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1. Association between type 2 diabetes and depressive symptoms after a 1-year follow-up in an older adult Mediterranean population

Author

Baenas, I., Camacho-Barcia, L., Granero, R., Razquin, C., Corella, D., Gómez-Martínez, C., Castañer-Niño, O., Martínez, J. A., Alonso-Gómez, Á. M., Wärnberg, J., Vioque, J., Romaguera, D., López-Miranda, J., Estruch, R., Tinahones, F. J., Lapetra, J., Serra-Majem, J. L., Cano-Ibáñez, N., Tur, J. A., Martín-Sánchez, V., Pintó, X., Gaforio, J. J., Matía-Martín, P., Vidal, J., Vázquez, C., Daimiel, L., Ros, E., Jiménez-Murcia, S., Dalsgaard, S., Garcia-Arellano, A., Babio, N., Sorli, J. V., Lassale, C., García-de-la-Hera, M., Gómez-García, E., Zulet, M. A., Konieczna, J., Martín-Peláez, S., Tojal-Sierra, L., Basterra-Gortari, F. J., de las Heras-Delgado, S., Portoles, O., Muñoz-Pérez, M. Á., Arenas-Larriva, A. P., Compañ-Gabucio, L., Eguaras, S., Shyam, S., Fitó, M., Baños, R. M., Salas-Salvadó, J., and Fernández-Aranda, F.

Published
2024
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3. Protein network analysis reveals selectively vulnerable regions and biological processes in FTD

Author

Bonham, Luke W, Steele, Natasha ZR, Karch, Celeste M, Manzoni, Claudia, Geier, Ethan G, Wen, Natalie, Ofori-Kuragu, Aaron, Momeni, Parastoo, Hardy, John, Miller, Zachary A, Hess, Christopher P, Lewis, Patrick, Miller, Bruce L, Seeley, William W, Baranzini, Sergio E, Desikan, Rahul S, Ferrari, Raffaele, Yokoyama, Jennifer S, Ferrari, R, Hernandez, DG, Nalls, MA, Rohrer, JD, Ramasamy, A, Kwok, JBJ, Dobson-Stone, C, Schofield, PR, Halliday, GM, Hodges, JR, Piguet, O, Bartley, L, Thompson, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, NJ, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Waldö, M Landqvist, Nilsson, K, Nilsson, C, Mackenzie, IRA, Hsiung, G-YR, Mann, D, Grafman, J, Morris, CM, Attems, J, Griffiths, TD, McKeith, IG, Thomas, AJ, Pietrini, P, Huey, ED, Wassermann, EM, Baborie, A, Jaros, E, Tierney, MC, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, St George-Hyslop, P, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, JB, Schlachetzki, JCM, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin, VM, Grossman, M, Trojanowski, JQ, van der Zee, J, Van Broeckhoven, C, Cappa, SF, Leber, I, Hannequin, D, and Golfier, V

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Aging, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease Related Dementias (ADRD), Frontotemporal Dementia (FTD), Acquired Cognitive Impairment, Dementia, Biotechnology, Neurodegenerative, Rare Diseases, Neurosciences, Brain Disorders, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Neurological, International FTD-Genomics Consortium, Clinical sciences
Abstract

ObjectiveThe neuroanatomical profile of behavioral variant frontotemporal dementia (bvFTD) suggests a common biological etiology of disease despite disparate pathologic causes; we investigated the genetic underpinnings of this selective regional vulnerability to identify new risk factors for bvFTD.MethodsWe used recently developed analytical techniques designed to address the limitations of genome-wide association studies to generate a protein interaction network of 63 bvFTD risk genes. We characterized this network using gene expression data from healthy and diseased human brain tissue, evaluating regional network expression patterns across the lifespan as well as the cell types and biological processes most affected in bvFTD.ResultsWe found that bvFTD network genes show enriched expression across the human lifespan in vulnerable neuronal populations, are implicated in cell signaling, cell cycle, immune function, and development, and are differentially expressed in pathologically confirmed frontotemporal lobar degeneration cases. Five of the genes highlighted by our differential expression analyses, BAIAP2, ERBB3, POU2F2, SMARCA2, and CDC37, appear to be novel bvFTD risk loci.ConclusionsOur findings suggest that the cumulative burden of common genetic variation in an interacting protein network expressed in specific brain regions across the lifespan may influence susceptibility to bvFTD.

Published
2018

5. Proteomics and recurrence of atrial fibrillation: a pilot study nested in the PREDIMAR trial

Author

Razquin, C, primary, Fernandez-Irigoyen, J, additional, Barrio-Lopez, M T, additional, Ramos, P, additional, Macias, R, additional, Ibanez-Criado, A, additional, Santamaria, E, additional, Goni, L, additional, Castellanos, E, additional, Ibanez-Criado, J L, additional, Tercedor, L, additional, Garcia-Bolao, I, additional, Martinez-Gonzalez, M A, additional, Almendral, J, additional, and Ruiz-Canela, M, additional

Published
2023
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6. Exploratory dietary patterns and cognitive function in the “Seguimiento Universidad de Navarra” (SUN) Prospective Cohort

Author

Muñoz-García, M. I., Martínez-González, M. A., Razquin, C., Fernández-Matarrubia, M., Guillén-Grima, F., and Toledo, E.

Abstract

Background: Dementia is projected to affect 135 million by 2050. Diet is a pertinent target for primary prevention, but firm recommendations for dementia prevention are not available yet. Our aim was to address the association between exploratory (empirically derived) dietary patterns (DP) and changes in the Spanish Telephone Interview for Cognitive Status (STICS-m, maximum score = 41 points) over 6 years. Method: Information on diet was collected with a validated 136-item food-frequency questionnaire from 803 participants in the Mediterranean cohort “Seguimiento Universidad de Navarra.” We used principal component analysis to derive exploratory DP. The derived DP were associated with change in STICS-m scores over 6 years, through adjusted multiple linear regression models. Results: Two main DP were identified. The first DP resembled a Western dietary pattern (WDP)—high in sugar, fat, processed foods, and red meat—and the second DP resembled a Mediterranean dietary pattern (MDP)—high in vegetables, fruits, nuts, fish, and olive oil. Adherence to the WDP (tertile 3 vs tertile 1) was significantly associated with negative STICS-m changes after 6 years (between-tertile difference in changes: –0.80 points; 95% confidence interval [CI] –1.51, –0.08, pvalue = 0.03). Meanwhile, the MDP showed a positive +0.71 point (95% CI 0.15, 1.26, pvalue = 0.01) between-tertile difference in changes in the STICS-m score. Conclusions: A healthy, prudent, MDP was associated with less decline in cognitive function and, thus, could help to lower dementia incidence. Western-type diets were associated with a greater decline in cognitive performance and could increase dementia incidence.

Published
2024
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8. Association between ideal cardiovascular health and telomere length in participants older than 55 years old from the SUN cohort

Author

Alonso-Pedrero, L. (Lucía), Ojeda-Rodríguez, A. (Ana), Zalba, G. (Guillermo), Razquin, C. (Cristina), Martinez-Gonzalez, M.A. (Miguel Ángel), Bes-Rastrollo, M. (Maira), and Marti, A. (Amelia)

Subjects
Telomere length, Riesgo cardiovascular, Cohorte SUN, Índice de Salud Cardiovascular, Longitud telomérica, Cardiovascular health score, Cardiovascular risk, Cross-sectional study, Estudio transversal, SUN study
Abstract

Introduction and objectives: Telomeres are noncoding regions located at the end of chromosomes and their shortening has been associated with risk factors and cardiovascular disease. The aim of this study was to evaluate the association between ideal cardiovascular health (Life’s simple 7) and the odds of having short telomeres in a subsample of participants older than 55 years from the Seguimiento Universidad de Navarra (SUN) study. Methods: We included 886 participants older than 55 years (645 men and 241 women). Telomere length was measured using a real-time quantitative polymerase chain reaction. Cardiovascular health score was defined by the American Heart Association as a composite score of 7 key risk factors (smoking status, physical activity, diet, body mass index, blood pressure, total cholesterol, and fasting blood glucose) with 0 to 2 points for each factor. We categorized this score in tertiles as poor (0-9 points), intermediate (10- 11 points) and ideal (12-14 points). The odds of having short telomeres was defined as telomere length below the 20th percentile. Results: Individuals with higher ideal cardiovascular health had a lower prevalence of having short telomeres (adjusted OR, 0.60; 95%CI, 0.34-1.05; P trend = .052). This association was statistically significant in men (adjusted OR, 0.37; 95%CI, 0.17-0.83; P trend = .025) but not in women. Conclusions: An inverse association between cardiovascular health score and short telomeres was found especially for men older than 55 years in the SUN population. Introducción y objetivos: Los telómeros son regiones no codificantes localizadas al final de los cromosomas de células eucariotas, y su acortamiento se ha visto relacionado con la enfermedad cardiovascular y sus factores de riesgo. El objetivo de este estudio es evaluar la asociación entre el índice de salud cardiovascular ideal y el riesgo de telómero corto en una población de sujetos de edad avanzada de la cohorte Seguimiento Universidad de Navarra (SUN). Métodos: Se valoró a 886 adultos mayores de 55 años (645 varones y 241 mujeres). La longitud telomérica se midió utilizando qPCR (quantitative protein chain reaction) en tiempo real y reacción única. El índice de salud cardiovascular «Life’s simple 7» se definió según la American Heart Association mediante la puntuación de 7 ítems con valores de 0 a 2 para cada uno: tabaquismo, actividad física, dieta, índice de masa corporal, presión arterial, colesterol total y glucosa en sangre. La máxima puntuación del índice corresponde a 14 puntos. Se categorizó en terciles: pobre (0-9 puntos), intermedio (10-11 puntos) e ideal (12-14 puntos). El riesgo de telómero corto se definió como una longitud telomérica por debajo del percentil 20. Resultados: Sujetos con altos valores en el índice de salud cardiovascular ideal tenían menos riesgo de telómero corto (OR ajustada = 0,60; IC95%, 0,34-1,05; p de tendencia lineal = 0,052). Esta asociación fue significativa en varones (OR ajustada = 0,37; IC95%, 0,17-0,83; p de tendencia lineal = 0,025), pero no en mujeres. Conclusiones: En varones mayores de 55 años, existe una asociación inversa entre el índice de salud cardiovascular y el riesgo de tener telómeros cortos.

Published
2022

9. Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimerʼs and Parkinsonʼs diseases

Author

Ferrari, Raffaele, Wang, Yunpeng, Vandrovcova, Jana, Guelfi, Sebastian, Witeolar, Aree, Karch, Celeste M, Schork, Andrew J, Fan, Chun C, Brewer, James B, Momeni, Parastoo, Schellenberg, Gerard D, Dillon, William P, Sugrue, Leo P, Hess, Christopher P, Yokoyama, Jennifer S, Bonham, Luke W, Rabinovici, Gil D, Miller, Bruce L, Andreassen, Ole A, Dale, Anders M, Hardy, John, Desikan, Rahul S, Hernandez, D G, Nalls, M A, Rohrer, J D, Ramasamy, A, Kwok, J B J, Dobson-Stone, C, Schofield, P R, Halliday, G M, Hodges, J R, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, N J, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Landqvist Waldö, M, Nilsson, K, Nilsson, C, Mackenzie, I R A, Hsiung, G-Y R, Mann, D M A, Grafman, J, Morris, C M, Attems, J, Griffiths, T D, McKeith, I G, Thomas, A J, Pietrini, P, Huey, E D, Wassermann, E M, Baborie, A, Jaros, E, Tierney, M C, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, St George-Hyslop, P, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, J B, Schlachetzki, J C M, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin, V M, Grossman, M, Trojanowski, J Q, van der Zee, J, Cruts, M, Van Broeckhoven, C, Cappa, S F, Leber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, J E, Hjermind, L E, Riemenschneider, M, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, Rossor, M N, Fox, N C, Warren, J D, Spillantini, M G, Morris, H R, Rizzu, P, Heutink, P, Snowden, J S, Rollinson, S, Richardson, A, Gerhard, A, Bruni, A C, Maletta, R, Frangipane, F, Cupidi, C, Bernardi, L, Anfossi, M, Gallo, M, Conidi, M E, Smirne, N, Rademakers, R, Baker, M, Dickson, D W, Graff-Radford, N R, Petersen, R C, Knopman, D, Josephs, K A, Boeve, B F, Parisi, J E, Seeley, W W, Karydas, A M, Rosen, H, van Swieten, J C, Dopper, E G P, Seelaar, H, Pijnenburg, Y A L, Scheltens, P, Logroscino, G, Capozzo, R, Novelli, V, Puca, A A, Franceschi, M, Postiglione, A, Milan, G, Sorrentino, P, Kristiansen, M, Chiang, H-H, Graff, C, Pasquier, F, Rollin, A, Deramecourt, V, Lebouvier, T, Kapogiannis, D, Ferrucci, L, Pickering-Brown, S, and Singleton, A B

Published
2017
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11. A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers

Author

Zhang M1, 2 3, Ferrari R4, Tartaglia MC3, 5 6, Keith J7, Surace EI8, Wolf U9, Sato C3, Grinberg M3, Liang Y3, Xi Z3, Dupont K3, McGoldrick P3, Weichert A3, McKeever PM3, Schneider R3, 6 7, McCorkindale MD4, Manzoni C10, Rademakers R11, Graff-Radford NR12, Dickson DW11, Parisi JE13, Boeve BF14, Petersen RC14, Miller BL15, Seeley WW16, van Swieten JC17, van Rooij J17, Pijnenburg Y18, van der Zee J19, Van Broeckhoven C19, Le Ber I21, Van Deerlin V23, Suh E23, Rohrer JD24, Mead S25, Graff C26, Öijerstedt L26, Pickering-Brown S28, Rollinson S28, Rossi G29, Tagliavini F30, Brooks WS31, Dobson-Stone C32, Halliday GM32, Hodges JR32, Piguet O34, Binetti G36, Benussi L37, Ghidoni R37, Nacmias B38, Sorbi S38, Bruni AC40, Galimberti D41, Scarpini E41, Rainero I42, Rubino E42, Clarimon J43, Lleó A43, Ruiz A45, Hernández I45, Pastor P46, Diez-Fairen M46, Borroni B48, Pasquier F49, Deramecourt V49, Lebouvier T49, Perneczky R50, 51 52, Diehl-Schmid J50, Grafman J53, Huey ED55, Mayeux R55, Nalls MA57, Hernandez D57, Singleton A57, Momeni P58, Zeng Z59, Hardy J4, Robertson J3, Zinman L6, 7, Rogaeva E3, 6, International FTD-Genomics Consortium (IFGC), Ferrari R, Hernandez DG, Nalls MA, Rohrer JD, Ramasamy A, Kwok JBJ, Dobson-Stone C, Brooks WS, Schofield PR, Halliday GM, Hodges JR, Piguet O, Bartley L, Thompson E, Hernández I, Ruiz A, Boada M, Borroni B, Padovani A, Cruchaga C, Cairns NJ, Benussi L, Binetti G, Ghidoni R, Forloni G, Albani D, Galimberti D, Fenoglio C, Serpente M, Scarpini E, Clarimón J, Lleó A, Blesa R, Wald Ouml ML, Nilsson K, Nilsson C, Mackenzie IRA, Hsiung GR, Mann DMA, Grafman J, Morris CM, Attems J, Griffiths TD, McKeith IG, Thomas AJ, Pietrini P, Huey ED, Wassermann EM, Baborie A, Jaros E, Tierney MC, Pastor P, Razquin C, Ortega-Cubero S, Alonso E, Perneczky R, Diehl-Schmid J, Alexopoulos P, Kurz A, Rainero I, Rubino E, Pinessi L, Rogaeva E, St George-Hyslop P, Rossi G, Tagliavini F, Giaccone G, Rowe JB, Schlachetzki JCM, Uphill J, Collinge J, Mead S, Danek A, Van Deerlin VM, Grossman M, Trojanowski JQ, van der Zee J, Van Broeckhoven C, Cappa SF, Leber I, Hannequin D, Golfier V, Vercelletto M, Brice A, Nacmias B, Sorbi S, Bagnoli S, Piaceri I, Nielsen JE, Hjermind LE, Riemenschneider M, Mayhaus M, Ibach B, Gasparoni G, Pichler S, Gu W, Rossor MN, Fox NC, Warren JD, Grazia Spillantini M, Morris HR, Rizzu P, Heutink P, Snowden JS, Rollinson S, Richardson A, Gerhard A, Bruni AC, Maletta R, Frangipane F, Cupidi C, Bernardi L, Anfossi M, Gallo M, Elena Conidi M, Smirne N, Rademakers R, Baker M, Dickson DW, Graff-Radford NR, Petersen RC, Knopman D, Josephs KA, Boeve BF, Parisi JE, Seeley WW, Miller BL, Karydas AM, Rosen H, van Swieten JC, Dopper EGP, Seelaar H, Pijnenburg YAL, Scheltens P, Logroscino G, Capozzo R, Novelli V, Puca AA, Franceschi M, Postiglione A, Milan G, Sorrentino P, Kristiansen M, Chiang HH, Graff C, Pasquier F, Rollin A, Deramecourt V, Lebouvier T, Kapogiannis D, Ferrucci L, Pickering-Brown S, Singleton AB, Hardy J, Momeni P, Human genetics, Amsterdam Neuroscience - Neurodegeneration, Neurology, Divisions, Zhang, M1, 2, 3, Ferrari, R4, Tartaglia, Mc3, 5, 6, Keith, J7, Surace, Ei8, Wolf, U9, Sato, C3, Grinberg, M3, Liang, Y3, Xi, Z3, Dupont, K3, Mcgoldrick, P3, Weichert, A3, Mckeever, Pm3, Schneider, R3, 6, 7, Mccorkindale, Md4, Manzoni, C10, Rademakers, R11, Graff-Radford, Nr12, Dickson, Dw11, Parisi, Je13, Boeve, Bf14, Petersen, Rc14, Miller, Bl15, Seeley, Ww16, van Swieten, Jc17, van Rooij, J17, Pijnenburg, Y18, van der Zee, J19, Van Broeckhoven, C19, Le Ber, I21, Van Deerlin, V23, Suh, E23, Rohrer, Jd24, Mead, S25, Graff, C26, Öijerstedt, L26, Pickering-Brown, S28, Rollinson, S28, Rossi, G29, Tagliavini, F30, Brooks, Ws31, Dobson-Stone, C32, Halliday, Gm32, Hodges, Jr32, Piguet, O34, Binetti, G36, Benussi, L37, Ghidoni, R37, Nacmias, B38, Sorbi, S38, Bruni, Ac40, Galimberti, D41, Scarpini, E41, Rainero, I42, Rubino, E42, Clarimon, J43, Lleó, A43, Ruiz, A45, Hernández, I45, Pastor, P46, Diez-Fairen, M46, Borroni, B48, Pasquier, F49, Deramecourt, V49, Lebouvier, T49, Perneczky, R50, 51, 52, Diehl-Schmid, J50, Grafman, J53, Huey, Ed55, Mayeux, R55, Nalls, Ma57, Hernandez, D57, Singleton, A57, Momeni, P58, Zeng, Z59, Hardy, J4, Robertson, J3, Zinman, L6, Rogaeva, E3, International FTD-Genomics Consortium, (IFGC), Ferrari, R, Hernandez, Dg, Nalls, Ma, Rohrer, Jd, Ramasamy, A, Kwok, Jbj, Dobson-Stone, C, Brooks, W, Schofield, Pr, Halliday, Gm, Hodges, Jr, Piguet, O, Bartley, L, Thompson, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, Nj, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Wald Ouml, Ml, Nilsson, K, Nilsson, C, Mackenzie, Ira, Hsiung, Gr, Mann, Dma, Grafman, J, Morris, Cm, Attems, J, Griffiths, Td, Mckeith, Ig, Thomas, Aj, Pietrini, P, Huey, Ed, Wassermann, Em, Baborie, A, Jaros, E, Tierney, Mc, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, St George-Hyslop, P, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, Jb, Schlachetzki, Jcm, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin, Vm, Grossman, M, Trojanowski, Jq, van der Zee, J, Van Broeckhoven, C, Cappa, Sf, Leber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, Je, Hjermind, Le, Riemenschneider, M, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, Rossor, Mn, Fox, Nc, Warren, Jd, Grazia Spillantini, M, Morris, Hr, Rizzu, P, Heutink, P, Snowden, J, Rollinson, S, Richardson, A, Gerhard, A, Bruni, Ac, Maletta, R, Frangipane, F, Cupidi, C, Bernardi, L, Anfossi, M, Gallo, M, Elena Conidi, M, Smirne, N, Rademakers, R, Baker, M, Dickson, Dw, Graff-Radford, Nr, Petersen, Rc, Knopman, D, Josephs, Ka, Boeve, Bf, Parisi, Je, Seeley, Ww, Miller, Bl, Karydas, Am, Rosen, H, van Swieten, Jc, Dopper, Egp, Seelaar, H, Pijnenburg, Yal, Scheltens, P, Logroscino, G, Capozzo, R, Novelli, V, Puca, Aa, Franceschi, M, Postiglione, A, Milan, G, Sorrentino, P, Kristiansen, M, Chiang, Hh, Graff, C, Pasquier, F, Rollin, A, Deramecourt, V, Lebouvier, T, Kapogiannis, D, Ferrucci, L, Pickering-Brown, S, Singleton, Ab, Hardy, J, Momeni, P, and Int FTD-Genomics Consortium IFGC

Subjects
Male, Heterozygote, amyotrophic lateral sclerosis, Genotype, genetic association, Age of onset, Polymorphism, Single Nucleotide, frontotemporal dementia, age of onset, C9orf72, Humans, amyotrophic lateral sclerosi, Aged, C9orf72 Protein, Original Articles, DNA Methylation, Middle Aged, Amyotrophic lateral sclerosis, Gene Expression Regulation, Genetic association, CpG Islands, Female, Human medicine, Neurology (clinical), Frontotemporal dementia
Abstract

Discovery of disease age-of-onset modifiers is important for clinical trials and drug design. Zhang et al. perform a genome-wide analysis of epigenetic functional polymorphisms and identify an association between the C6orf10/LOC101929163 locus and age of FTD/ALS onset. The risk allele may be associated with a pro-inflammatory state in the brain., The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium block tagged by top-significant variation, rs9357140, and containing two overlapping genes (LOC101929163 and C6orf10). A meta-analysis of all 331 C9orf72 carriers revealed that every A-allele of rs9357140 reduced hazard by 30% (P = 0.0002); and the median age of onset in AA-carriers was 6 years later than GG-carriers. In addition, we investigated a cohort of C9orf72 negative patients (n = 2634) affected by frontotemporal dementia and/or amyotrophic lateral sclerosis; and also found that the AA-genotype of rs9357140 was associated with a later age of onset (adjusted P = 0.007 for recessive model). Phenotype analyses detected significant association only in the largest subgroup of patients with frontotemporal dementia (n = 2142, adjusted P = 0.01 for recessive model). Gene expression studies of frontal cortex tissues from 25 autopsy cases affected by amyotrophic lateral sclerosis revealed that the G-allele of rs9357140 is associated with increased brain expression of LOC101929163 (a non-coding RNA) and HLA-DRB1 (involved in initiating immune responses), while the A-allele is associated with their reduced expression. Our findings suggest that carriers of the rs9357140 GG-genotype (linked to an earlier age of onset) might be more prone to be in a pro-inflammatory state (e.g. by microglia) than AA-carriers. Further, investigating the functional links within the C6orf10/LOC101929163/HLA-DRB1 pathway will be critical to better define age-dependent pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.

Published
2018

12. Association between coffee consumption and total dietary caffeine intake with cognitive functioning: cross-sectional assessment in an elderly Mediterranean population

Author

Paz-Graniel, I, Babio, N, Becerra-Tomas, N, Toledo, E, Camacho-Barcia, L, Corella, D, Castaner-Nino, O, Romaguera, D, Vioque, J, Alonso-Gomez, AM, Warnberg, J, Martinez, JA, Serra-Majem, L, Estruch, R, Tinahones, FJ, Fernandez-Aranda, F, Lapetra, J, Pinto, X, Tur, JA, Garcia-Rios, A, Bueno-Cavanillas, A, Gaforio, JJ, Matia-Martin, P, Daimiel, L, Sanchez, VM, Vidal, J, Prieto-Sanchez, L, Ros, E, Razquin, C, Mestres, C, Sorli, JV, Cuenca-Royo, AM, Rios, A, Torres-Collado, L, Vaquero-Luna, J, Perez-Farinos, N, Zulet, MA, Sanchez-Villegas, A, Casas, R, Bernal-Lopez, MR, Santos-Lozano, JM, Corbella, X, Mateos, D, Buil-Cosiales, P, Jimenez-Murcia, S, Fernandez-Carrion, R, Forcano-Gamazo, L, Lopez, M, Sempere-Pascual, MA, Moreno-Rodriguez, A, Gea, A, De la Torre-Fornell, R, Salas-Salvado, J, Perez, A, and Lozano Madrid, Maria

Subjects
Cognitive impairment, Caffeine, Mini-Mental State Examination, PREDIMED-plus, Coffee
Abstract

Purpose Coffee is rich in compounds such as polyphenols, caffeine, diterpenes, melanoidins and trigonelline, which can stimulate brain activity. Therefore, the possible association of coffee consumption with cognition is of considerable research interest. In this paper, we assess the association of coffee consumption and total dietary caffeine intake with the risk of poor cognitive functioning in a population of elderly overweight/obese adults with metabolic syndrome (MetS). Methods PREDIMED-plus study participants who completed the Mini-Mental State Examination test (MMSE) (n = 6427; mean age = 65 +/- 5 years) or a battery of neuropsychological tests were included in this cross-sectional analysis. Coffee consumption and total dietary caffeine intake were assessed at baseline using a food frequency questionnaire. Logistic regression models were fitted to evaluate the association between total, caffeinated and decaffeinated coffee consumption or total dietary caffeine intake and cognitive impairment. Results Total coffee consumers and caffeinated coffee consumers had better cognitive functioning than non-consumers when measured by the MMSE and after adjusting for potential confounders (OR 0.63; 95% CI 0.44-0.90 and OR 0.56; 95% CI 0.38-0.83, respectively). Results were similar when cognitive performance was measured using the Clock Drawing Test (CDT) and Trail Making Test B (TMT-B). These associations were not observed for decaffeinated coffee consumption. Participants in the highest tertile of total dietary caffeine intake had lower odds of poor cognitive functioning than those in the reference tertile when screened by the MMSE (OR 0.64; 95% CI 0.47-0.87) or other neurophysiological tests evaluating a variety of cognitive domains (i.e., CDT and TMT-A). Conclusions Coffee consumption and total dietary caffeine intake were associated with better cognitive functioning as measured by various neuropsychological tests in a Mediterranean cohort of elderly individuals with MetS.

Published
2021

13. Milk and Dairy Products Intake Is Related to Cognitive Impairment at Baseline in Predimed Plus Trial

Author

Garach AM, Cornejo-Pareja I, Martínez-González MÁ, Bulló M, Corella D, Castañer O, Romaguera D, Vioque J, Alonso-Gómez ÁM, Wärnberg J, Martínez JA, Serra-Majem L, Estruch R, Bernal-López MR, Lapetra J, Pintó X, Tur JA, López-Miranda J, Bueno-Cavanillas A, Delgado-Rodríguez M, Matía-Martín P, Daimiel L, Sánchez VM, Vidal J, Prieto L, Ros E, Fernández-Aranda F, Camacho-Barcia L, Ortega-Azorin C, Soria M, Fiol M, Compañ-Gabucio L, Goicolea-Güemez L, Pérez-López J, Goñi N, Pérez-Cabrera J, Sacanella E, Fernández-García JC, Miró-Moriano L, Gimenez-Gracia M, Razquin C, Paz-Graniel I, Guillem P, Zomeño MD, Moñino M, Oncina-Canovas A, Salaverria-Lete I, Toledo E, Salas-Salvadó J, Schröder H, Tinahones FJ, and Predimed-Plus Investigators

Subjects
cognition, milk, consumption, dairy products, cognitive decline
Abstract

Scope To examine the association between milk and dairy products intake and the prevalence of cognitive decline among Spanish individuals at high cardiovascular risk. Methods and results Cross-sectional analyses are performed on baseline data from 6744 adults (aged 55-75 years old). Intake of milk and dairy products is estimated using a food frequency questionnaire grouped into quartiles. The risk of developing cognitive impairment is based on the Mini-Mental State Examination (MMSE). A higher prevalence of cognitive decline was found in subjects who consumed more grams. Patients with worse MMSE score (10-24) consumed a mean of 395.14 +/- 12.21 g, while patients with better MMSE score (27-30) consumed a mean of 341.23 +/- 2.73 g (p < 0.05). Those subjects with the lower milk consumption (

Published
2021

14. Glycemic Dysregulations Are Associated With Worsening Cognitive Function in Older Participants at High Risk of Cardiovascular Disease: Two-Year Follow-up in the PREDIMED-Plus Study

Author

Gomez-Martinez C, Babio N, Julvez J, Becerra-Tomas N, Martinez-Gonzalez M, Corella D, Castaner O, Romaguera D, Vioque J, Alonso-Gomez A, Warnberg J, Martinez J, Serra-Majem L, Estruch R, Tinahones F, Lapetra J, Pinto X, Tur J, Lopez-Miranda J, Bueno-Cavanillas A, Gaforio J, Matia-Martin P, Daimiel L, Martin-Sanchez V, Vidal J, Vazquez C, Ros E, Dalsgaard S, Sayon-Orea C, Sorli J, de la Torre R, Abete I, Tojal-Sierra L, Baron-Lopez F, Fernandez-Brufal N, Konieczna J, Garcia-Rios A, Sacanella E, Bernal-Lopez M, Santos-Lozano J, Razquin C, Alvarez-Sala A, Goday A, Zulet M, Vaquero-Luna J, Diez-Espino J, Cuenca-Royo A, Fernandez-Aranda F, Bullo M, Salas-Salvado J, and PREDIMED-Plus Investigators

Subjects
insulin resistance, type 2 diabetes, prediabetes, diabetes duration, glycated (glycosylated) hemoglobin, cognitive function
Abstract

Introduction Type 2 diabetes has been linked to greater cognitive decline, but other glycemic parameters such as prediabetes, diabetes control and treatment, and HOMA-IR and HbA(1c) diabetes-related biomarkers have shown inconsistent results. Furthermore, there is limited research assessing these relationships in short-term studies. Thus, we aimed to examine 2-year associations between baseline diabetes/glycemic status and changes in cognitive function in older participants at high risk of cardiovascular disease. Methods We conducted a 2-year prospective cohort study (n=6,874) within the framework of the PREDIMED-Plus study. The participants (with overweight/obesity and metabolic syndrome; mean age 64.9 years; 48.5% women) completed a battery of 8 cognitive tests, and a global cognitive function Z-score (GCF) was estimated. At baseline, participants were categorized by diabetes status (no-diabetes, prediabetes, and = 5-year diabetes duration), and also by diabetes control. Furthermore, insulin resistance (HOMA-IR) and glycated hemoglobin (HbA(1c)) levels were measured, and antidiabetic medications were recorded. Linear and logistic regression models, adjusted by potential confounders, were fitted to assess associations between glycemic status and changes in cognitive function. Results Prediabetes status was unrelated to cognitive decline. However, compared to participants without diabetes, those with >= 5-year diabetes duration had greater reductions in GCF (beta=-0.11 (95%CI -0.16;-0.06)], as well as in processing speed and executive function measurements. Inverse associations were observed between baseline HOMA-IR and changes in GCF [beta=-0.0094 (95%CI -0.0164;-0.0023)], but also between HbA(1c) levels and changes in GCF [beta=-0.0085 (95%CI -0.0115, -0.0055)], the Mini-Mental State Examination, and other executive function tests. Poor diabetes control was inversely associated with phonologic fluency. The use of insulin treatment was inversely related to cognitive function as measured by the GCF [beta=-0.31 (95%CI -0.44, -0.18)], and other cognitive tests. Conclusions Insulin resistance, diabetes status, longer diabetes duration, poor glycemic control, and insulin treatment were associated with worsening cognitive function changes in the short term in a population at high cardiovascular risk.

Published
2021

20. Correction to:A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity (Acta Neuropathologica, (2019), 138, 2, (237-250), 10.1007/s00401-019-02026-8)

Author

van der Lee, Sven J., Conway, Olivia J., Jansen, Iris, Carrasquillo, Minerva M., Kleineidam, Luca, van den Akker, Erik, Hernández, Isabel, van Eijk, Kristel R., Stringa, Najada, Chen, Jason A., Zettergren, Anna, Andlauer, Till F.M., Diez-Fairen, Monica, Simon-Sanchez, Javier, Lleó, Alberto, Zetterberg, Henrik, Nygaard, Marianne, Blauwendraat, Cornelis, Savage, Jeanne E., Mengel-From, Jonas, Moreno-Grau, Sonia, Wagner, Michael, Fortea, Juan, Keogh, Michael J., Blennow, Kaj, Skoog, Ingmar, Friese, Manuel A., Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, de Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Tesi, Niccolo, Morris, Christopher M., Indakoetxea, Begoña, Collij, Lyduine E., Scherer, Martin, Morenas-Rodríguez, Estrella, Ironside, James W., van Berckel, Bart N.M., Alcolea, Daniel, Wiendl, Heinz, Strickland, Samantha L., Pastor, Pau, Rodríguez Rodríguez, Eloy, Mead, S., Synofzik, M., van Swieten, J. C., Leber, I., Ferrari, R., Hernandez, D. G., Nalls, M. A., Rohrer, J. D., Ramasamy, A., Kwok, J. B.J., Dobson-Stone, C., Schofield, P. R., Halliday, G. M., Hodges, J. R., Piguet, O., Bartley, L., Thompson, E., Borroni, B., Padovani, A., Cruchaga, C., Cairns, N. J., Benussi, L., Binetti, G., Ghidoni, R., Forloni, G., Albani, D., Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Blesa, R., Landqvist Waldö, M., Nilsson, K., Nilsson, C., Mackenzie, I. R.A., Hsiung, G. Y.R., Mann, D. M.A., Grafman, J., Morris, C. M., Attems, J., Griffiths, T. D., McKeith, I. G., Thomas, A. J., Pietrini, P., Huey, E. D., Wassermann, E. M., Baborie, A., Jaros, E., Tierney, M. C., Razquin, C., Ortega-Cubero, S., Alonso, E., Perneczky, R., Diehl-Schmid, J., Alexopoulos, P., Kurz, A., Rainero, I., Rubino, E., Pinessi, L., Rogaeva, E., St George-Hyslop, P., Rossi, G., Tagliavini, F., Giaccone, G., Rowe, J. B., Schlachetzki, J. C.M., Uphill, J., Collinge, J., Danek, A., Van Deerlin, V. M., Grossman, M., Trojanowski, J. Q., van der Zee, J., Van Broeckhoven, C., Cappa, S. F., Hannequin, D., Golfier, V., Vercelletto, M., Brice, A., Nacmias, B., Sorbi, S., Bagnoli, S., Piaceri, I., Nielsen, J. E., Hjermind, L. E., Riemenschneider, M., Mayhaus, M., Ibach, B., Gasparoni, G., Pichler, S., Gu, W., Rossor, M. N., Fox, N. C., Warren, J. D., Spillantini, M. G., Morris, H. R., Rizzu, P., Snowden, J. S., Rollinson, S., Richardson, A., Gerhard, A., Bruni, A. C., Maletta, R., Frangipane, F., Cupidi, C., Bernardi, L., Anfossi, M., Gallo, M., Conidi, M. E., Smirne, N., Baker, M., Josephs, K. A., Parisi, J. E., Seeley, W. W., Miller, B. L., Karydas, A. M., Rosen, H., Dopper, E. G.P., Seelaar, H., Logroscino, G., Capozzo, R., Novelli, V., Puca, A. A., Franceschi, M., Postiglione, A., Milan, G., Sorrentino, P., Kristiansen, M., Chiang, H. H., Graff, C., Pasquier, F., Rollin, A., Deramecourt, V., Lebouvier, T., Kapogiannis, D., Ferrucci, L., Pickering-Brown, S., Singleton, A. B., Hardy, J., Momeni, P., Boeve, Bradley F., Petersen, Ronald C., Ferman, Tanis J., van Gerpen, Jay A., Reinders, Marcel J.T., Uitti, Ryan J., Tárraga, Lluís, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, Boada, Mercè, Zettl, Uwe K., van Schoor, Natasja M., Beekman, Marian, Allen, Mariet, Masliah, Eliezer, de Munain, Adolfo López, Pantelyat, Alexander, Wszolek, Zbigniew K., Ross, Owen A., Dickson, Dennis W., Graff-Radford, Neill R., Knopman, David, Rademakers, Rosa, Lemstra, Afina W., Pijnenburg, Yolande A.L., Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F., Hemmer, Bernhard, Huisman, Martijn A., Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A., Sørensen, Thorkild I.A., Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, Coppola, G., Varpetian, A., Foroud, T. M., Levey, A. I., Kukull, W. A., Mendez, M. F., Ringman, J., Chui, H., Cotman, C., DeCarli, C., Geschwind, D. H., Clarimón, Jordi, Christensen, Kaare, Ertekin-Taner, Nilüfer, Scholz, Sonja W., Ramirez, Alfredo, Ruiz, Agustín, Slagboom, Eline, van der Flier, Wiesje M., and Holstege, Henne

Abstract

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.

Published
2020

21. Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity (Acta Neuropathologica, (2019), 138, 2, (237-250), 10.1007/s00401-019-02026-8)

Author

van der Lee, S. J., Conway, O. J., Jansen, I., Carrasquillo, M. M., Kleineidam, L., van den Akker, E., Hernandez, I., van Eijk, K. R., Stringa, N., Chen, J. A., Zettergren, A., Andlauer, T. F. M., Diez-Fairen, M., Simon-Sanchez, J., Lleo, A., Zetterberg, H., Nygaard, M., Blauwendraat, C., Savage, J. E., Mengel-From, J., Moreno-Grau, S., Wagner, M., Fortea, J., Keogh, M. J., Blennow, K., Skoog, I., Friese, M. A., Pletnikova, O., Zulaica, M., Lage, C., de Rojas, I., Riedel-Heller, S., Illan-Gala, I., Wei, W., Jeune, B., Orellana, A., Then Bergh, F., Wang, X., Hulsman, M., Beker, N., Tesi, N., Morris, C. M., Indakoetxea, B., Collij, L. E., Scherer, M., Morenas-Rodriguez, E., Ironside, J. W., van Berckel, B. N. M., Alcolea, D., Wiendl, H., Strickland, S. L., Pastor, P., Rodriguez Rodriguez, E., Mead, S., Synofzik, M., van Swieten, J. C., Leber, I., Ferrari, R., Hernandez, D. G., Nalls, M. A., Rohrer, J. D., Ramasamy, A., Kwok, J. B. J., Dobson-Stone, C., Schofield, P. R., Halliday, G. M., Hodges, J. R., Piguet, O., Bartley, L., Thompson, E., Borroni, B., Padovani, A., Cruchaga, C., Cairns, N. J., Benussi, L., Binetti, G., Ghidoni, R., Forloni, G., Albani, D., Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Blesa, R., Landqvist Waldo, M., Nilsson, K., Nilsson, C., Mackenzie, I. R. A., Hsiung, G. -Y. R., Mann, D. M. A., Grafman, J., Attems, J., Griffiths, T. D., Mckeith, I. G., Thomas, A. J., Pietrini, P., Huey, E. D., Wassermann, E. M., Baborie, A., Jaros, E., Tierney, M. C., Razquin, C., Ortega-Cubero, S., Alonso, E., Perneczky, R., Diehl-Schmid, J., Alexopoulos, P., Kurz, A., Rainero, I., Rubino, E., Pinessi, L., Rogaeva, E., St George-Hyslop, P., Rossi, G., Tagliavini, F., Giaccone, G., Rowe, J. B., Schlachetzki, J. C. M., Uphill, J., Collinge, J., Danek, A., Van Deerlin, V. M., Grossman, M., Trojanowski, J. Q., van der Zee, J., Van Broeckhoven, C., Cappa, S. F., Hannequin, D., Golfier, V., Vercelletto, M., Brice, A., Nacmias, B., Sorbi, S., Bagnoli, S., Piaceri, I., Nielsen, J. E., Hjermind, L. E., Riemenschneider, M., Mayhaus, M., Ibach, B., Gasparoni, G., Pichler, S., Gu, W., Rossor, M. N., Fox, N. C., Warren, J. D., Spillantini, M. G., Morris, H. R., Rizzu, P., Snowden, J. S., Rollinson, S., Richardson, A., Gerhard, A., Bruni, A. C., Maletta, R., Frangipane, F., Cupidi, C., Bernardi, L., Anfossi, M., Gallo, M., Conidi, M. E., Smirne, N., Baker, M., Josephs, K. A., Parisi, J. E., Seeley, W. W., Miller, B. L., Karydas, A. M., Rosen, H., Dopper, E. G. P., Seelaar, H., Logroscino, G., Capozzo, R., Novelli, V., Puca, A. A., Franceschi, M., Postiglione, A., Milan, G., Sorrentino, P., Kristiansen, M., Chiang, H. -H., Graff, C., Pasquier, F., Rollin, A., Deramecourt, V., Lebouvier, T., Kapogiannis, D., Ferrucci, L., Pickering-Brown, S., Singleton, A. B., Hardy, J., Momeni, P., Boeve, B. F., Petersen, R. C., Ferman, T. J., van Gerpen, J. A., Reinders, M. J. T., Uitti, R. J., Tarraga, L., Maier, W., Dols-Icardo, O., Kawalia, A., Dalmasso, M. C., Boada, M., Zettl, U. K., van Schoor, N. M., Beekman, M., Allen, M., Masliah, E., de Munain, A. L., Pantelyat, A., Wszolek, Z. K., Ross, O. A., Dickson, D. W., Graff-Radford, N. R., Knopman, D., Rademakers, R., Lemstra, A. W., Pijnenburg, Y. A. L., Scheltens, P., Gasser, T., Chinnery, P. F., Hemmer, B., Huisman, M. A., Troncoso, J., Moreno, F., Nohr, E. A., Sorensen, T. I. A., Heutink, P., Sanchez-Juan, P., Posthuma, D., Coppola, G., Varpetian, A., Foroud, T. M., Levey, A. I., Kukull, W. A., Mendez, M. F., Ringman, J., Chui, H., Cotman, C., Decarli, C., Geschwind, D. H., Clarimon, J., Christensen, K., Ertekin-Taner, N., Scholz, S. W., Ramirez, A., Ruiz, A., Slagboom, E., van der Flier, W. M., Holstege, H., Neurology, Epidemiology and Data Science, Human genetics, APH - Societal Participation & Health, APH - Aging & Later Life, Amsterdam Neuroscience - Complex Trait Genetics, APH - Personalized Medicine, and APH - Methodology

Subjects
education
Abstract

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.

Published
2020

22. Cross-sectional association between non-soy legume consumption, serum uric acid and hyperuricemia: the PREDIMED-Plus study

Author

Becerra-Tomas N, Mena-Sanchez G, Diaz-Lopez A, Martinez-Gonzalez M, Babio N, Corella D, Freixer G, Romaguera D, Vioque J, Alonso-Gomez A, Warnberg J, Martinez J, Serra-Majem L, Estruch R, Fernandez-Garcia J, Lapetra J, Pinto X, Tur J, Lopez-Miranda J, Bueno-Cavanillas A, Gaforio J, Matia-Martin P, Daimiel L, Martin-Sanchez V, Vidal J, Vazquez C, Ros E, Razquin C, Abellan Cano I, Sorli J, Torres L, Morey M, Navarrete-Munoz E, Tojal Sierra L, Crespo-Oliva E, Zulet M, Sanchez-Villegas A, Casas R, Bernal-Lopez M, Santos-Lozano J, Corbella E, Del Mar Bibiloni M, Ruiz-Canela M, Fernandez-Carrion R, Quifer M, Prieto R, Fernandez-Brufal N, Salaverria Lete I, Cenoz J, Llimona R, Salas-Salvado J, PREDIMED-Plus Investigators, and PREDIMED Study Investigators

Subjects
Serum uric acid, Non-soy legumes, PREDIMED-Plus, Hyperuricemia
Abstract

Purpose To assess the association between the consumption of non-soy legumes and different subtypes of non-soy legumes and serum uric acid (SUA) or hyperuricemia in elderly individuals with overweight or obesity and metabolic syndrome. Methods A cross-sectional analysis was conducted in the framework of the PREDIMED-Plus study. We included 6329 participants with information on non-soy legume consumption and SUA levels. Non-soy legume consumption was estimated using a semi-quantitative food frequency questionnaire. Linear regression models and Cox regression models were used to assess the associations between tertiles of non-soy legume consumption, different subtypes of non-soy legume consumption and SUA levels or hyperuricemia prevalence, respectively. Results Individuals in the highest tertile (T3) of total non-soy legume, lentil and pea consumption, had 0.14 mg/dL, 0.19 mg/dL and 0.12 mg/dL lower SUA levels, respectively, compared to those in the lowest tertile (T1), which was considered the reference one. Chickpea and dry bean consumption showed no association. In multivariable models, participants located in the top tertile of total non-soy legumes [prevalence ratio (PR): 0.89; 95% CI 0.82-0.97;ptrend = 0.01, lentils (PR: 0.89; 95% CI 0.82-0.97;ptrend = 0.01), dry beans (PR: 0.91; 95% C: 0.84-0.99;ptrend = 0.03) and peas (PR: 0.89; 95% CI 0.82-0.97;ptrend = 0.01)] presented a lower prevalence of hyperuricemia (vs. the bottom tertile). Chickpea consumption was not associated with hyperuricemia prevalence. Conclusions In this study of elderly subjects with metabolic syndrome, we observed that despite being a purine-rich food, non-soy legumes were inversely associated with SUA levels and hyperuricemia prevalence.

Published
2020

23. Association Between Lifestyle and Hypertriglyceridemic Waist Phenotype in the PREDIMED-Plus Study

Author

Fern?ndez-Garc?a, J, Mu?oz-Garach, A, Mart?nez-Gonz?lez, M, Salas-Salvado, J, Corella, D, Hern?ez, A, Romaguera, D, Vioque, J, Alonso-G?mez, A, W?rnberg, J, Mart?nez, J, Serra-Majem, L, Estruch, R, Lapetra, J, Pint?, X, Tur, J, Garcia-Rios, A, Molina, L, Gaforio, J, Mat?a-Mart?n, P, Daimiel, L, S?nchez, V, Vidal, J, Prieto, L, Ros, E, Go?i, N, Babio, N, Ortega-Azorin, C, Casta?er, O, Konieczna, J, Barandiaran, L, Vaquero-Luna, J, Benavente-Mar?n, J, Zulet, M, Sanchez-Villegas, A, Sacanella, E, Huelgas, R, Mir?-Moriano, L, Gimenez-Gracia, M, Julibert, A, Razquin, C, Basora, J, Portol?s, O, Goday, A, Galm?s-Panad?s, A, L?pez-Garc?a, C, Moreno-Rodriguez, A, Toledo, E, D?az-L?pez, A, Fit?, M, Tinahones, F, Bernal-L?pez, M, and PREDIMED-Plus Investigators

Abstract

OBJECTIVE: The hypertriglyceridemic waist (HTGW) phenotype is characterized by abdominal obesity and high levels of triglycerides. In a cross-sectional assessment of PREDIMED-Plus trial participants at baseline, HTGW phenotype prevalence was evaluated, associated risk factors were analyzed, and the lifestyle of individuals with metabolic syndrome and HTGW was examined. METHODS: A total of 6,874 individuals aged 55 to 75 with BMI = 27 and < 40 kg/m(2) were included and classified by presence (HTGW(+) ) or absence (HTGW(-) ) of HTGW (waist circumference: men = 102 cm, women = 88 cm; fasting plasma triglycerides = 150 mg/dL). Analytical parameters and lifestyle (energy intake and expenditure) were analyzed. RESULTS: A total of 38.2% of the sample met HTGW(+) criteria. HTGW(+) individuals tended to be younger, have a greater degree of obesity, be sedentary, and be tobacco users. They had higher peripheral glucose, total cholesterol, and low-density lipoprotein cholesterol levels; had lower high-density lipoprotein cholesterol levels; and had increased prevalence of type 2 diabetes mellitus. Mediterranean diet (MedDiet) adherence and physical activity were greater in HTGW(-) patients. Age, BMI, tobacco use, total energy expenditure, hypertension, type 2 diabetes mellitus, and MedDiet adherence were associated with HTGW(+) . CONCLUSIONS: HTGW is a highly prevalent phenotype in this population associated with younger age, higher BMI, tobacco use, and decreased MedDiet adherence. HTGW(-) individuals were more physically active with greater total physical activity, and fewer had hypertension.

Published
2020

24. Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

Author

van der Lee, Sven J, Conway, Olivia J, Zettergren, Anna, Christensen, Kaare, Ertekin-Taner, Nilüfer, Scholz, Sonja W, Ramirez, Alfredo, Ruiz, Agustín, Slagboom, Eline, van der Flier, Wiesje M, Holstege, Henne, Mead, S., Synofzik, M., Andlauer, Till F M, van Swieten, J. C., Leber, I., Ferrari, R., Hernandez, D. G., Nalls, M. A., Rohrer, J. D., Ramasamy, A., Kwok, J. B. J., Dobson-Stone, C., Schofield, P. R., Diez-Fairen, Monica, Halliday, G. M., Hodges, J. R., Piguet, O., Bartley, L., Thompson, E., Borroni, B., Padovani, A., Cruchaga, C., Cairns, N. J., Benussi, L., Simon-Sanchez, Javier, Binetti, G., Ghidoni, R., Forloni, G., Albani, D., Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Blesa, R., Landqvist Waldö, M., Lleó, Alberto, Nilsson, K., Nilsson, C., Mackenzie, I. R. A., Hsiung, G-Y R, Mann, D. M. A., Grafman, J., Morris, C. M., Attems, J., Griffiths, T. D., McKeith, I. G., Zetterberg, Henrik, Thomas, A. J., Pietrini, P., Huey, E. D., Wassermann, E. M., Baborie, A., Jaros, E., Tierney, M. C., Razquin, C., Ortega-Cubero, S., Alonso, E., Nygaard, Marianne, Perneczky, R., Diehl-Schmid, J., Alexopoulos, P., Kurz, A., Rainero, I., Rubino, E., Pinessi, L., Rogaeva, E., St George-Hyslop, P., Rossi, G., Blauwendraat, Cornelis, Tagliavini, F., Giaccone, G., Rowe, J. B., Schlachetzki, J. C. M., Uphill, J., Collinge, J., Danek, A., Van Deerlin, V. M., Grossman, M., Trojanowski, J. Q., Savage, Jeanne E, van der Zee, J., Van Broeckhoven, C., Cappa, S. F., Hannequin, D., Golfier, V., Vercelletto, M., Brice, A., Nacmias, B., Sorbi, S., Bagnoli, S., Mengel-From, Jonas, Piaceri, I., Nielsen, J. E., Hjermind, L. E., Riemenschneider, M., Mayhaus, M., Ibach, B., Gasparoni, G., Pichler, S., Gu, W., Rossor, M. N., Jansen, Iris, Moreno-Grau, Sonia, Fox, N. C., Warren, J. D., Spillantini, M. G., Morris, H. R., Rizzu, P., Snowden, J. S., Rollinson, S., Richardson, A., Gerhard, A., Bruni, A. C., Wagner, Michael, Maletta, R., Frangipane, F., Cupidi, C., Bernardi, L., Anfossi, M., Gallo, M., Conidi, M. E., Smirne, N., Baker, M., Josephs, K. A., Fortea, Juan, Parisi, J. E., Seeley, W. W., Miller, B. L., Karydas, A. M., Rosen, H., Dopper, E. G. P., Seelaar, H., Logroscino, G., Capozzo, R., Novelli, V., Keogh, Michael J, Puca, A. A., Franceschi, M., Postiglione, A., Milan, G., Sorrentino, P., Kristiansen, M., Chiang, H-H, Graff, C., Pasquier, F., Rollin, A., Blennow, Kaj, Deramecourt, V., Lebouvier, T., Kapogiannis, D., Ferrucci, L., Pickering-Brown, S., Singleton, A. B., Hardy, J., Momeni, P., Coppola, G., Skoog, Ingmar, Varpetian, A., Foroud, T. M., Levey, A. I., Kukull, W. A., Mendez, M. F., Ringman, J., Chui, H., Cotman, C., DeCarli, C., Friese, Manuel A, Geschwind, D. H., Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, Carrasquillo, Minerva M, de Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Kleineidam, Luca, Tesi, Niccolo, Morris, Christopher M, Indakoetxea, Begoña, Collij, Lyduine E, Scherer, Martin, Morenas-Rodríguez, Estrella, Ironside, James W, van Berckel, Bart N M, Alcolea, Daniel, Wiendl, Heinz, van den Akker, Erik, Strickland, Samantha L, Pastor, Pau, Rodríguez Rodríguez, Eloy, DESGESCO, EADB, IFGC, IPDGC, RiMod-FTD, Bank, Netherlands Brain, Boeve, Bradley F, Hernández, Isabel, Petersen, Ronald C, Ferman, Tanis J, van Gerpen, Jay A, Reinders, Marcel J T, Uitti, Ryan J, Tárraga, Lluís, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, van Eijk, Kristel R, Boada, Mercè, Zettl, Uwe K, van Schoor, Natasja M, Beekman, Marian, Allen, Mariet, Masliah, Eliezer, de Munain, Adolfo López, Pantelyat, Alexander, Wszolek, Zbigniew K, Ross, Owen A, Stringa, Najada, Dickson, Dennis W, Graff-Radford, Neill R, Knopman, David, Rademakers, Rosa, Lemstra, Afina W, Pijnenburg, Yolande A L, Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F, Hemmer, Bernhard, Chen, Jason A, Huisman, Martijn A, Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A, Sørensen, Thorkild I A, Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, GIFT, and Clarimón, Jordi

Subjects
0301 basic medicine, Dementia with Lewy bodies, Disease, Bioinformatics, Neurodegenerative disease, 0302 clinical medicine, Missense mutation, media_common, 2. Zero hunger, Longevity, Brain, Parkinson Disease, Phospholipase C Gamma 2, Biobank, 3. Good health, ddc, Frontotemporal Dementia, Microglia, Alzheimer's disease, Alzheimer’s disease, Amyotrophic lateral sclerosis, Frontotemporal dementia, Multiple sclerosis, PLCG2, Parkinson’s disease, Progressive supranuclear palsy, Lewy Body Disease, Risk, Multiple Sclerosis, media_common.quotation_subject, education, Neuroimaging, Genomics, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, SDG 3 - Good Health and Well-being, Alzheimer Disease, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Alleles, Phospholipase C gamma, business.industry, Amyotrophic Lateral Sclerosis, Correction, medicine.disease, 030104 developmental biology, Mutation, Dementia, Neurology (clinical), business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target. The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.

Published
2019

26. genuMet: distinguish genuine untargeted metabolic features without quality control samples

Author

Cao, L, primary, Clish, C, additional, Hu, FB, additional, Martínez-González, MA, additional, Razquin, C, additional, Bullo-Bonet, M, additional, Corella, D, additional, Gómez-Gracia, E, additional, Fiol, M, additional, Estruch, R, additional, Lapetra, J, additional, Fitó, M, additional, Arós, F, additional, Serra-Majem, L, additional, Ros, E, additional, and Liang, L, additional

Published
2019
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28. Validation study of a Spanish version of the modified Telephone Interview for Cognitive Status (STICS-m)

Author

Muñoz-García, M.I. (Mariana Isabel), Cervantes-Ibáñez, S. (Sebastián), Razquin, C. (Cristina), Guillen-Grima, F. (Francisco), Toledo, J.B. (J.B.), Martinez-Gonzalez, M.A. (Miguel Ángel), and Toledo, E. (Estefanía)

Subjects
Status, Español, Entrevista telefónica para estatus cognitivo, Demencia, Dementia, Spanish, Modified telephone Interview for cognitive
Abstract

Objective To compare the Spanish version of the modified Telephone Interview of Cognitive Status (STICS-m) with the Mini-Mental State Examination (MMSE) and predict its ability to detect the development of dementia. Method 106 participants in a dietary intervention trial underwent face-to-face evaluation with the MMSE, and phone interview with the STICS-m. The correlation between STICS-m and MMSE was assessed with the intraclass correlation coefficient (ICC) of consistency. Secondly, 932 participants over 55 years old from the “Seguimiento Universidad de Navarra” cohort were evaluated with the STICS-m and data on dementia diagnosis were gathered (median follow-up time of 6.5 years). A logistic regression model evaluated the association between STICS-m score or 2-year changes in STICS-m score and risk of developing dementia, adjusting for ApoE, age and years of university education. Results The ICC between the MMSE and the STICS-m was 0.31 (95% confidence interval [95%CI]: 0.13-0.48). The adjusted odds ratio (OR) for the development of dementia for each additional point in the baseline STICS-m score was 0.85 (95%CI: 0.72-1.02; p = 0.084). When considering the 2-year change in the STICS-m score as exposure, the OR for the development of dementia was 0.79 (95%CI: 0.67-0.93; p = 0.006). Conclusions The weak correlation between the STICS-m and the MMSE reflects moderate-low concurrent validity. Even so, the STICS-m can be regarded as an useful tool in the epidemiological setting since increasing scores appear to be able to predict a lower risk of developing dementia. Objetivo Estudiar la correlación de la Telephone Interview for Cognitive Status modificada en español (STICS-m) con el Mini-Mental State Examination (MMSE) y predecir la capacidad de la primera para detectar el desarrollo de demencia. Método Ciento seis sujetos de un estudio de intervención dietética fueron evaluados personalmente con el MMSE y por teléfono con la STICS-m. La correlación entre ambos se midió con el coeficiente de correlación intraclase (CCI) de consistencia. Además, 932 participantes mayores de 55 años de la cohorte “Seguimiento Universidad de Navarra” fueron evaluados con la STICS-m. Durante una mediana de seguimiento de 6,5 años, se recogió información sobre el desarrollo de demencia. Mediante regresión logística se estudió la asociación entre la puntuación de la STICS-m o el cambio a 2 años en la puntuación y el riesgo de desarrollar demencia, ajustando por apolipoproteína E, edad y años de educación universitaria. Resultados El CCI entre el MMSE y la STICS-m fue de 0,31 (intervalo de confianza del 95% [IC95%]: 0,13-0,48). La odds ratio (OR) ajustada para el desarrollo de demencia para cada punto adicional en la puntuación basal de la STICS-m fue de 0,85 (IC95%: 0,72-1,02; p = 0,084). Al considerar el cambio en la puntuación a los 2 años como variable independiente, la OR fue de 0,79 (IC95%: 0,67-0,93; p = 0,006). Conclusiones La correlación débil entre la STICS-m y el MMSE refleja solo una moderada-baja validez concurrente. Aun así, la STICS-m puede considerarse útil en el contexto epidemiológico, ya que aumentos en la puntuación parecen predecir un menor riesgo de desarrollar demencia.

Published
2019

29. Sugar-sweetened and artificially-sweetened beverages and changes in cognitive function in the SUN project

Author

Muñoz-García MI, Martínez-González MA, Martín-Moreno JM, Razquin C, Cervantes S, Guillén-Grima F, and Toledo E

Subjects
skin and connective tissue diseases
Abstract

BACKGROUND: Sugar-sweetened beverages (SSB) and artificially-sweetened beverages (ASB) have been inconsistently associated with declines in cognitive function. Because of their low caloric content and replacement of sugar, ASB are often seen as 'healthy' alternatives to SSB. OBJECTIVE: We longitudinally assessed the association between the consumption of SSB or ASB and cognitive function. DESIGN: A subsample of the 'Seguimiento Universidad de Navarra' (SUN) cohort of university graduates aged over 55 years old was evaluated with the Spanish Telephone Interview for Cognitive Status (STICS-m) at two-time points, separated by 6 years. Consumption of SSB and ASB was appraised using a validated food-frequency questionnaire. Linear regression models were fitted, adjusting for potential confounders, including cardiometabolic variables, with the change in the STICS-m score at year 6 as the dependent variable. RESULTS: A significant association between the consumption of SSB and changes in cognitive function as measured by the STICS-m was observed in the total sample, with a change of -0.43 (95% CI -0.85, -0.02, p=0.04) in those that consumed >1 beverage/month compared to never/seldom consumers. The association was not significant for the consumption of ASB, but point estimates showed negative values, suggesting declines in cognition. CONCLUSIONS: Only the consumption of SSB, but not ASB, was significantly associated with a decline in cognitive function after 6 years. Further longitudinal studies are needed to explore the relationship between these beverages and cognitive function and the potential mechanisms through which they might be harmful.

Published
2019

30. Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia

Author

Bonham, L.W., Steele, N.Z.R., Karch, C.M., Broce, I., Geier, E.G., Wen, N.L., Momeni, P., Hardy, J., Miller, Z.A., Gorno-Tempini, M.L., Hess, C.P., Lewis, P., Miller, B.L., Seeley, W.W., Manzoni, C., Desikan, R.S., Baranzini, S.E., Ferrari, R., Yokoyama, J.S., Hernandez, D.G., Nalls, M.A., Rohrer, J.D., Ramasamy, A., Kwok, J.B.J., Dobson-Stone, C., Schofield, P.R., Halliday, G.M., Hodges, J.R., Piguet, O., Bartley, L., Thompson, E., Haan, E., Hernández, Isabel, Ruiz, A., Boada, M., Borroni, B., Padovani, A., Cruchaga, C., Cairns, N.J., Benussi, L., Binetti, G., Ghidoni, R., Forloni, G., Albani, Diego, Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Clarimón, J., Lleó, Alberto, Blesa, R., Landqvist Waldö, M., Nilsson, K., Nilsson, C., Mackenzie, I.R.A., Hsiung, G.Y.R., Mann, D.M.A., Grafman, J., Morris, C.M., Attems, J., Griffiths, T.D., McKeith, I.G., Thomas, A.J., Pietrini, P., Huey, E.D., Wassermann, E.M., Baborie, A., Jaros, E., Tierney, M.C., Pastor, Pau, Razquin, C., Ortega-Cubero, S., Alonso, E., Perneczky, R., Diehl-Schmid, J., Alexopoulos, P., Kurz, A., Rainero, I., Rubino, E., Pinessi, L., Rogaeva, E., St George-Hyslop, P., Rossi, G., Tagliavini, F., Giaccone, G., Rowe, J.B., Schlachetzki, J.C.M., Uphill, J., Collinge, J., Mead, S., Danek, A., Van Deerlin, V.M., Grossman, M., Trojanowski, J.Q., van der Zee, J., Cruts, M., Van Broeckhoven, C., Cappa, S.F., Leber, I., Hannequin, D., Golfier, V., Vercelletto, M., Brice, A., Nacmias, B., Sorbi, Sandro, Bagnoli, S., Piaceri, I., Nielsen, J.E., Hjermind, L.E., Riemenschneider, M., Mayhaus, M., Ibach, B., Gasparoni, G., Pichler, S., Gu, W., Rossor, M.N., Fox, N.C., Warren, J.D., Spillantini, M.G., Morris, H.R., Rizzu, P., Heutink, P., Snowden, J.S., Rollinson, S., Richardson, A., Gerhard, A., Bruni, A.C., Maletta, R., Frangipane, F., Cupidi, C., Bernardi, L., Anfossi, M., Gallo, M., Conidi, M.E., Smirne, N., Rademakers, R., Baker, M., Dickson, Dennis W., Graff-Radford, N.R., Petersen, R.C., Knopman, D., Josephs, K.A., Boeve, B.F., Parisi, J.E., Karydas, A.M., Rosen, H., van Swieten, J.C., Dopper, E.G.P., Seelaar, H., Pijnenburg, Y.A.L., Scheltens, Philip, Logroscino, G., Capozzo, R., Novelli, V., Puca, A.A., Franceschi, M., Postiglione, A., Milan, G., Sorrentino, P., Kristiansen, M., Chiang, H.H., Graff, C., Pasquier, F., Rollin, A., Deramecourt, V., Lebouvier, T., Kapogiannis, D., Ferrucci, L., Pickering-Brown, S., Singleton, A.B., Universitat Autònoma de Barcelona, Broce, Iris [0000-0003-4932-1430], Miller, Zachary A. [0000-0002-5991-3053], Lewis, Patrick [0000-0003-4537-0489], Baranzini, Sergio E. [0000-0003-0067-194X], Apollo - University of Cambridge Repository, Int FTD-Genomics Consortium, Neurology, Amsterdam Neuroscience - Neurodegeneration, Divisions, and CCA - Imaging and biomarkers

Subjects
0301 basic medicine, Aging, Transcription, Genetic, Gene regulatory network, lcsh:Medicine, Genome-wide association study, Apoptosis, Neurodegenerative, Primary progressive aphasia, Cohort Studies, 0302 clinical medicine, 692/617/375/132, Risk Factors, Databases, Genetic, 2.1 Biological and endogenous factors, Gene Regulatory Networks, Protein Interaction Maps, Aetiology, lcsh:Science, Multidisciplinary, Neurodegeneration, Neurodegenerative diseases, article, Frontotemporal lobar degeneration, 631/208/205, Single Nucleotide, Phenotype, ddc, 3. Good health, DNA-Binding Proteins, Frontotemporal Dementia (FTD), 692/617/375/365, Neurological, Medical genetics, 38/39, Engineering sciences. Technology, Transcription, Biotechnology, medicine.medical_specialty, Computational biology, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Databases, Rare Diseases, Genetic, medicine, Aphasia, Acquired Cognitive Impairment, Genetics, Humans, Primary Progressive Nonfluent Aphasia, Polymorphism, Gene, Genetic association study, International FTD-Genomics Consortium, lcsh:R, Human Genome, Neurosciences, medicine.disease, Brain Disorders, 631/208/199, 030104 developmental biology, Gene Expression Regulation, RNA, lcsh:Q, Dementia, Gene expression, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA’s relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify and characterize protein interaction networks associated with svPPA risk. We identified 64 svPPA risk genes that interact at the protein level. The protein pathways represented in this svPPA gene network are critical regulators of RNA metabolism and cell death, such as SMAD proteins and NOTCH1. Many of the genes in this network are involved in TDP-43 metabolism. Contrary to the conventional notion that svPPA is a clinical syndrome with few genetic risk factors, our analyses show that svPPA risk is complex and polygenic in nature. Risk for svPPA is likely driven by multiple common variants in genes interacting with TDP-43, along with cell death,x` working in combination to promote neurodegeneration.

Published
2019

32. CXCR4involvement in neurodegenerative diseases

Author

Bonham, Luke W, Karch, Celeste M, Ferrari, Raffaele, Danek, A., Van Deerlin, V. M., Grossman, M., Trojanowski, J. Q., van der Zee, J., Cruts, M., Van Broeckhoven, C., Cappa, S. F., Leber, I., Hannequin, D., Hardy, John, Golfier, V., Vercelletto, M., Brice, A., Nacmias, B., Sorbi, S., Bagnoli, S., Piaceri, I., Nielsen, J. E., Hjermind, L. E., Riemenschneider, M., Momeni, Parastoo, Mayhaus, M., Ibach, B., Gasparoni, G., Pichler, S., Gu, W., Rossor, M. N., Fox, N. C., Warren, J. D., Spillantini, M. G., Morris, H. R., Höglinger, Günter, Rizzu, P., Heutink, P., Snowden, J. S., Rollinson, S., Richardson, A., Gerhard, A., Bruni, A. C., Maletta, R., Frangipane, F., Cupidi, C., Müller, Ulrich, Bernardi, L., Anfossi, M., Gallo, M., Conidi, M. E., Smirne, N., Rademakers, R., Baker, M., Dickson, D. W., Graff-Radford, N. R., Petersen, R. C., Hess, Christopher P, Knopman, D., Josephs, K. A., Boeve, B. F., Parisi, J. E., Seeley, W. W., Miller, B. L., Karydas, A. M., Rosen, H., van Swieten, J. C., Dopper, E. G. P., Sugrue, Leo P, Seelaar, H., Pijnenburg, Y. A. L., Scheltens, P., Logroscino, G., Capozzo, R., Novelli, V., Puca, A. A., Franceschi, M., Postiglione, A., Milan, G., Dillon, William P, Sorrentino, P., Kristiansen, M., Chiang, H-H, Graff, C., Pasquier, F., Rollin, A., Deramecourt, V., Lebouvier, T., Kapogiannis, D., Ferrucci, L., Schellenberg, Gerard D, Pickering-Brown, S., Singleton, A. B., Hardy, J., Momeni, P., Miller, Bruce L, Fan, Chun C, Andreassen, Ole A, Dale, Anders M, Barkovich, A James, Yokoyama, Jennifer S, Desikan, Rahul S, Consortium, International FTD-Genomics, Consortium, International Parkinson’s Disease Genetics, Project, International Genomics of Alzheimer’s, Ferrari, R., Hernandez, D. G., Tan, Chin, Nalls, M. A., Rohrer, J. D., Ramasamy, A., Kwok, J. B. J., Dobson-Stone, C., Schofield, P. R., Halliday, G. M., Hodges, J. R., Piguet, O., Bartley, L., Geier, Ethan G, Thompson, E., Haan, E., Hernández, I., Ruiz, A., Boada, M., Borroni, B., Padovani, A., Cruchaga, C., Cairns, N. J., Benussi, L., Wang, Yunpeng, Binetti, G., Ghidoni, R., Forloni, G., Albani, D., Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Clarimón, J., Lleó, A., Wen, Natalie, Blesa, R., Waldö, M Landqvist, Nilsson, K., Nilsson, C., Mackenzie, I. R. A., Hsiung, G-Y R, Mann, D. M. A., Grafman, J., Morris, C. M., Attems, J., Broce, Iris J, Griffiths, T. D., McKeith, I. G., Thomas, A. J., Pietrini, P., Huey, E. D., Wassermann, E. M., Baborie, A., Jaros, E., Tierney, M. C., Pastor, P., Li, Yi, Razquin, C., Ortega-Cubero, S., Alonso, E., Perneczky, R., Diehl-Schmid, J., Alexopoulos, P., Kurz, A., Rainero, I., Rubino, E., Pinessi, L., Barkovich, Matthew J, Rogaeva, E., George-Hyslop, P St, Rossi, G., Tagliavini, F., Giaccone, G., Rowe, J. B., Schlachetzki, J. C. M., Uphill, J., Collinge, J., Mead, S., Bonham, Luke W., Karch, Celeste M., Fan, Chun C., Tan, Chin, Geier, Ethan G., Wang, Yunpeng, Wen, Natalie, Broce, Iris J., Li, Yi, Barkovich, Matthew J., Ferrari, Raffaele, Hardy, John, Momeni, Parastoo, Höglinger, Günter, Müller, Ulrich, Hess, Christopher P., Sugrue, Leo P., Dillon, William P., Schellenberg, Gerard D., Miller, Bruce L., Andreassen, Ole A., Dale, Anders M., Barkovich, A. Jame, Yokoyama, Jennifer S., Desikan, Rahul S., Hernandez, D. G., Nalls, M. A., Rohrer, J. D., Ramasamy, A., Kwok, J. B. J., Dobson-Stone, C., Schofield, P. R., Halliday, G. M., Hodges, J. R., Piguet, O., Bartley, L., Thompson, E., Haan, E., Hernández, I., Ruiz, A., Boada, M., Borroni, B., Padovani, A., Cruchaga, C., Cairns, N. J., Benussi, L., Binetti, G., Ghidoni, R., Forloni, G., Albani, D., Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Clarimón, J., Lleó, A., Blesa, R., Waldö, M. Landqvist., Nilsson, K., Nilsson, C., Mackenzie, I. R. A., Hsiung, G. -Y. R., Mann, D. M. A., Grafman, J., Morris, C. M., Attems, J., Griffiths, T. D., Mckeith, I. G., Thomas, A. J., Pietrini, P., Huey, E. D., Wassermann, E. M., Baborie, A., Jaros, E., Tierney, M. C., Pastor, P., Razquin, C., Ortega-Cubero, S., Alonso, E., Perneczky, R., Diehl-Schmid, J., Alexopoulos, P., Kurz, A., Rainero, I., Rubino, E., Pinessi, L., Rogaeva, E., George-Hyslop, P. St., Rossi, G., Tagliavini, F., Giaccone, G., Rowe, J. B., Schlachetzki, J. C. M., Uphill, J., Collinge, J., Mead, S., Danek, A., Van Deerlin, V. M., Grossman, M., Trojanowski, J. Q., Van Der Zee, J., Cruts, M., Van Broeckhoven, C., Cappa, S. F., Leber, I., Hannequin, D., Golfier, V., Vercelletto, M., Brice, A., Nacmias, B., Sorbi, S., Bagnoli, S., Piaceri, I., Nielsen, J. E., Hjermind, L. E., Riemenschneider, M., Mayhaus, M., Ibach, B., Gasparoni, G., Pichler, S., Gu, W., Rossor, M. N., Fox, N. C., Warren, J. D., Spillantini, M. G., Morris, H. R., Rizzu, P., Heutink, P., Snowden, J. S., Rollinson, S., Richardson, A., Gerhard, A., Bruni, A. C., Maletta, R., Frangipane, F., Cupidi, C., Bernardi, L., Anfossi, M., Gallo, M., Conidi, M. E., Smirne, N., Rademakers, R., Baker, M., Dickson, D. W., Graff-Radford, N. R., Petersen, R. C., Knopman, D., Josephs, K. A., Boeve, B. F., Parisi, J. E., Seeley, W. W., Karydas, A. M., Rosen, H., Van Swieten, J. C., Dopper, E. G. P., Seelaar, H., Pijnenburg, Y. A. L., Scheltens, P., Logroscino, G., Capozzo, R., Novelli, V., Puca, A. A., Franceschi, M., Postiglione, A., Milan, G., Sorrentino, P., Kristiansen, M., Chiang, H. -H., Graff, C., Pasquier, F., Rollin, A., Deramecourt, V., Lebouvier, T., Kapogiannis, D., Ferrucci, L., Pickering-Brown, S., Singleton, A. B., Rademakers, Rosa, International FTD-Genomics Consortium (IFGC), International Parkinsons Disease Genetics Consortium (IPDGC), and International Genomics of Alzheimers Project (IGAP)

Subjects
0301 basic medicine, Aging, Gene Expression, Genome-wide association study, metabolism [Microglia], Neurodegenerative, Bioinformatics, Alzheimer's Disease, Transgenic, Mice, 0302 clinical medicine, Risk Factors, Receptors, 2.1 Biological and endogenous factors, Psychology, Gene Regulatory Networks, Aetiology, Alzheimer's Disease Related Dementias (ADRD), 0303 health sciences, Gene Regulatory Network, Parkinson's Disease, International Genomics of Alzheimer’s Project, Neurodegeneration, Brain, Neurodegenerative Diseases, Single Nucleotide, International Parkinson’s Disease Genetics Consortium, Frontotemporal Dementia (FTD), Psychiatry and Mental Health, Neurological, Public Health and Health Services, Tauopathy, Microglia, Frontotemporal dementia, Human, Receptors, CXCR4, Tau protein, Clinical Sciences, Mice, Transgenic, Computational biology, Biology, Polymorphism, Single Nucleotide, Article, CXCR4 protein, human, Progressive supranuclear palsy, lcsh:RC321-571, Cellular and Molecular Neuroscience, 03 medical and health sciences, Rare Diseases, Text mining, Genetic predisposition, medicine, Genetics, Acquired Cognitive Impairment, Animals, Humans, Genetic Predisposition to Disease, ddc:610, Polymorphism, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, 030304 developmental biology, CXCR4, Neurodegenerative Disease, Animal, business.industry, Risk Factor, International FTD-Genomics Consortium, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), medicine.disease, genetics [Receptors, CXCR4], Brain Disorders, Genome-Wide Association Study, 030104 developmental biology, metabolism [Brain], genetics [Neurodegenerative Diseases], Expression quantitative trait loci, biology.protein, Dementia, Human medicine, metabolism [Receptors, CXCR4], business, 030217 neurology & neurosurgery
Abstract

Neurodegenerative diseases likely share common underlying pathobiology. Although prior work has identified susceptibility loci associated with various dementias, few, if any, studies have systematically evaluated shared genetic risk across several neurodegenerative diseases. Using genome-wide association data from large studies (total n = 82,337 cases and controls), we utilized a previously validated approach to identify genetic overlap and reveal common pathways between progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), Parkinson’s disease (PD) and Alzheimer’s disease (AD). In addition to the MAPT H1 haplotype, we identified a variant near the chemokine receptor CXCR4 that was jointly associated with increased risk for PSP and PD. Using bioinformatics tools, we found strong physical interactions between CXCR4 and four microglia related genes, namely CXCL12, TLR2, RALB, and CCR5. Evaluating gene expression from post-mortem brain tissue, we found that expression of CXCR4 and microglial genes functionally related to CXCR4 was dysregulated across a number of neurodegenerative diseases. Furthermore, in a mouse model of tauopathy, expression of CXCR4 and functionally associated genes was significantly altered in regions of the mouse brain that accumulate neurofibrillary tangles most robustly. Beyond MAPT, we show dysregulation of CXCR4 expression in PSP, PD, and FTD brains, and mouse models of tau pathology. Our multi-modal findings suggest that abnormal signaling across a ‘network’ of microglial genes may contribute to neurodegeneration and may have potential implications for clinical trials targeting immune dysfunction in patients with neurodegenerative diseases.

Published
2017

33. Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer’s and Parkinson’s diseases

Author

Ferrari R, Wang Y, Vandrovcova J, Guelfi S, Witeolar A, Karch CM, Schork AJ, Fan CC, Brewer JB, International FTD-Genomics Consortium (IFGC), International Parkinson's Disease Genomics Consortium (IPDGC), International Genomics of Alzheimer's Project (IGAP), Momeni P, Schellenberg GD, Dillon WP, Sugrue LP, Hess CP, Yokoyama JS, Bonham LW, Rabinovici GD, Miller BL, Andreassen OA, Dale AM, Hardy J, Desikan RS, Collaborators: Ferrari R, Hernandez DG, Nalls MA, Rohrer JD, Ramasamy A, Kwok JBJ, Dobson-Stone C, Schofield PR, Halliday GM, Hodges JR, Piguet O, Bartley L, Thompson E, Haan E, Hernández I, Ruiz A, Boada M, Borroni B, Padovani A, Cruchaga C, Cairns NJ, Benussi L, Binetti G, Ghidoni R, Forloni G, Albani D, Galimberti D, Fenoglio C, Serpente M, Scarpini E, Clarimón J, Lleó A, Blesa R, Landqvist Waldö M, Nilsson C, Mackenzie IRA, Hsiung GYR, Mann DMA, Grafman J, Morris CM, Attems J, Griffiths TD, McKeith IG, Thomas AJ, Pietrini P, Huey ED, Wassermann EM, Baborie A, Jaros E, Tierney MC, Pastor P, Razquin C, Ortega-Cubero S, Alonso E, Perneczky R, Diehl-Schmid J, Alexopoulos P, Kurz A, Rainero I, Rubino E, Pinessi L, Rogaeva E, St George-Hyslop P, Rossi G, Tagliavini F, Giaccone G, Rowe JB, Schlachetzki JCM, Uphill J, Collinge J, Mead S, Danek A, Van Deerlin VM, Grossman M, Trojanowski JQ, van der Zee J, Cruts M, Van Broeckhoven C, Cappa SF, Leber I, Hannequin D, Golfier V, Vercelletto M, Brice A, Nacmias B, Sorbi S, Bagnoli S, Piaceri I, Nielsen JE, Hjermind LE, Riemenschneider M, Mayhaus M, Ibach B, Gasparoni G, Pichler S, Gu W, Rossor MN, Fox NC, Warren JD, Spillantini MG, Morris HR, Rizzu P, Heutink P, Snowden JS, Rollinson S, Richardson A, Gerhard A, Bruni AC, Maletta R, Frangipane F, Cupidi C, Bernardi L, Anfossi M, Gallo M, Conidi ME, Smirne N, Rademakers R, Baker M, Dickson DW, Graff-Radford NR, Petersen RC, Knopman D, Josephs KA, Boeve BF, Parisi JE, Seeley WW, Karydas AM, Rosen H, van Swieten JC, Dopper EG, Seelaar H, Pijnenburg YAL, Scheltens P, Logroscino G, Capozzo R, Novelli V, Puca AA, Franceschi M, Postiglione A, Milan G, Sorrentino P, Kristiansen M, Chiang HH, Graff C, Pasquier F, Rollin A, Deramecourt V, Lebouvier T, Kapogiannis D, Ferrucci L, Pickering-Brown S, Singleton AB, Momeni P., Neurology, VU University medical center, Human genetics, Amsterdam Neuroscience - Neurodegeneration, CCA - Imaging and biomarkers, Divisions, Van Broeckhoven, Christine, Rademakers, Rosa, International FTD-Genomics Consortium (IFGC), International Parkinson's Disease Genomics Consortium (IPDGC), International Genomics of Alzheimer's Project (IGAP), Ferrari, R, Wang, Y, Vandrovcova, J, Guelfi, S, Witeolar, A, Karch, Cm, Schork, Aj, Fan, Cc, Brewer, Jb, International FTD-Genomics Consortium, (IFGC), International Parkinson's Disease Genomics Consortium, (IPDGC), International Genomics of Alzheimer's Project, (IGAP), Momeni, P, Schellenberg, Gd, Dillon, Wp, Sugrue, Lp, Hess, Cp, Yokoyama, J, Bonham, Lw, Rabinovici, Gd, Miller, Bl, Andreassen, Oa, Dale, Am, Hardy, J, Desikan, R, Collaborators: Ferrari, R, Hernandez, Dg, Nalls, Ma, Rohrer, Jd, Ramasamy, A, Kwok, Jbj, Dobson-Stone, C, Schofield, Pr, Halliday, Gm, Hodges, Jr, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, Nj, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Landqvist Waldö, M, Nilsson, C, Mackenzie, Ira, Hsiung, Gyr, Mann, Dma, Grafman, J, Morris, Cm, Attems, J, Griffiths, Td, Mckeith, Ig, Thomas, Aj, Pietrini, P, Huey, Ed, Wassermann, Em, Baborie, A, Jaros, E, Tierney, Mc, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, St George-Hyslop, P, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, Jb, Schlachetzki, Jcm, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin, Vm, Grossman, M, Trojanowski, Jq, van der Zee, J, Cruts, M, Van Broeckhoven, C, Cappa, Sf, Leber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, Je, Hjermind, Le, Riemenschneider, M, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, Rossor, Mn, Fox, Nc, Warren, Jd, Spillantini, Mg, Morris, Hr, Rizzu, P, Heutink, P, Snowden, J, Rollinson, S, Richardson, A, Gerhard, A, Bruni, Ac, Maletta, R, Frangipane, F, Cupidi, C, Bernardi, L, Anfossi, M, Gallo, M, Conidi, Me, Smirne, N, Rademakers, R, Baker, M, Dickson, Dw, Graff-Radford, Nr, Petersen, Rc, Knopman, D, Josephs, Ka, Boeve, Bf, Parisi, Je, Seeley, Ww, Karydas, Am, Rosen, H, van Swieten, Jc, Dopper, Eg, Seelaar, H, Pijnenburg, Yal, Scheltens, P, Logroscino, G, Capozzo, R, Novelli, V, Puca, Aa, Franceschi, M, Postiglione, A, Milan, G, Sorrentino, P, Kristiansen, M, Chiang, Hh, Graff, C, Pasquier, F, Rollin, A, Deramecourt, V, Lebouvier, T, Kapogiannis, D, Ferrucci, L, Pickering-Brown, S, Singleton, Ab, and Momeni, P.

Subjects
0301 basic medicine, Genotype, Single-nucleotide polymorphism, Genome-wide association study, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, mental disorders, Genetic Pleiotropy, Genetic predisposition, Medicine, Humans, Genetic Predisposition to Disease, Allele, Polymorphism, Biology, Alleles, Genetic association, Genetics, business.industry, Frontotemporal Dementia, Genome-Wide Association Study, Parkinson Disease, Surgery, Neurology (clinical), Psychiatry and Mental Health, Single Nucleotide, medicine.disease, Genetic architecture, nervous system diseases, 030104 developmental biology, Human medicine, business, Neuroscience, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract

Background Clinical, pathological and genetic overlap between sporadic frontotemporal dementia (FTD), Alzheimer9s disease (AD) and Parkinson9s disease (PD) has been suggested; however, the relationship between these disorders is still not well understood. Here we evaluated genetic overlap between FTD, AD and PD to assess shared pathobiology and identify novel genetic variants associated with increased risk for FTD. Methods Summary statistics were obtained from the International FTD Genomics Consortium, International PD Genetics Consortium and International Genomics of AD Project (n>75 000 cases and controls). We used conjunction false discovery rate (FDR) to evaluate genetic pleiotropy and conditional FDR to identify novel FTD-associated SNPs. Relevant variants were further evaluated for expression quantitative loci. Results We observed SNPs within the HLA , MAPT and APOE regions jointly contributing to increased risk for FTD and AD or PD. By conditioning on polymorphisms associated with PD and AD, we found 11 loci associated with increased risk for FTD. Meta-analysis across two independent FTD cohorts revealed a genome-wide signal within the APOE region (rs6857, 3′-UTR= PVRL2 , p=2.21×10 –12 ), and a suggestive signal for rs1358071 within the MAPT region (intronic= CRHR1 , p=4.91×10 −7 ) with the effect allele tagging the H1 haplotype. Pleiotropic SNPs at the HLA and MAPT loci associated with expression changes in cis -genes supporting involvement of intracellular vesicular trafficking, immune response and endo/lysosomal processes. Conclusions Our findings demonstrate genetic pleiotropy in these neurodegenerative diseases and indicate that sporadic FTD is a polygenic disorder where multiple pleiotropic loci with small effects contribute to increased disease risk.

Published
2016

34. Genetic risk for neurodegenerative disorders, and its overlap with cognitive ability and physical function

Author

Hagenaars, Sp, Radaković, R, Crockford, C, Fawns-Ritchie, C, Gale, Cr, Deary, Ij, J B, J Kwok, Dobson-Stone, C, R Schofield, P, Gmhalliday, R Hodges, J, Piguet, O, Bartley, L, Thompson, E, Hernaândez, I, Ruiz, A, Mboada, Borroni, B, Padovani, A, Cruchaga, C, J Cairns, N, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimoân, J, Lleoâ, A, Blesa, R, Mlandqvist, Waldoè, Nilsson, K, Nilsson, C, I R, A Mackenzie, G-Y, R Hsiung, Dma, Mann, Grafman, J, Cmmorris, Attems, J, D Griffiths, T, G McKeith, I, J Thomas, A, Pietrini, P, D Huey, E, Emwassermann, Baborie, A, Jaros, E, Tierney, Mc, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, P St George-Hyslop, Rossi, G, Tagliavini, F, Giaccone, G, B Rowe, J, Cmschlachetzki, J, Uphill, J, Collinge, J, Mead, S, Danek, A, Vmvan, Deerlin, Mgrossman, Q Trojanowski, J, J van der Zee, C Van Broeckhoven, F Cappa, S, Leber, I, Hannequin, D, Golfier, V, Mvercelletto, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, E Nielsen, J, E Hjermind, L, Mriemenschneider, Mmayhaus, Ibach, B, Gasparoni, G, Pichler, S, Wgu, Rossor, Mn, C Fox, N, D Warren, J, Spillantini, Mg, R Morris, H, Rizzu, P, Heutink, P, S Snowden, J, Rollinson, S, Richardson, A, Gerhard, A, C Bruni, A, Maletta, R, Frangipane, F, Cupidi, C, Bernardi, L, Manfossi, Mgallo, Conidi, Me, Smirne, N, Rademakers, R, Baker, M, Dwdickson, R Graff-Radford, N, C Petersen, R, Knopman, D, A Josephs, K, F Boeve, B, E Parisi, J, Wwseeley, L Miller, B, Amkarydas, Rosen, H, C van Swieten, J, E G, P Dopper, Seelaar, H, Y A, L Pijnenburg, Scheltens, P, Logroscino, G, Capozzo, R, Novelli, V, A Puca, A, Franceschi, M, Postiglione, A, Milan, G, Sorrentino, P, Mkristiansen, H-H, Chiang, Graff, C, Pasquier, F, Rollin, A, Deramecourt, V, Lebouvier, T, Kapogiannis, D, Ferrucci, L, Pickering-Brown, S, B Singleton, A, Hardy, J, and Momeni., P

Subjects
Genetics and Molecular Biology (all), Multifactorial Inheritance, Peak Expiratory Flow Rate, Disease, Physical function, Alzheimer's Disease, Biochemistry, Motor Neuron Diseases, 0302 clinical medicine, Cognition, Learning and Memory, Biochemistry, Genetics and Molecular Biology (all), Agricultural and Biological Sciences (all), Forced Expiratory Volume, Medicine and Health Sciences, Amyotrophic lateral sclerosis, Genetic risk, Cognitive Impairment, 0303 health sciences, Cognitive Neurology, Neurodegenerative Diseases, Middle Aged, Mental Status and Dementia Tests, Neurology, Frontotemporal Dementia, Clinical psychology, Frontotemporal dementia, Research Article, Adult, Cognitive Neuroscience, Risk Assessment, 03 medical and health sciences, Memory, Alzheimer Disease, Mental Health and Psychiatry, mental disorders, medicine, Genetics, Humans, Effects of sleep deprivation on cognitive performance, Muscle Strength, Genetic Association Studies, 030304 developmental biology, Aged, business.industry, Amyotrophic Lateral Sclerosis, Biology and Life Sciences, medicine.disease, United Kingdom, Physical Fitness, Genetics of Disease, Cognitive Science, Polygenic risk score, Dementia, business, 030217 neurology & neurosurgery, Neuroscience, Genome-Wide Association Study
Abstract

INTRODUCTIONIt is unclear whether polygenic risk for neurodegenerative disease is associated with cognitive performance and physical health.METHODSThis study tested whether polygenic scores for Alzheimer’s disease (AD), Amyotrophic Lateral Sclerosis (ALS), or frontotemporal dementia (FTD) are associated with cognitive performance and physical health. Group-based analyses were performed to compare associations with cognitive and physical function outcomes in the top and bottom 10% for the three neurodegenerative polygenic risk scores.RESULTSHigher polygenic risk scores for AD, ALS, and FTD were associated with lower cognitive performance. Higher polygenic risk scores for FTD was also associated with increased forced expiratory volume in 1s and peak expiratory flow. A significant group difference was observed on the symbol digit substitution task between individuals with high polygenic risk for FTD and high polygenic risk for ALS.DISCUSSIONOur results suggest overlap between polygenic risk for neurodegenerative disorders, cognitive function and physical health.

Published
2018

35. CXCR4 involvement in neurodegenerative diseases

Author

Bonham, LW, Karch, CM, Fan, CC, Tan, C, Geier, EG, Wang, Y, Wen, N, Broce, IJ, Li, Y, Barkovich, MJ, Ferrari, R, Hardy, J, Momeni, P, Höglinger, G, Müller, U, Hess, CP, Sugrue, LP, Dillon, WP, Schellenberg, GD, Miller, BL, Andreassen, OA, Dale, AM, Barkovich, AJ, Yokoyama, JS, Desikan, RS, Hernandez, DG, Nalls, MA, Rohrer, JD, Ramasamy, A, Kwok, JBJ, Dobson-Stone, C, Schofield, PR, Halliday, GM, Hodges, JR, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, NJ, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Waldö, ML, Nilsson, K, Nilsson, C, MacKenzie, IRA, Hsiung, GYR, Mann, DMA, Grafman, J, Morris, CM, Attems, J, Griffiths, TD, McKeith, IG, Thomas, AJ, Pietrini, P, Huey, ED, Wassermann, EM, Baborie, A, Jaros, E, Tierney, MC, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, George-Hyslop, PS, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, JB, Schlachetzki, JCM, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin, VM, Rowe, James [0000-0001-7216-8679], and Apollo - University of Cambridge Repository

Subjects
Receptors, CXCR4, Risk Factors, Animals, Brain, Gene Expression, Humans, Gene Regulatory Networks, Genetic Predisposition to Disease, Mice, Transgenic, Neurodegenerative Diseases, Microglia, Polymorphism, Single Nucleotide, Genome-Wide Association Study
Abstract

© 2017 The Author(s). Neurodegenerative diseases likely share common underlying pathobiology. Although prior work has identified susceptibility loci associated with various dementias, few, if any, studies have systematically evaluated shared genetic risk across several neurodegenerative diseases. Using genome-wide association data from large studies (total n = 82,337 cases and controls), we utilized a previously validated approach to identify genetic overlap and reveal common pathways between progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), Parkinson's disease (PD) and Alzheimer's disease (AD). In addition to the MAPT H1 haplotype, we identified a variant near the chemokine receptor CXCR4 that was jointly associated with increased risk for PSP and PD. Using bioinformatics tools, we found strong physical interactions between CXCR4 and four microglia related genes, namely CXCL12, TLR2, RALB, and CCR5. Evaluating gene expression from post-mortem brain tissue, we found that expression of CXCR4 and microglial genes functionally related to CXCR4 was dysregulated across a number of neurodegenerative diseases. Furthermore, in a mouse model of tauopathy, expression of CXCR4 and functionally associated genes was significantly altered in regions of the mouse brain that accumulate neurofibrillary tangles most robustly. Beyond MAPT, we show dysregulation of CXCR4 expression in PSP, PD, and FTD brains, and mouse models of tau pathology. Our multi-modal findings suggest that abnormal signaling across a 'network' of microglial genes may contribute to neurodegeneration and may have potential implications for clinical trials targeting immune dysfunction in patients with neurodegenerative diseases.

Published
2018
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36. Egg consumption and dyslipidemia in a Mediterranean cohort

Author

Vazquez-Ruiz, Z. (Zenaida), Fuente-Arrillaga, C. (Carmen) de la, Bes-Rastrollo, M. (Maira), Zazpe, I. (Itziar), Santiago, S. (Susana), Razquin, C. (Cristina), Toledo, E. (Estefanía), and Martinez-Gonzalez, M.A. (Miguel Ángel)

Subjects
Cohort. Cholesterol, Cholesterol, Dyslipidemia, Dislipidemia, Cohort, Egg consumption, HDL-c, Cohorte, Colesterol, Consumo de huevo, Triglycerides, Triglicéridos
Abstract

Introduction and objectives: Our aim was to prospectively evaluate the association between egg consumption and dyslipidemia in a Mediterranean cohort. Methods: We followed-up 13,104 Spanish university graduates for a mean period of 8 years. Dietary habits at baseline were assessed using a validated semi-quantitative 136-item food-frequency questionnaire. Self-reported blood concentrations of total cholesterol, high-density lipoproteins cholesterol (HDL-c) and triglycerides were evaluated according to categories of egg consumption after 6 and 8 years of follow-up. We also assessed the association between baseline egg consumption and the incidence of hypercholesterolemia, low HDL-c concentrations and hypertriglyceridemia during follow-up. Results: We observed a significant inverse association for intermediate levels of egg consumption (2 to 4 eggs/week vs. less than 1 egg/week) and hypertriglyceridemia with OR = 0.71 (95% confidence interval [CI]: 0.54 to 0.93, p < 0.05) in the multivariable-adjusted model. Using HDL-c values after 8-year follow-up, we found an association between higher egg consumption and lower HDL-c levels (p for trend = 0.02) with an adjusted difference of –4.01 mg/dl (-7.42 to -0.61) for > 4 vs. < 1 egg/week. Lower means of triglycerides were found in each of the three upper categories of egg consumption compared to the lowest category (< 1 egg/week) with significant results for some of these categories both after 6 and 8 year follow-up. Conclusions: Our data do not support that higher egg consumption was associated with abnormal blood levels of total cholesterol or triglycerides; an inverse association with HDL-c as a quantitative variable was found only in one of our analyses. Introducción y objetivos: evaluar prospectivamente la asociación entre el consumo de huevo y el riesgo de dislipidemia en una cohorte mediterránea. Métodos: se siguieron 13.104 graduados universitarios españoles durante un periodo medio de 8 años. La dieta se evaluó al inicio utilizando un cuestionario semicuantitativo de frecuencia de consumo de alimentos repetidamente validado. Las concentraciones sanguíneas de colesterol total, lipoproteínas de alta densidad (HDL-c) y triglicéridos autorreferidas fueron evaluadas según categorías de consumo de huevo tras 6 y 8 años de seguimiento. También se evaluó la asociación entre el consumo basal de huevo y la incidencia de hipercolesterolemia, concentraciones bajas de HDL-c e hipertrigliceridemia durante el seguimiento. Resultados: se observó una asociación entre los niveles intermedios de consumo de huevo (2-4 unidades/semana frente a < 1 unidad/semana) y menor riesgo de hipertrigliceridemia con OR = 0,71 (intervalo de confianza del 95% [IC]: 0,54 a 0,93, p < 0,05) en el modelo más ajustado. Tras 8 años de seguimiento, encontramos una asociación entre un mayor consumo de huevo y menores niveles de HDL-c (p tendencia lineal = 0,02) con una diferencia ajustada de -4,01 mg/dl (-7,42 a -0,61) para > 4 vs. < 1 unidad/semana. Se encontraron menores concentraciones de triglicéridos en las tres categorías superiores de consumo de huevo en comparación con la inferior con resultados significativos para algunas de estas categorías después de 6 y 8 años de seguimiento. Conclusiones: un mayor consumo de huevo no se asoció con niveles anormales de colesterol total o triglicéridos; se encontró una asociación inversa con HDL-c como variable cuantitativa solo en uno de nuestros análisis.

Published
2018

37. Protein network analysis reveals selectively vulnerable regions and biological processes in FTD

Author

Bonham, Lw1, Steele, Nzr1, Karch, Cm1, Manzoni, C1, Geier, Eg1, Wen, N1, Ofori-Kuragu, A1, Momeni, P1, Hardy, J1, Miller, Za1, Hess, Cp1, Lewis, P1, Miller, Bl1, Seeley, Ww1, Baranzini, Se1, Desikan, Rs1, Ferrari, R1, Yokoyama, Js1, ( Ferrari R, International FTD-Genomics Consortium, Hernandez, Dg, Nalls, Ma, Rohrer, Jd, Ramasamy, A, Kwok, Jbj, Dobson-Stone, C, Schofield, Pr, Halliday, Gm, Hodges, Jr, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, Nj, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Landqvist Waldö, M, Nilsson, C, Mackenzie, Ira, Hsiung, Gyr, Mann, Dma, Grafman, J, Morris, Cm, Attems, J, Griffiths, Td, Mckeith, Ig, Thomas, Aj, Pietrini, P, Huey, Ed, Wassermann, Em, Baborie, A, Jaros, E, Tierney, Mc, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, St George-Hyslop, P, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, Jb, Schlachetzki, Jcm, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin VM, Grossman, M, Trojanowski, Jq, van der Zee, J, Cruts, M, Van Broeckhoven, C, Cappa, Sf, Leber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, Je, Hjermind, Le, Riemenschneider, M, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, Rossor, Mn, Fox, Nc, Warren, Jd, Spillantini, Mg, Morris, Hr, Rizzu, P, Heutink, P, Snowden, Js, Rollinson, S, Richardson, A, Gerhard, A, Bruni, Ac, Maletta, R, Frangipane, F, Cupidi, C, Bernardi, L, Anfossi, M, Gallo, M, Conidi, Me, Smirne, N, Rademakers, R, Baker, M, Dickson, Dw, Graff-Radford, Nr, Petersen, Rc, Knopman, D, Josephs, Ka, Boeve, Bf, Parisi, Je, Seeley, Ww, Miller, Bl, Karydas, Am, Rosen, H, van Swieten JC, Dopper, Eg, Seelaar, H, Pijnenburg, Yal, Scheltens, P, Logroscino, G, Capozzo, R, Novelli, V, Puca, Aa, Franceschi, M, Postiglione, A, Milan, G, Sorrentino, P, Kristiansen, M, Chiang, Hh, Graff, C, Pasquier, F, Rollin, A, Deramecourt, V, Lebouvier, T, Kapogiannis, D, Ferrucci, L, Pickering-Brown, S, Singleton, Ab, Hardy, J, and Momeni, P.

Subjects
0301 basic medicine, Cell type, Disease, Frontotemporal lobar degeneration, Biology, medicine.disease, Article, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Interaction network, Genetic variation, medicine, Neurology (clinical), Gene, Neuroscience, 030217 neurology & neurosurgery, Genetics (clinical), Frontotemporal dementia, Genetic association
Abstract

ObjectiveThe neuroanatomical profile of behavioral variant frontotemporal dementia (bvFTD) suggests a common biological etiology of disease despite disparate pathologic causes; we investigated the genetic underpinnings of this selective regional vulnerability to identify new risk factors for bvFTD.MethodsWe used recently developed analytical techniques designed to address the limitations of genome-wide association studies to generate a protein interaction network of 63 bvFTD risk genes. We characterized this network using gene expression data from healthy and diseased human brain tissue, evaluating regional network expression patterns across the lifespan as well as the cell types and biological processes most affected in bvFTD.ResultsWe found that bvFTD network genes show enriched expression across the human lifespan in vulnerable neuronal populations, are implicated in cell signaling, cell cycle, immune function, and development, and are differentially expressed in pathologically confirmed frontotemporal lobar degeneration cases. Five of the genes highlighted by our differential expression analyses, BAIAP2, ERBB3, POU2F2, SMARCA2, and CDC37, appear to be novel bvFTD risk loci.ConclusionsOur findings suggest that the cumulative burden of common genetic variation in an interacting protein network expressed in specific brain regions across the lifespan may influence susceptibility to bvFTD.

Published
2018

38. Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies

Author

Broce, Iris, Karch, Celeste M., Wen, Natalie, Fan, Chun C., Wang, Yunpeng, Hong Tan, Chin, Kouri, Naomi, Ross, Owen A., Höglinger, Günter U., Muller, Ulrich, Hardy, John, Momeni, Parastoo, Hess, Christopher P., Dillon, William P., Miller, Zachary A., Bonham, Luke W., Rabinovici, Gil D., Rosen, Howard J., Schellenberg, Gerard D., Franke, Andre, Karlsen, Tom H., Veldink, Jan H., Ferrari, Raffaele, Yokoyama, Jennifer S., Miller, Bruce L., Andreassen, Ole A., Dale, Anders M., Desikan, Rahul S., Sugrue, Leo P., Ferrari R, Hernandez DG, Nalls MA, Rohrer JD, Ramasamy A, Kwok JBJ, Dobson-Stone C, Brooks WS, Schofield PR, Halliday GM, Hodges JR, Piguet O, Bartley L, Thompson E, Haan E, Hernández I, Ruiz A, Boada M, Borroni B, Padovani A, Cruchaga C, Cairns NJ, Benussi L, Binetti G, Ghidoni R, Forloni G, Galimberti D, Fenoglio C, Serpente M, Scarpini E, Clarimón J, Lleó A, Blesa R, Waldö ML, Nilsson K, Nilsson C, Mackenzie IRA, Hsuing GYR, Mann DMA, Grafman J, Morris CM, Attems J, Griffiths TD, McKeith IG, Thomas AJ, Pietrini P, Huey ED, Wasserman EM, Baborie A, Jaros E, Tierney MC, Pastor P, Razquin C, Ortega-Cubero S, Alonso E, Perneczky E, Diehl-Schmid J, Alexopoulos P, Kurz A, Rainero I, Rubino E, Pinessi L, Rogaeva E, St George-Hyslop P, Rossi G, Tagliavini F, Giaccone G, Rowe JB, Schlachetzki JCM, Uphill J, Collinge J, Mead S, Danek A, Van Deerlin VM, Grossmann M, Trojanowski JQ, van der Zee J, Deschamps W, Van Langenhove T, Cruts M, Van Broeckhoven C, Cappa SF, Le Ber I, Hannequin D, Golfier V, Vercelletto M, Brice A, Nacmias B, Sorbi S, Bagnoli S, Piaceri I, Nielsen JE, Hjermind LE, Riemenschneider M, Mayhaus M, Ibach B, Gasparoni G, Pichler S, Gu W, Rossor MN, Fox NC, Warren JD, Spillantini MG, Morris HR, Rizzu P, Heutnik P, Snowden J, Rollinson S, Richardson A, Gerhard A, Bruni AC, Maletta R, Frangipane F, Cupidi C, Bernardi L, Anfossi M, Gallo M, Conidi ME, Smirne N, Rademakers R, Baker M, Dickson DW, Graff-Radford NR, Peterson RC, Knopman D, Josephs KA, Boeve BF, Parisi JE, Seeley WW, Miller BL, Karydas AM, Rosen H, van Swieten JC, Dopper EGP, Seelaar H, Pijnenburg YAL, Scheltens P, Logroscino G, Capozzo R, Novelli V, Puca AA, Franceschi M, Postiglione A, Milan G, Sorrentino P, Kristiansen M, Chiang HH, Graff C, Pasquier F, Rollin A, Deramecourt V, Lebert F, Kapogiannis D, Ferucci L, Pickering-Brown S, Singleton AB, Hardy J, Momeni P., Broce, Iris [0000-0003-4932-1430], Karch, Celeste M [0000-0002-6854-5547], Wang, Yunpeng [0000-0001-9831-1090], Tan, Chin Hong [0000-0002-0980-9936], Kouri, Naomi [0000-0002-6841-9882], Hess, Christopher P [0000-0002-5132-5302], Miller, Zachary A [0000-0002-5991-3053], Bonham, Luke W [0000-0002-2533-1266], Veldink, Jan H [0000-0001-5572-9657], Dale, Anders M [0000-0002-6126-2966], Desikan, Rahul S [0000-0002-4151-6017], Sugrue, Leo P [0000-0001-7315-4519], Apollo - University of Cambridge Repository, Neurology, Human genetics, Amsterdam Neuroscience - Neurodegeneration, Divisions, Rademakers, Rosa, Int FTD-Genomics Consortium, Broce, Iri, Karch, Celeste M., Wen, Natalie, Fan, Chun C., Wang, Yunpeng, Hong Tan, Chin, Kouri, Naomi, Ross, Owen A., Höglinger, Günter U., Muller, Ulrich, Hardy, John, Momeni, Parastoo, Hess, Christopher P., Dillon, William P., Miller, Zachary A., Bonham, Luke W., Rabinovici, Gil D., Rosen, Howard J., Schellenberg, Gerard D., Franke, Andre, Karlsen, Tom H., Veldink, Jan H., Ferrari, Raffaele, Yokoyama, Jennifer S., Miller, Bruce L., Andreassen, Ole A., Dale, Anders M., Desikan, Rahul S., Sugrue, Leo P., Ferrari, R, Hernandez, Dg, Nalls, Ma, Rohrer, Jd, Ramasamy, A, Kwok, Jbj, Dobson-Stone, C, Brooks, W, Schofield, Pr, Halliday, Gm, Hodges, Jr, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, Nj, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Waldö, Ml, Nilsson, K, Nilsson, C, Mackenzie, Ira, Hsuing, Gyr, Mann, Dma, Grafman, J, Morris, Cm, Attems, J, Griffiths, Td, Mckeith, Ig, Thomas, Aj, Pietrini, P, Huey, Ed, Wasserman, Em, Baborie, A, Jaros, E, Tierney, Mc, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, E, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, St George-Hyslop, P, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, Jb, Schlachetzki, Jcm, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin, Vm, Grossmann, M, Trojanowski, Jq, van der Zee, J, Deschamps, W, Van Langenhove, T, Cruts, M, Van Broeckhoven, C, Cappa, Sf, Le Ber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, Je, Hjermind, Le, Riemenschneider, M, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, Rossor, Mn, Fox, Nc, Warren, Jd, Spillantini, Mg, Morris, Hr, Rizzu, P, Heutnik, P, Snowden, J, Rollinson, S, Richardson, A, Gerhard, A, Bruni, Ac, Maletta, R, Frangipane, F, Cupidi, C, Bernardi, L, Anfossi, M, Gallo, M, Conidi, Me, Smirne, N, Rademakers, R, Baker, M, Dickson, Dw, Graff-Radford, Nr, Peterson, Rc, Knopman, D, Josephs, Ka, Boeve, Bf, Parisi, Je, Seeley, Ww, Miller, Bl, Karydas, Am, Rosen, H, van Swieten, Jc, Dopper, Egp, Seelaar, H, Pijnenburg, Yal, Scheltens, P, Logroscino, G, Capozzo, R, Novelli, V, Puca, Aa, Franceschi, M, Postiglione, A, Milan, G, Sorrentino, P, Kristiansen, M, Chiang, Hh, Graff, C, Pasquier, F, Rollin, A, Deramecourt, V, Lebert, F, Kapogiannis, D, Ferucci, L, Pickering-Brown, S, Singleton, Ab, Hardy, J, and Momeni, P.

Subjects
0301 basic medicine, Linkage disequilibrium, Gene Expression, Genome-wide association study, Neurodegenerative, Medical and Health Sciences, Motor Neuron Diseases, 0302 clinical medicine, Medicine and Health Sciences, 2.1 Biological and endogenous factors, Corticobasal degeneration, genetics [Genetic Predisposition to Disease], genetics [Frontotemporal Dementia], Genetics, Medicine (all), Neurodegenerative Diseases, Single Nucleotide, Genomics, General Medicine, Middle Aged, Colitis, LRRK2, 3. Good health, Neurology, Manchester Institute for Collaborative Research on Ageing, Frontotemporal Dementia, Neurological, Medicine, Research Article, Frontotemporal dementia, ResearchInstitutes_Networks_Beacons/MICRA, Immunology, Rheumatoid Arthritis, Single-nucleotide polymorphism, Gastroenterology and Hepatology, Human leukocyte antigen, Biology, Autoimmune Disease, Polymorphism, Single Nucleotide, Autoimmune Diseases, 03 medical and health sciences, Rare Diseases, Rheumatology, Clinical Research, General & Internal Medicine, FTD GWA, Mental Health and Psychiatry, mental disorders, Acquired Cognitive Impairment, Genome-Wide Association Studies, medicine, Ulcerative Colitis, Humans, Inflammatory and Immune System, Genetic Predisposition to Disease, ddc:610, Polymorphism, Aged, Genetic association, Genome-Wide Association Study, International FTD-Genomics Consortium, Prevention, Arthritis, Human Genome, Inflammatory Bowel Disease, Amyotrophic Lateral Sclerosis, Neurosciences, Correction, Biology and Life Sciences, Computational Biology, nutritional and metabolic diseases, Human Genetics, Genome Analysis, medicine.disease, Brain Disorders, nervous system diseases, 030104 developmental biology, Genetic Loci, Genetics of Disease, Dementia, Clinical Immunology, Human medicine, Clinical Medicine, Digestive Diseases, 030217 neurology & neurosurgery
Abstract

Background Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed. Methods and findings Using large genome-wide association studies (GWASs) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with FTD-related disorders—namely, FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS)—and 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis. We found up to 270-fold genetic enrichment between FTD and RA, up to 160-fold genetic enrichment between FTD and UC, up to 180-fold genetic enrichment between FTD and T1D, and up to 175-fold genetic enrichment between FTD and CeD. In contrast, for CBD and PSP, only 1 of the 6 immune-mediated diseases produced genetic enrichment comparable to that seen for FTD, with up to 150-fold genetic enrichment between CBD and CeD and up to 180-fold enrichment between PSP and RA. Further, we found minimal enrichment between ALS and the immune-mediated diseases tested, with the highest levels of enrichment between ALS and RA (up to 20-fold). For FTD, at a conjunction false discovery rate < 0.05 and after excluding SNPs in linkage disequilibrium, we found that 8 of the 15 identified loci mapped to the human leukocyte antigen (HLA) region on Chromosome (Chr) 6. We also found novel candidate FTD susceptibility loci within LRRK2 (leucine rich repeat kinase 2), TBKBP1 (TBK1 binding protein 1), and PGBD5 (piggyBac transposable element derived 5). Functionally, we found that the expression of FTD–immune pleiotropic genes (particularly within the HLA region) is altered in postmortem brain tissue from patients with FTD and is enriched in microglia/macrophages compared to other central nervous system cell types. The main study limitation is that the results represent only clinically diagnosed individuals. Also, given the complex interconnectedness of the HLA region, we were not able to define the specific gene or genes on Chr 6 responsible for our pleiotropic signal. Conclusions We show immune-mediated genetic enrichment specifically in FTD, particularly within the HLA region. Our genetic results suggest that for a subset of patients, immune dysfunction may contribute to FTD risk. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD., Rahul Desikan and colleagues use summary data from genome-wide association studies to investigate genetic overlap between frontotemporal dementia and a several immune-mediated diseases, and identify microglia and inflammation-associated genes that may play a role in FTD pathogenesis., Author summary Why was this study done? Frontotemporal dementia (FTD) is the leading cause of dementia in individuals less than 65 years old. Currently, there is no approved treatment of FTD and no diagnostic tests for predicting disease onset or measuring progression. Increasing evidence suggests that inflammation and immune system dysfunction play an important role in the pathogenesis of FTD. What did the researchers do and find? We used summary data from genome-wide association studies to investigate genetic overlap, or “pleiotropy,” between FTD and a variety of immune-mediated diseases. Through this approach, we found extensive FTD–immune genetic overlap within the HLA region on Chromosome 6, an area rich in genes related to microglial function, as well as in 3 genes not previously identified as contributing to the pathophysiology of FTD. Pointing to the functional relevance of these genetic results, we found that these candidate FTD–immune genes are differentially expressed in postmortem brains from patients with FTD compared to controls, and in microglia/macrophages compared with other central nervous system cells. Using bioinformatics tools, we explored protein and genetic interactions among our candidate FTD–immune genes. These results suggest that rather than a few individual loci, large portions of the HLA region may be associated with increased FTD risk. What do these findings mean? Immune dysfunction may play a role in the pathophysiology of a subset of FTD cases. For a subset of patients in whom immune dysfunction in general—and microglial activation in particular—is central to disease pathophysiology, anti-inflammatory treatment is an important area for further investigation.

Published
2018

39. Susceptible genes and disease mechanisms identified in frontotemporal dementia and frontotemporal dementia with Amyotrophic Lateral Sclerosis by DNA-methylation and GWAS

Author

Taskesen, E, Mishra, A, van der Sluis, S, Ferrari, R, Veldink, Jh, van Es MA4, Smit, Ab5, Posthuma, D1, 2, Hernandez DG, Pijnenburg Y., Nalls, Ma, Rohrer, Jd, Ramasamy, A, Kwok, Jbj, Dobson-Stone, C, Schofield, Pr, Halliday, Gm, Hodges, Jr, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, Nj, Benussi, L, Binetti, G, Ghidoni, Roberta, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Waldö, Ml, Nilsson, K, Nilsson, C, Mackenzie, Ira, Hsiung, Gr, Mann, Dma, Grafman, J, Morris, Cm, Attems, J, Griffiths, Td, Mckeith, Ig, Thomas, Aj, Pietrini, P, Huey, Ed, Wassermann, Em, Baborie, A, Jaros, E, Tierney, Mc, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, George-Hyslop, Ps, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, Jb, Schlachetzki, Jcm, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin VM, Grossman, M, Trojanowski, Jq, van der Zee, J, Van Broeckhoven, C, Cappa, Sf, Leber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, Je, Hjermind, Le, Riemenschneider, GUNNAR MARKUS, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, Rossor, Mn, Fox, Nc, Warren, Jd, Spillantini, Mg, Morris, Hr, Rizzu, P, Heutink, P, Snowden, Js, Rollinson, S, Richardson, A, Gerhard, A, Bruni, Ac, Maletta, R, Frangipane, F, Cupidi, C, Bernardi, Lara, Anfossi, M, Gallo, M, Conidi, Me, Smirne, N, Rademakers, R, Baker, M, Dickson, Dw, Graff-Radford, Nr, Petersen, Rc, Knopman, D, Josephs, Ka, Boeve, Bf, Parisi, Je, Seeley, Ww, Miller, Bl, Karydas, Am, Rosen, H, van Swieten JC, Dopper, Egp, Seelaar, H, Scheltens, P, Logroscino, G, Capozzo, R, Novelli, V, Puca, Aa, Franceschi, M, Postiglione, Antonio, Milan, Gian Luca, Sorrentino, Paolo Luigi, Kristiansen, M, Chiang, Hh, Graff, C, Pasquier, F, Rollin, A, Deramecourt, V, Lebouvier, T, Kapogiannis, D, Ferrucci, L, Pickering-Brown, S, Singleton, Ab, Hardy, J, Momeni, P., Rademakers, Rosa, International FTD-Genomics Consortium, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience - Neurodegeneration, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Human genetics, APH - Quality of Care, Midwifery Science, Divisions, Neurology, Amsterdam Reproduction & Development (AR&D), Mishra, A [0000-0002-8141-1543], van der Sluis, S [0000-0001-9958-7216], van Es, MA [0000-0002-7709-5883], Posthuma, D [0000-0001-7582-2365], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Candidate gene, Science, Genome-wide association study, Biology, Neurodegenerative, Article, 03 medical and health sciences, 0302 clinical medicine, Rare Diseases, SDG 3 - Good Health and Well-being, mental disorders, medicine, Journal Article, Acquired Cognitive Impairment, Genetics, 2.1 Biological and endogenous factors, Amyotrophic lateral sclerosis, Aetiology, General, Alzheimer's Disease Related Dementias (ADRD), Genetic association, Multidisciplinary, Genetic heterogeneity, International FTD-Genomics Consortium, Neurodegeneration, Human Genome, Neurosciences, nutritional and metabolic diseases, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), medicine.disease, nervous system diseases, Brain Disorders, Frontotemporal Dementia (FTD), 030104 developmental biology, DNA methylation, Neurological, Medicine, Dementia, Human medicine, ALS, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract

Frontotemporal dementia (FTD) is a neurodegenerative disorder predominantly affecting the frontal and temporal lobes. Genome-wide association studies (GWAS) on FTD identified only a few risk loci. One of the possible explanations is that FTD is clinically, pathologically, and genetically heterogeneous. An important open question is to what extent epigenetic factors contribute to FTD and whether these factors vary between FTD clinical subgroup. We compared the DNA-methylation levels of FTD cases (n = 128), and of FTD cases with Amyotrophic Lateral Sclerosis (FTD-ALS; n = 7) to those of unaffected controls (n = 193), which resulted in 14 and 224 candidate genes, respectively. Cluster analysis revealed significant class separation of FTD-ALS from controls. We could further specify genes with increased susceptibility for abnormal gene-transcript behavior by jointly analyzing DNA-methylation levels with the presence of mutations in a GWAS FTD-cohort. For FTD-ALS, this resulted in 9 potential candidate genes, whereas for FTD we detected 1 candidate gene (ELP2). Independent validation-sets confirmed the genes DLG1, METTL7A, KIAA1147, IGHMBP2, PCNX, UBTD2, WDR35, and ELP2/SLC39A6 among others. We could furthermore demonstrate that genes harboring mutations and/or displaying differential DNA-methylation, are involved in common pathways, and may therefore be critical for neurodegeneration in both FTD and FTD-ALS.

Published
2017

40. Immune-related genetic enrichment in frontotemporal dementia

Author

Broce, Iris, Karch, Celeste M., Wen, Natalie, Fan, Chun C., Wang, Yunpeng, Hong Tan, Chin, Kouri, Naomi, Ross, Owen A., Höglinger, Günter U., Muller, Ulrich, Hardy, John, Momeni, Parastoo, Hess, Christopher P., Dillon, William P., Miller, Zachary A., Bonham, Luke W., Rabinovici, Gil D., Rosen, Howard J., Schellenberg, Gerard D., Franke, Andre, Karlsen, Tom H., Veldink, Jan H., Ferrari, Raffaele, Yokoyama, Jennifer S., Miller, Bruce L., Andreassen, Ole A., Dale, Anders M., Desikan, Rahul S., Sugrue, Leo P., Ferrari, R, Hernandez, D G, Nalls, M A, Rohrer, J D, Ramasamy, A, Kwok, J B J, Dobson-Stone, C, Schofield, P R, Halliday, G M, Hodges, J R, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, N J, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Landqvist Waldö, M, Nilsson, K, Nilsson, C, Mackenzie, I R A, Hsiung, G-Y R, Mann, D M A, Grafman, J, Morris, C M, Attems, J, Griffiths, T D, McKeith, I G, Thomas, A J, Pietrini, P, Huey, E D, Wassermann, E M, Baborie, A, Jaros, E, Tierney, M C, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, George-Hyslop, P St, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, J B, Schlachetzki, J C M, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin, V M, Grossman, M, Trojanowski, J Q, der Zee, J van, Cruts, M, Broeckhoven, C Van, Cappa, S F, Leber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, J E, Hjermind, L E, Riemenschneider, M, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, Rossor, M N, Fox, N C, Warren, J D, Spillantini, M G, Morris, H R, Rizzu, P, Heutink, P, Snowden, J S, Rollinson, S, Richardson, A, Gerhard, A, Bruni, A C, Maletta, R, Frangipane, F, Cupidi, C, Bernardi, L, Anfossi, M, Gallo, M, Conidi, M E, Smirne, N, Rademakers, R, Baker, M, Dickson, D W, Graff-Radford, N R, Petersen, R C, Knopman, D, Josephs, K A, Boeve, B F, Parisi, J E, Seeley, W W, Miller, B L, Karydas, A M, Rosen, H, van Swieten, J C, Dopper, E G P, Seelaar, H, Pijnenburg, Y A L, Scheltens, P, Logroscino, G, Capozzo, R, Novelli, V, Puca, A A, Franceschi, M, Postiglione, A, Milan, G, Sorrentino, P, Kristiansen, M, Chiang, H-H, Graff, C, Pasquier, F, Rollin, A, Deramecourt, V, Lebouvier, T, Kapogiannis, D, Ferrucci, L, Pickering-Brown, S, Singleton, A B, Hardy, J, and Momeni, P

Subjects
Genetics, 0303 health sciences, business.industry, nutritional and metabolic diseases, Single-nucleotide polymorphism, Genome-wide association study, Disease, medicine.disease, nervous system diseases, 3. Good health, Progressive supranuclear palsy, 03 medical and health sciences, 0302 clinical medicine, mental disorders, Immunology, Medicine, Corticobasal degeneration, Amyotrophic lateral sclerosis, business, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association, Frontotemporal dementia
Abstract

BackgroundConverging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed.Methods and findingsUsing large genome-wide association studies (GWAS) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs)jointlyassociated with ‘FTD-related disorders’ namely FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS) – and one or more immune-mediated diseases including Crohn’s disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis (PSOR). We found up to 270-fold genetic enrichment between FTD and RA and comparable enrichment between FTD and UC, T1D, and CeD. In contrast, we found only modest genetic enrichment between any of the immune-mediated diseases and CBD, PSP or ALS. At a conjunction false discovery rate (FDR) < 0.05, we identified numerous FTD-immune pleiotropic SNPs within the human leukocyte antigen (HLA)region on chromosome 6. By leveraging the immune diseases, we also found novel FTD susceptibility loci withinLRRK2(Leucine Rich Repeat Kinase 2), TBKBP1(TANK-binding kinase 1 Binding Protein 1), andPGBD5(PiggyBac Transposable Element Derived 5). Functionally, we found that expression of FTD-immune pleiotropic genes (particularly within theHLAregion) is altered in postmortem brain tissue from patients with frontotemporal dementia and is enriched in microglia compared to other central nervous system (CNS) cell types.ConclusionsWe show considerable immune-mediated genetic enrichment specifically in FTD, particularly within theHLAregion. Our genetic results suggest that for a subset of patients, immune dysfunction may contribute to risk for FTD. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD.

Published
2017

41. Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases

Author

Ferrari, R, Wang, Y, Vandrovcova, J, Guelfi, S, Witeolar, A, Karch, CM, Schork, AJ, Fan, CC, Brewer, JB, Momeni, P, Schellenberg, GD, Dillon, WP, Sugrue, LP, Hess, CP, Yokoyama, JS, Bonham, LW, Rabinovici, GD, Miller, BL, Andreassen, OA, Dale, AM, Hardy, J, Desikan, RS, Hernandez, DG, Nalls, MA, Rohrer, JD, Ramasamy, A, Kwok, JBJ, Dobson-Stone, C, Schofield, PR, Halliday, GM, Hodges, JR, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, NJ, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Landqvist Waldö, M, Nilsson, K, Nilsson, C, Mackenzie, IRA, Hsiung, GYR, Mann, DMA, Grafman, J, Morris, CM, Attems, J, Griffiths, TD, McKeith, IG, Thomas, AJ, Pietrini, P, Huey, ED, Wassermann, EM, Baborie, A, Jaros, E, Tierney, MC, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, St George-Hyslop, P, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, JB, Schlachetzki, JCM, and Uphill, J

Subjects
mental disorders, nervous system diseases
Abstract

© Published by the BMJ Publishing Group Limited. Background Clinical, pathological and genetic overlap between sporadic frontotemporal dementia (FTD), Alzheimer's disease (AD) and Parkinson's disease (PD) has been suggested; however, the relationship between these disorders is still not well understood. Here we evaluated genetic overlap between FTD, AD and PD to assess shared pathobiology and identify novel genetic variants associated with increased risk for FTD. Methods Summary statistics were obtained from the International FTD Genomics Consortium, International PD Genetics Consortium and International Genomics of AD Project (n>75000 cases and controls). We used conjunction false discovery rate (FDR) to evaluate genetic pleiotropy and conditional FDR to identify novel FTD-associated SNPs. Relevant variants were further evaluated for expression quantitative loci. Results We observed SNPs within the HLA, MAPT and APOE regions jointly contributing to increased risk for FTD and AD or PD. By conditioning on polymorphisms associated with PD and AD, we found 11 loci associated with increased risk for FTD. Meta-analysis across two independent FTD cohorts revealed a genome-wide signal within the APOE region (rs6857, 3′-UTR=PVRL2, p=2.21×10 -12), and a suggestive signal for rs1358071 within the MAPT region (intronic=CRHR1, p=4.91×10 -7) with the effect allele tagging the H1 haplotype. Pleiotropic SNPs at the HLA and MAPT loci associated with expression changes in cis-genes supporting involvement of intracellular vesicular trafficking, immune response and endo/lysosomal processes. Conclusions Our findings demonstrate genetic pleiotropy in these neurodegenerative diseases and indicate that sporadic FTD is a polygenic disorder where multiple pleiotropic loci with small effects contribute to increased disease risk.

Published
2017

42. Shared genetic risk between corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia

Author

Yokoyama, Jennifer S., Karch, Celeste M., Fan, Chun C., Bonham, Luke W., Naomi, Kouri, Ross, Owen A., Rosa, Rademakers, Jungsu, Kim, Yunpeng, Wang, Höglinger, Günter U., Ulrich, Muller, Raffaele, Ferrari, John, Hardy, International FTD-Genomics Consortium (IFGC Ferrari, R, Hernandez, Dg, Nalls, Ma, Rohrer, Jd, Ramasamy, A, Kwok, Jbj, Dobson-Stone, C, Schofield, Pr, Halliday, Gm, Hodges, Jr, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, Nj, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Landqvist Waldö, M, Nilsson, C, Mackenzie, Ira, Hsiung, Gyr, Mann, Dma, Grafman, J, Morris, Cm, Attems, J, Griffiths, Td, Mckeith, Ig, Thomas, Aj, Pietrini, P, Huey, Ed, Wassermann, Em, Baborie, A, Jaros, E, Tierney, Mc, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, St George-Hyslop, P, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, Jb, Schlachetzki, Jcm, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin VM, Grossman, M, Trojanowski, Jq, van der Zee, J, Cruts, M, Van Broeckhoven, C, Cappa, Sf, Leber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, Je, Hjermind, Le, Riemenschneider, M, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, Rossor, Mn, Fox, Nc, Warren, Jd, Spillantini, Mg, Morris, Hr, Rizzu, P, Heutink, P, Snowden, Js, Rollinson, S, Richardson, A, Gerhard, A, Bruni, Ac, Maletta, R, Frangipane, F, Cupidi, C, Bernardi, L, Anfossi, M, Gallo, M, Conidi, Me, Smirne, N, Rademakers, R, Baker, M, Dickson, Dw, Graff-Radford, Nr, Petersen, Rc, Knopman, D, Josephs, Ka, Boeve, Bf, Parisi, Je, Seeley, Ww, Miller, Bl, Karydas, Am, Rosen, H, van Swieten JC, Dopper, Eg, Seelaar, H, Pijnenburg, Yal, Scheltens, P, Logroscino, G, Capozzo, R, Novelli, V, Puca, Aa, Franceschi, M, Postiglione, A, Milan, G, Sorrentino, P, Kristiansen, M, Chiang, Hh, Graff, C, Pasquier, F, Rollin, A, Deramecourt, V, Lebouvier, T, Kapogiannis, D, Ferrucci, L, Pickering-Brown, S, Singleton, Ab, Hardy, J, Momeni, P. )., Parastoo, Momeni, Sugrue, Leo P., Hess, Christopher P., James Barkovich, A., Boxer, Adam L., Seele, William W., Rabinovici, Gil D., Rosen, Howard J., Miller, Bruce L., Schmansky, Nicholas J., Bruce, Fischl, Hyman, Bradley T., Dickson, Dennis W., Schellenberg, Gerard D., Andreassen, Ole A., Dale, Anders M., Desikan, and Rahul S., and Int FTD-Genomics Consortium

Subjects
pathology [Tauopathies], 0301 basic medicine, Pathology, Aging, genetics [Basal Ganglia Diseases], Genome-wide association study, Neurodegenerative, diagnosis [Supranuclear Palsy, Progressive], diagnosis [Frontotemporal Dementia], pathology [Inclusion Bodies], 0302 clinical medicine, Neurology (clinical), Cellular and Molecular Neuroscience, Risk Factors, pathology [Neurons], Corticobasal degeneration, Supranuclear Palsy, 2.1 Biological and endogenous factors, Aetiology, genetics [Frontotemporal Dementia], Alzheimer's Disease Related Dementias (ADRD), Genetics, Inclusion Bodies, Neurons, genetics [Supranuclear Palsy, Progressive], Frontotemporal Dementia (FTD), Tauopathies, Frontotemporal Dementia, Neurological, Supranuclear Palsy, Progressive, Frontotemporal dementia, medicine.medical_specialty, pathology [Supranuclear Palsy, Progressive], Clinical Sciences, MAPT protein, human, Locus (genetics), Single-nucleotide polymorphism, tau Proteins, Biology, Article, Pathology and Forensic Medicine, Progressive supranuclear palsy, 03 medical and health sciences, Rare Diseases, Progressive, Basal Ganglia Diseases, mental disorders, medicine, Acquired Cognitive Impairment, Humans, ddc:610, Genetic association, Neurology & Neurosurgery, International FTD-Genomics Consortium, Prevention, Haplotype, Human Genome, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), medicine.disease, metabolism [tau Proteins], digestive system diseases, Brain Disorders, 030104 developmental biology, pathology [Frontotemporal Dementia], Dementia, Human medicine, pathology [Basal Ganglia Diseases], 030217 neurology & neurosurgery
Abstract

Corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and a subset of frontotemporal dementia (FTD) are neurodegenerative disorders characterized by tau inclusions in neurons and glia (tauopathies). Although clinical, pathological and genetic evidence suggests overlapping pathobiology between CBD, PSP, and FTD, the relationship between these disorders is still not well understood. Using summary statistics (odds ratios and p values) from large genome-wide association studies (total n=14,286 cases and controls) and recently established genetic methods, we investigated the genetic overlap between CBD and PSP and CBD and FTD. We found up to 800-fold enrichment of genetic risk in CBD across different levels of significance for PSP or FTD. In addition to NSF (tagging the MAPT H1 haplotype), we observed that SNPs in or near MOBP, CXCR4, EGFR, and GLDC showed significant genetic overlap between CBD and PSP, whereas only SNPs tagging the MAPT haplotype overlapped between CBD and FTD. The risk alleles of the shared SNPs were associated with expression changes in cis-genes. Evaluating transcriptome levels across adult human brains, we found a unique neuroanatomic gene expression signature for each of the five overlapping gene loci (omnibus ANOVA p&nbsp

Published
2017

43. Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases

Author

Wang Y., Ferrari R., Hernandez, D. G, Nalls, M. A, Rohrer, J. D, Ramasamy, A, Kwok, J. B. J, Dobson Stone, C, Schofield, P. R, Halliday, G. M, Hodges, J. R, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, Barbara, Padovani, Alessandro, Cruchaga, C, Cairns, N. J, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Landqvist Waldö, M, Nilsson, K, Nilsson, C, Mackenzie, I. R. A, Hsiung, G. Y. R, Mann, D. M. A, Grafman, J, Morris, C. M, Attems, J, Griffiths, T. D, Mckeith, I. G, Thomas, A. J, Pietrini, P, Huey, E. D, Wassermann, E. M, Baborie, A, Jaros, E, Tierney, M. C, Pastor, P, Razquin, C, Ortega Cubero, S, Alonso, E, Perneczky, R, Diehl Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, St George Hyslop, P, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, J. B, Schlachetzki, J. C. M, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin, V. M, Grossman, M, Trojanowski, J. Q, van der Zee, J, Cruts, M, Van Broeckhoven, C, Cappa, S. F, Leber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, J. E, Hjermind, L. E, Riemenschneider, M, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, Rossor, M. N, Fox, N. C, Warren, J. D, Spillantini, M. G, Morris, H. R, Rizzu, P, Heutink, P, Snowden, J. S, Rollinson, S, Richardson, A, Gerhard, A, Bruni, A. C, Maletta, R, Frangipane, F, Cupidi, C, Bernardi, L, Anfossi, M, Gallo, M, Conidi, M. E, Smirne, N, Rademakers, R, Baker, M, Dickson, D. W, Graff Radford, N. R, Petersen, R. C, Knopman, D, Josephs, K. A, Boeve, B. F, Parisi, J. E, Seeley, W. W, Miller, B. L, Karydas, A. M, Rosen, H, van Swieten, J. C, Dopper, E. G. P, Seelaar, H, Pijnenburg, Y. A. L, Scheltens, P, Logroscino, G, Capozzo, R, Novelli, V, Puca, A. A, Franceschi, M, Postiglione, A, Milan, G, Sorrentino, P, Kristiansen, M, Chiang, H. H, Graff, C, Pasquier, F, Rollin, A, Deramecourt, V, Lebouvier, T, Kapogiannis, D, Ferrucci, L, Pickering Brown, S, Singleton, A. B, Hardy, J, and Momeni, P.

Published
2017

44. Gene-based association studies report genetic links for clinical subtypes of frontotemporal dementia

Author

Mishra, Aniket, Ferrari, Raffaele, Rohrer, J. D., Ibach, B., Gasparoni, G., Pichler, S., Gu, W., Rossor, M. N., Fox, N. C., Warren, J. D., Spillantini, M. G., Morris, H. R., Rizzu, P., Ramasamy, A., Heutink, P., Snowden, J. S., Rollinson, S., Richardson, A., Gerhard, A., Bruni, A. C., Maletta, R., Frangipane, F., Cupidi, C., Bernardi, L., Kwok, J. B. J., Anfossi, M., Gallo, M., Conidi, M. E., Smirne, N., Rademakers, R., Baker, M., Dickson, D. W., Graff-Radford, N. R., Petersen, R. C., Knopman, D., Dobson-Stone, C., Josephs, K. A., Boeve, B. F., Parisi, J. E., Seeley, W. W., Miller, B. L., Karydas, A. M., Rosen, H., van Swieten, J. C., Dopper, E. G. P., Seelaar, H., Schofield, P. R., Pijnenburg, Y. A. L., Scheltens, P., Logroscino, G., Capozzo, R., Novelli, V., Puca, A. A., Franceschi, M., Postiglione, A., Milan, G., Sorrentino, P., Halliday, G. M., Kristiansen, M., Chiang, H-H, Graff, C., Pasquier, F., Rollin, A., Deramecourt, V., Lebouvier, T., Kapogiannis, D., Ferrucci, L., Pickering-Brown, S., Hodges, J. R., Singleton, A. B., Hardy, J., Momeni, P., Piguet, O., Bartley, L., Thompson, E., Heutink, Peter, Haan, E., Hernández, I., Ruiz, A., Boada, M., Borroni, B., Padovani, A., Cruchaga, C., Cairns, N. J., Benussi, L., Binetti, G., Hardy, John, Ghidoni, R., Forloni, G., Albani, D., Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Clarimón, J., Lleó, A., Blesa, R., Pijnenburg, Yolande, Landqvist Waldö, M., Nilsson, K., Nilsson, C., Mackenzie, I. R. A., Hsiung, G-Y R, Mann, D. M. A., Grafman, J., Morris, C. M., Attems, J., Griffiths, T. D., Posthuma, Danielle, McKeith, I. G., Thomas, A. J., Pietrini, P., Huey, E. D., Wassermann, E. M., Baborie, A., Jaros, E., Tierney, M. C., Pastor, P., Razquin, C., Consortium, International FTD-Genomics, Ortega-Cubero, S., Alonso, E., Perneczky, R., Diehl-Schmid, J., Alexopoulos, P., Kurz, A., Rainero, I., Rubino, E., Pinessi, L., Rogaeva, E., Ferrari, R., St George-Hyslop, P., Rossi, G., Tagliavini, F., Giaccone, G., Rowe, J. B., Schlachetzki, J. C. M., Uphill, J., Collinge, J., Mead, S., Danek, A., Hernandez, D. G., Van Deerlin, V. M., Grossman, M., Trojanowski, J. Q., van der Zee, J., Cruts, M., Van Broeckhoven, C., Cappa, S. F., Leber, I., Hannequin, D., Golfier, V., Nalls, M. A., Vercelletto, M., Brice, A., Nacmias, B., Sorbi, S., Bagnoli, S., Piaceri, I., Nielsen, J. E., Hjermind, L. E., Riemenschneider, M., Mayhaus, M., International FTD-Genomics Consortium, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Human genetics, Neurology, Amsterdam Neuroscience - Neurodegeneration, and Amsterdam Reproduction & Development (AR&D)

Subjects
0301 basic medicine, Genome-wide association study, 0302 clinical medicine, diagnosis [Frontotemporal Dementia], ARHGAP35 protein, human, Risk Factors, Mitochondrial Precursor Protein Import Complex Proteins, MAGMA, GWAS, Guanine Nucleotide Exchange Factors, genetics [Genetic Predisposition to Disease], genetics [Frontotemporal Dementia], Genetics, genetics [Membrane Transport Proteins], FTD, genetics [Guanine Nucleotide Exchange Factors], TOMM40 protein, human, Frontotemporal Dementia, Allelic heterogeneity, medicine.symptom, Frontotemporal dementia, Semantic dementia, 03 medical and health sciences, Apolipoproteins E, Progressive nonfluent aphasia, stress-signalling pathway, SDG 3 - Good Health and Well-being, gene-based association study, Aphasia, medicine, Genetic predisposition, Journal Article, Humans, Genetic Predisposition to Disease, ddc:610, Alleles, Case-Control Studies, Genetic Association Studies, Membrane Transport Proteins, Protective Factors, Repressor Proteins, alpha 1-Antitrypsin, Neurology (clinical), Biology, Genetic association, business.industry, SERPINA1 protein, human, medicine.disease, genetics [alpha 1-Antitrypsin], genetics [Repressor Proteins], 030104 developmental biology, genetics [Apolipoproteins E], Human medicine, business, Neuroscience, 030217 neurology & neurosurgery, Meta-Analysis
Abstract

Genome-wide association studies in frontotemporal dementia showed limited success in identifying associated loci. This is possibly due to small sample size, allelic heterogeneity, small effect sizes of single genetic variants, and the necessity to statistically correct for testing millions of genetic variants. To overcome these issues, we performed gene-based association studies on 3348 clinically identified frontotemporal dementia cases and 9390 controls (discovery, replication and joint-cohort analyses). We report association of APOE and TOMM40 with behavioural variant frontotemporal dementia, and ARHGAP35 and SERPINA1 with progressive non-fluent aphasia. Further, we found the ɛ2 and ɛ4 alleles of APOE harbouring protective and risk increasing effects, respectively, in clinical subtypes of frontotemporal dementia against neurologically normal controls. The APOE-locus association with behavioural variant frontotemporal dementia indicates its potential risk-increasing role across different neurodegenerative diseases, whereas the novel genetic associations of ARHGAP35 and SERPINA1 with progressive non-fluent aphasia point towards a potential role of the stress-signalling pathway in its pathophysiology.

Published
2017

45. Deleterious ABCA7 mutations and transcript rescue mechanisms in early onset Alzheimer’s disease

Author

De Roeck A., Van den Bossche T., van der Zee J., Verheijen J., De Coster W., Van Dongen J., Dillen L., Baradaran-Heravi Y., Heeman B., Sanchez-Valle R., Lladó A., Nacmias B., Sorbi S., Gelpi E., Grau-Rivera O., Gómez-Tortosa E., Pastor P., Ortega-Cubero S., Pastor M.A., Graff C., Thonberg H., Benussi L., Ghidoni R., Binetti G., de Mendonça A., Martins M., Borroni B., Padovani A., Almeida M.R., Santana I., Diehl-Schmid J., Alexopoulos P., Clarimon J., Lleó A., Fortea J., Tsolaki M., Koutroumani M., Matej R., De Deyn P., Engelborghs S., Cras P., Van Broeckhoven C., Sleegers K., Bessi V., Bagnoli S., do Couto F.S., Verdelho A., Fratiglioni L., Rohan Z., Razquin C., Lorenzo E., Iglesias E., Seijo-Martínez M., Rene R., Gascon J., Campdelacreu J., and Blesa R.

Subjects
onset age, ABCA7 protein, human, Male, haplotype, frameshift mutation, prevalence, DNA sequence, nonsense mutation, gene frequency, Polymorphism, Single Nucleotide, Article, alternative RNA splicing, single nucleotide polymorphism, middle aged, Humans, controlled study, Genetic Predisposition to Disease, genetics, human, gene mutation, Age of Onset, protein expression, Genetic Association Studies, risk reduction, next generation sequencing, ABC transporter A7, missense mutation, adult, apolipoprotein E4, cohort analysis, major clinical study, gene linkage disequilibrium, unclassified drug, genetic code, aged, female, priority journal, genetic association study, Mutation, amino terminal sequence, ATP-Binding Cassette Transporters, disease severity, ABC transporter, Alzheimer disease, genetic predisposition, nonsense mediated mRNA decay
Abstract

Premature termination codon (PTC) mutations in the ATP-Binding Cassette, Sub-Family A, Member 7 gene (ABCA7) have recently been identified as intermediate-to-high penetrant risk factor for late-onset Alzheimer’s disease (LOAD). High variability, however, is observed in downstream ABCA7 mRNA and protein expression, disease penetrance, and onset age, indicative of unknown modifying factors. Here, we investigated the prevalence and disease penetrance of ABCA7 PTC mutations in a large early onset AD (EOAD)—control cohort, and examined the effect on transcript level with comprehensive third-generation long-read sequencing. We characterized the ABCA7 coding sequence with next-generation sequencing in 928 EOAD patients and 980 matched control individuals. With MetaSKAT rare variant association analysis, we observed a fivefold enrichment (p = 0.0004) of PTC mutations in EOAD patients (3%) versus controls (0.6%). Ten novel PTC mutations were only observed in patients, and PTC mutation carriers in general had an increased familial AD load. In addition, we observed nominal risk reducing trends for three common coding variants. Seven PTC mutations were further analyzed using targeted long-read cDNA sequencing on an Oxford Nanopore MinION platform. PTC-containing transcripts for each investigated PTC mutation were observed at varying proportion (5–41% of the total read count), implying incomplete nonsense-mediated mRNA decay (NMD). Furthermore, we distinguished and phased several previously unknown alternative splicing events (up to 30% of transcripts). In conjunction with PTC mutations, several of these novel ABCA7 isoforms have the potential to rescue deleterious PTC effects. In conclusion, ABCA7 PTC mutations play a substantial role in EOAD, warranting genetic screening of ABCA7 in genetically unexplained patients. Long-read cDNA sequencing revealed both varying degrees of NMD and transcript-modifying events, which may influence ABCA7 dosage, disease severity, and may create opportunities for therapeutic interventions in AD. © 2017, The Author(s).

Published
2017

46. Potato consumption does not increase blood pressure or incident hypertension in 2 cohorts of Spanish adults

Author

Hu, E.A., Martínez-González, Miguel Ángel, Salas-Salvadó, J., Corella, D., Ros, E., Fitó, Montserrat, García-Rodriguez, A., Estruch, R., Arós, F., Fiol, M., Lapetra, José, Tresserra-Rimbau, A., Amat, J., García Roselló, J., Sanchez-Villegas, A., Álvarez-Pérez, J., Amorós, M., Cervello, T., Díez Benítez, E., Rovira, M.A., Altirriba, J., Sáiz, C., Mata, M., Bautista-Castaño, Inmaculada, Maldonado Díaz, I., Fernández-Rodríguez, M. J., Duaso, I., Becerra-Tomás, Nerea, Trias, F., García, L., Brau, A., Sáez, G., Corbella, E., de Diego Salas, J., Fernández-Montero, A., Yuste, M.C., Prieto, R., Pérez-de-Ciriza, P., Bobe, I., Navajas, Sánchez-Ruiz, D., Schröder, H., Jurado-Ruiz, E., Portillo, M.P., Buil-Cosiales, P., Sarmiendo de la Fe, F., Sánchez Luque, J.J., Ferreira, C., Zazpe, I., Díez-Espino, Javier, Sarasa, I., Sanjulian, B., Marti, A., Sorlí, J.V., Portolés, O., Martínez, J. Alfredo, Baby, P., Ibarrola-Jurado, Nuria, Serrano-Martínez, M., Sánchez-Tainta, A., Fernández-Crehuet, Joaquín, Pascual, V., García-Arellano, A., Fernandez, M., Paris, F., Giménez, F.J., Basteara-Gortari, J., Extremera-Urabayen, J.V., Benítez Pont, R., Viñas, C., Algorta, J., Garcia-Pérez, L., Serra-Majem, L., Bonet, M.T., Riera, C., Arroyo-Azpa, C., Guarner, A., Sola-Larraza, A., Barcena, F., García, Y., Gutiérrez-Bedmar, M., Casas, R., Oreja-Arrayago, C., Lasanta-Sáez, M.J., Mena, G., Francisco, S., Cia-Lecumberri, P., García-Valdueza, M., Diáz, A., Elcarte-Lopez, T., Artal-Moneva, F., Martín, M.T., Vargas López, E., Medina-Remón, A., Iglesias, C., Esparza-López, J.M., Figuerido-Garmendia, E., Cabre, M., Coltell, O., Wärnberg, J., Tabar-Sarrias, J.A., Pages, M.A., Rebholz, C.M., Fernández-Urzainqui, L., Ariz-Arnedo, M.J., San Vicente, J., Martínez, P., Cabeza-Beunza, J.A., Simón, C., Rekondo, J., Sánchez, M.S., Pascual-Pascual, P., Martínez-Mazo, M.D., Arina-Vergara, E., Godoy, D., Ruiz-Gutiérrez, Valentina, Villanueva, P., Quinzavos, L., Manzano, E., Martin, F., de Juan, C., Basells, J., Pla, I., Tur, J.A., Vizcaino, J., Basora-Gallisa, J., Núñez-Córdoba, J.M., Segarra, R., Hernández, P., Araque, M., Giardina, S., Macua-Martínez, T., Gutierrez, E., Toledo, E., Pedret, R., Guasch-Ferré, Marta, Baena, J.M., Pintó, Xavier, Díaz-López, A., Rosique-Esteban, N., Fernández-Ballart, J., Parra, L., Velasco García, V., Balanza, R., Tello, S., Ramos, A., Simón García, C., Vila, J., Altés, A., Proenza, A., de la Torre, Rafael, Muñoz-Aguayo, D., Murillo, C., Fernández-Carrión, R., Rodríguez, M.A., Elosua, R., Tort, N., Casi, A., Falcón Sanabria, I., Marrugat, J., Ruiz-Canela, M., Carratalá-Calvo, A., Mengual, L., Guillem-Saiz, P., Molina, N., Maestre, E., Gómez-Huelgas, R., Corbella, X., Rovira, A., González, R., Castañer, O., Farré, M., Sanz, E., García, J., González-Monje, I., Sánchez-Navarro, S., Carrasco, P., Ortega-Azorín, C., Romaguera, D., Roura, P., Asensio, E.M., Vázquez-Ruiz, Z., Canudas, S., Osma, R., Barragán, R., Muñoz, M.A., Martínez-González, J., Razquin, C., Valero-Barceló, C., Felipe, I., Francés, F., Guillén, M., González, J.I., Macías Gutiérrez, B., Tafalla, M., Bulló, M., Salaverria, I., Loma-Osorio, A., Baca Osorio, A., Munuera, S., Alonso, A., Sorlí, J., Vivó, M., Benitez Pont, R., Llauradó, M., Bestard, F., Montero Romero, Emilio, Molina, C., Munar, J.A., Cofán, M., Papandreou, C., Frontera, G., Coll, L., Quiles, L., Isach, A., Bes-Rastrollo, M., Perona, Javier S., Fiol, F., del Hierro, T., Ginard, M., Jover, A., Liroz, M., Parra-Osés, A., Gómez-Gracia, Enrique, Montull, I., Santos-Lozano, J.M., Ortega-Calvo, M., Valls-Pedret, C., García, M., Leal, M., Gil Zarzosa, J., Rico, A., Serra-Mir, M., Martínez, E., Mellado, L., Babio, N., Santana Santana, A.J., Benavent, J., Miró-Moriano, L., De la Fuente-Arrillaga, C., Oller, M., Domínguez-Espinaco, C., Bianchi Alba, M., Vaquero-Diaz, S., Iglesias, P., Cabezas, C., Sala-Vila, A., de la Cruz, E., Román, P., Corchado, Y., Solis, E., Clos, J., Lozano-Rodríguez, J.M., Mestres, G., García-García, M., Lamuela-Raventós, Rosa M., López-Sabater, M.C., Santamaria, M.I., Salas-Huetos, A., Galera, A., Vinyoles, E., Castellote-Bargalló, A. I., Quifer-Rada, P., Gea, A., Pérez-Heras, A., Doménech, M., Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), and Junta de Andalucía

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Diastole, Medicine (miscellaneous), 030204 cardiovascular system & hematology, Mediterranean, 03 medical and health sciences, 0302 clinical medicine, Animal science, Glycemic load, SUN cohort, medicine, Humans, 030212 general & internal medicine, Intervention trial, Prospective cohort study, Potatoes, Generalized estimating equation, Aged, Solanum tuberosum, Aged, 80 and over, Nutrition and Dietetics, Increase blood pressure, business.industry, Incidence (epidemiology), PREDIMED study, Middle Aged, Diet, Blood pressure, Spain, Hypertension, Female, business
Abstract

5 Tablas, Background: Potatoes have a high glycemic load but also antioxidants, vitamins, and minerals. It is unclear what mechanisms are involved in relation to their effect on blood pressure (BP) and hypertension. Objectives: This study aimed to assess the association between potato consumption, BP changes, and the risk of hypertension in 2 Spanish populations. Methods: Separate analyses were performed in PREDIMED (PREvención con DIeta MEDiterránea), a multicenter nutrition intervention trial of adults aged 55-80 y, and the SUN (Seguimiento Universidad de Navarra) project, a prospective cohort made up of university graduates and educated adults with ages (means±SDs) of 42.7±13.3 y for men and 35.1± 10.7 y for women. In PREDIMED, generalized estimating equations adjusted for lifestyle and dietary characteristics were used to assess changes in BP across quintiles of total potato consumption during a 4-y follow-up. Controlled BP values (systolic BP < 140 mm Hg and diastolic BP < 90 mm Hg) during follow-up were also assessed. For SUN, multivariateadjusted HRs for incident hypertension during a mean 6.7-y follow-up were calculated. Results: In PREDIMED, the total potato intake was 81.9 ± 40.6 g/d. No overall differences in systolic or diastolic BP changes were detected based on consumption of potatoes. For total potatoes, the mean difference in change between quintile 5 (highest intake) and quintile 1 (lowest intake) in systolic BP after multivariate adjustment was 20.90 mm Hg (95% CI: -2.56, 0.76 mm Hg; P-trend = 0.1) and for diastolic BP was 20.02 mm Hg (95% CI: -0.93, 0.89 mm Hg; P-trend = 0.8). In SUN, the total potato consumption was 52.7 ± 33.6 g/d, and no significant association between potato consumption and hypertension incidence was observed in the fully adjusted HR for total potato consumption (quintile 5 compared with quintile 1: 0.98; 95% CI: 0.80, 1.19; P-trend = 0.8). Conclusions: Potato consumption is not associated with changes over 4 y in blood pressure among older adults in Spain or with the risk of hypertension among Spanish adults., Supported by the official funding agency for biomedical research of the Spanish Government, Instituto de Salud Carlos III through grants provided to research networks specifically developed for the trial (RTIC G03/140, to RE; RTIC RD 06/0045, to MAM-G) and through Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), and by grants from Centro Nacional de Investigaciones Cardiovasculares (CNIC 06/2007), Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Regional [Proyecto de Investigación (PI) 04-2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505 and PI13/00462], Ministerio de Ciencia e Innovación [Recursos y teconologia agroalimentarias (AGL)-2009-13906-C02 and AGL2010-22319-C03 and AGL2013-49083-C3-1-R], Fundación Mapfre 2010, the Consejería de Salud de la Junta de Andalucía (PI0105/2007), the Public Health Division of the Department of Health of the Autonomous Government of Catalonia, Generalitat Valenciana [Generalitat Valenciana Ayuda Complementaria (GVACOMP) 06109, GVACOMP2010-181, GVACOMP2011-151], Conselleria de Sanitat y AP; Atención Primaria (CS) 2010-AP-111 and CS2011-AP-042, and Regional Government of Navarra (P27/2011).

Published
2017

47. 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

48. Prediction of Cardiovascular Disease by the Framingham‐REGICOR Equation in the High‐Risk PREDIMED Cohort: Impact of the Mediterranean Diet Across Different Risk Strata

Author

Amor, Antonio J., primary, Serra‐Mir, Mercè, additional, Martínez‐González, Miguel A., additional, Corella, Dolores, additional, Salas‐Salvadó, Jordi, additional, Fitó, Montserrat, additional, Estruch, Ramón, additional, Serra‐Majem, Lluis, additional, Arós, Fernando, additional, Babio, Nancy, additional, Ros, Emilio, additional, Ortega, Emilio, additional, Pérez‐Heras, A., additional, Viñas, C., additional, Casas, R., additional, de Santamaría, L., additional, Romero, S., additional, Sacanella, E., additional, Chiva, G., additional, Valderas, P., additional, Arranz, S., additional, Baena, J. M., additional, García, M., additional, Oller, M., additional, Amat, J., additional, Duaso, I., additional, García, Y., additional, Iglesias, C., additional, Simón, C., additional, Quinzavos, Ll., additional, Parra, Ll., additional, Liroz, M., additional, Benavent, J., additional, Clos, J., additional, Pla, I., additional, Amorós, M., additional, Bonet, M. T., additional, Martin, M. T., additional, Sánchez, M. S., additional, Altirriba, J., additional, Manzano, E., additional, Altés, A., additional, Sala‐Vila, A., additional, Cofán, M., additional, Valls‐Pedret, C., additional, Freitas‐Simoes, T. M., additional, Doménech, M., additional, Gilabert, R., additional, Bargalló, N., additional, Bulló, M., additional, Basora, J., additional, González, R., additional, Díaz‐López, A., additional, Molina, C., additional, Mena, G., additional, Márquez, F., additional, Martínez, P., additional, Ibarrola, N., additional, Sorli, M., additional, García Roselló, J., additional, Martín, F., additional, Tort, N., additional, Isach, A., additional, Salas‐Huetos, A., additional, Becerra‐Tomás, N., additional, Rosique Esteban, N., additional, Cabré, J. J., additional, Mestres, G., additional, Paris, F., additional, Llaurado, M., additional, Pedret, R., additional, Basells, J., additional, Vizcaino, J., additional, Segarra, R., additional, Hernandez‐Alonso, P., additional, Giardina, S., additional, Ferreira‐Pego, C., additional, Papandreou, C., additional, Camacho, L., additional, Toledo, E., additional, Buil‐Cosiales, P., additional, Ruiz‐Canela, M., additional, Martínez, J. A., additional, Sanjulian, B., additional, Sánchez‐Tainta, A., additional, Diez‐Espino, J., additional, Razquin, C., additional, Garcia‐Arellano, A., additional, Goni, E., additional, Vazquez, Z., additional, Berrade, N., additional, Extremera‐Urabayen, V., additional, Eguaras, S., additional, Marti, A., additional, Arroyo‐Azpa, C., additional, García‐Pérez, L., additional, Villanueva Telleria, J., additional, Cortés Ugalde, F., additional, Sagredo Arce, T., additional, de la Noceda Montoy, M. D. García, additional, Vigata López, M. D., additional, Arceiz Campo, M. T., additional, Urtasun Samper, A., additional, Gueto Rubio, M. V., additional, Sola, A., additional, Goñi, N., additional, Lecea, O., additional, Tello, S., additional, Vila, J., additional, de la Torre, R., additional, Muñoz‐Aguayo, D., additional, Elosua, R., additional, Marrugat, J., additional, Schröder, H., additional, Molina, N., additional, Maestre, E., additional, Castañer, O., additional, Rovira, A., additional, Farre, M., additional, Sorli, J. V., additional, Zanon‐Moreno, V., additional, Carrasco, P., additional, Ortega‐Azorín, C., additional, Asensio, E. M., additional, Osma, R., additional, Barragán, R., additional, Francés, F., additional, Guillén, M., additional, González, J. I., additional, Saiz, C., additional, Portolés, O., additional, Giménez, F. J., additional, Coltell, O., additional, Guillem‐Saiz, P., additional, Quiles, L., additional, Pascual, V., additional, Riera, C., additional, Pages, M. A., additional, Godoy, D., additional, Carratala‐Calvo, A., additional, Martín‐Rillo, M. J., additional, Llopis‐Osorio, E., additional, Ruiz‐Baixauli, J., additional, Bertolín‐Muñoz, A., additional, Salaverría, I., additional, del Hierro, T., additional, Algorta, J., additional, Francisco, S., additional, Alonso‐Gómez, A., additional, Sanz, E., additional, Rekondo, J., additional, Bello, M. C., additional, Loma‐Osorio, A., additional, Gómez‐Gracia, E., additional, Warnberg, J., additional, Benítez Pont, R., additional, Bianchi Alba, M., additional, Gómez‐Huelgas, R., additional, Martínez‐González, J., additional, Velasco García, V., additional, de Diego Salas, J., additional, Baca Osorio, A., additional, Gil Zarzosa, J., additional, Sánchez Luque, J. J., additional, Vargas López, E., additional, Ruiz‐Gutiérrez, V., additional, Sánchez Perona, J., additional, Montero Romero, E., additional, García‐García, M., additional, Jurado‐Ruiz, E., additional, Fiol, M., additional, García‐Valdueza, M., additional, Moñino, M., additional, Proenza, A., additional, Prieto, R., additional, Frontera, G., additional, Ginard, M., additional, Fiol, F., additional, Jover, A., additional, Romaguera, D., additional, García, J., additional, Lapetra, J., additional, Santos‐Lozano, J. M., additional, Ortega‐Calvo, M., additional, Mellado, L., additional, Leal, M., additional, Martínez, E., additional, José García, F., additional, Román, P., additional, Iglesias, P., additional, Corchado, Y., additional, Miró, L., additional, Domínguez, C., additional, Lozano, J. M., additional, Mayoral, E., additional, Lamuela‐Raventós, R. M., additional, López‐Sabater, M. C., additional, Castellote‐Bargallo, A. 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Published
2017
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49. Assessing the role of the TREM2 p.R47H variant as a risk factor for Alzheimer's disease and frontotemporal dementia

Author

Ruiz A, Dols-Icardo O, Bullido MJ, Pastor P, Rodríguez-Rodríguez E, López de Munain A, de Pancorbo MM, Pérez-Tur J, Alvarez V, Antonell A, López-Arrieta J, Hernández I, Tárraga L, Boada M, Lleó A, Blesa R, Frank-García A, Sastre I, Razquin C, Ortega-Cubero S, Lorenzo E, Sánchez-Juan P, Combarros O, Moreno F, Gorostidi A, Elcoroaristizabal X, Baquero M, Coto E, Sánchez-Valle R, Clarimón J, and dementia genetic Spanish consortium (DEGESCO)

Subjects
mental disorders, Alzheimer's disease, Frontotemporal dementia, Genetic association, Rare variant, TREM2, p.R47H
Abstract

A non-synonymous genetic rare variant, rs75932628-T (p.R47H), in the TREM2 gene has recently been reported to be a strong genetic risk factor for Alzheimer's disease (AD). Also, rare recessive mutations have been associated with frontotemporal dementia (FTD). We aimed to investigate the role of p.R47H variant in AD and FTD through a multi-center study comprising 3172 AD and 682 FTD patients and 2169 healthy controls from Spain. We found that 0.6% of AD patients carried this variant compared to 0.1% of controls (odds ratio [OR] = 4.12, 95% confidence interval [CI] = 1.21-14.00, p = 0.014). A meta-analysis comprising 32,598 subjects from 4 previous studies demonstrated the large effect of the p.R47H variant in AD risk (OR = 4.11, 95% CI = 2.99-5.68, p = 5.27×10(-18)). We did not find an association between p.R47H and age of onset of AD or family history of dementia. Finally, none of the FTD patients harbored this genetic variant. These data strongly support the important role of p.R47H in AD risk, and suggest that this rare genetic variant is not related to FTD.

Published
2014

50. The Pro12Ala polymorphism of the PPARγ2 gene interacts with a Mediterranean Diet to prevent telomere shortening in the PREDIMED-NAVARRA randomized trial

Author

Marti, A. (Amelia), Zalba, G. (Guillermo), Martinez, J.A. (José Alfredo), Salas-Salvado, J. (Jordi), Corella, D. (Dolores), Razquin, C. (Cristina), Martinez-Gonzalez, M.A. (Miguel Ángel), and Garcia-Calzon, S. (Sonia)

Subjects
Nutrigenomics, Polymorphism, Telomere
Abstract

Background: The gene variant Pro/Ala (rs1801282) in the PPARγ2 has been associated with lower cardiovascular risk and greater benefit from lifestyle interventions. This polymorphism also seems to be associated with longer lifespan, but no information on telomere length (TL) is available. Our aim was to study the association between the Ala allele and changes in TL in high cardiovascular risk subjects, and the potential interaction with a Mediterranean Diet (MeDiet) pattern. Methods and Results: A total of 521 subjects (55-80 years) participating in the Prevención con Dieta Mediterránea (PREDIMED) randomized trial were genotyped. Changes in TL, measured by quantitative real-time PCR, were assessed over 5 years of a nutritional intervention which promoted adherence to the MeDiet. Interestingly, Ala carriers showed lower telomere shortening after 5 years, compared with the Pro/Pro genotype (P=0.031). This association was modulated by MeDiet since those Ala carriers who reported better conformity to the MeDiet exhibited increased TL (P

Published
2014

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