadena, California, USA., Department of Dermatology, the University of Texas Medical School, USA; M.D. Anderson Cancer Center, Houston, Texas, USA., Kayes, Lucille M., Schroeder, Wanda T., Marchuk, Douglas A., Collins, Francis S., Riccardi, Vincent M., Duvic, Madeleine, and Stephens, Karen
Abstract: Recently the M17S1 gene, encoding an epidermal antigen thought to play a role in cell adhesion, was mapped to chromosome bands 17q11-q12, placing it in the vicinity of the gene for the genetic disorder neurofi-bromatosis 1 (NF1). The pleomorphic cutaneous lesions of NF1 and the precedent for other genes being embedded within the NF1 gene prompted us to investigate whether the M17S1 gene mapped near, or within, the NF1 gene. Genetic linkage analyses revealed that M17S1 was tightly linked to NF1 and mapped within the interval bounded by D17S58 and D17S54. Physical mapping of an M17S1 cDNA on somatic cell hybrids, yeast artificial chromosomes, and an NF1 patient with a deletion involving an entire NF1 allele demonstrated that M17S1 is located at least 180 kb centromeric to the NF1 gene. The distance between the genes suggests that M17S1 is unlikely to contribute to the NF1 phenotype since a gross chromosomal rearrangement would be required to disrupt expression of both genes.
Published: 2006

4. Glucose regulation in non-insulin-dependent diabetes mellitus: Interaction between pancreatic islets and the liver

Author: Department of Internal Medicine, University of Michigan Medical School, and the Ann Arbor Veterans Administration Medical Center, Ann Arbor, Michigan, USA, Department of Medicine, University of Washington School of Medicine, and Seattle Veterans Administration Center, Seattle, Washington, USA, St. Vincent's Hospital, Fitzroy, Victoria, Australia, Department of Medicine, University of Louisville Medical School, and Louisville Veterans Administration Center, Louisville, Kentucky, USA, Halter, Jeffrey B., Kenneth Ward, W., Porte, Jr., Daniel, Best, James D., Pfeifer, Michael A., Department of Internal Medicine, University of Michigan Medical School, and the Ann Arbor Veterans Administration Medical Center, Ann Arbor, Michigan, USA, Department of Medicine, University of Washington School of Medicine, and Seattle Veterans Administration Center, Seattle, Washington, USA, St. Vincent's Hospital, Fitzroy, Victoria, Australia, Department of Medicine, University of Louisville Medical School, and Louisville Veterans Administration Center, Louisville, Kentucky, USA, Halter, Jeffrey B., Kenneth Ward, W., Porte, Jr., Daniel, Best, James D., and Pfeifer, Michael A.
Abstract: The degree of fasting hyperglycemia in patients with non-insulin-dependent diabetes mellitus is dependent on the rate of hepatic glucose production. The basal rate of hepatic glucose production is increased in patients with non-insulin-dependent diabetes mellitus, and there is a positive correlation between hepatic glucose production and fasting glucose levels. Diminished secretion of insulin, impaired hepatic sensitivity to insulin's effects, or a combination of these factors could contribute to the elevated hepatic glucose production in patients with non-insulin-dependent diabetes mellitus. The relationship between insulin secretion and hepatic glucose production is regulated by a closed feedback loop operating between glucose levels and pancreatic beta cells. Although fasting insulin levels are usually comparable between patients with non-insulin-dependent diabetes mellitus and normal subjects, insulin secretion is markedly impaired in non-insulin-dependent diabetes mellitus in relation to the degree of hyperglycemia present. In fact, the degree of fasting hyperglycemia in a given patient with non-insulin-dependent diabetes mellitus is closely related to the degree of impaired pancreatic beta-cell responsiveness to glucose. Such findings suggest that impaired insulin secretion leads to increased hepatic glucose production, which raises the plasma glucose level. The resulting hyperglycemia helps to maintain relatively normal basal insulin output. Chronic sulfonylurea drug therapy of patients with non-insulin-dependent diabetes mellitus enhances pancreatic islet sensitivity to glucose, leading to increased insulin secretion, suppression of hepatic glucose production, and a decline in the steady-state fasting glucose level.
Published: 2006

5. Sweet tooth reconsidered: Taste responsiveness in human obesity

Author: Human Nutrition Program, School of Public Health, The University of Michigan, Ann Arbor, MI 48109, USA, Department of Medicine, University of Washington, Seattle, WA 98195, USA, Department of Biology, Vassar College, Poughkeepsie, NY 12601, USA, Drewnowski, Adam, Brunzell, John D., Sande, Karon, Iverius, P.H., Greenwood, M.R.C., Human Nutrition Program, School of Public Health, The University of Michigan, Ann Arbor, MI 48109, USA, Department of Medicine, University of Washington, Seattle, WA 98195, USA, Department of Biology, Vassar College, Poughkeepsie, NY 12601, USA, Drewnowski, Adam, Brunzell, John D., Sande, Karon, Iverius, P.H., and Greenwood, M.R.C.
Abstract: Taste responses of normal-weight, obese, and formerly obese individuals for sucrose and fat containing stimuli were examined using a mathematical modelling technique known as the Response Surface Method. The subjects accurately rated intensities of sweetness, fatness, and creaminess of 20 different mixtures of milk, cream, and sugar, and no mixture phenomena or inter-group differences were observed. In contrast, hedonic taste responses varied across subject groups, and were affected differentially by the sucrose and lipid content of the stimuli. Normal-weight subjects optimally preferred stimuli containing 20% lipid and less than 10% sucrose. Obese subjects preferred high-fat stimuli (>34% lipid) that contained less than 5% sucrose, while formerly obese subjects showed enhanced responsiveness to both sugar and fat. Hedonic responsiveness as measured by the optimal sugar/fat ratio was negatively correlated with the degree of overweight (body mass index: weight/height2). We hypothesize that sensory preferences for dietary sugars and fats are determined by body-weight status and may affect the patterns of food consumption.
Published: 2006

6. Safety and efficacy of pralsetinib in RET fusion–positive non-small-cell lung cancer including as first-line therapy

Author: F. Griesinger, G. Curigliano, M. Thomas, V. Subbiah, C.S. Baik, D.S.W. Tan, D.H. Lee, D. Misch, E. Garralda, D.-W. Kim, A.J. van der Wekken, J.F. Gainor, L. Paz-Ares, S.V. Liu, G.P. Kalemkerian, Y. Houvras, D.W. Bowles, A.S. Mansfield, J.J. Lin, V. Smoljanovic, A. Rahman, S. Kong, A. Zalutskaya, M. Louie-Gao, A.L. Boral, J. Mazières, Institut Català de la Salut, [Griesinger F] Department of Hematology and Oncology, Pius-Hospital, University of Oldenburg, Oldenburg, Germany. [Curigliano G] European Institute of Oncology, IRCCS, Milan, Italy. Department of Oncology and Hemato-Oncology, University of Milano, Milan, Italy. [Thomas M] Department of Thoracic Oncology, Thoraxklinik, University Heidelberg and Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany. [Subbiah V] Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, USA. [Baik CS] Division of Oncology, Department of Medicine, University of Washington School of Medicine, Seattle, USA. [Tan DSW] Division of Medical Oncology, National Cancer Centre Singapore, Singapore. [Garralda E] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Otros calificadores::/uso terapéutico [Otros calificadores], Medicaments antineoplàstics - Ús terapèutic, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antineoplásicos [COMPUESTOS QUÍMICOS Y DROGAS], diagnóstico::pronóstico::resultado del tratamiento [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Hematology, Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms::Bronchial Neoplasms::Carcinoma, Bronchogenic::Carcinoma, Non-Small-Cell Lung [DISEASES], neoplasias::neoplasias por localización::neoplasias torácicas::neoplasias del tracto respiratorio::neoplasias pulmonares::neoplasias de los bronquios::carcinoma broncogénico::carcinoma de pulmón de células no pequeñas [ENFERMEDADES], Other subheadings::Other subheadings::/drug therapy [Other subheadings], Diagnosis::Prognosis::Treatment Outcome [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], targeted therapy, Oncology, non-small-cell lung cancer, pralsetinib, Avaluació de resultats (Assistència sanitària), Other subheadings::/therapeutic use [Other subheadings], Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents [CHEMICALS AND DRUGS], Pulmons - Càncer - Tractament, frontline therapy, RET fusion, RET inhibition
Abstract: RET inhibition; Pralsetinib; Targeted therapy Inhibición de RET; Pralsetinib; Terapia dirigida Inhibició de RET; Pralsetinib; Teràpia dirigida Background RET fusions are present in 1%-2% of non-small-cell lung cancer (NSCLC). Pralsetinib, a highly potent, oral, central nervous system-penetrant, selective RET inhibitor, previously demonstrated clinical activity in patients with RET fusion–positive NSCLC in the phase I/II ARROW study, including among treatment-naive patients. We report an updated analysis from the ARROW study. Patients and methods ARROW is a multi-cohort, open-label, phase I/II study. Eligible patients were ≥18 years of age with locally advanced or metastatic solid tumours and an Eastern Cooperative Oncology Group performance status of 0-2 (later 0-1). Patients initiated pralsetinib at the recommended phase II dose of 400 mg once daily until disease progression, intolerance, consent withdrawal, or investigator’s decision. The co-primary endpoints (phase II) were overall response rate (ORR) by blinded independent central review and safety. Results Between 17 March 2017 and 6 November 2020 (data cut-off), 281 patients with RET fusion–positive NSCLC were enrolled. The ORR was 72% [54/75; 95% confidence interval (CI) 60% to 82%] for treatment-naive patients and 59% (80/136; 95% CI 50% to 67%) for patients with prior platinum-based chemotherapy (enrolment cut-off for efficacy analysis: 22 May 2020); median duration of response was not reached for treatment-naive patients and 22.3 months for prior platinum-based chemotherapy patients. Tumour shrinkage was observed in all treatment-naive patients and in 97% of patients with prior platinum-based chemotherapy; median progression-free survival was 13.0 and 16.5 months, respectively. In patients with measurable intracranial metastases, the intracranial response rate was 70% (7/10; 95% CI 35% to 93%); all had received prior systemic treatment. In treatment-naive patients with RET fusion–positive NSCLC who initiated pralsetinib by the data cut-off (n = 116), the most common grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). Overall, 7% (20/281) discontinued due to TRAEs. Conclusions Pralsetinib treatment produced robust efficacy and was generally well tolerated in treatment-naive patients with advanced RET fusion–positive NSCLC. Results from the confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting are pending. This work was supported by Blueprint Medicines Corporation and F. Hoffmann-La Roche, Ltd, Switzerland (no grant number).
Published: 2022

7. A meta-analysis of genome-wide association studies identifies multiple longevity genes

Author: Jerome I. Rotter, Rachel Duncan, Lenore J. Launer, Iris E. Jansen, Sarah Cubaynes, Nir Barzilai, Elizabeth J. Becker, Wiesje M. van der Flier, Joris Deelen, Sharon L.R. Kardia, Birgit Debrabant, Wanlin Zheng, Michael A. Province, Janina Dose, Anne B. Newman, Vilmundur Gudnason, Carol Jagger, Kenny Ye, Gil Atzmon, Carmen Martin-Ruiz, Kathryn L. Lunetta, Claudio Franceschi, Marianne Nygaard, Diana van Heemst, Najaf Amin, P. Eline Slagboom, Thomas B. L. Kirkwood, Ilkka Seppälä, Chloé Sarnowski, Heather J. Cordell, Terho Lehtimäki, Jennifer A. Smith, Cornelia M. van Duijn, Marja Jylhä, Dan E. Arking, Hélène Blanché, Jessica D. Faul, Yi Zeng, Henne Holstege, Kent D. Taylor, Junxia Min, Alice M. Arnold, Kristin L. Ayers, Mika Kähönen, Olli T. Raitakari, Pilar Galan, Mary K. Wojczynski, Jean-Marie Robine, Lene Christiansen, David R. Weir, Karen Davies, J. Collerton, Kaare Christensen, Douglas P. Kiel, Niccolò Tesi, Andrew Kingston, Bruce M. Psaty, Joanne M. Murabito, Marcel J. T. Reinders, Albert V. Smith, Xiaomin Liu, Leo-Pekka Lyytikäinen, Mary L. Biggs, Almut Nebel, Sven J. van der Lee, Mikko Hurme, David Karasik, Jean-François Deleuze, Thomas T. Perls, Erin B. Ware, Martijn Huisman, Marian Beekman, Chao Nie, Tamara B. Harris, Ellen A. Nohr, Eric S. Orwoll, Steven R. Cummings, Paola Sebastiani, James W. Vaupel, Wolfgang Lieb, Daniel S. Evans, Thorkild I. A. Sørensen, André G. Uitterlinden, Ashley van der Spek, Max planck Institute for Biology of Ageing [Cologne], Leiden University Medical Center (LUMC), California Pacific Medical Center Research Institute, Johns Hopkins University School of Medicine [Baltimore], McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Department of Neurology, Alzheimer Centre, VU Medical Centre, Amsterdam, Department of Clinical Genetics (Academic Medical Center, University of Amsterdam), VU University Medical Center [Amsterdam], Delft Bioinformatics Lab [Delft], Delft University of Technology (TU Delft), University of Southern Denmark (SDU), Beijing Genomics Institute [Shenzhen] (BGI), China National GeneBank, Division of Statistical Genomics, Washington University School of Medicine, Department of Biostatistics, University of Washington [Seattle], Department of Medicine, Department of Epidemiology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Department of Medicine [Bronx, NY, USA], Albert Einstein College of Medicine [New York], Department of Biology, Faculty of Sciences and Science Education, Haifa University, University of Haifa [Haifa], Institute for Social Research, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Department of Biostatistics [Boston, MA, USA], Harvard T.H. Chan School of Public Health, Icelandic Heart Association [Kopavogur, Iceland] (IHA), Department of Clinical Chemistry, Tempere University, Institute of Genetic Medicine [Newcastle], Newcastle University [Newcastle], Institute of Clinical Molecular Biology, Kiel University, SEMA4, Department of Biostatistics, University of Washington, Boston University [Boston] (BU), Fondation Jean Dausset CEPH, Odense University Hospital, Odense, Copenhagen University Hospital, Institute of Health and Society, Mécanismes moléculaires dans les démences neurodégénératives (MMDN), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institute of Neuroscience [Newcastle] (ION), Institute of Clinical Research, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institute of Ageing and Health, Newcastle University, Newcastle Upon Tyne, Department of Applied Mathematics and Centre of Bioinformatics, Lobachevsky State University [Nizhni Novgorod], Institute of Neurological Sciences of Bologna IRCCS, Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Icelandic Heart Association, Heart Preventive Clinic and Research Institute, University of Iceland [Reykjavik], National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Department of Clinical Epidemiology and Biostatistics, VU Medical Centre, Amsterdam, Amsterdam Public Health Research Institute [The Netherlands], Department of Microbiology and Immunology, University of Tampere [Finland], Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, Institute of Health & Society, Department of Complex Trait Genetics, Vrije Universiteit Amsterdam [Amsterdam] (VU), Tampere University Hospital, School of Public Health, University of Michigan [Dearborn], Faculty of Medicine and Life Sciences [Tampere], Institute of Epidemiology and Biobank PopGen, Faculty of Medicine and Health Technology [Tampere, Finland], Zhejiang University School of Medicine [China], University of Pittsburgh Graduate School of Public Health, Oregon Health & Sciences University, Oregon Health and Science University [Portland] (OHSU), Boston University School of Medicine (BUSM), Department of Medicine, University of Washington, Department of Epidemiology, University of Washington, Kaiser Permanente Washington Health Research Institute [Seattle] (KPWHRI), Turku University Hospital (TYKS), University of Turku, School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), UCLA Medical Center, University of Michigan System, University of Copenhage, Faculty of Health and Medical Sciences, MRC Integrative Epidemiology Unit [Bristol, Royaume-Uni] (MRC IEU), University of Bristol [Bristol], Los Angeles Biomedical Research Institute (LA BioMed), Harbor UCLA Medical Center [Torrance, Ca.], Netherlands Genomics Initiative, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), Department of Internal Medicine (ROTTERDAM - Med Int), Maasstad Ziekenhuis = Maasstad Hospital, Alzheimercentre, department of Neurology, VU University Medical Center, Nuffield Department of Population Health [Oxford], University of Oxford, Max Planck Institute for Demographic Research (MPIDR), Max-Planck-Gesellschaft, Beijing Forestry University, Medical School of Duke University, Hinda and Arthur Marcus Institute for Aging Research,Hebrew SeniorLife, Harvard Medical School [Boston] (HMS), Broad Institute of MIT & Harvard, AUDOUX, Michèle, Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), University of California-University of California, Maasstad Hospital, University of Oxford [Oxford], Epidemiology and Data Science, APH - Aging & Later Life, APH - Societal Participation & Health, Neurology, Amsterdam Neuroscience - Complex Trait Genetics, Human genetics, APH - Personalized Medicine, APH - Methodology, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Epidemiology, Internal Medicine, Universiteit Leiden, and École Pratique des Hautes Études (EPHE)
Subjects: 0301 basic medicine, Percentile, Aging, Apolipoprotein E2, media_common.quotation_subject, Science, [SDV]Life Sciences [q-bio], Longevity, Apolipoprotein E4, Áhættuþættir, General Physics and Astronomy, Genome-wide association study, Diseases, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Genetic correlation, Genome-wide association studies, Article, General Biochemistry, Genetics and Molecular Biology, Odds, 03 medical and health sciences, 0302 clinical medicine, Genetics, Humans, lcsh:Science, Endoplasmic Reticulum Chaperone BiP, Heat-Shock Proteins, media_common, Genetic association, [SDV.GEN]Life Sciences [q-bio]/Genetics, Multidisciplinary, Öldrun, Sjúkdómar, Human Genome, General Chemistry, Genetic architecture, [SDV] Life Sciences [q-bio], Ageing, 030104 developmental biology, Risk factors, Meta-analysis, lcsh:Q, Erfðarannsóknir, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Publisher's version (útgefin grein)., Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity., Alexander von Humboldt-Stiftung
Published: 2019

8. Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia

Author: Geraldine Dawson, Sven Sandin, Frederico Duque, Peter Holmans, Marion Leboyer, Aarno Palotie, Fritz Poustka, Richard Delorme, Stephen Sanders, Alistair T. Pagnamenta, Lonnie Zwaigenbaum, Bridget A. Fernandez, A. Jeremy Willsey, Christine M. Freitag, Christa Lese Martin, Elena Maestrini, Elena Bacchelli, Guiomar Oliveira, Jeremy R. Parr, Guy A. Rouleau, Jonas Bybjerg-Grauholm, Joseph Piven, Latha Soorya, Lauren A. Weiss, Jonathan Green, Carsten Bøcker Pedersen, Louise Gallagher, Regina Regan, Stephan Ripke, Thomas Werge, Pat Levitt, Aravinda Chakravarti, Joana Almeida, Kathryn Roeder, Catalina Betancur, Bernie Devlin, Benjamin M. Neale, Gillian Baird, Jakob Grove, Thomas Bourgeron, David H. Ledbetter, Eftichia Duketis, Karola Rehnström, Gerard D. Schellenberg, Jillian P. Casey, Preben Bo Mortensen, Patrick Bolton, Igor Martsenkovsky, Elise Robinson, Hakon Hakonarson, Vanessa H. Bal, Stacy Steinberg, Christopher Gillberg, Kathryn Tsang, Jacob A. S. Vorstman, Verneri Anttila, Suma Jacob, Judith Conroy, J. Haines, William M. McMahon, Edwin H. Cook, Ann P. Thompson, Inês C. Conceição, Mark J. Daly, Arthur P. Goldberg, Sarah E. Medland, Milica Pejovic-Milovancevic, David M. Hougaard, Shrikant Mane, Christina M. Hultman, Susana Mouga, Hreinn Stefansson, Ellen M. Wijsman, Andreas G. Chiocchetti, Ole Mors, Phil Lee, Richard Anney, Astrid M. Vicente, Veronica J. Vieland, K. Stefansson, Stephen W. Scherer, Teimuraz Silagadze, Pall Magnusson, Donna M. Martin, Merete Nordentoft, Peter Szatmari, Patrícia B. S. Celestino-Soper, Ann S Le-Couteur, Cátia Café, Arthur L. Beaudet, Kerstin Wittemeyer, Anders D. Børglum, Joel S. Bader, Christopher S. Poultney, Hailiang Huang, Alexander Kolevzon, Margaret A. Pericak-Vance, Joachim Hallmayer, Rita M. Cantor, Eric Fombonne, Andrew Green, Dan E. Arking, M. Daniele Fallin, Matthew W. State, Christine Ladd-Acosta, Silvia Derubeis, Raphael Bernier, Regina Waltes, David G. Amaral, Manuel Mattheisen, Abraham Reichenberg, Lambertus Klei, Daniel Moreno-De-Luca, Marie Bækvad-Hansen, Maretha V. Dejonge, Susan G. McGrew, Joseph D. Buxbaum, Hilary Coon, Jennifer Reichert, Michael Gill, Herman Vanengeland, Christine Søholm Hansen, Anthony P. Monaco, Nadia Bolshakova, John I. Nurnberger, Nancy J. Minshew, Michael T. Murtha, Thomas H. Wassink, Evald Saemundsen, Simon Wallace, Sean Brennan, Sean Ennis, A. Gulhan Ercan-Sencicek, Sven Bölte, Oscar Svantesson, Susan L. Santangelo, Andrew D. Paterson, Robert L. Hendren, Timothy W. Yu, Dalila Pinto, D.E. Grice, Alison Merikangas, Stephen J. Guter, Anthony J. Bailey, Bernadette Rogé, Christopher A. Walsh, Susan E. Folstein, Wendy Roberts, Sabine M. Klauck, Marianne Giørtz Pedersen, Tiago R. Magalhaes, John R. Gilbert, Irva Hertz-Picciotto, James S. Sutcliffe, Evdokia Anagnostou, Catarina Correia, Eric M. Morrow, Daniel H. Geschwind, Jennifer K. Lowe, Agatino Battaglia, Bozenna Iliadou, Michael L. Cuccaro, Catherine Lord, MRC Centre for Neuropsychiatric Genetics and Genomics [Cardiff, UK], Cardiff University, The Autism Working Group of the Psychiatric Genomics Consortium was supported by National Institutes of Mental Health (NIMH, USA) grant MH109539, MH094432 and MH094421 to M.J.D. The ACE Network was supported by MH081754 and MH100027 to D.H.G. The Autism Genetic Resource Exchange (AGRE) is a program of Autism Speaks (USA) and was supported by grant MH081810. The Autism Genome Project (AGP) was supported by grants from Autism Speaks, the Canadian Institutes of Health Research (CIHR), Genome Canada, the Health Research Board (Ireland, AUT/ 2006/1, AUT/2006/2, PD/2006/48), the Hilibrand Foundation (USA), the Medical Research Council (UK), the National Institutes of Health (USA, the National Institute of Child Health and Human Development and the National Institute of Mental Health), the Ontario Genomics Institute, and the University of Toronto McLaughlin Centre. The Simons Simplex Collection (SSC) was supported by a grant from the Simons Foundation (SFARI 124827 to the investigators of the Simons Simplex Collection Genetic Consortium), approved researchers can obtain the SSC population dataset described in this study (http://sfari.org/resources/sfari-base) by applying at https://base.sfari.org. The Gene Discovery Project of Johns Hopkins was funded by MH060007, MH081754, and the Simons Foundation. The MonBos Collection study was funded in part through a grant from the Autism Consortium of Boston. Support for the Extreme Discordant Sib-Pair (EDSP) family sample (part of the MonBos collection) was provided by the NLM Family foundation. Support for the Massachusetts General Hospital (MGH)–Finnish collaborative sample was provided by NARSAD. The PAGES collection was funded by NIMH grant MH097849. The collection of data and biomaterials that participated in the NIMH Autism Genetics Initiative has been supported by National Institute of Health grants MH52708, MH39437, MH00219, and MH00980, National Health Medical Research Council grant 0034328, and by grants from the Scottish Rite, the Spunk Fund, Inc., the Rebecca and Solomon Baker Fund, the APEX Foundation, the National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD), the endowment fund of the Nancy Pritzker Laboratory (Stanford), and by gifts from the Autism Society of America, the Janet M. Grace Pervasive Developmental Disorders Fund, and families and friends of individuals with autism. The iPSYCH project is funded by The Lundbeck Foundation and the universities and university hospitals of Aarhus and Copenhagen. In addition, the genotyping of iPSYCH samples was supported by grants from the Stanley Foundation, the Simons Foundation (SFARI 311789 to MJD), and NIMH (5U01MH094432-02 to MJD). The Study to Explore Early Development (SEED) was funded by the Centers for Disease Control and Prevention (CDC) grants U10DD000180, U10DD000181, U10DD000182, U10DD000183, U10DD000184, and U10DD000498. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and financially supported by the Netherlands Scientific Organization (NWO 480-05-003), along with a supplement from the Dutch Brain Foundation and the VU University Amsterdam. Additional statistical analyses were performed and supported by the Trinity Centre for High Performance Computing (http://www.tchpc.tcd.ie/) funded through Science Foundation Ireland. Computational support for the PAGES collection was provided in part through the computational resources and staff expertise of the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai (https://hpc.mssm.edu). Data QC and statistical analyses of the iPSYCH samples were performed at the high-performance computing cluster GenomeDK (http://genome.au.dk) at the Center for Integrative Sequencing, iSEQ, Aarhus University. iSEQ provided computed time, data storage, and technical support for the study., Richard JL Anney, Email: anneyr@cardiff.ac.uk, Affiliation/s: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, CF24 4HQ, UK, Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. Stephan Ripke, Email: ripke@atgu.mgh.harvard.edu, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Stanley Center for Psychiatric Research and Program in Medical and Population Genetic, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA, Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, CCM, Berlin 10117, Germany. Verneri Anttila, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Stanley Center for Psychiatric Research and Program in Medical and Population Genetic, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Jakob Grove, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, iSEQ, Centre for Integrative Sequencing, Aarhus University, Aarhus, DK-8000, Denmark, Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, DK-8000, Denmark, Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark. Peter Holmans, Affiliation/s: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, CF24 4HQ, UK. Hailiang Huang, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Stanley Center for Psychiatric Research and Program in Medical and Population Genetic, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Lambertus Klei, Affiliation/s: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Phil H Lee, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Department of Psychiatry, Harvard Medical School, Boston, MA 02115, USA. Sarah E Medland, Affiliation/s: Queensland Institute of Medical Research Brisbane, QLD, 4006, Australia. Benjamin Neale, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Stanley Center for Psychiatric Research and Program in Medical and Population Genetic, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Elise Robinson, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Stanley Center for Psychiatric Research and Program in Medical and Population Genetic, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Lauren A Weiss, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA, Inst Human Genetics, University of California San Francisco, San Francisco, CA 94143, USA. Lonnie Zwaigenbaum, Affiliation/s: Department of Pediatrics, University of Alberta, Edmonton, AB, T6G 1C9, Canada. Timothy W Yu, Affiliation/s: Division of Genetics, Children ’ s Hospital Boston, Harvard Medical School, Boston, MA 02115, USA. Kerstin Wittemeyer, Affiliation/s: School of Education, University of Birmingham, Birmingham, B15 2TT, UK. A.Jeremy Willsey, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA. Ellen M Wijsman, Affiliation/s: Department of Medicine, University of Washington, Seattle, WA 98195, USA, Department of Biostatistics, University of Washington, Seattle, WA 98195, USA. Thomas Werge, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Institute of Biological Psychiatry, MHC Sct Hans, Mental Health Services Copenhagen, Roskilde, Denmark, Department of Clinical Medicine, University of Copenhagen, Copenhagen, DK-2200, Denmark. Thomas H Wassink, Affiliation/s: Department of Psychiatry, Carver College of Medicine, Iowa City, IA 52242, USA. Regina Waltes, Affiliation/s: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt am Main, 60528, Germany. Christopher A Walsh, Affiliation/s: Division of Genetics, Children ’ s Hospital Boston, Harvard Medical School, Boston, MA 02115, USA, Program in Genetics and Genomics, Harvard Medical School, Boston, MA 02115, USA, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA, Department of Neurology, Harvard Medical School, Boston, MA 02115, USA, Simon Wallace, Affiliation/s: Department of Psychiatry, University of Oxford and Warneford Hospital, Oxford, OX3 7JX, UK. Jacob AS Vorstman, Affiliation/s: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands. Veronica J Vieland, Affiliation/s: Battelle Center for Mathematical Medicine, The Research Institute at Nationwide Children ’ s Hospital, Columbus, OH 43205, USA. Astrid M Vicente, Affiliation/s: Instituto Nacional de Saúde Dr Ricardo Jorge, Lisboa, 1600, Portugal, Center for Biodiversity, Functional and Integrative Genomics, Campus da FCUL, Lisboa, 1649, Portugal. Herman vanEngeland, Affiliation/s: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands. Kathryn Tsang, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA, Inst Human Genetics, University of California San Francisco, San Francisco, CA 94143, USA. Ann P Thompson, Affiliation/s: Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, ON, L8S 4L8, Canada. Peter Szatmari, Affiliation/s: Department of Psychiatry, University of Toronto, ON, M5T 1R8, Canada. Oscar Svantesson, Affiliation/s: Karolinska Institutet, Solna, SE-171 77, Sweden. Stacy Steinberg, Affiliation/s: deCODE Genetics, Reykjavik, IS-101, Iceland. Kari Stefansson, Affiliation/s: deCODE Genetics, Reykjavik, IS-101, Iceland. Hreinn Stefansson, Affiliation/s: deCODE Genetics, Reykjavik, IS-101, Iceland. Matthew W State, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA. Latha Soorya, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Rush University Medical Center, Chicago, IL 60612, USA. Teimuraz Silagadze, Affiliation/s: Department of Psychiatry and Drug Addiction, Tbilisi State Medical University, Tbilisi, 0186, Georgia. Stephen W Scherer, Affiliation/s: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, M5G 1L4, Canada, McLaughlin Centre, University of Toronto, Toronto, ON, M5G 0A4, Canada, Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada. Gerard D Schellenberg, Affiliation/s: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19102, USA. Sven Sandin, Affiliation/s: Karolinska Institutet, Solna, SE-171 77, Sweden. Stephan J Sanders, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA. Evald Saemundsen, Affiliation/s: State Diagnostic and Counseling Centre, Kopavogur, IS-201, Iceland. Guy A Rouleau, Affiliation/s: Montreal Neurological Institute, Dept of Neurology and Neurosurgery, McGill University, Montreal, QC, H3A 2B4, Canada. Bernadette Rogé, Affiliation/s: Centre d ’ Etudes et de Recherches en Psychopathologie, Toulouse University, Toulouse, 31058, France. Kathryn Roeder, Affiliation/s: Department of Computational Biology, Carnegie Mellon University, Pittsburgh, PA 15213, USA, Department of Statistics, Carnegie Mellon University, Pittsburgh, PA 15213, USA. Wendy Roberts, Affiliation/s: Autism Research Unit, The Hospital for Sick Children, Toronto, ON, M5G 1L4, Canada. Jennifer Reichert, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Abraham Reichenberg, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Karola Rehnström, Affiliation/s: Sanger Institute, Hinxton, CB10 1SA, UK. Regina Regan, Affiliation/s: National Childrens Research Centre, Our Lady ’ s Hospital Crumlin, Dublin, D12, Ireland, Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland. Fritz Poustka, Affiliation/s: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt am Main, 60528, Germany. Christopher S Poultney, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Joseph Piven, Affiliation/s: University of North Carolina, Chapel Hill, NC 27599, USA. Dalila Pinto, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA Margaret A Pericak-Vance, Affiliation/s: The John P Hussman Institute for Human Genomics, University of Miami, Miami, FL 33101, USA. Milica Pejovic-Milovancevic, Affiliation/s: Institute of Mental Health and Medical Faculty, University of Belgrade, Belgrade, 11 000, Serbia. Marianne Giørtz Pedersen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, National Centre for Register-based Research, Aarhus University, Aarhus, Denmark, Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark. Carsten Bøcker Pedersen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark. Andrew D Paterson, Affiliation/s: Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada, The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, M5G 1L4, Canada, Dalla Lana School of Public Health, Toronto, ON, M5T 3M7, Canada. Jeremy R Parr, Affiliation/s: Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK, Institue of Health and Science, Newcastle University, Newcastle Upon Tyne, NE2 4AX, UK. Alistair T Pagnamenta, Affiliation/s: Wellcome Trust Centre for Human Genetics, OxfordUniversity,Oxford,OX37BN,UK. Guiomar Oliveira, Affiliation/s: Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, Coimbra, 3041-80, Portugal, University Clinic of Pediatrics and Institute for Biomedical Imaging and Life Science, Faculty of Medicine, University of Coimbra, Coimbra, 3041-80, Portugal. John I Nurnberger, Affiliation/s: Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202, USA, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA, Program in Medical Neuroscience, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Merete Nordentoft, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark. Michael T Murtha, Affiliation/s: Programs on Neurogenetics, Yale University School of Medicine, New Haven, CT 06520, USA. Susana Mouga, Affiliation/s: Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, Coimbra, 3041-80, Portugal, University Clinic of Pediatrics and Institute for Biomedical Imaging and Life Science, Faculty of Medicine, University of Coimbra, Coimbra, 3041-80, Portugal. Preben Bo Mortensen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Na- tional Centre for Register-based Research, Aarhus University, Aarhus, Denmark, Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark, Ole Mors, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark. Eric M Morrow, Affiliation/s: Department of Psychiatry and Human Behaviour, Brown University, Providence, RI 02912, USA. Daniel Moreno-De-Luca, Affiliation/s: Department of Psychiatry and Hu- man Behaviour, Brown University, Providence, RI 02912, USA. Anthony P Monaco, Affiliation/s: Wellcome Trust Centre for Human Genetics, Oxford University, Oxford, OX3 7BN, UK, Tufts University, Boston, MA 02155?, USA. Nancy Minshew, Affiliation/s: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Alison Merikangas, Affiliation/s: Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. William M McMahon, Affiliation/s: Department of Psychiatry, University of Utah, Salt Lake City, UT 84108, USA. Susan G McGrew, Affiliation/s: Department of Pediatrics, Vanderbilt University, Nashville, TN 37232, USA. Manuel Mattheisen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, DK-8000, Denmark. Igor Martsenkovsky, Affiliation/s: Department of Child, Adolescent Psychiatry and Medical-Social Rehabilitation, Ukrainian Research Institute of Social Fo- rensic Psychiatry and Drug Abuse, Kyiv, 04080, Ukraine. Donna M Martin, Affiliation/s: Department of Pediatrics and Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA. Shrikant M Mane, Affiliation/s: Yale Center for Genomic Analysis, Yale University School of Medicine, New Haven, CT 06516, USA. Pall Magnusson, Affiliation/s: Department of Child and Adolescent Psychiatry, National University Hospital, Reykjavik, IS-101, Iceland. Tiago Magalhaes, Affiliation/s: National Childrens Research Centre, Our Lady ’ s Hospital Crumlin, Dublin, D12, Ireland, Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland. Elena Maestrini, Affiliation/s: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, 40126, Italy. Jennifer K Lowe, Affiliation/s: Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA, Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA, Center for Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Catherine Lord, Affiliation/s: Department of Psychiatry, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA. Pat Levitt, Affiliation/s: Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA. Christa LeseMartin, Affiliation/s: Autism and Developmental Medicine Institute, Geisinger Health System, Danville, PA 17837, USA. David H Ledbetter, Affiliation/s: Chief Scientific Officer, Geisinger Health System, Danville, PA 17837, USA. Marion Leboyer, Affiliation/s: FondaMental Foundation, Créteil, 94000, France, INSERM U955, Paris, 94010, France, Faculté de Médecine, Université Paris Est, Créteil, 94000, France, Department of Psychiatry, Henri Mondor-Albert Chene- vier Hospital, Assistance Publique – Hôpitaux de Paris, Créteil, 94000, France, Ann S LeCouteur, Affiliation/s: Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK, Institue of Health and Science, Newcastle University, Newcastle Upon Tyne, NE2 4AX, UK. Christine Ladd-Acosta, Affiliation/s: Department of Epidemiology, Johns Hop- kins Bloomberg School of Public Health, Baltimore, MD 21205, USA. Alexander Kolevzon, Affiliation/s: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Sabine M Klauck, Affiliation/s: Division of Molecular Genome Analysis and Working Group Cancer Genome Research, Deutsches Krebsforschungszentrum, Heidelberg, D-69120, Germany. Suma Jacob, Affiliation/s: Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USA, Institute of Translational Neuroscience and Department of Psychiatry, University of Minnesota, Minneapolis, MN 55454, USA. Bozenna Iliadou, Affiliation/s: Karolinska Institutet, Solna, SE-171 77, Sweden. Christina M Hultman, Affiliation/s: Karolinska Institutet, Solna, SE-171 77, Sweden. David M Hougaard, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, DK-2300, Denmark. Irva Hertz-Picciotto, Affiliation/s: Department of Public Health Sciences, School of Medicine, University of California Davis, Davis, CA 95616, USA, The MIND Institute, School of Medicine, University of California Davis, Davis, CA 95817, USA. Robert Hendren, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA. Christine Søholm Hansen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, DK-2300, Denmark. Jonathan L Haines, Affiliation/s: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. Stephen J Guter, Affiliation/s: Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USA. Dorothy E Grice, Affiliation/s: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Jonathan M Green, Affiliation/s: Manchester Academic Health Sciences Centre, Manchester, M13 9NT, UK, Institute of Brain, Behaviour, and Mental Health, University of Manchester, Manchester, M13 9PT, UK. Andrew Green, Affiliation/s: Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland, Centre for Medical Genetics, Our Lady ’ s Hospital Crumlin, Dublin, D12, Ireland. Arthur P Goldberg, Affiliation/s: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Christopher Gillberg, Affiliation/s: Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, S-405 30, Sweden. John Gilbert, Affiliation/s: The John P Hussman Institute for Human Genomics, University of Miami, Miami, FL 33101, USA. Louise Gallagher, Affiliation/s: Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. Christine M Freitag, Affiliation/s: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt am Main, 60528, Germany. Eric Fombonne, Affiliation/s: Department of Psychiatry and Institute for Development and Disability, Oregon Health and Science University, Portland, OR 97239, USA. Susan E Folstein, Affiliation/s: Division of Child and Adolescent Psychiatry, Department of Psychiatry, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. Bridget Fernandez, Affiliation/s: Memorial University of Newfoundland, St John ’ s, NL, A1B 3X9, Canada. M.Daniele Fallin, Affiliation/s: Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. A.Gulhan Ercan-Sencicek, Affiliation/s: Programs on Neurogenetics, Yale Uni- versity School of Medicine, New Haven, CT 06520, USA. Sean Ennis, Affiliation/s: Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland, Centre for Medical Genetics, Our Lady ’ s Hospital Crumlin, Dublin, D12, Ireland. Frederico Duque, Affiliation/s: Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, Coimbra, 3041-80, Portugal, University Clinic of Pediatrics and Institute for Biomedical Imaging and Life Science, Faculty of Medicine, University of Coimbra, Coimbra, 3041-80, Portugal. Eftichia Duketis, Affiliation/s: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt am Main, 60528, Germany. Richard Delorme, Affiliation/s: FondaMental Foundation, Créteil, 94000, France, Human Genetics and Cognitive Functions Unit, Institut Pasteur, Paris, 75015, France, Centre National de la Recherche Scientifique URA 2182 Institut Pasteur, Paris, 75724, France, Department of Child and Adolescent Psychiatry, Robert Debré Hospital, Assistance Publique – Hôpitaux de Paris, Paris, 75019, France, Silvia DeRubeis, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Maretha V DeJonge, Affiliation/s: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands. Geraldine Dawson, Affiliation/s: Duke Center for Autism and Brain Developments, Duke University School of Medicine, Durham, NC 27705, USA, Duke Institute for Brain Sciences, Duke University School of Medicine, Durham, NC 27708, USA. Michael L Cuccaro, Affiliation/s: The John P Hussman Institute for Human Genomics, University of Miami, Miami, FL 33101, USA. Catarina T Correia, Affiliation/s: Instituto Nacional de Saúde Dr Ricardo Jorge, Lisboa, 1600, Portugal, Center for Biodiversity, Functional and Integrative Genomics, Campus da FCUL, Lisboa, 1649, Portugal. Judith Conroy, Affiliation/s: Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland, Temple Street Children ’ s University Hospital, Dublin, D1, Ireland. Ines C Conceição, Affiliation/s: Instituto Nacional de Saúde Dr Ricardo Jorge, Lisboa, 1600, Portugal, Center for Biodiversity, Functional and Integrative Genomics, Campus da FCUL, Lisboa, 1649, Portugal. Andreas G Chiocchetti, Affiliation/s: Depar tment of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goe the University Frankfurt, Frankfurt am Main, 60528, Germany. Patrícia BS Celestino-Soper, Affiliation/s: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indian- apolis, IN 46202, USA. Jillian Casey, Affiliation/s: Temple Street Children ’ s University Hospital, Dublin, D1, Ireland, Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland. Rita M Cantor, Affiliation/s: Department of Psychiatry, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA, Department of Human Genetics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA. Cátia Café, Affiliation/s: Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, Coimbra, 3041-80, Portugal. Jonas Bybjerg-Grauholm, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, DK-2300, Denmark. Sean Brennan, Affiliation/s: Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. Thomas Bourgeron, Affiliation/s: FondaMental Foundation, Créteil, 94000, France, University Paris Diderot, Sorbonne Paris Cité, Paris, 75013, France, Patrick F Bolton, Affiliation/s: Institute of Psychiatry, Kings College London, London, SE5 8AF, UK, South London and Maudsley Biomedical Research Centre for Mental Health, London, SE5 8AF, UK. Sven Bölte, Affiliation/s: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt am Main, 60528, Germany, Department of Women ’ s and Children ’ s Health, Center of Neurodevelopmental Disorders, Karolinska Institutet, Stockholm, SE- 113 30, Sweden, Child and Adolescent Psychiatry, Center for Psychiatry Re- search, Stockholm County Council, Stockholm, SE-171 77, Sweden. Nadia Bolshakova, Affiliation/s: Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. Catalina Betancur, Affiliation/s: INSERM U1130, Paris, 75005, France, CNRS UMR 8246, Paris, 75005, France, Sorbonne Universités, UPMC Univ Paris 6, Neuroscience Paris Seine, Paris, 75005, France. Raphael Bernier, Affiliation/s: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA. Arthur L Beaudet, Affiliation/s: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Agatino Battaglia, Affiliation/s: Stella Maris Institute for Child and Adolescent Neuropsychiatr, Pisa, 56018, Italy. Vanessa H Bal, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA. Gillian Baird, Affiliation/s: Paediatric Neurodisability, King ’ s Health Partners, Kings College London, London, SE1 7EH, UK. Anthony J Bailey, Affiliation/s: Department of Psychiatry, University of Oxford and Warneford Hospital, Oxford, OX3 7JX, UK, Mental Health and Addictions Research Unit, University of British Colombia, Vancouver, BC, V5Z 4H4, Canada. Marie Bækvad-Hansen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, DK-2300, Denmark. Joel S Bader, Affiliation/s: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21218, USA. Elena Bacchelli, Affiliation/s: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, 40126, Italy. Evdokia Anagnostou, Affiliation/s: Bloorview Research Institute, University of Toronto, Toronto, ON, M4G 1R8, Canada. David Amaral, Affiliation/s: The MIND Institute, School of Medicine, University of California Davis, Davis, CA 95817, USA, Department of Psychiatry, School of Medicine, University of California Davis, Davis, CA 95817, USA, Department of Behavioural Sciences, School of Medicine, University of California Davis, Davis, CA 95817, USA. Joana Almeida, Affiliation/s: Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, Coimbra, 3041-80, Portugal. Anders D Børglum, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, DK-8000, Denmark. Joseph D Buxbaum, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA Aravinda Chakravarti, Affiliation/s: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21218, USA. Edwin H Cook, Affiliation/s: Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USA. Hilary Coon, Affiliation/s: Department of Psychiatry, University of Utah, Salt Lake City, UT 84108, USA. Daniel H Geschwind, Affiliation/s: Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA, Center for Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA, Department of Human Genetics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA, Michael Gill, Affiliation/s: Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. Hakon Hakonarson, Affiliation/s: The Center for Applied Genomics and Division of Human Genetics, Children ’ s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA, Dept of Pediatrics, University of Pennsylvania, Philadelphia, PA 19104, USA. Joachim Hallmayer, Affiliation/s: Department of Psychiatry, Stanford University, Stanford, CA 94305, USA. Aarno Palotie, Affiliation/s: Sanger Institute, Hinxton, CB10 1SA, UK., Anney, Richard J. L., Ripke, Stephan, Anttila, Verneri, Grove, Jakob, Holmans, Peter, Huang, Hailiang, Klei, Lambertu, Lee, Phil H., Medland, Sarah E., Neale, Benjamin, Robinson, Elise, Weiss, Lauren A., Zwaigenbaum, Lonnie, Yu, Timothy W., Wittemeyer, Kerstin, Willsey, A. Jeremy, Wijsman, Ellen M., Werge, Thoma, Wassink, Thomas H., Waltes, Regina, Walsh, Christopher A., Wallace, Simon, Vorstman, Jacob A. S., Vieland, Veronica J., Vicente, Astrid M., Vanengeland, Herman, Tsang, Kathryn, Thompson, Ann P., Szatmari, Peter, Svantesson, Oscar, Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, State, Matthew W., Soorya, Latha, Silagadze, Teimuraz, Scherer, Stephen W., Schellenberg, Gerard D., Sandin, Sven, Sanders, Stephan J., Saemundsen, Evald, Rouleau, Guy A., Rogã©, Bernadette, Roeder, Kathryn, Roberts, Wendy, Reichert, Jennifer, Reichenberg, Abraham, Rehnstrã¶m, Karola, Regan, Regina, Poustka, Fritz, Poultney, Christopher S., Piven, Joseph, Pinto, Dalila, Pericak-Vance, Margaret A., Pejovic-Milovancevic, Milica, Pedersen, Marianne GiÃ¸rtz, Pedersen, Carsten BÃ¸cker, Paterson, Andrew D., Parr, Jeremy R., Pagnamenta, Alistair T., Oliveira, Guiomar, Nurnberger, John I., Nordentoft, Merete, Murtha, Michael T., Mouga, Susana, Mortensen, Preben Bo, Mors, Ole, Morrow, Eric M., Moreno-De-Luca, Daniel, Monaco, Anthony P., Minshew, Nancy, Merikangas, Alison, Mcmahon, William M., Mcgrew, Susan G., Mattheisen, Manuel, Martsenkovsky, Igor, Martin, Donna M., Mane, Shrikant M., Magnusson, Pall, Magalhaes, Tiago, Maestrini, Elena, Lowe, Jennifer K., Lord, Catherine, Levitt, Pat, Martin, Christa Lese, Ledbetter, David H., Leboyer, Marion, Lecouteur, Ann S., Ladd-Acosta, Christine, Kolevzon, Alexander, Klauck, Sabine M., Jacob, Suma, Iliadou, Bozenna, Hultman, Christina M., Hougaard, David M., Hertz-Picciotto, Irva, Hendren, Robert, Hansen, Christine SÃ¸holm, Haines, Jonathan L., Guter, Stephen J., Grice, Dorothy E., Green, Jonathan M., Green, Andrew, Goldberg, Arthur P., Gillberg, Christopher, Gilbert, John, Gallagher, Louise, Freitag, Christine M., Fombonne, Eric, Folstein, Susan E., Fernandez, Bridget, Fallin, M. Daniele, Ercan-Sencicek, A. Gulhan, Ennis, Sean, Duque, Frederico, Duketis, Eftichia, Delorme, Richard, Derubeis, Silvia, Dejonge, Maretha V., Dawson, Geraldine, Cuccaro, Michael L., Correia, Catarina T., Conroy, Judith, Conceiã§ã£o, Ines C., Chiocchetti, Andreas G., Celestino-Soper, PatrÃcia B. S., Casey, Jillian, Cantor, Rita M., Cafã©, Cã¡tia, Bybjerg-Grauholm, Jona, Brennan, Sean, Bourgeron, Thoma, Bolton, Patrick F., Bã¶lte, Sven, Bolshakova, Nadia, Betancur, Catalina, Bernier, Raphael, Beaudet, Arthur L., Battaglia, Agatino, Bal, Vanessa H., Baird, Gillian, Bailey, Anthony J., BÃ¦kvad-Hansen, Marie, Bader, Joel S., Bacchelli, Elena, Anagnostou, Evdokia, Amaral, David, Almeida, Joana, Bã¸rglum, Anders D., Buxbaum, Joseph D., Chakravarti, Aravinda, Cook, Edwin H., Coon, Hilary, Geschwind, Daniel H., Gill, Michael, Hallmayer, Joachim, Palotie, Aarno, Santangelo, Susan, Sutcliffe, James S., Arking, Dan E., Devlin, Bernie, Daly, Mark J., Hakonarson, Hakon, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Fondation FondaMental [Créteil], Génétique de l'autisme = Genetics of Autism (NPS-01), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Male, INTELLECTUAL DISABILITY, Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium, Autism, Neurodevelopment, Gene Expression, Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, lcsh:RC346-429, 0302 clinical medicine, 2.1 Biological and endogenous factors, Pair 10, Copy-number variation, Aetiology, Autism spectrum disorder, Genetics, Adaptor Proteins, Forkhead Transcription Factors, Serious Mental Illness, 3. Good health, Mental Health, Psychiatry and Mental Health, Meta-analysis, Female, Biotechnology, Human, Autismo, Genetic correlation, Intellectual and Developmental Disabilities (IDD), Clinical Sciences, Gene-set analysi, Genomics, Locus (genetics), FOXP1, Biology, Chromosomes, Heritability, 03 medical and health sciences, Plasma Membrane Calcium-Transporting ATPases, Developmental Neuroscience, REVEALS, mental disorders, LINKAGE, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Meta-analysi, GENOME-WIDE ASSOCIATION, COMMON, Genotyping, Molecular Biology, lcsh:Neurology. Diseases of the nervous system, COPY NUMBER VARIATION, Genetic association, Adaptor Proteins, Signal Transducing, Homeodomain Proteins, [SDV.GEN]Life Sciences [q-bio]/Genetics, Chromosomes, Human, Pair 10, Research, Human Genome, Signal Transducing, Neurosciences, Membrane Proteins, medicine.disease, RISK LOCI, R1, Brain Disorders, Repressor Proteins, 030104 developmental biology, Genetic Loci, Case-Control Studies, Perturbações do Desenvolvimento Infantil e Saúde Mental, Schizophrenia, Carrier Proteins, Gene-set analysis, MENTAL-RETARDATION, SCAN, 030217 neurology & neurosurgery, Transcription Factors, Developmental Biology
Abstract: Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium - Collaborators (162): Anney RJL, Ripke S, Anttila V, Grove J, Holmans P, Huang H, Klei L, Lee PH, Medland SE, Neale B, Robinson E, Weiss LA, Zwaigenbaum L, Yu TW, Wittemeyer K, Willsey AJ, Wijsman EM, Werge T, Wassink TH, Waltes R, Walsh CA, Wallace S, Vorstman JAS, Vieland VJ, Vicente AM, vanEngeland H, Tsang K, Thompson AP, Szatmari P, Svantesson O, Steinberg S, Stefansson K, Stefansson H, State MW, Soorya L, Silagadze T, Scherer SW, Schellenberg GD, Sandin S, Sanders SJ, Saemundsen E, Rouleau GA, Rogé B, Roeder K, Roberts W, Reichert J, Reichenberg A, Rehnström K, Regan R, Poustka F, Poultney CS, Piven J, Pinto D, Pericak-Vance MA, Pejovic-Milovancevic M, Pedersen MG, Pedersen CB, Paterson AD, Parr JR, Pagnamenta AT, Oliveira G, Nurnberger JI, Nordentoft M, Murtha MT, Mouga S, Mortensen PB, Mors O, Morrow EM, Moreno-De-Luca D, Monaco AP, Minshew N, Merikangas A, McMahon WM, McGrew SG, Mattheisen M, Martsenkovsky I, Martin DM, Mane SM, Magnusson P, Magalhaes T, Maestrini E, Lowe JK, Lord C, Levitt P, Martin CL, Ledbetter DH, Leboyer M, LeCouteur AS, Ladd-Acosta C, Kolevzon A, Klauck SM, Jacob S, Iliadou B, Hultman CM, Hougaard DM, Hertz-Picciotto I, Hendren R, Hansen CS, Haines JL, Guter SJ, Grice DE, Green JM, Green A, Goldberg AP, Gillberg C, Gilbert J, Gallagher L, Freitag CM, Fombonne E, Folstein SE, Fernandez B, Fallin MD, Ercan-Sencicek AG, Ennis S, Duque F, Duketis E, Delorme R, DeRubeis S, DeJonge MV, Dawson G, Cuccaro ML, Correia CT, Conroy J, Conceição IC, Chiocchetti AG, Celestino-Soper PBS, Casey J, Cantor RM, Café C, Bybjerg-Grauholm J, Brennan S, Bourgeron T, Bolton PF, Bölte S, Bolshakova N, Betancur C, Bernier R, Beaudet AL, Battaglia A, Bal VH, Baird G, Bailey AJ, Bækvad-Hansen M, Bader JS, Bacchelli E, Anagnostou E, Amaral D, Almeida J, Børglum AD, Buxbaum JD, Chakravarti A, Cook EH, Coon H, Geschwind DH, Gill M, Hallmayer J, Palotie A, Santangelo S, Sutcliffe JS, Arking DE, Devlin B, Daly MJ. Astrid M. Vicente .- Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis do INSA. PMS free full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441062/ Background: Over the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR)
Published: 2017

9. Multiethnic Genome-Wide Association Study of Cerebral White Matter Hyperintensities on MRI

Author: Susan H. Blanton, Ashley Beecham, Pamela J. Schreiner, Ralph L. Sacco, Stéphanie Debette, Ben A. Oostra, Marian Beekman, M. Arfan Ikram, Edith Hofer, Anna Maria Töglhofer, Alexander Teumer, Ganesh Chauhan, Clinton B. Wright, Meike W. Vernooij, Wiro J. Niessen, Aad van der Lugt, Cornelia M. van Duijn, Christophe Tzourio, Matthias Nauck, Bernard Mazoyer, Bettina von Sarnowski, Alexa S. Beiser, Susan R. Heckbert, André G. Uitterlinden, Alex P. Zijdenbos, David S. Knopman, Paul Freudenberger, Myriam Fornage, Maaike Schuur, Stephen Turner, Matthew Traylor, Qiong Yang, Fabrice Crivello, P. Eline Slagboom, Ian J. Deary, Sharon L.R. Kardia, Cora E. Lewis, Stella Trompet, Mike A. Nalls, Jennifer A. Smith, Katrin Hegenscheid, Hans J. Grabe, Lenore J. Launer, Reinhold Schmidt, Albert V. Smith, M. Kamran Ikram, Kumar B. Rajan, Mariza de Andrade, Sudha Seshadri, Lorna M. Lopez, Philip L. De Jager, Albert Hofman, Joshua C. Bis, Gerardo Heiss, Neelum T. Aggarwal, Elizabeth J. Atkinson, Carla A. Ibrahim-Verbaas, David C. Liewald, Anton J. M. de Craen, Jing Wang, David J. Stott, Sandra Barral, Adam M. Brickman, Mohamad Habes, Eric Boerwinkle, Katharina Wittfeld, Jerome I. Rotter, Saima Hilal, R. Nick Bryan, Charles C. DeCarli, Mark A. van Buchem, Mitchell S.V. Elkind, Rebecca F. Gottesman, Christiane Wolf, Vincent Chouraki, Jeroen van der Grond, Jiemin Liao, Joris Deelen, Stephen Sidney, Kenneth Rice, Vilmundur Guðnason, Hieab H.H. Adams, Benjamin F.J. Verhaaren, Tien Yin Wong, Oliver Martinez, Denis A. Evans, Helena Schmidt, W. T. Longstreth, J. Wouter Jukema, Richard Mayeux, Joanna M. Wardlaw, Thomas H. Mosley, Michelle Luciano, Sigurdur Sigurdsson, Carole Dufouil, Christopher Chen, Philippe Amouyel, Wei Zhao, John C. van Swieten, Bruce M. Psaty, Hae-Won Uh, B. Gwen Windham, Erasmus University Medical Center [Rotterdam] (Erasmus MC), INSERM U897, University of Bordeaux, France, University of Washington [Seattle], University of Michigan [Ann Arbor], University of Michigan System, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), John P. Hussman Institute for Human Genomics, University of Miami Leonard M. Miller School of Medicine (UMMSM), Rush University Medical Center [Chicago], University of Edinburgh, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands, Depts of Radiology, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Department of Materials Science and Metallurgy [Cambridge University] (DMSM), University of Cambridge [UK] (CAM), JRC Institute for Transuranium Elements [Karlsruhe] (ITU ), European Commission - Joint Research Centre [Karlsruhe] (JRC), Greifswald University Hospital, Division of Biomedical Statistics and Informatics, Mayo Clinic, Division of Biomedical Statistics and Informatics, Mayo Clinic, Laboratoire Interuniversitaire des Systèmes Atmosphériques (LISA (UMR_7583)), Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Genetics, The University of Texas Health Science Center at Houston (UTHealth), Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University [New York], Perelman School of Medicine, University of Pennsylvania, INSERM Research Center for Epidemiology and Biostatistics (U897) Team Neuroepidemiology, Bordeaux, France College of Health Sciences, University of Bordeaux, Bordeaux, France, Systèmes et Applications des Technologies de l'Information et de l'Energie (SATIE), École normale supérieure - Cachan (ENS Cachan)-Université Paris-Sud - Paris 11 (UP11)-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-École normale supérieure - Rennes (ENS Rennes)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Centre National de la Recherche Scientifique (CNRS), Université Lille Nord de France (COMUE), Department of neurology, Groupe d'Imagerie Neurofonctionnelle (GIN - UMR 5296), Service NEUROSPIN (NEUROSPIN), 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)-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)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Dept of Psychology, Molecular Epidemiology, Harvard Medical School [Boston] (HMS), Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Program in Translational NeuroPsychiatric Genomics, Brigham and Women's Hospital [Boston], Columbia Mailman School of Public Health, Laboratoire pharmaceutique Lilly France [Neuilly-sur-Seine], Institute of Molecular Biology & Biochemistry, Johns Hopkins University School of Medicine [Baltimore], Faculty of Medicine, University of Iceland [Reykjavik], The Icelandic Heart Association, Kopavogur, Iceland, Institutes for Community Medicine, Department of Epidemiology, University of Washington, Group Health Research Institute, Group Health Cooperative, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), National University of Singapore (NUS), Université Grenoble Alpes - UFR Sciences de l'Homme et de la Société (UGA UFR SHS), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Grenoble Alpes - UFR Langage, lettres et arts du spectacle, information et communication - Dpt Sciences de l'information et de la communication (UGA UFR LLASIC SIC), Mayo Clinic [Rochester], Academic Unit of Inflammation and Tumour Targeting, Dept. of Oncology, University of Sheffield Medical School, East China University of Science and Technology, Medstar Research Institute, Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Bioinformatics, GlaxoSmithKline, National Institutes of Health [Bethesda] (NIH), Institute of Clinical Chemistry and Laboratory Medicine, Universität Greifswald - University of Greifswald, Delft University of Technology (TU Delft), Cardiovascular Health Research Unit, University of Washington, Department of Medicine, University of Washington, Department of Health Services, University of Washington, Department of Biostatistics, University of Washington, Cedars-Sinai Medical Center, Dept of Neurology, Univ Medicine of Greifswald, Germany, Department of Physics [Stockholm], Stockholm University, University of Minnesota [Twin Cities] (UMN), University of Minnesota System, Kaiser Permanente, Broad Institute [Cambridge], Harvard University-Massachusetts Institute of Technology (MIT), Department of Medical Biochemistry and Microbiology, Uppsala University, Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, King‘s College London, Institute of Molecular Biology and Biochemistry, Centre for Molecular Medicine, Medical University of Graz, Graz, Austria, Research Centre for Stroke & Dementia, St George 's Univ of London, Interuniversity Cardiology Institute Netherlands, SAC, Bush Estate, School Medicine, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Singapore Eye Research Institute, Singapore National Eye Centre, University of Oslo (UiO), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Ninewells Hospital and Medical School, Biomedical Research Centre, University of Dundee, Dundee Technopole, CXR Biosciences Ltd, Department of Atmospheric, Oceanic, and Space Sciences [Ann Arbor] (AOSS), University of Michigan System-University of Michigan System, University of Miami [Coral Gables], Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biospective [Montréal], Dept of Epidemiology & Public Health Sciences, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Mississippi Medical Center (UMMC), Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento, University of California [Davis] (UC Davis), University of California (UC)-University of California (UC), Center for Medical Systems Biology, Netherlands Genomics Initiative, Leiden University Medical Center, Leiden, The Netherlands, Austrian Institute of Technology [Vienna] (AIT), Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], Department of Psychiatry and Psychotherapy, HELIOS Klinikum Stralsund Hanseatic-Greifswald University Hospital, Human Genetics Center, University of Pennsylvania [Philadelphia], Université Paris-Seine-Université Paris-Seine-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Service NEUROSPIN (NEUROSPIN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Memory Aging & Cognition Centre, National Univ of Singapore, Singapore, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China, Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Harvard University [Cambridge]-Massachusetts Institute of Technology (MIT), National Heart, Lung, and Blood Institute [Bethesda] (NHLBI)-Boston University [Boston] (BU), Dept of Ophthalmology, National Univ of Singapore & National Univ Health System, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), University of California-University of California, Radboud university [Nijmegen], Epidemiology, Radiology & Nuclear Medicine, General Practice, Neurology, Medical Informatics, Clinical Genetics, Internal Medicine, Human genetics, NCA - neurodegeneration, Hal, GIN, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), and HESAM Université (HESAM)-HESAM Université (HESAM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Oncology, Male, single nucleotide, Pathology, Genome-wide association study, leukoencephalopathies, polymorphisms, single nucleotide, Chromosomes, Human, Genetics (clinical), Aged, 80 and over, education.field_of_study, Continental Population Groups, cerebrovascular disorders, Middle Aged, White Matter, 3. Good health, Stroke, genetics [Stroke], Female, cerebral small vessel diseases, Alzheimer's disease, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, hypertension, Population, genetics [Chromosomes, Human], Article, Meta-Analysis as Topic, Internal medicine, Genetics, medicine, Dementia, Humans, ddc:610, 1000 Genomes Project, education, Genetic association, Aged, Intracerebral hemorrhage, genome-wide association study, Models, Genetic, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, Racial Groups, medicine.disease, ethnology [Stroke], Hyperintensity, Genetic Loci, pathology [Stroke], business, polymorphisms, Genome-Wide Association Study
Abstract: Background— The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies. Methods and Results— We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 ( P =2.7×10 −19 ) and identified novel loci on chr10q24 ( P =1.6×10 −9 ) and chr2p21 ( P =4.4×10 −8 ). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 ( P =2.0×10 −8 ) and chr2p16 ( P =1.5×10 −8 ). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16). Conclusions— We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.
Published: 2015

10. Common genetic variants influence human subcortical brain structures

Author: Hibar, Derrek P, Stein, Jason L, Aribisala, Benjamin S, de Zubicaray, Greig I, Dillman, Allissa, Duggirala, Ravi, Dyer, Thomas D, Erk, Susanne, Fedko, Iryna O, Ferrucci, Luigi, Foroud, Tatiana M, Fox, Peter T, Fukunaga, Masaki, Armstrong, Nicola J, Gibbs, J Raphael, Göring, Harald H H, Green, Robert C, Guelfi, Sebastian, Hansell, Narelle K, Hartman, Catharina A, Hegenscheid, Katrin, Heinz, Andreas, Hernandez, Dena G, Heslenfeld, Dirk J, Bernard, Manon, Hoekstra, Pieter J, Holsboer, Florian, Homuth, Georg, Hottenga, Jouke-Jan, Ikeda, Masashi, Jack, Clifford R, Jenkinson, Mark, Johnson, Robert, Kanai, Ryota, Keil, Maria, Bohlken, Marc M, Kent, Jack W, Kochunov, Peter, Kwok, John B, Lawrie, Stephen M, Liu, Xinmin, Longo, Dan L, McMahon, Katie L, Meisenzahl, Eva, Melle, Ingrid, Mohnke, Sebastian, Boks, Marco P, Montgomery, Grant W, Mostert, Jeanette C, Mühleisen, Thomas W, Nalls, Michael A, Nichols, Thomas E, Nilsson, Lars G, Nöthen, Markus M, Ohi, Kazutaka, Olvera, Rene L, Perez-Iglesias, Rocio, Bralten, Janita, Pike, G Bruce, Potkin, Steven G, Reinvang, Ivar, Reppermund, Simone, Rietschel, Marcella, Romanczuk-Seiferth, Nina, Rosen, Glenn D, Rujescu, Dan, Schnell, Knut, Schofield, Peter R, Brown, Andrew A, Smith, Colin, Steen, Vidar M, Sussmann, Jessika E, Thalamuthu, Anbupalam, Toga, Arthur W, Traynor, Bryan J, Troncoso, Juan, Turner, Jessica A, Valdés Hernández, Maria C, van 't Ent, Dennis, Chakravarty, M Mallar, van der Brug, Marcel, van der Wee, Nic J A, van Tol, Marie-Jose, Veltman, Dick J, Wassink, Thomas H, Westman, Eric, Zielke, Ronald H, Zonderman, Alan B, Ashbrook, David G, Hager, Reinmar, Chen, Qiang, Lu, Lu, McMahon, Francis J, Morris, Derek W, Williams, Robert W, Brunner, Han G, Buckner, Randy L, Buitelaar, Jan K, Cahn, Wiepke, Calhoun, Vince D, Cavalleri, Gianpiero L, Ching, Christopher R K, Crespo-Facorro, Benedicto, Dale, Anders M, Davies, Gareth E, Delanty, Norman, Depondt, Chantal, Djurovic, Srdjan, Drevets, Wayne C, Espeseth, Thomas, Gollub, Randy L, Ho, Beng-Choon, Renteria, Miguel E, Cuellar-Partida, Gabriel, Hoffmann, Wolfgang, Hosten, Norbert, Kahn, René S, Le Hellard, Stephanie, Meyer-Lindenberg, Andreas, Müller-Myhsok, Bertram, Nauck, Matthias, Nyberg, Lars, Pandolfo, Massimo, Penninx, Brenda W J H, den Braber, Anouk, Roffman, Joshua L, Sisodiya, Sanjay M, Smoller, Jordan W, van Bokhoven, Hans, van Haren, Neeltje E M, Völzke, Henry, Walter, Henrik, Weiner, Michael W, Wen, Wei, White, Tonya, Giddaluru, Sudheer, Agartz, Ingrid, Andreassen, Ole A, Blangero, John, Boomsma, Dorret I, Brouwer, Rachel M, Cannon, Dara M, Cookson, Mark R, de Geus, Eco J C, Deary, Ian J, Donohoe, Gary, Goldman, Aaron L, Fernández, Guillén, Fisher, Simon E, Francks, Clyde, Glahn, David C, Grabe, Hans J, Gruber, Oliver, Hardy, John, Hashimoto, Ryota, Hulshoff Pol, Hilleke E, Jönsson, Erik G, Grimm, Oliver, Kloszewska, Iwona, Lovestone, Simon, Mattay, Venkata S, Mecocci, Patrizia, McDonald, Colm, McIntosh, Andrew M, Ophoff, Roel A, Paus, Tomas, Pausova, Zdenka, Ryten, Mina, Guadalupe, Tulio, Sachdev, Perminder S, Saykin, Andrew J, Simmons, Andy, Singleton, Andrew, Soininen, Hilkka, Wardlaw, Joanna M, Weale, Michael E, Weinberger, Daniel R, Adams, Hieab H H, Launer, Lenore J, Hass, Johanna, Seiler, Stephan, Schmidt, Reinhold, Chauhan, Ganesh, Satizabal, Claudia L, Becker, James T, Yanek, Lisa, van der Lee, Sven J, Ebling, Maritza, Fischl, Bruce, Longstreth, W. T., Woldehawariat, Girma, Greve, Douglas, Schmidt, Helena, Nyquist, Paul, Vinke, Louis N, van Duijn, Cornelia M, Xue, Luting, Mazoyer, Bernard, Bis, Joshua C, Gudnason, Vilmundur, Seshadri, Sudha, Holmes, Avram J, Ikram, M Arfan, Initiative, Alzheimer’s Disease Neuroimaging, Consortium, CHARGE, EPIGEN, IMAGEN, SYS, Martin, Nicholas G, Wright, Margaret J, Schumann, Gunter, Franke, Barbara, Hoogman, Martine, Thompson, Paul M, Medland, Sarah E, Weiner, Michael, Aisen, Paul, Petersen, Ronald, Jagust, William, Trojanowki, John Q, Beckett, Laurel, Arias-Vasquez, Alejandro, Janowitz, Deborah, Morris, John, Shaw, Leslie M, Khachaturian, Zaven, Sorensen, Greg, Carrillo, Maria, Kuller, Lew, Raichle, Marc, Paul, Steven, Jia, Tianye, Davies, Peter, Fillit, Howard, Hefti, Franz, Holtzman, Davie, Mesulman, M Marcel, Potter, William, Snyder, Peter, Schwartz, Adam, Montine, Tom, Kim, Sungeun, Thomas, Ronald G, Donohue, Michael, Walter, Sarah, Gessert, Devon, Sather, Tamie, Jiminez, Gus, Harvey, Danielle, Klein, Marieke, Bernstein, Matthew, Fox, Nick, Thompson, Paul, Schuff, Norbert, DeCarli, Charles, Borowski, Bret, Gunter, Jeff, Senjem, Matt, Kraemer, Bernd, Vemuri, Prashanthi, Jones, David, Kantarci, Kejal, Ward, Chad, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Lee, Phil H, Landau, Susan, Cairns, Nigel J, Householder, Erin, Taylor-Reinwald, Lisa, Trojanowki, J. Q., Shaw, Les, Lee, Virginia M Y, Korecka, Magdalena, Figurski, Michal, Olde Loohuis, Loes M, Crawford, Karen, Neu, Scott, Potkin, Steven, Shen, Li, Faber, Kelley, Nho, Kwangsik, Luciano, Michelle, Thal, Leon, Frank, Richard, Snyder, Peter J, Buckholtz, Neil, Macare, Christine, Albert, Marilyn, Hsiao, John, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Carter, Raina, Dolen, Sara, Gutman, Boris A, Schneider, Lon S, Mather, Karen A, Pawluczyk, Sonia, Beccera, Mauricio, Teodoro, Liberty, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Fleisher, Adam, Heidebrink, Judith L, Lord, Joanne L, Desrivières, Sylvane, Mattheisen, Manuel, Mason, Sara S, Albers, Colleen S, Knopman, David, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Rountree, Susan, Dang, Mimi, Stern, Yaakov, Milaneschi, Yuri, Honig, Lawrence S, Bell, Karen L, Ances, Beau, Morris, John C, Carroll, Maria, Leon, Sue, Mintun, Mark A, Schneider, Stacy, Oliver, Angela, Marson, Daniel, Griffith, Randall, Clark, David, Geldmacher, David, Brockington, John, Roberson, Erik, Grossman, Hillel, Mitsis, Effie, deToledo-Morrell, Leyla, Shah, Raj C, Papmeyer, Martina, Duara, Ranjan, Varon, Daniel, Greig, Maria T, Roberts, Peggy, Onyike, Chiadi, D'Agostino, Daniel, Kielb, Stephanie, Galvin, James E, Pogorelec, Dana M, Ramasamy, Adaikalavan, Cerbone, Brittany, Michel, Christina A, Rusinek, Henry, de Leon, Mony J, Glodzik, Lidia, De Santi, Susan, Doraiswamy, P Murali, Petrella, Jeffrey R, Wong, Terence Z, Arnold, Steven E, Risacher, Shannon L, Karlawish, Jason H, Wolk, David, Smith, Charles D, Jicha, Greg, Hardy, Peter, Sinha, Partha, Oates, Elizabeth, Conrad, Gary, Lopez, Oscar L, Oakley, MaryAnn, Roiz-Santiañez, Roberto, Simpson, Donna M, Porsteinsson, Anton P, Goldstein, Bonnie S, Martin, Kim, Makino, Kelly M, Ismail, M Saleem, Brand, Connie, Mulnard, Ruth A, Thai, Gaby, Mc-Adams-Ortiz, Catherine, Rose, Emma J, Womack, Kyle, Mathews, Dana, Quiceno, Mary, Diaz-Arrastia, Ramon, King, Richard, Weiner, Myron, Martin-Cook, Kristen, DeVous, Michael, Levey, Allan I, Lah, James J, Salami, Alireza, Cellar, Janet S, Burns, Jeffrey M, Anderson, Heather S, Swerdlow, Russell H, Apostolova, Liana, Tingus, Kathleen, Woo, Ellen, Silverman, Daniel H S, Lu, Po H, Bartzokis, George, Sämann, Philipp G, Graff-Radford, Neill R, Parfitt, Francine, Kendall, Tracy, Johnson, Heather, Farlow, Martin R, Hake, Ann Marie, Matthews, Brandy R, Herring, Scott, Hunt, Cynthia, van Dyck, Christopher H, Jahanshad, Neda, Schmaal, Lianne, Carson, Richard E, MacAvoy, Martha G, Chertkow, Howard, Bergman, Howard, Hosein, Chris, Black, Sandra, Stefanovic, Bojana, Caldwell, Curtis, Hsiung, Yuek Robin, Feldman, Howard, Schork, Andrew J, Mudge, Benita, Assaly, Michele, Kertesz, Andrew, Rogers, John, Trost, Dick, Bernick, Charles, Munic, Donna, Kerwin, Diana, Mesulam, Marek-Marsel, Lipowski, Kristine, Shin, Jean, Wu, Chuang-Kuo, Johnson, Nancy, Sadowsky, Carl, Martinez, Walter, Villena, Teresa, Turner, Raymond Scott, Johnson, Kathleen, Reynolds, Brigid, Sperling, Reisa A, Johnson, Keith A, Strike, Lachlan T, Marshall, Gad, Frey, Meghan, Yesavage, Jerome, Taylor, Joy L, Lane, Barton, Rosen, Allyson, Tinklenberg, Jared, Sabbagh, Marwan N, Belden, Christine M, Jacobson, Sandra A, Teumer, Alexander, Sirrel, Sherye A, Kowall, Neil, Killiany, Ronald, Budson, Andrew E, Norbash, Alexander, Johnson, Patricia Lynn, Obisesan, Thomas O, Wolday, Saba, Allard, Joanne, Lerner, Alan, van Donkelaar, Marjolein M J, Ogrocki, Paula, Hudson, Leon, Fletcher, Evan, Carmichael, Owen, Olichney, John, Kittur, Smita, Borrie, Michael, Lee, T-Y, Bartha, Rob, van Eijk, Kristel R, Johnson, Sterling, Asthana, Sanjay, Carlsson, Cynthia M, Preda, Adrian, Nguyen, Dana, Tariot, Pierre, Reeder, Stephanie, Bates, Vernice, Walters, Raymond K, Capote, Horacio, Rainka, Michelle, Scharre, Douglas W, Kataki, Maria, Adeli, Anahita, Zimmerman, Earl A, Celmins, Dzintra, Brown, Alice D, Pearlson, Godfrey D, Blank, Karen, Westlye, Lars T, Anderson, Karen, Santulli, Robert B, Kitzmiller, Tamar J, Schwartz, Eben S, Sink, Kaycee M, Williamson, Jeff D, Garg, Pradeep, Watkins, Franklin, Ott, Brian R, Querfurth, Henry, Whelan, Christopher D, Tremont, Geoffrey, Salloway, Stephen, Malloy, Paul, Correia, Stephen, Rosen, Howard J, Miller, Bruce L, Mintzer, Jacobo, Spicer, Kenneth, Bachman, David, Finger, Elizabether, Toro, Roberto, Winkler, Anderson M, Pasternak, Stephen, Rachinsky, Irina, Drost, Dick, Pomara, Nunzio, Hernando, Raymundo, Sarrael, Antero, Schultz, Susan K, Ponto, Laura L Boles, Zwiers, Marcel P, Shim, Hyungsub, Smith, Karen Elizabeth, Relkin, Norman, Chaing, Gloria, Raudin, Lisa, Smith, Amanda, Fargher, Kristin, Raj, Balebail Ashok, Amin, Najaf, Becker, Diane, Alhusaini, Saud, Beiser, Alexa, Debette, Stéphanie, DeStefano, Anita, Hofer, Edith, Hofman, Albert, Niessen, Wiro J, Smith, Albert, Tzourio, Christophe, Vaidya, Dhananjay, Athanasiu, Lavinia, Vernooij, Meike W, Goldstein, David B, Heinzen, Erin L, Shianna, Kevin, Radtke, Rodney, Ottmann, Ruth, Albrecht, Lisa, Andrew, Chris, Arroyo, Mercedes, Artiges, Eric, Ehrlich, Stefan, Aydin, Semiha, Bach, Christine, Banaschewski, Tobias, Barbot, Alexis, Barker, Gareth, Boddaert, Nathalie, Bokde, Arun, Bricaud, Zuleima, Bromberg, Uli, Bruehl, Ruediger, Hakobjan, Marina M H, Büchel, Christian, Cachia, Arnaud, Cattrell, Anna, Conrod, Patricia, Constant, Patrick, Crombag, Hans, Czech, Katharina, Dalley, Jeffrey, Decideur, Benjamin, Desrivieres, Sylvane, Hartberg, Cecilie B, Fadai, Tahmine, Flor, Herta, Frouin, Vincent, Fuchs, Birgit, Gallinat, Jürgen, Garavan, Hugh, Briand, Fanny Gollier, Gowland, Penny, Head, Kay, Heinrichs, Bert, Haukvik, Unn K, Heym, Nadja, Hübner, Thomas, Ihlenfeld, Albrecht, Ireland, James, Ittermann, Bernd, Ivanov, Nikolay, Jones, Jennifer, Klaassen, Arno, Heister, Angelien J G A M, Lalanne, Christophe, Lathrop, Mark, Lanzerath, Dirk, Lemaitre, Hervé, Lüdemann, Katharina, Mallik, Catherine, Mangin, Jean-François, Mann, Karl, Mar, 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Helen, Whelan, Robert, Williams, Steve, Yacubian, Juliana, Ziesch, Veronika, Zilbovicius, Monica, Wong, C Peng, Lubbe, Steven, Naber, Marlies A M, Martinez-Medina, Lourdes, Kepa, Agnes, Fernandes, Alinda, Tahmasebi, Amir, Abrahamowicz, Michal, Gaudet, Daniel, Leonard, Gabriel, Perron, Michel, Richer, Louis, Seguin, Jean, McKay, D Reese, Veillette, Suzanne, Needham, Margaret, Nugent, Allison C, Pütz, Benno, Abramovic, Lucija, Royle, Natalie A, Sprooten, Emma, Trabzuni, Daniah, van der Marel, Saskia S L, van Hulzen, Kimm J E, Walton, Esther, Wolf, Christiane, Almasy, Laura, Ames, David, Andersson, Micael, Arepalli, Sampath, Assareh, Amelia A, Bastin, Mark E, Brodaty, Henry, Bulayeva, Kazima B, Carless, Melanie A, Cichon, Sven, Corvin, Aiden, Curran, Joanne E, Czisch, Michael, MUMC+: DA Klinische Genetica (5), RS: GROW - Developmental Biology, RS: GROW - R4 - Reproductive and Perinatal Medicine, Université de Montréal. Faculté de médecine. Département de psychiatrie et d'addictologie, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), QIMR Berghofer Medical Research Institute, Department of Psychiatry, Donders Centre for Neuroscience, Radboud University [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud University [Nijmegen]-Radboud University Medical Center [Nijmegen], Department of Human Genetics, Radboud University Medical Center [Nijmegen], Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, PRES Sorbonne Paris Cité, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Gènes, Synapses et Cognition (CNRS - UMR3571 ), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Greifswald University Hospital, University Medical Center [Utrecht], European Commission, University of Edinburgh, Lagos State University (LASU), Heriot-Watt University [Edinburgh] (HWU), Unité d'expérimentation sur les Ruminants de Theix, Institut National de la Recherche Agronomique (INRA), Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], University of Oslo (UiO), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], School of Technical Physics, Xidian University, Dept. of Mechanical Engineering, McMaster University [Hamilton, Ontario], Biological Psychology, Neuroscience Campus Amsterdam & EMGO Institute for Health and Care Research, VU University & VU Medical Center, Amsterdam 1081 BT, The Netherlands, Haukeland University Hospital, University of Bergen (UiB), Physicochimie des Processus de Combustion et de l’Atmosphère - UMR 8522 (PC2A), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Universität Heidelberg [Heidelberg] = Heidelberg University, Language and Genetics Department [Nijmegen], Max Planck Institute for Psycholinguistics, Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, International Max Planck Research School for Language Sciences (IMPRS ), Georgia Institute of Technology [Atlanta], National Institutes of Health [Bethesda] (NIH), Yale University [New Haven], Massachusetts General Hospital [Boston], Mental Health Sciences Unit, University College of London [London] (UCL), Beijing Normal University (BNU), Indiana University School of Medicine, Indiana University System, Indiana Alzheimer Disease Center, Indiana University System-Indiana University System, Center for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center, Goettingen 37075, Germany, Scottish Fish Immunology Research Centre, School of Biological Sciences, University of Aberdeen, University of California (UC), Medstar Research Institute, Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia, Department of Genomics, Life and Brain Center, Universität Bonn = University of Bonn, Institute of Human Genetics, Department of Biomedicine and the Centre for Integrative Sequencing, Aarhus University [Aarhus], VU University Medical Center [Amsterdam], Respiratory Epidemiology and Public Health, Imperial College London-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU)-MRC-HPA Centre for Environment and Health, Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Institut Parisien de Chimie Moléculaire (IPCM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Umeå Centre for Functional Brain Imaging (UFBI), Umeå University, Umeå 901 87, Sweden, Aging Research Center [Karolinska Institutet] (ARC ), Stockholm University-Karolinska Institutet [Stockholm], Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Department of Neurosciences [Univ California San Diego] (Neuro - UC San Diego), School of Medicine [Univ California San Diego] (UC San Diego), University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), Department of Cognitive Sciences [Univ California San Diego] (CogSci - UC San Diego), The Hospital for sick children [Toronto] (SickKids), Queensland Institute of Medical Research, School of Psychology, University of Queensland, Brisbane 4072, Australia, University of Queensland [Brisbane], Centre for Advanced Imaging, University of Queensland, Brisbane 4072, Australia, Department of Genomics of Common Disease, Imperial College London, Department of Psychology [Oslo], Faculty of Social Sciences [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Deutsche Bundesbank, Department of Neurology and Neurosurgery [Montreal], McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland (RCSI), MetaGenoPolis, Department of Psychiatric Research and Development, Diakonhjemmet Hospital, Oslo 0319, Norway, UCL Institute of Neurology and Epilepsy Society, Department of Medicine, Clinical And Experimental Epilepsy, Dpt of Psychiatry [New Haven], Yale School of Medicine [New Haven, Connecticut] (YSM), Hartford Hospital, Neuropsychiatric Genetics Research Group and Department of Psychiatry, Trinity College Institute of Psychiatry, Trinity College Dublin, Dublin 2, Ireland, Institute of Food & Health, University College Dublin, University College Dublin [Dublin] (UCD), Statistical Genetics Group, State Key Laboratory of Lead Compound Research, WuXi AppTec, Co., Ltd, Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL, Institute of Neurology [London], Department of Genetics, King Faisal Specialist Hospital and Research Centre (KFSH & RC), Centre épigénétique et destin cellulaire (EDC), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Dundee Technopole, CXR Biosciences Ltd, Ninewells Hospital and Medical School, Biomedical Research Centre, University of Dundee, Southwest Foundation for Biomedical Research, Department of Psychiatry and National Ageing Research Institute, University of Melbourne, Department of Clinical Genetics, Department of Medical Parasitology and Mycology, School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU)-Tehran University of Medical Siences, Centre for Healthy Brain Ageing, University of New South Wales [Sydney] (UNSW), Dementia Collaborative Research Centre, N.I. Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119333, Russia, Texas Biomedical Research Institute [San Antonio, TX], Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Division of Medical Genetics, University of Basel (Unibas), Trinity College Dublin-St. James's Hospital, Neuropsychiatric Genetics Research Group, Trinity College Dublin, Department of Materials Science & Metallurgy, University of Cambridge [UK] (CAM), Bijvoet Center of Biomolecular Research [Utrecht], Utrecht University [Utrecht], School of Psychology, University of Queensland, Laboratory of Neurogenetics, The University of Texas Health Science Center at Houston (UTHealth), Department of Genomics, Department of Medical and Molecular Genetics, South Texas Veterans Health Care System, San Antonio, Texas 78229, USA, Biofunctional Imaging, Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan, Public Health Genomics Unit, Department of Biomolecular Engineering, Rheinische Friedrich-Wilhelms-Universität Bonn, Estación Experimental de Pastos y Forrajes 'Indio Hatuey', University Medical Center Groningen [Groningen] (UMCG), Neuronal Plasticity / Mouse Behaviour, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Department of Psychiatry, Fujita Health University School of Medicine, Toyoake 470-1192, Japan, Department of Radiology, Mayo Clinic, Department of Clinical Neurology [Oxford], University of Oxford-FMRIB Centre- John Radcliffe Hospital [Oxford University Hospital], University of Maryland School of Medicine, University of Maryland System, University of Sussex, Institute of Cognitive Neuroscience, United Kingdom Met Office [Exeter], University of Maryland [Baltimore County] (UMBC), University of Maryland System-University of Maryland System-University of Maryland School of Medicine, Department of Civil and Structural Engineering, The Hong Kong Polytechnic University [Hong Kong] (POLYU)-The Hong Kong Polytechnic University [Hong Kong] (POLYU), Columbia University Irving Medical Center (CUIMC), Lymphocyte Cell Biology Unit, Laboratory of Genetics, Centre for Advanced Imaging, Psychiatry and Psychotherapy, KG Jebsen Centre for Psychosis Research, University of Oslo (UiO)-Institute of Clinical Medicine-Oslo University Hospital [Oslo], Division of Mental Health and Addiction, Oslo University Hospital [Oslo], Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Genetic Epidemiology Unit, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Department of Statistics [Warwick], University of Warwick [Coventry], Osaka University [Osaka], Institute of Psychiatry, King’s College London, London SE5 8AF, UK, University of Calgary, Psychiatry and Human Behavior, University of California, Irvine, California 92617, USA, University of California [Irvine] (UC Irvine), Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health [Mannheim], University Hospital Mannheim | Universitätsmedizin Mannheim-University Hospital Mannheim | Universitätsmedizin Mannheim, Space and Naval Warfare Systems Center, Klinik für Psychiatrie, Martin-Luther-University Halle-Wittenberg, Department of Psychiatry, Division of Medical Psychology, Genetics of Mental Illness and Brain Function, Neuroscience Research Australia, Développement et amélioration des plantes (UMR DAP), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney 2052, Australia, Laboratory of Neuro Imaging [Los Angeles] (LONI), Departamento de Física Aplicada, Universidade de Vigo, Georgia State University, University System of Georgia (USG), Genentech, Inc. [San Francisco], Psychiatry and Leiden Institute for Brain and Cognition, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Universiteit Leiden, Carver College of Medicine [Iowa City], University of Iowa [Iowa City]-University of Iowa [Iowa City], Department of Neurobiology, Care Sciences and Society, Karolinska Institutet [Stockholm], University of Manchester [Manchester], The University of Tennessee Health Science Center [Memphis] (UTHSC), iangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College of Nantong University, Nantong 226001, China, Centre for Ultrahigh Bandwidth Devices for Optical Systems (CUDOS), Macquarie University, Cognitive Neuroscience Laboratory (CNL), Harvard University, Donders Center for Cognitive Neuroimaging, Donders Centre for Cognitive Neuroimaging, Radboud University [Nijmegen]-Radboud University [Nijmegen], Icahn School of Medicine at Mount Sinai [New York] (MSSM), The Mind Research Network, Department of Electrical and Computer Engineering [Albuquerque] (ECE Department), The University of New Mexico [Albuquerque], Division of Molecular and Cellular Therapeutics, Scottish Association for Marine Science (SAMS), Structural Biology Laboratory, Department of Chemistry, University of York, Neurology Division, Beaumont Hospital, Dublin 9, Ireland, Beaumont Hospital, Department of Neurology, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Deparment of Medical Genetics, Human Genetics Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH), Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Department of Psychiatry, University of Iowa, University of Iowa [Iowa City], Institute for Community Medicine, Department Epidemiology of Health Care and Community Health, Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig-Universität Leipzig, Institute of Clinical Chemistry and Laboratory Medicine, Department of Health Science, Division of Health and Rehabilitation, Luleå University of Technology (LUT), Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Psychiatric and Neurodevelopmental Genetics Unit, 849 Department of Human Genetics, Institute for Community Medicine, Institute for Energy Systems and Thermodynamics, Renyi Institute, Neuropsychiatric Institute, Prince of Wales Hospital, Randwick, NSW, Department of Child and Adolescent Psychiatry, Erasmus University Medical Centre, Rotterdam 3000 CB, The Netherlands, Department of Radiology, Erasmus University Medical Centre, Rotterdam 3015 CN, The Netherlands, Vrije Universiteit Amsterdam [Amsterdam] (VU), Cell Biology and Gene Expression Section, National Institute of Health, Bethesda, Dept of Psychology, Laboratoire de Recherche Magellan, Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Institut d'Administration des Entreprises (IAE) - Lyon, Institut de Socio-économie des Entreprises et des ORganisations (ISEOR), Institut de socio-économie des entreprises et des organisations, Department of Psychiatry and Psychotherapy, HELIOS Klinikum Stralsund Hanseatic-Greifswald University Hospital, Laboratoire d'Informatique de Grenoble (LIG), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS), Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Centre for Allergy Research, Department of Medicine, Clinical Pharmacology Unit, Karolinska University Hospital [Stockholm], Medical University of Łódź (MUL), Psychiatry Institute, Department of Health and Human Services, Institute of Gerontology and Geriatrics, Università degli Studi di Perugia = University of Perugia (UNIPG), Commonwealth Scientific and Industrial Research Organisation [Canberra] (CSIRO), Australian Centre for Research into Injury in Sport and its Prevention, Monash University [Clayton], University Medical Center [Utrecht]-Brain Center Rudolf Magnus, School of Psychology [Nottingham], University of Nottingham, UK (UON), McConnell Brain Imaging Centre (MNI), SickKids - The Hospital for sick children, European Centre for Medium-Range Weather Forecasts (ECMWF), University of Eastern Finland, Centre for Population Health Sciences, Lieber Institute for Brain Development [Baltimore] (LIBD), Johns Hopkins University (JHU), Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Graz 8010, Austria, Austrian Institute of Technology [Vienna] (AIT), INSERM Research Center for Epidemiology and Biostatistics (U897) Team Neuroepidemiology, Bordeaux, France College of Health Sciences, University of Bordeaux, Bordeaux, France, INSERM, Neuroepidemiology U708, Bordeaux, France, Karlsruhe Institute of Technology (KIT), General Internal Medicine, Johns Hopkins School of Medicine, Johns Hopkins University School of Medicine [Baltimore], Harvard Medical School [Boston] (HMS), Computer Science and Artificial Intelligence Laboratory [Cambridge] (CSAIL), Massachusetts Institute of Technology (MIT), University of Washington [Seattle], Department of Physics [Stockholm], Stockholm University, Center for Medical Systems Biology, Netherlands Genomics Initiative, Leiden University Medical Center, Leiden, The Netherlands, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Boston University [Boston] (BU), Groupe d'Imagerie Neurofonctionnelle (GIN - UMR 5296), Service NEUROSPIN (NEUROSPIN), 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)-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)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Faculty of Medicine, University of Iceland [Reykjavik], Icelandic Heart Association, Kopavogur, Iceland., Boston University School of Medicine (BUSM), Laboratoire d'Ingénierie des Matériaux de Bretagne (LIMATB), Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université de Brest (UBO), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University of California-University of California, Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen], Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Gènes, Synapses et Cognition, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), UE 1354 Unité d'expérimentation sur les Ruminants de Theix, Institut National de la Recherche Agronomique (INRA)-Physiologie Animale et Systèmes d'Elevage (PHASE), Institut National de la Recherche Agronomique (INRA)-Unité d'expérimentation sur les Ruminants de Theix (UE RT), Radboud university [Nijmegen], McGill University, University of Bergen (UIB), Universität Heidelberg [Heidelberg], Beijing Normal University, University of California, University of Bonn, Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Department of Neurosciences [San Diego], Department of Cognitive Sciences [San Diego], The Hospital for Sick Children, University of Toronto, Toronto M5G 1X8, Canada, McGill University-McGill University, US 1367 MetaGénoPolis, Institut National de la Recherche Agronomique (INRA)-Département Microbiologie et Chaîne Alimentaire (MICA), Institut National de la Recherche Agronomique (INRA)-MetaGénoPolis (MGP), Yale University School of Medicine, King Faisal Specialist Hospital and Research Centre, Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Texas Biomedical Research Institute [San Antonio, Texas], Bijvoet Center of Biomolecular Research, Academic Unit for Psychiatry of Old Age, University of Melbourne, Melbourne 3101, Australia, Department of Genomics, Life & Brain Center, University of Bonn, Bonn D-53127, Germany, University of Oxford [Oxford]-FMRIB Centre- John Radcliffe Hospital [Oxford University Hospital], School of Psychology, University of Sussex, Brighton BN1 9QH, UK, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Department of Neurology [University of Calgary], Department of Clinical Neuroscience [University of Calgary], University of California [Irvine] (UCI), Medical Faculty [Mannheim]-Medical Faculty [Mannheim], Centre National de la Recherche Scientifique (CNRS)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Recherche Agronomique (INRA)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Universidate de Vigo, Harvard University [Cambridge], Radboud university [Nijmegen]-Radboud university [Nijmegen], Université Libre de Bruxelles [Bruxelles] (ULB)-Hôpital Erasme (Bruxelles), Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], Centre de Recherche Magellan, Institut d'Administration des Entreprises (IAE) - Lyon-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon, Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Università degli Studi di Perugia (UNIPG), Department of neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland, Department of neurology, University of Eastern Finland-University Hospital of Kuopio-University of Eastern Finland-University Hospital of Kuopio, Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Service NEUROSPIN (NEUROSPIN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université de Bretagne Sud (UBS)-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université de Brest (UBO)-Université de Brest (UBO), The Alzheimer’s Disease Neuroimaging Initiative, The CHARGE Consortium, EPIGEN, IMAGEN, SYS, Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen], Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), FMRIB Centre- John Radcliffe Hospital [Oxford University Hospital]-University of Oxford [Oxford], Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF), 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)-Université Paris-Saclay, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut Pasteur [Paris], Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), University of Oxford [Oxford]- John Radcliffe Hospital [Oxford University Hospital]-FMRIB Centre, Neurology, Psychiatry, Anatomy and neurosciences, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, Biological Psychology, Cognitive Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Neuroscience Campus Amsterdam - Brain Imaging Technology, EMGO+ - Mental Health, Child and Adolescent Psychiatry / Psychology, Epidemiology, Radiology & Nuclear Medicine, Laboratory of Neuro Imaging, David Geffen School of Medicine, University of California, Los Angeles, California, USA, Donders Centre for Neuroscience, Radboud University Nijmegen Medical Centre, MRC- SGDP Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK, Génétique humaine et Fonctions cognitives - Human Genetics and Cognitive Functions, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), German Center for Neurodegenerative Diseases (DZNE) Rostock/Greifswald, Greifswald 17487, Germany, Department of Psychiatry, University Medicine Greifswald, Greifswald 17489, Germany, Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands, Brain Research Imaging Centre, University of Edinburgh, Edinburgh EH4 2XU, UK, Department of Computer Science, Lagos State University, Lagos, Nigeria, Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) Collaboration, Department of Neuroimaging Sciences, University of Edinburgh, Edinburgh EH4 2XU, UK, Heriot-Watt University [Edinburgh] ( HWU ), Institut National de la Recherche Agronomique ( INRA ) -Physiologie Animale et Systèmes d'Elevage ( PHASE ) -Unité d'expérimentation sur les Ruminants de Theix ( UE RT ), Department of Human Genetics, Radboud university medical center, Nijmegen 6500 HB, The Netherlands, Department of Cognitive Neuroscience, Radboud university medical center, Nijmegen 6500 HB, The Netherlands, NORMENT - KG Jebsen Centre, Institute of Clinical Medicine, University of Oslo, Oslo N-0316, Norway, NORMENT - KG Jebsen Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo 0424, Norway, Montreal Neurological Institute [Montréal], NORMENT - KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway, Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen 5021, Norway, Physicochimie des Processus de Combustion et de l’Atmosphère - UMR 8522 ( PC2A ), Université de Lille-Centre National de la Recherche Scientifique ( CNRS ), Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen 6525 XD, The Netherlands, International Max Planck Research School for Language Sciences, Nijmegen 6525 XD, The Netherlands, Human Genetics Branch and Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health Intramural Research Program, Bethesda, Maryland 20892, USA, Department of Psychology, Yale University, New Haven, Connecticut 06511, USA, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02115, USA, University College of London [London] ( UCL ), Center for Neuroimaging, Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA, Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA, Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA, Center for Neurobehavioral Genetics, University of California, Los Angeles, California 90095, USA, Université de Bonn, Department of Psychiatry, Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest, Amsterdam 1081 HL, The Netherlands, Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh EH10 5HF, UK, Imperial College London-School of public health-MRC-HPA Centre for Environment and Health, Cibersam (Centro Investigación Biomédica en Red Salud Mental), Madrid 28029, Spain, Institut Parisien de Chimie Moléculaire ( IPCM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), Aging Research Center [Karolinska Institutet] ( ARC ), Max Planck Institute of Psychiatry, Munich 80804, Germany, Multimodal Imaging Laboratory, Department of Neurosciences, University of California, San Diego, California 92093, USA, Department of Cognitive Sciences, University of California, San Diego, California 92161, USA, Genetic Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland, Australia, Department of Psychology, University of Oslo, Oslo 0373, Norway, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal H3A 2B4, Canada, Molecular and Cellular Therapeutics, The Royal College of Surgeons, Dublin 2, Ireland, Institut National de la Recherche Agronomique ( INRA ) -MetaGénoPolis ( MGP ) -Microbiologie et Chaîne Alimentaire ( MICA ), UCL Institute of Neurology, London, United Kingdom and Epilepsy Society, London WC1N 3BG, UK, Department of Medicine, Imperial College London, London W12 0NN, UK, Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK, Yale School of Medicine, Olin Neuropsychiatric Research Center, Institute of Living, Hartford Hospital, Hartford, Connecticut 06106, USA, University College Dublin [Dublin] ( UCD ), Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK, Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia, Centre épigénétique et destin cellulaire ( EDC ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), School of public health-Tehran University of Medical Siences, University of New South Wales [Sydney] ( UNSW ), Texas Biomedical Research Institute, San Antonio, Texas 78245, USA, Institute of Neuroscience and Medicine ( INM-1 ), University of Basel ( Unibas ), Cambridge University, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA, University of Texas Health Science Center, San Antonio, Texas 78229, USA, Clinical Research Branch, National Institute on Aging, Baltimore, Maryland 20892, USA, Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald 17475, Germany, University Medical Center Groningen, University of Groningen, University of Greifswald, Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA, NICHD Brain and Tissue Bank for Developmental Disorders, University of Maryland Medical School, Baltimore, Maryland 21201, USA, nstitute of Cognitive Neuroscience, University College London, London WC1N 3AR, UK, Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland, Baltimore, Maryland 21201, USA, Department of Pathology and Cell Biology, Columbia University Medical Center, New York 10032, USA, Lymphocyte Cell Biology Unit, Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA, University of Oslo ( UiO ) -Institute of Clinical Medicine-Oslo University Hospital, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo ( UiO ) -European Network of Bipolar Research Expert Centers (ENBREC) Group, Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, CCM, Berlin 10117, Germany, Erasmus MC, Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, National Institutes of Health (NIH), Bethesda, Maryland, USA, Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA, Central Institute of Mental Health, UMR 1098 Développement et Amélioration des Plantes, Institut National de la Recherche Agronomique ( INRA ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -MontpellierSupAgro ( MontpellierSupAgro ) -Génétique et amélioration des plantes ( G.A.P. ) -Développement et Amélioration des Plantes ( DAP ), Laboratory of Neuro Imaging [Los Angeles] ( LONI ), University of California at Los Angeles [Los Angeles] ( UCLA ), Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH4 2XU, UK, Genentech, South San Francisco, California 94080, USA, Psychiatry and Leiden Institute for Brain and Cognition, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands, LUMC, Carver College of Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm SE-141 83, Sweden, Behavioral Epidemiology Section, National Institute on Aging Intramural Research Program, Baltimore, Maryland 20892, USA, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK, Center for Integrative and Translational Genomics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA, Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA, Centre Interlangues - Texte, Image, Langage ( TIL ), Université de Bourgogne ( UB ), Centre for Ultrahigh Bandwidth Devices for Optical Systems ( CUDOS ), Icahn School of Medicine at Mount Sinai [New York], The Mind Research Network & LBERI, Albuquerque, New Mexico 87106, USA, Department of ECE, University of New Mexico, Albuquerque, New Mexico 87131, USA, Scottish Association for Marine Science ( SAMS ), Department of Neurology, Hopital Erasme, Universite Libre de Bruxelles, Brussels 1070, Belgium, National Institutes of Health ( NIH ) -National Institute of Mental Health (NIMH), Harvard Medical School [Boston] ( HMS ) -Massachusetts General Hospital [Boston], Department of Psychiatry, University of Iowa, Iowa City, Iowa 52242, USA, Luleå University of Technology ( LUT ), Broad Institute of MIT and Harvard, Massachusetts General Hospital, Vrije Universiteit Amsterdam [Amsterdam] ( VU ), Université Jean Moulin - Lyon III-Institut d'Administration des Entreprises (IAE) - Lyon, Institut de Socio-économie des Entreprises et des ORganisations ( ISEOR ), University Medicine Greifswald,-HELIOS Hospital Stralsund, Laboratoire d'Informatique de Grenoble ( LIG ), Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut National Polytechnique de Grenoble ( INPG ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University, Osaka 565-0871, Japan, Karolinska University Hospital (Solna), Medical University of Łódź ( MUL ), National Institutes of Health ( NIH ), University of Perugia, Commonwealth Scientific and Industrial Research Organisation, University Medical Center Utrecht-Brain Center Rudolf Magnus, University of Nottingham, UK ( UON ), McConnell Brain Imaging Centre ( MNI ), The Hospital for sick children [Toronto] ( SickKids ), Department of Medical and Molecular Genetics, King’s College London, London SE1 9RT, UK, European Centre for Medium-Range Weather Forecasts ( ECMWF ), Lieber Institute for Brain Development, Baltimore, Maryland 21205, USA, Departments of Psychiatry, Neurology, Neuroscience and the Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique ( CNRS ), Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands, Austrian Institute of Technology [Vienna] ( AIT ), Karlsruhe Institute of Technology ( KIT ), General Internal Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA, Department of Radiology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA, Computer Science and Artificial Intelligence Laboratory [Cambridge] ( CSAIL ), Massachusetts Institute of Technology ( MIT ), Department of Epidemiology, University of Washington, Seattle, Washington, USA, Department of Neurology, University of Washington, Seattle, Washington, USA, Department of Physics, Stockholm University ( Department of Physics, Stockholm University ), Université de Lille, Sciences Humaines et Sociales, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA, Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands, Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA, Groupe d'Imagerie Neurofonctionnelle ( GIN - UMR 5296 ), Service NEUROSPIN ( NEUROSPIN ), Direction de Recherche Fondamentale (CEA) ( DRF (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) ( DRF (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université de Bordeaux ( UB ), Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA, Faculty of Medicine, University of Iceland, Reykjavik, Iceland, Department of Neurology, Boston University School of Medicine, Framingham Heart Study, Boston, MA, Department of Neurology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands, Laboratoire d'Ingénierie des Matériaux de Bretagne ( LIMATB ), Université de Bretagne Sud ( UBS ) -Institut Brestois du Numérique et des Mathématiques ( IBNM ), Université de Brest ( UBO ) -Université de Brest ( UBO ) -Université de Brest ( UBO ), King's College, Department of Psychiatry, Radboud university medical center, Nijmegen 6500 HB, The Netherlands, and Broad Institute of © 2012 Nature America, Inc. All rights reserved. Nature Ge N etics aDV a NCE ONLINE PUBLIC a TION 7 l e t t e r s Harvard and MIT, Cambridge, Massachusetts, US
Subjects: CHROMATIN, Male, Netherlands Twin Register (NTR), Aging, Identification, nervous-system, human geography, SEGMENTATION, Caudate nucleus, Apoptosis, Expression, Genome-wide association study, Striatum, Hippocampal formation, Hippocampus, BASAL GANGLIA, 130 000 Cognitive Neurology & Memory, Basal ganglia, genetics [Gene Expression Regulation, Developmental], Hippocampal, Child, anatomy & histology [Skull], Aged, 80 and over, Genetics, Sex Characteristics, KINECTIN, Genome-wide association, Multidisciplinary, Putamen, Brain, Gene Expression Regulation, Developmental, blood, brain, disease incidence, genetic variation, neurology, Organ Size, Human brain, Middle Aged, organization, Magnetic Resonance Imaging, genetics [Genetic Variation], Chromatin, Dynamics, genetics [Membrane Proteins], medicine.anatomical_structure, genetics [Aging], Anatomy & histology, [ SCCO.NEUR ] Cognitive science/Neuroscience, Female, ddc:500, anatomy & histology [Caudate Nucleus], Neuroinformatics, EXPRESSION, Adult, Adolescent, Evolution, anatomy & histology [Hippocampus], ORGANIZATION, genetics [Genetic Loci], Biology, Article, Young Adult, SDG 3 - Good Health and Well-being, Journal Article, medicine, Humans, GENOME-WIDE ASSOCIATION, General, genetics [Apoptosis], Kinectin, Aged, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], HIPPOCAMPAL, IDENTIFICATION, genetics [Organ Size], [SCCO.NEUR]Cognitive science/Neuroscience, Skull, segmentation, Genetic Variation, Membrane Proteins, NERVOUS-SYSTEM, anatomy & histology [Putamen], Genetic Loci, KTN1 protein, human, Caudate Nucleus, anatomy & histology [Brain], Neuroscience, Genome-Wide Association Study
Abstract: Contains fulltext : 144426.pdf (Publisher’s version ) (Closed access) Contains fulltext : 144426pre.pdf (Author’s version preprint ) (Open Access) The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 x 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction. 6 p.
Published: 2015

11. Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism

Author: Christophe Tzourio, Lasse Folkersen, Marieke C H De Visser, Sara Lindström, Ramin Monajemi, Noémie Saut, David M. Smadja, Antonio Fabio Di Narzo, Jean-François Dartigues, Paul M. Ridker, Marine Germain, Mete Civelek, Nicholas L. Smith, François Cambien, Ares Rocanin-Arjo, Christopher Kabrhel, Alison H. Goodall, Aaron R. Folsom, Pieter H. Reitsma, Saonli Basu, Eline Slagboom, Lu-Chen Weng, Kent D. Taylor, Hugoline G. de Haan, Jeanine Houwing-Duitermaat, Peter Kraft, Panos Deloukas, Christopher P. Nelson, Claudine Berr, Lynda M. Rose, Ke Hao, Bruce M. Psaty, Nilesh J. Samani, Jennifer A. Brody, Pierre Suchon, Philippe Amouyel, Jean-François Deleuze, Kerri L. Wiggins, Grégoire Le Gal, Daniel I. Chasman, John A. Heit, Dylan Aïssi, Astrid van Hylckama Vlieg, Pierre-Emmanuel Morange, Mariza de Andrade, Weihong Tang, Frits R. Rosendaal, David-Alexandre Trégouët, Per Eriksson, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Brigham and Women's Hospital [Boston], Department of Thrombosis and Haemostasis, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, University of Minnesota [Twin Cities] (UMN), University of Minnesota System, Program in Genetic Epidemiology and Statistical Genetics (PGESG - BOSTON), Harvard School of Public Health, Mayo Clinic (MC), Division of Biomedical Statistics and Informatics, Mayo Clinic, Einthoven Laboratory for Experimental Vascular Medicine (ELEVM - LEIDEN), Department of Epidemiology, University of Washington [Seattle], Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'hématologie, Assistance Publique - Hôpitaux de Marseille (APHM), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Innovations thérapeutiques en hémostase (IThEM - U1140), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique (CIC - Brest), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'angiologie et d'hémostase (MR), Hôpital Universitaire de Genève = University Hospitals of Geneva (HUG), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai [New York] (MSSM), NIHR Leicester Cardiovascular Biomedical Research Unit, University of Leicester, Department of Cardiovascular Sciences [Leicester], Department of PharmacoGenetics (DPG - COPENHAGEN), NOVO NORDISK PARK, Department of Medical Statistics and Bioinformatics, Harvard Medical School [Boston] (HMS), Section Molecular Epidemiology, Leiden University Medical Center (LUMC), Division of epidemiology, Dalla Lana School of Public Health, University of Toronto, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Princess Al Jawhara Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, William Harvey Research Institute, Barts and the London Medical School, Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Los Angeles Biomedical Research Institute and Department of Pediatrics (LA Biomed Res Institute), Harbor UCLA Medical Center [Torrance, Ca.], Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Atherosclerosis Research Unit, Karolinska Institutet [Stockholm]-Department of Medicine Solna-Cardiovascular Genetics Group, Group Health Research Institute, Group Health Cooperative, Université de Lille, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Division of Biostatistics (Biostat - MINNEAPOLIS), University of Minnesota System-University of Minnesota System, Department of Emergency Medicine, Massachusetts General Hospital [Boston], Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, Seattle Epidemiologic Research and Information Center of the Department of Veterans Affairs Office of Research and Development, Fibrinolyse et Pathologie Vasculaire, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Universitaire de Genève, Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-Université de Brest (UBO), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition ( ICAN ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP], Division of Epidemiology & Community Health, Univ of Minnesota, Minneapolis , MN, Program in Genetic Epidemiology and Statistical Genetics ( PGESG - BOSTON ), Mayo Clinic ( MC ), Einthoven Laboratory for Experimental Vascular Medicine ( ELEVM - LEIDEN ), Nutrition, obésité et risque thrombotique ( NORT ), Institut National de la Recherche Agronomique ( INRA ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance Publique - Hôpitaux de Marseille ( APHM ), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Innovations thérapeutiques en hémostase ( IThEM - U1140 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre d'Investigation Clinique ( CIC - Brest ), Université de Brest ( UBO ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'angiologie et d'hémostase ( MR ), Groupe d'Etude de la Thrombose de Bretagne Occidentale ( GETBO ), Université de Brest ( UBO ), Mount Sinai School of Medicine, Department of PharmacoGenetics ( DPG - COPENHAGEN ), Division of Preventive Medicine, Department of Medicine, Brigham and Women ’ s Hospital, Harvard Medical School, Boston, MA, USA, Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA, Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Neuropsychiatrie : recherche épidémiologique et clinique, Université Montpellier 1 ( UM1 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Los Angeles Biomedical Research Institute and Department of Pediatrics ( LA Biomed Res Institute ), Harbor UCLA Medical Center 1000 W Carson Street, Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ), Division of Biostatistics ( Biostat - MINNEAPOLIS ), University of Minnesota [Minneapolis], Massachusetts General Hospital, Harvard Medical School, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP], University of Minnesota [Twin Cities], Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), and Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)
Subjects: Genotype, Tetraspanins, [SDV]Life Sciences [q-bio], Genome-wide association study, Single-nucleotide polymorphism, Disease, 030204 cardiovascular system & hematology, Lung injury, Biology, Bioinformatics, Article, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Genetics, Odds Ratio, SNP, Humans, Genetics(clinical), Genetic Predisposition to Disease, cardiovascular diseases, Genetics (clinical), 030304 developmental biology, Genetic association, 0303 health sciences, Membrane Glycoproteins, [ SDV ] Life Sciences [q-bio], Membrane Transport Proteins, Odds ratio, Venous Thromboembolism, [ SDV.MHEP.CSC ] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, equipment and supplies, 3. Good health, Meta-analysis, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Genome-Wide Association Study
Abstract: International audience; Venous thromboembolism (VTE), the third leading cause of cardiovascular mortality, is a complex thrombotic disorder with environmental and genetic determinants. Although several genetic variants have been found associated with VTE, they explain a minor proportion of VTE risk in cases. We undertook a meta-analysis of genome-wide association studies (GWASs) to identify additional VTE susceptibility genes. Twelve GWASs totaling 7,507 VTE case subjects and 52,632 control subjects formed our discovery stage where 6,751,884 SNPs were tested for association with VTE. Nine loci reached the genome-wide significance level of 5 × 10(-8) including six already known to associate with VTE (ABO, F2, F5, F11, FGG, and PROCR) and three unsuspected loci. SNPs mapping to these latter were selected for replication in three independent case-control studies totaling 3,009 VTE-affected individuals and 2,586 control subjects. This strategy led to the identification and replication of two VTE-associated loci, TSPAN15 and SLC44A2, with lead risk alleles associated with odds ratio for disease of 1.31 (p = 1.67 × 10(-16)) and 1.21 (p = 2.75 × 10(-15)), respectively. The lead SNP at the TSPAN15 locus is the intronic rs78707713 and the lead SLC44A2 SNP is the non-synonymous rs2288904 previously shown to associate with transfusion-related acute lung injury. We further showed that these two variants did not associate with known hemostatic plasma markers. TSPAN15 and SLC44A2 do not belong to conventional pathways for thrombosis and have not been associated to other cardiovascular diseases nor related quantitative biomarkers. Our findings uncovered unexpected actors of VTE etiology and pave the way for novel mechanistic concepts of VTE pathophysiology.
Published: 2015

12. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study

Author: Winkler, Thomas W, Justice, Anne E, Graff, Mariaelisa, Barata, Llilda, Feitosa, Mary F, Chu, Su, Czajkowski, Jacek, Esko, Tõnu, Fall, Tove, Kilpeläinen, Tuomas O, Lu, Yingchang, Mägi, Reedik, Mihailov, Evelin, Pers, Tune H, Rüeger, Sina, Teumer, Alexander, Ehret, Georg B, Ferreira, Teresa, Heard-Costa, Nancy L, Karjalainen, Juha, Lagou, Vasiliki, Mahajan, Anubha, Neinast, Michael D, Prokopenko, Inga, Simino, Jeannette, Teslovich, Tanya M, Jansen, Rick, Westra, Harm-Jan, White, Charles C, Absher, Devin, Ahluwalia, Tarunveer S, Ahmad, Shafqat, Albrecht, Eva, Alves, Alexessander Couto, Bragg-Gresham, Jennifer L, de Craen, Anton JM, Bis, Joshua C, Bonnefond, Amélie, Boucher, Gabrielle, Cadby, Gemma, Cheng, Yu-Ching, Chiang, Charleston WK, Delgado, Graciela, Demirkan, Ayse, Dueker, Nicole, Eklund, Niina, Eiriksdottir, Gudny, Eriksson, Joel, Feenstra, Bjarke, Fischer, Krista, Frau, Francesca, Galesloot, Tessel E, Geller, Frank, Goel, Anuj, Gorski, Mathias, Grammer, Tanja B, Gustafsson, Stefan, Haitjema, Saskia, Hottenga, Jouke-Jan, Huffman, Jennifer E, Jackson, Anne U, Jacobs, Kevin B, Johansson, Åsa, Kaakinen, Marika, Kleber, Marcus E, Lahti, Jari, Mateo Leach, Irene, Lehne, Benjamin, Liu, Youfang, Lo, Ken Sin, Lorentzon, Mattias, Luan, Jian'an, Madden, Pamela AF, Mangino, Massimo, McKnight, Barbara, Medina-Gomez, Carolina, Monda, Keri L, Montasser, May E, Müller, Gabriele, Müller-Nurasyid, Martina, Nolte, Ilja M, Panoutsopoulou, Kalliope, Pascoe, Laura, Paternoster, Lavinia, Rayner, Nigel W, Renström, Frida, Rizzi, Federica, Rose, Lynda M, Ryan, Kathy A, Salo, Perttu, Sanna, Serena, Scharnagl, Hubert, Shi, Jianxin, Smith, Albert Vernon, Southam, Lorraine, Stančáková, Alena, Steinthorsdottir, Valgerdur, Strawbridge, Rona J, Sung, Yun Ju, Tachmazidou, Ioanna, Tanaka, Toshiko, Thorleifsson, Gudmar, Trompet, Stella, Pervjakova, Natalia, Tyrer, Jonathan P, Vandenput, Liesbeth, van der Laan, Sander W, van der Velde, Nathalie, van Setten, Jessica, van Vliet-Ostaptchouk, Jana V, Verweij, Niek, Vlachopoulou, Efthymia, Waite, Lindsay L, Wang, Sophie R, Wang, Zhaoming, Wild, Sarah H, Willenborg, Christina, Wilson, James F, Wong, Andrew, Yang, Jian, Yengo, Loïc, Yerges-Armstrong, Laura M, Yu, Lei, Zhang, Weihua, Zhao, Jing Hua, Andersson, Ehm A, Bakker, Stephan JL, Baldassarre, Damiano, Banasik, Karina, Barcella, Matteo, Barlassina, Cristina, Bellis, Claire, Benaglio, Paola, Blangero, John, Blüher, Matthias, Bonnet, Fabrice, Bonnycastle, Lori L, Boyd, Heather A, Bruinenberg, Marcel, Buchman, Aron S, Campbell, Harry, Chen, Yii-Der Ida, Chines, Peter S, Claudi-Boehm, Simone, Cole, John, Collins, Francis S, de Geus, Eco JC, de Groot, Lisette CPGM, Dimitriou, Maria, Duan, Jubao, Enroth, Stefan, Eury, Elodie, Farmaki, Aliki-Eleni, Forouhi, Nita G, Friedrich, Nele, Gejman, Pablo V, Gigante, Bruna, Glorioso, Nicola, Go, Alan S, Gottesman, Omri, Gräßler, Jürgen, Grallert, Harald, Grarup, Niels, Gu, Yu-Mei, Broer, Linda, Ham, Annelies C, Hansen, Torben, Harris, Tamara B, Hartman, Catharina A, Hassinen, Maija, Hastie, Nicholas, Hattersley, Andrew T, Heath, Andrew C, Henders, Anjali K, Hernandez, Dena, Hillege, Hans, Holmen, Oddgeir, Hovingh, Kees G, Hui, Jennie, Husemoen, Lise L, Hutri-Kähönen, Nina, Hysi, Pirro G, Illig, Thomas, De Jager, Philip L, Jalilzadeh, Shapour, Jørgensen, Torben, Jukema, J Wouter, Juonala, Markus, Kanoni, Stavroula, Karaleftheri, Maria, Khaw, Kay Tee, Kinnunen, Leena, Kittner, Steven J, Koenig, Wolfgang, Kolcic, Ivana, Kovacs, Peter, Krarup, Nikolaj T, Kratzer, Wolfgang, Krüger, Janine, Kuh, Diana, Kumari, Meena, Kyriakou, Theodosios, Langenberg, Claudia, Lannfelt, Lars, Lanzani, Chiara, Lotay, Vaneet, Launer, Lenore J, Leander, Karin, Lindström, Jaana, Linneberg, Allan, Liu, Yan-Ping, Lobbens, Stéphane, Luben, Robert, Lyssenko, Valeriya, Männistö, Satu, Magnusson, Patrik K, McArdle, Wendy L, Menni, Cristina, Merger, Sigrun, Milani, Lili, Montgomery, Grant W, Morris, Andrew P, Narisu, Narisu, Nelis, Mari, Ong, Ken K, Palotie, Aarno, Pérusse, Louis, Pichler, Irene, Pilia, Maria G, Pouta, Anneli, Rheinberger, Myriam, Ribel-Madsen, Rasmus, Richards, Marcus, Rice, Kenneth M, Rice, Treva K, Rivolta, Carlo, Salomaa, Veikko, Sanders, Alan R, Sarzynski, Mark A, Scholtens, Salome, Scott, Robert A, Scott, William R, Sebert, Sylvain, Sengupta, Sebanti, Sennblad, Bengt, Seufferlein, Thomas, Silveira, Angela, Slagboom, P Eline, Smit, Jan H, Sparsø, Thomas H, Stirrups, Kathleen, Stolk, Ronald P, Stringham, Heather M, Swertz, Morris A, Swift, Amy J, Syvänen, Ann-Christine, Tan, Sian-Tsung, Thorand, Barbara, Tönjes, Anke, Tremblay, Angelo, Tsafantakis, Emmanouil, van der Most, Peter J, Völker, Uwe, Vohl, Marie-Claude, Vonk, Judith M, Waldenberger, Melanie, Walker, Ryan W, Wennauer, Roman, Widén, Elisabeth, Willemsen, Gonneke, Wilsgaard, Tom, Wright, Alan F, Zillikens, M Carola, van Dijk, Suzanne C, van Schoor, Natasja M, Asselbergs, Folkert W, de Bakker, Paul IW, Beckmann, Jacques S, Beilby, John, Bennett, David A, Bergman, Richard N, Bergmann, Sven, Böger, Carsten A, Boehm, Bernhard O, Boerwinkle, Eric, Boomsma, Dorret I, Bornstein, Stefan R, Bottinger, Erwin P, Bouchard, Claude, Chambers, John C, Chanock, Stephen J, Chasman, Daniel I, Cucca, Francesco, Cusi, Daniele, Dedoussis, George, Erdmann, Jeanette, Eriksson, Johan G, Evans, Denis A, de Faire, Ulf, Farrall, Martin, Ferrucci, Luigi, Ford, Ian, Franke, Lude, Franks, Paul W, Froguel, Philippe, Gansevoort, Ron T, Gieger, Christian, Grönberg, Henrik, Gudnason, Vilmundur, Gyllensten, Ulf, Hall, Per, Hamsten, Anders, van der Harst, Pim, Hayward, Caroline, Heliövaara, Markku, Hengstenberg, Christian, Hicks, Andrew A, Hingorani, Aroon, Hofman, Albert, Hu, Frank, Huikuri, Heikki V, Hveem, Kristian, James, Alan L, Jordan, Joanne M, Jula, Antti, Kähönen, Mika, Kajantie, Eero, Kathiresan, Sekar, Kiemeney, Lambertus ALM, Kivimaki, Mika, Knekt, Paul B, Koistinen, Heikki A, Kooner, Jaspal S, Koskinen, Seppo, Kuusisto, Johanna, Maerz, Winfried, Martin, Nicholas G, Laakso, Markku, Lakka, Timo A, Lehtimäki, Terho, Lettre, Guillaume, Levinson, Douglas F, Lind, Lars, Lokki, Marja-Liisa, Mäntyselkä, Pekka, Melbye, Mads, Metspalu, Andres, Mitchell, Braxton D, Moll, Frans L, Murray, Jeffrey C, Musk, Arthur W, Nieminen, Markku S, Njølstad, Inger, Ohlsson, Claes, Oldehinkel, Albertine J, Oostra, Ben A, Palmer, Lyle J, Pankow, James S, Pasterkamp, Gerard, Pedersen, Nancy L, Pedersen, Oluf, Penninx, Brenda W, Perola, Markus, Peters, Annette, Polašek, Ozren, Pramstaller, Peter P, Psaty, Bruce M, Qi, Lu, Quertermous, Thomas, Raitakari, Olli T, Rankinen, Tuomo, Rauramaa, Rainer, Ridker, Paul M, Rioux, John D, Rivadeneira, Fernando, Rotter, Jerome I, Rudan, Igor, den Ruijter, Hester M, Saltevo, Juha, Sattar, Naveed, Schunkert, Heribert, Schwarz, Peter EH, Shuldiner, Alan R, Sinisalo, Juha, Snieder, Harold, Sørensen, Thorkild IA, Spector, Tim D, Staessen, Jan A, Stefania, Bandinelli, Thorsteinsdottir, Unnur, Stumvoll, Michael, Tardif, Jean-Claude, Tremoli, Elena, Tuomilehto, Jaakko, Uitterlinden, André G, Uusitupa, Matti, Verbeek, André LM, Vermeulen, Sita H, Viikari, Jorma S, Vitart, Veronique, Völzke, Henry, Vollenweider, Peter, Waeber, Gérard, Walker, Mark, Wallaschofski, Henri, Wareham, Nicholas J, Watkins, Hugh, Zeggini, Eleftheria, arcOGEN Consortium, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Chakravarti, Aravinda, Clegg, Deborah J, Cupples, L Adrienne, Gordon-Larsen, Penny, Jaquish, Cashell E, Rao, DC, Abecasis, Goncalo R, Assimes, Themistocles L, Barroso, Inês, Berndt, Sonja I, Boehnke, Michael, Deloukas, Panos, Fox, Caroline S, Groop, Leif C, Hunter, David J, Ingelsson, Erik, Kaplan, Robert C, McCarthy, Mark I, Mohlke, Karen L, O'Connell, Jeffrey R, Schlessinger, David, Strachan, David P, Stefansson, Kari, van Duijn, Cornelia M, Hirschhorn, Joel N, Lindgren, Cecilia M, Heid, Iris M, North, Kari E, Borecki, Ingrid B, Kutalik, Zoltán, Loos, Ruth JF, Division of Statistical Genomics, Washington University School of Medicine, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), Estonian Genome and Medicine, University of Tartu, Institute of Molecular and Cell Biology, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Institute of Metabolic Science, MRC, Brown University, Center for Biological Sequence Analysis [Lyngby], Technical University of Denmark [Lyngby] (DTU), King‘s College London, Groningen Bioinformatics Centre, GBB, University of Groningen [Groningen], University of Queensland [Brisbane], National Institut of Food Science and Technology, University of Agriculture, Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Department of neurology, Leiden University Medical Center (LUMC), University of Washington [Seattle], Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Genetic Epidemiology Unit, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Deptartment of Medical Biochemistry and Microbiology, Uppsala University, Infectious diseases division, Department of internal medicine, Washington University in Saint Louis (WUSTL), Limnology, Ecology, Department of Ecology and Evolutionary Biology, University of California, Core Genotyping Facility, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Division of Cancer Epidemiology and Genetics, Institute of Health Sciences and Biocenter Oulu, University of Oulu, Department of Chemical Engineering Taiwan (DCET - NTHU), National Tsing Hua University [Hsinchu] (NTHU), University of Oxford [Oxford], Department of Epidemiology, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Human Genetics, The Wellcome Trust Sanger Institute [Cambridge], Departments of Epidemiology and Nutrition, Harvard School of Public Health, Department of Clinical Sciences, Lund University [Lund]-Lund University Diabetes Centre, Genetic Epidemiology and Clinical Research Group, Umea University Hospital, Department of Medicine, University of Eastern Finland-Kuopio University Hospital, Department of Medical Sciences, Department of Educational Psychology and Counseling, National Taiwan Normal University (NTNU), Laboratory for Cardiovascular Genomics and Informatics [Yokohama] (RIKEN IMS), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN)-RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), deCODE Genetics, deCODE genetics [Reykjavik], Interuniversity Cardiology Institute Netherlands, Molecular Genetics Section, University of Groningen [Groningen]-University Medical Centre Groningen, Kidney Center, University Medical Center Groningen [Groningen] (UMCG), The University of Texas Health Science Center at Houston (UTHealth), Texas Biomedical Research Institute [San Antonio, TX], Medical Department III, Universität Leipzig [Leipzig], Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Dept. of Epidemiology Research, Statens Serum Institut [Copenhagen], GNS Science, Blackett Laboratory, Imperial College London, Medstar Research Institute, University of Rochester [USA], MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Dept Biochem & Mol Biol, Pennsylvania State University (Penn State), Penn State System-Penn State System, Genomic Research Laboratory, Service of Infectious Disease, Hôpitaux Universitaires de Genève (HUG), Epidemiology, University Medical Centre Groningen, Unit for Molecular Epidemiology, German Research Center for Environmental Health-Helmholtz-Zentrum München (HZM), Program in Translational NeuroPsychiatric Genomics, Brigham and Women's Hospital [Boston], Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Research Centre for Prevention and Health (RCPH), Department of Public Health [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Capital Region of Denmark, University of Copenhagen = Københavns Universitet (KU), Faculty of Medicine, Institute of Public Health, Aalborg University [Denmark] (AAU), Department of Nutrition-Dietetics, Harokopio University of Athens, Department of Medical Statistics, Epidemiology and Medical Informatics, University of Zagreb, MRC National Survey of Health and Development, MRC Unit for Lifelong Health and Ageing, Department of Epidemiology and Public Health, University College of London [London] (UCL), Department of Public health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden, Research Center for Prevention and Health, Glostrup Hospital, Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Cambridge Institute of Public Health, University of Cambridge [UK] (CAM), Chronic Disease Epidemiology and Prevention Unit, National Institute for Health and Welfare [Helsinki], Queensland Institute of Medical Research, Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Head of Medical Sequencing, Department of Biostatistics, University of Washington, Department of Chronic Disease Prevention, Molecular Epidemiology, Department of Genetics, Université Laval [Québec] (ULaval), Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Netherlands Genomics Initiative, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), Department of Internal Medicine, Université de Lausanne (UNIL), Carl Gustav Carus University Hospital, Loughborough University, Genomics and Bioinformatics Platform, Fondazione Filarete, Department of Medicine, Surgery, and Dentistry, University of Milano, Medizinische Klinik II, Universität zu Lübeck [Lübeck], Department of Genomic Medicine, University of Manchester [Manchester], The Wellcome Trust Centre for Human Genetics [Oxford], National Institutes of Health [Bethesda] (NIH), Department of Nephrology, University Medical Center, University of Groningen, Helmholtz-Zentrum München (HZM), Icelandic Heart Association, Kopavogur, Iceland., Faculty of Medicine, University of Iceland [Reykjavik], Genetics and Pathology, Department of child and adolescent psychiatry, Universität Duisburg-Essen [Essen], Department of Internal Medicine II, Division of Respirology, University of Regensburg, Regensburg, Germany, Universität Regensburg (UR), Franz-Volhard-Centrum für Klinische Forschung, ECRC, Department of Clinical Physiology, University of Tampere [Finland]-Tampere University Hospital, Finnish Institute of Occupational Health of Helsinki, Department of Clinical Chemistry, Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Department of Oncology, University of Tampere Medical School, University of Tampere, Department of Physiology, University of Eastern Finland-Institute of Biomedicine, Department of Medicine, Montreal, Developmental Brain and Behaviour Unit, University of Southampton, Division of Gastroenterology and Hepatology, Department of Immunology, Mayo Clinic, Centre for Bone and Arthritis Research, Institute of Medicine-University of Gothenburg (GU), Interdisciplinary Center for Psychiatric Epidemiology, Experimental Cardiology Laboratory, University Medical Center [Utrecht], Peter MacCallum Cancer Center, Faculty of Health Sciences, Aarhus University [Aarhus], Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Department of Health Services, University of Washington, Group Health Research Institute, Group Health Cooperative, Department of Epidemiology, University of Washington, Department of Medicine, University of Washington, Cardiovascular Health Research Unit, University of Washington, The Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku University Hospital (TYKS), Erasmus Medical Centre, Cedars-Sinai Medical Center, Department of Pathological Biochemistry, Royal Infirmary, Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University Medical Center Groningen, Department of Pediatrics, Augusta University - Medical College of Georgia, University System of Georgia (USG)-University System of Georgia (USG), Institute of Preventive Medicine, Copenhagen University Hospital-Bispebjerg and Frederiksberg Hospitals, Maastricht University [Maastricht], Department of Public Health, South Ostrobothnia Central Hospital, Department of Clinical and Preventive Medicine, Danube-University Krems, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Department of Epidemiology & Biostatistics, Radboud University Medical Center [Nijmegen], Institute for Community Medicine, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), MRC epidemiology Unit, Framingham Heart Study, National Heart, Lung, and Blood Institute [Bethesda] (NHLBI)-Boston University [Boston] (BU), Metabolic Disease Group, University of Cambridge Metabolic Research Laboratories, Department of Genetics and Biotechnology, Wellcome Trust, Divisions of Genetics and Endocrinology and Program in Genomics, Boston Children's Hospital, Metabolism Initiative and Program in Medical and Population Genetics, Endocrinology and Metabolism, The Churchill Hospital-Oxford Centre for Diabetes, Department of Epidemiology and Preventive Medicine, Regensburg University Medical Center, University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, Department of Medical Genetics, Epidemiology Unit, Addenbrooke's Hospital-Medical Research Council (MRC), P30 AG010161/AG/NIA NIH HHS/United States, Psychiatry, Epidemiology and Data Science, NCA - Neurobiology of mental health, EMGO - Lifestyle, overweight and diabetes, APH - Amsterdam Public Health, AMS - Amsterdam Movement Sciences, Geriatrics, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Other departments, Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, RS: CARIM - R3 - Vascular biology, MUMC+: DA BV AIOS Radiologie (9), Epidemiologie, Orthopedie, Institute for Molecular Medicine Finland, Helsinki Collegium for Advanced Studies, Behavioural Sciences, University of Helsinki, Transplantation Laboratory, Medicum, Research Programs Unit, Research Programme of Molecular Medicine, Aarno Palotie / Principal Investigator, Elisabeth Ingrid Maria Widen / Principal Investigator, Clinicum, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Children's Hospital, Lastentautien yksikkö, Marja-Liisa Lokki / Principal Investigator, Kardiologian yksikkö, Leif Groop Research Group, Quantitative Genetics, Developmental Psychology Research Group, Genomics of Neurological and Neuropsychiatric Disorders, Genomic Discoveries and Clinical Translation, Ehret, Georg Benedikt, Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Universiteit Leiden-Universiteit Leiden, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), University of California (UC), University of Oxford, Lund University [Lund], Universität Leipzig, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Helmholtz Zentrum München = German Research Center for Environmental Health, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH)-Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH)-Capital Region of Denmark, University of Copenhagen = Københavns Universitet (UCPH), Université de Lausanne = University of Lausanne (UNIL), Universität zu Lübeck = University of Lübeck [Lübeck], Universität Duisburg-Essen = University of Duisburg-Essen [Essen], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, University of Gothenburg (GU)-Institute of Medicine, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Luan, Jian'an [0000-0003-3137-6337], Tyrer, Jonathan [0000-0003-3724-4757], Forouhi, Nita [0000-0002-5041-248X], Khaw, Kay-Tee [0000-0002-8802-2903], Langenberg, Claudia [0000-0002-5017-7344], Luben, Robert [0000-0002-5088-6343], Ong, Kenneth [0000-0003-4689-7530], Johnson, Kathleen [0000-0002-6823-3252], Wareham, Nicholas [0000-0003-1422-2993], Barroso, Ines [0000-0001-5800-4520], Apollo - University of Cambridge Repository, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Biochemistry, Surgery, Internal Medicine, Public Health, Medical Oncology, Pathology, Erasmus MC other, Child and Adolescent Psychiatry / Psychology, and Clinical Genetics
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), Male, Cancer Research, endocrine system diseases, Biological pathways, QH426-470, Genome, Body Mass Index, Body Size, Genetics (clinical), ddc:616, Genetics & Heredity, Sex Characteristics, Loci, MAGIC Consortium, Mass index, Age Factors, Chromosome Mapping, Middle Aged, Genealogy, Self-reported height, Peripheral-blood, Scale (social sciences), ICBP Consortium, Female, Life Sciences & Biomedicine, Medical Genetics, Research Article, arcOGEN Consortium, musculoskeletal diseases, Adult, European Continental Ancestry Group, Natural menopause, Aged, Body Size/genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Waist-Hip Ratio, Biology, Body size, DIAGRAM Consortium, Age and sex, White People, Fat distribution, GLGC Consortium, 03 medical and health sciences, Life-course, Genetics, Weight-gain, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Medicinsk genetik, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0604 Genetics, Science & Technology, nutritional and metabolic diseases, Correction, 030104 developmental biology, GWAS meta-analysis, Global-BPGen Consortium, Common SNPS, CHARGE Consortium, 3111 Biomedicine, Developmental Biology
Abstract: Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR, Author Summary Adult body size and body shape differ substantially between men and women and change over time. More than 100 genetic variants that influence body mass index (measure of body size) or waist-to-hip ratio (measure of body shape) have been identified. While there is evidence that some genetic loci affect body shape differently in men than in women, little is known about whether genetic effects differ in older compared to younger adults, and whether such changes differ between men and women. Therefore, we conducted a systematic genome-wide search, including 114 studies (>320,000 individuals), to specifically identify genetic loci with age- and or sex-dependent effects on body size and shape. We identified 15 loci of which the effect on BMI was different in older compared to younger adults, whereas we found no evidence for loci with different effects in men compared to women. The opposite was seen for body shape as we identified 44 loci of which the effect on waist-to-hip ratio differed between men and women, but no difference between younger and older adults were observed. Our observations may provide new insights into the biology that underlies weight change with age or the sexual dimorphism of body shape.
Published: 2014

13. Luminal Lipid Regulates CD36 Levels and Downstream Signaling to Stimulate Chylomicron Synthesis

Author: Maurice M.A.L. Pelsers, Marie Claude Monnot, Jan F. C. Glatz, Pascal Degrace, Fatiha Nassir, Valérie Petit, Philippe Besnard, Lionel C. Clement, Nada A. Abumrad, Hélène Poirier, Isabelle Niot, Thi Thu Trang Tran, Physiologie de la Nutrition et Toxicologie (NUTox) (U866, Lipides et nutrition, équipe 7) (NUTox), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Department of Medicine, University of Washington, Department of Molecular Genetics [Maastricht, The Netherlands], Maastricht University [The Netherlands], Physiopathologie des Dyslipidémies (U866, Lipides et nutrition, équipe 6), Moleculaire Genetica, Genetica & Celbiologie, and RS: CARIM School for Cardiovascular Diseases
Subjects: CD36 Antigens, Male, MTP, CD36, [SDV]Life Sciences [q-bio], Biochemistry, Microsomal triglyceride transfer protein, Mice, 0302 clinical medicine, Intestinal mucosa, Cricetinae, Chylomicrons, Lipoprotein, Hypertriglyceridemia, Mice, Knockout, 0303 health sciences, Mitogen-Activated Protein Kinase 3, biology, Postprandial Period, Lipid-binding Protein, Intestine, ApoB48, ERK, medicine.anatomical_structure, Postprandial, lipids (amino acids, peptides, and proteins), Apolipoprotein B-48, MAP Kinase Signaling System, Enterocyte, CHO Cells, Chylomicron, 03 medical and health sciences, Cricetulus, parasitic diseases, medicine, Animals, Rats, Wistar, Molecular Biology, 030304 developmental biology, Ubiquitination, Lipid absorption, Lipid metabolism, Cell Biology, Lipid Metabolism, Rats, Enterocytes, Metabolism, biology.protein, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, 030217 neurology & neurosurgery
Abstract: International audience; The membrane glycoprotein CD36 binds nanomolar concentrations of long chain fatty acids (LCFA) and is highly expressed on the luminal surface of enterocytes. CD36 deficiency reduces chylomicron production through unknown mechanisms. In this report, we provide novel insights into some of the underlying mechanisms. Our in vivo data demonstrate that CD36 gene deletion in mice does not affect LCFA uptake and subsequent esterification into triglycerides by the intestinal mucosa exposed to the micellar LCFA concentrations prevailing in the intestine. In rodents, the CD36 protein disappears early from the luminal side of intestinal villi during the postprandial period, but only when the diet contains lipids. This drop is significant 1 h after a lipid supply and associates with ubiquitination of CD36. Using CHO cells expressing CD36, it is shown that the digestion products LCFA and diglycerides trigger CD36 ubiquitination. In vivo treatment with the proteasome inhibitor MG132 prevents the lipid-mediated degradation of CD36. In vivo and ex vivo, CD36 is shown to be required for lipid activation of ERK1/2, which associates with an increase of the key chylomicron synthesis proteins, apolipoprotein B48 and microsomal triglyceride transfer protein. Therefore, intestinal CD36, possibly through ERK1/2-mediated signaling, is involved in the adaptation of enterocyte metabolism to the postprandial lipid challenge by promoting the production of large triglyceride-rich lipoproteins that are rapidly cleared in the blood. This suggests that CD36 may be a therapeutic target for reducing the postprandial hypertriglyceridemia and associated cardiovascular risks.
Published: 2011

14. Genome-Wide Association Studies of Cerebral White Matter Lesion Burden: The CHARGE Consortium

Author: Jose R. Romero, Nicole L. Glazer, Jerome I. Rotter, Alex P. Zijdenbos, Thomas H. Mosley, Melissa Garcia, André G. Uitterlinden, Joshua C. Bis, Christophe Tzourio, M. Arfan Ikram, Tamara B. Harris, Thomas Lumley, Wiro J. Niessen, Jean-Charles Lambert, Philippe Amouyel, Bernard Mazoyer, Larry D. Atwood, Monique M.B. Breteler, Henri A. Vrooman, Sigurdur Sigurdsson, Meike W. Vernooij, Susan R. Heckbert, Albert Hofman, Philip A. Wolf, Carole Dufouil, Katja Petrovic, Lenore J. Launer, Pauline Maillard, Alexa S. Beiser, Diane J. Catellier, Richey Sharrett, Anita L. DeStefano, Mary Cushman, Haukur Gudnason, Mike A. Nalls, Margherita Cavalieri, Stéphanie Debette, Sudha Seshadri, Vilmundur Gudnason, Oscar L. Lopez, Albert V. Smith, Franz Fazekas, Eric Boerwinkle, Aad van der Lugt, Cornelia M. van Duijn, Qiong Yang, Myriam Fornage, Kenneth Rice, Renske de Boer, W. T. Longstreth, David S. Knopman, Reinhold Schmidt, Charles DeCarli, Gerardo Heiss, Rebecca F. Gottesman, Thor Aspelund, Rhoda Au, Nicholas L. Smith, Dean Shibata, Helena Schmidt, Kent D. Taylor, Christian Enzinger, Bruce M. Psaty, Epidemiology, Radiology & Nuclear Medicine, Cardiothoracic Surgery, Internal Medicine, The University of Texas Health Science Center at Houston (UTHealth), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Cardiovascular Health Research Unit, University of Washington, Department of Medicine, University of Washington, Institute of Molecular Biology and Biochemistry, Medical University Graz, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Université Pierre et Marie Curie - Paris 6 (UPMC), Icelandic Heart Association, Heart Preventive Clinic and Research Institute, Department of Biostatistics, University of Washington, Department of Neurology, Medical University Graz, Department of Radiology, University of Washington, Groupe d'Imagerie Neurofonctionnelle (GIN - UMR 5296), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Service NEUROSPIN (NEUROSPIN), 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)-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)-Université Paris-Saclay, Biospective [Montréal], Neurological Institute, McGill University, University of Vermont [Burlington], University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Mayo Clinic [Rochester], Department of Clinical and Experimental Medicine, Section of Internal Medicine, Gerontology, and Geriatrics, University of Ferrara, National Institutes of Health [Bethesda] (NIH), University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Johns Hopkins University School of Medicine [Baltimore], Department of Epidemiology, University of Washington, Group Health Research Institute, Group Health Cooperative, Seattle Epidemiologic Research and Information Center of the Department of Veterans Affairs Office of Research and Development, University of Iceland [Reykjavik], Cedars-Sinai Medical Center, Department of Health Services, University of Washington, University of Mississippi Medical Center (UMMC), Department of Neurology, University of Washington, University of California [Davis] (UC Davis), University of California, Service NEUROSPIN (NEUROSPIN), 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)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Ferrara = University of Ferrara (UniFE), University of California (UC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and Department of Medicine and Pathology, University of Vermont
Subjects: Male, Genotype, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, Biology, Nerve Fibers, Myelinated, Polymorphism, Single Nucleotide, White People, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Leukoencephalopathies, Residence Characteristics, Humans, Genetic Predisposition to Disease, RNA, Messenger, Allele, Allele frequency, 030304 developmental biology, Genetic association, Aged, Genetics, Aged, 80 and over, Cerebral Cortex, 0303 health sciences, Movement Disorders, [SCCO.NEUR]Cognitive science/Neuroscience, Middle Aged, Magnetic Resonance Imaging, Hyperintensity, 3. Good health, Chromosome 17 (human), Neurology, Female, Neurology (clinical), Cognition Disorders, 030217 neurology & neurosurgery, Chromosomes, Human, Pair 17, Genome-Wide Association Study
Abstract: International audience; OBJECTIVE: White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.METHODS: We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts.RESULTS: We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 × 10(-9) ; p(replication) = 1.3 × 10(-7) ; p(combined) = 4.0 × 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 × 10(-9) ), rs11869977 (p = 5.7 × 10(-9) ), rs936393 (p = 6.8 × 10(-9) ), rs3744017 (p = 7.3 × 10(-9) ), and rs1055129 (p = 4.1 × 10(-8) ). Variant alleles at these loci conferred a small increase in WMH burden (4-8% of the overall mean WMH burden in the sample).INTERPRETATION: This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.
Published: 2011

15. Machine learning reveals the diversity of human 3D chromatin contact patterns.

Author: Gilbertson EN, Brand CM, McArthur E, Rinker DC, Kuang S, Pollard KS, and Capra JA
Abstract: Understanding variation in chromatin contact patterns across diverse humans is critical for interpreting non-coding variants and their effects on gene expression and phenotypes. However, experimental determination of chromatin contact patterns across large samples is prohibitively expensive. To overcome this challenge, we develop and validate a machine learning method to quantify the variation in 3D chromatin contacts at 2 kilobase resolution from genome sequence alone. We apply this approach to thousands of human genomes from the 1000 Genomes Project and the inferred hominin ancestral genome. While patterns of 3D contact divergence genome-wide are qualitatively similar to patterns of sequence divergence, we find substantial differences in 3D divergence and sequence divergence in local 1 megabase genomic windows. In particular, we identify 392 windows with significantly greater 3D divergence than expected from sequence. Moreover, for 31\% of genomic windows, a single individual has a rare divergent 3D contact map pattern. Using in silico mutagenesis we find that most single nucleotide sequence changes do not result in changes to 3D chromatin contacts. However, in windows with substantial 3D divergence just one or a few variants can lead to divergent 3D chromatin contacts without the individuals carrying those variants having high sequence divergence. In summary, inferring 3D chromatin contact maps across human populations reveals variable contact patterns. We anticipate that these genetically diverse maps of 3D chromatin contact will provide a reference for future work on the function and evolution of 3D chromatin contact variation across human populations., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)
Published: 2024
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16. Intratumoral STING agonist reverses immune evasion in PD-(L)1-refractory Merkel cell carcinoma: mechanistic insights from detailed biomarker analyses.

Author: Pulliam T, Jani S, Goff PH, Bhakuni R, Tabachnick-Cherny S, Smythe K, Seaton BW, Tachiki L, Kulikauskas R, Church C, Koelle DM, Nghiem P, and Bhatia S
Subjects: Humans, Skin Neoplasms drug therapy, Skin Neoplasms immunology, Skin Neoplasms pathology, Biomarkers, Tumor metabolism, Male, B7-H1 Antigen metabolism, Aged, Programmed Cell Death 1 Receptor antagonists & inhibitors, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Carcinoma, Merkel Cell drug therapy, Carcinoma, Merkel Cell immunology, Membrane Proteins metabolism
Abstract: Background: Antibodies blocking programmed death (PD)-1 or its ligand (PD-L1) have revolutionized cancer care, but many patients do not experience durable benefits. Novel treatments to stimulate antitumor immunity are needed in the PD-(L)1 refractory setting. The stimulator of interferon genes (STING) protein, an innate sensor of cytoplasmic DNA, is a promising target with several agonists in development. However, response rates in most recent clinical trials have been low and mechanisms of response remain unclear. We report detailed biomarker analyses in a patient with anti-PD-L1 refractory, Merkel cell polyomavirus (MCPyV)-positive, metastatic Merkel cell carcinoma (MCC) who was treated with an intratumoral (IT) STING agonist (ADU-S100) plus intravenous anti-PD-1 antibody (spartalizumab) and experienced a durable objective response with regression of both injected and non-injected lesions., Methods: We analyzed pretreatment and post-treatment tumor and peripheral blood samples from our patient with single-cell RNA sequencing, 30-parameter flow cytometry, T cell receptor sequencing, and multiplexed immunohistochemistry. We analyzed cancer-specific CD8 T cells using human leukocyte antigen (HLA)-I tetramers loaded with MCPyV peptides. We also analyzed STING expression and signaling in the tumor microenvironment (TME) of 88 additional MCC tumor specimens and in MCC cell lines., Results: We observed high levels of MCPyV-specific T cells (12% of T cells) in our patient's tumor at baseline. These cancer-specific CD8 T cells exhibited characteristics of exhaustion including high TOX and low TCF1 proteins. Following treatment with STING-agonist plus anti-PD-1, IT CD8 T cells expanded threefold. We also observed evidence of likely improved antigen presentation in the MCC TME (greater than fourfold increase of HLA-I-positive cancer cells). STING expression was not detected in any cancer cells within our patient's tumor or in 88 other MCC tumors, however high STING expression was observed in immune and stromal cells within all 89 MCC tumors., Conclusions: Our results suggest that STING agonists may be able to work indirectly in MCC via signaling through immune and stromal cells in the TME, and may not necessarily need STING expression in the cancer cells. This approach may be particularly effective in tumors that are already infiltrated by inflammatory cells in the TME but are evading immune detection via HLA-I downregulation., Competing Interests: Competing interests: PN reports personal fees from Pfizer, Bristol Myers Squibb, EMD Serono, Rain Therapeutics, Almirall, and Instill Bio. In addition, PN and DK have pending patents for “Merkel cell polyomavirus T antigen-specific TCRs and uses thereof” and “Novel epitopes as T cell targets in Merkel Cell Carcinoma (MCC)”. CC has a pending patent “Merkel cell polyomavirus T antigen-specific TCRs and uses thereof”. LT reports research grant funding (to institution) from Seagen and Merck. SB has received consulting or advisory role fees and honoraria from Bristol Myers Squibb, Sanofi/Regeneron, and Incyte; and has received research funding from Bristol Myers Squibb, Merck, EMD Serono, Exicure, Incyte, Checkmate Pharmaceuticals, 4SC, Seven and Eight Pharmaceuticals, Amphivena Therapeutics, TriSalus Life Sciences, Novartis and Agenus. DK reports research funding from Sanofi Pasteur. DK has received consulting or advisory fees from Curevo Vaccine and MaxHealth LLC Pasteur. KS has received consulting or advisory role fees from Sensei Biotherapeutics., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Published: 2024
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17. Colorectal cancer-associated bacteria are broadly distributed in global microbiomes and drivers of precancerous change.

Author: Minot SS, Li N, Srinivasan H, Ayers JL, Yu M, Koester ST, Stangis MM, Dominitz JA, Halberg RB, Grady WM, and Dey N
Subjects: Animals, Humans, Mice, Metagenomics methods, Colorectal Neoplasms microbiology, Colorectal Neoplasms genetics, Gastrointestinal Microbiome genetics, Bacteria genetics, Bacteria classification, Precancerous Conditions microbiology
Abstract: The gut microbiome is implicated in the pathogenesis of colorectal cancer (CRC), but the full scope of this dialogue is unknown. Here we aimed to define the scale and membership of the body of CRC- and health-associated gut bacteria in global populations. We performed a microbiome-CRC correlation analysis of published ultra-deep shotgun metagenomic sequencing data from global microbiome surveys, utilizing a de novo (reference-agnostic) gene-level clustering approach to identify protein-coding co-abundant gene (CAGs) clusters. We link an unprecedented ~ 23-40% of gut bacteria to CRC or health, split nearly evenly as CRC- or health-associated. These microbes encode 2319 CAGs encompassing 427,261 bacterial genes significantly enriched or depleted in CRC. We identified many microbes that had not previously been linked to CRC, thus expanding the scope of "known unknowns" of CRC-associated microbes. We performed an agnostic CAG-based screen of bacterial isolates and validated predicted effects of previously unimplicated bacteria in preclinical models, in which we observed differential induction of precancerous adenomas and field effects. Single-cell RNA sequencing disclosed microbiome-induced senescence-associated gene expression signatures in discrete colonic populations including fibroblasts. In organoid co-cultures, primary colon fibroblasts from mice with microbiomes promoted significantly greater growth than fibroblasts from microbiome-depleted mice. These results offer proof-of-principle for gene-level metagenomic analysis enabling discovery of microbiome links to health and demonstrate that the microbiome can drive precancer states, thereby potentially revealing novel cancer prevention opportunities., (© 2024. The Author(s).)
Published: 2024
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18. Sequence-based machine learning reveals 3D genome differences between bonobos and chimpanzees.

Author: Brand CM, Kuang S, Gilbertson EN, McArthur E, Pollard KS, Webster TH, and Capra JA
Abstract: The 3D structure of the genome is an important mediator of gene expression. As phenotypic divergence is largely driven by gene regulatory variation, comparing genome 3D contacts across species can further understanding of the molecular basis of species differences. However, while experimental data on genome 3D contacts in humans is increasingly abundant, only a handful of 3D genome contact maps exist for other species. Here, we demonstrate that human experimental data can be used to close this data gap. We apply a machine learning model that predicts 3D genome contacts from DNA sequence to the genomes from 56 bonobos and chimpanzees and identify species-specific patterns of genome folding. We estimated 3D divergence between individuals from the resulting contact maps in 4,420 1 Mb genomic windows, of which ∼17% were substantially divergent in predicted genome contacts. Bonobos and chimpanzees diverged at 89 windows, overlapping genes associated with multiple traits implicated in Pan phenotypic divergence. We discovered 51 bonobo-specific variants that individually produce the observed bonobo contact pattern in bonobo-chimpanzee divergent windows. Our results demonstrate that machine learning methods can leverage human data to fill in data gaps across species, offering the first look at population-level 3D genome variation in non-human primates. We also identify loci where changes in 3D folding may contribute to phenotypic differences in our closest living relatives., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)
Published: 2024
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19. Targeting RSV-neutralizing B cell receptors with anti-idiotypic antibodies.

Author: Scharffenberger SC, Wan YH, Homad LJ, Kher G, Haynes AM, Poudel B, Sinha IR, Aldridge N, Pai A, Bibby M, Chhan CB, Davis AR, Moodie Z, Palacio MB, Escolano A, McElrath MJ, Boonyaratanakornkit J, Pancera M, and McGuire AT
Abstract: Respiratory syncytial virus (RSV) causes lower respiratory tract infections with significant morbidity and mortality at the extremes of age. Vaccines based on the viral fusion protein are approved for adults over 60, but infant protection relies on passive immunity via antibody transfer or maternal vaccination. An infant vaccine that rapidly elicits protective antibodies would fulfill a critical unmet need. Antibodies arising from the VH3-21/VL1-40 gene pairing can neutralize RSV without the need for affinity maturation, making them attractive to target through vaccination. Here, we develop an anti-idiotypic monoclonal antibody (ai-mAb) immunogen that is specific for unmutated VH3-21/VL1-40 B cell receptors (BCRs). The ai-mAb efficiently engages B cells with bona fide target BCRs and does not activate off-target non-neutralizing B cells, unlike recombinant pre-fusion (preF) protein used in current RSV vaccines. These results establish proof of concept for using an ai-mAb-derived vaccine to target B cells hardwired to produce RSV-neutralizing antibodies., Competing Interests: Declaration of interests A.T.M. and S.C.S. are co-inventors on a patent application 63/635,785 pertaining to the ai-mAbs described here., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Published: 2024
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20. Addressing financial hardship in malignant hematology and hematopoietic cell transplant: a team approach.

Author: Jones SMW, Ohlsen TJD, Karvonen KA, and Sorror M
Subjects: Humans, Financial Stress, Quality of Life, Health Care Costs, Patient Care Team, Cost of Illness, Hematopoietic Stem Cell Transplantation economics, Hematologic Neoplasms therapy, Hematologic Neoplasms economics
Abstract: Abstract: Financial hardship is a common experience for patients and their families after the diagnosis of a hematologic malignancy and is associated with worse outcomes. Health care costs, increased costs of living, income poverty, and inadequate wealth contribute to financial hardship after the diagnosis and treatment of a hematologic malignancy and/or hematopoietic cell transplant. Given the multidimensional nature of financial hardship, a multidisciplinary team-based approach is needed to address this public health hazard. Hematologists and oncologists may mitigate the impact of financial hardship by matching treatment options with patient goals of care and reducing symptom burden disruptive to employment. Social workers and financial navigators can assist with screening and resource deployment. Policymakers and researchers can identify structural and policy changes to prevent financial hardship. By alleviating this major health care burden from patients, care teams may improve survival and quality of life for patients with hematologic malignancies., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Published: 2024
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21. Health-related quality of life with gilteritinib vs placebo posttransplant for FLT3-ITD+ acute myeloid leukemia.

Author: Hamilton BK, Pandya BJ, Ivanescu C, Elsouda D, Hamadani M, Chen YB, Levis MJ, Ueda Oshima M, Litzow MR, Soiffer RJ, Ustun C, Perl AE, Singh AK, Geller N, Hasabou N, Rosales M, Cella D, Corredoira L, Pestana C, Horowitz MM, and Logan B
Subjects: Humans, Middle Aged, Female, Male, Adult, Aged, Quality of Life, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute therapy, fms-Like Tyrosine Kinase 3 genetics, Pyrazines therapeutic use, Aniline Compounds therapeutic use, Hematopoietic Stem Cell Transplantation methods
Abstract: Abstract: The Blood and Marrow Transplant (BMT) Clinical Trials Network conducted a phase 3 randomized trial comparing gilteritinib with placebo after allogeneic hematopoietic cell transplantation (HCT) for FLT3-ITD+ acute myeloid leukemia (AML). The primary analysis demonstrated no statistically significant difference in relapse-free survival (RFS); however, patients with FLT3-ITD measurable residual disease (MRD) peri-HCT had significantly longer RFS with gilteritinib. This analysis investigates the effect of post-HCT gilteritinib vs placebo on health-related quality of life (HRQOL). HRQOL was measured with Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), FACT-Leukemia (FACT-Leu), and EuroQOL-5 Dimensions (EQ-5D-5L) at post-HCT randomization; day 29; months 3, 6, 12, 18, 24; and/or end of therapy. HRQOL and clinically meaningful differences were summarized using descriptive statistics and compared using mixed model repeated measures to evaluate longitudinal change from baseline and stratified Cox model to evaluate time to improvement. HRQOL completion rate was acceptable (>70%) across all time points and measures. There were no differences in HRQOL scores at any time point between cohorts. Clinically meaningful and time to improvement in HRQOL were similar in both arms. Despite higher treatment-emergent adverse effects with gilteritinib, response to the question of being "bothered by side effects of treatment" did not differ between groups. Subgroup analysis of MRD-positive and negative patients demonstrated no differences in HRQOL between arms. For patients with FLT3-ITD+ AML undergoing HCT, gilteritinib maintenance was not associated with any difference in HRQOL or patient-reported impact of side effects. This trial was registered at www.ClinicalTrials.gov as #NCT02997202., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.)
Published: 2024
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22. Proximal Tubule Secretory Clearance, Injury, and Kidney Viability in Cirrhosis.

Author: Granda ML, Luitweiler E, Prince DK, Allegretti AS, Paine C, Pichler R, Sibulesky L, Biggins SW, and Kestenbaum B
Abstract: Objectives: Cirrhosis affects all structures of the kidney, in particular the tubules which are responsible for secretion of protein-bound metabolites and electrolyte/water homeostasis. Yet, prevailing assessments of kidney function focus solely on glomerular filtration rate (GFR) which may incompletely reflect these processes. We sought to characterize markers of tubular function, injury, and viability in patients with and without cirrhosis., Methods: We recruited outpatients undergoing liver transplantation evaluation for a collection of plasma and 24-hour urine, matching by GFR to control participants without cirrhosis. We measured urinary kidney injury molecule-1 (KIM-1), a marker of proximal tubular injury, as well as epidermal growth factor (EGF), a marker of viability necessary for tubular epithelial cell proliferation after injury. We also estimated secretory clearance by measuring several highly secreted endogenous metabolites in urine and plasma., Results: We recruited 39 patients with cirrhosis (mean MELD-Na 17±4, Child-Pugh 8±2, eGFR 66±20 ml/min/1.73m2) and 58 GFR-matched controls without cirrhosis (eGFR 66±21 ml/min/1.73m2). Urinary KIM-1 was 4.4-fold higher than controls (95% CI:2.9-6.5), and EGF averaged 7.41-fold higher than controls (95% CI:2.15-25.53). We found that of 8 solutes, 5 had significantly greater kidney clearance in cirrhosis (1.3-2.1-fold higher): indoxyl sulfate, p-cresol sulfate, pyridoxic acid, tiglylglycine, and xanthosine., Conclusions: Cirrhosis was characterized by molecular signs of tubular injury in stable outpatients without acute kidney injury, accompanied by largely preserved tubular secretory clearance and greater signs of tubular viability. Within the limitations of the study, this suggests a phenotype of chronic ischemic injury but with initial preservation of tubular function in cirrhosis., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)
Published: 2024
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23. Digital communication between mothers and community health workers to support neonatal health (CHV-NEO): study protocol for a randomized controlled trial.

Author: Ronen K, Pothan LC, Apondi V, Otieno FA, Mwakanema D, Otieno FO, Osborn L, Dettinger JC, Shrestha P, Manguerra H, Mukumbang F, Masinde M, Waweru E, Amulele M, Were C, Wasunna B, John-Stewart G, Weiner B, Means AR, Richardson BA, Hedstrom AB, Unger JA, and Kinuthia J
Subjects: Humans, Infant, Newborn, Female, Kenya, Pregnancy, Infant, Infant Mortality, Infant Health, Health Knowledge, Attitudes, Practice, Communication, Multicenter Studies as Topic, Community Health Workers, Text Messaging, Mothers psychology, Randomized Controlled Trials as Topic
Abstract: Background: Provision of essential newborn care at home, rapid identification of illness, and care-seeking by caregivers can prevent neonatal mortality. Mobile technology can connect caregivers with information and healthcare worker advice more rapidly and frequently than healthcare visits. Community health workers (CHWs) are well-suited to deliver such interventions. We developed an interactive short message service (SMS) intervention for neonatal health in Kenya, named CHV-NEO. CHV-NEO sends automated, theory-based, actionable, messages throughout the peripartum period that guide mothers to evaluate maternal and neonatal danger signs and facilitate real-time dialogue with a CHW via SMS. We integrated this intervention into Kenya's national electronic community health information system (eCHIS), which is currently used at scale to support CHW workflow., Methods: The effect of CHV-NEO on clinical and implementation outcomes will be evaluated through a non-blinded cluster randomized controlled trial. Twenty sites across Kisumu County in Western Kenya were randomized 1:1 to provide either the national eCHIS with integrated CHV-NEO messaging (intervention) or standard of care using eCHIS without CHV-NEO (control). We will compare neonatal mortality between arms based on abstracted eCHIS data from 7200 pregnant women. Secondary outcomes include self-reported provision of essential newborn care (appropriate cord care, thermal care, and timely initiation of breastfeeding), knowledge of neonatal danger signs, and care-seeking for neonatal illness, compared between arms based on questionnaires with a subgroup of 2000 women attending study visits at enrollment in pregnancy and 6 weeks postpartum. We will also determine CHV-NEO's effect on CHW workflows and evaluate determinants of intervention acceptability, adoption, and fidelity of use through questionnaires, individual interviews, and messaging data., Discussion: We hypothesize that the CHV-NEO direct-to-client communication strategy can be successfully integrated within existing CHW workflows and infrastructure, improve the provision of at-home essential newborn care, increase timely referral of neonatal illness to facilities, and reduce neonatal mortality. The intervention's integration into the national eCHIS tool will facilitate rapid scale-up if it is clinically effective and successfully implemented., Trial Registration: ClinicalTrials.gov, NCT05187897 . The CHV-NEO study was registered on January 12, 2022., (© 2024. The Author(s).)
Published: 2024
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24. The penetration of therapeutics across the blood-brain barrier: Classic case studies and clinical implications.

Author: Banks WA, Rhea EM, Reed MJ, and Erickson MA
Abstract: The blood-brain barrier (BBB) plays central roles in the maintenance and health of the brain. Its mechanisms to safeguard the brain against xenobiotics and endogenous toxins also make the BBB the primary obstacle to the development of drugs for the central nervous system (CNS). Here, we review classic examples of the intersection of clinical medicine, drug delivery, and the BBB. We highlight the role of lipid solubility (heroin), saturable brain-to-blood (efflux: opiates) and blood-to-brain (influx: nutrients, vitamins, and minerals) transport systems, and adsorptive transcytosis (viruses and incretin receptor agonists). We examine how the disruption of the BBB that occurs in certain diseases (tumors) can also be modulated (osmotic agents and microbubbles) and used to deliver treatments, and the role of extracellular pathways in gaining access to the CNS (albumin and antibodies). In summary, this review provides a historical perspective of the key role of the BBB in delivery of drugs to the brain in health and disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)
Published: 2024
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25. Impact of doxycycline post-exposure prophylaxis for sexually transmitted infections on the gut microbiome and antimicrobial resistome.

Author: Chu VT, Glascock A, Donnell D, Grabow C, Brown CE, Ward R, Love C, Kalantar KL, Cohen SE, Cannon C, Woodworth MH, Kelley CF, Celum C, Luetkemeyer AF, and Langelier CR
Abstract: Doxycycline post-exposure prophylaxis (doxy-PEP) reduces bacterial sexually transmitted infections among men who have sex with men and transgender women. Although poised for widespread clinical implementation, the impact of doxy-PEP on antimicrobial resistance remains a primary concern as its effects on the gut microbiome and resistome, or the antimicrobial resistance genes (ARGs) present in the gut microbiome, are unknown. To investigate these effects, we studied participants from the DoxyPEP trial, a randomized clinical trial comparing doxy-PEP use, a one-time doxycycline 200-mg dose taken after condomless sex (DP arm, n = 100), to standard of care (SOC arm, n = 50) among men who have sex with men and transgender women. From self-collected rectal swabs at enrollment (day-0) and after 6 months (month-6), we performed metagenomic DNA sequencing (DNA-seq) or metatranscriptomic RNA sequencing (RNA-seq). DNA-seq data were analyzable from 127 samples derived from 89 participants, and RNA-seq data were analyzable from 86 samples derived from 70 participants. We compared the bacterial microbiome and resistome between the two study arms and over time. The median number of doxycycline doses taken since enrollment by participants with DNA-seq data was zero (interquartile range (IQR): 0-7 doses) for the SOC arm and 42 (IQR: 27-64 doses) for the DP arm. Tetracycline ARGs were detected in all day-0 DNA-seq samples and in 85% of day-0 RNA-seq samples. The proportional mass of tetracycline ARGs in the resistome increased between day-0 and month-6 in DP participants from 46% to 51% in the metagenome (P = 2.3 × 10 -2 ) and from 4% to 15% in the metatranscriptome (P = 4.5 × 10 -6 ), but no statistically significant increases in other ARG classes were observed. Exposure to a higher number of doxycycline doses correlated with proportional enrichment of tetracycline ARGs in the metagenome (Spearman's ρ = 0.23, P = 9.0 × 10 -3 ) and metatranscriptome (Spearman's ρ = 0.55, P = 3.7 × 10 -8 ). Bacterial microbiome alpha diversity, beta diversity and total bacterial mass did not differ between day-0 and month-6 samples from DP participants when assessed by either DNA-seq or RNA-seq. In an abundance-based correlation analysis, we observed an increase over time in the strength of the correlation between tetracycline ARGs and specific bacterial taxa, including some common human pathogens. In sum, doxy-PEP use over a 6-month period was associated with an increase in the proportion of tetracycline ARGs comprising the gut resistome and an increase in the expression of tetracycline ARGs. At 6 months of doxy-PEP use, no residual differences were observed in alpha and beta diversity or taxonomic composition of the gut microbiome. As doxy-PEP is implemented as a public health strategy, further studies and population-level surveillance of doxycycline-resistant pathogens are needed to understand the implications of these findings. ClinicalTrials.gov registration number: NCT03980223 ., (© 2024. The Author(s).)
Published: 2024
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26. Whole-genome sequencing in 333,100 individuals reveals rare non-coding single variant and aggregate associations with height.

Author: Hawkes G, Beaumont RN, Li Z, Mandla R, Li X, Albert CM, Arnett DK, Ashley-Koch AE, Ashrani AA, Barnes KC, Boerwinkle E, Brody JA, Carson AP, Chami N, Chen YI, Chung MK, Curran JE, Darbar D, Ellinor PT, Fornage M, Gordeuk VR, Guo X, He J, Hwu CM, Kalyani RR, Kaplan R, Kardia SLR, Kooperberg C, Loos RJF, Lubitz SA, Minster RL, Naseri T, Viali S, Mitchell BD, Murabito JM, Palmer ND, Psaty BM, Redline S, Shoemaker MB, Silverman EK, Telen MJ, Weiss ST, Yanek LR, Zhou H, Liu CT, North KE, Justice AE, Locke JM, Owens N, Murray A, Patel K, Frayling TM, Wright CF, Wood AR, Lin X, Manning A, and Weedon MN
Subjects: Humans, Male, Female, Gene Frequency, Genome, Human, Genetic Variation, Phenotype, Whole Genome Sequencing, Body Height genetics, Polymorphism, Single Nucleotide, Genome-Wide Association Study
Abstract: The role of rare non-coding variation in complex human phenotypes is still largely unknown. To elucidate the impact of rare variants in regulatory elements, we performed a whole-genome sequencing association analysis for height using 333,100 individuals from three datasets: UK Biobank (N = 200,003), TOPMed (N = 87,652) and All of Us (N = 45,445). We performed rare ( < 0.1% minor-allele-frequency) single-variant and aggregate testing of non-coding variants in regulatory regions based on proximal-regulatory, intergenic-regulatory and deep-intronic annotation. We observed 29 independent variants associated with height at P < 6 × 10 - 10 after conditioning on previously reported variants, with effect sizes ranging from -7cm to +4.7 cm. We also identified and replicated non-coding aggregate-based associations proximal to HMGA1 containing variants associated with a 5 cm taller height and of highly-conserved variants in MIR497HG on chromosome 17. We have developed an approach for identifying non-coding rare variants in regulatory regions with large effects from whole-genome sequencing data associated with complex traits., (© 2024. The Author(s).)
Published: 2024
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27. Descriptive and molecular epidemiology of leishmaniasis diagnosed from clinical samples in the United States, 2021-2022.

Author: Truong TT, Crawford K, Wang-McGuire I, Jensen K, Mushtaq A, Lieberman NAP, Buckner FS, Van Voorhis WC, Cookson BT, Salipante SJ, and Lieberman JA
Subjects: Humans, United States epidemiology, Female, Male, Adult, Child, Adolescent, Child, Preschool, Young Adult, Middle Aged, Aged, Infant, Incidence, Aged, 80 and over, Leishmaniasis, Cutaneous epidemiology, Leishmaniasis, Cutaneous diagnosis, Leishmaniasis, Cutaneous parasitology, Travel, Military Personnel statistics & numerical data, Molecular Epidemiology, Leishmania genetics, Leishmania isolation & purification, Leishmania classification, Leishmaniasis epidemiology, Leishmaniasis diagnosis, Leishmaniasis parasitology
Abstract: Leishmaniasis is a rare disease in the United States, with an estimated annual incidence of dozens of cases occurring primarily in travelers, migrants, and military personnel. True disease incidence is unknown, since leishmaniasis is not a nationally notifiable condition. Here, we describe the results of molecular leishmaniasis over a 1-year interval (September 2021 to August 2022) when our laboratory served as the primary national reference laboratory for molecular diagnosis of civilian leishmaniasis. We tested 218 specimens submitted from 36 states yielding 94 of the 186 (50.5%) positive cases with species or species complex-level identification and 18 novel mini-exon alleles. Most species belonged to subgenus Viannia (75.6%) and associated with cutaneous or mucocutaneous disease. Cases were associated with recent travel (18.1%), travel timing unspecified (7.4%), migration (7.4%), remote travel (2.1%), military (1.1%), or unknown history (63.8%). These data illustrate the clinical utility of molecular testing for leishmaniasis and provide unique insight into disease epidemiology., Importance: Leishmaniasis is a disfiguring, neglected parasitic infection endemic to the Southern United States and the Americas. Despite significant populations at risk-travelers, military and foreign service members, and migrating persons-the epidemiology of the disease in the United States is poorly understood. Moreover, few clinical laboratories in the United States can test for the disease. Here, we present results from 1 year of testing for this disease at a major reference laboratory. These findings are particularly relevant because they coincide with a temporary "pause" on all clinical testing at the CDC. Our findings suggest at least several hundred cases occur each year in the United States. In particular, mucosal leishmaniasis may be more common than previously reported. We also highlight greater genetic diversity in Leishmania species endemic to the Americas than has been previously sampled, with implications for diagnostic specificity., Competing Interests: The authors declare no conflict of interest.
Published: 2024
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28. Implementing the Infectious Diseases Society of America Antimicrobial Stewardship Core Curriculum: Survey Results and Real-World Strategies to Guide Fellowship Programs.

Author: Hojat LS, Patel PK, Ince D, Kang AY, Fong G, Cherabuddi K, Nori P, Al Lawati H, Stohs EJ, Beeler C, Van Schooneveld TC, Lee MS, Hamilton KW, Justo JA, Spicer JO, Logan A, Bennani K, Williams R, Shnekendorf R, Bryson-Cahn C, Willis ZI, Moenster RP, Brennan-Krohn T, Paras ML, Holubar M, Gaston DC, Advani SD, and Luther VP
Abstract: Background: The Infectious Diseases Society of America (IDSA) developed the Core Antimicrobial Stewardship (AS) Curriculum to meet the increasing demand for infectious diseases (ID) providers with AS expertise. Notable diversity in implementation approaches has been observed among ID fellowship programs using the curriculum. We sought to describe individual approaches and develop a curriculum implementation roadmap., Methods: We surveyed ID fellowship programs that had previously implemented the IDSA Core AS curriculum. The survey included questions regarding program characteristics, curriculum participants and presentation format, resources and barriers, and implementation strategies. Commonly reported program features were summarized in the context of the self-reported implementation strategies. Implementation guides were developed based on the most common characteristics observed., Results: Of 159 programs that had purchased the curriculum, 37 responded, and 34 (21%) were included in the analysis. The curriculum was primarily taught by AS physicians (85%) and AS pharmacists (47%). The most common conference structure was a longitudinal conference series (32%), and eLearning was the most common presentation format. Limited AS faculty time (76%) and limited first-year fellow availability (62%) were frequently reported as barriers, and dedicated AS curricular time was a resource available to most programs (67%); implementation guides were created for these 3 program features., Conclusions: Programs reported a variety of implementation barriers and resources, with several common themes emerging, allowing for the development of tailored curriculum planners for 3 commonly observed program characteristics. This work will equip fellowship programs with curriculum implementation strategies and guide future enhancements of the IDSA Core and Advanced AS curricula., Competing Interests: Potential conflicts of interest. A. Y. K. has received research funding from Paratek Pharmaceuticals and American College of Clinical Pharmacy. G. F. has received funding from Critical Innovations, LLC, and grant funding from Melinta Therapeutics. K. C. has received research grants from the National Institutes of Health, Biomedical Advanced Research and Development Authority, and Merck and panel discussion honorarium from Ferring. E. J. S. has received research funding from Merck and bioMérieux. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
Published: 2024
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29. Interventions to Increase Follow-Up of Abnormal Stool-Based Colorectal Cancer Screening Tests in Safety Net Settings: A Systematic Review.

Author: Issaka RB, Bell-Brown A, Jewell T, Jackson SL, and Weiner BJ
Subjects: Humans, Feces chemistry, Occult Blood, Safety-net Providers, Colorectal Neoplasms diagnosis, Early Detection of Cancer methods
Published: 2024
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30. Immune correlates analysis of the Imbokodo (HVTN 705/HPX2008) efficacy trial of a mosaic HIV-1 vaccine regimen evaluated in Southern African people assigned female sex at birth: a two-phase case-control study.

Author: Kenny A, van Duijn J, Dintwe O, Heptinstall J, Burnham R, Sawant S, Zhang L, Mielke D, Khuzwayo S, Omar FL, Stanfield-Oakley S, Keyes T, Dunn B, Goodman D, Fong Y, Benkeser D, Zou R, Hural J, Hyrien O, Juraska M, Luedtke A, van der Laan L, Giorgi EE, Magaret C, Carpp LN, Pattacini L, van de Kerkhof T, Korber B, Willems W, Fisher LH, Schuitemaker H, Swann E, Kublin JG, Pau MG, Buchbinder S, Tomaka F, Nijs S, Lavreys L, Gelderblom HC, Corey L, Mngadi K, Gray GE, Borducchi E, Hendriks J, Seaton KE, Zolla-Pazner S, Barouch DH, Ferrari G, De Rosa SC, McElrath MJ, Andersen-Nissen E, Stieh DJ, Tomaras GD, and Gilbert PB
Subjects: Humans, Female, Case-Control Studies, Male, Adult, Vaccine Efficacy, HIV Antibodies blood, HIV Antibodies immunology, Immunoglobulin G blood, Immunoglobulin G immunology, env Gene Products, Human Immunodeficiency Virus immunology, Africa, Southern, Young Adult, Southern African People, AIDS Vaccines immunology, AIDS Vaccines administration & dosage, HIV Infections immunology, HIV Infections prevention & control, HIV Infections virology, HIV-1 immunology
Abstract: Background: The HVTN 705 Imbokodo trial of 2636 people without HIV and assigned female sex at birth, conducted in southern Africa, evaluated a heterologous HIV-1 vaccine regimen: mosaic adenovirus 26-based vaccine (Ad26.Mos4.HIV) at Months 0, 3, 6, 12 and alum-adjuvanted clade C gp140 at Months 6, 12. Per-protocol vaccine efficacy (VE) against HIV-1 diagnosis from seven to 24 months was 14.1% (95% CI: -22.0% to 39.5%). Immune correlates analysis was performed for markers selected based on prior evidence in efficacy trials and/or nonhuman primate models., Methods: Humoral and cellular immune response markers at Month 7 were evaluated as immune correlates of risk and of protection in a breakthrough case-control cohort (n = 52 cases, 246 non-cases). Primary markers were IgG binding to vaccine-strain gp140, IgG3 binding to diverse Env antigens (IgG3 Env breadth), IgG3 binding to diverse V1V2 antigens (IgG3 V1V2 breadth), antibody-dependent phagocytosis against the vaccine-strain gp140, Env-specific CD4+ and CD8+ T-cell responses, and multi-epitope functions., Findings: No immune markers were statistically significant correlates of risk. IgG3 V1V2 breadth trended toward an inverse association: hazard ratio 0.70 (95% CI: 0.36 to 1.35; p = 0.29) per 10-fold increase and 0.51 (95% CI: 0.21 to 1.24; p = 0.14) in a Cox model with all primary markers. The VE estimate was 11.8% (95% CI: -17.9% to 34.0%) at all IgG3 V1V2 breadth values below 667 weighted geometric mean net MFI; just above this value, the VE estimate sharply increased to 62.6% (95% CI: -17.9% to 89.6%), and further increased to 80.9% (95% CI: -17.9% to 99.5%) at 1471 MFI, the 95th percentile of the marker distribution. Mediation analysis yielded a VE of 35.7% (95% CI: 15.0% to 51.3%) attributable to the vaccine's impact on this marker., Interpretation: The trend in association of greater IgG3 V1V2 antibody breadth with lower likelihood of HIV acquisition is consistent with the identification of antibodies against V1V2 as immune correlates in three other HIV vaccine efficacy trials and suggests that a greater emphasis should be placed on studying this region in the HIV-1 envelope as a vaccine immunogen., Funding: National Institute of Allergy and Infectious Diseases and Janssen Vaccines & Prevention BV., Competing Interests: Declaration of interests TvdK has a patent application with Johnson & Johnson and has stocks in Johnson & Johnson. BK received internal support for the present manuscript from her employer (Los Alamos National Laboratory). In the past 36 months, she received support for attending meetings and/or travel from NIH NIAID and from the Gates foundation. Her institution (LANL) had a patent on this work, although she did not receive any personal funds through this patent and was not involved with the licensing of the design to Johnson & Johnson. DHB has a patent on the mosaic HIV vaccine, but no royalties. FT was an employee of Janssen/Johnson & Johnson at the time the work was conducted and owns stock in Johnson & Johnson. LL received support from Janssen Infectious Diseases BV, Beerse, Belgium for travel expenses to attend HIV conferences and has stock or stock options in Johnson & Johnson. JvD, MGP, WW, TvdK and JHen are employees of Janssen/Johnson & Johnson and hold stock or stock options in Johnson & Johnson. WW has a patent planned, issued, or pending with Johnson & Johnson. SCDR had contracts in the past 36 months to perform immunogenicity testing for Janssen, Sanofi, and Moderna. HS and DJS were employees of Janssen Vaccines & Prevention BV and had stock and/or stock options in Johnson & Johnson at the time the work was conducted. SN was an employee of Janssen Infectious Diseases BV and had stock and/or stock options in Johnson & Johnson at the time the work was conducted. LP was an employee of Janssen Vaccines & Prevention BV at the time the work was conducted. GDT has received consulting fees for a scientific consulting session. All other authors have no potential competing interests to disclose. Funding for the Imbokodo Study and Correlates Group is the same as listed in “Acknowledgments” for the current work., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
Published: 2024
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31. Ranolazine in chronic total occlusion percutaneous coronary intervention.

Author: Alexandrou M, Mutlu D, Rempakos A, Al Ogaili A, Choi JW, Poommipanit P, Alaswad K, Basir MB, Davies R, Jaffer FA, Dattilo P, Azzalini L, Aygul N, Reddy N, Jefferson BK, Gorgulu S, Khatri JJ, Young LD, Krestyaninov O, Khelimskii D, Frizzell J, Elbarouni B, Rangan BV, Mastrodemos OC, Burke MN, Sandoval Y, and Brilakis ES
Subjects: Humans, Male, Female, Aged, Middle Aged, Chronic Disease, Treatment Outcome, Coronary Angiography, Retrospective Studies, Ranolazine therapeutic use, Percutaneous Coronary Intervention methods, Coronary Occlusion diagnosis, Coronary Occlusion surgery, Registries
Abstract: Ranolazine is an anti-anginal medication given to patients with chronic angina and persistent symptoms despite medical therapy. We examined 11 491 chronic total occlusion (CTO) percutaneous coronary interventions (PCI) that were performed at 41 US and non-US centers between 2012 and 2023 in the PROGRESS-CTO Registry. Patients on ranolazine at baseline had more comorbidities, more complex lesions, lower procedural and technical success (based on univariable but not multivariable analysis), and higher incidence of major adverse cardiac events (MACE) (on both univariable and multivariable analysis).
Published: 2024
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32. Cachexia during anti-leukemia chemotherapy: it is not "just" the chemo.

Author: Rashidi A
Subjects: Humans, Leukemia drug therapy, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Agents adverse effects, Antineoplastic Agents therapeutic use, Cachexia etiology, Cachexia drug therapy
Published: 2024
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33. Bright New Resources for Syphilis Research: Genetically Encoded Fluorescent Tags for Treponema pallidum and Sf1Ep Cells.

Author: Grillová L, Romeis E, Lieberman NAP, Tantalo LC, Xu LH, Molini B, Trejos AT, Lacey G, Goulding D, Thomson NR, Greninger AL, and Giacani L
Subjects: Humans, Green Fluorescent Proteins genetics, Green Fluorescent Proteins metabolism, Red Fluorescent Protein, Virulence genetics, Treponema, Treponema pallidum genetics, Syphilis microbiology, Luminescent Proteins genetics, Luminescent Proteins metabolism
Abstract: The recently discovered methodologies to cultivate and genetically manipulate Treponema pallidum subsp. pallidum (T. pallidum) have significantly helped syphilis research, allowing the in vitro evaluation of antibiotic efficacy, performance of controlled studies to assess differential treponemal gene expression, and generation of loss-of-function mutants to evaluate the contribution of specific genetic loci to T. pallidum virulence. Building on this progress, we engineered the T. pallidum SS14 strain to express a red-shifted green fluorescent protein (GFP) and Sf1Ep cells to express mCherry and blue fluorescent protein (BFP) for enhanced visualization. These new resources improve microscopy- and cell sorting-based applications for T. pallidum, better capturing the physical interaction between the host and pathogen, among other possibilities. Continued efforts to develop and share new tools and resources are required to help our overall knowledge of T. pallidum biology and syphilis pathogenesis reach that of other bacterial pathogens, including spirochetes., (© 2024 The Author(s). Molecular Microbiology published by John Wiley & Sons Ltd.)
Published: 2024
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34. Bayesian Estimation of Muscle Mechanisms and Therapeutic Targets Using Variational Autoencoders.

Author: Tune T, Kooiker KB, Davis J, Daniel T, and Moussavi-Harami F
Abstract: Cardiomyopathies, often caused by mutations in genes encoding muscle proteins, are traditionally treated by phenotyping hearts and addressing symptoms post irreversible damage. With advancements in genotyping, early diagnosis is now possible, potentially introducing earlier treatment. However, the intricate structure of muscle and its myriad proteins make treatment predictions challenging. Here we approach the problem of estimating therapeutic targets for a mutation in mouse muscle using a spatially explicit half sarcomere muscle model. We selected 9 rate parameters in our model linked to both small molecules and cardiomyopathy-causing mutations. We then randomly varied these rate parameters and simulated an isometric twitch for each combination to generate a large training dataset. We used this dataset to train a Conditional Variational Autoencoder (CVAE), a technique used in Bayesian parameter estimation. Given simulated or experimental isometric twitches, this machine learning model is able to then predict the set of rate parameters which are most likely to yield that result. We then predict the set of rate parameters associated with twitches from control mice with the cardiac Troponin C (cTnC) I61Q variant and control twitches treated with the myosin activator Danicamtiv, as well as model parameters that recover the abnormal I61Q cTnC twitches., Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests.
Published: 2024
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35. Association between chlorine-treated drinking water, the gut microbiome, and enteric pathogen burden in young children in Haiti: An observational study.

Author: Chac D, Slater DM, Guillaume Y, Dunmire CN, Ternier R, Vissières K, Juin S, Lucien MAB, Boncy J, Sanchez VM, Dumayas MG, Augustin GC, Bhuiyan TR, Qadri F, Chowdhury F, Khan AI, Weil AA, Ivers LC, and Harris JB
Subjects: Humans, Haiti epidemiology, Infant, Child, Preschool, Male, Female, Water Purification, Chlorine pharmacology, Drinking Water microbiology, Gastrointestinal Microbiome drug effects, Feces microbiology
Abstract: Objective: The effects of sanitation and hygiene interventions on the gut microbiome and enteric pathogen burden are not well understood. We measured the association between free chlorine residue (FCR) levels in drinking water, microbiome composition, and stool enteric pathogens in infants and young children in Haiti., Methods: FCR levels were measured in household drinking water and enteric pathogen burden was evaluated using multiplex RT-PCR of stool among 131 children from one month to five years of age living in Mirebalais, Haiti. Microbiome profiling was performed using metagenomic sequencing., Results: Most individuals lived in households with undetectable FCR measured in the drinking water (112/131, 86%). Detection of enteric pathogen DNA in stool was common and did not correlate with household water FCR. The infant microbiome in households with detectable FCR demonstrated reduced richness (fewer total number of species, P = 0.04 Kruskall-Wallis test) and less diversity by Inverse Simpson measures (P = 0.05) than households with undetectable FCR. Infants in households with a detectable FCR were more likely to have abundant Bifidobacterium. Using in vitro susceptibility testing, we found that some Bifidobacterium species were resistant to chlorine., Conclusions: FCR in household drinking water did not correlate with enteric pathogen burden in our study., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Published: 2024
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36. Artificial intelligence for predicting primary antegrade wiring success of chronic total occlusion crossing.

Author: Alexandrou M, Rempakos A, Mutlu D, Strepkos D, Carvalho PEP, Al Ogaili A, Bahbah A, Milkas A, Tsiafoutis I, Alaswad K, Basir MB, Davies R, Jaffer FA, Nicholson W, Azzalini L, Gorgulu S, Khatri JJ, Bangalore S, Rangan BV, Mastrodemos OC, Burke MN, Sandoval Y, and Brilakis ES
Published: 2024
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37. Out-BREAK!: An IDWeek 2023 Escape Room to Break Out of the Educational Mold.

Author: Zhong D, Dong SW, Chu VT, Gabriel N, Lusardi K, Searns JB, Wattier RL, Ristagno EH, Bhimraj A, Boguniewicz J, and Pottinger P
Abstract: Background: An escape room is a cooperative game that has been adapted into medical education and major academic conferences., Methods: We describe the design, development, and implementation of an educational ID-themed escape room activity entitled "Out-BREAK!" at an international conference, IDWeek 2023. An anonymous survey was conducted to collect demographic data, assess participant satisfaction with the escape room puzzles, and gauge participant interest in game-based learning., Results: Thirty escape room sessions were held over 3 days and included 201 participants. Escape room survey respondents (n = 132) were younger and more likely to be trainees compared with in-person IDWeek attendants. Among 131 responses, all respondents enjoyed the experience and would recommend the escape room activity to friends. Survey respondents enjoyed the puzzle solving (93%), medical content (92%), and team building (79%) components. Only 35% of the respondents had ever previously participated in game-based learning; 95% thought the escape room was a valuable teaching method. Among the 72 survey respondents involved in medical education, almost all (90%) said they were interested in incorporating escape rooms into medical education., Conclusions: The Out-BREAK! escape room at IDWeek 2023 was successfully implemented and well received. Despite only a third of participants having prior experience with game-based learning, almost all respondents perceived the escape room to be an effective teaching method., Competing Interests: Potential conflicts of interest. D.Z., S.D., V.T.C., N.G., K.L., J.B.S., E.H.R., A.B., J.B., and P.P. report no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
Published: 2024
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38. Long-term air pollution exposure and incident physical disability in older US adults: a cohort study.

Author: Gao J, Mendes de Leon CF, Zhang B, Weuve J, Langa KM, D'Souza J, Szpiro A, Faul J, Kaufman JD, Hirth R, and Adar SD
Abstract: Background: Disability is a key marker of overall physical health in older adults and is often preceded by chronic disease. Although air pollution is a well recognised risk factor for multiple chronic diseases, its association with physical disability has not been well characterised. We investigated the associations of air pollutants with physical disability in a large cohort representative of older adults in the USA., Methods: We used biennial data on incident activities of daily living (ADL) disability collected from respondents of the Health and Retirement Survey between 2000 and 2016. As part of the Environmental Predictors of Cognitive Health and Aging study, we estimated 10-year average PM 2·5 , PM 10 - 2·5 ) concentrations at participant residences before each survey using spatiotemporal prediction models. We used a time-varying, weighted Cox model to estimate hazard ratios (HRs) for incident physical disability per interquartile increase of air pollution with detailed adjustments for confounders.2 ), and ozone (O 3 ) concentrations at participant residences before each survey using spatiotemporal prediction models. We used a time-varying, weighted Cox model to estimate hazard ratios (HRs) for incident physical disability per interquartile increase of air pollution with detailed adjustments for confounders., Findings: Among 15 411 respondents aged 65 years and older (mean age 70·2 [SD 6·5] years; 55% female, 45% male), 48% of respondents reported newly having ADL disability during a mean follow-up of 7·9 years (SD 4·7). In fully adjusted models, we found greater risks of ADL disability associated with higher concentrations of PM 2·5 (HR 1·03 per 3·7 μg/m³ [95% CI 0·99-1·08], p=0·16), PM 10 - 2·5 was associated with a lower risk of ADL disability (0·95 per 3·7 ppb [0·91-1·00], p=0·030). In a multi-pollutant model, associations were similar to the single-pollutant models for PM 2 (1·03 per 7·5 ppb [0·99-1·08]. p=0·064), although not all these associations were statistically significant. In contrast, O 3 was associated with a lower risk of ADL disability (0·95 per 3·7 ppb [0·91-1·00], p=0·030). In a multi-pollutant model, associations were similar to the single-pollutant models for PM 10 - 2·5 (1·05 per 4·9 μg/m³ [1·00-1·11], p=0·041) and O 3 (0·94 per 3·7 ppb [0·88-1·01], p=0·083)., Interpretation: Our findings suggest that air pollution might be an underappreciated risk factor for physical disability in later life, although additional research is needed., Funding: National Institutes of Environmental Health Sciences and National Institute on Aging., Competing Interests: Declaration of interests JW, JF, RH, SDA, AS, and KML received a grant from the National Institute of Environmental Health Sciences (NIEHS) and the National Institute on Aging (NIA), which supported the present manuscript. JW and SDA received grants from the National Institute of Health (NIH) and the NIA for other research and consulting fees outside the submitted work. AS participates on the data monitoring committee of Achieving HIV viral suppression in refugee settlements in Uganda with Head StART, outside the submitted work. JF received grants from the NIH and consulting fees from Tufts University and the University of Texas Medical Branch, outside the submitted work. JF is an Associate Editor of the journal Discover Social Science and Health. KML receives grants and consulting fees on NIH-funded projects at Harvard University, the University of Pennsylvania, the University of Minnesota, the University of Colorado, Dartmouth University, and the University of Southern California, outside the submitted work. KML received payment for expert testimony for a legal case related to decisional capacity in a person with dementia, outside the submitted work. JDK received grants and contracts from the NIH and the US Environmental Protection Agency, outside the submitted work. SDA receives grants from the NIH–NIA and Centers for Disease Control and Prevention, and is the review committee member of Health Effects Institute, outside the submitted work. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
Published: 2024
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39. Developmental regulation of endothelial-to-hematopoietic transition from induced pluripotent stem cells.

Author: Wellington R, Cheng X, Campbell CA, Trapnell C, Espin-Palazon R, Hadland B, and Doulatov S
Abstract: Hematopoietic stem cells (HSCs) arise in embryogenesis from a specialized hemogenic endothelium (HE). In this process, HE cells undergo a unique fate change termed endothelial-to-hematopoietic transition, or EHT. While induced pluripotent stem cells (iPSCs) give rise to HE with robust hemogenic potential, the generation of bona fide HSCs from iPSCs remains a challenge. Here, we map single cell dynamics of EHT during embryoid body differentiation from iPSCs and integrate it with human embryo datasets to identify key transcriptional differences between in vitro and in vivo cell states. We further map ligand-receptor interactions associated with differential expression of developmental programs in the iPSC system. We found that the expression of endothelial genes was incompletely repressed during iPSC EHT. Elevated FGF signaling by FGF23, an endothelial pathway ligand, was associated with differential gene expression between in vitro and in vivo EHT. Chemical inhibition of FGF signaling during EHT increased HSPC generation in the zebrafish, while an FGF agonist had the opposite effect. Consistently, chemical inhibition of FGF signaling increased hematopoietic output from iPSCs. In summary, we map the dynamics of EHT from iPSCs at single cell resolution and identify ligand-receptor interactions that can be modulated to improve iPSC differentiation protocols. We show, as proof of principle, that chemical inhibition of FGF signaling during EHT improves hematopoietic output in zebrafish and the iPSC system., Competing Interests: CONFLICT OF INTEREST The authors declare no potential conflicts of interest.
Published: 2024
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40. Cytomegalovirus immunity in high-risk liver transplant recipients following preemptive antiviral therapy versus prophylaxis.

Author: Zamora D, Dasgupta S, Stevens-Ayers T, Edmison B, Winston DJ, Razonable RR, Mehta AK, Lyon GM, Boeckh M, Singh N, Koelle DM, and Limaye AP
Subjects: Humans, Male, Middle Aged, Female, Adult, Transplant Recipients, Aged, Antibodies, Neutralizing immunology, Antibodies, Neutralizing blood, Antibodies, Viral immunology, Antibodies, Viral blood, Viremia immunology, Liver Transplantation, Cytomegalovirus Infections immunology, Cytomegalovirus Infections prevention & control, Antiviral Agents therapeutic use, Cytomegalovirus immunology, Killer Cells, Natural immunology
Abstract: CMV-specific T cells, NK cells, and neutralizing antibodies (nAbs) were assessed in a randomized trial of CMV prevention with preemptive antiviral therapy (PET) versus prophylactic antiviral therapy (PRO) in donor-seropositive/recipient-seronegative (D+R-) liver transplant recipients (LTxR) at 100 days (end of intervention) and at 6 and 12 months after transplant. The PET group had significantly increased numbers of circulating polyfunctional T cells, NK cells, and nAbs compared with the PRO group at day 100, and several CMV immune parameters remained significantly higher by 12 months after transplant. Among PET recipients, preceding CMV viremia (vs. no preceding viremia) was associated with significantly higher levels of most CMV immune parameters at day 100. Higher numbers of CMV-specific polyfunctional T cells and NKG2C+ NK cells at day 100 were associated with a decreased incidence of CMV disease in multivariable Cox regression. The strongest associations with protection against CMV disease were with increased numbers of CMV-specific polyfunctional CD4+ T cells, CD3negCD56dimCD57negNKG2Cpos cells, and CD3negCD56dimCD57posNKG2Cpos NK cells. Our results suggest that PET is superior to PRO for CMV disease prevention by allowing low-level CMV replication and associated antigen exposure that is promptly controlled by antiviral therapy and facilitates enhanced CMV protective immunity in D+R- LTxR.
Published: 2024
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41. Sympathetic innervation of interscapular brown adipose tissue is not a predominant mediator of OT-elicited reductions of body weight gain and adiposity in male diet-induced obese rats.

Author: Edwards MM, Nguyen HK, Dodson AD, Herbertson AJ, Honeycutt MK, Slattery JD, Rambousek JR, Tsui E, Wolden-Hanson T, Wietecha TA, Graham JL, Tapia GP, Sikkema CL, O'Brien KD, Mundinger TO, Peskind ER, Ryu V, Havel PJ, Khan AM, Taborsky GJ Jr, and Blevins JE
Abstract: Recent studies indicate that central administration of oxytocin (OT) reduces body weight (BW) in high fat diet-induced obese (DIO) rodents by reducing energy intake and increasing energy expenditure (EE). Previous studies in our lab have shown that administration of OT into the fourth ventricle (4V; hindbrain) elicits weight loss and stimulates interscapular brown adipose tissue temperature (T IBAT ) in DIO rats. We hypothesized that OT-elicited stimulation of sympathetic nervous system (SNS) activation of IBAT contributes to its ability to activate BAT and reduce BW in DIO rats. To test this, we determined the effect of disrupting SNS activation of IBAT on OT-elicited stimulation of T IBAT and reduction of BW in DIO rats. We first confirmed that bilateral surgical SNS denervation to IBAT was successful based on having achieved ≥ 60% reduction in IBAT norepinephrine (NE) content from DIO rats. NE content was selectively reduced in IBAT by 94.7 ± 2.7, 96.8 ± 1.8 and 85.9 ± 6.1% ( P <0.05) at 1, 6 and 7-weeks post-denervation, respectively, and was unchanged in liver or inguinal white adipose tissue. We then measured the impact of bilateral surgical SNS denervation to IBAT on the ability of acute 4V OT (1, 5 μg) to stimulate T IBAT in DIO rats. We found that the high dose of 4V OT (5 μg) stimulated T IBAT similarly between sham and denervated rats ( P =NS) and that the effects of 4V OT to stimulate T IBAT did not require beta-3 adrenergic receptor signaling. We subsequently measured the effect of bilateral surgical denervation of IBAT on the effect of chronic 4V OT (16 nmol/day) or vehicle infusion to reduce BW, adiposity and energy intake in DIO rats. Chronic 4V OT reduced BW gain by -7.2 ± 9.6 g and -14.1 ± 8.8 g in sham and denervated rats ( P <0.05 vs vehicle treatment), respectively, and this effect was similar between groups ( P =NS). These effects were associated with reductions in adiposity and energy intake ( P <0.05). Collectively, these findings support the hypothesis that sympathetic innervation of IBAT is not required for central OT to increase BAT thermogenesis and reduce BW gain and adiposity in male DIO rats.
Published: 2024
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42. Small DNA elements that act as both insulators and silencers in plants.

Author: Jores T, Mueth NA, Tonnies J, Char SN, Liu B, Grillo-Alvarado V, Abbitt S, Anand A, Deschamps S, Diehn S, Gordon-Kamm B, Jiao S, Munkvold K, Snowgren H, Sardesai N, Fields S, Yang B, Cuperus JT, and Queitsch C
Abstract: Insulators are cis -regulatory elements that separate transcriptional units, whereas silencers are elements that repress transcription regardless of their position. In plants, these elements remain largely uncharacterized. Here, we use the massively parallel reporter assay Plant STARR-seq with short fragments of eight large insulators to identify more than 100 fragments that block enhancer activity. The short fragments can be combined to generate more powerful insulators that abolish the capacity of the strong viral 35S enhancer to activate the 35S minimal promoter. Unexpectedly, when tested upstream of weak enhancers, these fragments act as silencers and repress transcription. Thus, these elements are capable of both insulating or repressing transcription dependent upon regulatory context. We validate our findings in stable transgenic Arabidopsis , maize, and rice plants. The short elements identified here should be useful building blocks for plant biotechnology efforts., Competing Interests: Competing interests T.J., J.T.C., and C.Q. have filed a patent application related to this work through the University of Washington. The remaining authors declare no competing interests.
Published: 2024
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43. The pathway to delivering injectable CAB for HIV prevention: strategies from global PrEP leaders leveraging an adapted version of the Intervention Scalability Assessment Tool (ISAT).

Author: Violette LR, Zewdie K, Gitahi N, Beima-Sofie K, and Heffron R
Abstract: Background: Longer-acting cabotegravir (CAB) is a novel, safe, and efficacious pre-exposure prophylaxis (PrEP) for HIV prevention. As we near a time for CAB scale-up, the experience of global leaders in PrEP research and implementation can be leveraged to identify optimal strategies for scaling and integrating CAB into existing PrEP infrastructure worldwide., Methods: We recruited leaders of HIV prevention clinical trials and large PrEP programs through a combination of purposive and snowball sampling for participation in individual interviews. We conducted interviews using a semi-structured guide that compared CAB to oral PrEP and sought perspectives on barriers and strategies for CAB scale-up. Interviews were conducted virtually, audio recorded, and transcribed. We used thematic analysis, grounded in an adapted version of the Intervention Scalability Assessment Tool (ISAT), to identify critical elements for optimizing delivery of CAB., Results: From October 2021 to April 2022, we interviewed 30 participants with extensive experience in PrEP research, care, and programming. Participants worked in all seven WHO regions and reported a median of 20 years working in HIV and 10 years in PrEP. Participants agreed that CAB was efficacious and discrete, therefore having the potential to address current concerns about oral PrEP adherence and stigma. Participants indicated direct and indirect costs for provider training, expansion of existing medical infrastructure, and the current medication cost of CAB as major concerns for roll out. The true cost to the end-user and health system were unknown. There were some conflicting strategies on how to best address product targeting, presentation of efficacy, and timing of product availability with scale-up. Some thought that targeting CAB for the general population could normalize PrEP and decrease stigma, while others thought that prioritizing key populations could optimize impact by targeting those with highest risk. Overall, participants emphasized that to ensure successful CAB scale-up, communities and stakeholders must be involved at every stage of planning and implementation., Conclusions: Our evaluation found that although there is a clear and urgent need for additional HIV PrEP options beyond daily oral PrEP, CAB scale-up must be thoughtful, flexible, and based in lessons learned from oral PrEP rollout., (© 2024. The Author(s).)
Published: 2024
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44. Incidence and risk of post-COVID-19 thromboembolic disease and the impact of aspirin prescription; nationwide observational cohort at the US Department of Veteran Affairs.

Author: Ware AD, Veigulis ZP, Hoover PJ, Blumke TL, Ioannou GN, Boyko EJ, and Osborne TF
Subjects: Humans, United States epidemiology, Male, Female, Aged, Middle Aged, Retrospective Studies, Incidence, SARS-CoV-2, Risk Factors, Aged, 80 and over, Aspirin therapeutic use, COVID-19 epidemiology, COVID-19 complications, COVID-19 prevention & control, Thromboembolism epidemiology, Thromboembolism prevention & control, Thromboembolism etiology, Thromboembolism drug therapy, United States Department of Veterans Affairs, Veterans
Abstract: Introduction: COVID-19 triggers prothrombotic and proinflammatory changes, with thrombotic disease prevalent in up to 30% SARS-CoV-2 infected patients. Early work suggests that aspirin could prevent COVID-19 related thromboembolic disorders in some studies but not others. This study leverages data from the largest integrated healthcare system in the United States to better understand this association. Our objective was to evaluate the incidence and risk of COVID-19 associated acute thromboembolic disorders and the potential impact of aspirin., Methods: This retrospective, observational study utilized national electronic health record data from the Veterans Health Administration. 334,374 Veterans who tested positive for COVID-19 from March 2, 2020, to June 13, 2022, were included, 81,830 of whom had preexisting aspirin prescription prior to their COVID-19 diagnosis. Patients with and without aspirin prescriptions were matched and the odds of post-COVID acute thromboembolic disorders were assessed., Results: 10.1% of Veterans had a documented thromboembolic disorder within 12 months following their COVID-19 diagnosis. Those with specific comorbidities were at greatest risk. Preexisting aspirin prescription was associated with a significant decrease risk of post-COVID-19 thromboembolic disorders, including pulmonary embolism (OR [95% CI]: 0.69 [0.65, 0.74]) and deep vein thrombosis (OR [95% CI]: 0.76 [0.69, 0.83], but an increased risk of acute arterial diseases, including ischemic stroke (OR [95% CI]: 1.54 [1.46, 1.60]) and acute ischemic heart disease (1.33 [1.26, 1.39])., Conclusions: Findings demonstrated that preexisting aspirin prescription prior to COVID-19 diagnosis was associated with significantly decreased risk of venous thromboembolism and pulmonary embolism but increased risk of acute arterial disease. The risk of arterial disease may be associated with increased COVID-19 prothrombotic effects superimposed on preexisting chronic cardiovascular disease for which aspirin was already prescribed. Prospective clinical trials may help to further assess the efficacy of aspirin use prior to COVID-19 diagnosis for the prevention of post-COVID-19 thromboembolic disorders., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)
Published: 2024
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45. The harms of promoting the lab leak hypothesis for SARS-CoV-2 origins without evidence.

Author: Alwine J, Goodrum F, Banfield B, Bloom D, Britt WJ, Broadbent AJ, Campos SK, Casadevall A, Chan GC, Cliffe AR, Dermody T, Duprex P, Enquist LW, Frueh K, Geballe AP, Gaglia M, Goldstein S, Greninger AL, Gronvall GK, Jung JU, Kamil JP, Lakdawala S, Liu S-L, Luftig M, Moore JP, Moscona A, Neuman BW, Nikolich JŽ, O'Connor C, Pekosz A, Permar S, Pfeiffer J, Purdy J, Rasmussen A, Semler B, Smith GA, Stein DA, Van Doorslaer K, Weller SK, Whelan SPJ, and Yurochko A
Subjects: Humans, Pandemics, Animals, SARS-CoV-2, COVID-19 virology, COVID-19 transmission
Abstract: Science is humanity's best insurance against threats from nature, but it is a fragile enterprise that must be nourished and protected. The preponderance of scientific evidence indicates a natural origin for SARS-CoV-2. Yet, the theory that SARS-CoV-2 was engineered in and escaped from a lab dominates media attention, even in the absence of strong evidence. We discuss how the resulting anti-science movement puts the research community, scientific research, and pandemic preparedness at risk., Competing Interests: T.D. is on the Board of Directors, Burroughs Wellcome Fund, and is an Editor for the Annual Review of Virology. P.D. receives funding from Moderna. K.F. has substantial financial interest in Vir Biotechnology, Inc., and is cofounder of the company and is coinventor of patents licensed to Vir and receives compensation for consulting. The potential conflict of interest has been reviewed and managed by OHSU. S.G. has done legal consulting on the origins of the pandemic. A.L.G. reports central testing contracts from Pfizer, Novavx, Sanofi, Abbott, Hologic, Cephid, and Quidel and has research support from Gilead. A.M. is scientific founder of Thylacine Biotherapeutics. G.A.S. is President of Thyreos, Inc. Most authors receive funding from the National Institutes of Health and other funding agencies.
Published: 2024
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46. Epigenetic programming of host lipid metabolism associated with resistance to TST/IGRA conversion after exposure to Mycobacterium tuberculosis .

Author: Dill-McFarland KA, Simmons JD, Peterson GJ, Nguyen FK, Campo M, Benchek P, Stein CM, Vaisar T, Mayanja-Kizza H, Boom WH, and Hawn TR
Subjects: Humans, Male, Adult, Female, Tuberculin Test, Interferon-gamma Release Tests, Monocytes metabolism, Monocytes immunology, DNA Methylation, Uganda epidemiology, Cohort Studies, Mycobacterium tuberculosis, Epigenesis, Genetic, Lipid Metabolism genetics, Latent Tuberculosis immunology, Latent Tuberculosis microbiology, Latent Tuberculosis genetics, Latent Tuberculosis metabolism
Abstract: Mycobacterium tuberculosis (Mtb) exposure leads to a range of outcomes including clearance, latent TB infection (LTBI), and pulmonary tuberculosis (TB). Some heavily exposed individuals resist tuberculin skin test (TST) and interferon-gamma (IFNγ) release assay (IGRA) conversion (RSTR), which suggests that they employ IFNγ-independent mechanisms of Mtb control. Here, we compare monocyte epigenetic profiles of RSTR and LTBI from a Ugandan household contact cohort. Chromatin accessibility did not differ between uninfected RSTR and LTBI monocytes. By contrast, methylation significantly differed at 174 CpG sites and across 63 genomic regions. Consistent with previous transcriptional findings in this cohort, differential methylation was enriched in lipid- and cholesterol-associated pathways including the genes APOC3, KCNQ1, and PLA2G3. In addition, methylation was enriched in Hippo signaling, which is associated with cholesterol homeostasis and includes CIT and SHANK2. Lipid export and Hippo signaling pathways were also associated with gene expression in response to Mtb in RSTR as well as IFN stimulation in monocyte-derived macrophages (MDMs) from an independent healthy donor cohort. Moreover, serum-derived high-density lipoprotein from RSTR had elevated ABCA1-mediated cholesterol efflux capacity (CEC) compared to LTBI. Our findings suggest that resistance to TST/IGRA conversion is linked to regulation of lipid accumulation in monocytes, which could facilitate early Mtb clearance among RSTR subjects through IFNγ-independent mechanisms.IMPORTANCETuberculosis (TB) remains an enduring global health challenge with millions of deaths and new cases each year. Despite recent advances in TB treatment, we lack an effective vaccine or a durable cure. While heavy exposure to Mycobacterium tuberculosis often results in latent TB latent infection (LTBI), subpopulations exist that are either resistant to infection or contain Mtb with interferon-gamma (IFNγ)-independent mechanisms not indicative of LTBI. These resisters provide an opportunity to investigate the mechanisms of TB disease and discover novel therapeutic targets. Here, we compare monocyte epigenetic profiles of RSTR and LTBI from a Ugandan household contact cohort. We identify methylation signatures in host lipid and cholesterol pathways with potential relevance to early TB clearance before the sustained IFN responses indicative of LTBI. This adds to a growing body of literature linking TB disease outcomes to host lipids., Competing Interests: The authors declare no conflict of interest.
Published: 2024
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47. RalB uncoupled exocyst mediates endothelial Weibel-Palade body exocytosis.

Author: Yang M, Boye-Doe A, Abosabie SAS, Barr AM, Mendez LM, and Sharda AV
Abstract: Ras-like (Ral) GTPases play essential regulatory roles in many cellular processes, including exocytosis. Cycling between GDP- and GTP-bound states, Ral GTPases function as molecular switches and regulate effectors, specifically the multi-subunit tethering complex exocyst. Here, we show that Ral isoform RalB controls regulated exocytosis of Weibel-Palade bodies (WPBs), the specialized endothelial secretory granules that store hemostatic protein von Willebrand factor. Remarkably, unlike typical small GTPase-effector interactions, RalB binds exocyst in its GDP-bound state in resting endothelium. Upon endothelial cell stimulation, exocyst is uncoupled from RalB-GTP resulting in WPB tethering and exocytosis. Furthermore, we report that PKC-dependent phosphorylation of the C-terminal hypervariable region (HVR) of RalB modulates its dynamic interaction with exocyst in endothelium. Exocyst preferentially interacts with phosphorylated RalB in resting endothelium. Dephosphorylation of RalB either by endothelial cell stimulation, or PKC inhibition, or expression of nonphosphorylatable mutant at a specific serine residue of RalB HVR, disengages exocyst and augments WPB exocytosis, resembling RalB exocyst-binding site mutant. In summary, it is the uncoupling of exocyst from RalB that mediates endothelial Weibel-Palade body exocytosis. Our data shows that Ral function may be more dynamically regulated by phosphorylation and may confer distinct functionality given high degree of homology and the shared set of effector protein between the two Ral isoforms., Competing Interests: Conflict of Interest The authors declare no financial conflict of interest.
Published: 2024
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48. Protocol for a clinically annotated biorepository of samples from Australian immune-compromised patients to investigate the host-microbiome interaction.

Author: Smibert OC, Trubiano JA, Kwong JC, Markey KA, and Slavin MA
Subjects: Humans, Australia, Host Microbial Interactions immunology, Biological Specimen Banks, Prospective Studies, Research Design, Specimen Handling methods, Gastrointestinal Microbiome
Abstract: Introduction: The human gut microbiota has the potential to modulate the outcomes of several human diseases. This effect is likely to be mediated through interaction with the host immune system. This protocol details the establishment of a biorepository of clinically annotated samples, which we will use to explore correlations between the gut microbiota and the immune system of immune-compromised patients. We aim to identify microbiome-related risk factors for adverse outcomes., Methods and Analyses: This is a protocol for the development of a biorepository of clinically annotated samples collected prospectively across three centres in Melbourne, Australia. Participants will be recruited across the following clinical streams: (1) acute leukaemia and allogeneic stem cell transplant; (2) end-stage liver disease and liver transplant; (3) patients receiving any cancer immunotherapies (eg, chimeric antigen receptor therapy); (4) deceased organ donors and (5) healthy adult controls. Participants will be asked to provide paired peripheral blood and microbiota samples (stool and saliva) at either (1) single time point for healthy controls and deceased organ donors or (2) longitudinally over multiple prespecified or event-driven time points for the remaining cohorts. Sampling of fluid from bronchoalveolar lavage and colonoscopy or biopsy of tissues undertaken during routine care will also be performed., Ethics and Dissemination: Ethical approval has been obtained from the relevant local ethics committee (The Royal Melbourne Hospital Human Research Ethics Committee). The results of this study will be disseminated by various scientific platforms including social media, international presentations and publication in peer-reviewed journals., Trial Registration Number: ACTRN12623001105639. Date registered 20 October 2023., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/disclosure-of-interest/ and declare: OS had financial support in the form of a postdoctoral scholarship from the National Health and Medical Research Council (NHMRC) for the submitted work (#1191571). MS is supported by NHMRC Leadership Investigator Grant (#1173791). KAM is on the advisory board for and holds equity in Postbiotics Plus Research, and she also reports consulting fees from Crestone and Incyte. All authors have no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work. KAM reports that she holds equity and is ok the advisory board for Postbiotics Plus, and consults for Crestone., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)
Published: 2024
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49. Study protocol for the Functional Communication Checklist for people living with primary progressive aphasia.

Author: Gallée J, Cartwright J, Henry ML, Mooney A, Stark BC, Volkmer A, Nakano C, Fredericksen RJ, Domoto-Reilly K, and Crane PK
Subjects: Humans, Checklist, Reproducibility of Results, Aphasia, Primary Progressive diagnosis, Communication
Abstract: This study protocol describes the development of the first instrument of functional communication for people living with primary progressive aphasia (PPA), with future applications to other progressive conditions, with expert validation, item-level reliability analyses, input from partners in research, and outcomes. Progressive conditions like PPA require monitoring, and as such, re-assessment. Re-assessment poses the high risk of being burdensome, destructive, and of little use to the patient. As such, there is a significant need to establish a validated and reliable measure that (1) poses minimal patient burden and (2) captures communication ability in a strengths-based manner for both clinical and research purposes. A strengths-based approach to assessment is widely recognized as the optimal way to promote patient autonomy, minimize harm, and implement functional treatment protocols and strategies. To date, there are no strengths-based assessment tools that were developed for people living with PPA nor ways to efficiently document functional communication performance. This study protocol outlines our work to address this gap in clinical practice and research., Competing Interests: The authors have declared that no competing interests exist. The experimental approach described in this manuscript is supported by a 2024-2025 University of Washington Alzheimer’s Disease Research Center Development Project Award (JG). This work was also supported by the National Institute on Aging (U24 AG074855: JG & PKC; P30 AG066509: KDR)., (Copyright: © 2024 Gallée et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Published: 2024
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50. Correction: Associations of residential green space with internalizing and externalizing behavior in early childhood.

Author: Hazlehurst MF, Hajat A, Tandon PS, Szpiro AA, Kaufman JD, Tylavsky FA, Hare ME, Sathyanarayana S, Loftus CT, LeWinn KZ, Bush NR, and Karr CJ
Published: 2024
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