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80 results on '"Longo, D.L."'

3. Recommendations for preclinical renal MRI: a comprehensive open-access protocol collection to improve training, reproducibility, and comparability of studies

Author

Pohlmann, A., Back, S.J., Fekete, A., Friedli, I., Hectors, S., Jerome, N.P., Ku, M.C., Longo, D.L., Meier, M., Millward, J.M., Periquito, J.S., Seeliger, E., Serai, S.D, Waiczies, S., Sourbron, S., Laustsen, C., Niendorf, T., Pohlmann, A., and Niendorf, T.

Subjects
Cardiovascular and Metabolic Diseases, Technology Platforms
Abstract

Renal MRI holds incredible promise for making a quantum leap in improving diagnosis and care of patients with a multitude of diseases, by moving beyond the limitations and restrictions of current routine clinical practice. Clinical and preclinical renal MRI is advancing with ever increasing rapidity, and yet, aside from a few examples of renal MRI in routine use, it is still not good enough. Several roadblocks are still delaying the pace of progress, particularly inefficient education of renal MR researchers, and lack of harmonization of approaches that limits the sharing of results among multiple research groups.Here we aim to address these limitations for preclinical renal MRI (predominantly in small animals), by providing a comprehensive collection of more than 40 publications that will serve as a foundational resource for preclinical renal MRI studies. This includes chapters describing the fundamental principles underlying a variety of renal MRI methods, step-by-step protocols for executing renal MRI studies, and detailed guides for data analysis. This collection will serve as a crucial part of a roadmap toward conducting renal MRI studies in a robust and reproducible way, that will promote the standardization and sharing of data.This chapter is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers.

Published
2021

5. Sarcoma treatment in the era of molecular medicine

Author

Grünewald, T.G., Alonso, M., Avnet, S., Banito, A., Burdach, S., Cidre-Aranaz, F., Pompo, G. Di, Distel, M., Dorado-Garcia, H., Garcia-Castro, J., González-González, L., Grigoriadis, A.E., Kasan, M., Koelsche, C., Krumbholz, M., Lecanda, F., Lemma, S., Longo, D.L., Madrigal-Esquivel, C., Morales-Molina, Á., Musa, J., Ohmura, S., Ory, B., Pereira-Silva, M., Perut, F., Rodriguez, R., Seeling, C., Shaaili, N. Al, Shaabani, S., Shiavone, K., Sinha, S., Tomazou, E.M., Trautmann, M., Vela, M., Versleijen-Jonkers, Y.M.H., Visgauss, J., Zalacain, M., Schober, S.J., Lissat, A., English, W.R., Baldini, N., Heymann, D., Grünewald, T.G., Alonso, M., Avnet, S., Banito, A., Burdach, S., Cidre-Aranaz, F., Pompo, G. Di, Distel, M., Dorado-Garcia, H., Garcia-Castro, J., González-González, L., Grigoriadis, A.E., Kasan, M., Koelsche, C., Krumbholz, M., Lecanda, F., Lemma, S., Longo, D.L., Madrigal-Esquivel, C., Morales-Molina, Á., Musa, J., Ohmura, S., Ory, B., Pereira-Silva, M., Perut, F., Rodriguez, R., Seeling, C., Shaaili, N. Al, Shaabani, S., Shiavone, K., Sinha, S., Tomazou, E.M., Trautmann, M., Vela, M., Versleijen-Jonkers, Y.M.H., Visgauss, J., Zalacain, M., Schober, S.J., Lissat, A., English, W.R., Baldini, N., and Heymann, D.

Abstract

Contains fulltext : 229496.pdf (publisher's version ) (Open Access), Sarcomas are heterogeneous and clinically challenging soft tissue and bone cancers. Although constituting only 1% of all human malignancies, sarcomas represent the second most common type of solid tumors in children and adolescents and comprise an important group of secondary malignancies. More than 100 histological subtypes have been characterized to date, and many more are being discovered due to molecular profiling. Owing to their mostly aggressive biological behavior, relative rarity, and occurrence at virtually every anatomical site, many sarcoma subtypes are in particular difficult-to-treat categories. Current multimodal treatment concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements have enabled a more precise molecular characterization of sarcoma subtypes and revealed novel therapeutic targets and prognostic/predictive biomarkers. This review aims at providing a comprehensive overview of the latest advances in the molecular biology of sarcomas and their effects on clinical oncology; it is meant for a broad readership ranging from novices to experts in the field of sarcoma.

Published
2020

10. Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis

Author

Rooij, F.J.A. (Frank) van, Qayyum, Q. (Rehan), Smith, A.V. (Albert Vernon), Zhou, Y. (Yi), Trompet, S. (Stella), Tanaka, T. (Toshiko), Keller, M.F. (Margaux), Chang, L.-C. (Li-Ching), Schmidt, H. (Helena), Yang, M.-L. (Min-Lee), Chen, M.-H. (Ming-Huei), Hayes, J. (James), Johnson, A.D. (Andrew), Yanek, L.R. (Lisa), Mueller, C. (Christian), Lange, L.A. (Leslie), Floyd, J. (James), Ghanbari, M. (Mohsen), Zonderman, A.B., Jukema, J.W., Hofman, A. (Albert), Duijn, C.M. (Cornelia) van, Desch, K.C. (Karl C.), Saba, Y. (Yasaman), Ozel, A.B. (Ayse), Snively, B.M. (Beverly M.), Wu, J.-Y. (Jer-Yuarn), Schmidt, R. (Reinhold), Fornage, M. (Myriam), Klein, R.J. (Robert J.), Fox, C.S. (Caroline), Matsuda, K. (Koichi), Kamatani, N. (Naoyuki), Wild, P.S. (Philipp S.), Stott, D.J. (David J.), Ford, I., Slagboom, P.E. (Eline), Yang, J. (Jaden), Chu, A.Y. (Audrey Y), Lambert, A.J. (Amy J.), Uitterlinden, A.G. (André), Franco, O.H. (Oscar), Hofer, E. (Edith), Ginsburg, D. (David), Hu, B. (Bella), Keating, J. (John), Schick, U.M. (Ursula), Brody, J.A. (Jennifer A.), Li, J.Z. (Jun Z.), Chen, Z. (Zhao), Zeller, T. (Tanja), Guralnik, J.M. (Jack M.), Chasman, D.I. (Daniel), Peters, L.L. (Luanne L.), Kubo, M. (Michiaki), Becker, D.M. (Diane M.), Li, J. (Jin), Eiriksdottir, G. (Gudny), Rotter, J.I. (Jerome I.), Levy, D. (Daniel), Grossmann, V. (Vera), Patel, K.V. (Kushang V.), Chen, C.-H., Ridker, P.M. (Paul M.), Tang, H. (Hua), Launer, L.J. (Lenore), Rice, K.M. (Kenneth M.), Li-Gao, R. (Ruifang), Ferrucci, L. (Luigi), Evans, M.K. (Michelle K.), Choudhuri, A. (Avik), Trompouki, E. (Eirini), Abraham, B.J. (Brian J.), Yang, S. (Song), Takahashi, A. (Atsushi), Kamatani, Y. (Yoichiro), Kooperberg, C. (Charles), Harris, T.B. (Tamara), Jee, S.H. (Sun Ha), Coresh, J. (Josef), Tsai, F.-J. (Fuu-Jen), Longo, D.L. (Dan L.), Chen, Y.-T. (Yuan-Tsong), Felix, J.F. (Janine), Yang, Q. (Qiong), Psaty, B.M. (Bruce), Boerwinkle, E.A. (Eric), Becker, L.C. (Lewis C.), Mook-Kanamori, D.O. (Dennis), Wilson, J.F. (James), Gudnason, V. (Vilmundur), O'Donnell, C.J. (Christopher J.), Dehghan, A. (Abbas), Cupples, L.A. (Adrienne), Nalls, M.A. (Michael), Morris, A.P. (Andrew), Okada, Y. (Yukinori), Reiner, A.P. (Alexander P.), Zon, L.I. (Leonard), Ganesh, S.K. (Santhi), Rooij, F.J.A. (Frank) van, Qayyum, Q. (Rehan), Smith, A.V. (Albert Vernon), Zhou, Y. (Yi), Trompet, S. (Stella), Tanaka, T. (Toshiko), Keller, M.F. (Margaux), Chang, L.-C. (Li-Ching), Schmidt, H. (Helena), Yang, M.-L. (Min-Lee), Chen, M.-H. (Ming-Huei), Hayes, J. (James), Johnson, A.D. (Andrew), Yanek, L.R. (Lisa), Mueller, C. (Christian), Lange, L.A. (Leslie), Floyd, J. (James), Ghanbari, M. (Mohsen), Zonderman, A.B., Jukema, J.W., Hofman, A. (Albert), Duijn, C.M. (Cornelia) van, Desch, K.C. (Karl C.), Saba, Y. (Yasaman), Ozel, A.B. (Ayse), Snively, B.M. (Beverly M.), Wu, J.-Y. (Jer-Yuarn), Schmidt, R. (Reinhold), Fornage, M. (Myriam), Klein, R.J. (Robert J.), Fox, C.S. (Caroline), Matsuda, K. (Koichi), Kamatani, N. (Naoyuki), Wild, P.S. (Philipp S.), Stott, D.J. (David J.), Ford, I., Slagboom, P.E. (Eline), Yang, J. (Jaden), Chu, A.Y. (Audrey Y), Lambert, A.J. (Amy J.), Uitterlinden, A.G. (André), Franco, O.H. (Oscar), Hofer, E. (Edith), Ginsburg, D. (David), Hu, B. (Bella), Keating, J. (John), Schick, U.M. (Ursula), Brody, J.A. (Jennifer A.), Li, J.Z. (Jun Z.), Chen, Z. (Zhao), Zeller, T. (Tanja), Guralnik, J.M. (Jack M.), Chasman, D.I. (Daniel), Peters, L.L. (Luanne L.), Kubo, M. (Michiaki), Becker, D.M. (Diane M.), Li, J. (Jin), Eiriksdottir, G. (Gudny), Rotter, J.I. (Jerome I.), Levy, D. (Daniel), Grossmann, V. (Vera), Patel, K.V. (Kushang V.), Chen, C.-H., Ridker, P.M. (Paul M.), Tang, H. (Hua), Launer, L.J. (Lenore), Rice, K.M. (Kenneth M.), Li-Gao, R. (Ruifang), Ferrucci, L. (Luigi), Evans, M.K. (Michelle K.), Choudhuri, A. (Avik), Trompouki, E. (Eirini), Abraham, B.J. (Brian J.), Yang, S. (Song), Takahashi, A. (Atsushi), Kamatani, Y. (Yoichiro), Kooperberg, C. (Charles), Harris, T.B. (Tamara), Jee, S.H. (Sun Ha), Coresh, J. (Josef), Tsai, F.-J. (Fuu-Jen), Longo, D.L. (Dan L.), Chen, Y.-T. (Yuan-Tsong), Felix, J.F. (Janine), Yang, Q. (Qiong), Psaty, B.M. (Bruce), Boerwinkle, E.A. (Eric), Becker, L.C. (Lewis C.), Mook-Kanamori, D.O. (Dennis), Wilson, J.F. (James), Gudnason, V. (Vilmundur), O'Donnell, C.J. (Christopher J.), Dehghan, A. (Abbas), Cupples, L.A. (Adrienne), Nalls, M.A. (Michael), Morris, A.P. (Andrew), Okada, Y. (Yukinori), Reiner, A.P. (Alexander P.), Zon, L.I. (Leonard), and Ganesh, S.K. (Santhi)

Abstract

Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPM

Published
2017
Full Text
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11. Novel genetic loci associated with hippocampal volume

Author

Hibar, D.P. (Derrek), Adams, H.H.H. (Hieab), Jahanshad, N. (Neda), Chauhan, G. (Ganesh), Stein, J.L., Hofer, E. (Edith), Rentería, M.E. (Miguel), Bis, J.C. (Joshua), Arias-Vásquez, A. (Alejandro), Ikram, M.K. (M. Kamran), Desrivières, S. (Sylvane), Vernooij, M.W. (Meike), Abramovic, L. (Lucija), Alhusaini, S. (Saud), Amin, N. (Najaf), Andersson, M. (Micael), Arfanakis, K. (Konstantinos), Aribisala, B. (Benjamin), Armstrong, N.J. (Nicola J.), Athanasiu, L. (Lavinia), Axelsson, T. (Tomas), Beecham, A.H. (Ashley), Beiser, A. (Alexa), Bernard, M. (Manon), Blanton, S.H. (Susan H.), Bohlken, M.M. (Marc M.), Boks, M.P.M. (Marco), Bralten, L.B.C. (Linda), Brickman, A.M. (Adam M.), Carmichael, O. (Owen), Chakravarty, M.M. (M. Mallar), Chen, Q. (Qiang), Ching, C.R.K. (Christopher), Chouraki, V. (Vincent), Cuellar-Partida, G. (Gabriel), Crivello, F. (Fabrice), Braber, A. (Anouk) den, Doan, N.T. (Nhat Trung), Ehrlich, S.M. (Stefan), Giddaluru, S. (Sudheer), Goldman, A.L. (Aaron L.), Gottesman, R.F. (Rebecca), Grimm, O. (Oliver), Griswold, M.D. (Michael), Guadalupe, T. (Tulio), Gutman, B.A. (Boris A.), Hass, J. (Johanna), Haukvik, U.K. (Unn), Hoehn, D. (David), Holmes, A.J. (Avram), Hoogman, M. (Martine), Janowitz, D. (Deborah), Jia, T. (Tianye), Jørgensen, K.N. (Kjetil N.), Karbalai, N. (Nazanin), Kasperaviciute, D. (Dalia), Kim, S. (Shinseog), Klein, M. (Marieke), Kraemer, B. (Bernd), Lee, P.H. (Phil), Liewald, D.C.M. (David), Lopez, L.M. (Lorna), Luciano, M. (Michelle), MacAre, C. (Christine), Marquand, A.F. (Andre F.), Matarin, M. (Mar), Mather, R., Mattheisen, M. (Manuel), McKay, D.R. (David R.), Milaneschi, Y. (Yuri), Muñoz Maniega, S. (Susana), Nho, K. (Kwangsik), Nugent, A.C. (Allison), Nyquist, P. (Paul), Loohuis, L.M.O. (Loes M. Olde), Oosterlaan, J. (Jaap), Papmeyer, M. (Martina), Pirpamer, L. (Lukas), Pütz, B. (Benno), Ramasamy, A. (Adaikalavan), Richards, J.S. (Jennifer S.), Risacher, S.L. (Shannon), Roiz-Santiañez, R. (Roberto), Rommelse, N. (Nanda), Ropele, S. (Stefan), Rose, E.J. (Emma), Royle, N.A. (Natalie), Rundek, T. (Tatjana), Sämann, P.G. (Philipp), Saremi, A. (Arvin), Satizabal, C.L. (Claudia), Schmaal, L. (Lianne), Schork, N.J. (Nicholas), Shen, L. (Li), Shin, J. (Jean), Shumskaya, E. (Elena), Smith, A.V. (Albert Vernon), Sprooten, R. (Roy), Strike, L.T. (Lachlan), Teumer, A. (Alexander), Tordesillas-Gutierrez, D. (Diana), Toro, R. (Roberto), Trabzuni, D. (Danyah), Trompet, S. (Stella), Vaidya, D. (Dhananjay), van der Grond, J. (Jeroen), Lee, S.J. (Sven) van der, Van Der Meer, D. (Dennis), Van Donkelaar, M.M.J. (Marjolein M. J.), Eijk, K.R. (Kristel) van, Erp, T.G.M. (Theo G.) van, Van Rooij, D. (Daan), Walton, E. (Esther), Westlye, L.T. (Lars), Whelan, C.D. (Christopher), Windham, B.G. (Gwen), Winkler, A.M. (Anderson), Wittfeld, K. (Katharina), Woldehawariat, G. (Girma), Björnsson, A. (Asgeir), Wolfers, T. (Thomas), Yanek, L.R. (Lisa), Yang, J. (Jingyun), Zijdenbos, A.P., Zwiers, M.P. (Marcel), Agartz, I. (Ingrid), Almasy, L. (Laura), Ames, D.J. (David), Amouyel, P. (Philippe), Andreassen, O.A. (Ole), Arepalli, S. (Sampath), Assareh, A.A., Barral, S. (Sandra), Bastin, M.E. (Mark), Becker, D.M. (Diane M.), Becker, J.T. (James), Bennett, D.A. (David A.), Blangero, J. (John), Bokhoven, H. (Hans) van, Boomsma, D.I. (Dorret), Brodaty, H. (Henry), Brouwer, R.M. (Rachel), Brunner, H.G., Buckner, M., Buitelaar, J.K. (Jan), Bulayeva, K. (Kazima), Cahn, W. (Wiepke), Calhoun, V.D. (Vince), Cannon, D.M. (Dara), Cavalleri, G. (Gianpiero), Cheng, C.-Y. (Ching-Yu), Cichon, S. (Sven), Cookson, M.R. (Mark), Corvin, A. (Aiden), Crespo-Facorro, B. (Benedicto), Curran, J.E. (Joanne), Czisch, M. (Michael), Dale, A.M. (Anders), Davies, G.E. (Gareth), Craen, A.J. (Anton) de, Geus, E.J.C. (Eco) de, Jager, P.L. (Philip) de, Zubicaray, G.I. (Greig) de, Deary, I.J. (Ian), Debette, S. (Stéphanie), DeCarli, C. (Charles), Delanty, N., Depondt, C. (Chantal), DeStefano, A.L. (Anita), Dillman, A. (Allissa), Djurovic, S. (Srdjan), Donohoe, D.J. (Dennis), Drevets, D.A. (Douglas), Duggirala, R. (Ravi), Dyer, M.D. (Matthew), Enzinger, C. (Christian), Erk, S., Espeseth, T. (Thomas), Fedko, I.O. (Iryna O.), Fernández, G. (Guillén), Ferrucci, L. (Luigi), Fisher, S.E. (Simon), Fleischman, D. (Debra), Ford, I. (Ian), Fornage, M. (Myriam), Foroud, T. (Tatiana), Fox, P.T. (Peter), Francks, C. (Clyde), Fukunaga, M. (Masaki), Gibbs, J.R. (J. Raphael), Glahn, D.C. (David), Gollub, R.L. (Randy), Göring, H.H.H. (Harald H.), Green, R.C. (Robert C.), Gruber, O. (Oliver), Gudnason, V. (Vilmundur), Guelfi, S. (Sebastian), Håberg, A.K. (Asta K.), Hansell, N.K. (Narelle), Hardy, J. (John), Hartman, C.A. (C.), Hashimoto, R. (Ryota), Hegenscheid, K. (Katrin), Heinz, J. (Judith), Le Hellard, S. (Stephanie), Hernandez, D.G. (Dena), Heslenfeld, D.J. (Dirk), Ho, B.-C. (Beng-Choon), Hoekstra, P.J. (Pieter), Hoffmann, W. (Wolfgang), Hofman, A. (Albert), Holsboer, F. (Florian), Homuth, G. (Georg), Hosten, N. (Norbert), Hottenga, J.J. (Jouke Jan), Huentelman, M.J. (Matthew), Pol, H.H., Ikeda, M. (Masashi), Jack, C.R. (Clifford R.), Jenkinson, S. (Sarah), Johnson, R. (Robert), Jönsson, E.G. (Erik G.), Jukema, J.W., Kahn, R. (René), Kanai, R. (Ryota), Kloszewska, I. (Iwona), Knopman, D.S. (David S.), Kochunov, P. (Peter), Kwok, J.B. (John B.), Lawrie, S. (Stephen), Lemaître, H. (Herve), Liu, X. (Xinmin), Longo, D.L. (Dan L.), Lopez, O.L. (Oscar L.), Lovestone, S. (Simon), Martinez, O. (Oliver), Martinot, J.-L. (Jean-Luc), Mattay, V.S. (Venkata S.), McDonald, C. (Colm), McIntosh, A.M. (Andrew), McMahon, F.J. (Francis J.), McMahon, K.L. (Katie L.), Mecocci, P. (Patrizia), Melle, I. (Ingrid), Meyer-Lindenberg, A. (Andreas), Mohnke, S. (Sebastian), Montgomery, G.W. (Grant W.), Morris, D.W. (Derek W), Mosley, T.H. (Thomas H.), Mühleisen, T.W. (Thomas), Müller-Myhsok, B. (B.), Nalls, M.A. (Michael), Nauck, M. (Matthias), Nichols, T.E. (Thomas), Niessen, W.J. (Wiro), Nöthen, M.M. (Markus), Nyberg, L. (Lars), Ohi, K. (Kazutaka), Olvera, R.L. (Rene), Ophoff, R.A. (Roel), Pandolfo, M. (Massimo), Paus, T. (Tomas), Pausova, Z. (Zdenka), Penninx, B.W.J.H. (Brenda), Pike, G.B. (G. Bruce), Potkin, S.G. (Steven), Psaty, B.M. (Bruce), Reppermund, S., Rietschel, M. (Marcella), Roffman, J.L. (Joshua), Seiferth, N. (Nina), Rotter, J.I. (Jerome I.), Ryten, M. (Mina), Sacco, R.L. (Ralph L.), Sachdev, P.S. (Perminder), Saykin, A.J. (Andrew), Schmidt, R. (Reinhold), Schmidt, H. (Helena), Schofield, C.J. (Christopher), Sigursson, S. (Sigurdur), Simmons, A. (Andrew), Singleton, A. (Andrew), Sisodiya, S.M. (Sanjay), Smith, C. (Colin), Smoller, J.W., Soininen, H. (H.), Steen, V.M. (Vidar), Stott, D.J. (David J.), Sussmann, J. (Jessika), Thalamuthu, A. (Anbupalam), Toga, A.W. (Arthur W.), Traynor, B. (Bryan), Troncoso, J.C. (Juan), Tsolaki, M. (Magda), Tzourio, C. (Christophe), Uitterlinden, A.G. (André), Hernández, M.C.V. (Maria C. Valdés), Brug, M.P. (Marcel) van der, Lugt, A. (Aad) van der, Wee, N.J. (Nic) van der, Haren, N.E.M. (Neeltje E.) van, Ent, D. (Dennis) van 't, Tol, M.J.D. (Marie-José) van, Vardarajan, B.N. (Badri), Vellas, B. (Bruno), Veltman, D.J. (Dick), Völzke, H. (Henry), Walter, H.J. (Henrik), Wardlaw, J. (Joanna), Wassink, A.M.J. (Annemarie), Weale, M.E. (Michael), Weinberger, D.R. (Daniel R.), Weiner, M.W. (Michael W.), Wen, W. (Wei), Westman, E. (Eric), White, T.J.H. (Tonya), Wong, T.Y. (Tien Y.), Wright, C.B. (Clinton B.), Zielke, R.H. (Ronald H.), Zonderman, A.B., Martin, N.G. (Nicholas), Duijn, C.M. (Cornelia) van, Wright, M.J. (Margaret), Longstreth Jr, W.T., Schumann, G. (Gunter), Grabe, H.J. (Hans Jörgen), Franke, B. (Barbara), Launer, L.J. (Lenore), Medland, S.E. (Sarah), Seshadri, S. (Sudha), Thompson, P.M. (Paul), Ikram, M.K. (Kamran), Hibar, D.P. (Derrek), Adams, H.H.H. (Hieab), Jahanshad, N. (Neda), Chauhan, G. (Ganesh), Stein, J.L., Hofer, E. (Edith), Rentería, M.E. (Miguel), Bis, J.C. (Joshua), Arias-Vásquez, A. (Alejandro), Ikram, M.K. (M. Kamran), Desrivières, S. (Sylvane), Vernooij, M.W. (Meike), Abramovic, L. (Lucija), Alhusaini, S. (Saud), Amin, N. (Najaf), Andersson, M. (Micael), Arfanakis, K. (Konstantinos), Aribisala, B. (Benjamin), Armstrong, N.J. (Nicola J.), Athanasiu, L. (Lavinia), Axelsson, T. (Tomas), Beecham, A.H. (Ashley), Beiser, A. (Alexa), Bernard, M. (Manon), Blanton, S.H. (Susan H.), Bohlken, M.M. (Marc M.), Boks, M.P.M. (Marco), Bralten, L.B.C. (Linda), Brickman, A.M. (Adam M.), Carmichael, O. (Owen), Chakravarty, M.M. (M. Mallar), Chen, Q. (Qiang), Ching, C.R.K. (Christopher), Chouraki, V. (Vincent), Cuellar-Partida, G. (Gabriel), Crivello, F. (Fabrice), Braber, A. (Anouk) den, Doan, N.T. (Nhat Trung), Ehrlich, S.M. (Stefan), Giddaluru, S. (Sudheer), Goldman, A.L. (Aaron L.), Gottesman, R.F. (Rebecca), Grimm, O. (Oliver), Griswold, M.D. (Michael), Guadalupe, T. (Tulio), Gutman, B.A. (Boris A.), Hass, J. (Johanna), Haukvik, U.K. (Unn), Hoehn, D. (David), Holmes, A.J. (Avram), Hoogman, M. (Martine), Janowitz, D. (Deborah), Jia, T. (Tianye), Jørgensen, K.N. (Kjetil N.), Karbalai, N. (Nazanin), Kasperaviciute, D. (Dalia), Kim, S. (Shinseog), Klein, M. (Marieke), Kraemer, B. (Bernd), Lee, P.H. (Phil), Liewald, D.C.M. (David), Lopez, L.M. (Lorna), Luciano, M. (Michelle), MacAre, C. (Christine), Marquand, A.F. (Andre F.), Matarin, M. (Mar), Mather, R., Mattheisen, M. (Manuel), McKay, D.R. (David R.), Milaneschi, Y. (Yuri), Muñoz Maniega, S. (Susana), Nho, K. (Kwangsik), Nugent, A.C. (Allison), Nyquist, P. (Paul), Loohuis, L.M.O. (Loes M. Olde), Oosterlaan, J. (Jaap), Papmeyer, M. (Martina), Pirpamer, L. (Lukas), Pütz, B. (Benno), Ramasamy, A. (Adaikalavan), Richards, J.S. (Jennifer S.), Risacher, S.L. (Shannon), Roiz-Santiañez, R. (Roberto), Rommelse, N. (Nanda), Ropele, S. (Stefan), Rose, E.J. (Emma), Royle, N.A. (Natalie), Rundek, T. (Tatjana), Sämann, P.G. (Philipp), Saremi, A. (Arvin), Satizabal, C.L. (Claudia), Schmaal, L. (Lianne), Schork, N.J. (Nicholas), Shen, L. (Li), Shin, J. (Jean), Shumskaya, E. (Elena), Smith, A.V. (Albert Vernon), Sprooten, R. (Roy), Strike, L.T. (Lachlan), Teumer, A. (Alexander), Tordesillas-Gutierrez, D. (Diana), Toro, R. (Roberto), Trabzuni, D. (Danyah), Trompet, S. (Stella), Vaidya, D. (Dhananjay), van der Grond, J. (Jeroen), Lee, S.J. (Sven) van der, Van Der Meer, D. (Dennis), Van Donkelaar, M.M.J. (Marjolein M. J.), Eijk, K.R. (Kristel) van, Erp, T.G.M. (Theo G.) van, Van Rooij, D. (Daan), Walton, E. (Esther), Westlye, L.T. (Lars), Whelan, C.D. (Christopher), Windham, B.G. (Gwen), Winkler, A.M. (Anderson), Wittfeld, K. (Katharina), Woldehawariat, G. (Girma), Björnsson, A. (Asgeir), Wolfers, T. (Thomas), Yanek, L.R. (Lisa), Yang, J. (Jingyun), Zijdenbos, A.P., Zwiers, M.P. (Marcel), Agartz, I. (Ingrid), Almasy, L. (Laura), Ames, D.J. (David), Amouyel, P. (Philippe), Andreassen, O.A. (Ole), Arepalli, S. (Sampath), Assareh, A.A., Barral, S. (Sandra), Bastin, M.E. (Mark), Becker, D.M. (Diane M.), Becker, J.T. (James), Bennett, D.A. (David A.), Blangero, J. (John), Bokhoven, H. (Hans) van, Boomsma, D.I. (Dorret), Brodaty, H. (Henry), Brouwer, R.M. (Rachel), Brunner, H.G., Buckner, M., Buitelaar, J.K. (Jan), Bulayeva, K. (Kazima), Cahn, W. (Wiepke), Calhoun, V.D. (Vince), Cannon, D.M. (Dara), Cavalleri, G. (Gianpiero), Cheng, C.-Y. (Ching-Yu), Cichon, S. (Sven), Cookson, M.R. (Mark), Corvin, A. (Aiden), Crespo-Facorro, B. (Benedicto), Curran, J.E. (Joanne), Czisch, M. (Michael), Dale, A.M. (Anders), Davies, G.E. (Gareth), Craen, A.J. (Anton) de, Geus, E.J.C. (Eco) de, Jager, P.L. (Philip) de, Zubicaray, G.I. (Greig) de, Deary, I.J. (Ian), Debette, S. (Stéphanie), DeCarli, C. (Charles), Delanty, N., Depondt, C. (Chantal), DeStefano, A.L. (Anita), Dillman, A. (Allissa), Djurovic, S. (Srdjan), Donohoe, D.J. (Dennis), Drevets, D.A. (Douglas), Duggirala, R. (Ravi), Dyer, M.D. (Matthew), Enzinger, C. (Christian), Erk, S., Espeseth, T. (Thomas), Fedko, I.O. (Iryna O.), Fernández, G. (Guillén), Ferrucci, L. (Luigi), Fisher, S.E. (Simon), Fleischman, D. (Debra), Ford, I. (Ian), Fornage, M. (Myriam), Foroud, T. (Tatiana), Fox, P.T. (Peter), Francks, C. (Clyde), Fukunaga, M. (Masaki), Gibbs, J.R. (J. Raphael), Glahn, D.C. (David), Gollub, R.L. (Randy), Göring, H.H.H. (Harald H.), Green, R.C. (Robert C.), Gruber, O. (Oliver), Gudnason, V. (Vilmundur), Guelfi, S. (Sebastian), Håberg, A.K. (Asta K.), Hansell, N.K. (Narelle), Hardy, J. (John), Hartman, C.A. (C.), Hashimoto, R. (Ryota), Hegenscheid, K. (Katrin), Heinz, J. (Judith), Le Hellard, S. (Stephanie), Hernandez, D.G. (Dena), Heslenfeld, D.J. (Dirk), Ho, B.-C. (Beng-Choon), Hoekstra, P.J. (Pieter), Hoffmann, W. (Wolfgang), Hofman, A. (Albert), Holsboer, F. (Florian), Homuth, G. (Georg), Hosten, N. (Norbert), Hottenga, J.J. (Jouke Jan), Huentelman, M.J. (Matthew), Pol, H.H., Ikeda, M. (Masashi), Jack, C.R. (Clifford R.), Jenkinson, S. (Sarah), Johnson, R. (Robert), Jönsson, E.G. (Erik G.), Jukema, J.W., Kahn, R. (René), Kanai, R. (Ryota), Kloszewska, I. (Iwona), Knopman, D.S. (David S.), Kochunov, P. (Peter), Kwok, J.B. (John B.), Lawrie, S. (Stephen), Lemaître, H. (Herve), Liu, X. (Xinmin), Longo, D.L. (Dan L.), Lopez, O.L. (Oscar L.), Lovestone, S. (Simon), Martinez, O. (Oliver), Martinot, J.-L. (Jean-Luc), Mattay, V.S. (Venkata S.), McDonald, C. (Colm), McIntosh, A.M. (Andrew), McMahon, F.J. (Francis J.), McMahon, K.L. (Katie L.), Mecocci, P. (Patrizia), Melle, I. (Ingrid), Meyer-Lindenberg, A. (Andreas), Mohnke, S. (Sebastian), Montgomery, G.W. (Grant W.), Morris, D.W. (Derek W), Mosley, T.H. (Thomas H.), Mühleisen, T.W. (Thomas), Müller-Myhsok, B. (B.), Nalls, M.A. (Michael), Nauck, M. (Matthias), Nichols, T.E. (Thomas), Niessen, W.J. (Wiro), Nöthen, M.M. (Markus), Nyberg, L. (Lars), Ohi, K. (Kazutaka), Olvera, R.L. (Rene), Ophoff, R.A. (Roel), Pandolfo, M. (Massimo), Paus, T. (Tomas), Pausova, Z. (Zdenka), Penninx, B.W.J.H. (Brenda), Pike, G.B. (G. Bruce), Potkin, S.G. (Steven), Psaty, B.M. (Bruce), Reppermund, S., Rietschel, M. (Marcella), Roffman, J.L. (Joshua), Seiferth, N. (Nina), Rotter, J.I. (Jerome I.), Ryten, M. (Mina), Sacco, R.L. (Ralph L.), Sachdev, P.S. (Perminder), Saykin, A.J. (Andrew), Schmidt, R. (Reinhold), Schmidt, H. (Helena), Schofield, C.J. (Christopher), Sigursson, S. (Sigurdur), Simmons, A. (Andrew), Singleton, A. (Andrew), Sisodiya, S.M. (Sanjay), Smith, C. (Colin), Smoller, J.W., Soininen, H. (H.), Steen, V.M. (Vidar), Stott, D.J. (David J.), Sussmann, J. (Jessika), Thalamuthu, A. (Anbupalam), Toga, A.W. (Arthur W.), Traynor, B. (Bryan), Troncoso, J.C. (Juan), Tsolaki, M. (Magda), Tzourio, C. (Christophe), Uitterlinden, A.G. (André), Hernández, M.C.V. (Maria C. Valdés), Brug, M.P. (Marcel) van der, Lugt, A. (Aad) van der, Wee, N.J. (Nic) van der, Haren, N.E.M. (Neeltje E.) van, Ent, D. (Dennis) van 't, Tol, M.J.D. (Marie-José) van, Vardarajan, B.N. (Badri), Vellas, B. (Bruno), Veltman, D.J. (Dick), Völzke, H. (Henry), Walter, H.J. (Henrik), Wardlaw, J. (Joanna), Wassink, A.M.J. (Annemarie), Weale, M.E. (Michael), Weinberger, D.R. (Daniel R.), Weiner, M.W. (Michael W.), Wen, W. (Wei), Westman, E. (Eric), White, T.J.H. (Tonya), Wong, T.Y. (Tien Y.), Wright, C.B. (Clinton B.), Zielke, R.H. (Ronald H.), Zonderman, A.B., Martin, N.G. (Nicholas), Duijn, C.M. (Cornelia) van, Wright, M.J. (Margaret), Longstreth Jr, W.T., Schumann, G. (Gunter), Grabe, H.J. (Hans Jörgen), Franke, B. (Barbara), Launer, L.J. (Lenore), Medland, S.E. (Sarah), Seshadri, S. (Sudha), Thompson, P.M. (Paul), and Ikram, M.K. (Kamran)

Abstract

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.

Published
2017
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12. Novel genetic loci associated with hippocampal volume

Author

Hibar, D.P., Adams, H.H.H., Jahanshad, N., Chauhan, G., Stein, J.L., Hofer, E., Renteria, M.E., Bis, J.C., Arias-Vasquez, A., Ikram, M.K., Desrivières, S., Vernooij, M.W., Abramovic, L., Alhusaini, S., Amin, N., Andersson, M., Arfanakis, K., Aribisala, B.S., Armstrong, N.J., Athanasiu, L., Axelsson, T., Beecham, A.H., Beiser, A., Bernard, M., Blanton, S.H., Bohlken, M.M., Boks, M.P., Bralten, J., Brickman, A.M., Carmichael, O., Chakravarty, M.M., Chen, Q., Ching, C.R.K., Chouraki, V., Cuellar-Partida, G., Crivello, F., den Braber, A., Doan, N.T., Ehrlich, S., Giddaluru, S., Goldman, A.L., Gottesman, R.F., Grimm, O., Griswold, M.E., Guadalupe, T., Gutman, B.A., Hass, J., Haukvik, U.K., Hoehn, D., Holmes, A.J., Hoogman, M., Janowitz, D., Jia, T., Jørgensen, K.N., Karbalai, N., Kasperaviciute, D., Kim, S., Klein, M., Kraemer, B., Lee, P.H., Liewald, D.C.M., Lopez, L.M., Luciano, M., Macare, C., Marquand, A.F., Matarin, M., Mather, K.A., Mattheisen, M., McKay, D.R., Milaneschi, Y., Munoz Maniega, S., Nho, K., Nugent, A.C., Nyquist, P., Loohuis, L.M.O., Oosterlaan, J., Papmeyer, M., Pirpamer, L., Putz, B., Ramasamy, A., Richards, J.S., Risacher, S.L., Roiz-Santiañez, R., Rommelse, N., Ropele, S., Rose, E.J., Royle, N.A., Rundek, T., Sämann, P.G., Saremi, A., Satizabal, C.L., Schmaal, L., Schork, A.J., Shen, L., Shin, J., Shumskaya, E., Smith, A.V., Sprooten, E., Strike, L.T., Teumer, A., Tordesillas-Gutierrez, D., Toro, R., Trabzuni, D., Trompet, S., Vaidya, D., Van der Grond, J., van der Lee, S.J., van der Meer, D., van Donkelaar, M.M.J., van Eijk, K.R., Van Erp, T.G.M., Van Rooij, D., Walton, E., Westlye, L.T., Whelan, C.D., Windham, B.G., Winkler, A.M., Wittfeld, K., Woldehawariat, G., Wolf, C., Wolfers, T., Yanek, L.R., Yang, J., Zijdenbos, A., Zwiers, M.P., Agartz, I., Almasy, L., Ames, D., Amouyel, P., Andreassen, O.A., Arepalli, S., Assareh, A.A., Barral, S., Bastin, M.E., Becker, D.M., Becker, J.T., Bennett, D.A., Blangero, J., van Bokhoven, H., Boomsma, D.I., Brodaty, H., Brouwer, R.M., Brunner, H.G., Buckner, R.L., Buitelaar, J.K., Bulayeva, K.B., Cahn, W., Calhoun, V.D., Cannon, D.M., Cavalleri, G.L., Cheng, C-Y, Cichon, S., Cookson, M.R., Corvin, A., Crespo-Facorro, B., Curran, J.E., Czisch, M., Dale, A.M., Davies, G.E., de Craen, A.J.M., de Geus, E.J.C., De Jager, P.L., de Zubicaray, G.I., Deary, I.J., Debette, S., DeCarli, C., Delanty, N., Depondt, C., DeStefano, A.L., Dillman, A., Djurovic, S., Donohoe, G., Drevets, W.C., Duggirala, R., Dyer, T.D., Enzinger, C., Erk, S., Espeseth, T., Fedko, I.O., Fernández, G., Ferrucci, L., Fisher, S.E., Fleischman, D.A., Ford, I., Fornage, M., Foroud, T.M., Fox, P.T., Francks, C., Fukunaga, M., Gibbs, J.R., Glahn, D.C., Gollub, R.L., Göring, H.H.H., Green, R.C., Gruber, O., Gudnason, V., Guelfi, S., Håberg, A.K., Hansell, N.K., Hardy, J., Hartman, C.A., Hashimoto, R., Hegenscheid, K., Heinz, A., Le Hellard, S., Hernandez, D.G., Heslenfeld, D.J., Ho, B-C., Hoekstra, P.J., Hoffmann, W., Hofman, A., Holsboer, F., Homuth, G., Hosten, N., Hottenga, J-J, Huentelman, M., Pol, H.E.H., Ikeda, M., Jack Jr, C.R., Jenkinson, M., Johnson, R., Jönsson, E.G., Jukema, J.W., Kahn, R.S., Kanai, R., Kloszewska, I., Knopman, D.S., Kochunov, P., Kwok, J.B., Lawrie, S.M., Lemaitre, H., Liu, X., Longo, D.L., Lopez, O.L., Lovestone, S., Martinez, O.P., Martinot, J-L, Mattay, V.S., McDonald, C., McIntosh, A.M., McMahon, F.J., McMahon, K.L., Mecocci, P., Melle, I., Meyer-Lindenberg, A., Mohnke, S., Montgomery, G.W., Morris, D.W., Mosley, T.H., Mühleisen, T.W., Müller-Myhsok, B., Nalls, M.A., Nauck, M., Nichols, T.E., Niessen, W.J., Nöthen, M.M., Nyberg, L., Ohi, K., Olvera, R.L., Ophoff, R.A., Pandolfo, M., Paus, T., Pausova, Z., Penninx, B.W.J.H., Pike, G.B., Potkin, S.G., Psaty, B.M., Reppermund, S., Rietschel, M., Roffman, J.L., Romanczuk-Seiferth, N., Rotter, J.I., Ryten, M., Sacco, R.L., Sachdev, P.S., Saykin, A.J., Schmidt, R., Schmidt, H., Schofield, P.R., Sigursson, S., Simmons, A., Singleton, A., Sisodiya, S.M., Smith, C., Smoller, J.W., Soininen, H., Steen, V.M., Stott, D.J., Sussmann, J.E., Thalamuthu, A., Toga, A.W., Traynor, B.J., Troncoso, J., Tsolaki, M., Tzourio, C., Uitterlinden, A.G., Hernández, M.C.V., van der Brug, M., van der Lugt, A., van der Wee, N.J.A., van Haren, N.E.M., van ’t Ent, D., van Tol, M-J, Vardarajan, B.N., Vellas, B., Veltman, D.J., Volzke, H., Walter, H., Wardlaw, J.M., Wassink, T.H., Weale, M.E., Weinberger, D.R., Weiner, M.W., Wen, W., Westman, E., White, T., Wong, T.Y., Wright, C.B., Zielke, R.H., Zonderman, A.B., Martin, N.G., van Duijn, C.M., Wright, M.J., Longstreth, W.T., Schumann, G., Grabe, H.J., Franke, B., Launer, L.J., Medland, S.E., Seshadri, S., Thompson, P.M., Ikram, M.A., Hibar, D.P., Adams, H.H.H., Jahanshad, N., Chauhan, G., Stein, J.L., Hofer, E., Renteria, M.E., Bis, J.C., Arias-Vasquez, A., Ikram, M.K., Desrivières, S., Vernooij, M.W., Abramovic, L., Alhusaini, S., Amin, N., Andersson, M., Arfanakis, K., Aribisala, B.S., Armstrong, N.J., Athanasiu, L., Axelsson, T., Beecham, A.H., Beiser, A., Bernard, M., Blanton, S.H., Bohlken, M.M., Boks, M.P., Bralten, J., Brickman, A.M., Carmichael, O., Chakravarty, M.M., Chen, Q., Ching, C.R.K., Chouraki, V., Cuellar-Partida, G., Crivello, F., den Braber, A., Doan, N.T., Ehrlich, S., Giddaluru, S., Goldman, A.L., Gottesman, R.F., Grimm, O., Griswold, M.E., Guadalupe, T., Gutman, B.A., Hass, J., Haukvik, U.K., Hoehn, D., Holmes, A.J., Hoogman, M., Janowitz, D., Jia, T., Jørgensen, K.N., Karbalai, N., Kasperaviciute, D., Kim, S., Klein, M., Kraemer, B., Lee, P.H., Liewald, D.C.M., Lopez, L.M., Luciano, M., Macare, C., Marquand, A.F., Matarin, M., Mather, K.A., Mattheisen, M., McKay, D.R., Milaneschi, Y., Munoz Maniega, S., Nho, K., Nugent, A.C., Nyquist, P., Loohuis, L.M.O., Oosterlaan, J., Papmeyer, M., Pirpamer, L., Putz, B., Ramasamy, A., Richards, J.S., Risacher, S.L., Roiz-Santiañez, R., Rommelse, N., Ropele, S., Rose, E.J., Royle, N.A., Rundek, T., Sämann, P.G., Saremi, A., Satizabal, C.L., Schmaal, L., Schork, A.J., Shen, L., Shin, J., Shumskaya, E., Smith, A.V., Sprooten, E., Strike, L.T., Teumer, A., Tordesillas-Gutierrez, D., Toro, R., Trabzuni, D., Trompet, S., Vaidya, D., Van der Grond, J., van der Lee, S.J., van der Meer, D., van Donkelaar, M.M.J., van Eijk, K.R., Van Erp, T.G.M., Van Rooij, D., Walton, E., Westlye, L.T., Whelan, C.D., Windham, B.G., Winkler, A.M., Wittfeld, K., Woldehawariat, G., Wolf, C., Wolfers, T., Yanek, L.R., Yang, J., Zijdenbos, A., Zwiers, M.P., Agartz, I., Almasy, L., Ames, D., Amouyel, P., Andreassen, O.A., Arepalli, S., Assareh, A.A., Barral, S., Bastin, M.E., Becker, D.M., Becker, J.T., Bennett, D.A., Blangero, J., van Bokhoven, H., Boomsma, D.I., Brodaty, H., Brouwer, R.M., Brunner, H.G., Buckner, R.L., Buitelaar, J.K., Bulayeva, K.B., Cahn, W., Calhoun, V.D., Cannon, D.M., Cavalleri, G.L., Cheng, C-Y, Cichon, S., Cookson, M.R., Corvin, A., Crespo-Facorro, B., Curran, J.E., Czisch, M., Dale, A.M., Davies, G.E., de Craen, A.J.M., de Geus, E.J.C., De Jager, P.L., de Zubicaray, G.I., Deary, I.J., Debette, S., DeCarli, C., Delanty, N., Depondt, C., DeStefano, A.L., Dillman, A., Djurovic, S., Donohoe, G., Drevets, W.C., Duggirala, R., Dyer, T.D., Enzinger, C., Erk, S., Espeseth, T., Fedko, I.O., Fernández, G., Ferrucci, L., Fisher, S.E., Fleischman, D.A., Ford, I., Fornage, M., Foroud, T.M., Fox, P.T., Francks, C., Fukunaga, M., Gibbs, J.R., Glahn, D.C., Gollub, R.L., Göring, H.H.H., Green, R.C., Gruber, O., Gudnason, V., Guelfi, S., Håberg, A.K., Hansell, N.K., Hardy, J., Hartman, C.A., Hashimoto, R., Hegenscheid, K., Heinz, A., Le Hellard, S., Hernandez, D.G., Heslenfeld, D.J., Ho, B-C., Hoekstra, P.J., Hoffmann, W., Hofman, A., Holsboer, F., Homuth, G., Hosten, N., Hottenga, J-J, Huentelman, M., Pol, H.E.H., Ikeda, M., Jack Jr, C.R., Jenkinson, M., Johnson, R., Jönsson, E.G., Jukema, J.W., Kahn, R.S., Kanai, R., Kloszewska, I., Knopman, D.S., Kochunov, P., Kwok, J.B., Lawrie, S.M., Lemaitre, H., Liu, X., Longo, D.L., Lopez, O.L., Lovestone, S., Martinez, O.P., Martinot, J-L, Mattay, V.S., McDonald, C., McIntosh, A.M., McMahon, F.J., McMahon, K.L., Mecocci, P., Melle, I., Meyer-Lindenberg, A., Mohnke, S., Montgomery, G.W., Morris, D.W., Mosley, T.H., Mühleisen, T.W., Müller-Myhsok, B., Nalls, M.A., Nauck, M., Nichols, T.E., Niessen, W.J., Nöthen, M.M., Nyberg, L., Ohi, K., Olvera, R.L., Ophoff, R.A., Pandolfo, M., Paus, T., Pausova, Z., Penninx, B.W.J.H., Pike, G.B., Potkin, S.G., Psaty, B.M., Reppermund, S., Rietschel, M., Roffman, J.L., Romanczuk-Seiferth, N., Rotter, J.I., Ryten, M., Sacco, R.L., Sachdev, P.S., Saykin, A.J., Schmidt, R., Schmidt, H., Schofield, P.R., Sigursson, S., Simmons, A., Singleton, A., Sisodiya, S.M., Smith, C., Smoller, J.W., Soininen, H., Steen, V.M., Stott, D.J., Sussmann, J.E., Thalamuthu, A., Toga, A.W., Traynor, B.J., Troncoso, J., Tsolaki, M., Tzourio, C., Uitterlinden, A.G., Hernández, M.C.V., van der Brug, M., van der Lugt, A., van der Wee, N.J.A., van Haren, N.E.M., van ’t Ent, D., van Tol, M-J, Vardarajan, B.N., Vellas, B., Veltman, D.J., Volzke, H., Walter, H., Wardlaw, J.M., Wassink, T.H., Weale, M.E., Weinberger, D.R., Weiner, M.W., Wen, W., Westman, E., White, T., Wong, T.Y., Wright, C.B., Zielke, R.H., Zonderman, A.B., Martin, N.G., van Duijn, C.M., Wright, M.J., Longstreth, W.T., Schumann, G., Grabe, H.J., Franke, B., Launer, L.J., Medland, S.E., Seshadri, S., Thompson, P.M., and Ikram, M.A.

Abstract

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer’s disease (rg=−0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.

Published
2017

13. Novel genetic loci underlying human intracranial volume identified through genome-wide association

Author

Adams, H.H.H., Hibar, D.P., Chouraki, V., Stein, J.L., Nyquist, P.A., Renteria, M.E., Trompet, S., Arias-Vasquez, A., Seshadri, S., Desrivières, S., Beecham, A.H., Jahanshad, N., Wittfeld, K., van der Lee, S.J., Abramovic, L., Alhusaini, S., Amin, N., Andersson, M., Arfanakis, K., Aribisala, B.S., Armstrong, N.J., Athanasiu, L., Axelsson, T., Beiser, A., Bernard, M., Bis, J.C., Blanken, L.M.E., Blanton, S.H., Bohlken, M.M., Boks, M.P., Bralten, J., Brickman, A.M., Carmichael, O., Chakravarty, M.M., Chauhan, G., Chen, Q., Ching, C.R.K., Cuellar-Partida, G., Braber, A.D., Doan, N.T., Ehrlich, S., Filippi, I., Ge, T., Giddaluru, S., Goldman, A.L., Gottesman, R.F., Greven, C.U., Grimm, O., Griswold, M.E., Guadalupe, T., Hass, J., Haukvik, U.K., Hilal, S., Hofer, E., Hoehn, D., Holmes, A.J., Hoogman, M., Janowitz, D., Jia, T., Kasperaviciute, D., Kim, S., Klein, M., Kraemer, B., Lee, P.H., Liao, J., Liewald, D.C.M., Lopez, L.M., Luciano, M., Macare, C., Marquand, A., Matarin, M., Mather, K.A., Mattheisen, M., Mazoyer, B., McKay, D.R., McWhirter, R., Milaneschi, Y., Mirza-Schreiber, N., Muetzel, R.L., Maniega, S.M., Nho, K., Nugent, A.C., Loohuis, L.M.O., Oosterlaan, J., Papmeyer, M., Pappa, I., Pirpamer, L., Pudas, S., Pütz, B., Rajan, K.B., Ramasamy, A., Richards, J.S., Risacher, S.L., Roiz-Santiañez, R., Rommelse, N., Rose, E.J., Royle, N.A., Rundek, T., Sämann, P.G., Satizabal, C.L., Schmaal, L., Schork, A.J., Shen, L., Shin, J., Shumskaya, E., Smith, A.V., Sprooten, E., Strike, L.T., Teumer, A., Thomson, R., Tordesillas-Gutierrez, D., Toro, R., Trabzuni, D., Vaidya, D., Van der Grond, J., van der Meer, D., van Donkelaar, M.M.J., van Eijk, K.R., Van Erp, T.G.M., Van Rooij, D., Walton, E., Westlye, L.T., Whelan, C.D., Windham, B.G., Winkler, A.M., Woldehawariat, G., Wolf, C., Wolfers, T., Xu, B., Yanek, L.R., Yang, J., Zijdenbos, A., Zwiers, M.P., Agartz, I., Aggarwal, N.T., Almasy, L., Ames, D., Amouyel, P., Andreassen, O.A., Arepalli, S., Assareh, A.A., Barral, S., Bastin, M.E., Becker, D.M., Becker, J.T., Bennett, D.A., Blangero, J., van Bokhoven, H., Boomsma, D.I., Brodaty, H., Brouwer, R.M., Brunner, H.G., Buckner, R.L., Buitelaar, J.K., Bulayeva, K.B., Cahn, W., Calhoun, V.D., Cannon, D.M., Cavalleri, G.L., Chen, C., Cheng, C-Y, Cichon, S., Cookson, M.R., Corvin, A., Crespo-Facorro, B., Curran, J.E., Czisch, M., Dale, A.M., Davies, G.E., De Geus, E.J.C., De Jager, P.L., de Zubicaray, G.I., Delanty, N., Depondt, C., DeStefano, A.L., Dillman, A., Djurovic, S., Donohoe, G., Drevets, W.C., Duggirala, R., Dyer, T.D., Erk, S., Espeseth, T., Evans, D.A., Fedko, I.O., Fernández, G., Ferrucci, L., Fisher, S.E., Fleischman, D.A., Ford, I., Foroud, T.M., Fox, P.T., Francks, C., Fukunaga, M., Gibbs, J.R., Glahn, D.C., Gollub, R.L., Göring, H.H.H., Grabe, H.J., Green, R.C., Gruber, O., Gudnason, V., Guelfi, S., Hansell, N.K., Hardy, J., Hartman, C.A., Hashimoto, R., Hegenscheid, K., Heinz, A., Le Hellard, S., Hernandez, D.G., Heslenfeld, D.J., Ho, B-C., Hoekstra, P.J., Hoffmann, W., Hofman, A., Holsboer, F., Homuth, G., Hosten, N., Hottenga, J-J, Pol, H.E.H., Ikeda, M., Ikram, M.K., Jack, C.R., Jenkinson, M., Johnson, R., Jönsson, E.G., Jukema, J.W., Kahn, R.S., Kanai, R., Kloszewska, I., Knopman, D.S., Kochunov, P., Kwok, J.B., Lawrie, S.M., Lemaitre, H., Liu, X., Longo, D.L., Longstreth, W.T., Lopez, O.L., Lovestone, S., Martinez, O.P., Martinot, J-L, Mattay, V.S., McDonald, C., McIntosh, A.M., McMahon, K.L., McMahon, F.J., Mecocci, P., Melle, I., Meyer-Lindenberg, A., Mohnke, S., Montgomery, G.W., Morris, D.W., Mosley, T.H., Mühleisen, T.W., Müller-Myhsok, B., Nalls, M.A., Nauck, M., Nichols, T.E., Niessen, W.J., Nöthen, M.M., Nyberg, L., Ohi, K., Olvera, R.L., Ophoff, R.A., Pandolfo, M., Paus, T., Pausova, Z., Penninx, B.W.J.H., Pike, G.B., Potkin, S.G., Psaty, B.M., Reppermund, S., Rietschel, M., Roffman, J.L., Romanczuk-Seiferth, N., Rotter, J.I., Ryten, M., Sacco, R.L., Sachdev, P.S., Saykin, A.J., Schmidt, R., Schofield, P.R., Sigurdsson, S., Simmons, A., Singleton, A., Sisodiya, S.M., Smith, C., Smoller, J.W., Soininen, H., Srikanth, V., Steen, V.M., Stott, D.J., Sussmann, J.E., Thalamuthu, A., Tiemeier, H., Toga, A.W., Traynor, B.J., Troncoso, J., Turner, J.A., Tzourio, C., Uitterlinden, A.G., Hernández, M.C.V., van der Brug, M., Van der Lugt, A., van der Wee, N.J.A., van Duijn, C.M., van Haren, N.E.M., Van′t Ent, D., van Tol, M-J, Vardarajan, B.N., Veltman, D.J., Vernooij, M.W., Volzke, H., Walter, H., Wardlaw, J.M., Wassink, T.H., Weale, M.E., Weinberger, D.R., Weiner, M.W., Wen, W., Westman, E., White, T., Wong, T.Y., Wright, C.B., Zielke, H.R., Zonderman, A.B., Deary, I.J., DeCarli, C., Schmidt, H., Martin, N.G., de Craen, A.J.M., Wright, M.J., Launer, L.J., Schumann, G., Fornage, M., Franke, B., Debette, S., Medland, S.E., Ikram, M.A., Thompson, P.M., Adams, H.H.H., Hibar, D.P., Chouraki, V., Stein, J.L., Nyquist, P.A., Renteria, M.E., Trompet, S., Arias-Vasquez, A., Seshadri, S., Desrivières, S., Beecham, A.H., Jahanshad, N., Wittfeld, K., van der Lee, S.J., Abramovic, L., Alhusaini, S., Amin, N., Andersson, M., Arfanakis, K., Aribisala, B.S., Armstrong, N.J., Athanasiu, L., Axelsson, T., Beiser, A., Bernard, M., Bis, J.C., Blanken, L.M.E., Blanton, S.H., Bohlken, M.M., Boks, M.P., Bralten, J., Brickman, A.M., Carmichael, O., Chakravarty, M.M., Chauhan, G., Chen, Q., Ching, C.R.K., Cuellar-Partida, G., Braber, A.D., Doan, N.T., Ehrlich, S., Filippi, I., Ge, T., Giddaluru, S., Goldman, A.L., Gottesman, R.F., Greven, C.U., Grimm, O., Griswold, M.E., Guadalupe, T., Hass, J., Haukvik, U.K., Hilal, S., Hofer, E., Hoehn, D., Holmes, A.J., Hoogman, M., Janowitz, D., Jia, T., Kasperaviciute, D., Kim, S., Klein, M., Kraemer, B., Lee, P.H., Liao, J., Liewald, D.C.M., Lopez, L.M., Luciano, M., Macare, C., Marquand, A., Matarin, M., Mather, K.A., Mattheisen, M., Mazoyer, B., McKay, D.R., McWhirter, R., Milaneschi, Y., Mirza-Schreiber, N., Muetzel, R.L., Maniega, S.M., Nho, K., Nugent, A.C., Loohuis, L.M.O., Oosterlaan, J., Papmeyer, M., Pappa, I., Pirpamer, L., Pudas, S., Pütz, B., Rajan, K.B., Ramasamy, A., Richards, J.S., Risacher, S.L., Roiz-Santiañez, R., Rommelse, N., Rose, E.J., Royle, N.A., Rundek, T., Sämann, P.G., Satizabal, C.L., Schmaal, L., Schork, A.J., Shen, L., Shin, J., Shumskaya, E., Smith, A.V., Sprooten, E., Strike, L.T., Teumer, A., Thomson, R., Tordesillas-Gutierrez, D., Toro, R., Trabzuni, D., Vaidya, D., Van der Grond, J., van der Meer, D., van Donkelaar, M.M.J., van Eijk, K.R., Van Erp, T.G.M., Van Rooij, D., Walton, E., Westlye, L.T., Whelan, C.D., Windham, B.G., Winkler, A.M., Woldehawariat, G., Wolf, C., Wolfers, T., Xu, B., Yanek, L.R., Yang, J., Zijdenbos, A., Zwiers, M.P., Agartz, I., Aggarwal, N.T., Almasy, L., Ames, D., Amouyel, P., Andreassen, O.A., Arepalli, S., Assareh, A.A., Barral, S., Bastin, M.E., Becker, D.M., Becker, J.T., Bennett, D.A., Blangero, J., van Bokhoven, H., Boomsma, D.I., Brodaty, H., Brouwer, R.M., Brunner, H.G., Buckner, R.L., Buitelaar, J.K., Bulayeva, K.B., Cahn, W., Calhoun, V.D., Cannon, D.M., Cavalleri, G.L., Chen, C., Cheng, C-Y, Cichon, S., Cookson, M.R., Corvin, A., Crespo-Facorro, B., Curran, J.E., Czisch, M., Dale, A.M., Davies, G.E., De Geus, E.J.C., De Jager, P.L., de Zubicaray, G.I., Delanty, N., Depondt, C., DeStefano, A.L., Dillman, A., Djurovic, S., Donohoe, G., Drevets, W.C., Duggirala, R., Dyer, T.D., Erk, S., Espeseth, T., Evans, D.A., Fedko, I.O., Fernández, G., Ferrucci, L., Fisher, S.E., Fleischman, D.A., Ford, I., Foroud, T.M., Fox, P.T., Francks, C., Fukunaga, M., Gibbs, J.R., Glahn, D.C., Gollub, R.L., Göring, H.H.H., Grabe, H.J., Green, R.C., Gruber, O., Gudnason, V., Guelfi, S., Hansell, N.K., Hardy, J., Hartman, C.A., Hashimoto, R., Hegenscheid, K., Heinz, A., Le Hellard, S., Hernandez, D.G., Heslenfeld, D.J., Ho, B-C., Hoekstra, P.J., Hoffmann, W., Hofman, A., Holsboer, F., Homuth, G., Hosten, N., Hottenga, J-J, Pol, H.E.H., Ikeda, M., Ikram, M.K., Jack, C.R., Jenkinson, M., Johnson, R., Jönsson, E.G., Jukema, J.W., Kahn, R.S., Kanai, R., Kloszewska, I., Knopman, D.S., Kochunov, P., Kwok, J.B., Lawrie, S.M., Lemaitre, H., Liu, X., Longo, D.L., Longstreth, W.T., Lopez, O.L., Lovestone, S., Martinez, O.P., Martinot, J-L, Mattay, V.S., McDonald, C., McIntosh, A.M., McMahon, K.L., McMahon, F.J., Mecocci, P., Melle, I., Meyer-Lindenberg, A., Mohnke, S., Montgomery, G.W., Morris, D.W., Mosley, T.H., Mühleisen, T.W., Müller-Myhsok, B., Nalls, M.A., Nauck, M., Nichols, T.E., Niessen, W.J., Nöthen, M.M., Nyberg, L., Ohi, K., Olvera, R.L., Ophoff, R.A., Pandolfo, M., Paus, T., Pausova, Z., Penninx, B.W.J.H., Pike, G.B., Potkin, S.G., Psaty, B.M., Reppermund, S., Rietschel, M., Roffman, J.L., Romanczuk-Seiferth, N., Rotter, J.I., Ryten, M., Sacco, R.L., Sachdev, P.S., Saykin, A.J., Schmidt, R., Schofield, P.R., Sigurdsson, S., Simmons, A., Singleton, A., Sisodiya, S.M., Smith, C., Smoller, J.W., Soininen, H., Srikanth, V., Steen, V.M., Stott, D.J., Sussmann, J.E., Thalamuthu, A., Tiemeier, H., Toga, A.W., Traynor, B.J., Troncoso, J., Turner, J.A., Tzourio, C., Uitterlinden, A.G., Hernández, M.C.V., van der Brug, M., Van der Lugt, A., van der Wee, N.J.A., van Duijn, C.M., van Haren, N.E.M., Van′t Ent, D., van Tol, M-J, Vardarajan, B.N., Veltman, D.J., Vernooij, M.W., Volzke, H., Walter, H., Wardlaw, J.M., Wassink, T.H., Weale, M.E., Weinberger, D.R., Weiner, M.W., Wen, W., Westman, E., White, T., Wong, T.Y., Wright, C.B., Zielke, H.R., Zonderman, A.B., Deary, I.J., DeCarli, C., Schmidt, H., Martin, N.G., de Craen, A.J.M., Wright, M.J., Launer, L.J., Schumann, G., Fornage, M., Franke, B., Debette, S., Medland, S.E., Ikram, M.A., and Thompson, P.M.

Abstract

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.

Published
2016

14. The transcriptional landscape of age in human peripheral blood

Author

Peters, M.J. (Marjolein), Joehanes, R. (Roby), Pilling, L.C. (Luke), Schurmann, C. (Claudia), Conneely, K.N. (Karen N.), Powell, J.E. (Joseph), Reinmaa, E. (Eva), Sutphin, G.L. (George L.), Zhernakova, A. (Alexandra), Schramm, K. (Katharina), Wilson, Y.A. (Yana A.), Kobes, S. (Sayuko), Tukiainen, T. (Taru), Ramos, Y.F.M. (Yolande), Göring, H.H.H. (Harald H.), Fornage, M. (Myriam), Liu, Y. (YongMei), Gharib, S.A. (Sina), Stranger, B.E. (Barbara), Jager, P.L. (Philip) de, Aviv, A. (Abraham), Levy, D. (Daniel), Murabito, J. (Joanne), Munson, P.J. (Peter J.), Huan, T. (Tianxiao), Hofman, A. (Albert), Uitterlinden, A.G. (André), Rivadeneira Ramirez, F. (Fernando), Rooij, J.G.J. (Jeroen) van, Stolk, L. (Lisette), Broer, L. (Linda), Verbiest, M.M.P.J. (Michael), Jhamai, M. (Mila), Arp, P.P. (Pascal), Metspalu, A. (Andres), Tserel, L. (Liina), Milani, L. (Lili), Samani, N.J. (Nilesh), Peterson, P. (Pärt), Kasela, S. (Silva), Codd, V. (Veryan), Peters, A. (Annette), Ward-Caviness, C.K. (Cavin K.), Herder, C. (Christian), Waldenberger, M. (Melanie), Roden, M. (Michael), Singmann, P. (Paula), Zeilinger, S. (Sonja), Illig, T. (Thomas), Homuth, G. (Georg), Grabe, H.J. (Hans Jörgen), Völzke, H. (Henry), Steil, L. (Leif), Kocher, T. (Thomas), Murray, A. (Anna), Melzer, D. (David), Yaghootkar, H. (Hanieh), Bandinelli, S., Moses, E.K. (Eric), Kent, J.W. (Jack), Curran, J.E. (Joanne), Johnson, M.P. (Matthew), Williams-Blangero, S. (Sarah), Westra, H.J. (Harm-Jan), McRae, A.F. (Allan F.), Smith, J.A. (Jennifer A), Kardia, S.L.R. (Sharon), Hovatta, I. (Iiris), Perola, M. (Markus), Ripatti, S. (Samuli), Salomaa, V. (Veikko), Henders, A.K. (Anjali), Martin, N.G. (Nicholas), Smith, A.K. (Alicia K.), Mehta, D. (Divya), Binder, E.B. (Elisabeth B.), Nylocks, K.M. (K. Maria), Kennedy, E.M. (Elizabeth M.), Klengel, T. (Torsten), Ding, J. (Jingzhong), Suchy-Dicey, A. (Astrid), Enquobahrie, D., Brody, J.A. (Jennifer A.), Rotter, J.I. (Jerome I.), Chen, Y.-D.I. (Yii-Der I.), Houwing-Duistermaat, J.J. (Jeanine), Kloppenburg, M. (Margreet), Slagboom, P.E. (Eline), Helmer, Q. (Quinta), Hollander, W. (Wouter) den, Bean, S. (Shannon), Raj, T. (Towfique), Bakhshi, N. (Noman), Wang, Q.P. (Qiao Ping), Oyston, L.J. (Lisa J.), Psaty, B.M. (Bruce), Tracy, R.P. (Russell), Montgomery, G.W. (Grant), Turner, S.T. (Stephen), Blangero, J. (John), Meulenbelt, I. (Ingrid), Ressler, K.J. (Kerry), Yang, J. (Jian), Franke, L. (Lude), Kettunen, J. (Johannes), Visscher, P.M. (Peter), Neely, G.G. (G. Gregory), Korstanje, R. (Ron), Hanson, R.L. (Robert L.), Prokisch, H. (Holger), Ferrucci, L. (Luigi), Esko, T. (Tõnu), Teumer, A. (Alexander), Meurs, J.B.J. (Joyce) van, Johnson, A.D. (Andrew D.), Nalls, M.A. (Michael), Hernandez, D.G. (Dena), Cookson, M.R. (Mark), Gibbs, R.J. (Raphael J.), Hardy, J. (John), Ramasamy, A. (Adaikalavan), Zonderman, A.B. (Alan B.), Dillman, A. (Allissa), Traynor, B. (Bryan), Smith, C. (Colin), Longo, D.L. (Dan L.), Trabzuni, D. (Danyah), Troncoso, J.C. (Juan), Brug, M.P. (Marcel) van der, Weale, M.E. (Michael), O'Brien, R. (Richard), Johnson, R. (Robert), Walker, R. (Robert), Zielke, R.H. (Ronald H.), Arepalli, S. (Sampath), Ryten, M. (Mina), Singleton, A., Peters, M.J. (Marjolein), Joehanes, R. (Roby), Pilling, L.C. (Luke), Schurmann, C. (Claudia), Conneely, K.N. (Karen N.), Powell, J.E. (Joseph), Reinmaa, E. (Eva), Sutphin, G.L. (George L.), Zhernakova, A. (Alexandra), Schramm, K. (Katharina), Wilson, Y.A. (Yana A.), Kobes, S. (Sayuko), Tukiainen, T. (Taru), Ramos, Y.F.M. (Yolande), Göring, H.H.H. (Harald H.), Fornage, M. (Myriam), Liu, Y. (YongMei), Gharib, S.A. (Sina), Stranger, B.E. (Barbara), Jager, P.L. (Philip) de, Aviv, A. (Abraham), Levy, D. (Daniel), Murabito, J. (Joanne), Munson, P.J. (Peter J.), Huan, T. (Tianxiao), Hofman, A. (Albert), Uitterlinden, A.G. (André), Rivadeneira Ramirez, F. (Fernando), Rooij, J.G.J. (Jeroen) van, Stolk, L. (Lisette), Broer, L. (Linda), Verbiest, M.M.P.J. (Michael), Jhamai, M. (Mila), Arp, P.P. (Pascal), Metspalu, A. (Andres), Tserel, L. (Liina), Milani, L. (Lili), Samani, N.J. (Nilesh), Peterson, P. (Pärt), Kasela, S. (Silva), Codd, V. (Veryan), Peters, A. (Annette), Ward-Caviness, C.K. (Cavin K.), Herder, C. (Christian), Waldenberger, M. (Melanie), Roden, M. (Michael), Singmann, P. (Paula), Zeilinger, S. (Sonja), Illig, T. (Thomas), Homuth, G. (Georg), Grabe, H.J. (Hans Jörgen), Völzke, H. (Henry), Steil, L. (Leif), Kocher, T. (Thomas), Murray, A. (Anna), Melzer, D. (David), Yaghootkar, H. (Hanieh), Bandinelli, S., Moses, E.K. (Eric), Kent, J.W. (Jack), Curran, J.E. (Joanne), Johnson, M.P. (Matthew), Williams-Blangero, S. (Sarah), Westra, H.J. (Harm-Jan), McRae, A.F. (Allan F.), Smith, J.A. (Jennifer A), Kardia, S.L.R. (Sharon), Hovatta, I. (Iiris), Perola, M. (Markus), Ripatti, S. (Samuli), Salomaa, V. (Veikko), Henders, A.K. (Anjali), Martin, N.G. (Nicholas), Smith, A.K. (Alicia K.), Mehta, D. (Divya), Binder, E.B. (Elisabeth B.), Nylocks, K.M. (K. Maria), Kennedy, E.M. (Elizabeth M.), Klengel, T. (Torsten), Ding, J. (Jingzhong), Suchy-Dicey, A. (Astrid), Enquobahrie, D., Brody, J.A. (Jennifer A.), Rotter, J.I. (Jerome I.), Chen, Y.-D.I. (Yii-Der I.), Houwing-Duistermaat, J.J. (Jeanine), Kloppenburg, M. (Margreet), Slagboom, P.E. (Eline), Helmer, Q. (Quinta), Hollander, W. (Wouter) den, Bean, S. (Shannon), Raj, T. (Towfique), Bakhshi, N. (Noman), Wang, Q.P. (Qiao Ping), Oyston, L.J. (Lisa J.), Psaty, B.M. (Bruce), Tracy, R.P. (Russell), Montgomery, G.W. (Grant), Turner, S.T. (Stephen), Blangero, J. (John), Meulenbelt, I. (Ingrid), Ressler, K.J. (Kerry), Yang, J. (Jian), Franke, L. (Lude), Kettunen, J. (Johannes), Visscher, P.M. (Peter), Neely, G.G. (G. Gregory), Korstanje, R. (Ron), Hanson, R.L. (Robert L.), Prokisch, H. (Holger), Ferrucci, L. (Luigi), Esko, T. (Tõnu), Teumer, A. (Alexander), Meurs, J.B.J. (Joyce) van, Johnson, A.D. (Andrew D.), Nalls, M.A. (Michael), Hernandez, D.G. (Dena), Cookson, M.R. (Mark), Gibbs, R.J. (Raphael J.), Hardy, J. (John), Ramasamy, A. (Adaikalavan), Zonderman, A.B. (Alan B.), Dillman, A. (Allissa), Traynor, B. (Bryan), Smith, C. (Colin), Longo, D.L. (Dan L.), Trabzuni, D. (Danyah), Troncoso, J.C. (Juan), Brug, M.P. (Marcel) van der, Weale, M.E. (Michael), O'Brien, R. (Richard), Johnson, R. (Robert), Walker, R. (Robert), Zielke, R.H. (Ronald H.), Arepalli, S. (Sampath), Ryten, M. (Mina), and Singleton, A.

Abstract

Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.

Published
2015
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15. Common genetic variants influence human subcortical brain structures

Author

Hibar, D.P. (Derrek), Stein, J.L., Rentería, M.E. (Miguel), Arias-Vásquez, A. (Alejandro), Desrivières, S. (Sylvane), Jahanshad, N. (Neda), Toro, R. (Roberto), Wittfeld, K. (Katharina), Abramovic, L. (Lucija), Andersson, M. (Micael), Aribisala, B. (Benjamin), Armstrong, N.J. (Nicola J.), Bernard, M. (Manon), Bohlken, M.M. (Marc M.), Boks, M.P.M. (Marco), Bralten, L.B.C. (Linda), Brown, A.A. (Andrew), Chakravarty, M.M. (M. Mallar), Chen, Q. (Qiang), Ching, C.R.K. (Christopher), Cuellar-Partida, G. (Gabriel), Braber, A. (Anouk) den, Giddaluru, S. (Sudheer), Goldman, A.L. (Aaron L.), Grimm, O. (Oliver), Guadalupe, T. (Tulio), Hass, J. (Johanna), Woldehawariat, G. (Girma), Holmes, A.J. (Avram), Hoogman, M. (Martine), Janowitz, D. (Deborah), Jia, T. (Tianye), Kim, S. (Shinseog), Klein, M. (Marieke), Kraemer, B. (Bernd), Lee, P.H. (Phil H.), Olde Loohuis, L.M. (Loes M.), Luciano, M. (Michelle), MacAre, C. (Christine), Mather, R., Mattheisen, M. (Manuel), Milaneschi, Y. (Yuri), Nho, K. (Kwangsik), Papmeyer, M. (Martina), Ramasamy, A. (Adaikalavan), Risacher, S.L. (Shannon), Roiz-Santiañez, R. (Roberto), Rose, E.J. (Emma), Salami, A. (Alireza), Sämann, P.G. (Philipp), Schmaal, L. (Lianne), Schork, N.J. (Nicholas), Shin, J. (Jean), Strike, L.T. (Lachlan), Teumer, A. (Alexander), Van Donkelaar, M.M.J. (Marjolein M. J.), Eijk, K.R. (Kristel) van, Walters, R.K. (Raymond), Westlye, L.T. (Lars), Whelan, C.D. (Christopher), Winkler, A.M. (Anderson), Zwiers, M.P. (Marcel), Alhusaini, S. (Saud), Athanasiu, L. (Lavinia), Ehrlich, S.M. (Stefan), Hakobjan, M. (Marina), Hartberg, C.B. (Cecilie B.), Haukvik, U.K. (Unn), Heister, A.J.G.A.M. (Angelien J. G. A. M.), Hoehn, D. (David), Kasperaviciute, D. (Dalia), Liewald, D.C.M. (David), Lopez, L.M. (Lorna), Makkinje, R.R.R. (Remco R. R.), Matarin, M. (Mar), Naber, M.A.M. (Marlies A. M.), McKay, D.R. (Reese), Needham, M. (Margaret), Nugent, A.C. (Allison), Pütz, B. (Benno), Royle, N.A. (Natalie), Shen, L. (Li), Sprooten, R. (Roy), Trabzuni, D. (Danyah), Van Der Marel, S.S.L. (Saskia S. L.), Van Hulzen, K.J.E. (Kimm J. E.), Walton, E. (Esther), Björnsson, A. (Asgeir), Almasy, L. (Laura), Ames, D.J. (David), Arepalli, S. (Sampath), Assareh, A.A., Bastin, M.E. (Mark), Brodaty, H. (Henry), Bulayeva, K. (Kazima), Carless, M.A. (Melanie), Cichon, S. (Sven), Corvin, A. (Aiden), Curran, J.E. (Joanne), Czisch, M. (Michael), Zubicaray, G.I. (Greig) de, Dillman, A. (Allissa), Duggirala, A. (Aparna), Dyer, M.D. (Matthew), Erk, S., Fedko, I. (Iryna), Ferrucci, L. (Luigi), Foroud, T. (Tatiana), Fox, P.T. (Peter), Fukunaga, M. (Masaki), Raphael Gibbs, J., Göring, H.H.H. (Harald H.), Green, R.C. (Robert C.), Guelfi, S. (Sebastian), Hansell, N.K. (Narelle), Hartman, C.A. (Catharina), Hegenscheid, K. (Katrin), Heinz, J. (Judith), Hernandez, D.G. (Dena), Heslenfeld, D.J. (Dirk), Hoekstra, P.J. (Pieter), Holsboer, F., Homuth, G. (Georg), Hottenga, J.J. (Jouke Jan), Ikeda, M. (Masashi), Jack Jr., C.R. (Clifford), Jenkinson, S. (Sarah), Johnson, R. (Robert), Kanai, R. (Ryota), Keil, M. (Maria), Kent, J.W. (Jack W.), Kochunov, P. (Peter), Kwok, J.B. (John B.), Lawrie, S. (Stephen), Liu, X. (Xinmin), Longo, D.L. (Dan L.), Mcmahon, K.L. (Katie), Meisenzahl, E. (Eva), Melle, I. (Ingrid), Mohnke, S. (Sebastian), Montgomery, G.W. (Grant), Mostert, J.C. (Jeanette C.), Mühleisen, T.W. (Thomas), Nalls, M.A. (Michael), Nichols, T.E. (Thomas), Nilsson, L.G., Nöthen, M.M. (Markus), Ohi, K. (Kazutaka), Olvera, R.L. (Rene), Perez-Iglesias, R. (Rocio), Pike, G.B. (Bruce), Potkin, S.G. (Steven), Reinvang, I. (Ivar), Reppermund, S., Rietschel, M. (Marcella), Seiferth, N. (Nina), Rosen, G.D. (Glenn D.), Rujescu, D. (Dan), Schnell, K. (Kerry), Schofield, C.J. (Christopher), Smith, C. (Colin), Steen, V.M. (Vidar), Sussmann, J. (Jessika), Thalamuthu, A. (Anbupalam), Toga, A.W. (Arthur W.), Traynor, B. (Bryan), Troncoso, J.C. (Juan), Turner, J. (Jessica), Valdés Hernández, M.C. (Maria), Ent, D. (Dennis) van 't, Brug, M.P. (Marcel) van der, Wee, N.J. (Nic) van der, Tol, M.J.D. (Marie-José) van, Veltman, D.J. (Dick), Wassink, A.M.J. (Annemarie), Westman, E. (Eric), Zielke, R.H. (Ronald H.), Zonderman, A.B. (Alan B.), Ashbrook, D.G. (David G.), Hager, R. (Reinmar), Lu, L. (Lu), Mcmahon, F.J. (Francis J), Morris, D.W. (Derek W), Williams, R.W. (Robert W.), Brunner, H.G., Buckner, M., Buitelaar, J.K. (Jan K.), Cahn, W. (Wiepke), Calhoun, V.D. (Vince), Cavalleri, G. (Gianpiero), Crespo-Facorro, B. (Benedicto), Dale, A.M. (Anders), Davies, G.E. (Gareth), Delanty, N., Depondt, C. (Chantal), Djurovic, S. (Srdjan), Drevets, D.A. (Douglas), Espeseth, T. (Thomas), Gollub, R.L. (Randy), Ho, B.C. (Beng ), Hoffmann, W. (Wolfgang), Hosten, N. (Norbert), Kahn, R. (René), Le Hellard, S. (Stephanie), Meyer-Lindenberg, A., Müller-Myhsok, B. (B.), Nauck, M. (Matthias), Nyberg, L. (Lars), Pandolfo, M. (Massimo), Penninx, B.W.J.H. (Brenda), Roffman, J.L. (Joshua), Sisodiya, S.M. (Sanjay), Smoller, J.W., Bokhoven, H. (Hans) van, Haren, N.E.M. (Neeltje E.) van, Völzke, H. (Henry), Walter, H.J. (Henrik), Weiner, M.W. (Michael), Wen, W. (Wei), White, T.J.H. (Tonya), Agartz, I. (Ingrid), Andreassen, O.A. (Ole), Blangero, J. (John), Boomsma, D.I. (Dorret), Brouwer, R.M. (Rachel), Cannon, D.M. (Dara), Cookson, M.R. (Mark), Geus, E.J.C. (Eco) de, Deary, I.J. (Ian), Donohoe, D.J. (Dennis), Fernandez, G. (Guillén), Fisher, S.E. (Simon), Francks, C. (Clyde), Glahn, D.C. (David), Grabe, H.J. (Hans Jörgen), Gruber, O. (Oliver), Hardy, J. (John), Hashimoto, R. (Ryota), Hulshoff Pol, H.E. (Hilleke), Jönsson, E.G. (Erik), Kloszewska, I. (Iwona), Lovestone, S. (Simon), Mattay, V.S. (Venkata S.), Mecocci, P. (Patrizia), McDonald, C. (Colm), McIntosh, A.M. (Andrew), Ophoff, R.A. (Roel), Paus, T. (Tomas), Pausova, Z. (Zdenka), Ryten, M. (Mina), Sachdev, P.S. (Perminder), Saykin, A.J. (Andrew), Simmons, A. (Andrew), Singleton, A. (Andrew), Soininen, H. (H.), Wardlaw, J.M. (J.), Weale, M.E. (Michael), Weinberger, D.R. (Daniel), Adams, H.H.H. (Hieab), Launer, L.J. (Lenore), Seiler, S. (Stephan), Schmidt, R. (Reinhold), Chauhan, G. (Ganesh), Satizabal, C.L. (Claudia), Becker, J.T. (James), Yanek, L.R. (Lisa), Lee, S.J. (Sven) van der, Ebling, M. (Maritza), Fischl, B. (Bruce), Longstreth Jr, W.T., Greve, D. (Douglas), Nyquist, P. (Paul), Vinke, L.N. (Louis N.), Duijn, C.M. (Cornelia) van, Xue, L. (Luting), Mazoyer, B. (Bernard), Bis, J.C. (Joshua), Gudnason, V. (Vilmundur), Seshadri, S. (Sudha), Ikram, M.A. (Arfan), Martin, N.G. (Nicholas), Wright, M.J. (Margaret), Schumann, G. (Gunter), Franke, B. (Barbara), Thompson, P.M. (Paul), Medland, S.E. (Sarah), Hibar, D.P. (Derrek), Stein, J.L., Rentería, M.E. (Miguel), Arias-Vásquez, A. (Alejandro), Desrivières, S. (Sylvane), Jahanshad, N. (Neda), Toro, R. (Roberto), Wittfeld, K. (Katharina), Abramovic, L. (Lucija), Andersson, M. (Micael), Aribisala, B. (Benjamin), Armstrong, N.J. (Nicola J.), Bernard, M. (Manon), Bohlken, M.M. (Marc M.), Boks, M.P.M. (Marco), Bralten, L.B.C. (Linda), Brown, A.A. (Andrew), Chakravarty, M.M. (M. Mallar), Chen, Q. (Qiang), Ching, C.R.K. (Christopher), Cuellar-Partida, G. (Gabriel), Braber, A. (Anouk) den, Giddaluru, S. (Sudheer), Goldman, A.L. (Aaron L.), Grimm, O. (Oliver), Guadalupe, T. (Tulio), Hass, J. (Johanna), Woldehawariat, G. (Girma), Holmes, A.J. (Avram), Hoogman, M. (Martine), Janowitz, D. (Deborah), Jia, T. (Tianye), Kim, S. (Shinseog), Klein, M. (Marieke), Kraemer, B. (Bernd), Lee, P.H. (Phil H.), Olde Loohuis, L.M. (Loes M.), Luciano, M. (Michelle), MacAre, C. (Christine), Mather, R., Mattheisen, M. (Manuel), Milaneschi, Y. (Yuri), Nho, K. (Kwangsik), Papmeyer, M. (Martina), Ramasamy, A. (Adaikalavan), Risacher, S.L. (Shannon), Roiz-Santiañez, R. (Roberto), Rose, E.J. (Emma), Salami, A. (Alireza), Sämann, P.G. (Philipp), Schmaal, L. (Lianne), Schork, N.J. (Nicholas), Shin, J. (Jean), Strike, L.T. (Lachlan), Teumer, A. (Alexander), Van Donkelaar, M.M.J. (Marjolein M. J.), Eijk, K.R. (Kristel) van, Walters, R.K. (Raymond), Westlye, L.T. (Lars), Whelan, C.D. (Christopher), Winkler, A.M. (Anderson), Zwiers, M.P. (Marcel), Alhusaini, S. (Saud), Athanasiu, L. (Lavinia), Ehrlich, S.M. (Stefan), Hakobjan, M. (Marina), Hartberg, C.B. (Cecilie B.), Haukvik, U.K. (Unn), Heister, A.J.G.A.M. (Angelien J. G. A. M.), Hoehn, D. (David), Kasperaviciute, D. (Dalia), Liewald, D.C.M. (David), Lopez, L.M. (Lorna), Makkinje, R.R.R. (Remco R. R.), Matarin, M. (Mar), Naber, M.A.M. (Marlies A. M.), McKay, D.R. (Reese), Needham, M. (Margaret), Nugent, A.C. (Allison), Pütz, B. (Benno), Royle, N.A. (Natalie), Shen, L. (Li), Sprooten, R. (Roy), Trabzuni, D. (Danyah), Van Der Marel, S.S.L. (Saskia S. L.), Van Hulzen, K.J.E. (Kimm J. E.), Walton, E. (Esther), Björnsson, A. (Asgeir), Almasy, L. (Laura), Ames, D.J. (David), Arepalli, S. (Sampath), Assareh, A.A., Bastin, M.E. (Mark), Brodaty, H. (Henry), Bulayeva, K. (Kazima), Carless, M.A. (Melanie), Cichon, S. (Sven), Corvin, A. (Aiden), Curran, J.E. (Joanne), Czisch, M. (Michael), Zubicaray, G.I. (Greig) de, Dillman, A. (Allissa), Duggirala, A. (Aparna), Dyer, M.D. (Matthew), Erk, S., Fedko, I. (Iryna), Ferrucci, L. (Luigi), Foroud, T. (Tatiana), Fox, P.T. (Peter), Fukunaga, M. (Masaki), Raphael Gibbs, J., Göring, H.H.H. (Harald H.), Green, R.C. (Robert C.), Guelfi, S. (Sebastian), Hansell, N.K. (Narelle), Hartman, C.A. (Catharina), Hegenscheid, K. (Katrin), Heinz, J. (Judith), Hernandez, D.G. (Dena), Heslenfeld, D.J. (Dirk), Hoekstra, P.J. (Pieter), Holsboer, F., Homuth, G. (Georg), Hottenga, J.J. (Jouke Jan), Ikeda, M. (Masashi), Jack Jr., C.R. (Clifford), Jenkinson, S. (Sarah), Johnson, R. (Robert), Kanai, R. (Ryota), Keil, M. (Maria), Kent, J.W. (Jack W.), Kochunov, P. (Peter), Kwok, J.B. (John B.), Lawrie, S. (Stephen), Liu, X. (Xinmin), Longo, D.L. (Dan L.), Mcmahon, K.L. (Katie), Meisenzahl, E. (Eva), Melle, I. (Ingrid), Mohnke, S. (Sebastian), Montgomery, G.W. (Grant), Mostert, J.C. (Jeanette C.), Mühleisen, T.W. (Thomas), Nalls, M.A. (Michael), Nichols, T.E. (Thomas), Nilsson, L.G., Nöthen, M.M. (Markus), Ohi, K. (Kazutaka), Olvera, R.L. (Rene), Perez-Iglesias, R. (Rocio), Pike, G.B. (Bruce), Potkin, S.G. (Steven), Reinvang, I. (Ivar), Reppermund, S., Rietschel, M. (Marcella), Seiferth, N. (Nina), Rosen, G.D. (Glenn D.), Rujescu, D. (Dan), Schnell, K. (Kerry), Schofield, C.J. (Christopher), Smith, C. (Colin), Steen, V.M. (Vidar), Sussmann, J. (Jessika), Thalamuthu, A. (Anbupalam), Toga, A.W. (Arthur W.), Traynor, B. (Bryan), Troncoso, J.C. (Juan), Turner, J. (Jessica), Valdés Hernández, M.C. (Maria), Ent, D. (Dennis) van 't, Brug, M.P. (Marcel) van der, Wee, N.J. (Nic) van der, Tol, M.J.D. (Marie-José) van, Veltman, D.J. (Dick), Wassink, A.M.J. (Annemarie), Westman, E. (Eric), Zielke, R.H. (Ronald H.), Zonderman, A.B. (Alan B.), Ashbrook, D.G. (David G.), Hager, R. (Reinmar), Lu, L. (Lu), Mcmahon, F.J. (Francis J), Morris, D.W. (Derek W), Williams, R.W. (Robert W.), Brunner, H.G., Buckner, M., Buitelaar, J.K. (Jan K.), Cahn, W. (Wiepke), Calhoun, V.D. (Vince), Cavalleri, G. (Gianpiero), Crespo-Facorro, B. (Benedicto), Dale, A.M. (Anders), Davies, G.E. (Gareth), Delanty, N., Depondt, C. (Chantal), Djurovic, S. (Srdjan), Drevets, D.A. (Douglas), Espeseth, T. (Thomas), Gollub, R.L. (Randy), Ho, B.C. (Beng ), Hoffmann, W. (Wolfgang), Hosten, N. (Norbert), Kahn, R. (René), Le Hellard, S. (Stephanie), Meyer-Lindenberg, A., Müller-Myhsok, B. (B.), Nauck, M. (Matthias), Nyberg, L. (Lars), Pandolfo, M. (Massimo), Penninx, B.W.J.H. (Brenda), Roffman, J.L. (Joshua), Sisodiya, S.M. (Sanjay), Smoller, J.W., Bokhoven, H. (Hans) van, Haren, N.E.M. (Neeltje E.) van, Völzke, H. (Henry), Walter, H.J. (Henrik), Weiner, M.W. (Michael), Wen, W. (Wei), White, T.J.H. (Tonya), Agartz, I. (Ingrid), Andreassen, O.A. (Ole), Blangero, J. (John), Boomsma, D.I. (Dorret), Brouwer, R.M. (Rachel), Cannon, D.M. (Dara), Cookson, M.R. (Mark), Geus, E.J.C. (Eco) de, Deary, I.J. (Ian), Donohoe, D.J. (Dennis), Fernandez, G. (Guillén), Fisher, S.E. (Simon), Francks, C. (Clyde), Glahn, D.C. (David), Grabe, H.J. (Hans Jörgen), Gruber, O. (Oliver), Hardy, J. (John), Hashimoto, R. (Ryota), Hulshoff Pol, H.E. (Hilleke), Jönsson, E.G. (Erik), Kloszewska, I. (Iwona), Lovestone, S. (Simon), Mattay, V.S. (Venkata S.), Mecocci, P. (Patrizia), McDonald, C. (Colm), McIntosh, A.M. (Andrew), Ophoff, R.A. (Roel), Paus, T. (Tomas), Pausova, Z. (Zdenka), Ryten, M. (Mina), Sachdev, P.S. (Perminder), Saykin, A.J. (Andrew), Simmons, A. (Andrew), Singleton, A. (Andrew), Soininen, H. (H.), Wardlaw, J.M. (J.), Weale, M.E. (Michael), Weinberger, D.R. (Daniel), Adams, H.H.H. (Hieab), Launer, L.J. (Lenore), Seiler, S. (Stephan), Schmidt, R. (Reinhold), Chauhan, G. (Ganesh), Satizabal, C.L. (Claudia), Becker, J.T. (James), Yanek, L.R. (Lisa), Lee, S.J. (Sven) van der, Ebling, M. (Maritza), Fischl, B. (Bruce), Longstreth Jr, W.T., Greve, D. (Douglas), Nyquist, P. (Paul), Vinke, L.N. (Louis N.), Duijn, C.M. (Cornelia) van, Xue, L. (Luting), Mazoyer, B. (Bernard), Bis, J.C. (Joshua), Gudnason, V. (Vilmundur), Seshadri, S. (Sudha), Ikram, M.A. (Arfan), Martin, N.G. (Nicholas), Wright, M.J. (Margaret), Schumann, G. (Gunter), Franke, B. (Barbara), Thompson, P.M. (Paul), and Medland, S.E. (Sarah)

Abstract

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, a

Published
2015
Full Text
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16. Common genetic variants influence human subcortical brain structures

Author

Hibar, D.P., Stein, J.L., Renteria, M.E., Arias-Vasquez, A., Desrivières, S., Jahanshad, N., Toro, R., Wittfeld, K., Abramovic, L., Andersson, M., Aribisala, B.S., Armstrong, N.J., Bernard, M., Bohlken, M.M., Boks, M.P., Bralten, J., Brown, A.A., Mallar Chakravarty, M., Chen, Q., Ching, C.R.K., Cuellar-Partida, G., den Braber, A., Giddaluru, S., Goldman, A.L., Grimm, O., Guadalupe, T., Hass, J., Woldehawariat, G., Holmes, A.J., Hoogman, M., Janowitz, D., Jia, T., Kim, S., Klein, M., Kraemer, B., Lee, P.H., Olde Loohuis, L.M., Luciano, M., Macare, C., Mather, K.A., Mattheisen, M., Milaneschi, Y., Nho, K., Papmeyer, M., Ramasamy, A., Risacher, S.L., Roiz-Santiañez, R., Rose, E.J., Salami, A., Sämann, P.G., Schmaal, L., Schork, A.J., Shin, J., Strike, L.T., Teumer, A., van Donkelaar, M.M.J., van Eijk, K.R., Walters, R.K., Westlye, L.T., Whelan, C.D., Winkler, A.M., Zwiers, M.P., Alhusaini, S., Athanasiu, L., Ehrlich, S., Hakobjan, M.M.H., Hartberg, C.B., Haukvik, U.K., Heister, A.J.G.A.M., Hoehn, D., Kasperaviciute, D., Liewald, D.C.M., Lopez, L.M., Makkinje, R.R.R., Matarin, M., Naber, M.A.M., Reese McKay, D., Needham, M., Nugent, A.C., Pütz, B., Royle, N.A., Shen, Li, Sprooten, E., Trabzuni, D., van der Marel, S.S.L., van Hulzen, K.J.E., Walton, E., Wolf, C., Almasy, L., Ames, D., Arepalli, S., Assareh, A.A., Bastin, M.E., Brodaty, H., Bulayeva, K.B., Carless, M.A., Cichon, S., Corvin, A., Curran, J.E., Czisch, M., de Zubicaray, G.I., Dillman, A., Duggirala, R., Dyer, T.D., Erk, S., Fedko, I.O., Ferrucci, L., Foroud, T.M., Fox, P.T., Fukunaga, M., Raphael Gibbs, J., Göring, H.H.H., Green, R.C., Guelfi, S., Hansell, N.K., Hartman, C.A., Hegenscheid, K., Heinz, A., Hernandez, D.G., Heslenfeld, D.J., Hoekstra, P.J., Holsboer, F., Homuth, G., Hottenga, J-J, Ikeda, M., Jack, C.R., Jenkinson, M., Johnson, R., Kanai, R., Keil, M., Kent, J.W., Kochunov, P., Kwok, J.B., Lawrie, S.M., Liu, X., Longo, D.L., McMahon, K.L., Meisenzahl, E., Melle, I., Mohnke, S., Montgomery, G.W., Mostert, J.C., Mühleisen, T.W., Nalls, M.A., Nichols, T.E., Nilsson, L.G., Nöthen, M.M., Ohi, K., Olvera, R.L., Perez-Iglesias, R., Bruce Pike, G., Potkin, S.G., Reinvang, I., Reppermund, S., Rietschel, M., Romanczuk-Seiferth, N., Rosen, G.D., Rujescu, D., Schnell, K., Schofield, P.R., Smith, C., Steen, V.M., Sussmann, J.E., Thalamuthu, A., Toga, A.W., Traynor, B.J., Troncoso, J., Turner, J.A., Valdés Hernández, M.C., van 't Ent, D., van der Brug, M., van der Wee, N.J.A., van Tol, M-J, Veltman, D.J., Wassink, T.H., Westman, E., Zielke, R.H., Zonderman, A.B., Ashbrook, D.G., Hager, R., Lu, L., McMahon, F.J., Morris, D.W., Williams, R.W., Brunner, H.G., Buckner, R.L., Buitelaar, J.K., Cahn, W., Calhoun, V.D., Cavalleri, G.L., Crespo-Facorro, B., Dale, A.M., Davies, G.E., Delanty, N., Depondt, C., Djurovic, S., Drevets, W.C., Espeseth, T., Gollub, R.L., Ho, B-C., Hoffmann, W., Hosten, N., Kahn, R.S., Le Hellard, S., Meyer-Lindenberg, A., Müller-Myhsok, B., Nauck, M., Nyberg, L., Pandolfo, M., Penninx, B.W.J.H., Roffman, J.L., Sisodiya, S.M., Smoller, J.W., van Bokhoven, H., van Haren, N.E.M., Völzke, H., Walter, H., Weiner, M.W., Wen, W., White, T., Agartz, I., Andreassen, O.A., Blangero, J., Boomsma, D.I., Brouwer, R.M., Cannon, D.M., Cookson, M.R., de Geus, E.J.C., Deary, I.J., Donohoe, G., Fernández, G., Fisher, S.E., Francks, C., Glahn, D.C., Grabe, H.J., Gruber, O., Hardy, J., Hashimoto, R., Hulshoff Pol, H.E., Jönsson, E.G., Kloszewska, I., Lovestone, S., Mattay, V.S., Mecocci, P., McDonald, C., McIntosh, A.M., Ophoff, R.A., Paus, T., Pausova, Z., Ryten, M., Sachdev, P.S., Saykin, A.J., Simmons, A., Singleton, A., Soininen, H., Wardlaw, J.M., Weale, M.E., Weinberger, D.R., Adams, H.H.H., Launer, L.J., Seiler, S., Schmidt, R., Chauhan, G., Satizabal, C.L., Becker, J.T., Yanek, L., van der Lee, S.J., Ebling, M., Fischl, B., Longstreth, W.T., Greve, D., Schmidt, H., Nyquist, P., Vinke, L.N., van Duijn, C.M., Xue, L., Mazoyer, B., Bis, J.C., Gudnason, V., Seshadri, S., Ikram, M.A., Martin, N.G., Wright, M.J., Schumann, G., Franke, B., Thompson, P.M., Medland, S.E., Hibar, D.P., Stein, J.L., Renteria, M.E., Arias-Vasquez, A., Desrivières, S., Jahanshad, N., Toro, R., Wittfeld, K., Abramovic, L., Andersson, M., Aribisala, B.S., Armstrong, N.J., Bernard, M., Bohlken, M.M., Boks, M.P., Bralten, J., Brown, A.A., Mallar Chakravarty, M., Chen, Q., Ching, C.R.K., Cuellar-Partida, G., den Braber, A., Giddaluru, S., Goldman, A.L., Grimm, O., Guadalupe, T., Hass, J., Woldehawariat, G., Holmes, A.J., Hoogman, M., Janowitz, D., Jia, T., Kim, S., Klein, M., Kraemer, B., Lee, P.H., Olde Loohuis, L.M., Luciano, M., Macare, C., Mather, K.A., Mattheisen, M., Milaneschi, Y., Nho, K., Papmeyer, M., Ramasamy, A., Risacher, S.L., Roiz-Santiañez, R., Rose, E.J., Salami, A., Sämann, P.G., Schmaal, L., Schork, A.J., Shin, J., Strike, L.T., Teumer, A., van Donkelaar, M.M.J., van Eijk, K.R., Walters, R.K., Westlye, L.T., Whelan, C.D., Winkler, A.M., Zwiers, M.P., Alhusaini, S., Athanasiu, L., Ehrlich, S., Hakobjan, M.M.H., Hartberg, C.B., Haukvik, U.K., Heister, A.J.G.A.M., Hoehn, D., Kasperaviciute, D., Liewald, D.C.M., Lopez, L.M., Makkinje, R.R.R., Matarin, M., Naber, M.A.M., Reese McKay, D., Needham, M., Nugent, A.C., Pütz, B., Royle, N.A., Shen, Li, Sprooten, E., Trabzuni, D., van der Marel, S.S.L., van Hulzen, K.J.E., Walton, E., Wolf, C., Almasy, L., Ames, D., Arepalli, S., Assareh, A.A., Bastin, M.E., Brodaty, H., Bulayeva, K.B., Carless, M.A., Cichon, S., Corvin, A., Curran, J.E., Czisch, M., de Zubicaray, G.I., Dillman, A., Duggirala, R., Dyer, T.D., Erk, S., Fedko, I.O., Ferrucci, L., Foroud, T.M., Fox, P.T., Fukunaga, M., Raphael Gibbs, J., Göring, H.H.H., Green, R.C., Guelfi, S., Hansell, N.K., Hartman, C.A., Hegenscheid, K., Heinz, A., Hernandez, D.G., Heslenfeld, D.J., Hoekstra, P.J., Holsboer, F., Homuth, G., Hottenga, J-J, Ikeda, M., Jack, C.R., Jenkinson, M., Johnson, R., Kanai, R., Keil, M., Kent, J.W., Kochunov, P., Kwok, J.B., Lawrie, S.M., Liu, X., Longo, D.L., McMahon, K.L., Meisenzahl, E., Melle, I., Mohnke, S., Montgomery, G.W., Mostert, J.C., Mühleisen, T.W., Nalls, M.A., Nichols, T.E., Nilsson, L.G., Nöthen, M.M., Ohi, K., Olvera, R.L., Perez-Iglesias, R., Bruce Pike, G., Potkin, S.G., Reinvang, I., Reppermund, S., Rietschel, M., Romanczuk-Seiferth, N., Rosen, G.D., Rujescu, D., Schnell, K., Schofield, P.R., Smith, C., Steen, V.M., Sussmann, J.E., Thalamuthu, A., Toga, A.W., Traynor, B.J., Troncoso, J., Turner, J.A., Valdés Hernández, M.C., van 't Ent, D., van der Brug, M., van der Wee, N.J.A., van Tol, M-J, Veltman, D.J., Wassink, T.H., Westman, E., Zielke, R.H., Zonderman, A.B., Ashbrook, D.G., Hager, R., Lu, L., McMahon, F.J., Morris, D.W., Williams, R.W., Brunner, H.G., Buckner, R.L., Buitelaar, J.K., Cahn, W., Calhoun, V.D., Cavalleri, G.L., Crespo-Facorro, B., Dale, A.M., Davies, G.E., Delanty, N., Depondt, C., Djurovic, S., Drevets, W.C., Espeseth, T., Gollub, R.L., Ho, B-C., Hoffmann, W., Hosten, N., Kahn, R.S., Le Hellard, S., Meyer-Lindenberg, A., Müller-Myhsok, B., Nauck, M., Nyberg, L., Pandolfo, M., Penninx, B.W.J.H., Roffman, J.L., Sisodiya, S.M., Smoller, J.W., van Bokhoven, H., van Haren, N.E.M., Völzke, H., Walter, H., Weiner, M.W., Wen, W., White, T., Agartz, I., Andreassen, O.A., Blangero, J., Boomsma, D.I., Brouwer, R.M., Cannon, D.M., Cookson, M.R., de Geus, E.J.C., Deary, I.J., Donohoe, G., Fernández, G., Fisher, S.E., Francks, C., Glahn, D.C., Grabe, H.J., Gruber, O., Hardy, J., Hashimoto, R., Hulshoff Pol, H.E., Jönsson, E.G., Kloszewska, I., Lovestone, S., Mattay, V.S., Mecocci, P., McDonald, C., McIntosh, A.M., Ophoff, R.A., Paus, T., Pausova, Z., Ryten, M., Sachdev, P.S., Saykin, A.J., Simmons, A., Singleton, A., Soininen, H., Wardlaw, J.M., Weale, M.E., Weinberger, D.R., Adams, H.H.H., Launer, L.J., Seiler, S., Schmidt, R., Chauhan, G., Satizabal, C.L., Becker, J.T., Yanek, L., van der Lee, S.J., Ebling, M., Fischl, B., Longstreth, W.T., Greve, D., Schmidt, H., Nyquist, P., Vinke, L.N., van Duijn, C.M., Xue, L., Mazoyer, B., Bis, J.C., Gudnason, V., Seshadri, S., Ikram, M.A., Martin, N.G., Wright, M.J., Schumann, G., Franke, B., Thompson, P.M., and Medland, S.E.

Abstract

The highly complex structure of the human brain is strongly shaped by genetic influences1. Subcortical brain regions form circuits with cortical areas to coordinate movement2, learning, memory3 and motivation4, and altered circuits can lead to abnormal behaviour and disease2. 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 volume5 and intracranial volume6. 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 × 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.

Published
2015

17. Antitumor antibiotics

Author

Verweij, Jaap, Sparreboom, A, Nooter, K (Kees), Chabner, B.A., Longo, D.L., and Medical Oncology

Published
2006

20. Identification of nine novel loci associated with white blood cell subtypes in a Japanese population

Author

Okada, Y. (Yukinori), Hirota, T. (Tomomitsu), Kamatani, Y. (Yoichiro), Takahashi, A. (Atsushi), Ohmiya, H. (Hiroko), Kumasaka, N. (Natsuhiko), Higasa, K. (Koichiro), Yamaguchi-Kabata, Y. (Yumi), Hosono, N. (Naoya), Nalls, M.A. (Michael), Chen, M-H. (Ming-Huei), Rooij, F.J.A. (Frank) van, Smith, A.V. (Albert Vernon), Tanaka, T. (Toshiko), Couper, D. (David), Zakai, N.A. (Neil), Ferrucci, L. (Luigi), Longo, D.L. (Dan), Hernandez, D.G. (Dena), Witteman, J.C.M. (Jacqueline), Harris, T.B. (Tamara), O'Donnell, C.J. (Christopher), Ganesh, S.K. (Santhi), Matsuda, K. (Koichi), Tsunoda, T. (Tatsuhiko), Kubo, M. (Michiaki), Nakamura, Y. (Yusuke), Tamari, M. (Mayumi), Yamamoto, K. (Kazuhiko), Okada, Y. (Yukinori), Hirota, T. (Tomomitsu), Kamatani, Y. (Yoichiro), Takahashi, A. (Atsushi), Ohmiya, H. (Hiroko), Kumasaka, N. (Natsuhiko), Higasa, K. (Koichiro), Yamaguchi-Kabata, Y. (Yumi), Hosono, N. (Naoya), Nalls, M.A. (Michael), Chen, M-H. (Ming-Huei), Rooij, F.J.A. (Frank) van, Smith, A.V. (Albert Vernon), Tanaka, T. (Toshiko), Couper, D. (David), Zakai, N.A. (Neil), Ferrucci, L. (Luigi), Longo, D.L. (Dan), Hernandez, D.G. (Dena), Witteman, J.C.M. (Jacqueline), Harris, T.B. (Tamara), O'Donnell, C.J. (Christopher), Ganesh, S.K. (Santhi), Matsuda, K. (Koichi), Tsunoda, T. (Tatsuhiko), Kubo, M. (Michiaki), Nakamura, Y. (Yusuke), Tamari, M. (Mayumi), and Yamamoto, K. (Kazuhiko)

Abstract

White blood cells (WBCs) mediate immune systems and consist of various subtypes with distinct roles. Elucidation of the mechanism that regulates the counts of the WBC subtypes would provide useful insights into both the etiology of the immune system and disease pathogenesis. In this study, we report results of genome-wide association studies (GWAS) and a replication study for the counts of the 5 main WBC subtypes (neutrophils, lymphocytes, monocytes, basophils, and eosinophils) using 14,792 Japanese subjects enrolled in the BioBank Japan Project. We identified 12 significantly associated loci that satisfied the genome-wide significance threshold of P<5.0×10-8, of which 9 loci were novel (the CDK6 locus for the neutrophil count; the ITG

Published
2011
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21. Multiple loci are associated with white blood cell phenotypes

Author

Nalls, M.A. (Michael), Couper, D. (David), Tanaka, T. (Toshiko), Rooij, F.J.A. (Frank) van, Chen, M-H. (Ming-Huei), Smith, A.V. (Albert Vernon), Toniolo, D. (Daniela), Zakai, N.A. (Neil), Yang, Q. (Qiong Fang), Greinacher, A. (Andreas), Wood, A.R. (Andrew), Garcia, M. (Melissa), Gasparini, P. (Paolo), Liu, Y. (YongMei), Lumley, T. (Thomas), Folsom, A.R. (Aaron), Reiner, A.P. (Alex), Gieger, C. (Christian), Lagou, V. (Vasiliki), Felix, J.F. (Janine), Völzke, H. (Henry), Gouskova, N.A. (Natalia), Biffi, A. (Alessandro), Döring, A. (Angela), Völker, U. (Uwe), Chong, S. (Sean), Wiggins, K.L. (Kerri), Rendon, A. (Augusto), Dehghan, A. (Abbas), Moore, M. (Matt), Taylor, K.D. (Kent), Wilson, J.G. (James), Lettre, G. (Guillaume), Hofman, A. (Albert), Bis, J.C. (Joshua), Pirastu, N. (Nicola), Fox, C.S. (Caroline), Meisinger, C. (Christa), Sambrook, J.G. (Jennifer), Arepalli, S. (Sampath), Nauck, M. (Matthias), Prokisch, H. (Holger), Stephens, J. (Jonathan), Glazer, N.L. (Nicole), Cupples, L.A. (Adrienne), Okada, Y. (Yukinori), Takahashi, A. (Atsushi), Kamatani, Y. (Yoichiro), Matsuda, K. (Koichi), Tsunoda, T. (Tatsuhiko), Kubo, M. (Michiaki), Nakamura, Y. (Yusuke), Yamamoto, K. (Kazuhiko), Stumvoll, M. (Michael), Tönjes, A. (Anke), Prokopenko, I. (Inga), Illig, T. (Thomas), Patel, K.V. (Kushang), Garner, S.F. (Stephen), Kuhnel, B. (Brigitte), Mangino, M. (Massimo), Oostra, B.A. (Ben), Thein, S.L., Coresh, J. (Josef), Wichmann, H.E. (Heinz Erich), Menzel, S. (Stephan), Lin, J., Pistis, G. (Giorgio), Uitterlinden, A.G. (André), Spector, T.D. (Timothy), Teumer, A. (Alexander), Eiriksdottir, G. (Gudny), Gudnason, V. (Vilmundur), Bandinelli, S. (Stefania), Frayling, T.M. (Timothy), Chakravarti, A. (Aravinda), Tikka-Kleemola, P. (Päivi), Melzer, D. (David), Ouwehand, W.H. (Willem), Levy, D. (Daniel), Boerwinkle, E.A. (Eric), Singleton, A. (Andrew), Hernandez, D.G. (Dena), Longo, D.L. (Dan), Soranzo, N. (Nicole), Witteman, J.C.M. (Jacqueline), Psaty, B.M. (Bruce), Ferrucci, L. (Luigi), Harris, T.B. (Tamara), O'Donnell, C.J. (Christopher), Ganesh, S.K. (Santhi), Nalls, M.A. (Michael), Couper, D. (David), Tanaka, T. (Toshiko), Rooij, F.J.A. (Frank) van, Chen, M-H. (Ming-Huei), Smith, A.V. (Albert Vernon), Toniolo, D. (Daniela), Zakai, N.A. (Neil), Yang, Q. (Qiong Fang), Greinacher, A. (Andreas), Wood, A.R. (Andrew), Garcia, M. (Melissa), Gasparini, P. (Paolo), Liu, Y. (YongMei), Lumley, T. (Thomas), Folsom, A.R. (Aaron), Reiner, A.P. (Alex), Gieger, C. (Christian), Lagou, V. (Vasiliki), Felix, J.F. (Janine), Völzke, H. (Henry), Gouskova, N.A. (Natalia), Biffi, A. (Alessandro), Döring, A. (Angela), Völker, U. (Uwe), Chong, S. (Sean), Wiggins, K.L. (Kerri), Rendon, A. (Augusto), Dehghan, A. (Abbas), Moore, M. (Matt), Taylor, K.D. (Kent), Wilson, J.G. (James), Lettre, G. (Guillaume), Hofman, A. (Albert), Bis, J.C. (Joshua), Pirastu, N. (Nicola), Fox, C.S. (Caroline), Meisinger, C. (Christa), Sambrook, J.G. (Jennifer), Arepalli, S. (Sampath), Nauck, M. (Matthias), Prokisch, H. (Holger), Stephens, J. (Jonathan), Glazer, N.L. (Nicole), Cupples, L.A. (Adrienne), Okada, Y. (Yukinori), Takahashi, A. (Atsushi), Kamatani, Y. (Yoichiro), Matsuda, K. (Koichi), Tsunoda, T. (Tatsuhiko), Kubo, M. (Michiaki), Nakamura, Y. (Yusuke), Yamamoto, K. (Kazuhiko), Stumvoll, M. (Michael), Tönjes, A. (Anke), Prokopenko, I. (Inga), Illig, T. (Thomas), Patel, K.V. (Kushang), Garner, S.F. (Stephen), Kuhnel, B. (Brigitte), Mangino, M. (Massimo), Oostra, B.A. (Ben), Thein, S.L., Coresh, J. (Josef), Wichmann, H.E. (Heinz Erich), Menzel, S. (Stephan), Lin, J., Pistis, G. (Giorgio), Uitterlinden, A.G. (André), Spector, T.D. (Timothy), Teumer, A. (Alexander), Eiriksdottir, G. (Gudny), Gudnason, V. (Vilmundur), Bandinelli, S. (Stefania), Frayling, T.M. (Timothy), Chakravarti, A. (Aravinda), Tikka-Kleemola, P. (Päivi), Melzer, D. (David), Ouwehand, W.H. (Willem), Levy, D. (Daniel), Boerwinkle, E.A. (Eric), Singleton, A. (Andrew), Hernandez, D.G. (Dena), Longo, D.L. (Dan), Soranzo, N. (Nicole), Witteman, J.C.M. (Jacqueline), Psaty, B.M. (Bruce), Ferrucci, L. (Luigi), Harris, T.B. (Tamara), O'Donnell, C.J. (Christopher), and Ganesh, S.K. (Santhi)

Abstract

White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count-6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count-17q21; basophil count-3p21 near RPN1 and C3orf27; lymphocyte count-6p21, 19p13 at EPS15L1; monocyte count-2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse

Published
2011
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22. Mitomycins

Author

Verweij, Jaap, Sparreboom, A, Nooter, K (Kees), Pinedo, H.M., Longo, D.L., Chabner, B.A., and Medical Oncology

Published
1999

34. Hodgkin's disease.

Author

Urba, W.J. and Longo, D.L.

Subjects
*HODGKIN'S disease
Abstract

Presents an overview of Hodgkin's disease. Unknown cause of the disease; Pathologic features; Identification of the Reed-Sternberg cell; Staging; Projected cure rate in 1992; Treatment of choice for patients with advanced disease; Early-stage Hodgkin's disease; Salvage therapy; Bone marrow transplantation; Late complications of Hodgkin's disease and its treatment; Amenorrhea and chemotherapy; More.

Published
1992
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35. Positive and negative selection of antigen-specific B cells in transgenic mice expressing variant forms of the V<SUB>H</SUB>1 (T15) heavy chain

Author

Derby, E.G., Hill, S.A., Tucker, P.W., Claflin, J.L., Kenny, J.J., Yoder, J.A., Fischer, R.T., and Longo, D.L.

Abstract

Four variant forms of the V1 (T15-H chain) gene are synthesized in mice. Each V1 variant pairs with a distinct L chain to produce a binding site having specificity for phosphocholine (PC). Transgenic mice expressing variant forms of the V1 gene were analyzed to elucidate the factors driving B cell selection into the peripheral repertoire. In all four lines of H chain transgenic mice analyzed, transgene expression caused complete allelic exclusion of endogenous H chains in the bone marrow (BM), whereas most splenic B cells expressed endogenous H chains. The number of sIgM+ BM B cells and their sIg receptor number was reduced compared to that of normal transgene-negative controls, suggesting that B cells expressing transgene-encoded H chains were being negatively selected in the BM. Mice expressing autoreactive forms of the V1 transgene with lower affinity for PC (M603H and M167H) exhibit positive selection of PC-specific B cells into the spleen, whereas mice expressing the higher affinity T15H variant exhibited elevated PC-specific B cells in the peritoneal cavity but few VH1+ splenic B cells. These data suggest that the higher affinity T15-id+ B cells preferentially survive in the peritoneal cavity. When these H chain transgenes were crossed into the μMT knockout mouse in which surface expression of endogenous H chains is blocked, the percent of splenic VH1+ PC-specific B cells increased up to 5-fold and T15-id+ B cells were detectable in the spleen of T15H mice. This implies that T15-id+ PC-specific B cells can be selected into the periphery, but they compete poorly with follicular B cells expressing endogenous Ig.

Published
2000

37. Myeloproliferative Syndromes: A Unique Presentation of Chronic Myelogenous Leukemia (CML) as a Primary Tumor of Bone

Author

Longo, D.L., Whang-Peng, J., Jaffe, E., Triche, T.J., and Young, R.C.

Abstract

A 45-yr-old female presented with a rapidly enlarging bony tumor that was eventually identified as a Philadelphia chromosome (Ph1)-positive myeloproliferative disorder with extramedullary blastic transformation. This transformation occurred in the absence of demonstrable chronic or acute leukemic phase. She had no history of a chronic or prodromal illness in spite of a bone marrow biopsy showing myelofibrosis and liver biopsy documenting extramedullary hematopoiesis. This case represents a unique constellation of features of the myeloproliferative syndrome in which the diagnosis was obscure until special stains of the bony tumor and cytogenetic studies were performed.

Published
1978
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38. Cytogenetic Studies in Patients With Secondary Leukemia/Dysmyelopoietic Syndrome After Different Treatment Modalities

Author

Whang-Peng, J., Young, R.C., Lee, E.C., Longo, D.L., Schechter, G.P., and DeVita, V.T.

Abstract

Cytogenetic studies of 68 patients who developed secondary leukemia (SL)/dysmyelopoietic syndrome (DMS) after extensive chemotherapy and/or radiation therapy as well as patients who developed SL/DMS without such treatment showed that those patients who received radiation alone or with chemotherapy had more extensive numerical and structural abnormalities than those who received only chemotherapy. In terms of the specific chromosomal abnormalities, there are no differences between the various treatment groups. Hypodiploidy is the most common form of aneuploidy in these patients, with the most com- mon numerical abnormality being the loss of chromosome 7. The most common structural abnormalities involved chromosomes 3 and 5. When compared with patients with de novo leukemia and DMS, the chromosomal abnormalities in these patients are more complex and extensive. Serial studies revealed that cytogenetic abnormalities do not precede the development of hematologic changes by significant time periods. This is a US government work. There are no restrictions on its use.

Published
1988
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39. Immunization with granulocyte-macrophage colony-stimulating factor-transduced, but not B7-1-transduced, lymphoma cells primes idiotype-specific T cells and generates potent systemic antitumor immunity

Author

Levitsky, H.I., Montgomery, J., Ahmadzadeh, M., Staveleyocarroll, K., Guarnieri, F., Longo, D.L., and Kwak, L.W.

Subjects
Granulocyte-macrophage colony stimulating factor -- Health aspects -- Research, Immunization -- Research -- Health aspects -- Physiological aspects, Lymphomas -- Physiological aspects -- Research, Health, Physiological aspects, Research, Health aspects
Abstract

According to the authors' abstract of an article published in Journal of Immunology, 'Recently, genetically modified tumor cell vaccines have been described for nonhematopoietic cancers in which the relevant Ags [...]

Published
1996

40. Gene transfer of multidrug resistance into a factor-dependent human hematopoietic progenitor cell line: in vivo model for genetically transferred chemoprotection

Author

Schwarzenberger, P., Spence, S., Lohrey, N., Kmiecik, T., Longo, D.L., Murphy, W.J., Ruscetti, F.W., and Keller, J.R.

Subjects
Hematopoietic stem cells -- Protection and preservation, Drug resistance -- Genetic aspects, Gene therapy -- Research, Business, Health care industry
Abstract

According to the authors' abstract of an article published in Blood, 'To develop a rapid preclinical in vivo model to study gene transfer into human hematopoietic progenitor cells, MO-7e cells [...]

Published
1996

42. Adoptive transfer of anti-CD3-activated CD4+ T cells plus cyclophosphamide and liposome-encapsulated interleukin-2 cure murine MC-38 and 3LL tumors and establish tumor-specific immunity

Author

Saxton, M.L., Longo, D.L., Wetzel, H.E., Tribble, H., Alvord, W.G., Kwak, L.W., Leonard, A.S., Ullmann, C.D., Curti, B.D., and Ochoa, A.C.

Subjects
Cellular therapy -- Models, Cancer -- Care and treatment, Health, Care and treatment, Models
Abstract

Saxton, M.L.; Longo, D.L.; Wetzel, H.E.; Tribble, H.; Alvord, W.G.; Kwak, L.W.; Leonard, A.S.; Ullmann, C.D.; Curti, B.D.; Ochoa, A.C. 'Adoptive Trans- fer of Anti-CD3-Activated CD4(+) T Cells Plus Cyclophosphamide [...]

Published
1997

43. Effects of CD40 stimulation in the prevention of human EBV-lymphomagenesis

Author

Funakoshi, S., Taub, D.D., Asai, O., Hirano, A., Ruscetti, F.W., Longo, D.L., and Murphy, W.J.

Subjects
Epstein-Barr virus diseases -- Prevention, Lymphomas -- Prevention, Health, Prevention
Abstract

Effects of CD40 Stimulation in the Prevention of Human EBV-Lymphomagenesis Epstein-Barr Virus Funakoshi, S.; Taub, D.D.; Asai, O.; Hirano, A.; Ruscetti, F.W.; Longo, D.L.; Murphy, W.J. 'Effects of CD40 Stimulation [...]

Published
1997

44. Myositis associated with interleukin-2 therapy in a patient with metastatic renal cell carcinoma

Author

Estevalorenzo, F., Janik, J.E., Fenton, R.G., Emsliesmith, A., Engel, A.G., and Longo, D.L.

Subjects
Complications and side effects, Causes of, Myositis -- Causes of -- Complications and side effects, Renal cell carcinoma -- Complications and side effects, Interleukin-2, Carcinoma, Renal cell -- Complications and side effects
Abstract

According to the authors' abstract of an article published in Cancer, 'BACKGROUND: Interleukin-2 (IL-2) has been used successfully in the treatment of some patients with metastatic renal cell carcinoma and [...]

Published
1995

45. Allogeneic fibroblasts engineered to secrete IL-2 can be potent adjuvants for a lymphoma-derived immunoglobulin antigen vaccine

Author

Kwak, L.W., Fakhrai, H., Shawler, D.L., Royston, I., and Longo, D.L.

Subjects
Immunological adjuvants -- Research, Lymphomas -- Care and treatment, Fibroblasts -- Health aspects, Interleukin-2 -- Health aspects, Business, Health care industry
Abstract

AUTHORS: L.W. Kwak 1, H. Fakhrai 2, D.L. Shawler 2, I. Royston 2 and D.L. Longo 1. 1Biological Response Modifiers Program, National Cancer Institute, Frederick, Maryland and 2San Diego Regional [...]

Published
1994

46. Hodgkin's disease (HD) following non-Hodgkin's lymphoma (NHL)

Author

Kingma, D.W., Medeiros, L.J., Zarate-Osorno, A., Longo, D.L., Ambinder, R.F., and Jaffe, E.S.

Subjects
Non-Hodgkin's lymphomas -- Complications and side effects -- Diagnosis, Hodgkin's disease -- Diagnosis -- Complications and side effects
Abstract

AUTHORS: D.W. Kingma( 1), L.J. Medeiros( 1), A. Zarate -Osorno( 1), D.L. Longo( 1), R.F. Ambinder( 2) and E.S. Jaffe( 1). (1)National Cancer Institute, Bethesda, Maryland, and (2)The Johns Hopkins [...]

Published
1993

49. The release of inflammatory mediators from acid-stimulated mesenchymal stromal cells favours tumour invasiveness and metastasis in osteosarcoma

Author

Dominique Heymann, Nicoletta Zini, Lorena Consolino, Maria Veronica Lipreri, Sofia Avnet, Marta Columbaro, Laura Roncuzzi, Alberto Righi, Dario Livio Longo, Costantino Errani, Francesca Perut, Massimo Dominici, Nicola Baldini, Cristina Nanni, Silvia Lemma, Giulia Grisendi, Giulia Golinelli, Margherita Cortini, Gemma Di Pompo, Alessandra Longhi, Avnet S., Lemma S., Cortini M., Di Pompo G., Perut F., Lipreri M.V., Roncuzzi L., Columbaro M., Errani C., Longhi A., Zini N., Heymann D., Dominici M., Grisendi G., Golinelli G., Consolino L., Longo D.L., Nanni C., Righi A., Baldini N., University of Bologna, Rizzoli Orthopedic Institute [Bologna, Italy], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Università degli Studi di Modena e Reggio Emilia, University of Turin, CNR - Italian National Research Council (CNR), Heymann, Dominique, University of Bologna/Università di Bologna, Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), and Università degli studi di Torino = University of Turin (UNITO)

Subjects
Cancer Research, [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Stromal cell, Inflammatory cytokine, Acid microenvironment, Mesenchymal stromal cells, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Metastasi, Article, Metastasis, Proinflammatory cytokine, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.CAN] Life Sciences [q-bio]/Cancer, In vivo, Inflammatory cytokines, Osteosarcoma, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], medicine, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Interleukin 8, RC254-282, 030304 developmental biology, Acidosis, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Chemistry, Mesenchymal stromal cell, Mesenchymal stem cell, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, 3. Good health, Oncology, osteosarcoma, metastasis, acid microenvironment, mesenchymal stromal cells, inflammatory cytokines, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, 030220 oncology & carcinogenesis, Cancer research, medicine.symptom
Abstract

Simple Summary We aimed to validate the correlation between tumour glycolysis/acidosis and inflammation in osteosarcoma-associated mesenchymal stromal cells and investigate the role of acidity-induced inflammation in the development of metastasis in this very aggressive cancer. We confirmed the presence of an acidic microenvironment in osteosarcoma xenografts, both subcutaneous and orthotopic, using state-of-the-art imaging technologies; corroborated the correlation between tumour glycolysis, acidosis, and inflammatory markers in human patients; and finally, explored the use of anti-IL6 antibody to target these pathogenic pathways, using advanced 3D microfluidic models. In the future, advanced imaging systems for the measurement of tumour glycolysis and/or pH may help identify osteosarcoma patients who would benefit from anti-IL6 therapies to complement conventional therapy. Abstract Osteosarcoma is the most frequent primary malignant bone tumour with an impressive tendency to metastasise. Highly proliferative tumour cells release a remarkable amount of protons into the extracellular space that activates the NF-kB inflammatory pathway in adjacent stromal cells. In this study, we further validated the correlation between tumour glycolysis/acidosis and its role in metastases. In patients, at diagnosis, we found high circulating levels of inflammatory mediators (IL6, IL8 and miR-136-5p-containing extracellular vesicles). IL6 serum levels significantly correlated with disease-free survival and 18F-FDG PET/CT uptake, an indirect measurement of tumour glycolysis and, hence, of acidosis. In vivo subcutaneous and orthotopic models, co-injected with mesenchymal stromal (MSC) and osteosarcoma cells, formed an acidic tumour microenvironment (mean pH 6.86, as assessed by in vivo MRI-CEST pH imaging). In these xenografts, we enlightened the expression of both IL6 and the NF-kB complex subunit in stromal cells infiltrating the tumour acidic area. The co-injection with MSC also significantly increased lung metastases. Finally, by using 3D microfluidic models, we directly showed the promotion of osteosarcoma invasiveness by acidosis via IL6 and MSC. In conclusion, osteosarcoma-associated MSC react to intratumoural acidosis by triggering an inflammatory response that, in turn, promotes tumour invasiveness at the primary site toward metastasis development.

Published
2021
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50. Exploring Metabolic Adaptations to the Acidic Microenvironment of Osteosarcoma Cells Unveils Sphingosine 1-Phosphate as a Valuable Therapeutic Target

Author

Elena Cannas, Nicola Baldini, Gemma Di Pompo, Andrea Armirotti, Dario Livio Longo, Alessandra Maresca, Costantino Errani, Marta Columbaro, Alessandra Longhi, Margherita Cortini, Alberto Righi, Sofia Avnet, Valerio Carelli, Cortini M., Armirotti A., Columbaro M., Longo D.L., Di Pompo G., Cannas E., Maresca A., Errani C., Longhi A., Righi A., Carelli V., Baldini N., and Avnet S.

Subjects
0301 basic medicine, FTY720, Cancer Research, lcsh:RC254-282, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Lipid droplet, osteosarcoma, medicine, tumor microenvironment, Sphingosine-1-phosphate, acidity, sphingosine 1-phosphate, Tumor microenvironment, Sphingosine, Lipidomic, Acidity, Lipidomics, Osteosarcoma, Sphingolipid, Sphingosine 1-phosphate, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 030104 developmental biology, Oncology, chemistry, 030220 oncology & carcinogenesis, Cancer research, lipidomics, lipids (amino acids, peptides, and proteins), Sarcoma, sphingolipid, Sphingomyelin
Abstract

Acidity is a key player in cancer progression, modelling a microenvironment that prevents immune surveillance and enhances invasiveness, survival, and drug resistance. Here, we demonstrated in spheroids from osteosarcoma cell lines that the exposure to acidosis remarkably caused intracellular lipid droplets accumulation. Lipid accumulation was also detected in sarcoma tissues in close proximity to tumor area that express the acid-related biomarker LAMP2. Acid-induced lipid droplets-accumulation was not functional to a higher energetic request, but rather to cell survival. As a mechanism, we found increased levels of sphingomyelin and secretion of the sphingosine 1-phosphate, and the activation of the associated sphingolipid pathway and the non-canonical NF-ĸB pathway, respectively. Moreover, decreasing sphingosine 1-phosphate levels (S1P) by FTY720 (Fingolimod) impaired acid-induced tumor survival and migration. As a confirmation of the role of S1P in osteosarcoma, we found S1P high circulating levels (30.8 &plusmn, 2.5 nmol/mL, n = 17) in the serum of patients. Finally, when we treated osteosarcoma xenografts with FTY720 combined with low-serine/glycine diet, both lipid accumulation (as measured by magnetic resonance imaging) and tumor growth were greatly inhibited. For the first time, this study profiles the lipidomic rearrangement of sarcomas under acidic conditions, suggesting the use of anti-S1P strategies in combination with standard chemotherapy.

Published
2021

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