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1. Learning in the COVID-19 pandemic and beyond: development and rapid uptake of an online learning platform for vascular surgery

Author

Nortley, MC, Bera, KD, Dixon, F, Warner, N-R, Sideso, E, and Darby, C

Subjects
Education, Distance, COVID-19, Humans, Vascular Surgery, Surgery, Curriculum, General Medicine, Pandemics, Vascular Surgical Procedures
Abstract

Introduction With the onset of the COVID-19 pandemic, alternative methods of delivering medical education were rapidly required. An online learning platform was developed with the aim of providing high-quality, accessible learning to vascular specialty trainees. We describe the design, delivery and analysis of the first 15 months of the platform. Although originally a regional initiative, we discuss how popularity and feedback led to a rapid expansion of the training programme internationally. Methods A fully online educational platform for vascular surgery specialist trainees was developed. The primary aims and ethos of the programme were that it should be easily accessible from any location, convenient, flexible, cooperative and collaborative, social and free financially to access. All learning resources were researched carefully and based on the UK vascular surgery curriculum and 20 seminal papers targeted in the Vascular Specialist Fellow of the Royal College of Surgeons (FRCSVasc) examination. Results The project demonstrated that it is feasible to design, build and deliver a postgraduate clinical teaching platform with minimal time requirement, resources and cost while creating and maintaining high-quality content. Rapid national and international uptake has proven there is demand – in addition to overwhelmingly positive feedback from educators and learners, this demonstrates that previously perceived barriers to online education can be overcome. At present, 53 educational sessions have been delivered and are available in the online library, and in the past year (8 December 2020 to 8 December 2021) the website has been accessed 3,877 times. Conclusions Although the programme has grown and evolved, a strong focus is being kept on its original ethos and aims – easily accessible, collaborative, free learning resources for all vascular professionals, based on the UK vascular surgery curriculum. Making learning convenient is key. The COVID-19 pandemic may be a watershed moment for a new era of learning. It is an opportunity for people from different backgrounds to share experiences and to develop cohesion within a hospital and network, nationally and worldwide.

Published
2022
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2. Chromosomal numeric aberrations and rare copy number variation in patients with inflammatory bowel disease

Author

Dirvanskyte, P, Gurram, B, Bolton, C, Warner, N, Jones, KDJ, Griffin, HR, Park, JY, Keller, K-M, Gilmour, KC, Hambleton, S, Muise, AM, Wysocki, C, Uhlig, HH, and Consortium, Genomics England Research

Subjects
Gastroenterology, General Medicine
Abstract

Background and AimsInflammatory bowel diseases [IBD] have a complex polygenic aetiology. Rare genetic variants can cause monogenic intestinal inflammation. The impact of chromosomal aberrations and large structural abnormalities on IBD susceptibility is not clear. We aimed to comprehensively characterise the phenotype and prevalence of patients with IBD who possess rare numerical and structural chromosomal abnormalities.MethodsWe performed a systematic literature search of databases PubMed and Embase; and analysed gnomAD, Clinvar, the 100 000 Genomes Project, and DECIPHER databases. Further, we analysed international paediatric IBD cohorts to investigate the role of IL2RA duplications in IBD susceptibility.ResultsA meta-analysis suggests that monosomy X [Turner syndrome] is associated with increased expressivity of IBD that exceeds the population baseline (1.86%, 95% confidence interval [CI] 1.48 to 2.34%) and causes a younger age of IBD onset. There is little evidence that Klinefelter syndrome, Trisomy 21, Trisomy 18, mosaic Trisomy 9 and 16, or partial trisomies contribute to IBD susceptibility. Copy number analysis studies suggest inconsistent results. Monoallelic loss of X-linked or haploinsufficient genes is associated with IBD by hemizygous or heterozygous deletions, respectively. However, haploinsufficient gene deletions are detected in healthy reference populations, suggesting that the expressivity of IBD might be overestimated. One duplication that has previously been identified as potentially contributing to IBD risk involves the IL2RA/IL15R loci. Here we provide additional evidence that a microduplication of this locus may predispose to very-early-onset IBD by identifying a second case in a distinct kindred. However, the penetrance of intestinal inflammation in this genetic aberration is low [ConclusionsTurner syndrome is associated with increased susceptibility to intestinal inflammation. Duplication of the IL2RA/IL15R loci may contribute to disease risk.

Published
2022

3. Results from InSight's First Full Martian Year

Author

Panning, M., Banerdt, B., Smrekar, S., Antonangeli, D., Asmar, Sami, Banfield, D., Beghein, C., Beucler, E., Bowles, Neil, Bozdag, E., Ceylan, S., Chi, P. J., Christensen, U., Clinton, J., Collins, G., Daubar, I., Dehant, V, Fillingim, Matthew, Folkner, W., Garcia, R., Garvin, J., Giardini, D., Golombek, M., Grant, J.A., Grott, Matthias, Grygorczuk, J., Hudson, T.L., Irving, J., Johnson, C. L., Kargl, G., Kawamura, T., Kedar, S., King, S., Knapmeyer, Martin, Knapmeyer-Endrun, B., Lemmon, M., Lognonne, P., Lorenz, R., Maki, J., Margerin, L., McLennan, S M, Michaut, C., Mimoun, D., Morgan, P., Müller, Nils, Nagihara, S., Newman, C., Nimmo, F., Pike, T., Plesa, Ana-Catalina, Rodriguez-Manfredi, J. -A., Schmerr, N., Siegler, M.A., Spiga, A., Spohn, Tilman, Stanley, S., Teanby, N., Tromp, J., Warner, N., Weber, R., Wieczorek, M., and Insight, Science Team

Subjects
Mars, InSight
Published
2021

4. Ustekinumab as Induction and Maintenance Therapy for Ulcerative Colitis

Author

Sands, B. E., Sandborn, W. J., Panaccione, R., O'Brien, C. D., Zhang, H., Johanns, J., Adedokun, O. J., Li, K., Peyrin-Biroulet, L., Van Assche, G., Danese, S., Targan, S., Abreu, M. T., Hisamatsu, T., Szapary, P., Brown S, Marano C., Connor, S, De Cruz, P, Ding, Nj, Florin, T, Hendy, P, Leong, R, Moore, G, Pavli, P, Sparrow, M, Gassner, S, Vogelsang, H, Baert, F, Colard, A, De Vos, M, D'Heygere, F, Ferrante, M, Louis, E, Staessen, D, Berova, T, Churchev, J, Draganova, R, Gancheva, D, Ivanova, N, Marinova, I, Markov, M, Nikolov, R, Tsonev, N, Vassileva, G, Afif, W, Berstein, C, Bressler, B, Jairath, V, Lachance, Jr, Singh, R, Tilbe, K, Komarek, V, Kozeluhova, J, Lukas, M, Volfova, M, Dahlerup, J, Altwegg, R, Beorchia, S, Bouguen, G, Cadiot, G, Dupas, Jl, Desreumaux, P, Flourie, B, Grimaud, Jc, Guillaud, O, Moreau, J, Roblin, X, Zerbib, F, Baumgart, D, Beckebaum, S, Bokemeyer, B, Ebert, M, Hasselblatt, P, Lügering, A, Maaser, C, Schiefke, I, Schreiber, S, Seidler, U, Altorjay, I, Kiss, Gg, Literati-Nagy, B, Patai, A, Pecsi, G, Salamon, A, Schnabel, R, Székely, A, Tulassay, Z, Varga, M, Fich, A, Fishman, S, Konikoff, F, Lichtenstein, L, Rainis, T, Sbeit, W, Schwartz, D, Annese, V, Biancone, L, Bossa, F, Costintino, R, Danese, S, Fries, W, Gasbarrini, A, Guidi, L, Kohn, A, Maconi, G, Rocca, R, Rogai, F, Villa, E, Zoli, G, Akiho, H, Aoyama, N, Arisawa, T, Hidaka, H, Hisamatsu, T, Horiki, N, Inaba, T, Inoue, S, Ishida, T, Ishida, H, Ishiguro, Y, Ishihara, S, Iwabuchi, M, Kato, J, Katsushima, S, Kobayashi, T, Kojima, Y, Kurihara, H, Masuo, T, Matsui, T, Matsumoto, T, Matsuoka, K, Mitsuyama, K, Motoya, S, Nakagawa, T, Nakai, K, Nakamura, S, Niihara, T, Ohnishi, Y, Ohta, A, Osada, T, Ryuichi, I, Sakai, Y, Sakata, Y, Sameshima, Y, Sano, K, Shibatoge, M, Shibuya, T, Suzuki, Y, Takeshima, F, Tanaka, S, Taruishi, M, Tokito, S, Ueo, T, Watanabe, K, Yamagami, H, Cheon, Jh, Cho, Kb, Knowles, Kim, Kim, Hj, Kim, Y, Lee, Km, Yang, Sk, D'Haens, G, Pierik, M, Gearry, R, Inns, S, Rowbotham, D, Schultz, M, Bochenek, A, Gawdis-Wojnarska, B, Kleczkowski, D, Leszczyszyn, J, Malecka-Panas, E, Mamos, A, Petryka, R, Regula, J, Rozciecha, J, Stefanuik, P, Wozniak-Stolarska, B, Cimpoeru, N, Craciun, E, Ovidiu, Cf, Goldis, E, Ionita-Radu, F, Lazar, D, Suciu, I, Abdulkhakov, R, Alikhanov, B, Apartsin, K, Bakulin, I, Belousova, E, Gofman, A, Grinevich, V, Kulyapin, A, Nizov, A, Osipenko, M, Simanenkov, V, Tkachev, A, Uspenskiy, Y, Valuyskikh, E, Jovanovic, I, Nagorni, A, Svorcan, P, Zdravkovic, N, Bunganic, I, Abrahamovych, O, Bilianskyi, L, Datsenko, O, Golovchenko, O, Kharchenko, N, Klymenko, V, Levchenko, O, Lozynskyy, Y, Murenets, N, Oliinyk, O, Prystupa, L, Pyrogovskyi, V, Reznikova, V, Rishko, I, Stanislavchuk, M, Vizir, V, Yatsyshyn, R, Arasaradnam, R, Bloom, S, Cummings, F, Iqbal, T, Irving, P, Kaser, A, Shonde, A, Subramanian, S, Aberra, F, Aguilar, H, Araya, V, Bakken, A, Beaulieu, D, Cappa, Ja, Chiorean, M, Cohen, N, Dryden, G, Duvall, G, Ehrlich, A, Eisner, M, Ertan, A, Fogel, R, Friedenberg, K, Gatof, D, Glover, S, Grosman, I, Gunaratnam, N, Gupta, N, Haynes, P, Hemaidan, A, Higgins, P, Hou, J, Hudesman, D, Iskandar, H, Jazrawi, S, Jones, M, Karnam, U, Khurana, S, Killpack, M, Kreines, M, Lawlor, G, Lee, S, Loftus, E, Lukin, Dj, Marcet, J, Mattar, M, Melmed, G, Minor, T, Mirkin, K, Mutlu, E, Nichols, M, Nudell, J, Rai, R, Ramos, C, Mcleod, Randall, Rausher, D, Ritter, T, Singh Saini, S, Salzberg, B, Saubermann, L, Scherl, E, Sedghi, S, Sellin, J, Shafran, I, Sorrentino, D, Suiter, D, Swaminath, A, Tiongco, F, Vrabie, R, Walp, K, Warner, N, Winstead, N, Wolf, Dc, Woods, J, Yen, E, Younes, Z., Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Humanitas Clinical and Research Center [Rozzano, Milan, Italy], RS: NUTRIM - R2 - Liver and digestive health, MUMC+: MA Maag Darm Lever (9), Interne Geneeskunde, Sands, Be, Sandborn, Wj, Panaccione, R, O'Brien, Cd, Zhang, H, Johanns, J, Adedokun, Oj, Li, K, Peyrin-Biroulet, L, Van Assche, G, Danese, S, Targan, S, Abreu, Mt, Hisamatsu, T, Szapary, P, and Marano, C

Subjects
Adult, Male, Infusions, [SDV]Life Sciences [q-bio], Injections, Subcutaneous, Anti-Inflammatory Agents, Ulcerative, Klinikai orvostudományok, Article, Injections, Maintenance Chemotherapy, Dose-Response Relationship, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, INFLIXIMAB, Colitis, Ulcerative, Dose-Response Relationship, Drug, Female, Humans, Induction Chemotherapy, Infusions, Intravenous, Patient Acuity, Remission Induction, Ustekinumab, ComputingMilieux_MISCELLANEOUS, ACTIVITY INDEXES, Subcutaneous, Orvostudományok, General Medicine, EFFICACY, Colitis, 3. Good health, INFECTIONS, 030220 oncology & carcinogenesis, 030211 gastroenterology & hepatology, Drug, Intravenous
Abstract

The efficacy of ustekinumab, an antagonist of the p40 subunit of interleukin-12 and interleukin-23, as induction and maintenance therapy in patients with ulcerative colitis is unknown.We evaluated ustekinumab as 8-week induction therapy and 44-week maintenance therapy in patients with moderate-to-severe ulcerative colitis. A total of 961 patients were randomly assigned to receive an intravenous induction dose of ustekinumab (either 130 mg [320 patients] or a weight-range-based dose that approximated 6 mg per kilogram of body weight [322]) or placebo (319). Patients who had a response to induction therapy 8 weeks after administration of intravenous ustekinumab were randomly assigned again to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 12 weeks [172 patients] or every 8 weeks [176]) or placebo (175). The primary end point in the induction trial (week 8) and the maintenance trial (week 44) was clinical remission (defined as a total score of ≤2 on the Mayo scale [range, 0 to 12, with higher scores indicating more severe disease] and no subscore1 [range, 0 to 3] on any of the four Mayo scale components).The percentage of patients who had clinical remission at week 8 among patients who received intravenous ustekinumab at a dose of 130 mg (15.6%) or 6 mg per kilogram (15.5%) was significantly higher than that among patients who received placebo (5.3%) (P0.001 for both comparisons). Among patients who had a response to induction therapy with ustekinumab and underwent a second randomization, the percentage of patients who had clinical remission at week 44 was significantly higher among patients assigned to 90 mg of subcutaneous ustekinumab every 12 weeks (38.4%) or every 8 weeks (43.8%) than among those assigned to placebo (24.0%) (P = 0.002 and P0.001, respectively). The incidence of serious adverse events with ustekinumab was similar to that with placebo. Through 52 weeks of exposure, there were two deaths (one each from acute respiratory distress syndrome and hemorrhage from esophageal varices) and seven cases of cancer (one each of prostate, colon, renal papillary, and rectal cancer and three nonmelanoma skin cancers) among 825 patients who received ustekinumab and no deaths and one case of cancer (testicular cancer) among 319 patients who received placebo.Ustekinumab was more effective than placebo for inducing and maintaining remission in patients with moderate-to-severe ulcerative colitis. (Funded by Janssen Research and Development; UNIFI ClinicalTrials.gov number, NCT02407236.).

Published
2019
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6. Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates A beta, tau, immunity and lipid processing (vol 51, pg 414, 2019)

Author

Kunkle, BW, Grenier-Boley, B, Sims, R, Bis, JC, Damotte, V, Naj, AC, Boland, A, Vronskaya, M, van der Lee, SJ, Amlie-Wolf, A, Bellenguez, C, Frizatti, A, Chouraki, V, Martin, ER, Sleegers, K, Badarinarayan, N, Jakobsdottir, J, Hamilton-Nelson, KL, Moreno-Grau, S, Olaso, R, Raybould, R, Chen, YN, Kuzma, AB, Hiltunen, M, Morgan, T, Ahmad, S, Vardarajan, BN, Epelbaum, J, Hoffmann, P, Boada, M, Beecham, GW, Garnier, JG, Harold, D, Fitzpatrick, AL, Valladares, O, Moutet, ML, Gerrish, A, Smith, AV, Qu, LM, Bacq, D, Denning, N, Jian, XQ, Zhao, Y, Del Zompo, M, Fox, NC, Choi, SH, Mateo, I, Hughes, JT, Adams, HH, Malamon, J, Sanchez-Garcia, F, Patel, Y, Brody, JA, Dombroski, BA, Naranjo, MCD, Daniilidou, M, Eiriksdottir, G, Mukherjee, S, Wallon, D, Uphill, J, Aspelund, T, Cantwell, LB, Garzia, F, Galimberti, D, Hofer, E, Butkiewicz, M, Fin, B, Scarpini, E, Sarnowski, C, Bush, WS, Meslage, S, Kornhuber, J, White, CC, Song, Y, Barber, RC, Engelborghs, S, Sordon, S, Voijnovic, D, Adams, PM, Vandenberghe, R, Mayhaus, M, Cupples, LA, Albert, MS, De Deyn, PP, Gu, W, Himali, JJ, Beekly, D, Squassina, A, Hartmann, AM, Orellana, A, Blacker, D, Rodriguez-Rodriguez, E, Lovestone, S, Garcia, ME, Doody, RS, Munoz-Fernadez, C, Sussams, R, Lin, HH, Fairchild, TJ, Benito, YA, Holmes, C, Karamujic-Comic, H, Frosch, MP, Thonberg, H, Maier, W, Roshchupkin, G, Ghetti, B, Giedraitis, V, Kawalia, A, Li, S, Huebinger, RM, Kilander, L, Moebus, S, Hernandez, I, Kamboh, MI, Brundin, R, Turton, J, Yang, Q, Katz, MJ, Concari, L, Lord, J, Beiser, AS, Keene, CD, Helisalmi, S, Kloszewska, I, Kukull, WA, Koivisto, AM, Lynch, A, Tarraga, L, Larson, EB, Haapasalo, A, Lawlor, B, Mosley, TH, Lipton, RB, Solfrizzi, V, Gill, M, Longstreth, WT, Montine, TJ, Frisardi, V, Diez-Fairen, M, Rivadeneira, F, Petersen, RC, Deramecourt, V, Alvarez, I, Salani, F, Ciaramella, A, Boerwinkle, E, Reiman, EM, Fievet, N, Rotter, JI, Reisch, JS, Hanon, O, Cupidi, C, Uitterlinden, AGA, Royall, DR, Dufouil, C, Maletta, RG, de Rojas, I, Sano, M, Brice, A, Cecchetti, R, St George-Hyslop, P, Ritchie, K, Tsolaki, M, Tsuang, DW, Dubois, B, Craig, D, Wu, CK, Soininen, H, Avramidou, D, Albin, RL, Fratiglioni, L, Germanou, A, Apostolova, LG, Keller, L, Koutroumani, M, Arnold, SE, Panza, F, Gkatzima, O, Asthana, S, Hannequin, D, Whitehead, P, Atwood, CS, Caffarra, P, Hampel, H, Quintela, I, Carracedo, A, Lannfelt, L, Rubinsztein, DC, Barnes, LL, Pasquier, F, Frolich, L, Barral, S, McGuinness, B, Beach, TG, Johnston, JA, Becker, JT, Passmore, P, Bigio, EH, Schott, JM, Bird, TD, Warren, JD, Boeve, BF, Lupton, MK, Bowen, JD, Proitsi, P, Boxer, A, Powell, JF, Burke, JR, Kauwe, JSK, Burns, JM, Mancuso, M, Buxbaum, JD, Bonuccelli, U, Cairns, NJ, McQuillin, A, Cao, CH, Livingston, G, Carlson, CS, Bass, NJ, Carlsson, CM, Hardy, J, Carney, RM, Bras, J, Carrasquillo, MM, Guerreiro, R, Allen, M, Chui, HC, Fisher, E, Masullo, C, Crocco, EA, DeCarli, C, Bisceglio, G, Dick, M, Ma, L, Duara, R, Graff-Radford, NR, Evans, DA, Hodges, A, Faber, KM, Scherer, M, Fallon, KB, Riemenschneider, M, Fardo, DW, Heun, R, Farlow, MR, Kolsch, H, Ferris, S, Leber, M, Foroud, TM, Heuser, I, Galasko, DR, Giegling, I, Gearing, M, Hull, M, Geschwind, DH, Gilbert, JR, Morris, J, Green, RC, Mayo, K, Growdon, JH, Feulner, T, Hamilton, RL, Harrell, LE, Drichel, D, Honig, LS, Cushion, TD, Huentelman, MJ, Hollingworth, P, Hulette, CM, Hyman, BT, Marshall, R, Jarvik, GP, Meggy, A, Abner, E, Menzies, GE, Jin, LW, Leonenko, G, Real, LM, Jun, GR, Baldwin, CT, Grozeva, D, Karydas, A, Russo, G, Kaye, JA, Kim, R, Jessen, F, Kowall, NW, Vellas, B, Kramer, JH, Vardy, E, LaFerla, FM, Jockel, KH, Lah, JJ, Dichgans, M, Leverenz, JB, Mann, D, Levey, AI, Pickering-Brown, S, Lieberman, AP, Klopp, N, Lunetta, KL, Wichmann, HE, Lyketsos, CG, Morgan, K, Marson, DC, Brown, K, Martiniuk, F, Medway, C, Mash, DC, Nothen, MM, Masliah, E, Hooper, NM, McCormick, WC, Daniele, A, McCurry, SM, Bayer, A, McDavid, AN, Gallacher, J, Mckee, AC, van den Bussche, H, Mesulam, M, Brayne, C, Miller, BL, Riedel-Heller, S, Miller, CA, Miller, JW, Al-Chalabi, A, Morris, JC, Shaw, CE, Myers, AJ, Wiltfang, J, O'Bryant, S, Olichney, JM, Alvarez, V, Parisi, JE, Singleton, AB, Paulson, HL, Collinge, J, Perry, WR, Mead, S, Peskind, E, Cribbs, DH, Rossor, M, Pierce, A, Ryan, NS, Poon, WW, Nacmias, B, Potter, H, Sorbi, S, Quinn, JF, Sacchinelli, E, Raj, A, Spalletta, G, Raskind, M, Caltagirone, C, Bossu, P, Orfei, MD, Reisberg, B, Clarke, R, Reitz, C, Smith, AD, Ringman, JM, Warden, D, Roberson, ED, Wilcock, G, Rogaeva, E, Bruni, AC, Rosen, HJ, Gallo, M, Rosenberg, RN, Ben-Shlomo, Y, Sager, MA, Mecocci, P, Saykin, AJ, Pastor, P, Cuccaro, ML, Vance, JM, Schneider, JA, Schneider, LS, Slifer, S, Seeley, WW, Smith, AG, Sonnen, JA, Spina, S, Stern, RA, Swerdlow, RH, Tang, M, Tanzi, RE, Trojanowski, JQ, Troncoso, JC, Van Deerlin, VM, Van Eldik, LJ, Vinters, HV, Vonsattel, JP, Weintraub, S, Welsh-Bohmer, KA, Wilhelmsen, KC, Williamson, J, Wingo, TS, Woltjer, RL, Wright, CB, Yu, CE, Yu, L, Saba, Y, Pilotto, A, Bullido, MJ, Peters, O, Crane, PK, Bennett, D, Bosco, P, Coto, E, Boccardi, V, De Jager, PL, Lleo, A, Warner, N, Lopez, OL, Ingelsson, M, Deloukas, P, Cruchaga, C, Graff, C, Gwilliam, R, Fornage, M, Goate, AM, Sanchez-Juan, P, Kehoe, PG, Amin, N, Ertekin-Taner, N, Berr, C, Debette, S, Love, S, Launer, LJ, Younkin, SG, Dartigues, JF, Corcoran, C, Ikram, MA, Dickson, DW, Nicolas, G, Campion, D, Tschanz, J, Schmidt, H, Hakonarson, H, Clarimon, J, Munger, R, Schmidt, R, Farrer, LA, Van Broeckhoven, C, O'Donovan, MC, DeStefano, AL, Jones, L, Haines, JL, Deleuze, JF, Owen, MJ, Gudnason, V, Mayeux, R, Escott-Price, V, Psaty, BM, Ramirez, A, Wang, LS, Ruiz, A, van Duijn, CM, Holmans, PA, Seshadri, S, Williams, J, Amouyel, P, Schellenberg, GD, Lambert, JC, Pericak-Vance, MA, ADGC, EADI, Cohorts Heart Aging Res Genomic, and Genetic Environm Risk AD Defining

Published
2019

7. Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates A beta, tau, immunity and lipid processing

Author

KUNKLE, B. W., GRENIER-BOLEY, B., SIMS, R., BIS, J. C., DAMOTTE, V., NAJ, A. C., BOLAND, A., VRONSKAYA, M., VAN DER LEE, S. J., AMLIE-WOLF, A., BELLENGUEZ, C., FRIZATTI, A., CHOURAKI, V., MARTIN, E. R., SLEEGERS, K., BADARINARAYAN, N., JAKOBSDOTTIR, J., HAMILTON-NELSON, K. L., MORENO-GRAU, S., OLASO, R., RAYBOULD, R., CHEN, Y., KUZMA, A. B., HILTUNEN, M., MORGAN, T., AHMAD, S., VARDARAJAN, B. N., EPELBAUM, J., HOFFMANN, P., BOADA, M., BEECHAM, G. W., GARNIER, J. G., HAROLD, D., FITZPATRICK, A. L., VALLADARES, O., MOUTET, M. L., GERRISH, A., SMITH, A. V., QU, L., BACQ, D., DENNING, N., JIAN, X., ZHAO, Y., DEL ZOMPO, M., FOX, N. C., CHOI, S. H., MATEO, I., HUGHES, J. T., ADAMS, H. H., MALAMON, J., SANCHEZ-GARCIA, F., PATEL, Y., BRODY, J. A., DOMBROSKI, B. A., NARANJO, M. C. D., DANIILIDOU, M., EIRIKSDOTTIR, G., MUKHERJEE, S., WALLON, D., UPHILL, J., ASPELUND, T., CANTWELL, L. B., GARZIA, F., GALIMBERTI, D., HOFER, E., BUTKIEWICZ, M., FIN, B., SCARPINI, E., SARNOWSKI, C., BUSH, W. S., MESLAGE, S., KORNHUBER, J., WHITE, C. C., SONG, Y., BARBER, R. C., ENGELBORGHS, S., SORDON, S., VOIJNOVIC, D., ADAMS, P. M., VANDENBERGHE, R., MAYHAUS, M., CUPPLES, L. A., ALBERT, M. S., DE DEYN, P. P., GU, W., HIMALI, J. J., BEEKLY, D., SQUASSINA, A., HARTMANN, A. M., ORELLANA, A., BLACKER, D., RODRIGUEZ-RODRIGUEZ, E., LOVESTONE, S., GARCIA, M. E., DOODY, R. S., MUNOZ-FERNADEZ, C., SUSSAMS, R., LIN, H., FAIRCHILD, T. J., BENITO, Y. A., HOLMES, C., KARAMUJIC-COMIC, H., FROSCH, M. P., THONBERG, H., MAIER, W., ROSCHUPKIN, G., GHETTI, B., GIEDRAITIS, V., KAWALIA, A., LI, S., HUEBINGER, R. M., KILANDER, L., MOEBUS, S., HERNANDEZ, I., KAMBOH, M. I., BRUNDIN, R., TURTON, J., YANG, Q., KATZ, M. J., CONCARI, L., LORD, J., BEISER, A. S., KEENE, C. D., HELISALMI, S., KLOSZEWSKA, I., KUKULL, W. A., KOIVISTO, A. M., LYNCH, A., TARRAGA, L., LARSON, E. B., HAAPASALO, A., LAWLOR, B., MOSLEY, T. H., LIPTON, R. B., SOLFRIZZI, V., GILL, M., LONGSTRETH, W. T. Jr., MONTINE, T. J., FRISARDI, V., DIEZ-FAIREN, M., RIVADENEIRA, F., PETERSEN, R. C., DERAMECOURT, V., ALVAREZ, I., SALANI, F., CIARAMELLA, A., BOERWINKLE, E., REIMAN, E. M., FIEVET, N., ROTTER, J. I., REISCH, J. S., HANON, O., CUPIDI, C., ANDRE UITTERLINDEN, A. G., ROYALL, D. R., DUFOUIL, Carole, MALETTA, R. G., DE ROJAS, I., SANO, M., BRICE, A., CECCHETTI, R., GEORGE-HYSLOP, P. S., RITCHIE, K., TSOLAKI, M., TSUANG, D. W., DUBOIS, B., CRAIG, D., WU, C. K., SOININEN, H., AVRAMIDOU, D., ALBIN, R. L., FRATIGLIONI, L., GERMANOU, A., APOSTOLOVA, L. G., KELLER, L., KOUTROUMANI, M., ARNOLD, S. E., PANZA, F., GKATZIMA, O., ASTHANA, S., HANNEQUIN, D., WHITEHEAD, P., ATWOOD, C. S., CAFFARRA, P., HAMPEL, H., QUINTELA, I., CARRACEDO, A., LANNFELT, L., RUBINSZTEIN, D. C., BARNES, L. L., PASQUIER, F., FROLICH, L., BARRAL, S., MCGUINNESS, B., BEACH, T. G., JOHNSTON, J. A., BECKER, J. T., PASSMORE, P., BIGIO, E. H., SCHOTT, J. M., BIRD, T. D., WARREN, J. D., BOEVE, B. F., LUPTON, M. K., BOWEN, J. D., PROITSI, P., BOXER, A., POWELL, J. F., BURKE, J. R., KAUWE, J. S. K., BURNS, J. M., MANCUSO, M., BUXBAUM, J. D., BONUCCELLI, U., CAIRNS, N. J., MCQUILLIN, A., CAO, C., LIVINGSTON, G., CARLSON, C. S., BASS, N. J., CARLSSON, C. M., HARDY, J., CARNEY, R. M., BRAS, J., CARRASQUILLO, M. M., GUERREIRO, R., ALLEN, M., CHUI, H. C., FISHER, E., MASULLO, C., CROCCO, E. A., DECARLI, C., BISCEGLIO, G., DICK, M., MA, L., DUARA, R., GRAFF-RADFORD, N. R., EVANS, D. A., HODGES, A., FABER, K. M., SCHERER, M., FALLON, K. B., RIEMENSCHNEIDER, M., FARDO, D. W., HEUN, R., FARLOW, M. R., KOLSCH, H., FERRIS, S., LEBER, M., FOROUD, T. M., HEUSER, I., GALASKO, D. R., GIEGLING, I., GEARING, M., HULL, M., GESCHWIND, D. H., GILBERT, J. R., MORRIS, J., GREEN, R. C., MAYO, K., GROWDON, J. H., FEULNER, T., HAMILTON, R. L., HARRELL, L. E., DRICHEL, D., HONIG, L. S., CUSHION, T. D., HUENTELMAN, M. J., HOLLINGWORTH, P., HULETTE, C. M., HYMAN, B. T., MARSHALL, R., JARVIK, G. P., MEGGY, A., ABNER, E., MENZIES, G. E., JIN, L. W., LEONENKO, G., REAL, L. M., JUN, G. R., BALDWIN, C. T., GROZEVA, D., KARYDAS, A., RUSSO, G., KAYE, J. A., KIM, R., JESSEN, F., KOWALL, N. W., VELLAS, B., KRAMER, J. H., VARDY, E., LAFERLA, F. M., JOCKEL, K. H., LAH, J. J., DICHGANS, M., LEVERENZ, J. B., MANN, D., LEVEY, A. I., PICKERING-BROWN, S., LIEBERMAN, A. P., KLOPP, N., LUNETTA, K. L., WICHMANN, H. E., LYKETSOS, C. G., MORGAN, K., MARSON, D. C., BROWN, K., MARTINIUK, F., MEDWAY, C., MASH, D. C., NOTHEN, M. M., MASLIAH, E., HOOPER, N. M., MCCORMICK, W. C., DANIELE, A., MCCURRY, S. M., BAYER, A., MCDAVID, A. N., GALLACHER, J., MCKEE, A. C., VAN DEN BUSSCHE, H., MESULAM, M., BRAYNE, C., MILLER, B. L., RIEDEL-HELLER, S., MILLER, C. A., MILLER, J. W., AL-CHALABI, A., MORRIS, J. C., SHAW, C. E., MYERS, A. J., WILTFANG, J., O'BRYANT, S., OLICHNEY, J. M., ALVAREZ, V., PARISI, J. E., SINGLETON, A. B., PAULSON, H. L., COLLINGE, J., PERRY, W. R., MEAD, S., PESKIND, E., CRIBBS, D. H., ROSSOR, M., PIERCE, A., RYAN, N. S., POON, W. W., NACMIAS, B., POTTER, H., SORBI, S., QUINN, J. F., SACCHINELLI, E., RAJ, A., SPALLETTA, G., RASKIND, M., CALTAGIRONE, C., BOSSU, P., ORFEI, M. D., REISBERG, B., CLARKE, R., REITZ, C., SMITH, A. D., RINGMAN, J. M., WARDEN, D., ROBERSON, E. D., WILCOCK, G., ROGAEVA, E., BRUNI, A. C., ROSEN, H. J., GALLO, M., ROSENBERG, R. N., BEN-SHLOMO, Y., SAGER, M. A., MECOCCI, P., SAYKIN, A. J., PASTOR, P., CUCCARO, M. L., VANCE, J. M., SCHNEIDER, J. A., SCHNEIDER, L. S., SLIFER, S., SEELEY, W. W., SMITH, A. G., SONNEN, J. A., SPINA, S., STERN, R. A., SWERDLOW, R. H., TANG, M., TANZI, R. E., TROJANOWSKI, J. Q., TRONCOSO, J. C., VAN DEERLIN, V. M., VAN ELDIK, L. J., VINTERS, H. V., VONSATTEL, J. P., WEINTRAUB, S., WELSH-BOHMER, K. A., WILHELMSEN, K. C., WILLIAMSON, J., WINGO, T. S., WOLTJER, R. L., WRIGHT, C. B., YU, C. E., YU, L., SABA, Y., ALZHEIMER DISEASE GENETICS, Consortium, EUROPEAN ALZHEIMER'S DISEASE, Initiative, COHORTS FOR, Heart, AGING RESEARCH IN GENOMIC EPIDEMIOLOGY, Consortium, GENETIC ENVIRONMENTAL RISK IN AD/DEFINING GENETIC, Polygenic, ENVIRONMENTAL RISK FOR ALZHEIMER'S DISEASE, Consortium, PILOTTO, A., BULLIDO, M. J., PETERS, O., CRANE, P. K., BENNETT, D., BOSCO, P., COTO, E., BOCCARDI, V., DE JAGER, P. L., LLEO, A., WARNER, N., LOPEZ, O. L., INGELSSON, M., DELOUKAS, P., CRUCHAGA, C., GRAFF, C., GWILLIAM, R., FORNAGE, M., GOATE, A. M., SANCHEZ-JUAN, P., KEHOE, P. G., AMIN, N., ERTEKIN-TANER, N., BERR, C., DEBETTE, Stephanie, LOVE, S., LAUNER, L. J., YOUNKIN, S. G., DARTIGUES, Jean-Francois, CORCORAN, C., IKRAM, M. A., DICKSON, D. W., NICOLAS, G., CAMPION, D., TSCHANZ, J., SCHMIDT, H., HAKONARSON, H., CLARIMON, J., MUNGER, R., SCHMIDT, R., FARRER, L. A., VAN BROECKHOVEN, C., M, C. O' Donovan, DESTEFANO, A. L., JONES, L., HAINES, J. L., DELEUZE, J. F., OWEN, M. J., GUDNASON, V., MAYEUX, R., ESCOTT-PRICE, V., PSATY, B. M., RAMIREZ, A., WANG, L. S., RUIZ, A., VAN DUIJN, C. M., HOLMANS, P. A., SESHADRI, S., WILLIAMS, J., AMOUYEL, P., SCHELLENBERG, G. D., LAMBERT, J. C., PERICAK-VANCE, M. A., Epidemiology, Internal Medicine, Neurology, Radiology & Nuclear Medicine, Amsterdam Reproduction & Development (AR&D), Clinical sciences, Pathologic Biochemistry and Physiology, Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Medizin, Gene Expression, genetics [Alzheimer Disease], Genome-wide association study, methods [Genome-Wide Association Study], SEPIA, Genome-wide association studies, genetic meta-analysis, 0302 clinical medicine, genetics [Immunity], genetics [Amyloid beta-Peptides], genetics, tau, genetics [Genetic Predisposition to Disease], new risk loci, Aβ, Genetics, Medicine(all), 0303 health sciences, medicine.diagnostic_test, Alzheimer's disease, Lipids, 3. Good health, Settore MED/26 - NEUROLOGIA, VINTAGE, Female, Amyloid beta, methods [Genetic Testing], Tau protein, lipid processing, tau Proteins, genetics [Genetic Loci], Biology, Article, FR, 03 medical and health sciences, Alzheimer Disease, ddc:570, genetics [Haplotypes], medicine, Genetic predisposition, Humans, Dementia, Genetic Predisposition to Disease, Genetic Testing, LOAD, genetics [Lipids], Risk factor, immunity, Aged, 030304 developmental biology, Genetic testing, Amyloid beta-Peptides, Lipid Metabolism, medicine.disease, Gene expression, genetics [tau Proteins], Haplotypes, Genetic Loci, Case-Control Studies, genetics [Lipid Metabolism], genome-wide association studies, biology.protein, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Human medicine, 030217 neurology & neurosurgery, Genome-Wide Association Study, dementia
Abstract

Risk for late-onset Alzheimers disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimers or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimers disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 ׫2009»10−7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

Published
2019
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9. Meta-analysis of genetic association with diagnosed Alzheimer's disease identifies novel risk loci and implicates Abeta, Tau, immunity and lipid processing

Author

Kunkle, BW, Grenier-Boley, B, Sims, R, Bis, JC, Naj, AC, Boland, A, Vronskaya, M, van der Lee, SJ, Amlie-Wolf, A, Bellenguez, C, Frizatti, A, Chouraki, V, Martin, ER, Sleegers, K, Badarinarayan, N, Jakobsdottir, J, Hamilton-Nelson, KL, Aloso, R, Raybould, R, Chen, Y, Kuzma, AB, Hiltunen, M, Morgan, T, Ahmad, S, Vardarajan, BN, Epelbaum, J, Hoffmann, P, Boada, M, Beecham, GW, Garnier, JG, Harold, D, Fitzpatrick, AL, Valladares, O, Moutet, ML, Gerrish, A, Smith, AV, Qu, L, Bacq, D, Denning, N, Jian, X, Zhao, Y, Zompo, MD, Fox, NC, Grove, ML, Choi, SH, Mateo, I, Hughes, JT, Adams, HH, Malamon, J, Garcia, FS, Patel, Y, Brody, JA, Dombroski, B, Naranjo, MCD, Daniilidou, M, Eiriksdottir, G, Mukherjee, S, Wallon, D, Uphill, J, Aspelund, T, Cantwell, LB, Garzia, F, Galimberti, D, Hofer, E, Butkiewics, M, Fin, B, Scarpini, E, Sarnowski, C, Bush, W, Meslage, S, Kornhuber, J, White, CC, Song, Y, Barber, RC, Engelborghs, S, Pichler, S, Voijnovic, D, Adams, PM, Vandenberghe, R, Mayhaus, M, Cupples, LA, Albert, MS, De Deyn, PP, Gu, W, Himali, JJ, Beekly, D, Squassina, A, Hartmann, AM, Orellana, A, Blacker, D, Rodriguez-Rodriguez, E, Lovestone, S, Garcia, ME, Doody, RS, Fernadez, CM, Sussams, R, Lin, H, Fairchild, TJ, Benito, YA, Holmes, C, Comic, H, Frosch, MP, Thonberg, H, Maier, W, Roschupkin, G, Ghetti, B, Giedraitis, V, Kawalia, A, Li, S, Huebinger, RM, Kilander, L, Moebus, S, Hernández, I, Kamboh, MI, Brundin, R, Turton, J, Yang, Q, Katz, MJ, Concari, L, Lord, J, Beiser, AS, Keene, CD, Helisalmi, S, Kloszewska, I, Kukull, WA, Koivisto, AM, Lynch, A, Tarraga, L, Larson, EB, Haapasalo, A, Lawlor, B, Mosley, TH, Lipton, RB, Solfrizzi, V, Gill, M, Longstreth Jr, WT, Montine, TJ, Frisardi, V, Ortega-Cubero, S, Rivadeneira, F, Petersen, RC, Deramecourt, V, Ciaramella, A, Boerwinkle, E, Reiman, EM, Fievet, N, Caltagirone, C, Rotter, JI, Reisch, JS, Hanon, O, Cupidi, C, Uitterlinden, AG, Royall, DR, Dufouil, C, Maletta, RG, Moreno-Grau, S, Sano, M, Brice, A, Cecchetti, R, St George-Hyslop, P, Ritchie, K, Tsolaki, M, Tsuang, DW, Dubois, B, Craig, D, Wu, CK, Soininen, H, Avramidou, D, Albin, RL, Fratiglioni, L, Germanou, A, Apostolova, LG, Keller, L, Koutroumani, M, Arnold, SE, Panza, F, Gkatzima, O, Asthana, S, Hannequin, D, Whitehead, P, Atwood, CS, Caffarra, P, Hampel, H, Baldwin, CT, Lannfelt, L, Rubinsztein, DC, Barnes, LL, Pasquier, F, Frölich, L, Barral, S, McGuinness, B, Beach, TG, Johnston, JI, Becker, JT, Passmore, P, Bigio, EH, Schott, JM, Bird, TD, Warren, JD, Boeve, BF, Lupton, MK, Bowen, JD, Proitsi, P, Boxer, A, Powell, JF, Burke, JR, Kauwe, JK, Burns, JM, Mancuso, M, Buxbaum, JD, Bonuccelli, U, Cairns, NJ, McQuillin, A, Cao, C, Livingston, G, Carlson, CS, Bass, NJ, Carlsson, CM, Hardy, J, Carney, RM, Bras, J, Carrasquillo, MM, Guerreiro, R, Allen, M, Chui, HC, Fisher, E, Cribbs, DH, Masullo, C, Crocco, EA, DeCarli, C, Bisceglio, G, Dick, M, Ma, L, Duara, R, Graff-Radford, NR, Evans, DA, Hodges, A, Faber, KM, Scherer, M, Fallon, KB, Riemenschneider, M, Fardo, DW, Heun, R, Farlow, MR, Ferris, S, Leber, M, Foroud, TM, Heuser, I, Galasko, DR, Giegling, I, Gearing, M, Hüll, M, Geschwind, DH, Gilbert, JR, Morris, J, Green, RC, Mayo, K, Growdon, JH, Feulner, T, Hamilton, RL, Harrell, LE, Drichel, D, Honig, LS, Cushion, TD, Huentelman, MJ, Hollingworth, P, Hulette, CM, Hyman, BT, Marshall, R, Jarvik, GP, Meggy, A, Abner, E, Menzies, G, Jin, LW, Leonenko, G, Jun, G, Grozeva, D, Karydas, A, Russo, G, Kaye, JA, Kim, R, Jessen, F, Kowall, NW, Vellas, B, Kramer, JH, Vardy, E, LaFerla, FM, Jöckel, KH, Lah, JJ, Dichgans, M, Leverenz, JB, Mann, D, Levey, AI, Pickering-Brown, S, Lieberman, AP, Klopp, N, Lunetta, KL, Wichmann, HE, Lyketsos, CG, Morgan, K, Marson, DC, Brown, K, Martiniuk, F, Medway, C, Mash, DC, Nöthen, MM, Masliah, E, Hooper, NM, McCormick, WC, Daniele, A, McCurry, SM, Bayer, A, McDavid, AN, Gallacher, J, McKee, AC, van den Bussche, H, Mesulam, M, Brayne, C, Miller, BL, Riedel-Heller, S, Miller, CA, Miller, JW, Al-Chalabi, A, Morris, JC, Shaw, CE, Myers, AJ, Wiltfang, J, O’Bryant, S, Coto, E, Olichney, JM, Alvarez, V, Parisi, JE, Singleton, AB, Paulson, HL, Collinge, J, Perry, W, Mead, S, Peskind, E, Rosser, M, Pierce, A, Ryan, N, Poon, WW, Nacmias, B, Potter, H, Sorbi, S, Quinn, JF, Sacchinelli, E, Raj, A, Spalletta, G, Raskind, M, Bossù, P, Reisberg, B, Clarke, R, Reitz, C, Smith, AD, Ringman, JM, Warden, D, Roberson, ED, Wilcock, G, Rogaeva, E, Bruni, AC, Rosen, HJ, Gallo, M, Rosenberg, RN, Ben-Shlomo, Y, Sager, MA, Mecocci, P, Saykin, AJ, Pastor, P, Cuccaro, ML, Vance, JM, Schneider, JA, Schneider, LS, Seeley, WW, Smith, AG, Sonnen, JA, Spina, S, Stern, RA, Swerdlow, RH, Tanzi, RE, Trojanowski, JQ, Troncoso, JC, Van Deerlin, VM, Van Eldik, LJ, Vinters, HV, Vonsattel, JP, Weintraub, S, Welsh-Bohmer, KA, Wilhelmsen, KC, Williamson, J, Wingo, TS, Woltjer, RL, Wright, CB, Yu, CE, Yu, L, Crane, PK, Bennett, DA, Boccardi, V, De Jager, PL, Warner, N, Lopez, OL, McDonough, S, Ingelsson, M, Deloukas, P, Cruchaga, C, Graff, C, Gwilliam, R, Fornage, M, Goate, AM, Sanchez-Juan, P, Kehoe, PG, Amin, N, Ertekin-Taner, N, Berr, C, Debette, S, Love, S, Launer, LJ, Younkin, SG, Dartigues, JF, Corcoran, C, Ikram, MA, Dickson, DW, Campion, D, Tschanz, J, Schmidt, H, Hakonarson, H, Munger, R, Schmidt, R, Farrer, LA, Van Broeckhoven, C, O’Donovan, MC, DeStefano, AL, Jones, L, Haines, JL, Deleuze, JF, Owen, MJ, Gudnason, V, Mayeux, R, Escott-Price, V, Psaty, BM, Ruiz, A, Ramirez, A, Wang, LS, van Duijn, CM, Holmans, PA, Seshadri, S, Williams, J, Amouyel, P, Schellenberg, GD, Lambert, JC, Pericak-Vance, MA, Bis, JC [0000-0002-3409-1110], Garnier, JG [0000-0003-4991-763X], Smith, AV [0000-0001-9088-234X], Denning, N [0000-0001-8467-7382], Vandenberghe, R [0000-0001-6237-2502], Himali, JJ [0000-0003-1391-9481], Rodriguez-Rodriguez, E [0000-0001-7742-677X], Frisardi, V [0000-0003-0764-7387], Ortega-Cubero, S [0000-0003-0520-9439], Hanon, O [0000-0002-4697-122X], Brice, A [0000-0002-0941-3990], Albin, RL [0000-0002-0629-608X], Buxbaum, JD [0000-0001-8898-8313], Bass, NJ [0000-0002-4481-778X], Fisher, E [0000-0003-2850-9936], Bayer, A [0000-0002-7514-248X], Gallacher, J [0000-0002-2394-5299], Brayne, C [0000-0001-5307-663X], Riedel-Heller, S [0000-0003-4321-6090], Al-Chalabi, A [0000-0002-4924-7712], and Apollo - University of Cambridge Repository

Subjects
Aging, 4202 Epidemiology, Genome-wide association study, Disease, Neurodegenerative, Biology, 3101 Biochemistry and Cell Biology, Alzheimer's Disease, 3105 Genetics, 03 medical and health sciences, 0302 clinical medicine, Clinical Research, Acquired Cognitive Impairment, Genetics, medicine, 2.1 Biological and endogenous factors, Dementia, Gene, 030304 developmental biology, Genetic association, 2 Aetiology, 0303 health sciences, Prevention, Human Genome, 42 Health Sciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Lipid metabolism, medicine.disease, Brain Disorders, 3. Good health, Meta-analysis, Neurological, Alzheimer's disease, 030217 neurology & neurosurgery, 31 Biological Sciences
Abstract

IntroductionLate-onset Alzheimer’s disease (LOAD, onset age > 60 years) is the most prevalent dementia in the elderly1, and risk is partially driven by genetics2. Many of the loci responsible for this genetic risk were identified by genome-wide association studies (GWAS)3–8. To identify additional LOAD risk loci, the we performed the largest GWAS to date (89,769 individuals), analyzing both common and rare variants. We confirm 20 previous LOAD risk loci and identify four new genome-wide loci (IQCK, ACE, ADAM10, and ADAMTS1). Pathway analysis of these data implicates the immune system and lipid metabolism, and for the first time tau binding proteins and APP metabolism. These findings show that genetic variants affecting APP and Aβ processing are not only associated with early-onset autosomal dominant AD but also with LOAD. Analysis of AD risk genes and pathways show enrichment for rare variants (P = 1.32 × 10−7) indicating that additional rare variants remain to be identified.

Published
2018
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11. Asteroid (16) Psyche: Visiting a metal world

Author

Elkins-Tanton, L.T., Asphaug, E., Bell, J., Bercovici, D., Bills, B.G., Rinzel, R.P., Bottke, W.F., Brown, M., Goldsten, J., Jaumann, R., Jun, I., Lawrence, D.J., Lord, P., Marchi, S., McCoy, T., Oh, D., Park, R.S., Peplowski, P.N., Polanskey, C.A., Potter, D., Prettyman, T.H., Raymond, C.A., Russell, C.T., Scott, S., Stone, H., Sukhatme, K.G., Warner, N., Weiss, B.P., Wenkert, D.D., Wieczorek, M.A., and Zuber, M.T.

Subjects
metal asteroid, Psyche
Published
2017

12. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease

Author

Lambert, J. C., Ibrahim-Verbaas, C. A., Russo, G., Mayhaus, M., Lannefelt, L., Hakonarson, H., Pichler, S., Carrasquillo, M. M., Ingelsson, M., Beekly, D., Alvarez, V., Zou, F., Valladares, O., Thorton-Wells, T. A., Younkin, S. G., Coto, E., Hamilton-Nelson, K. L., Gu, W., Razquin, C., Pastor, P., Mateo, I., Owen, M. J., Faber, K. M., Jonsson, P. V., Jones, N., Combarros, O., O'Donovan, M. C., Cantwell, L. B., Soininen, H., Blacker, D., Mead, S., Mosley, T. H., Bennett, D. A., Harris, T. B., Fratiglioni, L., Smith, A. V., Holmes, C., de Bruijn, R. F., Passmore, P., Montine, T. J., Bettens, K., Rotter, J. I., Brice, A., Morgan, K., Foroud, T. M., Kukull, W. A., Chouraki, V., Hannequin, D., Powell, J. F., Nalls, M. A., Ritchie, K., Lunetta, K. L., Kauwe, J. S., Boerwinkle, E., Riemenschneider, M., Boada, M., Hiltuenen, M., Thomas, C., Martin, E. R., Schmidt, R., Rujescu, D., Wang, L. S., Dartigues, J. F., Mayeux, R., Tzourio, C., Hofman, A., Nöthen, M. M., Graff, C., Ikram, M. A., Psaty, B. M., Jones, L., Haines, J. L., Holmans, P. A., Lathrop, M., Pericak-Vance, M. A., Launer, L. J., Farrer, L. A., van Duijn, C. M., Van Broeckhoven, C., Zelenika, D., Moskvina, V., Seshadri, S., Williams, J., Schellenberg, G. D., Amouyel, P., Alpérovitch, A., Boland, A., Delépoine, M., Dubois, B., Duron, E., Vardarajan, B. N., Epelbaum, J., Van Cauwenberghe, C., Engelborghs, S., Vandenberghe, R., De Deyn, P. P., Ferri, R., Romano, C., Caltagirone, C., Orfei, M. D., Ciaramella, A., Kamatani, Y., Scarpini, E., Fenoglio, C., Siciliano, G., Bonuccelli, U., Bagnoli, S., Bracco, L., Bessi, V., Cecchetti, R., Bastgiani, P., Squassina, A., Harold, D., Lin, C. F., Seripa, D., Frank-García, A., Sastre, I., Blesa, R., Alcolea, D., Suárez-Clavet, M., Sánchez-Juan, P., Muñoz Fernandez, C., Aladro Benito, Y., Thonberg, H., Gerrish, A., Forshell, C., Lilus, L., Kinhult-Ståhlbom, A., Giedraitis, V., Kilander, L., Brundin, R. M., Concari, L., Helisalmi, S., Koivisto, A. M., Haapasalo, A., Schmidt, H., Solfrizzi, V., Frisardi, V., Ott, J., Carney, R. M., Mash, D. C., Albert, M. S., Albin, R. L., Apostolova, L. G., Arnold, S. E., Barmada, M. M., Kunkle, B., Barnes, L. L., Beach, T. G., Bigio, E. H., Bird, T. D., Boeve, B. F., Bowen, J. D., Boxer, A., Burk, J. R., Cairns, N. J., Cao, C., Dunstan, M. L., Carlson, C. S., Carroll, S. L., Chibnik, L. B., Chui, H. C., Clark, D. G., Corneveaux, J., Cribbs, D. G., DeCarli, C., DeKosky, S. T., Demirci, F. Y., Ruiz, A., Dick, M., Dickson, D. W., Duara, R., Ertekin-Taner, N., Fallon, K. B., Farlow, M. R., Ferris, S., Frosch, M. P., Galasko, G. R., Ganguli, M., Bihoreau, M. T., Gearing, M., Geschwind, D. H., Ghetti, B., Gilman, S., Glass, J. D., Growdon, J. H., Hamilton, R. L., Harrell, L. E., Head, E., Honig, L. S., Choi, S. H., Hulette, C. M., Hyman, B. T., Jarvik, G. P., Jicha, G. A., Jin, L. W., Karydas, A., Kaye, J. A., Kim, R., Koo, E. H., Reitz, C., Kowall, N. W., Kramer, J. H., Kramer, P., LaFerla, F. M., Lah, J. J., Levernez, J. B., Levey, A. I., Li, G., Lieberman, A. P., Lyketsos, C. G., Pasquier, F., Mack, W. J., Marson, D. C., Martiniuk, F., Masliah, E., McCormick, W. C., McCurry, S. M., McDavid, A. N., McKee, A. C., Mesulam, M., Miller, B. L., Naj, A. C., Cruchaga, C., Miller, C. A., Miller, J. W., Morris, J. C., Murrell, J. R., Olichney, J. M., Pankratz, V. S., Parasi, J. E., Peskind, E., Peterson, R. C., Pierce, A., Craig, D., Poon, W. W., Potter, H., Quinn, J. F., Raj, A., Raskind, M., Raiman, E. M., Reisberg, B., Ringman, J. M., Roberson, E. D., Rosen, H. J., Amin, N., Rosenberg, R. N., Sano, M., Saykin, A. J., Schneider, J. A., Schneider, L. S., Seely, W. W., Smith, A. G., Sonnen, J. A., Spina, S., Stern, R. A., Berr, C., Tanzi, R. E., Trojanowski, J. Q., Troncoso, J. C., Van Deerlin, V. M., Van Eldik, L. J., Vinters, H. V., Vonsattel, J. P., Weintraub, S., Welsh-Bohmer, K. A., Williamson, J., Lopez, O. L., Woltjer, R. L., Yu, C. E., Barber, R., Au, R., Wolf, P. A., Beiser, A., Debette, S., Yang, Q., Weinstein, G., Johnson, A. D., De Jager, P. L., Wang, J., Uitterlinden, A. G., Rivadeneira, F., Koudstgaal, P. J., Longstreth, W. T., Becker, J. T., Kuller, L. H., Lumley, T., Rice, K., Garcia, M., Deramecourt, V., Aspelund, T., Marksteiner, J. J., Dal-Bianco, P., Töglhofer, A. M., Freudenberger, P., Ransmayr, G., Benke, T., Toeglhofer, A. M., Bressler, J., Breteler, M. M., Johnston, J. A., Fornage, M., Hernández, I., Rosende Roca, M., Ana Mauleón, M., Alegrat, M., RamÍrez-Lorca, R., González-Perez, A., Chapman, J., Stretton, A., Morgan, A., Evans, D., Kehoe, P. G., Medway, C., Lord, J., Turton, J., Hooper, N. M., Vardy, E., Warren, J. D., Schott, J. M., Uphill, J., Ryan, N., Lovestone, S., Rossor, M., Ben-Shlomo, Y., Makrina, D., Gkatzima, O., Lupton, M., Koutroumani, M., Avramidou, D., Germanou, A., Jessen, F., Riedel-Heller, S., Sims, R., Letenneur, L., Dichgans, M., Heun, R., Kölsch, H., Schürmann, B., Herold, C., Lacour, A., Drichel, D., Hoffman, P., Kornhuber, J., Morón, F. J., Feulner, T., van den Bussche, H., Lawlor, B., Lynch, A., Mann, D., Smith, A. D., Warden, D., Wilcock, G., Heuser, I., Wiltgang, J., Rubinsztein, D. C., Frölich, L., Hüll, M., Mayo, K., Livingston, G., Bass, N. J., Gurling, H., McQuillen, A., Gwilliam, R., Deloukas, P., Al-Chalabi, A., Eiriksdottir, G., Shaw, C. E., Singleton, A. B., Guerreiro, R., Jöckel, K. H., Klopp, N., Wichmann, H. E., Graff-Radford, N. R., Ma, L., Bisceglio, G., Sleegers, K., Fisher, E., Warner, N., Pickering-Brown, S., Becker, Tim, Goate, A. M., Fiévet, N., Huentelman, M. W., Gill, M., Brown, K., Bellenguez, C., Kamboh, M. I., Keller, L., Barberger-Gateau, P., McGuiness, B., Larson, E. B., Green, R., Myers, A. J., Dufouil, C., Todd, S., Wallon, D., DeStafano, A. L., Love, S., Rogaeva, E., Gallacher, J., St George-Hyslop, P., Clarimon, J., Lleo, A., Bayer, A., Tsuang, D. W., Yu, L., Tsolaki, M., Bis, J. C., Bossù, P., Spalletta, G., Proitsi, P., Collinge, J., Sorbi, S., Sanchez-Garcia, F., Fox, N. C., Hardy, J., Deniz Naranjo, M. C., Bosco, P., Beecham, G. W., Clarke, R., Brayne, C., Galimberti, D., Mancuso, M., Matthews, F., Initiative, European Alzheimer's Disease, Disease, Genetic and Environmental Risk in Alzheimer's, Consortium, Alzheimer's Disease Genetic, Epidemiology, Cohorts for Heart and Aging Research in Genomic, Moebus, S., Grenier-Boley, B., Mecocci, P., Del Zompo, M., Maier, W., Hampel, H., Pilotto, A., Bullido, M., Panza, F., Caffarra, P., Nacmias, B., Gilbert, J. R., Neurology, Radiology & Nuclear Medicine, and Epidemiology

Subjects
Male, Apolipoprotein E, epidemiology [Alzheimer Disease], SORL1, Medizin, genetics [Alzheimer Disease], Genome-wide association study, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, PICALM, Cohort Studies, Alzheimer Disease, ddc:570, PSEN2, Genetics, medicine, Humans, Genetic Predisposition to Disease, Age of Onset, Aged, Genetic association, Aged, 80 and over, Middle Aged, medicine.disease, Genetic Loci, Case-Control Studies, Female, Human medicine, Alzheimer's disease, statistics & numerical data [Genome-Wide Association Study], Genome-Wide Association Study
Abstract

Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 x 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.

Published
2013
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14. The effect of masculinity and femininity on pitch

Author

Bezooijen, R.A.M.G. van, Warner, N., Ahlers, J., Bilmes, L., Oliver, M., Wertheim, S., Chen, M., Warner, N., Ahlers, J., Bilmes, L., Oliver, M., Wertheim, S., and Chen, M.

Subjects
Variation and standard language (VAST), Variatie en standaardtaal (VAST)
Abstract

Item does not contain fulltext

Published
1998

15. The effect of pitch on the attribution of gender related personality traits

Author

Bezooijen, R.A.M.G. van, Warner, N., Ahlers, J., Bilmes, L., Oliver, M., Wertheim, S., Chen, M., Warner, N., Ahlers, J., Bilmes, L., Oliver, M., Wertheim, S., and Chen, M.

Subjects
Variation and standard language (VAST), Taal in sociale context, Variatie en standaardtaal (VAST)
Abstract

Item does not contain fulltext Women and Language Conference, 19 april 1996 Berkeley : [s.n.]

Published
1998

16. Holographic Duals of a Family of N=1 Fixed Points

Author

Halmagyi, N., Pilch, K., Romelsberger, C., and Warner, N. P.

Subjects
High Energy Physics - Theory, High Energy Physics - Theory (hep-th), FOS: Physical sciences
Abstract

We construct a family of warped AdS_5 compactifications of IIB supergravity that are the holographic duals of the complete set of N=1 fixed points of a Z_2 quiver gauge theory. This family interpolates between the T^{1,1} compactification with no three-form flux and the Z_2 orbifold of the Pilch-Warner geometry which contains three-form flux. This family of solutions is constructed by making the most general Ansatz allowed by the symmetries of the field theory. We use Killing spinor methods because the symmetries impose two simple projection conditions on the Killing spinors, and these greatly reduce the problem. We see that generic interpolating solution has a nontrivial dilaton in the internal five-manifold. We calculate the central charge of the gauge theories from the supergravity backgrounds and find that it is 27/32 of the parent N=2, quiver gauge theory. We believe that the projection conditions that we derived here will be useful for a much larger class of N=1 holographic RG-flows., Comment: 49 pages, 3 figures

Published
2005
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17. Variability in direction of dorsal movement during production of /l

Author

Warner, N., Jongman, A., and Mücke, D.

Abstract

This paper presents articulatory data on the production of /l/ in various environments in Dutch, and shows that the direction of movement of the tongue dorsum varies across environments. This makes it impossible to measure tongue position at the peak of the dorsal gesture. We argue for an alternative method in such cases: measurement of position of one articulator at a time point defined by the gesture of another. We present new data measured this way which confirms a previous finding on the articulation of Dutch /l/.

Published
2002
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18. Stop epenthesis at syllable boundaries

Author

Warner, N. and Weber, A.

Abstract

This paper investigates the production and perception of epenthetic stops at syllable boundaries in Dutch and compares the experimental data with lexical statistics for Dutch and English. This extends past work on epenthesis in coda position [1]. The current work is particularly informative regarding the question of phonotactic constraints’ influence on parsing of speech variability.

Published
2002
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19. Introduction

Author

Gussenhoven, C., Warner, N., and Warner, C.

Published
2002

20. N=1 Special Geometry, Mixed Hodge Variations and Toric Geometry

Author

Lerche, W., Mayr, P., and Warner, N.

Subjects
High Energy Physics - Theory, High Energy Physics::Theory, High Energy Physics - Theory (hep-th), High Energy Physics::Phenomenology, FOS: Physical sciences, Particle Physics - Theory
Abstract

We study the superpotential of a certain class of N=1 supersymmetric type II compactifications with fluxes and D-branes. We show that it has an important two-dimensional meaning in terms of a chiral ring of the topologically twisted theory on the world-sheet. In the open-closed string B-model, this chiral ring is isomorphic to a certain relative cohomology group V, which is the appropriate mathematical concept to deal with both the open and closed string sectors. The family of mixed Hodge structures on V then implies for the superpotential to have a certain geometric structure. This structure represents a holomorphic, N=1 supersymmetric generalization of the well-known N=2 special geometry. It defines an integrable connection on the topological family of open-closed B-models, and a set of special coordinates on the space \cal M of vev's in N=1 chiral multiplets. We show that it can be given a very concrete and simple realization for linear sigma models, which leads to a powerful and systematic method for computing the exact non-perturbative N=1 superpotentials for a broad class of toric D-brane geometries., Comment: 40p, harvmac-b

Published
2002
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21. Introduction

Author

Gussenhoven, C., Warner, N., Gussenhoven, C., and Warner, C.

Subjects
Structuur in uitvoering, Structure in Use
Abstract

Item does not contain fulltext

Published
2002

22. New Vacua of Gauged N=8 Supergravity

Author

Khavaev, A., Pilch, K., and Warner, N. P.

Subjects
High Energy Physics - Theory, General Relativity and Quantum Cosmology, High Energy Physics::Theory, High Energy Physics - Theory (hep-th), High Energy Physics::Phenomenology, FOS: Physical sciences
Abstract

We analyze a particular SU(2) invariant sector of the scalar manifold of gauged N=8 supergravity in five dimensions, and find all the critical points of the potential within this sector. The critical points give rise to Anti-de Sitter vacua, and preserve at least an SU(2) gauge symmetry. Consistent truncation implies that these solutions correspond to Anti-de Sitter compactifications of IIB supergravity, and hence to possible near-horizon geometries of 3-branes. Thus we find new conformal phases of softly broken N=4 Yang--Mills theory. One of the critical points preserves N=2 supersymmetry in the bulk and is therefore completely stable, and corresponds to an N=1 superconformal fixed point of the Yang--Mills theory. The corresponding renormalization group flow from the N=4 point has c_{IR}/c_{UV} = 27/32. We also discuss the ten-dimensional geometries corresponding to these critical points., Comment: 14 pages, 1 table, harvmac

Published
1998
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23. $N=2$ Supersymmetric Integrable Models and Topological Field Theories

Author

Warner, N. P.

Subjects
High Energy Physics - Theory, High Energy Physics::Theory, High Energy Physics - Theory (hep-th), FOS: Physical sciences
Abstract

These lectures review some of the basic properties of $N=2$ superconformal field theories and the corresponding topological field theories. One of my basic aims is to show how the techniques of topological field theory can be used to compute effective \LG potentials for perturbed $N=2$ superconformal field theories. In particular, I will briefly discuss the application of these ideas to $N=2$ supersymmetric quantum integrable models. (Lectures given at the Summer School on High Energy Physics and Cosmology, Trieste, Italy, June 15th -- July 3rd, 1992. To appear in the proceedings.), Comment: 37 pages, harvmac, USC-93/001

Published
1993
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24. Lattice models and $N=2$ supersymmetry

Author

Saleur, H. and Warner, N. P.

Subjects
High Energy Physics - Theory, High Energy Physics - Theory (hep-th), Condensed Matter (cond-mat), FOS: Physical sciences, Condensed Matter
Abstract

We review the construction of exactly solvable lattice models whose continuum limits are $N=2$ supersymmetric models. Both critical and off-critical models are discussed. The approach we take is to first find lattice models with natural topological sectors, and then identify the continuum limits of these sectors with topologically twisted $N=2$ supersymmetric field theories. From this, we then describe how to recover the complete lattice versions of the $N=2$ supersymmetric field theories. We discuss a number of simple physical examples and we describe how to construct a broad class of models. We also give a brief review of the scattering matrices for the excitations of these models. (Contribution to the procedings of the Cargese meeting on ``String Theory, Conformal Models and Topological Field Theories'', May 12-21, 1993.), Comment: 49 pages, 12 figures, Latex, USC preprint 93/026

Published
1993
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25. High frequency of immune dysfunctions in asbestos workers and in patients with malignant mesothelioma

Author

Irving J. Selikoff, J G Bekesi, F. Lew, Tsang Ph, James F. Holland, and Warner N

Subjects
Cytotoxicity, Immunologic, Mesothelioma, T-Lymphocytes, Immunology, Asbestosis, Occupational disease, medicine.disease_cause, Asbestos, Cell Line, Natural killer cell, Immune system, Interferon, medicine, Humans, Immunology and Allergy, Immunity, Cellular, business.industry, Respiratory disease, T-Lymphocytes, Helper-Inducer, Flow Cytometry, medicine.disease, Recombinant Proteins, Killer Cells, Natural, Phenotype, medicine.anatomical_structure, Leukemia, Myeloid, Interferons, business, medicine.drug
Abstract

We have examined the primary immune responses, the numbers of total T (T11+) cells, T-helper (T4+) cells, T-suppressor (T8+) cells, and natural killer (NK) (Leu7+) cells, in 118 healthy control subjects and compared the data to those obtained from 20 patients with clinically diagnosed malignant mesothelioma and 375 long-term asbestos workers without neoplasia. The absolute numbers of total T (T11+) and T-helper (T4+) cells were normal in asbestos workers without neoplasia but were significantly reduced in patients with mesothelioma. T-suppressor (T8+) cells, on the other hand, remained unchanged in the patients but were significantly elevated among the asbestos workers. This resulted in a marked reduction in T-helper (Th) to T-suppressor (Ts) ratios in mesothelioma patients and in asbestos workers. Seventy percent of the mesothelioma patients (14 of 20) had significantly depressed NK-cell activity which could be augmented but not normalized by coincubation in patients' peripheral blood lymphocytes (PBL) with interferon (IFN). Among the asbestos workers three distinctive subgroups could be identified: heightened (H-NK), normal (N-NK), and low (L-NK) NK activity. The NK activity of the L-NK group could be stimulated but not normalized by coincubation with IFN, a finding closely resembling that in malignant mesothelioma patients. Phenotyping of the circulating NK cells revealed a unique Leu7+ subset in increased numbers with a brightly fluorescent property in stable mesothelioma patients with relatively stable or slowly progressive disease and in more than 30% of the asbestos workers. The reduced Th/Ts ratio and NK-cell function among these asbestos workers at high risk may be a direct consequence of asbestos exposure and might not be related to neoplastic processes.

Published
1986
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26. The structure of $N=16$ supergravity in two dimensions

Author

Nicolai, H. and Warner, N. P.

Subjects
High Energy Physics::Theory, 81G25, High Energy Physics::Phenomenology, 83E50
Abstract

We extend the previously constructed linear system for N = 16 supergravity in two dimensions by including the unphysical gravitino degrees of freedom. This theory has a residual N = 16 "superconformal" in variance that can be bosonized to local E9 transformations. The modifications to the linear system described here suggest a further extension to an infinite hierarchy of fields and associated gauge transformations related to E9.

Published
1989

28. Location and Setting of the Mars InSight Lander, Instruments, and Landing Site

Author

H. Abarca, L. Mora-Sotomayor, Matthew P. Golombek, M. G. Williams, Robert G. Deen, L. K. Tamppari, John A. Grant, E. Sklyanskiy, Ingrid Daubar, N. Baugh, Miles J. Johnson, Nicholas H. Warner, J. Ladewig, Nathan R. Williams, Alfred S. McEwen, Karin A. Block, W. A. Weems, T. Kennedy, Justin N. Maki, A. Stoltz, N. Ruoff, Philip Bailey, J. Torres, T. J. Parker, Fred Calef, J. Call, Unidad de Excelencia Científica María de Maeztu Centro de Astrobiología del Instituto Nacional de Técnica Aeroespacial y CSIC, MDM-2017-0737, Warner, N. [0000-0002-7615-2524], Williams, N. [0000-0003-0602-484X], Golombek, M. [0000-0002-1928-2293], Parker, T. [0000-0003-3524-9220], Deen, R. [0000-0002-5693-641X], Maki, J. [0000-0002-7887-0343], Mora Stomayor, L. [0000-0002-8209-1190], National Aeronautics and Space Administration (NASA), National Aeronautics & Space Administration (NASA), and InSight Contribution

Subjects
Bedform, lcsh:Astronomy, Location, General or Miscellaneous, Mars, Surface location, Environmental Science (miscellaneous), Elysium, Remote Sensing, lcsh:QB1-991, Planetary Sciences: Solar System Objects, Impact crater, Geoid, Geodesy and Gravity, Instruments and Techniques, Digital elevation model, Planetary Sciences: Solid Surface Planets, Research Articles, InSight, Orbital and Rotational Dynamics, Spacecraft, business.industry, surface location, lcsh:QE1-996.5, Mars Exploration Program, Mars lander, Geodesy, InSight at Mars, Lunar and Planetary Geodesy and Gravity, lcsh:Geology, Viewshed analysis, General Earth and Planetary Sciences, business, Geology, location, Research Article
Abstract

Knowing precisely where a spacecraft lands on Mars is important for understanding the regional and local context, setting, and the offset between the inertial and cartographic frames. For the InSight spacecraft, the payload of geophysical and environmental sensors also particularly benefits from knowing exactly where the instruments are located. A ~30 cm/pixel image acquired from orbit after landing clearly resolves the lander and the large circular solar panels. This image was carefully georeferenced to a hierarchically generated and coregistered set of decreasing resolution orthoimages and digital elevation models to the established positive east, planetocentric coordinate system. The lander is located at 4.502384°N, 135.623447°E at an elevation of −2,613.426 m with respect to the geoid in Elysium Planitia. Instrument locations (and the magnetometer orientation) are derived by transforming from Instrument Deployment Arm, spacecraft mechanical, and site frames into the cartographic frame. A viewshed created from 1.5 m above the lander and the high‐resolution orbital digital elevation model shows the lander is on a shallow regional slope down to the east that reveals crater rims on the east horizon ~400 m and 2.4 km away. A slope up to the north limits the horizon to about 50 m away where three rocks and an eolian bedform are visible on the rim of a degraded crater rim. Azimuths to rocks and craters identified in both surface panoramas and high‐resolution orbital images reveal that north in the site frame and the cartographic frame are the same (within 1°)., Key Points A carefully georeferenced high‐resolution image of the InSight lander shows it is located at 4.5024N, 135.6234E in Elysium Planitia, MarsInstrument locations are derived by transforming from spacecraft and site frames into the cartographic frameA viewshed shows the lander is on a shallow regional slope down to the east and a local slope up to the north

Published
2020
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29. The E3 ubiquitin ligase UBR5 interacts with TTC7A and may be associated with very early onset inflammatory bowel disease

Author

Scott B. Snapper, Qi Li, Christoph Klein, Neil Warner, Neel Dhingani, Sasha Jardine, Claudia Gonzaga-Jauregui, Daniel Kotlarz, Aleixo M. Muise, Conghui Guo, Jie Pan, Gabriella Leung, Víctor Manuel Navas-López, [Dhingani,N, Jardine,S, Muise,AM] Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada. [Dhingani,N, Guo,C, Pan,J, Li,Q, Warner,N, Leung,G, Muise,AM] SickKids Infammatory Bowel Disease Centre, Research Institute, Hospital for Sick Children, Toronto, ON, Canada. [Kotlarz,D, Klein,C] Department of Pediatrics, Dr. Von Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany. [Gonzaga-Jauregui,C] Regeneron Genetics Center, Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA. [Snapper,SB] Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA. [Navas-López,VM] Pediatric Gastroenterology and Nutrition Unit, IBIMA, Hospital Regional Universitario de Málaga, Málaga, Spain. [Muise,AM] Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada. [Muise,AM] Department of Pediatrics, Institute of Medical Science, University of Toronto, Toronto, Canada. [Snapper,SB] Division of Gastroenterology, Brigham and Women’s Hospital, Boston, MA, USA., and AMM is funded by a Canada Research Chair (Tier 1) in Pediatric IBD, CIHR Foundation Grant and NIDDK (RC2DK118640) Grant. AMM, SBS, CK, DK are supported by the Leona M. and Harry B. Helmsley Charitable Trust. CK and DK are supported by the Collaborative Research Consortium SFB1054 project A05.

Subjects
0301 basic medicine, Male, Enfermedades inflamatorias del intestino, lcsh:Medicine, Compound heterozygosity, Inflammatory bowel disease, Diseases::Digestive System Diseases::Gastrointestinal Diseases::Intestinal Diseases::Inflammatory Bowel Diseases [Medical Subject Headings], Unión proteica, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], 0302 clinical medicine, Age of Onset, lcsh:Science, Child, Immunodeficiency, Exome sequencing, Multidisciplinary, biology, Intestinal atresia, Gastroenterology, Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Signal Transduction [Medical Subject Headings], Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins [Medical Subject Headings], Colitis, 3. Good health, Ubiquitin ligase, Ubiquitin-protein ligases, Tetratricopeptide, 030220 oncology & carcinogenesis, Niño, Child, Preschool, Protein Binding, Signal Transduction, Cell biology, Ubiquitin-Protein Ligases, Check Tags::Male [Medical Subject Headings], Inflammatory bowel diseases, Article, Amino acid sequence, 03 medical and health sciences, Ubiquitina-proteína ligasas, Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Protein Binding [Medical Subject Headings], medicine, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Ligases::Ubiquitin-Protein Ligase Complexes::Ubiquitin-Protein Ligases [Medical Subject Headings], Protein binding, Humans, Secuencia de aminoácidos, Amino Acid Sequence, Health Care::Health Care Quality, Access, and Evaluation::Quality of Health Care::Epidemiologic Factors::Age Factors::Age of Onset [Medical Subject Headings], Diseases::Digestive System Diseases::Gastrointestinal Diseases::Intestinal Diseases::Colonic Diseases::Colitis [Medical Subject Headings], Sequence Homology, Amino Acid, business.industry, lcsh:R, Proteins, medicine.disease, Inflammatory Bowel Diseases, 030104 developmental biology, Immunology, biology.protein, Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Molecular Structure::Amino Acid Sequence [Medical Subject Headings], lcsh:Q, business, Persons::Persons::Age Groups::Child::Child, Preschool [Medical Subject Headings]
Abstract

Very early onset inflammatory bowel disease (VEOIBD) denotes children with onset of IBD before six years of age. A number of monogenic disorders are associated with VEOIBD including tetratricopeptide repeat domain 7A (TTC7A) deficiency. TTC7A-deficiency is characterized by apoptotic colitis in milder cases with severe intestinal atresia and immunodeficiency in cases with complete loss of protein. We used whole exome sequencing in a VEOIBD patient presenting with colitis characterized by colonic apoptosis and no identified known VEOIBD variants, to identify compound heterozygous deleterious variants in the Ubiquitin protein ligase E3 component N-recognin 5 (UBR5) gene. Functional studies demonstrated that UBR5 co-immunoprecipitates with the TTC7A and the UBR5 variants had reduced interaction between UBR5 and TTC7A. Together this implicates UBR5 in regulating TTC7A signaling in VEOIBD patients with apoptotic colitis.

Published
2019

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