History of clinical transplantation

The emergence of transplantation has seen the development of increasingly potent immunosuppressive agents, progressively better methods of tissue and organ preservation, refinements in histocompatibility matching, and numerous innovations is surgical techniques. Such efforts in combination ultimately made it possible to successfully engraft all of the organs and bone marrow cells in humans. At a more fundamental level, however, the transplantation enterprise hinged on two seminal turning points. The first was the recognition by Billingham, Brent, and Medawar in 1953 that it was possible to induce chimerism-associated neonatal tolerance deliberately. This discovery escalated over the next 15 years to the first successful bone marrow transplantations in humans in 1968. The second turning point was the demonstration during the early 1960s that canine and human organ allografts could self-induce tolerance with the aid of immunosuppression. By the end of 1962, however, it had been incorrectly concluded that turning points one and two involved different immune mechanisms. The error was not corrected until well into the 1990s. In this historical account, the vast literature that sprang up during the intervening 30 years has been summarized. Although admirably documenting empiric progress in clinical transplantation, its failure to explain organ allograft acceptance predestined organ recipients to lifetime immunosuppression and precluded fundamental changes in the treatment policies. After it was discovered in 1992 that long-surviving organ transplant recipient had persistent microchimerism, it was possible to see the mechanistic commonality of organ and bone marrow transplantation. A clarifying central principle of immunology could then be synthesized with which to guide efforts to induce tolerance systematically to human tissues and perhaps ultimately to xenografts

Effects of sulfur-based hemostatic agents and gingival retraction cords handled with latex gloves on the polymerization of polyvinyl siloxane impression materials

OBJECTIVES: This study investigated the possible interactions between three addition silicone materials (Express(®), Aquasil Ultra(®) and Adsil(®)), three hemostatic agents (ferric sulfate, StatGel FS(®); aluminum sulfate, GelCord(®); and aluminum chloride, Hemostop(®)) and gingival retraction cords previously handled with latex gloves to determine whether direct contact with medicaments or indirect contamination by latex in conditions similar to those found in clinical practice inhibit or affect the setting of the impression materials. MATERIAL AND METHODS: A portable device for the simultaneous test of several specimens was specifically developed for this study. Polymerization inhibition was analyzed by examination of the impressions and the molded surface. Ten trials were performed for each addition silicone material used in the study, at a total of 240 study samples. RESULTS: All the samples tested (N=240) were nonreactive regardless of the type of combination used. CONCLUSIONS: Aluminum sulfate, ferric sulfate and aluminum chloride hemostatic solutions did not show any inhibitory potential on the addition silicone samples under study, and there were no changes in polymerization as a result of contact between addition silicone and retraction cords handled with latex gloves

Factors influencing citrus fruit scarring caused by Pezothrips kellyanus

[EN] Kelly s citrus thrips (KCT) Pezothrips kellyanus (Bagnall) (Thysanoptera: Thripidae) is a recently recorded cosmopolitan citrus pest, causing fruit scarring that results in downgrading of fruit. Due to the detrimental effects caused on fruits by KCT, we wanted to study some of the factors influencing fruit scarring. Specifically, the objectives were: (1) to determine the fruit development stage when citrus fruits are damaged by KCT and the population structure of KCT during this period, (2) to study the influence of temperature on intensity of damage, and finally, (3) to identify alternative host plants. KCT populations on flowers and fruitlets and alternate plant hosts were sampled in four citrus orchards from 2008 to 2010. The percentage of damaged fruits was also recorded. The exotic vine Araujia sericifera (Apocynaceae) was recorded as a new host for KCT. Thrips scarring started to increase at 350 650 degree-days (DD) above 10.2 C, coinciding with a peak abundance of the second instar larval stages over all 3 years of the study. The maximum percentage of larval stages of KCT was observed in the 3 years at about 500 DD, a period which corresponds to the end of May or early June. Variation in the severity of fruit scarring appeared to be related to air temperature. Temperature likely affects the synchronisation between the peak in abundance of KCT larvae, and the period when fruitlets are susceptible to thrips damage. Temperature can also influence the survival and development of KCT populations in citrus and other host plants in the citrus agro-ecosystem.The authors thank Alejandro Tena for his valuable suggestions and two anonymous referees for their careful review and helpful comments. We also extend our thanks to the owners of the commercial orchards for giving us permission to use their citrus orchards. The first author was awarded an FPI fellowship from the Polytechnic University of Valencia to obtain her PhD degree.Navarro Campos, C.; Pekas, A.; Aguilar Martí, MA.; Garcia Marí, F. (2013). Factors influencing citrus fruit scarring caused by Pezothrips kellyanus. Journal of Pest Science. (86):459-467. doi:10.1007/s10340-013-0489-7S45946786Baker GJ (2006) Kelly citrus thrips management. Fact sheet. Government of South Australia, primary industries and resources SA. http://www.sardi.sa.gov.au/__data/assets/pdf_file/0010/44875/kctfact_sheet.pdf . Accessed 16 July 2012Baker GJ, Jackman DJ, Keller M, MacGregor A, Purvis S (2002) Development of an integrated pest management system for thrips in Citrus. HAL Final Report CT97007. http://www.sardi.sa.gov.au/pestsdiseases/horticulture/horticultural_pests/kelly_citrus_thrips/research_report_1997-2000 . Accessed 16 July 2012Bedford ECG (1998) Thrips, wind and other blemishes. Citrus pests in the Republic of South Africa. In: Bedford ECG, van den Berg MA, de Villiers EA (eds) ARC-Institute for tropical and subtropical crops, Nelspruit, South Africa, pp 170–183Blank RH, Gill GSC (1997) Thrips (Thysanoptera: Terebrantia) on flowers and fruit of citrus in New Zealand. N Z J Crop Hortic Sci 25:319–332Chellemi D, Funderburk F, Hall D (1994) Seasonal abundance of flower-inhabiting Frankliniella species (Thysanoptera: Thripidae) on wild plant species. Environ Entomol 23:337–342Conti F, Tuminelli R, Amico C, Fisicaro R, Frittitta C, Perrotta G, Marullo R (2001) Monitoring Pezothrips kellyanus on citrus in eastern Sicily, Thrips and tospoviruses. In: Proceedings of the 7th international symposium on Thysanoptera, Reggio Calabria, 1–8 July 2001, Italy, pp 207–210Costa L, Mateus C, zurStrassen R, Franco JC (2006) Thrips (Thysanoptera) associated to lemon orchards in the Oeste region of Portugal. IOBC/WPRS Bull 29:285–291European Plant Protection Organisation Reporting Service [EPPO] (2006) Pezothrips kellyanus. http://www.eppo.org/QUARANTINE/Pest_Risk_Analysis/PRAdocs_insects/06-12760%20DS%20PEZTKE.doc. Accessed 18 June 2012European Plant ProtectionOrganisation Reporting Service [EPPO] (2005) Scirtothrips aurantii, Scirtothrips citri, Scirtothrips dorsalis. EPPO Bull 35:353–356Franco JC, Garcia-Marí F, Ramos AP, Besri M (2006) Survey on the situation of citrus pest management in Mediterranean countries. IOBC/WPRS Bull 29:335–346Froud KJ, Stevens PS, Steven D (2001) Survey of alternative host plants for Kelly’s citrus thrips (Pezothrips kellyanus) in citrus growing regions. N Z Plant Prot 54:15–20Gomez-Clemente F (1952) Un tisanóptero causante de daños en las naranjas de algunas zonas de Levante. Boletín de Patología Vegetal y Entomología Agrícola 19:135–146Grout TG, Morse JG, O’Connell NV, Flaherty DL, Goodell PB, Freeman MW, Coviello RL (1986) Citrus thrips (Thysanoptera: Thripidae) phenology and sampling in the San Joaquin Valley. J Econ Entomol 79:1516–1523Horton J (1918) The citrus thrips. US Dep Agric Bull 616:1–42Kirk WDJ (1987) A key to the larvae of some common Australian flower thrips (Insecta: Thysanoptera), with a host-plant survey. Aust J Zool 35:173–185Lacasa A, Llorens JM, Sánchez JA (1996) Un Scirtothrips (Thysanoptera: Thripidae) causa daños en los cítricos en España. Bol San Veg Plagas 22:79–95Lewis HC (1935) Factors influencing citrus thrips damage. J Econ Entomol 28:1011–1015Lewis T (1997) Distribution, abundance and population dynamics. In: Lewis T (ed) Thrips as crop pests. CAB International, Wallingford, pp 217–258Lovatt C, Streeter S, Minter T, O’connell N, Flaherty D, Freeman M, Goodell P (1984) Phenology of flowering in Citrus sinensis (L.) Osbeck, cv. Washington navel orange. Proc Int Soc Citric 1:186–190Marullo R (1998) Pezothrips kellyanus, un nuovo tripide parassita delle colture meridionali. Informatore Fitopatologico 48:72–75Milne JR, Milne M, Walter GH (1997) A key to larval thrips (Thysanoptera) from Granite Belt stonefruit trees and a first description of Pseudanaphothrips achaetus (Bagnall) larvae. Aust J Entomol 36:319–326Mound LA, Jackman DJ (1998) Thrips in the economy and ecology of Australia, In: Zalucki MP, RAI Drew RAI, White GG (eds) Pest Management: future challenges, Proceedings of the sixth Australian applied entomological research conference, University of Queensland, St. Lucia, pp 472–478Mound LA, Marullo R (1996) The thrips of Central and South America (Insecta: Thysanoptera): an introduction. Mem Entomol Int 6:1–487Mound LA, Walker AK (1982) Terebrantia (Insecta: Thysanoptera). Fauna N Z 1:1–113Navarro-Campos C, Marzal C, Aguilar A, GarciaMarí F (2010) Presencia del microlepidóptero Anatrachyntisbadia en cítricos: descripción, comportamiento y daños al fruto. Levante Agrícola 402:270–276Navarro-Campos C, Aguilar A, Garcia-Marí F (2011) Population trend and fruit damage of Pezothrips kellyanus in citrus orchards in Valencia (Spain). IOBC/WPRS Bull 62: 285–292Navarro-Campos C, Aguilar A, Garcia-Marí F (2012) Aggregation pattern, sampling plan and intervention threshold for Pezothrips kellyanus in citrus groves. Entomol Exp Appl 142:130–139Northfield TD, Paini DR, Funderburk JE, Reitz SR (2008) Annual cycles of Frankliniella spp. (Thysanoptera: Thripidae) thrips abundance on North Florida uncultivated reproductive hosts: predicting possible sources of pest outbreaks. Ann Entomol Soc Am 101:769–778Orphanides G (1997) Thrips on citrus. Annual Review for 1997. 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A statistical framework for cross-tissue transcriptome-wide association analysis

Transcriptome-wide association analysis is a powerful approach to studying the genetic architecture of complex traits. A key component of this approach is to build a model to impute gene expression levels from genotypes by using samples with matched genotypes and gene expression data in a given tissue. However, it is challenging to develop robust and accurate imputation models with a limited sample size for any single tissue. Here, we first introduce a multi-task learning method to jointly impute gene expression in 44 human tissues. Compared with single-tissue methods, our approach achieved an average of 39% improvement in imputation accuracy and generated effective imputation models for an average of 120% more genes. We describe a summary-statistic-based testing framework that combines multiple single-tissue associations into a powerful metric to quantify the overall gene–trait association. We applied our method, called UTMOST (unified test for molecular signatures), to multiple genome-wide-association results and demonstrate its advantages over single-tissue strategies

Proteomic characterization of HIV-modulated membrane receptors, kinases and signaling proteins involved in novel angiogenic pathways

<p>Abstract</p> <p>Background</p> <p>Kaposi's sarcoma (KS), hemangioma, and other angioproliferative diseases are highly prevalent in HIV-infected individuals. While KS is etiologically linked to the human herpesvirus-8 (HHV8) infection, HIV-patients without HHV-8 and those infected with unrelated viruses also develop angiopathies. Further, HIV-Tat can activate protein-tyrosine-kinase (PTK-activity) of the vascular endothelial growth factor receptor involved in stimulating angiogenic processes. However, Tat by itself or HHV8-genes alone cannot induce angiogenesis <it>in vivo </it>unless specific proteins/enzymes are produced synchronously by different cell-types. We therefore tested a hypothesis that <it>chronic </it>HIV-<it>replication in non-endothelial cells </it>may produce novel factors that provoke angiogenic pathways.</p> <p>Methods</p> <p>Genome-wide proteins from HIV-infected and uninfected T-lymphocytes were tested by subtractive proteomics analyses at various stages of virus and cell growth <it>in vitro </it>over a period of two years. Several thousand differentially regulated proteins were identified by mass spectrometry (MS) and >200 proteins were confirmed in multiple gels. Each protein was scrutinized extensively by protein-interaction-pathways, bioinformatics, and statistical analyses.</p> <p>Results</p> <p>By functional categorization, 31 proteins were identified to be associated with various signaling events involved in angiogenesis. 88% proteins were located in the plasma membrane or extracellular matrix and >90% were found to be essential for regeneration, neovascularization and angiogenic processes during embryonic development.</p> <p>Conclusion</p> <p>Chronic HIV-infection of T-cells produces membrane receptor-PTKs, serine-threonine kinases, growth factors, adhesion molecules and many diffusible signaling proteins that have not been previously reported in HIV-infected cells. Each protein has been associated with endothelial cell-growth, morphogenesis, sprouting, microvessel-formation and other biological processes involved in angiogenesis (p = 10^-4to 10^-12). Bioinformatics analyses suggest that overproduction of PTKs and other kinases in HIV-infected cells has <it>suppressed </it>VEGF/VEGFR-PTK expression and promoted <it>VEGFR-independent </it>pathways. This unique mechanism is similar to that observed in neovascularization and angiogenesis during embryogenesis. Validation of clinically relevant proteins by gene-silencing and translational studies <it>in vivo </it>would identify specific targets that can be used for early diagnosis of angiogenic disorders and future development of inhibitors of angiopathies. This is the first comprehensive study to demonstrate that HIV-infection alone, without any co-infection or treatment, can induce numerous "embryonic" proteins and kinases capable of generating novel <it>VEGF-independent </it>angiogenic pathways.</p

Intra- and Inter-Individual Differences in Adolescent Depressive Mood: the Role of Relationships with Parents and Friends

Abstract: Utilizing four waves of data from 1126 secondary school Dutch adolescents (Mage = 13.95 at the first wave; 53% boys), the current study examined the interplay between parent-adolescent and friend-adolescent relationship quality (satisfaction and conflict) in relation to adolescents’ depressive mood. Using multilevel analyses, the interacting effects of parent/friend relationship quality on depressive mood were tested at both the intra- and inter-individual level. Analyses at the intra-individual level investigated whether individual depressive mood fluctuated along with changes in their social relationships regardless of one’s general level of depressive mood; and analyses at the inter-individual level examined whether the average differences in depressive mood between adolescents were associated with different qualities of social relationships. We interpreted the patterns of interactions between parent and friend relationships using four theoretical models: the reinforcement, toxic friends, compensation, and additive model. The results demonstrate the covariation of parent- and friend- relationship quality with adolescents’ depressive mood, and highlight that parent and peer effects are not independent from each other—affirming the compensation and additive models at the intra-individual and the reinforcement and additive models at the inter-individual level. The findings highlight the robustness of the protective effects of parent and peer support and the deleterious effects of conflictual relationships for adolescent mental health. The results have implications for both the theoretical and practical design of (preventive) interventions aimed at decreasing adolescents’ depressive mood

Meta-analysis of genetic association with diagnosed Alzheimer’s disease identifies novel risk loci and implicates Abeta, Tau, immunity and lipid processing

Introduction Late-onset Alzheimer’s disease (LOAD, onset age > 60 years) is the most prevalent dementia in the elderly 1 , and risk is partially driven by genetics 2 . Many of the loci responsible for this genetic risk were identified by genome-wide association studies (GWAS) 3–8 . To identify additional LOAD risk loci, the we performed the largest GWAS to date (89,769 individuals), analyzing both common and rare variants. We confirm 20 previous LOAD risk loci and identify four new genome-wide loci ( IQCK , ACE , ADAM10 , and ADAMTS1 ). Pathway analysis of these data implicates the immune system and lipid metabolism, and for the first time tau binding proteins and APP metabolism. These findings show that genetic variants affecting APP and Aβ processing are not only associated with early-onset autosomal dominant AD but also with LOAD. Analysis of AD risk genes and pathways show enrichment for rare variants ( P = 1.32 × 10 −7 ) indicating that additional rare variants remain to be identified.ADGC. The National Institutes of Health, National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC, U01 AG032984, RC2 AG036528; Samples from the National Cell Repository for Alzheimer’s Disease (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA), were used in this study. We thank contributors who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible; Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer’s Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689-01); NACC, U01 AG016976; NIA LOAD (Columbia University), U24 AG026395, U24 AG026390, R01AG041797; Banner Sun Health Research Institute P30 AG019610; Boston University, P30 AG013846, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG017173, R01 AG025259, R01 AG048927, R01AG33193, R01 AG009029; Columbia University, P50 AG008702, R37 AG015473, R01 AG037212, R01 AG028786; Duke University, P30 AG028377, AG05128; Emory University, AG025688; Group Health Research Institute, UO1 AG006781, UO1 HG004610, UO1 HG006375, U01 HG008657; Indiana University, P30 AG10133, R01 AG009956, RC2 AG036650; Johns Hopkins University, P50 AG005146, R01 AG020688; Massachusetts General Hospital, P50 AG005134; Mayo Clinic, P50 AG016574, R01 AG032990, KL2 RR024151; Mount Sinai School of Medicine, P50 AG005138, P01 AG002219; New York University, P30 AG08051, UL1 RR029893, 5R01AG012101, 5R01AG022374, 5R01AG013616, 1RC2AG036502, 1R01AG035137; North Carolina A&T University, P20 MD000546, R01 AG28786-01A1; Northwestern University, P30 AG013854; Oregon Health & Science University, P30 AG008017, R01 AG026916; Rush University, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG030146, R01 AG01101, RC2 AG036650, R01 AG22018; TGen, R01 NS059873; University of Alabama at Birmingham, P50 AG016582; University of Arizona, R01 AG031581; University of California, Davis, P30 AG010129; University of California, Irvine, P50 AG016573; University of California, Los Angeles, P50 AG016570; University of California, San Diego, P50 AG005131; University of California, San Francisco, P50 AG023501, P01 AG019724; University of Kentucky, P30 AG028383, AG05144; University of Michigan, P50 AG008671; University of Pennsylvania, P30 AG010124; University of Pittsburgh, P50 AG005133, AG030653, AG041718, AG07562, AG02365; University of Southern California, P50 AG005142; University of Texas Southwestern, P30 AG012300; University of Miami, R01 AG027944, AG010491, AG027944, AG021547, AG019757; University of Washington, P50 AG005136, R01 AG042437; University of Wisconsin, P50 AG033514; Vanderbilt University, R01 AG019085; and Washington University, P50 AG005681, P01 AG03991, P01 AG026276. The Kathleen Price Bryan Brain Bank at Duke University Medical Center is funded by NINDS grant # NS39764, NIMH MH60451 and by Glaxo Smith Kline. Support was also from the Alzheimer’s Association (LAF, IIRG-08-89720; MP-V, IIRG-05-14147), the US Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program, and BrightFocus Foundation (MP-V, A2111048). P.S.G.-H. is supported by Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institute of Health Research. Genotyping of the TGEN2 cohort was supported by Kronos Science. The TGen series was also funded by NIA grant AG041232 to AJM and MJH, The Banner Alzheimer’s Foundation, The Johnnie B. Byrd Sr. Alzheimer’s Institute, the Medical Research Council, and the state of Arizona and also includes samples from the following sites: Newcastle Brain Tissue Resource (funding via the Medical Research Council, local NHS trusts and Newcastle University), MRC London Brain Bank for Neurodegenerative Diseases (funding via the Medical Research Council),South West Dementia Brain Bank (funding via numerous sources including the Higher Education Funding Council for England (HEFCE), Alzheimer’s Research Trust (ART), BRACE as well as North Bristol NHS Trust Research and Innovation Department and DeNDRoN), The Netherlands Brain Bank (funding via numerous sources including Stichting MS Research, Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds, Internationale Stiching Alzheimer Onderzoek), Institut de Neuropatologia, Servei Anatomia Patologica, Universitat de Barcelona. ADNI data collection and sharing was funded by the National Institutes of Health Grant U01 AG024904 and Department of Defense award number W81XWH-12-2-0012. ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. We thank Drs. D. Stephen Snyder and Marilyn Miller from NIA who are ex-officio ADGC members. EADI. This work has been developed and supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease) including funding from MEL (Metropole européenne de Lille), ERDF (European Regional Development Fund) and Conseil Régional Nord Pas de Calais. This work was supported by INSERM, the National Foundation for Alzheimer’s disease and related disorders, the Institut Pasteur de Lille and the Centre National de Génotypage, the JPND PERADES, GENMED, and the FP7 AgedBrainSysBio. The Three-City Study was performed as part of collaboration between the Institut National de la Santé et de la Recherche Médicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi- Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne Regional Councils, Agence Nationale de la Recherche, ANR supported the COGINUT and COVADIS projects. Fondation de France and the joint French Ministry of Research/INSERM “Cohortes et collections de données biologiques” programme. Lille Génopôle received an unconditional grant from Eisai. The Three-city biological bank was developed and maintained by the laboratory for genomic analysis LAG-BRC - Institut Pasteur de Lille. This work was further supported by the CoSTREAM project (http://www.costream.eu/) and funding from the European Union's Horizon 2020 research and innovation program under grant agreement 667375. Belgium samples: Research at the Antwerp site is funded in part by the Belgian Science Policy Office Interuniversity Attraction Poles program, the Belgian Alzheimer Research Foundation, the Flemish government-initiated Flanders Impulse Program on Networks for Dementia Research (VIND) and the Methusalem excellence program, the Research Foundation Flanders (FWO), and the University of Antwerp Research Fund, Belgium. The Antwerp site authors thank the personnel of the VIB Neuromics Support Facility, the Biobank of the Institute Born-Bunge and neurology departments at the contributing hospitals. The authors acknowledge the members of the BELNEU consortium for their contributions to the clinical and pathological characterization of Belgium patients and the personnel of the Diagnostic Service Facility for the genetic testing. Finish sample collection: Financial support for this project was provided by Academy of Finland (grant number 307866), Sigrid Jusélius Foundation and the Strategic Neuroscience Funding of the University of Eastern Finland. Swedish sample collection: Financially supported in part by the Swedish Brain Power network, the Marianne and Marcus Wallenberg Foundation, the Swedish Research Council (521-2010-3134, 2015-02926), the King Gustaf V and Queen Victoria’s Foundation of Freemasons, the Regional Agreement on Medical Training and Clinical Research (ALF) between Stockholm County Council and the Karolinska Institutet, the Swedish Brain Foundation and the Swedish Alzheimer Foundation”. CHARGE. Infrastructure for the CHARGE Consortium is supported in part by National Heart, Lung, and Blood Institute grant HL105756 (Psaty) and RC2HL102419 (Boerwinkle) and the neurology working group by grants from the National Institute on Aging, R01 AG033193, U01 AG049505 and U01AG52409. Rotterdam (RS). This study was funded by the Netherlands Organisation for Health Research and Development (ZonMW) as part of the Joint Programming for Neurological Disease (JPND)as part of the PERADES Program (Defining Genetic Polygenic, and Environmental Risk for Alzheimer’s disease using multiple powerful cohorts, focused Epigenetics and Stem cell metabolomics), Project number 733051021. This work was funded also by the European Union Innovative Medicine Initiative (IMI) programme under grant agreement No. 115975 as part of the Alzheimer’s Disease Apolipoprotein Pathology for Treatment Elucidation and Development (ADAPTED, https://www.imi-adapted.eu);and the European Union’s Horizon 2020 research and innovation programme as part of the Common mechanisms and pathways in Stroke and Alzheimer’s disease CoSTREAM project (www.costream.eu, grant agreement No. 667375). The current study is supported by the Deltaplan Dementie and Memorabel supported by ZonMW (Project number 733050814) and Alzheimer Nederland. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The generation and management of GWAS genotype data for the Rotterdam Study (RS-I, RS-II, RS-III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The GWAS datasets are supported by the Netherlands Organization of Scientific Research NWO Investments (Project number 175.010.2005.011, 911-03-012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project number 050-060-810. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera and Marjolein Peters, MSc, and Carolina Medina-Gomez, MSc, for their help in creating the GWAS database, and Karol Estrada, PhD, Yurii Aulchenko, PhD, and Carolina Medina-Gomez, MSc, for the creation and analysis of imputed data. AGES. The AGES study has been funded by NIA contracts N01-AG-12100 and HHSN271201200022C with contributions from NEI, NIDCD, and NHLBI, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). Cardiovascular Health Study (CHS). This research was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086 and grant U01HL080295 and U01HL130114 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG033193, R01AG023629, R01AG15928, and R01AG20098 and by U01AG049505 from the National Institute on Aging (NIA). The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. A full list of CHS principal investigators and institutions can be found at https://chs-nhlbi.org/. The content is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health. Framingham Heart Study. This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (contracts N01-HC-25195 and HHSN268201500001I). This study was also supported by grants from the National Institute on Aging: R01AG033193, U01AG049505, U01AG52409, R01AG054076 (S. Seshadri). S. Seshadri and A.L.D. were also supported by additional grants from the National Institute on Aging (R01AG049607, R01AG033040) and the National Institute of Neurological Disorders and Stroke (R01- NS017950, NS100605). The content is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health. GR@ACE cohort. Fundació ACE We would like to thank patients and controls who participated in this project. Genome Resesarch @ Fundació ACE project (GR@ACE) is supported by Fundación bancaria “La Caixa”, Grifols SA, Fundació ACE and ISCIII. We also want to thank other private sponsors supporting the basic and clinical projects of our institution (Piramal AG, Laboratorios Echevarne, Araclon Biotech S.A. and Fundació ACE). We are indebted to Trinitat Port-Carbó legacy and her family for their support of Fundació ACE research programs. Fundació ACE collaborates with the Centro de Investigación Biomédica en Red sobreEnfermedades Neurodegenerativas (CIBERNED, Spain) and is one of the participating centers of the Dementia Genetics Spanish Consortium (DEGESCO). A.R. and M.B. are receiving support from the European Union/EFPIA Innovative Medicines Initiative Joint Undertaking ADAPTED and MOPEAD projects (Grants No. 115975 and 115985 respectively). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861 and PI17/01474. Acción Estratégica en Salud integrated in the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER- “Una manera de Hacer Europa”). Control samples and data from patients included in this study were provided in part by the National DNA Bank Carlos III (www.bancoadn.org, University of Salamanca, Spain) and Hospital Universitario Virgen de Valme (Sevilla, Spain) and they were processed following standard operating procedures with the appropriate approval of the Ethical and Scientific Committee. GERAD/PERADES. We thank all individuals who participated in this study. Cardiff University was supported by the Wellcome Trust, Alzheimer’s Society (AS; grant RF014/164), the Medical Research Council (MRC; grants G0801418/1, MR/K013041/1, MR/L023784/1), the European Joint Programme for Neurodegenerative Disease (JPND, grant MR/L501517/1), Alzheimer’s Research UK (ARUK, grant ARUK-PG2014-1), Welsh Assembly Government (grant SGR544:CADR), a donation from the Moondance Charitable Foundation, and the UK Dementia Research Institute at Cardiff. Cambridge University acknowledges support from the MRC. ARUK supported sample collections at the Kings College London, the South West Dementia Bank, Universities of Cambridge, Nottingham, Manchester and Belfast. King’s College London was supported by the NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at the South London and Maudsley NHS Foundation Trust and Kings College London and the MRC. Alzheimer’s Research UK (ARUK) and the Big Lottery Fund provided support to Nottingham University. Ulster Garden Villages, AS, ARUK, American Federation for Aging Research, NI R&D Office and the Royal College of Physicians/Dunhill Medical Trust provided support for Queen’s University, Belfast. The University of Southampton acknowledges support from the AS. The MRC and Mercer’s Institute for Research on Ageing supported the Trinity College group. DCR is a Wellcome Trust Principal Research fellow. The South West Dementia Brain Bank acknowledges support from Bristol Research into Alzheimer’s and Care of the Elderly. The Charles Wolfson Charitable Trust supported the OPTIMA group. Washington University was funded by NIH grants, Barnes Jewish Foundation and the Charles and Joanne Knight Alzheimer’s Research Initiative. Patient recruitment for the MRC Prion Unit/UCL Department of Neurodegenerative Disease collection was supported by the UCLH/UCL Biomed- ical Centre and their work was supported by the NIHR Queen Square Dementia BRU. LASER-AD was funded by Lundbeck SA. The Bonn group would like to thank Dr. Heike Koelsch for her scientific support. The Bonn group was funded by the German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant number 01GI0102, 01GI0711, 01GI0420. The AgeCoDe study group was supported by the German Federal Ministry for Education and Research grants 01 GI 0710, 01 GI 0712, 01 GI 0713, 01 GI 0714, 01 GI 0715, 01 GI 0716, 01 GI 0717. Genotyping of the Bonn case-control sample was funded by the German centre for Neurodegenerative Diseases (DZNE), Germany. The GERAD Consortium also used samples ascertained by the NIMH AD Genetics Initiative. HH was supported by a grant of the Katharina-Hardt-Foundation, Bad Homburg vor der Höhe, Germany. The KORA F4 studies were financed by Helmholtz Zentrum München; German Research Center for Environmental Health; BMBF; German National Genome Research Network and the Munich Center of Health Sciences. The Heinz Nixdorf Recall cohort was funded by the Heinz Nixdorf Foundation (Dr. Jur. G.Schmidt, Chairman) and BMBF. Coriell Cell Repositories is supported by NINDS and the Intramural Research Program of the National Institute on Aging. We acknowledge use of genotype data from the 1958 Birth Cohort collection, funded by the MRC and the Wellcome Trust which was genotyped by the Wellcome Trust Case Control Consortium and the Type-1 Diabetes Genetics Consortium, sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Allergy and Infectious Diseases, National Human Genome Research Institute, National Institute of Child Health and Human Development and Juvenile Diabetes Research Foundation International. The Bonn samples are part of the German Dementia Competance Network (DCN) and the German Research Network on Degenerative Dementia (KNDD), which are funded by the German Federal Ministry of Education and Research (grants KND: 01G10102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 04GI0434; grants KNDD: 01GI1007A, 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716, 01ET1006B). Markus M Nothen is a member of the German Research Foundation (DFG) cluster of excellence ImmunoSensation. Funding for Saarland University was provided by the German Federal Ministry of Education and Research (BMBF), grant number 01GS08125 to Matthias Riemenschneider. The University of Washington was supported by grants from the National Institutes of Health (R01-NS085419 and R01-AG044546), the Alzheimer’s Association (NIRG-11-200110) and the American Federation for Aging Research (Carlos Cruchaga was recipient of a New Investigator Award in Alzhei