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1. Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Author

Le Guen, Yann, Luo, Guo, Ambati, Aditya, Damotte, Vincent, Jansen, Iris, Yu, Eric, Nicolas, Aude, de Rojasj, Itziar, Leal, Thiago Peixoto, Miyashita, Akinori, Bellenguez, Celine, Lian, Michelle Mulan, Parveen, Kayenat, Morizono, Takashi, Park, Hyeonseul, Grenier-Boley, Benjamin, Naito, Tatsuhiko, Kucukali, Fahri, Talyansky, Seth D., Yogeshwar, Selina Maria, Sempere, Vicente, Satake, Wataru, Alvarez, Victoria, Arosio, Beatrice, Belloy, Michael E., Benussi, Luisa, Boland, Anne, Borroni, Barbara, Bullido, Maria J., Caffarra, Paolo, Clarimon, Jordi, Daniele, Antonio, Darling, Daniel, Debette, Stephanie, Deleuze, Jean-Francois, Dichgans, Martin, Dufouil, Carole, During, Emmanuel, Duzel, Emrah, Galimberti, Daniela, Garcia-Ribas, Guillermo, Maria Garcia-Alberca, Jose, Garcia-Gonzalez, Pablo, Giedraitis, Vilmantas, Goldhardt, Oliver, Graff, Caroline, Grunblatt, Edna, Hanon, Olivier, Hausner, Lucrezia, Heilmann-Heimbach, Stefanie, Holstege, Henne, Hort, Jakub, Jung, Yoo Jin, Jurgen, Deckert, Kern, Silke, Kuulasmaa, Teemu, Lee, Kun Ho, Lin, Ling, Masullo, Carlo, Mecocci, Patrizia, Mehrabian, Shima, de Mendonca, Alexandre, Boada, Merce, Mir, Pablo, Moebus, Susanne, Moreno, Fermin, Nacmias, Benedetta, Nicolas, Gael, Niida, Shumpei, Nordestgaard, Borge G., Papenberg, Goran, Papma, Janne, Parnetti, Lucilla, Pasquier, Florence, Pastor, Pau, Peters, Oliver, Pijnenburg, Yolande A. L., Pinol-Ripoll, Gerard, Popp, Julius, Porcel, Laura Molina, Jordi Perez-Tur, Raquel Puertaj, Rainero, Innocenzo, Ramakers, Inez, Real, Luis M., Riedel-Heller, Steffi, Rodriguez-Rodriguez, Eloy, Ross, Owen A., Royo, Jose Luis, Rujescu, Dan, Scarmeas, Nikolaos, Scheltens, Philip, Scherbaum, Norbert, Schneider, Anja, Seripa, Davide, Skoog, Ingmar, Solfrizzi, Vincenzo, Spalletta, Gianfranco, Squassina, Alessio, van Swieten, John, Sanchez-Valle, Raquel, Tan, Eng-King, Tegos, Thomas, Teunissen, Charlotte, Thomassen, Jesper Qvist, Tremolizzo, Lucio, Vyhnalek, Martin, Verhey, Frans, Waern, Margda, Wiltfang, Jens, Zhangc, Jing, Zetterberg, Henrik, Blennow, Kaj, He, Zihuai, Williams, Julie, Amouyel, Philippe, Jessen, Frank, Kehoe, Patrick G., Andreassen, Ole A., Van Duin, Cornelia, Tsolaki, Magda, Sanchez-Juan, Pascual, Frikke-Schmidt, Ruth, Sleegers, Kristel, Todau, Tatsushi, Zettergren, Anna, Ingelsson, Martin, Okada, Yukinori, Rossi, Giacomina, Hiltunen, Mikko, Gim, Jungsoo, Ozaki, Kouichi, Sims, Rebecca, Foo, Jia Nee, van der Fliere, Wiesje, Ikeuchi, Takeshi, Ramirez, Alfredo, Mata, Ignacio, Ruiz, Agustin, Gan-Or, Ziv, Lambert, Jean-Charles, Greicius, Michael D., Mignot, Emmanuel, Le Guen, Yann, Luo, Guo, Ambati, Aditya, Damotte, Vincent, Jansen, Iris, Yu, Eric, Nicolas, Aude, de Rojasj, Itziar, Leal, Thiago Peixoto, Miyashita, Akinori, Bellenguez, Celine, Lian, Michelle Mulan, Parveen, Kayenat, Morizono, Takashi, Park, Hyeonseul, Grenier-Boley, Benjamin, Naito, Tatsuhiko, Kucukali, Fahri, Talyansky, Seth D., Yogeshwar, Selina Maria, Sempere, Vicente, Satake, Wataru, Alvarez, Victoria, Arosio, Beatrice, Belloy, Michael E., Benussi, Luisa, Boland, Anne, Borroni, Barbara, Bullido, Maria J., Caffarra, Paolo, Clarimon, Jordi, Daniele, Antonio, Darling, Daniel, Debette, Stephanie, Deleuze, Jean-Francois, Dichgans, Martin, Dufouil, Carole, During, Emmanuel, Duzel, Emrah, Galimberti, Daniela, Garcia-Ribas, Guillermo, Maria Garcia-Alberca, Jose, Garcia-Gonzalez, Pablo, Giedraitis, Vilmantas, Goldhardt, Oliver, Graff, Caroline, Grunblatt, Edna, Hanon, Olivier, Hausner, Lucrezia, Heilmann-Heimbach, Stefanie, Holstege, Henne, Hort, Jakub, Jung, Yoo Jin, Jurgen, Deckert, Kern, Silke, Kuulasmaa, Teemu, Lee, Kun Ho, Lin, Ling, Masullo, Carlo, Mecocci, Patrizia, Mehrabian, Shima, de Mendonca, Alexandre, Boada, Merce, Mir, Pablo, Moebus, Susanne, Moreno, Fermin, Nacmias, Benedetta, Nicolas, Gael, Niida, Shumpei, Nordestgaard, Borge G., Papenberg, Goran, Papma, Janne, Parnetti, Lucilla, Pasquier, Florence, Pastor, Pau, Peters, Oliver, Pijnenburg, Yolande A. L., Pinol-Ripoll, Gerard, Popp, Julius, Porcel, Laura Molina, Jordi Perez-Tur, Raquel Puertaj, Rainero, Innocenzo, Ramakers, Inez, Real, Luis M., Riedel-Heller, Steffi, Rodriguez-Rodriguez, Eloy, Ross, Owen A., Royo, Jose Luis, Rujescu, Dan, Scarmeas, Nikolaos, Scheltens, Philip, Scherbaum, Norbert, Schneider, Anja, Seripa, Davide, Skoog, Ingmar, Solfrizzi, Vincenzo, Spalletta, Gianfranco, Squassina, Alessio, van Swieten, John, Sanchez-Valle, Raquel, Tan, Eng-King, Tegos, Thomas, Teunissen, Charlotte, Thomassen, Jesper Qvist, Tremolizzo, Lucio, Vyhnalek, Martin, Verhey, Frans, Waern, Margda, Wiltfang, Jens, Zhangc, Jing, Zetterberg, Henrik, Blennow, Kaj, He, Zihuai, Williams, Julie, Amouyel, Philippe, Jessen, Frank, Kehoe, Patrick G., Andreassen, Ole A., Van Duin, Cornelia, Tsolaki, Magda, Sanchez-Juan, Pascual, Frikke-Schmidt, Ruth, Sleegers, Kristel, Todau, Tatsushi, Zettergren, Anna, Ingelsson, Martin, Okada, Yukinori, Rossi, Giacomina, Hiltunen, Mikko, Gim, Jungsoo, Ozaki, Kouichi, Sims, Rebecca, Foo, Jia Nee, van der Fliere, Wiesje, Ikeuchi, Takeshi, Ramirez, Alfredo, Mata, Ignacio, Ruiz, Agustin, Gan-Or, Ziv, Lambert, Jean-Charles, Greicius, Michael D., and Mignot, Emmanuel

Abstract

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1* 04:07, and intermediary with HLA-DRB1* 04:01 and HLA- DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased A beta 42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

Published
2023
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2. Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease

Author

European Research Council, Instituto de Salud Carlos III, Pérez-Tur, Jordi [0000-0002-9111-1712], European Alzheimer’s & Dementia Biobank Mendelian Randomization (EADB-MR), Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Celine, Grenier-Boley, Benjamin, Rojas, Itziar de, Castillo, Atahualpa, Parveen, Kayenat, Kucukali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Jurgen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Molina Porcel, Laura, Duzel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimón, Jordi, Moreno, Fermín, Pérez-Tur, Jordi, Bullido, Maria J., Pastor, Pau, Sánchez-Valle, Raquel, Álvarez, Victoria, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis Miguel, Piñol-Ripoll, Gerard, García-Alberca, José María, Royo, José Luis, Rodríguez-Rodríguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, Mendonça, Alexandre de, Mehrabian, Shima, Hort, Jakub, Vyhnalek, Martin, van der Lee, Sven, Graff, Caroline, Papenberg, Goran, Giedraitis, Vilmantas, Boland, Anne, Bacq-Daian, Delphine, Deleuze, Jean-Francois, Nicolas, Gael, Dufouil, Carole, Pasquier, Florence, Hanon, Olivier, Debette, Stephanie, Grunblatt, Edna, Popp, Julius, Benussi, Luisa, Galimberti, Daniela, Arosio, Beatrice, Mecocci, Patrizia, Solfrizzi, Vincenzo, Parnetti, Lucilla, Squassina, Alessio, Tremolizzo, Lucio, Borroni, Barbara, Nacmias, Benedetta, Sorbi, Sandro, Caffarra, Paolo, Seripa, Davide, Rainero, Innocenzo, Daniele, Antonio, Masullo, Carlo, Spalletta, Gianfranco, Williams, Julie, Amouyel, Philippe, Jessen, Frank, Kehoe, Patrick, Magda, Tsolaki, Rossi, Giacomina, Sánchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Andreassen, Ole A., Hiltunen, Mikko, Van Duijn, Cornelia, Sims, Rebecca, van der Flier, Wiesje, Ruiz, Agustín, Ramírez, Alfredo, Lambert, Jean-Charles, Frikke-Schmidt, Ruth, European Research Council, Instituto de Salud Carlos III, Pérez-Tur, Jordi [0000-0002-9111-1712], European Alzheimer’s & Dementia Biobank Mendelian Randomization (EADB-MR), Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Celine, Grenier-Boley, Benjamin, Rojas, Itziar de, Castillo, Atahualpa, Parveen, Kayenat, Kucukali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Jurgen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Molina Porcel, Laura, Duzel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimón, Jordi, Moreno, Fermín, Pérez-Tur, Jordi, Bullido, Maria J., Pastor, Pau, Sánchez-Valle, Raquel, Álvarez, Victoria, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis Miguel, Piñol-Ripoll, Gerard, García-Alberca, José María, Royo, José Luis, Rodríguez-Rodríguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, Mendonça, Alexandre de, Mehrabian, Shima, Hort, Jakub, Vyhnalek, Martin, van der Lee, Sven, Graff, Caroline, Papenberg, Goran, Giedraitis, Vilmantas, Boland, Anne, Bacq-Daian, Delphine, Deleuze, Jean-Francois, Nicolas, Gael, Dufouil, Carole, Pasquier, Florence, Hanon, Olivier, Debette, Stephanie, Grunblatt, Edna, Popp, Julius, Benussi, Luisa, Galimberti, Daniela, Arosio, Beatrice, Mecocci, Patrizia, Solfrizzi, Vincenzo, Parnetti, Lucilla, Squassina, Alessio, Tremolizzo, Lucio, Borroni, Barbara, Nacmias, Benedetta, Sorbi, Sandro, Caffarra, Paolo, Seripa, Davide, Rainero, Innocenzo, Daniele, Antonio, Masullo, Carlo, Spalletta, Gianfranco, Williams, Julie, Amouyel, Philippe, Jessen, Frank, Kehoe, Patrick, Magda, Tsolaki, Rossi, Giacomina, Sánchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Andreassen, Ole A., Hiltunen, Mikko, Van Duijn, Cornelia, Sims, Rebecca, van der Flier, Wiesje, Ruiz, Agustín, Ramírez, Alfredo, Lambert, Jean-Charles, and Frikke-Schmidt, Ruth

Abstract

Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, setting, and participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main outcomes and measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK

Published
2023

3. Genetic Associations between Modifiable Risk Factors and Alzheimer Disease

Author

Danish Heart Foundation, Lundbeck Foundation, Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Celine, Grenier-Boley, Benjamin, Rojas, Itziar de, Castillo, Atahualpa, Parveen, Kayenat, Kucukali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Jurgen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Molina Porcel, Laura, Duzel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimón, Jordi, Moreno, Fermín, Pérez-Tur, Jordi, Bullido, Maria J, Pastor, Pau, Sánchez-Valle, Raquel, Álvarez, Victoria, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis M, Pinol-Ripoll, Gerard, García-Alberca, José María, Royo, José Luis, Rodríguez-Rodríguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, Mendonça, Alexandre de, Mehrabian, Shima, Hort, Jakub, Vyhnalek, Martin, Van der Lee, Sven, Graff, Caroline, Papenberg, Goran, Giedraitis, Vilmantas, Boland, Anne, Bacq-Daian, Delphine, Deleuze, Jean-Francois, Nicolas, Gael, Dufouil, Carole, Pasquier, Florence, Hanon, Olivier, Debette, Stephanie, Grunblatt, Edna, Popp, Julius, Benussi, Luisa, Galimberti, Daniela, Arosio, Beatrice, Mecocci, Patrizia, Solfrizzi, Vincenzo, Parnetti, Lucilla, Squassina, Alessio, Tremolizzo, Lucio, Borroni, Barbara, Nacmias, Benedetta, Sorbi, Sandro, Caffarra, Paolo, Seripa, Davide, Rainero, Innocenzo, Daniele, Antonio, Masullo, Carlo, Spalletta, Gianfranco, Williams, Julie, Amouyel, Philippe, Jessen, Frank, Kehoe, Patrick, Magda, Tsolaki, Rossi, Giacomina, Sánchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Andreassen, Ole A., Hiltunen, Mikko, Van Duijn, Cornelia, Sims, Rebecca, Van der Flier, Wiesje, Ruiz, Agustin, Ramírez, Alfredo, Lambert, Jean-Charles, Frikke-Schmidt, Ruth, Danish Heart Foundation, Lundbeck Foundation, Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Celine, Grenier-Boley, Benjamin, Rojas, Itziar de, Castillo, Atahualpa, Parveen, Kayenat, Kucukali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Jurgen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Molina Porcel, Laura, Duzel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimón, Jordi, Moreno, Fermín, Pérez-Tur, Jordi, Bullido, Maria J, Pastor, Pau, Sánchez-Valle, Raquel, Álvarez, Victoria, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis M, Pinol-Ripoll, Gerard, García-Alberca, José María, Royo, José Luis, Rodríguez-Rodríguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, Mendonça, Alexandre de, Mehrabian, Shima, Hort, Jakub, Vyhnalek, Martin, Van der Lee, Sven, Graff, Caroline, Papenberg, Goran, Giedraitis, Vilmantas, Boland, Anne, Bacq-Daian, Delphine, Deleuze, Jean-Francois, Nicolas, Gael, Dufouil, Carole, Pasquier, Florence, Hanon, Olivier, Debette, Stephanie, Grunblatt, Edna, Popp, Julius, Benussi, Luisa, Galimberti, Daniela, Arosio, Beatrice, Mecocci, Patrizia, Solfrizzi, Vincenzo, Parnetti, Lucilla, Squassina, Alessio, Tremolizzo, Lucio, Borroni, Barbara, Nacmias, Benedetta, Sorbi, Sandro, Caffarra, Paolo, Seripa, Davide, Rainero, Innocenzo, Daniele, Antonio, Masullo, Carlo, Spalletta, Gianfranco, Williams, Julie, Amouyel, Philippe, Jessen, Frank, Kehoe, Patrick, Magda, Tsolaki, Rossi, Giacomina, Sánchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Andreassen, Ole A., Hiltunen, Mikko, Van Duijn, Cornelia, Sims, Rebecca, Van der Flier, Wiesje, Ruiz, Agustin, Ramírez, Alfredo, Lambert, Jean-Charles, and Frikke-Schmidt, Ruth

Abstract

Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, Setting, and Participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main Outcomes and Measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39106 participants with clinically diagnosed AD and 401577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK B

Published
2023

4. Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease

Author

European Alzheimer’s & Dementia Biobank Mendelian Randomization (EADB-MR), Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Celine, Grenier-Boley, Benjamin, Rojas, Itziar de, Castillo, Atahualpa, Parveen, Kayenat, Kucukali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Jurgen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Molina Porcel, Laura, Duzel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimón, Jordi, Moreno, Fermín, Pérez-Tur, Jordi, Bullido, Maria J., Pastor, Pau, Sánchez-Valle, Raquel, Álvarez, Victoria, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis M., Pinol-Ripoll, Gerard, García-Alberca, José María, Royo, José Luis, Rodríguez-Rodríguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, Mendonça, Alexandre de, Mehrabian, Shima, Hort, Jakub, Vyhnalek, Martin, van der Lee, Sven, Graff, Caroline, Papenberg, Goran, Giedraitis, Vilmantas, Boland, Anne, Bacq-Daian, Delphine, Deleuze, Jean-Francois, Nicolas, Gael, Dufouil, Carole, Pasquier, Florence, Hanon, Olivier, Debette, Stephanie, Grunblatt, Edna, Popp, Julius, Benussi, Luisa, Galimberti, Daniela, Arosio, Beatrice, Mecocci, Patrizia, Solfrizzi, Vincenzo, Parnetti, Lucilla, Squassina, Alessio, Tremolizzo, Lucio, Borroni, Barbara, Nacmias, Benedetta, Sorbi, Sandro, Caffarra, Paolo, Seripa, Davide, Rainero, Innocenzo, Daniele, Antonio, Masullo, Carlo, Spalletta, Gianfranco, Williams, Julie, Amouyel, Philippe, Jessen, Frank, Kehoe, Patrick, Magda, Tsolaki, Rossi, Giacomina, Sánchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Andreassen, Ole A., Hiltunen, Mikko, Van Duijn, Cornelia, Sims, Rebecca, van der Flier, Wiesje, Ruiz, Agustin, Ramírez, Alfredo, Lambert, Jean-Charles, Frikke-Schmidt, Ruth, European Research Council, Instituto de Salud Carlos III, and Pérez-Tur, Jordi

Subjects
Aged, 80 and over, Male, Causality, epidemiology [Alzheimer Disease], Risk Factors, Cholesterol, HDL, Humans, ethyl 4-azidophenyl-1,4-dithiobutyrimidate, Female, genetics [Alzheimer Disease], ddc:610, Aged
Abstract

17 páginas, 3 figuras, 2 tablas. Material suplementario accesible en : https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2805006, Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, setting, and participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main outcomes and measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]). Conclusions and relevance: This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation., The work for this manuscript was further supported by the CoSTREAM project (www.costream.eu) and funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 667375. Acción Estratégica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)–Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER–‘Una manera de hacer Europa’).

Published
2023
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5. Protective association of HLA‐DRB1*04 subtypes in neurodegenerative diseases implicates acetylated tau PHF6 sequences

Author

Guen, Yann Le, primary, Luo, Guo, additional, Ambati, Aditya, additional, Damotte, Vincent, additional, Jansen, Iris E, additional, Yu, Eric, additional, Nicolas, Aude, additional, de Rojas, Itziar, additional, Leal, Thiago Peixoto, additional, Miyashita, Akinori, additional, Bellenguez, Céline, additional, Lian, Michelle Mulan, additional, Parveen, Kayenat, additional, Morizono, Takashi, additional, Park, Hyeonseul, additional, Grenier‐Boley, Benjamin, additional, Naito, Tatsuhiko, additional, Küçükali, Fahri, additional, Talyansky, Seth D., additional, Yogeshwar, Selina Marie, additional, Sempere, Vicente, additional, Satake, Wataru, additional, Álvarez‐Martínez, Victoria, additional, Arosio, Beatrice, additional, Belloy, Michael E, additional, Benussi, Luisa, additional, Boland, Anne, additional, Borroni, Barbara, additional, Bullido, María J., additional, Caffarra, Paolo, additional, Clarimon, Jordi, additional, Daniele, Antonio, additional, Darling, Daniel, additional, Debette, Stéphanie, additional, Deleuze, Jean‐François, additional, Dichgans, Martin, additional, Dufouil, Carole, additional, During, Emmanuel, additional, Duzel, Emrah, additional, Galimberti, Daniela, additional, García‐Ribas, Guillermo, additional, García‐Alberca, Jose María, additional, García‐González, Pablo, additional, Giedraitis, Vilmantas, additional, Goldhardt, Oliver, additional, Graff, Caroline, additional, Grunblatt, Edna, additional, Hanon, Olivier, additional, Hausner, Lucrezia, additional, Heilmann‐Heimbach, Stefanie, additional, Holstege, Henne, additional, Hort, Jakub, additional, Jung, Yoo Jin, additional, Jurgen, Deckert, additional, Kern, Silke, additional, Kuulasmaa, Teemu, additional, Lee, Kun Ho, additional, Ling, Ling, additional, Masullo, Carlo, additional, Mecocci, Patrizia, additional, Mehrabian, Shima, additional, de Mendonça, Alexandre, additional, Boada, Mercè, additional, Mir, Pablo, additional, Moebus, Susanne, additional, Moreno, Fermin, additional, Nacmias, Benedetta, additional, Nicolas, Gaël, additional, Niida, Shumpei, additional, Nordestgaard, Børge G., additional, Papenberg, Goran, additional, Papma, Janne M., additional, Parnetti, Lucilla, additional, Pasquier, Florence, additional, Pastor, Pau, additional, Peters, Oliver, additional, Pijnenburg, Yolande A.L., additional, Piñol‐Ripoll, Gerard, additional, Popp, Julius, additional, Molina, Laura, additional, Puerta, Raquel, additional, Pérez‐Tur, Jordi, additional, Rainero, Innocenzo, additional, Real, Luis Miguel, additional, Riedel‐Heller, Steffi G., additional, Rodríguez, Eloy Rodríguez, additional, Royo, José Luís, additional, Rujescu, Dan, additional, Scarmeas, Nikolaos, additional, Scheltens, Philip, additional, Scherbaum, Norbert, additional, Schneider, Anja, additional, Seripa, Davide, additional, Skoog, Ingmar, additional, Solfrizzi, Vincenzo, additional, Spalletta, Gianfranco, additional, Squassina, Alessio, additional, van Swieten, John C, additional, Sanchez‐Valle, Raquel, additional, Tan, Eng‐King, additional, Tegos, Thomas, additional, Teunissen, Charlotte E., additional, Thomassen, Jesper Qvist, additional, Tremolizzo, Lucio, additional, Vyhnalek, Martin, additional, Verhey, Frans R.J., additional, Waern, Margda, additional, Wiltfang, Jens, additional, Zhang, Jing, additional, Zetterberg, Henrik, additional, Blennow, Kaj, additional, Williams, Julie, additional, Amouyel, Philippe, additional, Jessen, Frank, additional, Kehoe, Patrick G, additional, Andreassen, Ole, additional, van Duijn, Cornelia M, additional, Tsolaki, Magda, additional, Sanchez‐Juan, Pascual, additional, Frikke‐Schmidt, Ruth, additional, Sleegers, Kristel, additional, Toda, Tatsushi, additional, Zettergren, Anna, additional, Ingelsson, Martin, additional, Okada, Yukinori, additional, Rossi, Giacomina, additional, Hiltunen, Mikko, additional, Gim, Jungsoo, additional, Ozaki, Kouichi, additional, Sims, Rebecca, additional, Foo, Jia Nee, additional, van der Flier, Wiesje M., additional, Ikeuchi, Takeshi, additional, Ramirez, Alfredo, additional, Mata, Ignacio, additional, Ruiz, Agustin, additional, Gan‐Or, Ziv, additional, Lambert, Jean‐Charles, additional, Greicius, Michael D, additional, and Mignot, Emmanuel, additional

Published
2022
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6. Rare missense variant (R251G) on APOE counterbalances the Alzheimer’s disease risk associated with APOE‐ε4

Author

Guen, Yann Le, primary, Belloy, Michael E, additional, Grenier‐Boley, Benjamin, additional, de Rojas, Itziar, additional, Castillo, Atahualpa, additional, Jansen, Iris E, additional, Nicolas, Aude, additional, Bellenguez, Céline, additional, Dalmasso, Carolina, additional, Küçükali, Fahri, additional, Eger, Sarah J, additional, Álvarez‐Martínez, Victoria, additional, Arosio, Beatrice, additional, Benussi, Luisa, additional, Boland, Anne, additional, Borroni, Barbara, additional, Bullido, María J., additional, Caffarra, Paolo, additional, Clarimón, Jordi, additional, Daian, Delphine, additional, Daniele, Antonio, additional, Debette, Stéphanie, additional, Deleuze, Jean‐François, additional, Dichgans, Martin, additional, Dufouil, Carole, additional, Duzel, Emrah, additional, Galimberti, Daniela, additional, García‐Alberca, Jose María, additional, García‐González, Pablo, additional, Giedraitis, Vilmantas, additional, Grimmer, Timo, additional, Graff, Caroline, additional, Grunblatt, Edna, additional, Hanon, Olivier, additional, Hausner, Lucrezia, additional, Heilmann‐Heimbach, Stefanie, additional, Holstege, Henne, additional, Hort, Jakub, additional, Jurgen, Deckert, additional, Kuulasmaa, Teemu, additional, van der Lugt, Aad, additional, Masullo, Carlo, additional, Mecocci, Patrizia, additional, Mehrabian, Shima, additional, de Mendonça, Alexandre, additional, Boada, Mercè, additional, Mir, Pablo, additional, Moebus, Susanne, additional, Moreno, Fermin, additional, Nacmias, Benedetta, additional, Nicolas, Gaël, additional, Papenberg, Goran, additional, Parnetti, Lucilla, additional, Pasquier, Florence, additional, Pastor, Pau, additional, Peters, Oliver, additional, Pijnenburg, Yolande A.L., additional, Piñol‐Ripoll, Gerard, additional, Popp, Julius, additional, Molina, Laura, additional, Puerta, Raquel, additional, Pérez‐Tur, Jordi, additional, Rainero, Innocenzo, additional, Ramakers, Inez H.G.B., additional, Rasmussen, Katrine Laura, additional, Real, Luis Miguel, additional, Riedel‐Heller, Steffi G., additional, Rodríguez, Eloy Rodríguez, additional, Royo, José Luís, additional, Rujescu, Dan, additional, Scarmeas, Nikolaos, additional, Scheltens, Philip, additional, Scherbaum, Norbert, additional, Schneider, Anja, additional, Seripa, Davide, additional, Soininen, Hilkka, additional, Solfrizzi, Vincenzo, additional, Spalletta, Gianfranco, additional, Squassina, Alessio, additional, van Swieten, John C, additional, Sanchez‐Valle, Raquel, additional, Tegos, Thomas, additional, Thomassen, Jesper Qvist, additional, Tremolizzo, Lucio, additional, Verhey, Frans R.J., additional, Vyhnalek, Martin, additional, Wiltfang, Jens, additional, He, Zihuai, additional, Napolioni, Valerio, additional, Amouyel, Philippe, additional, Jessen, Frank, additional, Kehoe, Patrick G, additional, van Duijn, Cornelia M, additional, Tsolaki, Magda, additional, Sanchez‐Juan, Pascual, additional, Sleegers, Kristel, additional, Ingelsson, Martin, additional, Rossi, Giacomina, additional, Hiltunen, Mikko, additional, Sims, Rebecca, additional, van der Flier, Wiesje M., additional, Ramirez, Alfredo, additional, Andreassen, Ole, additional, Frikke‐Schmidt, Ruth, additional, Williams, Julie, additional, Ruiz, Agustin, additional, Lambert, Jean‐Charles, additional, and Greicius, Michael D, additional

Published
2022
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7. Rare copy number variation in posttraumatic stress disorder

Author

Adam X, Maihofer, Worrawat, Engchuan, Guillaume, Huguet, Marieke, Klein, Jeffrey R, MacDonald, Omar, Shanta, Bhooma, Thiruvahindrapuram, Martineau, Jean-Louis, Zohra, Saci, Sebastien, Jacquemont, Stephen W, Scherer, Elizabeth, Ketema, Allison E, Aiello, Ananda B, Amstadter, Esmina, Avdibegović, Dragan, Babic, Dewleen G, Baker, Jonathan I, Bisson, Marco P, Boks, Elizabeth A, Bolger, Richard A, Bryant, Angela C, Bustamante, Jose Miguel, Caldas-de-Almeida, Graça, Cardoso, Jurgen, Deckert, Douglas L, Delahanty, Katharina, Domschke, Boadie W, Dunlop, Alma, Dzubur-Kulenovic, Alexandra, Evans, Norah C, Feeny, Carol E, Franz, Aarti, Gautam, Elbert, Geuze, Aferdita, Goci, Rasha, Hammamieh, Miro, Jakovljevic, Marti, Jett, Ian, Jones, Milissa L, Kaufman, Ronald C, Kessler, Anthony P, King, William S, Kremen, Bruce R, Lawford, Lauren A M, Lebois, Catrin, Lewis, Israel, Liberzon, Sarah D, Linnstaedt, Bozo, Lugonja, Jurjen J, Luykx, Michael J, Lyons, Matig R, Mavissakalian, Katie A, McLaughlin, Samuel A, McLean, Divya, Mehta, Rebecca, Mellor, Charles Phillip, Morris, Seid, Muhie, Holly K, Orcutt, Matthew, Peverill, Andrew, Ratanatharathorn, Victoria B, Risbrough, Albert, Rizzo, Andrea L, Roberts, Alex O, Rothbaum, Barbara O, Rothbaum, Peter, Roy-Byrne, Kenneth J, Ruggiero, Bart P F, Rutten, Dick, Schijven, Julia S, Seng, Christina M, Sheerin, Michael A, Sorenson, Martin H, Teicher, Monica, Uddin, Robert J, Ursano, Christiaan H, Vinkers, Joanne, Voisey, Heike, Weber, Sherry, Winternitz, Miguel, Xavier, Ruoting, Yang, Ross, McD Young, Lori A, Zoellner, Rany M, Salem, Richard A, Shaffer, Tianying, Wu, Kerry J, Ressler, Murray B, Stein, Karestan C, Koenen, Jonathan, Sebat, Caroline M, Nievergelt, MUMC+: MA Psychiatrie (3), Psychiatrie & Neuropsychologie, RS: MHeNs - R3 - Neuroscience, Anatomy and neurosciences, Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, Centro de Estudos de Doenças Crónicas (CEDOC), and NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)

Subjects
Stress Disorders, Post-Traumatic, Cellular and Molecular Neuroscience, Psychiatry and Mental health, Genome, SDG 3 - Good Health and Well-being, DNA Copy Number Variations, Humans, Brain, Genetic Predisposition to Disease, Molecular Biology, Polymorphism, Single Nucleotide, Genome-Wide Association Study
Abstract

Funding Information: This work was supported by the National Institute of Mental Health/U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, MBS, KJRe, and KCK]), and National Institutes of Health (Grant No. 5U01MH109539 [to the Psychiatric Genomics Consortium] and Grant No. U19 MH069056 [to BWD])). Financial support for the PTSD PGC was provided by the Cohen Veterans Bioscience, Stanley Center for Psychiatric Research at the Broad Institute, and One Mind. Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience Statistical analyses were carried out on the LISA/Genetic Cluster Computer ( https://userinfo.surfsara.nl/systems/lisa ) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). Posttraumatic stress disorder (PTSD) is a heritable (h2 = 24–71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10−8). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q < 0.05), but these associations were not significant once NDD regions were removed. A larger sample size, better detection methods, and annotated resources of CNV are needed to explore this relationship further. publishersversion published

Published
2022
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8. Hormonal interactions with benzodiazepine binding sites in vitro

Author

Jurgen Deckert and Paul J. Marangos

Subjects
Male, medicine.drug_class, Stereochemistry, Prostaglandin, In Vitro Techniques, Pharmacology, Binding, Competitive, Clonazepam, General Biochemistry, Genetics and Molecular Biology, Radioligand Assay, chemistry.chemical_compound, Adrenal Cortex Hormones, medicine, Animals, General Pharmacology, Toxicology and Pharmaceutics, Binding site, Benzodiazepinones, Chemistry, musculoskeletal, neural, and ocular physiology, Rats, Inbred Strains, General Medicine, Receptors, GABA-A, Hormones, In vitro, Rats, Thyroxine, Benzodiazepine binding, Prostaglandins, Corticosteroid, Cortisone, medicine.drug, Hormone
Abstract

Prostaglandin A1 and hormones like corticosteroids and DL-Thyroxin (T4) inhibit binding of [3H]RO 5-4864 and [3H] Clonazepam to their respective binding sites with inhibition constants in the low micromolar range. The corticosteroid Cortisone inhibits [3H] RO 5-4864, but not [3H] Clonazepam binding in a competitive manner with an inhibition constant of 4.3 +/- 0.7 microM, Prostaglandin A1 inhibits [3H] Clonazepam, but not [3H] RO 5-4864 binding in a competitive manner with an inhibition constant of 6 +/- 1.2 microM and DL-Thyroxin (T4) inhibits both [3H] RO 5-4864 and [3H] Clonazepam binding with inhibition constants of 12.1 +/- 2.2 and 1.6 +/- 0.4 microM respectively. While the inhibition of [3H] RO 5-4864 binding by DL-Thyroxin (T4) is competitive, the inhibition of [3H] Clonazepam binding is of the mixed type as indicated by Scatchard Plot.

Published
1986
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