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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
Full Text: View/download PDF

2. 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
Full Text: View/download PDF

3. 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
Full Text: View/download PDF

4. 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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5. Genetic Associations between Modifiable Risk Factors and Alzheimer Disease:[Inkl. correction]

Author: Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Céline, Grenier-Boley, Benjamin, De Rojas, Itziar, Castillo, Atahualpa, Parveen, Kayenat, Küçükali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Jürgen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Porcel, Laura Molina, Düzel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimon, Jordi, Moreno, Fermin, Pérez-Tur, Jordi, Bullido, María J., Pastor, Pau, Sánchez-Valle, Raquel, Álvarez, Victoria, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis M., Piñol-Ripoll, Gerard, García-Alberca, Jose María, Royo, Jose Luís, Rodriguez-Rodriguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, De Mendonça, Alexandre, Mehrabian, Shima, Hort, Jakub, Vyhnalek, Martin, Van Der Lee, Sven, Graff, Caroline, Papenberg, Goran, Giedraitis, Vilmantas, Boland, Anne, Bacq-Daian, Delphine, Deleuze, Jean François, Nicolas, Gael, Dufouil, Carole, Pasquier, Florence, Hanon, Olivier, Debette, Stéphanie, Grünblatt, 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, Ramirez, Alfredo, Lambert, Jean Charles, Frikke-Schmidt, Ruth, Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Céline, Grenier-Boley, Benjamin, De Rojas, Itziar, Castillo, Atahualpa, Parveen, Kayenat, Küçükali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Jürgen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Porcel, Laura Molina, Düzel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimon, Jordi, Moreno, Fermin, Pérez-Tur, Jordi, Bullido, María J., Pastor, Pau, Sánchez-Valle, Raquel, Álvarez, Victoria, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis M., Piñol-Ripoll, Gerard, García-Alberca, Jose María, Royo, Jose Luís, Rodriguez-Rodriguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, De Mendonça, Alexandre, Mehrabian, Shima, Hort, Jakub, Vyhnalek, Martin, Van Der Lee, Sven, Graff, Caroline, Papenberg, Goran, Giedraitis, Vilmantas, Boland, Anne, Bacq-Daian, Delphine, Deleuze, Jean François, Nicolas, Gael, Dufouil, Carole, Pasquier, Florence, Hanon, Olivier, Debette, Stéphanie, Grünblatt, 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, Ramirez, 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 minimiz, 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 enti
Published: 2023

6. Genetic insights into resting heart rate and its role in cardiovascular disease

Author: van de Vegte, Yordi, Eppinga, Ruben P., van der Ende, M. Yldau, Hagemeijer, Yanick, Mahendran, Yuvaraj V., Salfati, Elias Y., Smith, Albert E., Tan, Vanessa, Arking, Dan V., Ntalla, Ioanna, Appel, Emil A., Schurmann, Claudia, Brody, Jennifer, Rueedi, Rico, Polasek, Ozren, Sveinbjornsson, Gardar, Lecoeur, Cecile, Ladenvall, Claes, Zhao, Jing Hua, Isaacs, Aaron, Wang, Lihua, Luan, Jian'an, Hwang, Shih-Jen, Mononen, Nina U., Auro, Kirsi F., Jackson, Anne, Bielak, Lawrence, Zeng, Linyao, Shah, Nabi, Nethander, Maria, Campbell, Archie, Rankinen, Tuomo, Pechlivanis, Sonali, Qi, Lu, Zhao, Wei, Rizzi, Federica, Tanaka, Toshiko, Robino, Antonietta, Cocca, Massimiliano, Lange, Leslie, Mueller-Nurasyid, Martina, Roselli, Carolina E., Zhang, Weihua, Kleber, Marcus J., Guo, Xiuqing, Lin, Henry E., Pavani, Francesca, Galesloot, Tessel, Noordam, Raymond E., Milaneschi, Yuri, Schraut, Katharina, den Hoed, Marcel, Degenhardt, Frauke E., Trompet, Stella, van den Berg, Marten, Pistis, Giorgio, Tham, Yih-Chung S., Weiss, Stefan L., Sim, Xueling J., Li, Hengtong M., van der Most, Peter, Nolte, Ilja, Lyytikaeinen, Leo-Pekka R., Said, M. Abdullah, Witte, Daniel, Iribarren, Carlos M., Launer, Lenore S., Ring, Susan, de Vries, Paul, Sever, Peter P., Linneberg, Allan, Bottinger, Erwin M., Padmanabhan, Sandosh, Psaty, Bruce, Sotoodehnia, Nona, Kolcic, Ivana, Roshandel, Delnaz D., Paterson, Andrew O., Arnar, David F., Gudbjartsson, Daniel, Holm, Hilma, Balkau, Beverley T., Silva, Claudia H., Newton-Cheh, Christopher, Nikus, Kjell, Salo, Perttu L., Mohlke, Karen A., Peyser, Patricia, Schunkert, Heribert, Lorentzon, Mattias, Lahti, Jari C., Rao, Dabeeru C., Cornelis, Marilyn D., Faul, Jessica A., Smith, Jennifer, Stolarz-Skrzypek, Katarzyna, Bandinelli, Stefania, Concas, Maria Pina, Sinagra, Gianfranco, Meitinger, Thomas, Waldenberger, Melanie F., Sinner, Moritz, Strauch, Konstantin E., Delgado, Graciela D., Taylor, Kent, Yao, Jie, Foco, Luisa, Melander, Olle, de Graaf, Jacqueline, de Mutsert, Renee, de Geus, Eco J. C., Johansson, Åsa, Joshi, Peter K., Lind, Lars, Franke, Andre W., Macfarlane, Peter V., Tarasov, Kirill, Tan, Nicholas B., Felix, Stephan, Tai, E-Shyong Q., Quek, Debra, Snieder, Harold, Ormel, Johan, Ingelsson, Martin, Lindgren, Cecilia P., Morris, Andrew T., Raitakari, Olli, Hansen, Torben, Assimes, Themistocles, Gudnason, Vilmundur J., Timpson, Nicholas C., Morrison, Alanna B., Munroe, Patricia P., Strachan, David, Grarup, Niels, Loos, Ruth J. F. R., Heckbert, Susan, Vollenweider, Peter, Hayward, Caroline, Stefansson, Kari, Froguel, Philippe, Groop, Leif J., Wareham, Nicholas M., van Duijn, Cornelia F., Feitosa, Mary J., O'Donnell, Christopher, Kaehoenen, Mika, Perola, Markus, Boehnke, Michael, Kardia, Sharon L. R., Erdmann, Jeanette, Palmer, Colin N. A., Ohlsson, Claes J., Porteous, David G., Eriksson, Johan, Bouchard, Claude, Moebus, Susanne, Kraft, Peter R., Weir, David, Cusi, Daniele, Ferrucci, Luigi, Ulivi, Sheila, Girotto, Giorgia, Correa, Adolfo, Kaeaeb, Stefan, Peters, Annette C., Chambers, John S., Kooner, Jaspal, Maerz, Winfried I., Rotter, Jerome A., Hicks, Andrew, Smith, J. Gustav, Kiemeney, Lambertus A. L. M. O., Mook-Kanamori, Dennis, Penninx, Brenda W. J. H., Gyllensten, Ulf, Wilson, James, Burgess, Stephen, Sundström, Johan, Lieb, Wolfgang, Jukema, J. Wouter, Eijgelsheim, Mark, Lakatta, Edward L. M., Cheng, Ching-Yu, Doerr, Marcus, Wong, Tien-Yin, Sabanayagam, Charumathi J., Oldehinkel, Albertine, Riese, Harriette, Lehtimaeki, Terho, Verweij, Niek, van der Harst, Pim, van de Vegte, Yordi, Eppinga, Ruben P., van der Ende, M. Yldau, Hagemeijer, Yanick, Mahendran, Yuvaraj V., Salfati, Elias Y., Smith, Albert E., Tan, Vanessa, Arking, Dan V., Ntalla, Ioanna, Appel, Emil A., Schurmann, Claudia, Brody, Jennifer, Rueedi, Rico, Polasek, Ozren, Sveinbjornsson, Gardar, Lecoeur, Cecile, Ladenvall, Claes, Zhao, Jing Hua, Isaacs, Aaron, Wang, Lihua, Luan, Jian'an, Hwang, Shih-Jen, Mononen, Nina U., Auro, Kirsi F., Jackson, Anne, Bielak, Lawrence, Zeng, Linyao, Shah, Nabi, Nethander, Maria, Campbell, Archie, Rankinen, Tuomo, Pechlivanis, Sonali, Qi, Lu, Zhao, Wei, Rizzi, Federica, Tanaka, Toshiko, Robino, Antonietta, Cocca, Massimiliano, Lange, Leslie, Mueller-Nurasyid, Martina, Roselli, Carolina E., Zhang, Weihua, Kleber, Marcus J., Guo, Xiuqing, Lin, Henry E., Pavani, Francesca, Galesloot, Tessel, Noordam, Raymond E., Milaneschi, Yuri, Schraut, Katharina, den Hoed, Marcel, Degenhardt, Frauke E., Trompet, Stella, van den Berg, Marten, Pistis, Giorgio, Tham, Yih-Chung S., Weiss, Stefan L., Sim, Xueling J., Li, Hengtong M., van der Most, Peter, Nolte, Ilja, Lyytikaeinen, Leo-Pekka R., Said, M. Abdullah, Witte, Daniel, Iribarren, Carlos M., Launer, Lenore S., Ring, Susan, de Vries, Paul, Sever, Peter P., Linneberg, Allan, Bottinger, Erwin M., Padmanabhan, Sandosh, Psaty, Bruce, Sotoodehnia, Nona, Kolcic, Ivana, Roshandel, Delnaz D., Paterson, Andrew O., Arnar, David F., Gudbjartsson, Daniel, Holm, Hilma, Balkau, Beverley T., Silva, Claudia H., Newton-Cheh, Christopher, Nikus, Kjell, Salo, Perttu L., Mohlke, Karen A., Peyser, Patricia, Schunkert, Heribert, Lorentzon, Mattias, Lahti, Jari C., Rao, Dabeeru C., Cornelis, Marilyn D., Faul, Jessica A., Smith, Jennifer, Stolarz-Skrzypek, Katarzyna, Bandinelli, Stefania, Concas, Maria Pina, Sinagra, Gianfranco, Meitinger, Thomas, Waldenberger, Melanie F., Sinner, Moritz, Strauch, Konstantin E., Delgado, Graciela D., Taylor, Kent, Yao, Jie, Foco, Luisa, Melander, Olle, de Graaf, Jacqueline, de Mutsert, Renee, de Geus, Eco J. C., Johansson, Åsa, Joshi, Peter K., Lind, Lars, Franke, Andre W., Macfarlane, Peter V., Tarasov, Kirill, Tan, Nicholas B., Felix, Stephan, Tai, E-Shyong Q., Quek, Debra, Snieder, Harold, Ormel, Johan, Ingelsson, Martin, Lindgren, Cecilia P., Morris, Andrew T., Raitakari, Olli, Hansen, Torben, Assimes, Themistocles, Gudnason, Vilmundur J., Timpson, Nicholas C., Morrison, Alanna B., Munroe, Patricia P., Strachan, David, Grarup, Niels, Loos, Ruth J. F. R., Heckbert, Susan, Vollenweider, Peter, Hayward, Caroline, Stefansson, Kari, Froguel, Philippe, Groop, Leif J., Wareham, Nicholas M., van Duijn, Cornelia F., Feitosa, Mary J., O'Donnell, Christopher, Kaehoenen, Mika, Perola, Markus, Boehnke, Michael, Kardia, Sharon L. R., Erdmann, Jeanette, Palmer, Colin N. A., Ohlsson, Claes J., Porteous, David G., Eriksson, Johan, Bouchard, Claude, Moebus, Susanne, Kraft, Peter R., Weir, David, Cusi, Daniele, Ferrucci, Luigi, Ulivi, Sheila, Girotto, Giorgia, Correa, Adolfo, Kaeaeb, Stefan, Peters, Annette C., Chambers, John S., Kooner, Jaspal, Maerz, Winfried I., Rotter, Jerome A., Hicks, Andrew, Smith, J. Gustav, Kiemeney, Lambertus A. L. M. O., Mook-Kanamori, Dennis, Penninx, Brenda W. J. H., Gyllensten, Ulf, Wilson, James, Burgess, Stephen, Sundström, Johan, Lieb, Wolfgang, Jukema, J. Wouter, Eijgelsheim, Mark, Lakatta, Edward L. M., Cheng, Ching-Yu, Doerr, Marcus, Wong, Tien-Yin, Sabanayagam, Charumathi J., Oldehinkel, Albertine, Riese, Harriette, Lehtimaeki, Terho, Verweij, Niek, and van der Harst, Pim
Abstract: The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
Published: 2023
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7. Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease

Author: Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Celine, Grenier-Boley, Benjamin, de Rojas, Itziar, Castillo, Atahualpa, Parveen, Kayenat, Kuecuekali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Juergen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Porcel, Laura Molina, Duezel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimon, Jordi, Moreno, Fermin, Perez-Tur, Jordi, Bullido, Maria J., Pastor, Pau, Sanchez-Valle, Raquel, Alvarez, Victoria, Boada, Merce, Garcia-Gonzalez, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis M., Pinol-Ripoll, Gerard, Garcia-Alberca, Jose Maria, Royo, Jose Luis, Rodriguez-Rodriguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, de Mendonca, Alexandre, 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, Gruenblatt, 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, Sanchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Andreassen, Ole A., Hiltunen, Mikko, Van Duijn, Cornelia, Sims, Rebecca, van der Flier, Wiesje, Ruiz, Agustin, Ramirez, Alfredo, Lambert, Jean-Charles, Frikke-Schmidt, Ruth, Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Celine, Grenier-Boley, Benjamin, de Rojas, Itziar, Castillo, Atahualpa, Parveen, Kayenat, Kuecuekali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Juergen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Porcel, Laura Molina, Duezel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimon, Jordi, Moreno, Fermin, Perez-Tur, Jordi, Bullido, Maria J., Pastor, Pau, Sanchez-Valle, Raquel, Alvarez, Victoria, Boada, Merce, Garcia-Gonzalez, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis M., Pinol-Ripoll, Gerard, Garcia-Alberca, Jose Maria, Royo, Jose Luis, Rodriguez-Rodriguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, de Mendonca, Alexandre, 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, Gruenblatt, 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, Sanchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Andreassen, Ole A., Hiltunen, Mikko, Van Duijn, Cornelia, Sims, Rebecca, van der Flier, Wiesje, Ruiz, Agustin, Ramirez, 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 Bio
Published: 2023
Full Text: View/download PDF

8. Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease

Author: Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Celine, Grenier-Boley, Benjamin, de Rojas, Itziar, Castillo, Atahualpa, Parveen, Kayenat, Kuecuekali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Juergen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Porcel, Laura Molina, Duezel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimon, Jordi, Moreno, Fermin, Perez-Tur, Jordi, Bullido, Maria J., Pastor, Pau, Sanchez-Valle, Raquel, Alvarez, Victoria, Boada, Merce, Garcia-Gonzalez, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis M., Pinol-Ripoll, Gerard, Garcia-Alberca, Jose Maria, Royo, Jose Luis, Rodriguez-Rodriguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, de Mendonca, Alexandre, 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, Gruenblatt, 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, Sanchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Andreassen, Ole A., Hiltunen, Mikko, Van Duijn, Cornelia, Sims, Rebecca, van der Flier, Wiesje, Ruiz, Agustin, Ramirez, Alfredo, Lambert, Jean-Charles, Frikke-Schmidt, Ruth, Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Celine, Grenier-Boley, Benjamin, de Rojas, Itziar, Castillo, Atahualpa, Parveen, Kayenat, Kuecuekali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Juergen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Porcel, Laura Molina, Duezel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimon, Jordi, Moreno, Fermin, Perez-Tur, Jordi, Bullido, Maria J., Pastor, Pau, Sanchez-Valle, Raquel, Alvarez, Victoria, Boada, Merce, Garcia-Gonzalez, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis M., Pinol-Ripoll, Gerard, Garcia-Alberca, Jose Maria, Royo, Jose Luis, Rodriguez-Rodriguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, de Mendonca, Alexandre, 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, Gruenblatt, 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, Sanchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Andreassen, Ole A., Hiltunen, Mikko, Van Duijn, Cornelia, Sims, Rebecca, van der Flier, Wiesje, Ruiz, Agustin, Ramirez, 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 Bio
Published: 2023
Full Text: View/download PDF

9. Genetic insights into resting heart rate and its role in cardiovascular disease

Author: van de Vegte, Yordi, Eppinga, Ruben P., van der Ende, M. Yldau, Hagemeijer, Yanick, Mahendran, Yuvaraj V., Salfati, Elias Y., Smith, Albert E., Tan, Vanessa, Arking, Dan V., Ntalla, Ioanna, Appel, Emil A., Schurmann, Claudia, Brody, Jennifer, Rueedi, Rico, Polasek, Ozren, Sveinbjornsson, Gardar, Lecoeur, Cecile, Ladenvall, Claes, Zhao, Jing Hua, Isaacs, Aaron, Wang, Lihua, Luan, Jian'an, Hwang, Shih-Jen, Mononen, Nina U., Auro, Kirsi F., Jackson, Anne, Bielak, Lawrence, Zeng, Linyao, Shah, Nabi, Nethander, Maria, Campbell, Archie, Rankinen, Tuomo, Pechlivanis, Sonali, Qi, Lu, Zhao, Wei, Rizzi, Federica, Tanaka, Toshiko, Robino, Antonietta, Cocca, Massimiliano, Lange, Leslie, Mueller-Nurasyid, Martina, Roselli, Carolina E., Zhang, Weihua, Kleber, Marcus J., Guo, Xiuqing, Lin, Henry E., Pavani, Francesca, Galesloot, Tessel, Noordam, Raymond E., Milaneschi, Yuri, Schraut, Katharina, den Hoed, Marcel, Degenhardt, Frauke E., Trompet, Stella, van den Berg, Marten, Pistis, Giorgio, Tham, Yih-Chung S., Weiss, Stefan L., Sim, Xueling J., Li, Hengtong M., van der Most, Peter, Nolte, Ilja, Lyytikaeinen, Leo-Pekka R., Said, M. Abdullah, Witte, Daniel, Iribarren, Carlos M., Launer, Lenore S., Ring, Susan, de Vries, Paul, Sever, Peter P., Linneberg, Allan, Bottinger, Erwin M., Padmanabhan, Sandosh, Psaty, Bruce, Sotoodehnia, Nona, Kolcic, Ivana, Roshandel, Delnaz D., Paterson, Andrew O., Arnar, David F., Gudbjartsson, Daniel, Holm, Hilma, Balkau, Beverley T., Silva, Claudia H., Newton-Cheh, Christopher, Nikus, Kjell, Salo, Perttu L., Mohlke, Karen A., Peyser, Patricia, Schunkert, Heribert, Lorentzon, Mattias, Lahti, Jari C., Rao, Dabeeru C., Cornelis, Marilyn D., Faul, Jessica A., Smith, Jennifer, Stolarz-Skrzypek, Katarzyna, Bandinelli, Stefania, Concas, Maria Pina, Sinagra, Gianfranco, Meitinger, Thomas, Waldenberger, Melanie F., Sinner, Moritz, Strauch, Konstantin E., Delgado, Graciela D., Taylor, Kent, Yao, Jie, Foco, Luisa, Melander, Olle, de Graaf, Jacqueline, de Mutsert, Renee, de Geus, Eco J. C., Johansson, Åsa, Joshi, Peter K., Lind, Lars, Franke, Andre W., Macfarlane, Peter V., Tarasov, Kirill, Tan, Nicholas B., Felix, Stephan, Tai, E-Shyong Q., Quek, Debra, Snieder, Harold, Ormel, Johan, Ingelsson, Martin, Lindgren, Cecilia P., Morris, Andrew T., Raitakari, Olli, Hansen, Torben, Assimes, Themistocles, Gudnason, Vilmundur J., Timpson, Nicholas C., Morrison, Alanna B., Munroe, Patricia P., Strachan, David, Grarup, Niels, Loos, Ruth J. F. R., Heckbert, Susan, Vollenweider, Peter, Hayward, Caroline, Stefansson, Kari, Froguel, Philippe, Groop, Leif J., Wareham, Nicholas M., van Duijn, Cornelia F., Feitosa, Mary J., O'Donnell, Christopher, Kaehoenen, Mika, Perola, Markus, Boehnke, Michael, Kardia, Sharon L. R., Erdmann, Jeanette, Palmer, Colin N. A., Ohlsson, Claes J., Porteous, David G., Eriksson, Johan, Bouchard, Claude, Moebus, Susanne, Kraft, Peter R., Weir, David, Cusi, Daniele, Ferrucci, Luigi, Ulivi, Sheila, Girotto, Giorgia, Correa, Adolfo, Kaeaeb, Stefan, Peters, Annette C., Chambers, John S., Kooner, Jaspal, Maerz, Winfried I., Rotter, Jerome A., Hicks, Andrew, Smith, J. Gustav, Kiemeney, Lambertus A. L. M. O., Mook-Kanamori, Dennis, Penninx, Brenda W. J. H., Gyllensten, Ulf, Wilson, James, Burgess, Stephen, Sundström, Johan, Lieb, Wolfgang, Jukema, J. Wouter, Eijgelsheim, Mark, Lakatta, Edward L. M., Cheng, Ching-Yu, Doerr, Marcus, Wong, Tien-Yin, Sabanayagam, Charumathi J., Oldehinkel, Albertine, Riese, Harriette, Lehtimaeki, Terho, Verweij, Niek, van der Harst, Pim, van de Vegte, Yordi, Eppinga, Ruben P., van der Ende, M. Yldau, Hagemeijer, Yanick, Mahendran, Yuvaraj V., Salfati, Elias Y., Smith, Albert E., Tan, Vanessa, Arking, Dan V., Ntalla, Ioanna, Appel, Emil A., Schurmann, Claudia, Brody, Jennifer, Rueedi, Rico, Polasek, Ozren, Sveinbjornsson, Gardar, Lecoeur, Cecile, Ladenvall, Claes, Zhao, Jing Hua, Isaacs, Aaron, Wang, Lihua, Luan, Jian'an, Hwang, Shih-Jen, Mononen, Nina U., Auro, Kirsi F., Jackson, Anne, Bielak, Lawrence, Zeng, Linyao, Shah, Nabi, Nethander, Maria, Campbell, Archie, Rankinen, Tuomo, Pechlivanis, Sonali, Qi, Lu, Zhao, Wei, Rizzi, Federica, Tanaka, Toshiko, Robino, Antonietta, Cocca, Massimiliano, Lange, Leslie, Mueller-Nurasyid, Martina, Roselli, Carolina E., Zhang, Weihua, Kleber, Marcus J., Guo, Xiuqing, Lin, Henry E., Pavani, Francesca, Galesloot, Tessel, Noordam, Raymond E., Milaneschi, Yuri, Schraut, Katharina, den Hoed, Marcel, Degenhardt, Frauke E., Trompet, Stella, van den Berg, Marten, Pistis, Giorgio, Tham, Yih-Chung S., Weiss, Stefan L., Sim, Xueling J., Li, Hengtong M., van der Most, Peter, Nolte, Ilja, Lyytikaeinen, Leo-Pekka R., Said, M. Abdullah, Witte, Daniel, Iribarren, Carlos M., Launer, Lenore S., Ring, Susan, de Vries, Paul, Sever, Peter P., Linneberg, Allan, Bottinger, Erwin M., Padmanabhan, Sandosh, Psaty, Bruce, Sotoodehnia, Nona, Kolcic, Ivana, Roshandel, Delnaz D., Paterson, Andrew O., Arnar, David F., Gudbjartsson, Daniel, Holm, Hilma, Balkau, Beverley T., Silva, Claudia H., Newton-Cheh, Christopher, Nikus, Kjell, Salo, Perttu L., Mohlke, Karen A., Peyser, Patricia, Schunkert, Heribert, Lorentzon, Mattias, Lahti, Jari C., Rao, Dabeeru C., Cornelis, Marilyn D., Faul, Jessica A., Smith, Jennifer, Stolarz-Skrzypek, Katarzyna, Bandinelli, Stefania, Concas, Maria Pina, Sinagra, Gianfranco, Meitinger, Thomas, Waldenberger, Melanie F., Sinner, Moritz, Strauch, Konstantin E., Delgado, Graciela D., Taylor, Kent, Yao, Jie, Foco, Luisa, Melander, Olle, de Graaf, Jacqueline, de Mutsert, Renee, de Geus, Eco J. C., Johansson, Åsa, Joshi, Peter K., Lind, Lars, Franke, Andre W., Macfarlane, Peter V., Tarasov, Kirill, Tan, Nicholas B., Felix, Stephan, Tai, E-Shyong Q., Quek, Debra, Snieder, Harold, Ormel, Johan, Ingelsson, Martin, Lindgren, Cecilia P., Morris, Andrew T., Raitakari, Olli, Hansen, Torben, Assimes, Themistocles, Gudnason, Vilmundur J., Timpson, Nicholas C., Morrison, Alanna B., Munroe, Patricia P., Strachan, David, Grarup, Niels, Loos, Ruth J. F. R., Heckbert, Susan, Vollenweider, Peter, Hayward, Caroline, Stefansson, Kari, Froguel, Philippe, Groop, Leif J., Wareham, Nicholas M., van Duijn, Cornelia F., Feitosa, Mary J., O'Donnell, Christopher, Kaehoenen, Mika, Perola, Markus, Boehnke, Michael, Kardia, Sharon L. R., Erdmann, Jeanette, Palmer, Colin N. A., Ohlsson, Claes J., Porteous, David G., Eriksson, Johan, Bouchard, Claude, Moebus, Susanne, Kraft, Peter R., Weir, David, Cusi, Daniele, Ferrucci, Luigi, Ulivi, Sheila, Girotto, Giorgia, Correa, Adolfo, Kaeaeb, Stefan, Peters, Annette C., Chambers, John S., Kooner, Jaspal, Maerz, Winfried I., Rotter, Jerome A., Hicks, Andrew, Smith, J. Gustav, Kiemeney, Lambertus A. L. M. O., Mook-Kanamori, Dennis, Penninx, Brenda W. J. H., Gyllensten, Ulf, Wilson, James, Burgess, Stephen, Sundström, Johan, Lieb, Wolfgang, Jukema, J. Wouter, Eijgelsheim, Mark, Lakatta, Edward L. M., Cheng, Ching-Yu, Doerr, Marcus, Wong, Tien-Yin, Sabanayagam, Charumathi J., Oldehinkel, Albertine, Riese, Harriette, Lehtimaeki, Terho, Verweij, Niek, and van der Harst, Pim
Abstract: The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
Published: 2023
Full Text: View/download PDF

10. Genetic insights into resting heart rate and its role in cardiovascular disease

Author: van de Vegte, Yordi, Eppinga, Ruben P., van der Ende, M. Yldau, Hagemeijer, Yanick, Mahendran, Yuvaraj V., Salfati, Elias Y., Smith, Albert E., Tan, Vanessa, Arking, Dan V., Ntalla, Ioanna, Appel, Emil A., Schurmann, Claudia, Brody, Jennifer, Rueedi, Rico, Polasek, Ozren, Sveinbjornsson, Gardar, Lecoeur, Cecile, Ladenvall, Claes, Zhao, Jing Hua, Isaacs, Aaron, Wang, Lihua, Luan, Jian'an, Hwang, Shih-Jen, Mononen, Nina U., Auro, Kirsi F., Jackson, Anne, Bielak, Lawrence, Zeng, Linyao, Shah, Nabi, Nethander, Maria, Campbell, Archie, Rankinen, Tuomo, Pechlivanis, Sonali, Qi, Lu, Zhao, Wei, Rizzi, Federica, Tanaka, Toshiko, Robino, Antonietta, Cocca, Massimiliano, Lange, Leslie, Mueller-Nurasyid, Martina, Roselli, Carolina E., Zhang, Weihua, Kleber, Marcus J., Guo, Xiuqing, Lin, Henry E., Pavani, Francesca, Galesloot, Tessel, Noordam, Raymond E., Milaneschi, Yuri, Schraut, Katharina, den Hoed, Marcel, Degenhardt, Frauke E., Trompet, Stella, van den Berg, Marten, Pistis, Giorgio, Tham, Yih-Chung S., Weiss, Stefan L., Sim, Xueling J., Li, Hengtong M., van der Most, Peter, Nolte, Ilja, Lyytikaeinen, Leo-Pekka R., Said, M. Abdullah, Witte, Daniel, Iribarren, Carlos M., Launer, Lenore S., Ring, Susan, de Vries, Paul, Sever, Peter P., Linneberg, Allan, Bottinger, Erwin M., Padmanabhan, Sandosh, Psaty, Bruce, Sotoodehnia, Nona, Kolcic, Ivana, Roshandel, Delnaz D., Paterson, Andrew O., Arnar, David F., Gudbjartsson, Daniel, Holm, Hilma, Balkau, Beverley T., Silva, Claudia H., Newton-Cheh, Christopher, Nikus, Kjell, Salo, Perttu L., Mohlke, Karen A., Peyser, Patricia, Schunkert, Heribert, Lorentzon, Mattias, Lahti, Jari C., Rao, Dabeeru C., Cornelis, Marilyn D., Faul, Jessica A., Smith, Jennifer, Stolarz-Skrzypek, Katarzyna, Bandinelli, Stefania, Concas, Maria Pina, Sinagra, Gianfranco, Meitinger, Thomas, Waldenberger, Melanie F., Sinner, Moritz, Strauch, Konstantin E., Delgado, Graciela D., Taylor, Kent, Yao, Jie, Foco, Luisa, Melander, Olle, de Graaf, Jacqueline, de Mutsert, Renee, de Geus, Eco J. C., Johansson, Åsa, Joshi, Peter K., Lind, Lars, Franke, Andre W., Macfarlane, Peter V., Tarasov, Kirill, Tan, Nicholas B., Felix, Stephan, Tai, E-Shyong Q., Quek, Debra, Snieder, Harold, Ormel, Johan, Ingelsson, Martin, Lindgren, Cecilia P., Morris, Andrew T., Raitakari, Olli, Hansen, Torben, Assimes, Themistocles, Gudnason, Vilmundur J., Timpson, Nicholas C., Morrison, Alanna B., Munroe, Patricia P., Strachan, David, Grarup, Niels, Loos, Ruth J. F. R., Heckbert, Susan, Vollenweider, Peter, Hayward, Caroline, Stefansson, Kari, Froguel, Philippe, Groop, Leif J., Wareham, Nicholas M., van Duijn, Cornelia F., Feitosa, Mary J., O'Donnell, Christopher, Kaehoenen, Mika, Perola, Markus, Boehnke, Michael, Kardia, Sharon L. R., Erdmann, Jeanette, Palmer, Colin N. A., Ohlsson, Claes J., Porteous, David G., Eriksson, Johan, Bouchard, Claude, Moebus, Susanne, Kraft, Peter R., Weir, David, Cusi, Daniele, Ferrucci, Luigi, Ulivi, Sheila, Girotto, Giorgia, Correa, Adolfo, Kaeaeb, Stefan, Peters, Annette C., Chambers, John S., Kooner, Jaspal, Maerz, Winfried I., Rotter, Jerome A., Hicks, Andrew, Smith, J. Gustav, Kiemeney, Lambertus A. L. M. O., Mook-Kanamori, Dennis, Penninx, Brenda W. J. H., Gyllensten, Ulf, Wilson, James, Burgess, Stephen, Sundström, Johan, Lieb, Wolfgang, Jukema, J. Wouter, Eijgelsheim, Mark, Lakatta, Edward L. M., Cheng, Ching-Yu, Doerr, Marcus, Wong, Tien-Yin, Sabanayagam, Charumathi J., Oldehinkel, Albertine, Riese, Harriette, Lehtimaeki, Terho, Verweij, Niek, van der Harst, Pim, van de Vegte, Yordi, Eppinga, Ruben P., van der Ende, M. Yldau, Hagemeijer, Yanick, Mahendran, Yuvaraj V., Salfati, Elias Y., Smith, Albert E., Tan, Vanessa, Arking, Dan V., Ntalla, Ioanna, Appel, Emil A., Schurmann, Claudia, Brody, Jennifer, Rueedi, Rico, Polasek, Ozren, Sveinbjornsson, Gardar, Lecoeur, Cecile, Ladenvall, Claes, Zhao, Jing Hua, Isaacs, Aaron, Wang, Lihua, Luan, Jian'an, Hwang, Shih-Jen, Mononen, Nina U., Auro, Kirsi F., Jackson, Anne, Bielak, Lawrence, Zeng, Linyao, Shah, Nabi, Nethander, Maria, Campbell, Archie, Rankinen, Tuomo, Pechlivanis, Sonali, Qi, Lu, Zhao, Wei, Rizzi, Federica, Tanaka, Toshiko, Robino, Antonietta, Cocca, Massimiliano, Lange, Leslie, Mueller-Nurasyid, Martina, Roselli, Carolina E., Zhang, Weihua, Kleber, Marcus J., Guo, Xiuqing, Lin, Henry E., Pavani, Francesca, Galesloot, Tessel, Noordam, Raymond E., Milaneschi, Yuri, Schraut, Katharina, den Hoed, Marcel, Degenhardt, Frauke E., Trompet, Stella, van den Berg, Marten, Pistis, Giorgio, Tham, Yih-Chung S., Weiss, Stefan L., Sim, Xueling J., Li, Hengtong M., van der Most, Peter, Nolte, Ilja, Lyytikaeinen, Leo-Pekka R., Said, M. Abdullah, Witte, Daniel, Iribarren, Carlos M., Launer, Lenore S., Ring, Susan, de Vries, Paul, Sever, Peter P., Linneberg, Allan, Bottinger, Erwin M., Padmanabhan, Sandosh, Psaty, Bruce, Sotoodehnia, Nona, Kolcic, Ivana, Roshandel, Delnaz D., Paterson, Andrew O., Arnar, David F., Gudbjartsson, Daniel, Holm, Hilma, Balkau, Beverley T., Silva, Claudia H., Newton-Cheh, Christopher, Nikus, Kjell, Salo, Perttu L., Mohlke, Karen A., Peyser, Patricia, Schunkert, Heribert, Lorentzon, Mattias, Lahti, Jari C., Rao, Dabeeru C., Cornelis, Marilyn D., Faul, Jessica A., Smith, Jennifer, Stolarz-Skrzypek, Katarzyna, Bandinelli, Stefania, Concas, Maria Pina, Sinagra, Gianfranco, Meitinger, Thomas, Waldenberger, Melanie F., Sinner, Moritz, Strauch, Konstantin E., Delgado, Graciela D., Taylor, Kent, Yao, Jie, Foco, Luisa, Melander, Olle, de Graaf, Jacqueline, de Mutsert, Renee, de Geus, Eco J. C., Johansson, Åsa, Joshi, Peter K., Lind, Lars, Franke, Andre W., Macfarlane, Peter V., Tarasov, Kirill, Tan, Nicholas B., Felix, Stephan, Tai, E-Shyong Q., Quek, Debra, Snieder, Harold, Ormel, Johan, Ingelsson, Martin, Lindgren, Cecilia P., Morris, Andrew T., Raitakari, Olli, Hansen, Torben, Assimes, Themistocles, Gudnason, Vilmundur J., Timpson, Nicholas C., Morrison, Alanna B., Munroe, Patricia P., Strachan, David, Grarup, Niels, Loos, Ruth J. F. R., Heckbert, Susan, Vollenweider, Peter, Hayward, Caroline, Stefansson, Kari, Froguel, Philippe, Groop, Leif J., Wareham, Nicholas M., van Duijn, Cornelia F., Feitosa, Mary J., O'Donnell, Christopher, Kaehoenen, Mika, Perola, Markus, Boehnke, Michael, Kardia, Sharon L. R., Erdmann, Jeanette, Palmer, Colin N. A., Ohlsson, Claes J., Porteous, David G., Eriksson, Johan, Bouchard, Claude, Moebus, Susanne, Kraft, Peter R., Weir, David, Cusi, Daniele, Ferrucci, Luigi, Ulivi, Sheila, Girotto, Giorgia, Correa, Adolfo, Kaeaeb, Stefan, Peters, Annette C., Chambers, John S., Kooner, Jaspal, Maerz, Winfried I., Rotter, Jerome A., Hicks, Andrew, Smith, J. Gustav, Kiemeney, Lambertus A. L. M. O., Mook-Kanamori, Dennis, Penninx, Brenda W. J. H., Gyllensten, Ulf, Wilson, James, Burgess, Stephen, Sundström, Johan, Lieb, Wolfgang, Jukema, J. Wouter, Eijgelsheim, Mark, Lakatta, Edward L. M., Cheng, Ching-Yu, Doerr, Marcus, Wong, Tien-Yin, Sabanayagam, Charumathi J., Oldehinkel, Albertine, Riese, Harriette, Lehtimaeki, Terho, Verweij, Niek, and van der Harst, Pim
Abstract: The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
Published: 2023
Full Text: View/download PDF

11. Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease

Author: Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Celine, Grenier-Boley, Benjamin, de Rojas, Itziar, Castillo, Atahualpa, Parveen, Kayenat, Kuecuekali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Juergen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Porcel, Laura Molina, Duezel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimon, Jordi, Moreno, Fermin, Perez-Tur, Jordi, Bullido, Maria J., Pastor, Pau, Sanchez-Valle, Raquel, Alvarez, Victoria, Boada, Merce, Garcia-Gonzalez, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis M., Pinol-Ripoll, Gerard, Garcia-Alberca, Jose Maria, Royo, Jose Luis, Rodriguez-Rodriguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, de Mendonca, Alexandre, 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, Gruenblatt, 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, Sanchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Andreassen, Ole A., Hiltunen, Mikko, Van Duijn, Cornelia, Sims, Rebecca, van der Flier, Wiesje, Ruiz, Agustin, Ramirez, Alfredo, Lambert, Jean-Charles, Frikke-Schmidt, Ruth, Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Celine, Grenier-Boley, Benjamin, de Rojas, Itziar, Castillo, Atahualpa, Parveen, Kayenat, Kuecuekali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Juergen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Porcel, Laura Molina, Duezel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimon, Jordi, Moreno, Fermin, Perez-Tur, Jordi, Bullido, Maria J., Pastor, Pau, Sanchez-Valle, Raquel, Alvarez, Victoria, Boada, Merce, Garcia-Gonzalez, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis M., Pinol-Ripoll, Gerard, Garcia-Alberca, Jose Maria, Royo, Jose Luis, Rodriguez-Rodriguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, de Mendonca, Alexandre, 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, Gruenblatt, 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, Sanchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Andreassen, Ole A., Hiltunen, Mikko, Van Duijn, Cornelia, Sims, Rebecca, van der Flier, Wiesje, Ruiz, Agustin, Ramirez, 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 Bio
Published: 2023
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12. Genetic insights into resting heart rate and its role in cardiovascular disease

Author: van de Vegte, Yordi, Eppinga, Ruben P., van der Ende, M. Yldau, Hagemeijer, Yanick, Mahendran, Yuvaraj V., Salfati, Elias Y., Smith, Albert E., Tan, Vanessa, Arking, Dan V., Ntalla, Ioanna, Appel, Emil A., Schurmann, Claudia, Brody, Jennifer, Rueedi, Rico, Polasek, Ozren, Sveinbjornsson, Gardar, Lecoeur, Cecile, Ladenvall, Claes, Zhao, Jing Hua, Isaacs, Aaron, Wang, Lihua, Luan, Jian'an, Hwang, Shih-Jen, Mononen, Nina U., Auro, Kirsi F., Jackson, Anne, Bielak, Lawrence, Zeng, Linyao, Shah, Nabi, Nethander, Maria, Campbell, Archie, Rankinen, Tuomo, Pechlivanis, Sonali, Qi, Lu, Zhao, Wei, Rizzi, Federica, Tanaka, Toshiko, Robino, Antonietta, Cocca, Massimiliano, Lange, Leslie, Mueller-Nurasyid, Martina, Roselli, Carolina E., Zhang, Weihua, Kleber, Marcus J., Guo, Xiuqing, Lin, Henry E., Pavani, Francesca, Galesloot, Tessel, Noordam, Raymond E., Milaneschi, Yuri, Schraut, Katharina, den Hoed, Marcel, Degenhardt, Frauke E., Trompet, Stella, van den Berg, Marten, Pistis, Giorgio, Tham, Yih-Chung S., Weiss, Stefan L., Sim, Xueling J., Li, Hengtong M., van der Most, Peter, Nolte, Ilja, Lyytikaeinen, Leo-Pekka R., Said, M. Abdullah, Witte, Daniel, Iribarren, Carlos M., Launer, Lenore S., Ring, Susan, de Vries, Paul, Sever, Peter P., Linneberg, Allan, Bottinger, Erwin M., Padmanabhan, Sandosh, Psaty, Bruce, Sotoodehnia, Nona, Kolcic, Ivana, Roshandel, Delnaz D., Paterson, Andrew O., Arnar, David F., Gudbjartsson, Daniel, Holm, Hilma, Balkau, Beverley T., Silva, Claudia H., Newton-Cheh, Christopher, Nikus, Kjell, Salo, Perttu L., Mohlke, Karen A., Peyser, Patricia, Schunkert, Heribert, Lorentzon, Mattias, Lahti, Jari C., Rao, Dabeeru C., Cornelis, Marilyn D., Faul, Jessica A., Smith, Jennifer, Stolarz-Skrzypek, Katarzyna, Bandinelli, Stefania, Concas, Maria Pina, Sinagra, Gianfranco, Meitinger, Thomas, Waldenberger, Melanie F., Sinner, Moritz, Strauch, Konstantin E., Delgado, Graciela D., Taylor, Kent, Yao, Jie, Foco, Luisa, Melander, Olle, de Graaf, Jacqueline, de Mutsert, Renee, de Geus, Eco J. C., Johansson, Åsa, Joshi, Peter K., Lind, Lars, Franke, Andre W., Macfarlane, Peter V., Tarasov, Kirill, Tan, Nicholas B., Felix, Stephan, Tai, E-Shyong Q., Quek, Debra, Snieder, Harold, Ormel, Johan, Ingelsson, Martin, Lindgren, Cecilia P., Morris, Andrew T., Raitakari, Olli, Hansen, Torben, Assimes, Themistocles, Gudnason, Vilmundur J., Timpson, Nicholas C., Morrison, Alanna B., Munroe, Patricia P., Strachan, David, Grarup, Niels, Loos, Ruth J. F. R., Heckbert, Susan, Vollenweider, Peter, Hayward, Caroline, Stefansson, Kari, Froguel, Philippe, Groop, Leif J., Wareham, Nicholas M., van Duijn, Cornelia F., Feitosa, Mary J., O'Donnell, Christopher, Kaehoenen, Mika, Perola, Markus, Boehnke, Michael, Kardia, Sharon L. R., Erdmann, Jeanette, Palmer, Colin N. A., Ohlsson, Claes J., Porteous, David G., Eriksson, Johan, Bouchard, Claude, Moebus, Susanne, Kraft, Peter R., Weir, David, Cusi, Daniele, Ferrucci, Luigi, Ulivi, Sheila, Girotto, Giorgia, Correa, Adolfo, Kaeaeb, Stefan, Peters, Annette C., Chambers, John S., Kooner, Jaspal, Maerz, Winfried I., Rotter, Jerome A., Hicks, Andrew, Smith, J. Gustav, Kiemeney, Lambertus A. L. M. O., Mook-Kanamori, Dennis, Penninx, Brenda W. J. H., Gyllensten, Ulf, Wilson, James, Burgess, Stephen, Sundström, Johan, Lieb, Wolfgang, Jukema, J. Wouter, Eijgelsheim, Mark, Lakatta, Edward L. M., Cheng, Ching-Yu, Doerr, Marcus, Wong, Tien-Yin, Sabanayagam, Charumathi J., Oldehinkel, Albertine, Riese, Harriette, Lehtimaeki, Terho, Verweij, Niek, van der Harst, Pim, van de Vegte, Yordi, Eppinga, Ruben P., van der Ende, M. Yldau, Hagemeijer, Yanick, Mahendran, Yuvaraj V., Salfati, Elias Y., Smith, Albert E., Tan, Vanessa, Arking, Dan V., Ntalla, Ioanna, Appel, Emil A., Schurmann, Claudia, Brody, Jennifer, Rueedi, Rico, Polasek, Ozren, Sveinbjornsson, Gardar, Lecoeur, Cecile, Ladenvall, Claes, Zhao, Jing Hua, Isaacs, Aaron, Wang, Lihua, Luan, Jian'an, Hwang, Shih-Jen, Mononen, Nina U., Auro, Kirsi F., Jackson, Anne, Bielak, Lawrence, Zeng, Linyao, Shah, Nabi, Nethander, Maria, Campbell, Archie, Rankinen, Tuomo, Pechlivanis, Sonali, Qi, Lu, Zhao, Wei, Rizzi, Federica, Tanaka, Toshiko, Robino, Antonietta, Cocca, Massimiliano, Lange, Leslie, Mueller-Nurasyid, Martina, Roselli, Carolina E., Zhang, Weihua, Kleber, Marcus J., Guo, Xiuqing, Lin, Henry E., Pavani, Francesca, Galesloot, Tessel, Noordam, Raymond E., Milaneschi, Yuri, Schraut, Katharina, den Hoed, Marcel, Degenhardt, Frauke E., Trompet, Stella, van den Berg, Marten, Pistis, Giorgio, Tham, Yih-Chung S., Weiss, Stefan L., Sim, Xueling J., Li, Hengtong M., van der Most, Peter, Nolte, Ilja, Lyytikaeinen, Leo-Pekka R., Said, M. Abdullah, Witte, Daniel, Iribarren, Carlos M., Launer, Lenore S., Ring, Susan, de Vries, Paul, Sever, Peter P., Linneberg, Allan, Bottinger, Erwin M., Padmanabhan, Sandosh, Psaty, Bruce, Sotoodehnia, Nona, Kolcic, Ivana, Roshandel, Delnaz D., Paterson, Andrew O., Arnar, David F., Gudbjartsson, Daniel, Holm, Hilma, Balkau, Beverley T., Silva, Claudia H., Newton-Cheh, Christopher, Nikus, Kjell, Salo, Perttu L., Mohlke, Karen A., Peyser, Patricia, Schunkert, Heribert, Lorentzon, Mattias, Lahti, Jari C., Rao, Dabeeru C., Cornelis, Marilyn D., Faul, Jessica A., Smith, Jennifer, Stolarz-Skrzypek, Katarzyna, Bandinelli, Stefania, Concas, Maria Pina, Sinagra, Gianfranco, Meitinger, Thomas, Waldenberger, Melanie F., Sinner, Moritz, Strauch, Konstantin E., Delgado, Graciela D., Taylor, Kent, Yao, Jie, Foco, Luisa, Melander, Olle, de Graaf, Jacqueline, de Mutsert, Renee, de Geus, Eco J. C., Johansson, Åsa, Joshi, Peter K., Lind, Lars, Franke, Andre W., Macfarlane, Peter V., Tarasov, Kirill, Tan, Nicholas B., Felix, Stephan, Tai, E-Shyong Q., Quek, Debra, Snieder, Harold, Ormel, Johan, Ingelsson, Martin, Lindgren, Cecilia P., Morris, Andrew T., Raitakari, Olli, Hansen, Torben, Assimes, Themistocles, Gudnason, Vilmundur J., Timpson, Nicholas C., Morrison, Alanna B., Munroe, Patricia P., Strachan, David, Grarup, Niels, Loos, Ruth J. F. R., Heckbert, Susan, Vollenweider, Peter, Hayward, Caroline, Stefansson, Kari, Froguel, Philippe, Groop, Leif J., Wareham, Nicholas M., van Duijn, Cornelia F., Feitosa, Mary J., O'Donnell, Christopher, Kaehoenen, Mika, Perola, Markus, Boehnke, Michael, Kardia, Sharon L. R., Erdmann, Jeanette, Palmer, Colin N. A., Ohlsson, Claes J., Porteous, David G., Eriksson, Johan, Bouchard, Claude, Moebus, Susanne, Kraft, Peter R., Weir, David, Cusi, Daniele, Ferrucci, Luigi, Ulivi, Sheila, Girotto, Giorgia, Correa, Adolfo, Kaeaeb, Stefan, Peters, Annette C., Chambers, John S., Kooner, Jaspal, Maerz, Winfried I., Rotter, Jerome A., Hicks, Andrew, Smith, J. Gustav, Kiemeney, Lambertus A. L. M. O., Mook-Kanamori, Dennis, Penninx, Brenda W. J. H., Gyllensten, Ulf, Wilson, James, Burgess, Stephen, Sundström, Johan, Lieb, Wolfgang, Jukema, J. Wouter, Eijgelsheim, Mark, Lakatta, Edward L. M., Cheng, Ching-Yu, Doerr, Marcus, Wong, Tien-Yin, Sabanayagam, Charumathi J., Oldehinkel, Albertine, Riese, Harriette, Lehtimaeki, Terho, Verweij, Niek, and van der Harst, Pim
Abstract: The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
Published: 2023
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13. Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease

Author: Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Celine, Grenier-Boley, Benjamin, de Rojas, Itziar, Castillo, Atahualpa, Parveen, Kayenat, Kuecuekali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Juergen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Porcel, Laura Molina, Duezel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimon, Jordi, Moreno, Fermin, Perez-Tur, Jordi, Bullido, Maria J., Pastor, Pau, Sanchez-Valle, Raquel, Alvarez, Victoria, Boada, Merce, Garcia-Gonzalez, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis M., Pinol-Ripoll, Gerard, Garcia-Alberca, Jose Maria, Royo, Jose Luis, Rodriguez-Rodriguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, de Mendonca, Alexandre, 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, Gruenblatt, 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, Sanchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Andreassen, Ole A., Hiltunen, Mikko, Van Duijn, Cornelia, Sims, Rebecca, van der Flier, Wiesje, Ruiz, Agustin, Ramirez, Alfredo, Lambert, Jean-Charles, Frikke-Schmidt, Ruth, Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Celine, Grenier-Boley, Benjamin, de Rojas, Itziar, Castillo, Atahualpa, Parveen, Kayenat, Kuecuekali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Juergen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Porcel, Laura Molina, Duezel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimon, Jordi, Moreno, Fermin, Perez-Tur, Jordi, Bullido, Maria J., Pastor, Pau, Sanchez-Valle, Raquel, Alvarez, Victoria, Boada, Merce, Garcia-Gonzalez, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis M., Pinol-Ripoll, Gerard, Garcia-Alberca, Jose Maria, Royo, Jose Luis, Rodriguez-Rodriguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, de Mendonca, Alexandre, 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, Gruenblatt, 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, Sanchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Andreassen, Ole A., Hiltunen, Mikko, Van Duijn, Cornelia, Sims, Rebecca, van der Flier, Wiesje, Ruiz, Agustin, Ramirez, 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 Bio
Published: 2023
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14. 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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15. Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease

Author: Luo, J, Thomassen, J, Bellenguez, C, Grenier-Boley, B, de Rojas, I, Castillo, A, Parveen, K, Küçükali, F, Nicolas, A, Peters, O, Schneider, A, Dichgans, M, Rujescu, D, Scherbaum, N, Jürgen, D, Riedel-Heller, S, Hausner, L, Porcel, L, Düzel, E, Grimmer, T, Wiltfang, J, Heilmann-Heimbach, S, Moebus, S, Tegos, T, Scarmeas, N, Clarimon, J, Moreno, F, Pérez-Tur, J, Bullido, M, Pastor, P, Sánchez-Valle, R, Álvarez, V, Boada, M, García-González, P, Puerta, R, Mir, P, Real, L, Piñol-Ripoll, G, García-Alberca, J, Royo, J, Rodriguez-Rodriguez, E, Soininen, H, Kuulasmaa, T, de Mendonça, A, Mehrabian, S, Hort, J, Vyhnalek, M, van der Lee, S, Graff, C, Papenberg, G, Giedraitis, V, Boland, A, Bacq-Daian, D, Deleuze, J, Nicolas, G, Dufouil, C, Pasquier, F, Hanon, O, Debette, S, Grünblatt, E, Popp, J, Benussi, L, Galimberti, D, Arosio, B, Mecocci, P, Solfrizzi, V, Parnetti, L, Squassina, A, Tremolizzo, L, Borroni, B, Nacmias, B, Sorbi, S, Caffarra, P, Seripa, D, Rainero, I, Daniele, A, Masullo, C, Spalletta, G, Williams, J, Amouyel, P, Jessen, F, Kehoe, P, Magda, T, Rossi, G, Sánchez-Juan, P, Sleegers, K, Ingelsson, M, Andreassen, O, Hiltunen, M, Van Duijn, C, Sims, R, van der Flier, W, Ruiz, A, Ramirez, A, Lambert, J, Frikke-Schmidt, R, Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Céline, Grenier-Boley, Benjamin, de Rojas, Itziar, Castillo, Atahualpa, Parveen, Kayenat, Küçükali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Jürgen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Porcel, Laura Molina, Düzel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimon, Jordi, Moreno, Fermin, Pérez-Tur, Jordi, Bullido, María J, Pastor, Pau, Sánchez-Valle, Raquel, Álvarez, Victoria, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis M, Piñol-Ripoll, Gerard, García-Alberca, Jose María, Royo, Jose Luís, Rodriguez-Rodriguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, de Mendonça, Alexandre, Mehrabian, Shima, Hort, Jakub, Vyhnalek, Martin, van der Lee, Sven, Graff, Caroline, Papenberg, Goran, Giedraitis, Vilmantas, Boland, Anne, Bacq-Daian, Delphine, Deleuze, Jean-François, Nicolas, Gael, Dufouil, Carole, Pasquier, Florence, Hanon, Olivier, Debette, Stéphanie, Grünblatt, 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, Ramirez, Alfredo, Lambert, Jean-Charles, Frikke-Schmidt, Ruth, Luo, J, Thomassen, J, Bellenguez, C, Grenier-Boley, B, de Rojas, I, Castillo, A, Parveen, K, Küçükali, F, Nicolas, A, Peters, O, Schneider, A, Dichgans, M, Rujescu, D, Scherbaum, N, Jürgen, D, Riedel-Heller, S, Hausner, L, Porcel, L, Düzel, E, Grimmer, T, Wiltfang, J, Heilmann-Heimbach, S, Moebus, S, Tegos, T, Scarmeas, N, Clarimon, J, Moreno, F, Pérez-Tur, J, Bullido, M, Pastor, P, Sánchez-Valle, R, Álvarez, V, Boada, M, García-González, P, Puerta, R, Mir, P, Real, L, Piñol-Ripoll, G, García-Alberca, J, Royo, J, Rodriguez-Rodriguez, E, Soininen, H, Kuulasmaa, T, de Mendonça, A, Mehrabian, S, Hort, J, Vyhnalek, M, van der Lee, S, Graff, C, Papenberg, G, Giedraitis, V, Boland, A, Bacq-Daian, D, Deleuze, J, Nicolas, G, Dufouil, C, Pasquier, F, Hanon, O, Debette, S, Grünblatt, E, Popp, J, Benussi, L, Galimberti, D, Arosio, B, Mecocci, P, Solfrizzi, V, Parnetti, L, Squassina, A, Tremolizzo, L, Borroni, B, Nacmias, B, Sorbi, S, Caffarra, P, Seripa, D, Rainero, I, Daniele, A, Masullo, C, Spalletta, G, Williams, J, Amouyel, P, Jessen, F, Kehoe, P, Magda, T, Rossi, G, Sánchez-Juan, P, Sleegers, K, Ingelsson, M, Andreassen, O, Hiltunen, M, Van Duijn, C, Sims, R, van der Flier, W, Ruiz, A, Ramirez, A, Lambert, J, Frikke-Schmidt, R, Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Céline, Grenier-Boley, Benjamin, de Rojas, Itziar, Castillo, Atahualpa, Parveen, Kayenat, Küçükali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Jürgen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Porcel, Laura Molina, Düzel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimon, Jordi, Moreno, Fermin, Pérez-Tur, Jordi, Bullido, María J, Pastor, Pau, Sánchez-Valle, Raquel, Álvarez, Victoria, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis M, Piñol-Ripoll, Gerard, García-Alberca, Jose María, Royo, Jose Luís, Rodriguez-Rodriguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, de Mendonça, Alexandre, Mehrabian, Shima, Hort, Jakub, Vyhnalek, Martin, van der Lee, Sven, Graff, Caroline, Papenberg, Goran, Giedraitis, Vilmantas, Boland, Anne, Bacq-Daian, Delphine, Deleuze, Jean-François, Nicolas, Gael, Dufouil, Carole, Pasquier, Florence, Hanon, Olivier, Debette, Stéphanie, Grünblatt, 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, Ramirez, 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
Published: 2023

16. Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease

Author: Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Celine, Grenier-Boley, Benjamin, de Rojas, Itziar, Castillo, Atahualpa, Parveen, Kayenat, Kuecuekali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Juergen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Porcel, Laura Molina, Duezel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimon, Jordi, Moreno, Fermin, Perez-Tur, Jordi, Bullido, Maria J., Pastor, Pau, Sanchez-Valle, Raquel, Alvarez, Victoria, Boada, Merce, Garcia-Gonzalez, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis M., Pinol-Ripoll, Gerard, Garcia-Alberca, Jose Maria, Royo, Jose Luis, Rodriguez-Rodriguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, de Mendonca, Alexandre, 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, Gruenblatt, 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, Sanchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Andreassen, Ole A., Hiltunen, Mikko, Van Duijn, Cornelia, Sims, Rebecca, van der Flier, Wiesje, Ruiz, Agustin, Ramirez, Alfredo, Lambert, Jean-Charles, Frikke-Schmidt, Ruth, Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Celine, Grenier-Boley, Benjamin, de Rojas, Itziar, Castillo, Atahualpa, Parveen, Kayenat, Kuecuekali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Juergen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Porcel, Laura Molina, Duezel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimon, Jordi, Moreno, Fermin, Perez-Tur, Jordi, Bullido, Maria J., Pastor, Pau, Sanchez-Valle, Raquel, Alvarez, Victoria, Boada, Merce, Garcia-Gonzalez, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis M., Pinol-Ripoll, Gerard, Garcia-Alberca, Jose Maria, Royo, Jose Luis, Rodriguez-Rodriguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, de Mendonca, Alexandre, 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, Gruenblatt, 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, Sanchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Andreassen, Ole A., Hiltunen, Mikko, Van Duijn, Cornelia, Sims, Rebecca, van der Flier, Wiesje, Ruiz, Agustin, Ramirez, 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 Bio
Published: 2023
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17. Genetic insights into resting heart rate and its role in cardiovascular disease

Author: van de Vegte, Yordi, Eppinga, Ruben P., van der Ende, M. Yldau, Hagemeijer, Yanick, Mahendran, Yuvaraj V., Salfati, Elias Y., Smith, Albert E., Tan, Vanessa, Arking, Dan V., Ntalla, Ioanna, Appel, Emil A., Schurmann, Claudia, Brody, Jennifer, Rueedi, Rico, Polasek, Ozren, Sveinbjornsson, Gardar, Lecoeur, Cecile, Ladenvall, Claes, Zhao, Jing Hua, Isaacs, Aaron, Wang, Lihua, Luan, Jian'an, Hwang, Shih-Jen, Mononen, Nina U., Auro, Kirsi F., Jackson, Anne, Bielak, Lawrence, Zeng, Linyao, Shah, Nabi, Nethander, Maria, Campbell, Archie, Rankinen, Tuomo, Pechlivanis, Sonali, Qi, Lu, Zhao, Wei, Rizzi, Federica, Tanaka, Toshiko, Robino, Antonietta, Cocca, Massimiliano, Lange, Leslie, Mueller-Nurasyid, Martina, Roselli, Carolina E., Zhang, Weihua, Kleber, Marcus J., Guo, Xiuqing, Lin, Henry E., Pavani, Francesca, Galesloot, Tessel, Noordam, Raymond E., Milaneschi, Yuri, Schraut, Katharina, den Hoed, Marcel, Degenhardt, Frauke E., Trompet, Stella, van den Berg, Marten, Pistis, Giorgio, Tham, Yih-Chung S., Weiss, Stefan L., Sim, Xueling J., Li, Hengtong M., van der Most, Peter, Nolte, Ilja, Lyytikaeinen, Leo-Pekka R., Said, M. Abdullah, Witte, Daniel, Iribarren, Carlos M., Launer, Lenore S., Ring, Susan, de Vries, Paul, Sever, Peter P., Linneberg, Allan, Bottinger, Erwin M., Padmanabhan, Sandosh, Psaty, Bruce, Sotoodehnia, Nona, Kolcic, Ivana, Roshandel, Delnaz D., Paterson, Andrew O., Arnar, David F., Gudbjartsson, Daniel, Holm, Hilma, Balkau, Beverley T., Silva, Claudia H., Newton-Cheh, Christopher, Nikus, Kjell, Salo, Perttu L., Mohlke, Karen A., Peyser, Patricia, Schunkert, Heribert, Lorentzon, Mattias, Lahti, Jari C., Rao, Dabeeru C., Cornelis, Marilyn D., Faul, Jessica A., Smith, Jennifer, Stolarz-Skrzypek, Katarzyna, Bandinelli, Stefania, Concas, Maria Pina, Sinagra, Gianfranco, Meitinger, Thomas, Waldenberger, Melanie F., Sinner, Moritz, Strauch, Konstantin E., Delgado, Graciela D., Taylor, Kent, Yao, Jie, Foco, Luisa, Melander, Olle, de Graaf, Jacqueline, de Mutsert, Renee, de Geus, Eco J. C., Johansson, Åsa, Joshi, Peter K., Lind, Lars, Franke, Andre W., Macfarlane, Peter V., Tarasov, Kirill, Tan, Nicholas B., Felix, Stephan, Tai, E-Shyong Q., Quek, Debra, Snieder, Harold, Ormel, Johan, Ingelsson, Martin, Lindgren, Cecilia P., Morris, Andrew T., Raitakari, Olli, Hansen, Torben, Assimes, Themistocles, Gudnason, Vilmundur J., Timpson, Nicholas C., Morrison, Alanna B., Munroe, Patricia P., Strachan, David, Grarup, Niels, Loos, Ruth J. F. R., Heckbert, Susan, Vollenweider, Peter, Hayward, Caroline, Stefansson, Kari, Froguel, Philippe, Groop, Leif J., Wareham, Nicholas M., van Duijn, Cornelia F., Feitosa, Mary J., O'Donnell, Christopher, Kaehoenen, Mika, Perola, Markus, Boehnke, Michael, Kardia, Sharon L. R., Erdmann, Jeanette, Palmer, Colin N. A., Ohlsson, Claes J., Porteous, David G., Eriksson, Johan, Bouchard, Claude, Moebus, Susanne, Kraft, Peter R., Weir, David, Cusi, Daniele, Ferrucci, Luigi, Ulivi, Sheila, Girotto, Giorgia, Correa, Adolfo, Kaeaeb, Stefan, Peters, Annette C., Chambers, John S., Kooner, Jaspal, Maerz, Winfried I., Rotter, Jerome A., Hicks, Andrew, Smith, J. Gustav, Kiemeney, Lambertus A. L. M. O., Mook-Kanamori, Dennis, Penninx, Brenda W. J. H., Gyllensten, Ulf, Wilson, James, Burgess, Stephen, Sundström, Johan, Lieb, Wolfgang, Jukema, J. Wouter, Eijgelsheim, Mark, Lakatta, Edward L. M., Cheng, Ching-Yu, Doerr, Marcus, Wong, Tien-Yin, Sabanayagam, Charumathi J., Oldehinkel, Albertine, Riese, Harriette, Lehtimaeki, Terho, Verweij, Niek, van der Harst, Pim, van de Vegte, Yordi, Eppinga, Ruben P., van der Ende, M. Yldau, Hagemeijer, Yanick, Mahendran, Yuvaraj V., Salfati, Elias Y., Smith, Albert E., Tan, Vanessa, Arking, Dan V., Ntalla, Ioanna, Appel, Emil A., Schurmann, Claudia, Brody, Jennifer, Rueedi, Rico, Polasek, Ozren, Sveinbjornsson, Gardar, Lecoeur, Cecile, Ladenvall, Claes, Zhao, Jing Hua, Isaacs, Aaron, Wang, Lihua, Luan, Jian'an, Hwang, Shih-Jen, Mononen, Nina U., Auro, Kirsi F., Jackson, Anne, Bielak, Lawrence, Zeng, Linyao, Shah, Nabi, Nethander, Maria, Campbell, Archie, Rankinen, Tuomo, Pechlivanis, Sonali, Qi, Lu, Zhao, Wei, Rizzi, Federica, Tanaka, Toshiko, Robino, Antonietta, Cocca, Massimiliano, Lange, Leslie, Mueller-Nurasyid, Martina, Roselli, Carolina E., Zhang, Weihua, Kleber, Marcus J., Guo, Xiuqing, Lin, Henry E., Pavani, Francesca, Galesloot, Tessel, Noordam, Raymond E., Milaneschi, Yuri, Schraut, Katharina, den Hoed, Marcel, Degenhardt, Frauke E., Trompet, Stella, van den Berg, Marten, Pistis, Giorgio, Tham, Yih-Chung S., Weiss, Stefan L., Sim, Xueling J., Li, Hengtong M., van der Most, Peter, Nolte, Ilja, Lyytikaeinen, Leo-Pekka R., Said, M. Abdullah, Witte, Daniel, Iribarren, Carlos M., Launer, Lenore S., Ring, Susan, de Vries, Paul, Sever, Peter P., Linneberg, Allan, Bottinger, Erwin M., Padmanabhan, Sandosh, Psaty, Bruce, Sotoodehnia, Nona, Kolcic, Ivana, Roshandel, Delnaz D., Paterson, Andrew O., Arnar, David F., Gudbjartsson, Daniel, Holm, Hilma, Balkau, Beverley T., Silva, Claudia H., Newton-Cheh, Christopher, Nikus, Kjell, Salo, Perttu L., Mohlke, Karen A., Peyser, Patricia, Schunkert, Heribert, Lorentzon, Mattias, Lahti, Jari C., Rao, Dabeeru C., Cornelis, Marilyn D., Faul, Jessica A., Smith, Jennifer, Stolarz-Skrzypek, Katarzyna, Bandinelli, Stefania, Concas, Maria Pina, Sinagra, Gianfranco, Meitinger, Thomas, Waldenberger, Melanie F., Sinner, Moritz, Strauch, Konstantin E., Delgado, Graciela D., Taylor, Kent, Yao, Jie, Foco, Luisa, Melander, Olle, de Graaf, Jacqueline, de Mutsert, Renee, de Geus, Eco J. C., Johansson, Åsa, Joshi, Peter K., Lind, Lars, Franke, Andre W., Macfarlane, Peter V., Tarasov, Kirill, Tan, Nicholas B., Felix, Stephan, Tai, E-Shyong Q., Quek, Debra, Snieder, Harold, Ormel, Johan, Ingelsson, Martin, Lindgren, Cecilia P., Morris, Andrew T., Raitakari, Olli, Hansen, Torben, Assimes, Themistocles, Gudnason, Vilmundur J., Timpson, Nicholas C., Morrison, Alanna B., Munroe, Patricia P., Strachan, David, Grarup, Niels, Loos, Ruth J. F. R., Heckbert, Susan, Vollenweider, Peter, Hayward, Caroline, Stefansson, Kari, Froguel, Philippe, Groop, Leif J., Wareham, Nicholas M., van Duijn, Cornelia F., Feitosa, Mary J., O'Donnell, Christopher, Kaehoenen, Mika, Perola, Markus, Boehnke, Michael, Kardia, Sharon L. R., Erdmann, Jeanette, Palmer, Colin N. A., Ohlsson, Claes J., Porteous, David G., Eriksson, Johan, Bouchard, Claude, Moebus, Susanne, Kraft, Peter R., Weir, David, Cusi, Daniele, Ferrucci, Luigi, Ulivi, Sheila, Girotto, Giorgia, Correa, Adolfo, Kaeaeb, Stefan, Peters, Annette C., Chambers, John S., Kooner, Jaspal, Maerz, Winfried I., Rotter, Jerome A., Hicks, Andrew, Smith, J. Gustav, Kiemeney, Lambertus A. L. M. O., Mook-Kanamori, Dennis, Penninx, Brenda W. J. H., Gyllensten, Ulf, Wilson, James, Burgess, Stephen, Sundström, Johan, Lieb, Wolfgang, Jukema, J. Wouter, Eijgelsheim, Mark, Lakatta, Edward L. M., Cheng, Ching-Yu, Doerr, Marcus, Wong, Tien-Yin, Sabanayagam, Charumathi J., Oldehinkel, Albertine, Riese, Harriette, Lehtimaeki, Terho, Verweij, Niek, and van der Harst, Pim
Abstract: The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
Published: 2023
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18. Genetic Associations between Modifiable Risk Factors and Alzheimer Disease

Author: Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Céline, Grenier-Boley, Benjamin, De Rojas, Itziar, Castillo, Atahualpa, Parveen, Kayenat, Küçükali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Jürgen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Porcel, Laura Molina, Düzel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimon, Jordi, Moreno, Fermin, Pérez-Tur, Jordi, Bullido, María J., Pastor, Pau, Sánchez-Valle, Raquel, Álvarez, Victoria, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis M., Piñol-Ripoll, Gerard, García-Alberca, Jose María, Royo, Jose Luís, Rodriguez-Rodriguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, De Mendonça, Alexandre, Mehrabian, Shima, Hort, Jakub, Vyhnalek, Martin, Van Der Lee, Sven, Graff, Caroline, Papenberg, Goran, Giedraitis, Vilmantas, Boland, Anne, Bacq-Daian, Delphine, Deleuze, Jean François, Nicolas, Gael, Dufouil, Carole, Pasquier, Florence, Hanon, Olivier, Debette, Stéphanie, Grünblatt, 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, Ramirez, Alfredo, Lambert, Jean Charles, Frikke-Schmidt, Ruth, Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Céline, Grenier-Boley, Benjamin, De Rojas, Itziar, Castillo, Atahualpa, Parveen, Kayenat, Küçükali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Jürgen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Porcel, Laura Molina, Düzel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimon, Jordi, Moreno, Fermin, Pérez-Tur, Jordi, Bullido, María J., Pastor, Pau, Sánchez-Valle, Raquel, Álvarez, Victoria, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis M., Piñol-Ripoll, Gerard, García-Alberca, Jose María, Royo, Jose Luís, Rodriguez-Rodriguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, De Mendonça, Alexandre, Mehrabian, Shima, Hort, Jakub, Vyhnalek, Martin, Van Der Lee, Sven, Graff, Caroline, Papenberg, Goran, Giedraitis, Vilmantas, Boland, Anne, Bacq-Daian, Delphine, Deleuze, Jean François, Nicolas, Gael, Dufouil, Carole, Pasquier, Florence, Hanon, Olivier, Debette, Stéphanie, Grünblatt, 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, Ramirez, 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 enti
Published: 2023

19. Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease

Author: Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Céline, Grenier-Boley, Benjamin, de Rojas, Itziar, Castillo, Atahualpa, Parveen, Kayenat, Küçükali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Jürgen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Porcel, Laura Molina, Düzel, Emrah, Grimmer, Timo, Wiltfang, Jen, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thoma, Scarmeas, Nikolao, Clarimon, Jordi, Moreno, Fermin, Pérez-Tur, Jordi, Bullido, María J, Pastor, Pau, Sánchez-Valle, Raquel, Álvarez, Victoria, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis M, Piñol-Ripoll, Gerard, García-Alberca, Jose María, Royo, Jose Luí, Rodriguez-Rodriguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, de Mendonça, Alexandre, Mehrabian, Shima, Hort, Jakub, Vyhnalek, Martin, van der Lee, Sven, Graff, Caroline, Papenberg, Goran, Giedraitis, Vilmanta, Boland, Anne, Bacq-Daian, Delphine, Deleuze, Jean-Françoi, Nicolas, Gael, Dufouil, Carole, Pasquier, Florence, Hanon, Olivier, Debette, Stéphanie, Grünblatt, Edna, Popp, Juliu, 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, Ramirez, Alfredo, Lambert, Jean-Charle, Frikke-Schmidt, Ruth, Daniele, Antonio (ORCID:0000-0003-1641-5852), Masullo, Carlo (ORCID:0000-0001-7798-3410), Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Céline, Grenier-Boley, Benjamin, de Rojas, Itziar, Castillo, Atahualpa, Parveen, Kayenat, Küçükali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Jürgen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Porcel, Laura Molina, Düzel, Emrah, Grimmer, Timo, Wiltfang, Jen, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thoma, Scarmeas, Nikolao, Clarimon, Jordi, Moreno, Fermin, Pérez-Tur, Jordi, Bullido, María J, Pastor, Pau, Sánchez-Valle, Raquel, Álvarez, Victoria, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis M, Piñol-Ripoll, Gerard, García-Alberca, Jose María, Royo, Jose Luí, Rodriguez-Rodriguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, de Mendonça, Alexandre, Mehrabian, Shima, Hort, Jakub, Vyhnalek, Martin, van der Lee, Sven, Graff, Caroline, Papenberg, Goran, Giedraitis, Vilmanta, Boland, Anne, Bacq-Daian, Delphine, Deleuze, Jean-Françoi, Nicolas, Gael, Dufouil, Carole, Pasquier, Florence, Hanon, Olivier, Debette, Stéphanie, Grünblatt, Edna, Popp, Juliu, 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, Ramirez, Alfredo, Lambert, Jean-Charle, Frikke-Schmidt, Ruth, Daniele, Antonio (ORCID:0000-0003-1641-5852), and Masullo, Carlo (ORCID:0000-0001-7798-3410)
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 entir
Published: 2023

20. 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

21. Genetic Associations between Modifiable Risk Factors and Alzheimer Disease:[Inkl. correction]

Author: Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Céline, Grenier-Boley, Benjamin, De Rojas, Itziar, Castillo, Atahualpa, Parveen, Kayenat, Küçükali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Jürgen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Porcel, Laura Molina, Düzel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimon, Jordi, Moreno, Fermin, Pérez-Tur, Jordi, Bullido, María J., Pastor, Pau, Sánchez-Valle, Raquel, Álvarez, Victoria, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis M., Piñol-Ripoll, Gerard, García-Alberca, Jose María, Royo, Jose Luís, Rodriguez-Rodriguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, De Mendonça, Alexandre, Mehrabian, Shima, Hort, Jakub, Vyhnalek, Martin, Van Der Lee, Sven, Graff, Caroline, Papenberg, Goran, Giedraitis, Vilmantas, Boland, Anne, Bacq-Daian, Delphine, Deleuze, Jean François, Nicolas, Gael, Dufouil, Carole, Pasquier, Florence, Hanon, Olivier, Debette, Stéphanie, Grünblatt, 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, Ramirez, Alfredo, Lambert, Jean Charles, Frikke-Schmidt, Ruth, Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Céline, Grenier-Boley, Benjamin, De Rojas, Itziar, Castillo, Atahualpa, Parveen, Kayenat, Küçükali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Jürgen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Porcel, Laura Molina, Düzel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimon, Jordi, Moreno, Fermin, Pérez-Tur, Jordi, Bullido, María J., Pastor, Pau, Sánchez-Valle, Raquel, Álvarez, Victoria, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis M., Piñol-Ripoll, Gerard, García-Alberca, Jose María, Royo, Jose Luís, Rodriguez-Rodriguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, De Mendonça, Alexandre, Mehrabian, Shima, Hort, Jakub, Vyhnalek, Martin, Van Der Lee, Sven, Graff, Caroline, Papenberg, Goran, Giedraitis, Vilmantas, Boland, Anne, Bacq-Daian, Delphine, Deleuze, Jean François, Nicolas, Gael, Dufouil, Carole, Pasquier, Florence, Hanon, Olivier, Debette, Stéphanie, Grünblatt, 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, Ramirez, 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 minimiz, 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 enti
Published: 2023

22. 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

23. Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease

Author: Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Céline, Grenier-Boley, Benjamin, de Rojas, Itziar, Castillo, Atahualpa, Parveen, Kayenat, Küçükali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Jürgen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Porcel, Laura Molina, Düzel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimon, Jordi, Moreno, Fermin, Pérez-Tur, Jordi, Bullido, María J, et al, Grünblatt, Edna; https://orcid.org/0000-0001-8505-7265, Popp, Julius; https://orcid.org/0000-0002-0068-0312, Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Céline, Grenier-Boley, Benjamin, de Rojas, Itziar, Castillo, Atahualpa, Parveen, Kayenat, Küçükali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Jürgen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Porcel, Laura Molina, Düzel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimon, Jordi, Moreno, Fermin, Pérez-Tur, Jordi, Bullido, María J, et al, Grünblatt, Edna; https://orcid.org/0000-0001-8505-7265, and Popp, Julius; https://orcid.org/0000-0002-0068-0312
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

24. Definition-independent Formalization of Soundscapes: Towards a Formal Methodology

Author: Jedrusiak, Mikel D., Harweg, Thomas, Haselhoff, Timo, Lawrence, Bryce T., Moebus, Susanne, Weichert, Frank, Jedrusiak, Mikel D., Harweg, Thomas, Haselhoff, Timo, Lawrence, Bryce T., Moebus, Susanne, and Weichert, Frank
Abstract: Soundscapes have been studied by researchers from various disciplines, each with different perspectives, goals, approaches, and terminologies. Accordingly, depending on the field, the concept of a soundscape's components changes, consequently changing the basic definition. This results in complicating interdisciplinary communication and comparison of results. Especially when soundscape-unrelated research areas are involved. For this reason, we present a potential formalization that is independent of the underlying soundscape definition, with the goal of being able to capture the heterogeneous structure of the data as well as the different ideologies in one model. In an exemplary analysis of frequency correlation matrices for land use type detection as an alternative to features like MFCCs, we show a practical application of our presented formalization.
Published: 2023

25. First genome-wide association study of esophageal atresia identifies three genetic risk loci at CTNNA3, FOXF1/FOXC2/FOXL1, and HNF1B

Author: Gehlen, Jan, Giel, Ann-Sophie, Koellges, Ricarda, Haas, Stephan L., Zhang, Rong, Trcka, Jiri, Sungur, Ayse O., Renziehausen, Florian, Bornholdt, Dorothea, Jung, Daphne, Hoyer, Paul D., Nordenskjold, Agneta, Tibboel, Dick, Vlot, John, Spaander, Manon C. W., Smigiel, Robert, Patkowski, Dariusz, Roeleveld, Nel, van Rooij, Iris Alm, de Blaauw, Ivo, Hoelscher, Alice, Pauly, Marcus, Leutner, Andreas, Fuchs, Joerg, Niethammer, Joel, Melissari, Maria-Theodora, Jenetzky, Ekkehart, Zwink, Nadine, Thiele, Holger, Hilger, Alina Christine, Hess, Timo, Trautmann, Jessica, Marks, Matthias, Baumgarten, Martin, Blaess, Gaby, Landen, Mikael, Fundin, Bengt, Bulik, Cynthia M., Pennimpede, Tracie, Ludwig, Michael, Ludwig, Kerstin U., Mangold, Elisabeth, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Herrmann, Bernhard G., Alsabeah, Kristina, Burgos, Carmen M., Engstrand Lilja, Helene, Azodi, Sahar, Stenstrom, Pernilla, Arnbjornsson, Einar, Frybova, Barbora, Lebensztejn, Dariusz M., Debek, Wojciech, Kolodziejczyk, Elwira, Kozera, Katarzyna, Kierkus, Jaroslaw, Kalicinski, Piotr, Stefanowicz, Marek, Socha-Banasiak, Anna, Kolejwa, Michal, Piaseczna-Piotrowska, Anna, Czkwianianc, Elzbieta, Noethen, Markus M., Grote, Phillip, Rygl, Michal, Reinshagen, Konrad, Spychalski, Nicole, Ludwikowski, Barbara, Hubertus, Jochen, Heydweiller, Andreas, Ure, Benno, Muensterer, Oliver J., Aubert, Ophelia, Gosemann, Jan-Hendrik, Lacher, Martin, Degenhardt, Petra, Boemers, Thomas M., Mokrowiecka, Anna, Malecka-Panas, Ewa, Woehr, Markus, Knapp, Michael, Seitz, Guido, de Klein, Annelies, Oracz, Grzegorz, Brosens, Erwin, Reutter, Heiko, Schumacher, Johannes, Gehlen, Jan, Giel, Ann-Sophie, Koellges, Ricarda, Haas, Stephan L., Zhang, Rong, Trcka, Jiri, Sungur, Ayse O., Renziehausen, Florian, Bornholdt, Dorothea, Jung, Daphne, Hoyer, Paul D., Nordenskjold, Agneta, Tibboel, Dick, Vlot, John, Spaander, Manon C. W., Smigiel, Robert, Patkowski, Dariusz, Roeleveld, Nel, van Rooij, Iris Alm, de Blaauw, Ivo, Hoelscher, Alice, Pauly, Marcus, Leutner, Andreas, Fuchs, Joerg, Niethammer, Joel, Melissari, Maria-Theodora, Jenetzky, Ekkehart, Zwink, Nadine, Thiele, Holger, Hilger, Alina Christine, Hess, Timo, Trautmann, Jessica, Marks, Matthias, Baumgarten, Martin, Blaess, Gaby, Landen, Mikael, Fundin, Bengt, Bulik, Cynthia M., Pennimpede, Tracie, Ludwig, Michael, Ludwig, Kerstin U., Mangold, Elisabeth, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Herrmann, Bernhard G., Alsabeah, Kristina, Burgos, Carmen M., Engstrand Lilja, Helene, Azodi, Sahar, Stenstrom, Pernilla, Arnbjornsson, Einar, Frybova, Barbora, Lebensztejn, Dariusz M., Debek, Wojciech, Kolodziejczyk, Elwira, Kozera, Katarzyna, Kierkus, Jaroslaw, Kalicinski, Piotr, Stefanowicz, Marek, Socha-Banasiak, Anna, Kolejwa, Michal, Piaseczna-Piotrowska, Anna, Czkwianianc, Elzbieta, Noethen, Markus M., Grote, Phillip, Rygl, Michal, Reinshagen, Konrad, Spychalski, Nicole, Ludwikowski, Barbara, Hubertus, Jochen, Heydweiller, Andreas, Ure, Benno, Muensterer, Oliver J., Aubert, Ophelia, Gosemann, Jan-Hendrik, Lacher, Martin, Degenhardt, Petra, Boemers, Thomas M., Mokrowiecka, Anna, Malecka-Panas, Ewa, Woehr, Markus, Knapp, Michael, Seitz, Guido, de Klein, Annelies, Oracz, Grzegorz, Brosens, Erwin, Reutter, Heiko, and Schumacher, Johannes
Abstract: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is the most common congenital malformation of the upper digestive tract. This study represents the first genome-wide association study (GWAS) to identify risk loci for EA/TEF. We used a European case-control sample comprising 764 EA/TEF patients and 5,778 controls and observed genome-wide significant associations at three loci. On chromosome 10q21 within the gene CTNNA3 (p = 2.11 x 10(-8); odds ratio [OR] = 3.94; 95% confidence interval [CI], 3.10-5.00), on chromosome 16q24 next to the FOX gene cluster (p = 2.25 x 10(-10); OR = 1.47; 95% CI, 1.38-1.55) and on chromosome 17q12 next to the gene HNF1B (p = 3.35 x 10(-16); OR = 1.75; 95% CI, 1.64-1.87). We next carried out an esophageal/tracheal transcriptome profiling in rat embryos at four selected embryonic time points. Based on these data and on already published data, the implicated genes at all three GWAS loci are promising candidates for EA/TEF development. We also analyzed the genetic EA/TEF architecture beyond the single marker level, which revealed an estimated single-nucleotide polymorphism (SNP)-based heritability of around 37% +/- 14% standard deviation. In addition, we examined the polygenicity of EA/TEF and found that EA/TEF is less polygenic than other complex genetic diseases. In conclusion, the results of our study contribute to a better understanding on the underlying genetic architecture of ET/TEF with the identification of three risk loci and candidate genes.
Published: 2022
Full Text: View/download PDF

26. First genome-wide association study of esophageal atresia identifies three genetic risk loci at CTNNA3, FOXF1/FOXC2/FOXL1, and HNF1B

Author: Gehlen, Jan, Giel, Ann-Sophie, Koellges, Ricarda, Haas, Stephan L., Zhang, Rong, Trcka, Jiri, Sungur, Ayse O., Renziehausen, Florian, Bornholdt, Dorothea, Jung, Daphne, Hoyer, Paul D., Nordenskjold, Agneta, Tibboel, Dick, Vlot, John, Spaander, Manon C. W., Smigiel, Robert, Patkowski, Dariusz, Roeleveld, Nel, van Rooij, Iris Alm, de Blaauw, Ivo, Hoelscher, Alice, Pauly, Marcus, Leutner, Andreas, Fuchs, Joerg, Niethammer, Joel, Melissari, Maria-Theodora, Jenetzky, Ekkehart, Zwink, Nadine, Thiele, Holger, Hilger, Alina Christine, Hess, Timo, Trautmann, Jessica, Marks, Matthias, Baumgarten, Martin, Blaess, Gaby, Landen, Mikael, Fundin, Bengt, Bulik, Cynthia M., Pennimpede, Tracie, Ludwig, Michael, Ludwig, Kerstin U., Mangold, Elisabeth, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Herrmann, Bernhard G., Alsabeah, Kristina, Burgos, Carmen M., Engstrand Lilja, Helene, Azodi, Sahar, Stenstrom, Pernilla, Arnbjornsson, Einar, Frybova, Barbora, Lebensztejn, Dariusz M., Debek, Wojciech, Kolodziejczyk, Elwira, Kozera, Katarzyna, Kierkus, Jaroslaw, Kalicinski, Piotr, Stefanowicz, Marek, Socha-Banasiak, Anna, Kolejwa, Michal, Piaseczna-Piotrowska, Anna, Czkwianianc, Elzbieta, Noethen, Markus M., Grote, Phillip, Rygl, Michal, Reinshagen, Konrad, Spychalski, Nicole, Ludwikowski, Barbara, Hubertus, Jochen, Heydweiller, Andreas, Ure, Benno, Muensterer, Oliver J., Aubert, Ophelia, Gosemann, Jan-Hendrik, Lacher, Martin, Degenhardt, Petra, Boemers, Thomas M., Mokrowiecka, Anna, Malecka-Panas, Ewa, Woehr, Markus, Knapp, Michael, Seitz, Guido, de Klein, Annelies, Oracz, Grzegorz, Brosens, Erwin, Reutter, Heiko, Schumacher, Johannes, Gehlen, Jan, Giel, Ann-Sophie, Koellges, Ricarda, Haas, Stephan L., Zhang, Rong, Trcka, Jiri, Sungur, Ayse O., Renziehausen, Florian, Bornholdt, Dorothea, Jung, Daphne, Hoyer, Paul D., Nordenskjold, Agneta, Tibboel, Dick, Vlot, John, Spaander, Manon C. W., Smigiel, Robert, Patkowski, Dariusz, Roeleveld, Nel, van Rooij, Iris Alm, de Blaauw, Ivo, Hoelscher, Alice, Pauly, Marcus, Leutner, Andreas, Fuchs, Joerg, Niethammer, Joel, Melissari, Maria-Theodora, Jenetzky, Ekkehart, Zwink, Nadine, Thiele, Holger, Hilger, Alina Christine, Hess, Timo, Trautmann, Jessica, Marks, Matthias, Baumgarten, Martin, Blaess, Gaby, Landen, Mikael, Fundin, Bengt, Bulik, Cynthia M., Pennimpede, Tracie, Ludwig, Michael, Ludwig, Kerstin U., Mangold, Elisabeth, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Herrmann, Bernhard G., Alsabeah, Kristina, Burgos, Carmen M., Engstrand Lilja, Helene, Azodi, Sahar, Stenstrom, Pernilla, Arnbjornsson, Einar, Frybova, Barbora, Lebensztejn, Dariusz M., Debek, Wojciech, Kolodziejczyk, Elwira, Kozera, Katarzyna, Kierkus, Jaroslaw, Kalicinski, Piotr, Stefanowicz, Marek, Socha-Banasiak, Anna, Kolejwa, Michal, Piaseczna-Piotrowska, Anna, Czkwianianc, Elzbieta, Noethen, Markus M., Grote, Phillip, Rygl, Michal, Reinshagen, Konrad, Spychalski, Nicole, Ludwikowski, Barbara, Hubertus, Jochen, Heydweiller, Andreas, Ure, Benno, Muensterer, Oliver J., Aubert, Ophelia, Gosemann, Jan-Hendrik, Lacher, Martin, Degenhardt, Petra, Boemers, Thomas M., Mokrowiecka, Anna, Malecka-Panas, Ewa, Woehr, Markus, Knapp, Michael, Seitz, Guido, de Klein, Annelies, Oracz, Grzegorz, Brosens, Erwin, Reutter, Heiko, and Schumacher, Johannes
Abstract: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is the most common congenital malformation of the upper digestive tract. This study represents the first genome-wide association study (GWAS) to identify risk loci for EA/TEF. We used a European case-control sample comprising 764 EA/TEF patients and 5,778 controls and observed genome-wide significant associations at three loci. On chromosome 10q21 within the gene CTNNA3 (p = 2.11 x 10(-8); odds ratio [OR] = 3.94; 95% confidence interval [CI], 3.10-5.00), on chromosome 16q24 next to the FOX gene cluster (p = 2.25 x 10(-10); OR = 1.47; 95% CI, 1.38-1.55) and on chromosome 17q12 next to the gene HNF1B (p = 3.35 x 10(-16); OR = 1.75; 95% CI, 1.64-1.87). We next carried out an esophageal/tracheal transcriptome profiling in rat embryos at four selected embryonic time points. Based on these data and on already published data, the implicated genes at all three GWAS loci are promising candidates for EA/TEF development. We also analyzed the genetic EA/TEF architecture beyond the single marker level, which revealed an estimated single-nucleotide polymorphism (SNP)-based heritability of around 37% +/- 14% standard deviation. In addition, we examined the polygenicity of EA/TEF and found that EA/TEF is less polygenic than other complex genetic diseases. In conclusion, the results of our study contribute to a better understanding on the underlying genetic architecture of ET/TEF with the identification of three risk loci and candidate genes.
Published: 2022
Full Text: View/download PDF

27. First genome-wide association study of esophageal atresia identifies three genetic risk loci at CTNNA3, FOXF1/FOXC2/FOXL1, and HNF1B

Author: Gehlen, Jan, Giel, Ann-Sophie, Koellges, Ricarda, Haas, Stephan L., Zhang, Rong, Trcka, Jiri, Sungur, Ayse O., Renziehausen, Florian, Bornholdt, Dorothea, Jung, Daphne, Hoyer, Paul D., Nordenskjold, Agneta, Tibboel, Dick, Vlot, John, Spaander, Manon C. W., Smigiel, Robert, Patkowski, Dariusz, Roeleveld, Nel, van Rooij, Iris Alm, de Blaauw, Ivo, Hoelscher, Alice, Pauly, Marcus, Leutner, Andreas, Fuchs, Joerg, Niethammer, Joel, Melissari, Maria-Theodora, Jenetzky, Ekkehart, Zwink, Nadine, Thiele, Holger, Hilger, Alina Christine, Hess, Timo, Trautmann, Jessica, Marks, Matthias, Baumgarten, Martin, Blaess, Gaby, Landen, Mikael, Fundin, Bengt, Bulik, Cynthia M., Pennimpede, Tracie, Ludwig, Michael, Ludwig, Kerstin U., Mangold, Elisabeth, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Herrmann, Bernhard G., Alsabeah, Kristina, Burgos, Carmen M., Engstrand Lilja, Helene, Azodi, Sahar, Stenstrom, Pernilla, Arnbjornsson, Einar, Frybova, Barbora, Lebensztejn, Dariusz M., Debek, Wojciech, Kolodziejczyk, Elwira, Kozera, Katarzyna, Kierkus, Jaroslaw, Kalicinski, Piotr, Stefanowicz, Marek, Socha-Banasiak, Anna, Kolejwa, Michal, Piaseczna-Piotrowska, Anna, Czkwianianc, Elzbieta, Noethen, Markus M., Grote, Phillip, Rygl, Michal, Reinshagen, Konrad, Spychalski, Nicole, Ludwikowski, Barbara, Hubertus, Jochen, Heydweiller, Andreas, Ure, Benno, Muensterer, Oliver J., Aubert, Ophelia, Gosemann, Jan-Hendrik, Lacher, Martin, Degenhardt, Petra, Boemers, Thomas M., Mokrowiecka, Anna, Malecka-Panas, Ewa, Woehr, Markus, Knapp, Michael, Seitz, Guido, de Klein, Annelies, Oracz, Grzegorz, Brosens, Erwin, Reutter, Heiko, Schumacher, Johannes, Gehlen, Jan, Giel, Ann-Sophie, Koellges, Ricarda, Haas, Stephan L., Zhang, Rong, Trcka, Jiri, Sungur, Ayse O., Renziehausen, Florian, Bornholdt, Dorothea, Jung, Daphne, Hoyer, Paul D., Nordenskjold, Agneta, Tibboel, Dick, Vlot, John, Spaander, Manon C. W., Smigiel, Robert, Patkowski, Dariusz, Roeleveld, Nel, van Rooij, Iris Alm, de Blaauw, Ivo, Hoelscher, Alice, Pauly, Marcus, Leutner, Andreas, Fuchs, Joerg, Niethammer, Joel, Melissari, Maria-Theodora, Jenetzky, Ekkehart, Zwink, Nadine, Thiele, Holger, Hilger, Alina Christine, Hess, Timo, Trautmann, Jessica, Marks, Matthias, Baumgarten, Martin, Blaess, Gaby, Landen, Mikael, Fundin, Bengt, Bulik, Cynthia M., Pennimpede, Tracie, Ludwig, Michael, Ludwig, Kerstin U., Mangold, Elisabeth, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Herrmann, Bernhard G., Alsabeah, Kristina, Burgos, Carmen M., Engstrand Lilja, Helene, Azodi, Sahar, Stenstrom, Pernilla, Arnbjornsson, Einar, Frybova, Barbora, Lebensztejn, Dariusz M., Debek, Wojciech, Kolodziejczyk, Elwira, Kozera, Katarzyna, Kierkus, Jaroslaw, Kalicinski, Piotr, Stefanowicz, Marek, Socha-Banasiak, Anna, Kolejwa, Michal, Piaseczna-Piotrowska, Anna, Czkwianianc, Elzbieta, Noethen, Markus M., Grote, Phillip, Rygl, Michal, Reinshagen, Konrad, Spychalski, Nicole, Ludwikowski, Barbara, Hubertus, Jochen, Heydweiller, Andreas, Ure, Benno, Muensterer, Oliver J., Aubert, Ophelia, Gosemann, Jan-Hendrik, Lacher, Martin, Degenhardt, Petra, Boemers, Thomas M., Mokrowiecka, Anna, Malecka-Panas, Ewa, Woehr, Markus, Knapp, Michael, Seitz, Guido, de Klein, Annelies, Oracz, Grzegorz, Brosens, Erwin, Reutter, Heiko, and Schumacher, Johannes
Abstract: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is the most common congenital malformation of the upper digestive tract. This study represents the first genome-wide association study (GWAS) to identify risk loci for EA/TEF. We used a European case-control sample comprising 764 EA/TEF patients and 5,778 controls and observed genome-wide significant associations at three loci. On chromosome 10q21 within the gene CTNNA3 (p = 2.11 x 10(-8); odds ratio [OR] = 3.94; 95% confidence interval [CI], 3.10-5.00), on chromosome 16q24 next to the FOX gene cluster (p = 2.25 x 10(-10); OR = 1.47; 95% CI, 1.38-1.55) and on chromosome 17q12 next to the gene HNF1B (p = 3.35 x 10(-16); OR = 1.75; 95% CI, 1.64-1.87). We next carried out an esophageal/tracheal transcriptome profiling in rat embryos at four selected embryonic time points. Based on these data and on already published data, the implicated genes at all three GWAS loci are promising candidates for EA/TEF development. We also analyzed the genetic EA/TEF architecture beyond the single marker level, which revealed an estimated single-nucleotide polymorphism (SNP)-based heritability of around 37% +/- 14% standard deviation. In addition, we examined the polygenicity of EA/TEF and found that EA/TEF is less polygenic than other complex genetic diseases. In conclusion, the results of our study contribute to a better understanding on the underlying genetic architecture of ET/TEF with the identification of three risk loci and candidate genes.
Published: 2022
Full Text: View/download PDF

28. First genome-wide association study of esophageal atresia identifies three genetic risk loci at CTNNA3, FOXF1/FOXC2/FOXL1, and HNF1B

Author: Gehlen, Jan, Giel, Ann-Sophie, Koellges, Ricarda, Haas, Stephan L., Zhang, Rong, Trcka, Jiri, Sungur, Ayse O., Renziehausen, Florian, Bornholdt, Dorothea, Jung, Daphne, Hoyer, Paul D., Nordenskjold, Agneta, Tibboel, Dick, Vlot, John, Spaander, Manon C. W., Smigiel, Robert, Patkowski, Dariusz, Roeleveld, Nel, van Rooij, Iris Alm, de Blaauw, Ivo, Hoelscher, Alice, Pauly, Marcus, Leutner, Andreas, Fuchs, Joerg, Niethammer, Joel, Melissari, Maria-Theodora, Jenetzky, Ekkehart, Zwink, Nadine, Thiele, Holger, Hilger, Alina Christine, Hess, Timo, Trautmann, Jessica, Marks, Matthias, Baumgarten, Martin, Blaess, Gaby, Landen, Mikael, Fundin, Bengt, Bulik, Cynthia M., Pennimpede, Tracie, Ludwig, Michael, Ludwig, Kerstin U., Mangold, Elisabeth, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Herrmann, Bernhard G., Alsabeah, Kristina, Burgos, Carmen M., Engstrand Lilja, Helene, Azodi, Sahar, Stenstrom, Pernilla, Arnbjornsson, Einar, Frybova, Barbora, Lebensztejn, Dariusz M., Debek, Wojciech, Kolodziejczyk, Elwira, Kozera, Katarzyna, Kierkus, Jaroslaw, Kalicinski, Piotr, Stefanowicz, Marek, Socha-Banasiak, Anna, Kolejwa, Michal, Piaseczna-Piotrowska, Anna, Czkwianianc, Elzbieta, Noethen, Markus M., Grote, Phillip, Rygl, Michal, Reinshagen, Konrad, Spychalski, Nicole, Ludwikowski, Barbara, Hubertus, Jochen, Heydweiller, Andreas, Ure, Benno, Muensterer, Oliver J., Aubert, Ophelia, Gosemann, Jan-Hendrik, Lacher, Martin, Degenhardt, Petra, Boemers, Thomas M., Mokrowiecka, Anna, Malecka-Panas, Ewa, Woehr, Markus, Knapp, Michael, Seitz, Guido, de Klein, Annelies, Oracz, Grzegorz, Brosens, Erwin, Reutter, Heiko, Schumacher, Johannes, Gehlen, Jan, Giel, Ann-Sophie, Koellges, Ricarda, Haas, Stephan L., Zhang, Rong, Trcka, Jiri, Sungur, Ayse O., Renziehausen, Florian, Bornholdt, Dorothea, Jung, Daphne, Hoyer, Paul D., Nordenskjold, Agneta, Tibboel, Dick, Vlot, John, Spaander, Manon C. W., Smigiel, Robert, Patkowski, Dariusz, Roeleveld, Nel, van Rooij, Iris Alm, de Blaauw, Ivo, Hoelscher, Alice, Pauly, Marcus, Leutner, Andreas, Fuchs, Joerg, Niethammer, Joel, Melissari, Maria-Theodora, Jenetzky, Ekkehart, Zwink, Nadine, Thiele, Holger, Hilger, Alina Christine, Hess, Timo, Trautmann, Jessica, Marks, Matthias, Baumgarten, Martin, Blaess, Gaby, Landen, Mikael, Fundin, Bengt, Bulik, Cynthia M., Pennimpede, Tracie, Ludwig, Michael, Ludwig, Kerstin U., Mangold, Elisabeth, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Herrmann, Bernhard G., Alsabeah, Kristina, Burgos, Carmen M., Engstrand Lilja, Helene, Azodi, Sahar, Stenstrom, Pernilla, Arnbjornsson, Einar, Frybova, Barbora, Lebensztejn, Dariusz M., Debek, Wojciech, Kolodziejczyk, Elwira, Kozera, Katarzyna, Kierkus, Jaroslaw, Kalicinski, Piotr, Stefanowicz, Marek, Socha-Banasiak, Anna, Kolejwa, Michal, Piaseczna-Piotrowska, Anna, Czkwianianc, Elzbieta, Noethen, Markus M., Grote, Phillip, Rygl, Michal, Reinshagen, Konrad, Spychalski, Nicole, Ludwikowski, Barbara, Hubertus, Jochen, Heydweiller, Andreas, Ure, Benno, Muensterer, Oliver J., Aubert, Ophelia, Gosemann, Jan-Hendrik, Lacher, Martin, Degenhardt, Petra, Boemers, Thomas M., Mokrowiecka, Anna, Malecka-Panas, Ewa, Woehr, Markus, Knapp, Michael, Seitz, Guido, de Klein, Annelies, Oracz, Grzegorz, Brosens, Erwin, Reutter, Heiko, and Schumacher, Johannes
Abstract: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is the most common congenital malformation of the upper digestive tract. This study represents the first genome-wide association study (GWAS) to identify risk loci for EA/TEF. We used a European case-control sample comprising 764 EA/TEF patients and 5,778 controls and observed genome-wide significant associations at three loci. On chromosome 10q21 within the gene CTNNA3 (p = 2.11 x 10(-8); odds ratio [OR] = 3.94; 95% confidence interval [CI], 3.10-5.00), on chromosome 16q24 next to the FOX gene cluster (p = 2.25 x 10(-10); OR = 1.47; 95% CI, 1.38-1.55) and on chromosome 17q12 next to the gene HNF1B (p = 3.35 x 10(-16); OR = 1.75; 95% CI, 1.64-1.87). We next carried out an esophageal/tracheal transcriptome profiling in rat embryos at four selected embryonic time points. Based on these data and on already published data, the implicated genes at all three GWAS loci are promising candidates for EA/TEF development. We also analyzed the genetic EA/TEF architecture beyond the single marker level, which revealed an estimated single-nucleotide polymorphism (SNP)-based heritability of around 37% +/- 14% standard deviation. In addition, we examined the polygenicity of EA/TEF and found that EA/TEF is less polygenic than other complex genetic diseases. In conclusion, the results of our study contribute to a better understanding on the underlying genetic architecture of ET/TEF with the identification of three risk loci and candidate genes.
Published: 2022
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29. Supplemental Online Content. Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease

Author: Le Guen, Yann, Belloy, Michael E, Grenier-Boley, Benjamin, de Rojas, Itziar, Castillo-Morales, Atahualpa, Jansen, Iris, Nicolas, Aude, Bellenguez, Céline, Dalmasso, Carolina, Küçükali, Fahri, Eger, Sarah J, Jürgen, Deckert, Kuulasmaa, Teemu, van der Lugt, Aad, Masullo, Carlo, Mecocci, Patrizia, Mehrabian, Shima, de Mendonça, Alexandre, Moebus, Susanne, Nacmias, Benedetta, Nicolas, Gael, Olaso, Robert, Papenberg, Goran, Parnetti, Lucilla, Pasquier, Florence, Peters, Oliver, Pijnenburg, Yolande A L, Popp, Julius, Rainero, Innocenzo, Ramakers, Inez, Riedel-Heller, Steffi, Scarmeas, Nikolaos, Scheltens, Philip, Scherbaum, Norbert, Schneider, Anja, Seripa, Davide, Soininen, Hilkka, Solfrizzi, Vincenzo, Spalletta, Gianfranco, Squassina, Alessio, van Swieten, John, Tegos, Thomas J, Tremolizzo, Lucio, Verhey, Frans, Vyhnalek, Martin, Wiltfang, Jens, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Real, Luis Miguel, Álvarez, Victoria, Bullido, María J., Clarimón, Jordi, García-Alberca, José María, Mir, Pablo, Moreno, Fermín, Pastor, Pau, Piñol-Ripoll, Gerard, Molina-Porcel, Laura, Pérez-Tur, Jordi, Rodríguez Martínez, Eloy, Royo, José Luis, Sánchez-Valle, Raquel, Dichgans, Martin, Rujescu, Dan, Rasmussen, Katrine Laura, Thomassen, Jesper Qvist, Deleuze, Jean-François, He, Zihuai, Napolioni, Valerio, Amouyel, Philippe, Jessen, Frank, Kehoe, Patrick G., van Duijn, Cornelia, Tsolaki, Magda, Sánchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Rossi, Giacomina, Hiltunen, Mikko, Sims, Rebecca, van der Flier, Wiesje M., Ramírez, Alfredo, Andreassen, Ole A., Frikke-Schmidt, Ruth, Williams, Julie, Ruiz, Agustín, Lambert, Jean-Charles, Greicius, Michael D, Arosio, Beatrice, Benussi, Luisa, Boland, Anne, Borroni, Barbara, Caffarra, Paolo, Daian, Delphine, Daniele, Antonio, Debette, Stéphanie, Dufouil, Carole, Düzel, Emrah, Galimberti, Daniela, Giedraitis, Vilmantas, Grimmer, Timo, Graff, Caroline, Grünblatt, Edna, Hanon, Olivier, Hausner, Lucrezia, Heilmann-Heimbach, Stefanie, Holstege, Henne, Hort, Jakub, Le Guen, Yann, Belloy, Michael E, Grenier-Boley, Benjamin, de Rojas, Itziar, Castillo-Morales, Atahualpa, Jansen, Iris, Nicolas, Aude, Bellenguez, Céline, Dalmasso, Carolina, Küçükali, Fahri, Eger, Sarah J, Jürgen, Deckert, Kuulasmaa, Teemu, van der Lugt, Aad, Masullo, Carlo, Mecocci, Patrizia, Mehrabian, Shima, de Mendonça, Alexandre, Moebus, Susanne, Nacmias, Benedetta, Nicolas, Gael, Olaso, Robert, Papenberg, Goran, Parnetti, Lucilla, Pasquier, Florence, Peters, Oliver, Pijnenburg, Yolande A L, Popp, Julius, Rainero, Innocenzo, Ramakers, Inez, Riedel-Heller, Steffi, Scarmeas, Nikolaos, Scheltens, Philip, Scherbaum, Norbert, Schneider, Anja, Seripa, Davide, Soininen, Hilkka, Solfrizzi, Vincenzo, Spalletta, Gianfranco, Squassina, Alessio, van Swieten, John, Tegos, Thomas J, Tremolizzo, Lucio, Verhey, Frans, Vyhnalek, Martin, Wiltfang, Jens, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Real, Luis Miguel, Álvarez, Victoria, Bullido, María J., Clarimón, Jordi, García-Alberca, José María, Mir, Pablo, Moreno, Fermín, Pastor, Pau, Piñol-Ripoll, Gerard, Molina-Porcel, Laura, Pérez-Tur, Jordi, Rodríguez Martínez, Eloy, Royo, José Luis, Sánchez-Valle, Raquel, Dichgans, Martin, Rujescu, Dan, Rasmussen, Katrine Laura, Thomassen, Jesper Qvist, Deleuze, Jean-François, He, Zihuai, Napolioni, Valerio, Amouyel, Philippe, Jessen, Frank, Kehoe, Patrick G., van Duijn, Cornelia, Tsolaki, Magda, Sánchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Rossi, Giacomina, Hiltunen, Mikko, Sims, Rebecca, van der Flier, Wiesje M., Ramírez, Alfredo, Andreassen, Ole A., Frikke-Schmidt, Ruth, Williams, Julie, Ruiz, Agustín, Lambert, Jean-Charles, Greicius, Michael D, Arosio, Beatrice, Benussi, Luisa, Boland, Anne, Borroni, Barbara, Caffarra, Paolo, Daian, Delphine, Daniele, Antonio, Debette, Stéphanie, Dufouil, Carole, Düzel, Emrah, Galimberti, Daniela, Giedraitis, Vilmantas, Grimmer, Timo, Graff, Caroline, Grünblatt, Edna, Hanon, Olivier, Hausner, Lucrezia, Heilmann-Heimbach, Stefanie, Holstege, Henne, and Hort, Jakub
Abstract: Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer’s Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689), funded by the National Institute on Aging.
Published: 2022

30. New insights into the genetic etiology of Alzheimer's disease and related dementias

Author: Bellenguez, Celine, Kucukali, Fahri, Jansen, Iris E., Kleineidam, Luca, Moreno-Grau, Sonia, Amin, Najaf, Naj, Adam C., Campos-Martin, Rafael, Grenier-Boley, Benjamin, Andrade, Victor, Holmans, Peter A., Boland, Anne, Damotte, Vincent, van der Lee, Sven J., Costa, Marcos R., Kuulasmaa, Teemu, Yang, Qiong, De Rojas, Itziar, Bis, Joshua C., Yaqub, Amber, Prokic, Ivana, Chapuis, Julien, Ahmad, Shahzad, Giedraitis, Vilmantas, Aarsland, Dag, Garcia-Gonzalez, Pablo, Abdelnour, Carla, Alarcon-Martin, Emilio, Alcolea, Daniel, Alegret, Montserrat, Alvarez, Ignacio, Alvarez, Victoria, Armstrong, Nicola J., Tsolaki, Anthoula, Antunez, Carmen, Appollonio, Ildebrando, Arcaro, Marina, Archetti, Silvana, Arias Pastor, Alfonso, Arosio, Beatrice, Athanasiu, Lavinia, Bailly, Henri, Banaj, Nerisa, Baquero, Miquel, Barral, Sandra, Beiser, Alexa, Pastor, Ana Belen, Below, Jennifer E., Benchek, Penelope, Benussi, Luisa, Berr, Claudine, Besse, Celine, Bessi, Valentina, Binetti, Giuliano, Bizarro, Alessandra, Blesa, Rafael, Boada, Merce, Boerwinkle, Eric, Borroni, Barbara, Boschi, Silvia, Bossu, Paola, Brathen, Geir, Bressler, Jan, Bresner, Catherine, Brodaty, Henry, Brookes, Keeley J., Ignacio Brusco, Luis, Buiza-Rueda, Dolores, Burger, Katharina, Burholt, Vanessa, Bush, William S., Calero, Miguel, Cantwell, Laura B., Chene, Genevieve, Chung, Jaeyoon, Cuccaro, Michael L., Cecchetti, Roberta, Cervera-Carles, Laura, Charbonnier, Camille, Chen, Hung-Hsin, Chillotti, Caterina, Ciccone, Simona, Claassen, Jurgen A. H. R., Clark, Christopher, Conti, Elisa, Corma-Gomez, Anais, Costantini, Emanuele, Custodero, Carlo, Daian, Delphine, Dalmasso, Maria Carolina, Daniele, Antonio, Dardiotis, Efthimios, Dartigues, Jean-Francois, de Deyn, Peter Paul, Lopes, Katia de Paiva, De Witte, Lot D., Debette, Stephanie, Deckert, Jurgen, del Ser, Teodoro, Denning, Nicola, Destefano, Anita, Dichgans, Martin, Diehl-Schmid, Janine, Diez-Fairen, Monica, Rossi, Paolo Dionigi, Djurovic, Srdjan, Duron, Emmanuelle, Duzel, Emrah, Dufouil, Carole, Eiriksdottir, Gudny, Engelborghs, Sebastiaan, Escott-Price, Valentina, Espinosa, Ana, Ewers, Michael, Faber, Kelley M., Fabrizio, Tagliavini, Nielsen, Sune Fallgaard, Fardo, David W., Farotti, Lucia, Fenoglio, Chiara, Fernandez-Fuertes, Marta, Ferrari, Raffaele, Ferreira, Catarina B., Ferri, Evelyn, Fin, Bertrand, Fischer, Peter, Fladby, Tormod, Fliessbach, Klaus, Fongang, Bernard, Fornage, Myriam, Fortea, Juan, Foroud, Tatiana M., Fostinelli, Silvia, Fox, Nick C., Franco-Macias, Emlio, Bullido, Maria J., Frank-Garcia, Ana, Froelich, Lutz, Fulton-Howard, Brian, Galimberti, Daniela, Maria Garcia-Alberca, Jose, Garcia-Madrona, Sebastian, Garcia-Ribas, Guillermo, Ghidoni, Roberta, Giegling, Ina, Giorgio, Giaccone, Goate, Alison M., Goldhardt, Oliver, Gomez-Fonseca, Duber, Gonzalez-Perez, Antonio, Graff, Caroline, Grande, Giulia, Green, Emma, Grimmer, Timo, Grunblatt, Edna, Grunin, Michelle, Gudnason, Vilmundur, Guetta-Baranes, Tamar, Haapasalo, Annakaisa, Hadjigeorgiou, Georgios, Haines, Jonathan L., Hamilton-Nelson, Kara L., Hampel, Harald, Hanon, Olivier, Hardy, John, Hartmann, Annette M., Hausner, Lucrezia, Harwood, Janet, Heilmann-Heimbach, Stefanie, Helisalmi, Seppo, Heneka, Michael T., Hernandez, Isabel, Herrmann, Martin J., Hoffmann, Per, Holmes, Clive, Holstege, Henne, Huerto Vilas, Raquel, Hulsman, Marc, Humphrey, Jack, Biessels, Geert Jan, Jian, Xueqiu, Johansson, Charlotte, Jun, Gyungah R., Kastumata, Yuriko, Kauwe, John, Kehoe, Patrick G., Kilander, Lena, Stahlbom, Anne Kinhult, Kivipelto, Miia, Koivisto, Anne, Kornhuber, Johannes, Kosmidis, Mary H., Kukull, Walter A., Kuksa, Pavel P., Kunkle, Brian W., Kuzma, Amanda B., Lage, Carmen, Laukka, Erika J., Launer, Lenore, Lauria, Alessandra, Lee, Chien-Yueh, Lehtisalo, Jenni, Lerch, Ondrej, Lleo, Alberto, Longstreth, William, Jr., Lopez, Oscar, Lopez de Munain, Adolfo, Love, Seth, Lowemark, Malin, Luckcuck, Lauren, Lunetta, Kathryn L., Ma, Yiyi, Macias, Juan, Macleod, Catherine A., Maier, Wolfgang, Mangialasche, Francesca, Spallazzi, Marco, Marquie, Marta, Marshall, Rachel, Martin, Eden R., Martin Montes, Angel, Martinez Rodriguez, Carmen, Masullo, Carlo, Mayeux, Richard, Mead, Simon, Mecocci, Patrizia, Medina, Miguel, Meggy, Alun, Mehrabian, Shima, Mendoza, Silvia, Menendez-Gonzalez, Manuel, Mir, Pablo, Moebus, Susanne, Mol, Merel, Molina-Porcel, Laura, Montrreal, Laura, Morelli, Laura, Moreno, Fermin, Morgan, Kevin, Mosley, Thomas, Nothen, Markus M., Muchnik, Carolina, Mukherjee, Shubhabrata, Nacmias, Benedetta, Ngandu, Tiia, Nicolas, Gael, Nordestgaard, Borge G., Olaso, Robert, Orellana, Adelina, Orsini, Michela, Ortega, Gemma, Padovani, Alessandro, Paolo, Caffarra, Papenberg, Goran, Parnetti, Lucilla, Pasquier, Florence, Pastor, Pau, Peloso, Gina, Perez-Cordon, Alba, Perez-Tur, Jordi, Pericard, Pierre, Peters, Oliver, Pijnenburg, Yolande A. L., Pineda, Juan A., Pinol-Ripoll, Gerard, Pisanu, Laudia, Polak, Thomas, Popp, Julius, Posthuma, Danielle, Priller, Josef, Puerta, Raquel, Quenez, Olivier, Quintela, Ines, Thomassen, Jesper Qvist, Rabano, Alberto, Rainero, Innocenzo, Rajabli, Farid, Ramakers, Inez, Real, Luis M., Reinders, Marcel J. T., Reitz, Christiane, Reyes-Dumeyer, Dolly, Ridge, Perry, Riedel-Heller, Steffi, Riederer, Peter, Roberto, Natalia, Rodriguez-Rodriguez, Eloy, Rongve, Arvid, Rosas Allende, Irene, Rosende-Roca, Maitee, Luis Royo, Jose, Rubino, Elisa, Rujescu, Dan, Eugenia Saez, Maria, Sakka, Paraskevi, Saltvedt, Ingvild, Bernal Sanchez-Arjona, Maria, Sanchez-Garcia, Florentino, Sanchez Juan, Pascual, Sanchez-Valle, Raquel, Sando, Sigrid B., Sarnowski, Chloe, Satizabal, Claudia L., Scamosci, Michela, Scarmeas, Nikolaos, Scarpini, Elio, Scheltens, Philip, Scherbaum, Norbert, Scherer, Martin, Schmid, Matthias, Schneider, Anja, Schott, Jonathan M., Selbaek, Geir, Seripa, Davide, Serrano, Manuel, Sha, Jin, Shadrin, Alexey A., Skrobot, Olivia, Slifer, Susan, Snijders, Gijsje J. L., Soininen, Hilkka, Solfrizzi, Vincenzo, Solomon, Alina, Song, Yeunjoo, Sorbi, Sandro, Sotolongo-Grau, Oscar, Spalletta, Gianfranco, Spottke, Annika, Squassina, Alessio, Stordal, Eystein, Pablo Tartan, Juan, Tarraga, Lluis, Tesi, Niccolo, Thalamuthu, Anbupalam, Thomas, Tegos, Tosto, Giuseppe, Traykov, Latchezar, Tremolizzo, Lucio, Tybjaerg-Hansen, Anne, Uitterlinden, Andre, Ullgren, Abbe, Ulstein, Ingun, Valero, Sergi, Valladares, Otto, Van Broeckhoven, Christine, Vance, Jeffery, Vardarajan, Badri N., van der Lugt, Aad, Van Dongen, Jasper, van Rooij, Jeroen, van Swieten, John, Vandenberghe, Rik, Verhey, Frans, Vidal, Jean-Sebastien, Vogelgsang, Jonathan, Vyhnalek, Martin, Wagner, Michael, Wallon, David, Wang, Li-San, Wang, Ruiqi, Weinhold, Leonie, Wiltfang, Jens, Windle, Gill, Woods, Bob, Yannakoulia, Mary, Zare, Habil, Zhao, Yi, Zhang, Xiaoling, Zhu, Congcong, Zulaica, Miren, Farrer, Lindsay A., Psaty, Bruce M., Ghanbari, Mohsen, Raj, Towfique, Sachdev, Perminder, Mather, Karen, Jessen, Frank, Ikram, M. Arfan, de Mendonca, Alexandre, Hort, Jakub, Tsolaki, Magda, Pericak-Vance, Margaret A., Amouyel, Philippe, Williams, Julie, Frikke-Schmidt, Ruth, Clarimon, Jordi, Deleuze, Jean-Francois, Rossi, Giacomina, Seshadri, Sudha, Andreassen, Ole A., Ingelsson, Martin, Hiltunen, Mikko, Sleegers, Kristel, Schellenberg, Gerard D., van Duijn, Cornelia M., Sims, Rebecca, van der Flier, Wiesje M., Ruiz, Agustin, Ramirez, Alfredo, Lambert, Jean-Charles, Bellenguez, Celine, Kucukali, Fahri, Jansen, Iris E., Kleineidam, Luca, Moreno-Grau, Sonia, Amin, Najaf, Naj, Adam C., Campos-Martin, Rafael, Grenier-Boley, Benjamin, Andrade, Victor, Holmans, Peter A., Boland, Anne, Damotte, Vincent, van der Lee, Sven J., Costa, Marcos R., Kuulasmaa, Teemu, Yang, Qiong, De Rojas, Itziar, Bis, Joshua C., Yaqub, Amber, Prokic, Ivana, Chapuis, Julien, Ahmad, Shahzad, Giedraitis, Vilmantas, Aarsland, Dag, Garcia-Gonzalez, Pablo, Abdelnour, Carla, Alarcon-Martin, Emilio, Alcolea, Daniel, Alegret, Montserrat, Alvarez, Ignacio, Alvarez, Victoria, Armstrong, Nicola J., Tsolaki, Anthoula, Antunez, Carmen, Appollonio, Ildebrando, Arcaro, Marina, Archetti, Silvana, Arias Pastor, Alfonso, Arosio, Beatrice, Athanasiu, Lavinia, Bailly, Henri, Banaj, Nerisa, Baquero, Miquel, Barral, Sandra, Beiser, Alexa, Pastor, Ana Belen, Below, Jennifer E., Benchek, Penelope, Benussi, Luisa, Berr, Claudine, Besse, Celine, Bessi, Valentina, Binetti, Giuliano, Bizarro, Alessandra, Blesa, Rafael, Boada, Merce, Boerwinkle, Eric, Borroni, Barbara, Boschi, Silvia, Bossu, Paola, Brathen, Geir, Bressler, Jan, Bresner, Catherine, Brodaty, Henry, Brookes, Keeley J., Ignacio Brusco, Luis, Buiza-Rueda, Dolores, Burger, Katharina, Burholt, Vanessa, Bush, William S., Calero, Miguel, Cantwell, Laura B., Chene, Genevieve, Chung, Jaeyoon, Cuccaro, Michael L., Cecchetti, Roberta, Cervera-Carles, Laura, Charbonnier, Camille, Chen, Hung-Hsin, Chillotti, Caterina, Ciccone, Simona, Claassen, Jurgen A. H. R., Clark, Christopher, Conti, Elisa, Corma-Gomez, Anais, Costantini, Emanuele, Custodero, Carlo, Daian, Delphine, Dalmasso, Maria Carolina, Daniele, Antonio, Dardiotis, Efthimios, Dartigues, Jean-Francois, de Deyn, Peter Paul, Lopes, Katia de Paiva, De Witte, Lot D., Debette, Stephanie, Deckert, Jurgen, del Ser, Teodoro, Denning, Nicola, Destefano, Anita, Dichgans, Martin, Diehl-Schmid, Janine, Diez-Fairen, Monica, Rossi, Paolo Dionigi, Djurovic, Srdjan, Duron, Emmanuelle, Duzel, Emrah, Dufouil, Carole, Eiriksdottir, Gudny, Engelborghs, Sebastiaan, Escott-Price, Valentina, Espinosa, Ana, Ewers, Michael, Faber, Kelley M., Fabrizio, Tagliavini, Nielsen, Sune Fallgaard, Fardo, David W., Farotti, Lucia, Fenoglio, Chiara, Fernandez-Fuertes, Marta, Ferrari, Raffaele, Ferreira, Catarina B., Ferri, Evelyn, Fin, Bertrand, Fischer, Peter, Fladby, Tormod, Fliessbach, Klaus, Fongang, Bernard, Fornage, Myriam, Fortea, Juan, Foroud, Tatiana M., Fostinelli, Silvia, Fox, Nick C., Franco-Macias, Emlio, Bullido, Maria J., Frank-Garcia, Ana, Froelich, Lutz, Fulton-Howard, Brian, Galimberti, Daniela, Maria Garcia-Alberca, Jose, Garcia-Madrona, Sebastian, Garcia-Ribas, Guillermo, Ghidoni, Roberta, Giegling, Ina, Giorgio, Giaccone, Goate, Alison M., Goldhardt, Oliver, Gomez-Fonseca, Duber, Gonzalez-Perez, Antonio, Graff, Caroline, Grande, Giulia, Green, Emma, Grimmer, Timo, Grunblatt, Edna, Grunin, Michelle, Gudnason, Vilmundur, Guetta-Baranes, Tamar, Haapasalo, Annakaisa, Hadjigeorgiou, Georgios, Haines, Jonathan L., Hamilton-Nelson, Kara L., Hampel, Harald, Hanon, Olivier, Hardy, John, Hartmann, Annette M., Hausner, Lucrezia, Harwood, Janet, Heilmann-Heimbach, Stefanie, Helisalmi, Seppo, Heneka, Michael T., Hernandez, Isabel, Herrmann, Martin J., Hoffmann, Per, Holmes, Clive, Holstege, Henne, Huerto Vilas, Raquel, Hulsman, Marc, Humphrey, Jack, Biessels, Geert Jan, Jian, Xueqiu, Johansson, Charlotte, Jun, Gyungah R., Kastumata, Yuriko, Kauwe, John, Kehoe, Patrick G., Kilander, Lena, Stahlbom, Anne Kinhult, Kivipelto, Miia, Koivisto, Anne, Kornhuber, Johannes, Kosmidis, Mary H., Kukull, Walter A., Kuksa, Pavel P., Kunkle, Brian W., Kuzma, Amanda B., Lage, Carmen, Laukka, Erika J., Launer, Lenore, Lauria, Alessandra, Lee, Chien-Yueh, Lehtisalo, Jenni, Lerch, Ondrej, Lleo, Alberto, Longstreth, William, Jr., Lopez, Oscar, Lopez de Munain, Adolfo, Love, Seth, Lowemark, Malin, Luckcuck, Lauren, Lunetta, Kathryn L., Ma, Yiyi, Macias, Juan, Macleod, Catherine A., Maier, Wolfgang, Mangialasche, Francesca, Spallazzi, Marco, Marquie, Marta, Marshall, Rachel, Martin, Eden R., Martin Montes, Angel, Martinez Rodriguez, Carmen, Masullo, Carlo, Mayeux, Richard, Mead, Simon, Mecocci, Patrizia, Medina, Miguel, Meggy, Alun, Mehrabian, Shima, Mendoza, Silvia, Menendez-Gonzalez, Manuel, Mir, Pablo, Moebus, Susanne, Mol, Merel, Molina-Porcel, Laura, Montrreal, Laura, Morelli, Laura, Moreno, Fermin, Morgan, Kevin, Mosley, Thomas, Nothen, Markus M., Muchnik, Carolina, Mukherjee, Shubhabrata, Nacmias, Benedetta, Ngandu, Tiia, Nicolas, Gael, Nordestgaard, Borge G., Olaso, Robert, Orellana, Adelina, Orsini, Michela, Ortega, Gemma, Padovani, Alessandro, Paolo, Caffarra, Papenberg, Goran, Parnetti, Lucilla, Pasquier, Florence, Pastor, Pau, Peloso, Gina, Perez-Cordon, Alba, Perez-Tur, Jordi, Pericard, Pierre, Peters, Oliver, Pijnenburg, Yolande A. L., Pineda, Juan A., Pinol-Ripoll, Gerard, Pisanu, Laudia, Polak, Thomas, Popp, Julius, Posthuma, Danielle, Priller, Josef, Puerta, Raquel, Quenez, Olivier, Quintela, Ines, Thomassen, Jesper Qvist, Rabano, Alberto, Rainero, Innocenzo, Rajabli, Farid, Ramakers, Inez, Real, Luis M., Reinders, Marcel J. T., Reitz, Christiane, Reyes-Dumeyer, Dolly, Ridge, Perry, Riedel-Heller, Steffi, Riederer, Peter, Roberto, Natalia, Rodriguez-Rodriguez, Eloy, Rongve, Arvid, Rosas Allende, Irene, Rosende-Roca, Maitee, Luis Royo, Jose, Rubino, Elisa, Rujescu, Dan, Eugenia Saez, Maria, Sakka, Paraskevi, Saltvedt, Ingvild, Bernal Sanchez-Arjona, Maria, Sanchez-Garcia, Florentino, Sanchez Juan, Pascual, Sanchez-Valle, Raquel, Sando, Sigrid B., Sarnowski, Chloe, Satizabal, Claudia L., Scamosci, Michela, Scarmeas, Nikolaos, Scarpini, Elio, Scheltens, Philip, Scherbaum, Norbert, Scherer, Martin, Schmid, Matthias, Schneider, Anja, Schott, Jonathan M., Selbaek, Geir, Seripa, Davide, Serrano, Manuel, Sha, Jin, Shadrin, Alexey A., Skrobot, Olivia, Slifer, Susan, Snijders, Gijsje J. L., Soininen, Hilkka, Solfrizzi, Vincenzo, Solomon, Alina, Song, Yeunjoo, Sorbi, Sandro, Sotolongo-Grau, Oscar, Spalletta, Gianfranco, Spottke, Annika, Squassina, Alessio, Stordal, Eystein, Pablo Tartan, Juan, Tarraga, Lluis, Tesi, Niccolo, Thalamuthu, Anbupalam, Thomas, Tegos, Tosto, Giuseppe, Traykov, Latchezar, Tremolizzo, Lucio, Tybjaerg-Hansen, Anne, Uitterlinden, Andre, Ullgren, Abbe, Ulstein, Ingun, Valero, Sergi, Valladares, Otto, Van Broeckhoven, Christine, Vance, Jeffery, Vardarajan, Badri N., van der Lugt, Aad, Van Dongen, Jasper, van Rooij, Jeroen, van Swieten, John, Vandenberghe, Rik, Verhey, Frans, Vidal, Jean-Sebastien, Vogelgsang, Jonathan, Vyhnalek, Martin, Wagner, Michael, Wallon, David, Wang, Li-San, Wang, Ruiqi, Weinhold, Leonie, Wiltfang, Jens, Windle, Gill, Woods, Bob, Yannakoulia, Mary, Zare, Habil, Zhao, Yi, Zhang, Xiaoling, Zhu, Congcong, Zulaica, Miren, Farrer, Lindsay A., Psaty, Bruce M., Ghanbari, Mohsen, Raj, Towfique, Sachdev, Perminder, Mather, Karen, Jessen, Frank, Ikram, M. Arfan, de Mendonca, Alexandre, Hort, Jakub, Tsolaki, Magda, Pericak-Vance, Margaret A., Amouyel, Philippe, Williams, Julie, Frikke-Schmidt, Ruth, Clarimon, Jordi, Deleuze, Jean-Francois, Rossi, Giacomina, Seshadri, Sudha, Andreassen, Ole A., Ingelsson, Martin, Hiltunen, Mikko, Sleegers, Kristel, Schellenberg, Gerard D., van Duijn, Cornelia M., Sims, Rebecca, van der Flier, Wiesje M., Ruiz, Agustin, Ramirez, Alfredo, and Lambert, Jean-Charles
Abstract: Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE epsilon 4 allele. Meta-analysis of genome-wide association studies on Alzheimer's disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer's disease and dementia.
Published: 2022

31. First genome-wide association study of esophageal atresia identifies three genetic risk loci at CTNNA3, FOXF1/FOXC2/FOXL1, and HNF1B

Author: Gehlen, Jan, Giel, Ann-Sophie, Koellges, Ricarda, Haas, Stephan L., Zhang, Rong, Trcka, Jiri, Sungur, Ayse O., Renziehausen, Florian, Bornholdt, Dorothea, Jung, Daphne, Hoyer, Paul D., Nordenskjold, Agneta, Tibboel, Dick, Vlot, John, Spaander, Manon C. W., Smigiel, Robert, Patkowski, Dariusz, Roeleveld, Nel, van Rooij, Iris Alm, de Blaauw, Ivo, Hoelscher, Alice, Pauly, Marcus, Leutner, Andreas, Fuchs, Joerg, Niethammer, Joel, Melissari, Maria-Theodora, Jenetzky, Ekkehart, Zwink, Nadine, Thiele, Holger, Hilger, Alina Christine, Hess, Timo, Trautmann, Jessica, Marks, Matthias, Baumgarten, Martin, Blaess, Gaby, Landen, Mikael, Fundin, Bengt, Bulik, Cynthia M., Pennimpede, Tracie, Ludwig, Michael, Ludwig, Kerstin U., Mangold, Elisabeth, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Herrmann, Bernhard G., Alsabeah, Kristina, Burgos, Carmen M., Lilja, Helene E., Azodi, Sahar, Stenstrom, Pernilla, Arnbjornsson, Einar, Frybova, Barbora, Lebensztejn, Dariusz M., Debek, Wojciech, Kolodziejczyk, Elwira, Kozera, Katarzyna, Kierkus, Jaroslaw, Kalicinski, Piotr, Stefanowicz, Marek, Socha-Banasiak, Anna, Kolejwa, Michal, Piaseczna-Piotrowska, Anna, Czkwianianc, Elzbieta, Noethen, Markus M., Grote, Phillip, Rygl, Michal, Reinshagen, Konrad, Spychalski, Nicole, Ludwikowski, Barbara, Hubertus, Jochen, Heydweiller, Andreas, Ure, Benno, Muensterer, Oliver J., Aubert, Ophelia, Gosemann, Jan-Hendrik, Lacher, Martin, Degenhardt, Petra, Boemers, Thomas M., Mokrowiecka, Anna, Malecka-Panas, Ewa, Woehr, Markus, Knapp, Michael, Seitz, Guido, de Klein, Annelies, Oracz, Grzegorz, Brosens, Erwin, Reutter, Heiko, Schumacher, Johannes, Gehlen, Jan, Giel, Ann-Sophie, Koellges, Ricarda, Haas, Stephan L., Zhang, Rong, Trcka, Jiri, Sungur, Ayse O., Renziehausen, Florian, Bornholdt, Dorothea, Jung, Daphne, Hoyer, Paul D., Nordenskjold, Agneta, Tibboel, Dick, Vlot, John, Spaander, Manon C. W., Smigiel, Robert, Patkowski, Dariusz, Roeleveld, Nel, van Rooij, Iris Alm, de Blaauw, Ivo, Hoelscher, Alice, Pauly, Marcus, Leutner, Andreas, Fuchs, Joerg, Niethammer, Joel, Melissari, Maria-Theodora, Jenetzky, Ekkehart, Zwink, Nadine, Thiele, Holger, Hilger, Alina Christine, Hess, Timo, Trautmann, Jessica, Marks, Matthias, Baumgarten, Martin, Blaess, Gaby, Landen, Mikael, Fundin, Bengt, Bulik, Cynthia M., Pennimpede, Tracie, Ludwig, Michael, Ludwig, Kerstin U., Mangold, Elisabeth, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Herrmann, Bernhard G., Alsabeah, Kristina, Burgos, Carmen M., Lilja, Helene E., Azodi, Sahar, Stenstrom, Pernilla, Arnbjornsson, Einar, Frybova, Barbora, Lebensztejn, Dariusz M., Debek, Wojciech, Kolodziejczyk, Elwira, Kozera, Katarzyna, Kierkus, Jaroslaw, Kalicinski, Piotr, Stefanowicz, Marek, Socha-Banasiak, Anna, Kolejwa, Michal, Piaseczna-Piotrowska, Anna, Czkwianianc, Elzbieta, Noethen, Markus M., Grote, Phillip, Rygl, Michal, Reinshagen, Konrad, Spychalski, Nicole, Ludwikowski, Barbara, Hubertus, Jochen, Heydweiller, Andreas, Ure, Benno, Muensterer, Oliver J., Aubert, Ophelia, Gosemann, Jan-Hendrik, Lacher, Martin, Degenhardt, Petra, Boemers, Thomas M., Mokrowiecka, Anna, Malecka-Panas, Ewa, Woehr, Markus, Knapp, Michael, Seitz, Guido, de Klein, Annelies, Oracz, Grzegorz, Brosens, Erwin, Reutter, Heiko, and Schumacher, Johannes
Abstract: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is the most common congenital malformation of the upper digestive tract. This study represents the first genome-wide association study (GWAS) to identify risk loci for EA/TEF. We used a European case-control sample comprising 764 EA/TEF patients and 5,778 controls and observed genome-wide significant associations at three loci. On chromosome 10q21 within the gene CTNNA3 (p = 2.11 x 10(-8); odds ratio [OR] = 3.94; 95% confidence interval [CI], 3.10-5.00), on chromosome 16q24 next to the FOX gene cluster (p = 2.25 x 10(-10); OR = 1.47; 95% CI, 1.38-1.55) and on chromosome 17q12 next to the gene HNF1B (p = 3.35 x 10(-16); OR = 1.75; 95% CI, 1.64-1.87). We next carried out an esophageal/tracheal transcriptome profiling in rat embryos at four selected embryonic time points. Based on these data and on already published data, the implicated genes at all three GWAS loci are promising candidates for EA/TEF development. We also analyzed the genetic EA/TEF architecture beyond the single marker level, which revealed an estimated single-nucleotide polymorphism (SNP)-based heritability of around 37% +/- 14% standard deviation. In addition, we examined the polygenicity of EA/TEF and found that EA/TEF is less polygenic than other complex genetic diseases. In conclusion, the results of our study contribute to a better understanding on the underlying genetic architecture of ET/TEF with the identification of three risk loci and candidate genes.
Published: 2022

32. eQTL Set-Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma

Author: Wang, Xiaoyu, Gharahkhani, Puya, Levine, David M., Fitzgerald, Rebecca C., Gockel, Ines, Corley, Douglas A., Risch, Harvey A., Bernstein, Leslie, Chow, Wong-Ho, Onstad, Lynn, Shaheen, Nicholas J., Lagergren, Jesper, Hardie, Laura J., Wu, Anna H., Pharoah, Paul D. P., Liu, Geoffrey, Anderson, Lesley A., Iyer, Prasad G., Gammon, Marilie D., Caldas, Carlos, Ye, Weimin, Barr, Hugh, Moayyedi, Paul, Harrison, Rebecca, Watson, R. G. Peter, Attwood, Stephen, Chegwidden, Laura, Love, Sharon B., MacDonald, David, DeCaestecker, John, Prenen, Hans, Ott, Katja, Moebus, Susanne, Venerito, Marino, Lang, Hauke, Mayershofer, Rupert, Knapp, Michael, Veits, Lothar, Gerges, Christian, Weismueller, Josef, Reeh, Matthias, Noethen, Markus M., Izbicki, Jakob R., Manner, Hendrik, Neuhaus, Horst, Roesch, Thomas, Boehmer, Anne C., Hoelscher, Arnulf H., Anders, Mario, Pech, Oliver, Schumacher, Brigitte, Schmidt, Claudia, Schmidt, Thomas, Noder, Tania, Lorenz, Dietmar, Vieth, Michael, May, Andrea, Hess, Timo, Kreuser, Nicole, Becker, Jessica, Ell, Christian, Tomlinson, Ian, Palles, Claire, Jankowski, Janusz A., Whiteman, David C., MacGregor, Stuart, Schumacher, Johannes, Vaughan, Thomas L., Buas, Matthew F., Dai, James Y., Wang, Xiaoyu, Gharahkhani, Puya, Levine, David M., Fitzgerald, Rebecca C., Gockel, Ines, Corley, Douglas A., Risch, Harvey A., Bernstein, Leslie, Chow, Wong-Ho, Onstad, Lynn, Shaheen, Nicholas J., Lagergren, Jesper, Hardie, Laura J., Wu, Anna H., Pharoah, Paul D. P., Liu, Geoffrey, Anderson, Lesley A., Iyer, Prasad G., Gammon, Marilie D., Caldas, Carlos, Ye, Weimin, Barr, Hugh, Moayyedi, Paul, Harrison, Rebecca, Watson, R. G. Peter, Attwood, Stephen, Chegwidden, Laura, Love, Sharon B., MacDonald, David, DeCaestecker, John, Prenen, Hans, Ott, Katja, Moebus, Susanne, Venerito, Marino, Lang, Hauke, Mayershofer, Rupert, Knapp, Michael, Veits, Lothar, Gerges, Christian, Weismueller, Josef, Reeh, Matthias, Noethen, Markus M., Izbicki, Jakob R., Manner, Hendrik, Neuhaus, Horst, Roesch, Thomas, Boehmer, Anne C., Hoelscher, Arnulf H., Anders, Mario, Pech, Oliver, Schumacher, Brigitte, Schmidt, Claudia, Schmidt, Thomas, Noder, Tania, Lorenz, Dietmar, Vieth, Michael, May, Andrea, Hess, Timo, Kreuser, Nicole, Becker, Jessica, Ell, Christian, Tomlinson, Ian, Palles, Claire, Jankowski, Janusz A., Whiteman, David C., MacGregor, Stuart, Schumacher, Johannes, Vaughan, Thomas L., Buas, Matthew F., and Dai, James Y.
Abstract: Background: Over 20 susceptibility single-nucleotide poly-morphisms (SNP) have been identified for esophageal adenocarcinoma (EAC) and its precursor, Barrett esophagus (BE), explaining a small portion of heritability.Methods: Using genetic data from 4,323 BE and 4,116 EAC patients aggregated by international consortia including the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), we conducted a comprehensive transcriptome-wide association study (TWAS) for BE/EAC, leveraging Genotype Tissue Expression (GTEx) gene-expression data from six tissue types of plausible relevance to EAC etiology: mucosa and muscularis from the esophagus, gastroesophageal (GE) junction, stomach, whole blood, and visceral adipose. Two analytical approaches were taken: standard TWAS using the predicted gene expression from local expression quantitative trait loci (eQTL), and set-based SKAT association using selected eQTLs that predict the gene expression. Results: Although the standard approach did not identify significant signals, the eQTL set-based approach identified eight novel associations, three of which were validated in independent external data (eQTL SNP sets for EXOC3, ZNF641, and HSP90AA1). Conclusions: This study identified novel genetic susceptibility loci for EAC and BE using an eQTL set-based genetic association approach.Impact: This study expanded the pool of genetic susceptibility loci for EAC and BE, suggesting the potential of the eQTL set-based genetic association approach as an alternative method for TWAS analysis.
Published: 2022

33. Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease

Author: Le Guen, Yann, Belloy, Michael E, Grenier-Boley, Benjamin, de Rojas, Itziar, Castillo-Morales, Atahualpa, Jansen, Iri, Nicolas, Aude, Bellenguez, Céline, Dalmasso, Carolina, Küçükali, Fahri, Eger, Sarah J, Rasmussen, Katrine Laura, Thomassen, Jesper Qvist, Deleuze, Jean-Françoi, He, Zihuai, Napolioni, Valerio, Amouyel, Philippe, Jessen, Frank, Kehoe, Patrick G, van Duijn, Cornelia, Tsolaki, Magda, Sánchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Rossi, Giacomina, Hiltunen, Mikko, Sims, Rebecca, van der Flier, Wiesje M, Ramirez, Alfredo, Andreassen, Ole A, Frikke-Schmidt, Ruth, Williams, Julie, Ruiz, Agustín, Lambert, Jean-Charle, Greicius, Michael D, Arosio, Beatrice, Benussi, Luisa, Boland, Anne, Borroni, Barbara, Caffarra, Paolo, Daian, Delphine, Daniele, Antonio, Debette, Stéphanie, Dufouil, Carole, Düzel, Emrah, Galimberti, Daniela, Giedraitis, Vilmanta, Grimmer, Timo, Graff, Caroline, Grünblatt, Edna, Hanon, Olivier, Hausner, Lucrezia, Heilmann-Heimbach, Stefanie, Holstege, Henne, Hort, Jakub, Jürgen, Deckert, Kuulasmaa, Teemu, van der Lugt, Aad, Masullo, Carlo, Mecocci, Patrizia, Mehrabian, Shima, de Mendonça, Alexandre, Moebus, Susanne, Nacmias, Benedetta, Nicolas, Gael, Olaso, Robert, Papenberg, Goran, Parnetti, Lucilla, Pasquier, Florence, Peters, Oliver, Pijnenburg, Yolande A L, Popp, Juliu, Rainero, Innocenzo, Ramakers, Inez, Riedel-Heller, Steffi, Scarmeas, Nikolao, Scheltens, Philip, Scherbaum, Norbert, Schneider, Anja, Seripa, Davide, Soininen, Hilkka, Solfrizzi, Vincenzo, Spalletta, Gianfranco, Squassina, Alessio, van Swieten, John, Tegos, Thomas J, Tremolizzo, Lucio, Verhey, Fran, Vyhnalek, Martin, Wiltfang, Jen, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Real, Luis M, Álvarez, Victoria, Bullido, María J, Clarimon, Jordi, García-Alberca, José María, Mir, Pablo, Moreno, Fermin, Pastor, Pau, Piñol-Ripoll, Gerard, Molina-Porcel, Laura, Pérez-Tur, Jordi, Rodríguez-Rodríguez, Eloy, Royo, Jose Luí, Sánchez-Valle, Raquel, Dichgans, Martin, Rujescu, Dan, Daniele, Antonio (ORCID:0000-0003-1641-5852), Masullo, Carlo (ORCID:0000-0001-7798-3410), Le Guen, Yann, Belloy, Michael E, Grenier-Boley, Benjamin, de Rojas, Itziar, Castillo-Morales, Atahualpa, Jansen, Iri, Nicolas, Aude, Bellenguez, Céline, Dalmasso, Carolina, Küçükali, Fahri, Eger, Sarah J, Rasmussen, Katrine Laura, Thomassen, Jesper Qvist, Deleuze, Jean-Françoi, He, Zihuai, Napolioni, Valerio, Amouyel, Philippe, Jessen, Frank, Kehoe, Patrick G, van Duijn, Cornelia, Tsolaki, Magda, Sánchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Rossi, Giacomina, Hiltunen, Mikko, Sims, Rebecca, van der Flier, Wiesje M, Ramirez, Alfredo, Andreassen, Ole A, Frikke-Schmidt, Ruth, Williams, Julie, Ruiz, Agustín, Lambert, Jean-Charle, Greicius, Michael D, Arosio, Beatrice, Benussi, Luisa, Boland, Anne, Borroni, Barbara, Caffarra, Paolo, Daian, Delphine, Daniele, Antonio, Debette, Stéphanie, Dufouil, Carole, Düzel, Emrah, Galimberti, Daniela, Giedraitis, Vilmanta, Grimmer, Timo, Graff, Caroline, Grünblatt, Edna, Hanon, Olivier, Hausner, Lucrezia, Heilmann-Heimbach, Stefanie, Holstege, Henne, Hort, Jakub, Jürgen, Deckert, Kuulasmaa, Teemu, van der Lugt, Aad, Masullo, Carlo, Mecocci, Patrizia, Mehrabian, Shima, de Mendonça, Alexandre, Moebus, Susanne, Nacmias, Benedetta, Nicolas, Gael, Olaso, Robert, Papenberg, Goran, Parnetti, Lucilla, Pasquier, Florence, Peters, Oliver, Pijnenburg, Yolande A L, Popp, Juliu, Rainero, Innocenzo, Ramakers, Inez, Riedel-Heller, Steffi, Scarmeas, Nikolao, Scheltens, Philip, Scherbaum, Norbert, Schneider, Anja, Seripa, Davide, Soininen, Hilkka, Solfrizzi, Vincenzo, Spalletta, Gianfranco, Squassina, Alessio, van Swieten, John, Tegos, Thomas J, Tremolizzo, Lucio, Verhey, Fran, Vyhnalek, Martin, Wiltfang, Jen, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Real, Luis M, Álvarez, Victoria, Bullido, María J, Clarimon, Jordi, García-Alberca, José María, Mir, Pablo, Moreno, Fermin, Pastor, Pau, Piñol-Ripoll, Gerard, Molina-Porcel, Laura, Pérez-Tur, Jordi, Rodríguez-Rodríguez, Eloy, Royo, Jose Luí, Sánchez-Valle, Raquel, Dichgans, Martin, Rujescu, Dan, Daniele, Antonio (ORCID:0000-0003-1641-5852), and Masullo, Carlo (ORCID:0000-0001-7798-3410)
Abstract: IMPORTANCE The APOE epsilon 2 and APOE epsilon 4 alleles are the strongest protective and risk-increasing, respectively, genetic variants for late-onset Alzheimer disease (AD). However, the mechanisms linking APOE to AD-particularly the apoE protein's role in AD pathogenesis and how this is affected by APOE variants-remain poorly understood. Identifying missense variants in addition to APOE epsilon 2 and APOE epsilon 4 could provide critical new insights, but given the low frequency of additional missense variants, AD genetic cohorts have previously been too small to interrogate this question robustly.OBJECTIVE To determine whether rare missense variants on APOE are associated with AD risk.DESIGN, SETTING, AND PARTICIPANTS Association with case-control status was tested in a sequenced discovery sample (stage 1) and followed up in several microarray imputed cohorts as well as the UK Biobank whole-exome sequencing resource using a proxy-AD phenotype (stages 2 and 3). This study combined case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Stage 1 induded 37 409 nonunique participants of European or admixed European ancestry, with 11868 individuals with AD and 11 934 controls passing analysis inclusion criteria. In stages 2 and 3, 475 473 participants were considered across 8 cohorts, of which 84513 individuals with AD and proxy-AD and 328 372 controls passed inclusion criteria. Selection criteria were cohort specific, and this study was performed a posteriori on individuals who were genotyped. Among the available genotypes, 76 195 were excluded. All data were retrieved between September 2015 and November 2021 and analyzed between April and November 2021.MAIN OUTCOMES AND MEASURES In primary analyses, the AD risk associated with each missense variant was estimated, as appropriate, with either linear mixed-model regression or logistic regression. In secondary analyses, associations were est
Published: 2022

34. First genome-wide association study of esophageal atresia identifies three genetic risk loci at CTNNA3, FOXF1/FOXC2/FOXL1, and HNF1B

Author: Gehlen, Jan, Giel, Ann-Sophie, Koellges, Ricarda, Haas, Stephan L., Zhang, Rong, Trcka, Jiri, Sungur, Ayse O., Renziehausen, Florian, Bornholdt, Dorothea, Jung, Daphne, Hoyer, Paul D., Nordenskjold, Agneta, Tibboel, Dick, Vlot, John, Spaander, Manon C. W., Smigiel, Robert, Patkowski, Dariusz, Roeleveld, Nel, van Rooij, Iris Alm, de Blaauw, Ivo, Hoelscher, Alice, Pauly, Marcus, Leutner, Andreas, Fuchs, Joerg, Niethammer, Joel, Melissari, Maria-Theodora, Jenetzky, Ekkehart, Zwink, Nadine, Thiele, Holger, Hilger, Alina Christine, Hess, Timo, Trautmann, Jessica, Marks, Matthias, Baumgarten, Martin, Blaess, Gaby, Landen, Mikael, Fundin, Bengt, Bulik, Cynthia M., Pennimpede, Tracie, Ludwig, Michael, Ludwig, Kerstin U., Mangold, Elisabeth, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Herrmann, Bernhard G., Alsabeah, Kristina, Burgos, Carmen M., Engstrand Lilja, Helene, Azodi, Sahar, Stenstrom, Pernilla, Arnbjornsson, Einar, Frybova, Barbora, Lebensztejn, Dariusz M., Debek, Wojciech, Kolodziejczyk, Elwira, Kozera, Katarzyna, Kierkus, Jaroslaw, Kalicinski, Piotr, Stefanowicz, Marek, Socha-Banasiak, Anna, Kolejwa, Michal, Piaseczna-Piotrowska, Anna, Czkwianianc, Elzbieta, Noethen, Markus M., Grote, Phillip, Rygl, Michal, Reinshagen, Konrad, Spychalski, Nicole, Ludwikowski, Barbara, Hubertus, Jochen, Heydweiller, Andreas, Ure, Benno, Muensterer, Oliver J., Aubert, Ophelia, Gosemann, Jan-Hendrik, Lacher, Martin, Degenhardt, Petra, Boemers, Thomas M., Mokrowiecka, Anna, Malecka-Panas, Ewa, Woehr, Markus, Knapp, Michael, Seitz, Guido, de Klein, Annelies, Oracz, Grzegorz, Brosens, Erwin, Reutter, Heiko, Schumacher, Johannes, Gehlen, Jan, Giel, Ann-Sophie, Koellges, Ricarda, Haas, Stephan L., Zhang, Rong, Trcka, Jiri, Sungur, Ayse O., Renziehausen, Florian, Bornholdt, Dorothea, Jung, Daphne, Hoyer, Paul D., Nordenskjold, Agneta, Tibboel, Dick, Vlot, John, Spaander, Manon C. W., Smigiel, Robert, Patkowski, Dariusz, Roeleveld, Nel, van Rooij, Iris Alm, de Blaauw, Ivo, Hoelscher, Alice, Pauly, Marcus, Leutner, Andreas, Fuchs, Joerg, Niethammer, Joel, Melissari, Maria-Theodora, Jenetzky, Ekkehart, Zwink, Nadine, Thiele, Holger, Hilger, Alina Christine, Hess, Timo, Trautmann, Jessica, Marks, Matthias, Baumgarten, Martin, Blaess, Gaby, Landen, Mikael, Fundin, Bengt, Bulik, Cynthia M., Pennimpede, Tracie, Ludwig, Michael, Ludwig, Kerstin U., Mangold, Elisabeth, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Herrmann, Bernhard G., Alsabeah, Kristina, Burgos, Carmen M., Engstrand Lilja, Helene, Azodi, Sahar, Stenstrom, Pernilla, Arnbjornsson, Einar, Frybova, Barbora, Lebensztejn, Dariusz M., Debek, Wojciech, Kolodziejczyk, Elwira, Kozera, Katarzyna, Kierkus, Jaroslaw, Kalicinski, Piotr, Stefanowicz, Marek, Socha-Banasiak, Anna, Kolejwa, Michal, Piaseczna-Piotrowska, Anna, Czkwianianc, Elzbieta, Noethen, Markus M., Grote, Phillip, Rygl, Michal, Reinshagen, Konrad, Spychalski, Nicole, Ludwikowski, Barbara, Hubertus, Jochen, Heydweiller, Andreas, Ure, Benno, Muensterer, Oliver J., Aubert, Ophelia, Gosemann, Jan-Hendrik, Lacher, Martin, Degenhardt, Petra, Boemers, Thomas M., Mokrowiecka, Anna, Malecka-Panas, Ewa, Woehr, Markus, Knapp, Michael, Seitz, Guido, de Klein, Annelies, Oracz, Grzegorz, Brosens, Erwin, Reutter, Heiko, and Schumacher, Johannes
Abstract: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is the most common congenital malformation of the upper digestive tract. This study represents the first genome-wide association study (GWAS) to identify risk loci for EA/TEF. We used a European case-control sample comprising 764 EA/TEF patients and 5,778 controls and observed genome-wide significant associations at three loci. On chromosome 10q21 within the gene CTNNA3 (p = 2.11 x 10(-8); odds ratio [OR] = 3.94; 95% confidence interval [CI], 3.10-5.00), on chromosome 16q24 next to the FOX gene cluster (p = 2.25 x 10(-10); OR = 1.47; 95% CI, 1.38-1.55) and on chromosome 17q12 next to the gene HNF1B (p = 3.35 x 10(-16); OR = 1.75; 95% CI, 1.64-1.87). We next carried out an esophageal/tracheal transcriptome profiling in rat embryos at four selected embryonic time points. Based on these data and on already published data, the implicated genes at all three GWAS loci are promising candidates for EA/TEF development. We also analyzed the genetic EA/TEF architecture beyond the single marker level, which revealed an estimated single-nucleotide polymorphism (SNP)-based heritability of around 37% +/- 14% standard deviation. In addition, we examined the polygenicity of EA/TEF and found that EA/TEF is less polygenic than other complex genetic diseases. In conclusion, the results of our study contribute to a better understanding on the underlying genetic architecture of ET/TEF with the identification of three risk loci and candidate genes.
Published: 2022
Full Text: View/download PDF

35. First genome-wide association study of esophageal atresia identifies three genetic risk loci at CTNNA3, FOXF1/FOXC2/FOXL1, and HNF1B

Author: Gehlen, Jan, Giel, Ann Sophie, Köllges, Ricarda, Haas, Stephan L., Zhang, Rong, Trcka, Jiri, Sungur, Ayse, Renziehausen, Florian, Bornholdt, Dorothea, Jung, Daphne, Hoyer, Paul D., Nordenskjöld, Agneta, Tibboel, Dick, Vlot, John, Spaander, Manon C.W., Smigiel, Robert, Patkowski, Dariusz, Roeleveld, Nel, van Rooij, Iris ALM, de Blaauw, Ivo, Hölscher, Alice, Pauly, Marcus, Leutner, Andreas, Fuchs, Joerg, Niethammer, Joel, Melissari, Maria Theodora, Jenetzky, Ekkehart, Zwink, Nadine, Thiele, Holger, Hilger, Alina Christine, Hess, Timo, Trautmann, Jessica, Marks, Matthias, Baumgarten, Martin, Bläss, Gaby, Landén, Mikael, Fundin, Bengt, Bulik, Cynthia M., Pennimpede, Tracie, Ludwig, Michael, Ludwig, Kerstin U., Mangold, Elisabeth, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Herrmann, Bernhard G., Alsabeah, Kristina, Burgos, Carmen M., Lilja, Helene E., Azodi, Sahar, Stenström, Pernilla, Arnbjörnsson, Einar, Frybova, Barbora, Lebensztejn, Dariusz M., Debek, Wojciech, Kolodziejczyk, Elwira, Kozera, Katarzyna, Kierkus, Jaroslaw, Kaliciński, Piotr, Stefanowicz, Marek, Socha-Banasiak, Anna, Kolejwa, Michal, Piaseczna-Piotrowska, Anna, Czkwianianc, Elzbieta, Nöthen, Markus M., Grote, Phillip, Rygl, Michal, Reinshagen, Konrad, Spychalski, Nicole, Ludwikowski, Barbara, Hubertus, Jochen, Heydweiller, Andreas, Ure, Benno, Muensterer, Oliver J., Aubert, Ophelia, Gosemann, Jan Hendrik, Lacher, Martin, Degenhardt, Petra, Boemers, Thomas M., Mokrowiecka, Anna, Małecka-Panas, Ewa, Wöhr, Markus, Knapp, Michael, Seitz, Guido, de Klein, Annelies, Oracz, Grzegorz, Brosens, Erwin, Reutter, Heiko, Schumacher, Johannes, Gehlen, Jan, Giel, Ann Sophie, Köllges, Ricarda, Haas, Stephan L., Zhang, Rong, Trcka, Jiri, Sungur, Ayse, Renziehausen, Florian, Bornholdt, Dorothea, Jung, Daphne, Hoyer, Paul D., Nordenskjöld, Agneta, Tibboel, Dick, Vlot, John, Spaander, Manon C.W., Smigiel, Robert, Patkowski, Dariusz, Roeleveld, Nel, van Rooij, Iris ALM, de Blaauw, Ivo, Hölscher, Alice, Pauly, Marcus, Leutner, Andreas, Fuchs, Joerg, Niethammer, Joel, Melissari, Maria Theodora, Jenetzky, Ekkehart, Zwink, Nadine, Thiele, Holger, Hilger, Alina Christine, Hess, Timo, Trautmann, Jessica, Marks, Matthias, Baumgarten, Martin, Bläss, Gaby, Landén, Mikael, Fundin, Bengt, Bulik, Cynthia M., Pennimpede, Tracie, Ludwig, Michael, Ludwig, Kerstin U., Mangold, Elisabeth, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Herrmann, Bernhard G., Alsabeah, Kristina, Burgos, Carmen M., Lilja, Helene E., Azodi, Sahar, Stenström, Pernilla, Arnbjörnsson, Einar, Frybova, Barbora, Lebensztejn, Dariusz M., Debek, Wojciech, Kolodziejczyk, Elwira, Kozera, Katarzyna, Kierkus, Jaroslaw, Kaliciński, Piotr, Stefanowicz, Marek, Socha-Banasiak, Anna, Kolejwa, Michal, Piaseczna-Piotrowska, Anna, Czkwianianc, Elzbieta, Nöthen, Markus M., Grote, Phillip, Rygl, Michal, Reinshagen, Konrad, Spychalski, Nicole, Ludwikowski, Barbara, Hubertus, Jochen, Heydweiller, Andreas, Ure, Benno, Muensterer, Oliver J., Aubert, Ophelia, Gosemann, Jan Hendrik, Lacher, Martin, Degenhardt, Petra, Boemers, Thomas M., Mokrowiecka, Anna, Małecka-Panas, Ewa, Wöhr, Markus, Knapp, Michael, Seitz, Guido, de Klein, Annelies, Oracz, Grzegorz, Brosens, Erwin, Reutter, Heiko, and Schumacher, Johannes
Abstract: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is the most common congenital malformation of the upper digestive tract. This study represents the first genome-wide association study (GWAS) to identify risk loci for EA/TEF. We used a European case-control sample comprising 764 EA/TEF patients and 5,778 controls and observed genome-wide significant associations at three loci. On chromosome 10q21 within the gene CTNNA3 (p = 2.11 × 10−8; odds ratio [OR] = 3.94; 95% confidence interval [CI], 3.10–5.00), on chromosome 16q24 next to the FOX gene cluster (p = 2.25 × 10−10; OR = 1.47; 95% CI, 1.38–1.55) and on chromosome 17q12 next to the gene HNF1B (p = 3.35 × 10−16; OR = 1.75; 95% CI, 1.64–1.87). We next carried out an esophageal/tracheal transcriptome profiling in rat embryos at four selected embryonic time points. Based on these data and on already published data, the implicated genes at all three GWAS loci are promising candidates for EA/TEF development. We also analyzed the genetic EA/TEF architecture beyond the single marker level, which revealed an estimated single-nucleotide polymorphism (SNP)-based heritability of around 37% ± 14% standard deviation. In addition, we examined the polygenicity of EA/TEF and found that EA/TEF is less polygenic than other complex genetic diseases. In conclusion, the results of our study contribute to a better understanding on the underlying genetic architecture of ET/TEF with the identification of three risk loci and candidate genes.
Published: 2022

36. Germline variation in the insulin-like growth factor pathway and risk of Barrett's esophagus and esophageal adenocarcinoma

Author: Dighe, Shruti G., Chen, Jianhong, Yan, Li, He, Qianchuan, Gharahkhani, Puya, Onstad, Lynn, Levine, David M., Palles, Claire, Ye, Weimin, Gammon, Marilie D., Iyer, Prasad G., Anderson, Lesley A., Liu, Geoffrey, Wu, Anna H., Dai, James Y., Chow, Wong-Ho, Risch, Harvey A., Lagergren, Jesper, Shaheen, Nicholas J., Bernstein, Leslie, Corley, Douglas A., Prenen, Hans, DeCaestecker, John, MacDonald, David, Moayyedi, Paul, Barr, Hugh, Love, Sharon B., Chegwidden, Laura, Attwood, Stephen, Watson, Peter, Harrison, Rebecca, Ott, Katja, Moebus, Susanne, Venerito, Marino, Lang, Hauke, Mayershofer, Rupert, Knapp, Michael, Veits, Lothar, Gerges, Christian, Weismueller, Josef, Gockel, Ines, Vashist, Yogesh, Noethen, Markus M., Izbicki, Jakob R., Manner, Hendrik, Neuhaus, Horst, Roesch, Thomas, Boehmer, Anne C., Hoelscher, Arnulf H., Anders, Mario, Pech, Oliver, Schumacher, Brigitte, Schmidt, Claudia, Schmidt, Thomas, Noder, Tania, Lorenz, Dietmar, Vieth, Michael, May, Andrea, Hess, Timo, Kreuser, Nicole, Becker, Jessica, Ell, Christian, Ambrosone, Christine B., Moysich, Kirsten B., MacGregor, Stuart, Tomlinson, Ian, Whiteman, David C., Jankowski, Janusz, Schumacher, Johannes, Vaughan, Thomas L., Madeleine, Margaret M., Hardie, Laura J., Buas, Matthew F., Dighe, Shruti G., Chen, Jianhong, Yan, Li, He, Qianchuan, Gharahkhani, Puya, Onstad, Lynn, Levine, David M., Palles, Claire, Ye, Weimin, Gammon, Marilie D., Iyer, Prasad G., Anderson, Lesley A., Liu, Geoffrey, Wu, Anna H., Dai, James Y., Chow, Wong-Ho, Risch, Harvey A., Lagergren, Jesper, Shaheen, Nicholas J., Bernstein, Leslie, Corley, Douglas A., Prenen, Hans, DeCaestecker, John, MacDonald, David, Moayyedi, Paul, Barr, Hugh, Love, Sharon B., Chegwidden, Laura, Attwood, Stephen, Watson, Peter, Harrison, Rebecca, Ott, Katja, Moebus, Susanne, Venerito, Marino, Lang, Hauke, Mayershofer, Rupert, Knapp, Michael, Veits, Lothar, Gerges, Christian, Weismueller, Josef, Gockel, Ines, Vashist, Yogesh, Noethen, Markus M., Izbicki, Jakob R., Manner, Hendrik, Neuhaus, Horst, Roesch, Thomas, Boehmer, Anne C., Hoelscher, Arnulf H., Anders, Mario, Pech, Oliver, Schumacher, Brigitte, Schmidt, Claudia, Schmidt, Thomas, Noder, Tania, Lorenz, Dietmar, Vieth, Michael, May, Andrea, Hess, Timo, Kreuser, Nicole, Becker, Jessica, Ell, Christian, Ambrosone, Christine B., Moysich, Kirsten B., MacGregor, Stuart, Tomlinson, Ian, Whiteman, David C., Jankowski, Janusz, Schumacher, Johannes, Vaughan, Thomas L., Madeleine, Margaret M., Hardie, Laura J., and Buas, Matthew F.
Abstract: Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS metaanalysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.
Published: 2021

37. Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression

Author: Forstner, Andreas J., Awasthi, Swapnil, Wolf, Christiane, Maron, Eduard, Erhardt, Angelika, Czamara, Darina, Eriksson, Elias, Lavebratt, Catharina, Allgulander, Christer, Friedrich, Nina, Becker, Jessica, Hecker, Julian, Rambau, Stefanie, Conrad, Rupert, Geiser, Franziska, McMahon, Francis J., Moebus, Susanne, Hess, Timo, Buerfent, Benedikt C., Hoffmann, Per, Herms, Stefan, Heilmann-Heimbach, Stefanie, Kockum, Ingrid, Olsson, Tomas, Alfredsson, Lars, Weber, Heike, Alpers, Georg W., Arolt, Volker, Fehm, Lydia, Fydrich, Thomas, Gerlach, Alexander L., Hamm, Alfons, Kircher, Tilo, Pane-Farre, Christiane A., Pauli, Paul, Rief, Winfried, Strohle, Andreas, Plag, Jens, Lang, Thomas, Wittchen, Hans-Ulrich, Mattheisen, Manuel, Meier, Sandra, Metspalu, Andres, Domschke, Katharina, Reif, Andreas, Hovatta, Iiris, Lindefors, Nils, Andersson, Evelyn, Schalling, Martin, Mbarek, Hamdi, Milaneschi, Yuri, de Geus, Eco J. C., Boomsma, Dorret, I, Penninx, Brenda W. J. H., Thorgeirsson, Thorgeir E., Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, Muller-Myhsok, Bertram, Hansen, Thomas Folkmann, Borglum, Anders D., Werge, Thomas, Mortensen, Preben Bo, Nordentoft, Merete, Hougaard, David M., Hultman, Christina M., Sullivan, Patrick F., Nothen, Markus M., Woldbye, David P. D., Mors, Ole, Binder, Elisabeth B., Rueck, Christian, Ripke, Stephan, Deckert, Juergen, Schumacher, Johannes, Forstner, Andreas J., Awasthi, Swapnil, Wolf, Christiane, Maron, Eduard, Erhardt, Angelika, Czamara, Darina, Eriksson, Elias, Lavebratt, Catharina, Allgulander, Christer, Friedrich, Nina, Becker, Jessica, Hecker, Julian, Rambau, Stefanie, Conrad, Rupert, Geiser, Franziska, McMahon, Francis J., Moebus, Susanne, Hess, Timo, Buerfent, Benedikt C., Hoffmann, Per, Herms, Stefan, Heilmann-Heimbach, Stefanie, Kockum, Ingrid, Olsson, Tomas, Alfredsson, Lars, Weber, Heike, Alpers, Georg W., Arolt, Volker, Fehm, Lydia, Fydrich, Thomas, Gerlach, Alexander L., Hamm, Alfons, Kircher, Tilo, Pane-Farre, Christiane A., Pauli, Paul, Rief, Winfried, Strohle, Andreas, Plag, Jens, Lang, Thomas, Wittchen, Hans-Ulrich, Mattheisen, Manuel, Meier, Sandra, Metspalu, Andres, Domschke, Katharina, Reif, Andreas, Hovatta, Iiris, Lindefors, Nils, Andersson, Evelyn, Schalling, Martin, Mbarek, Hamdi, Milaneschi, Yuri, de Geus, Eco J. C., Boomsma, Dorret, I, Penninx, Brenda W. J. H., Thorgeirsson, Thorgeir E., Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, Muller-Myhsok, Bertram, Hansen, Thomas Folkmann, Borglum, Anders D., Werge, Thomas, Mortensen, Preben Bo, Nordentoft, Merete, Hougaard, David M., Hultman, Christina M., Sullivan, Patrick F., Nothen, Markus M., Woldbye, David P. D., Mors, Ole, Binder, Elisabeth B., Rueck, Christian, Ripke, Stephan, Deckert, Juergen, and Schumacher, Johannes
Abstract: Panic disorder (PD) has a lifetime prevalence of 2-4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0-34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 x 10(-4) were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10 x 10(-7)). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD.
Published: 2021

38. Public Health A Public-Health-Strategy of Germany

Author: Altgeld, Thomas, Baernighausen, Till, Boehm, Claudia, Boehm, Katharina, De Bock, Freia, Dierks, Marie-Luise, Dragano, Nico, Geene, Raimund, Geffert, Karin, Geisel, Bertram, Gepp, Sophie, Gerhardus, Ansgar, Hamouda, Osamah, Hoffmann, Wolfgang, Kuhn, Joseph, Kurth, Tobias, Loss, Julika, Moebus, Susanne, Pfaff, Holger, von Philipsborn, Peter, Pospiech, Stefan, Razum, Oliver, Rexroth, Ute, Thaiss, Heidrun M., Thyen, Ute, Tinnemann, Peter, Wieler, Lothar H., Wildner, Manfred, Zeeb, Hajo, Ziese, Thomas, Altgeld, Thomas, Baernighausen, Till, Boehm, Claudia, Boehm, Katharina, De Bock, Freia, Dierks, Marie-Luise, Dragano, Nico, Geene, Raimund, Geffert, Karin, Geisel, Bertram, Gepp, Sophie, Gerhardus, Ansgar, Hamouda, Osamah, Hoffmann, Wolfgang, Kuhn, Joseph, Kurth, Tobias, Loss, Julika, Moebus, Susanne, Pfaff, Holger, von Philipsborn, Peter, Pospiech, Stefan, Razum, Oliver, Rexroth, Ute, Thaiss, Heidrun M., Thyen, Ute, Tinnemann, Peter, Wieler, Lothar H., Wildner, Manfred, Zeeb, Hajo, and Ziese, Thomas
Published: 2021

39. Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression

Author: Forstner, Andreas J, Awasthi, Swapnil, Wolf, Christiane, Maron, Eduard, Erhardt, Angelika, Czamara, Darina, Eriksson, Elias, Lavebratt, Catharina, Allgulander, Christer, Friedrich, Nina, Becker, Jessica, Hecker, Julian, Rambau, Stefanie, Conrad, Rupert, Geiser, Franziska, McMahon, Francis J, Moebus, Susanne, Hess, Timo, Buerfent, Benedikt C, Hoffmann, Per, Herms, Stefan, Heilmann-Heimbach, Stefanie, Kockum, Ingrid, Olsson, Tomas, Alfredsson, Lars, Weber, Heike, Alpers, Georg W, Arolt, Volker, Fehm, Lydia, Fydrich, Thomas, Gerlach, Alexander L, Hamm, Alfons, Kircher, Tilo, Pané-Farré, Christiane A, Pauli, Paul, Rief, Winfried, Ströhle, Andreas, Plag, Jens, Lang, Thomas, Wittchen, Hans-Ulrich, Mattheisen, Manuel, Meier, Sandra, Metspalu, Andres, Domschke, Katharina, Reif, Andreas, Hovatta, Iiris, Lindefors, Nils, Andersson, Evelyn, Schalling, Martin, Mbarek, Hamdi, Milaneschi, Yuri, de Geus, Eco J C, Boomsma, Dorret I, Penninx, Brenda W J H, Thorgeirsson, Thorgeir E, Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, Müller-Myhsok, Bertram, Hansen, Thomas Folkmann, Børglum, Anders D, Werge, Thomas, Mortensen, Preben Bo, Nordentoft, Merete, Hougaard, David M, Hultman, Christina M, Sullivan, Patrick F, Nöthen, Markus M, Woldbye, David P D, Mors, Ole, Binder, Elisabeth B, Rück, Christian, Ripke, Stephan, Deckert, Jürgen, Schumacher, Johannes, Forstner, Andreas J, Awasthi, Swapnil, Wolf, Christiane, Maron, Eduard, Erhardt, Angelika, Czamara, Darina, Eriksson, Elias, Lavebratt, Catharina, Allgulander, Christer, Friedrich, Nina, Becker, Jessica, Hecker, Julian, Rambau, Stefanie, Conrad, Rupert, Geiser, Franziska, McMahon, Francis J, Moebus, Susanne, Hess, Timo, Buerfent, Benedikt C, Hoffmann, Per, Herms, Stefan, Heilmann-Heimbach, Stefanie, Kockum, Ingrid, Olsson, Tomas, Alfredsson, Lars, Weber, Heike, Alpers, Georg W, Arolt, Volker, Fehm, Lydia, Fydrich, Thomas, Gerlach, Alexander L, Hamm, Alfons, Kircher, Tilo, Pané-Farré, Christiane A, Pauli, Paul, Rief, Winfried, Ströhle, Andreas, Plag, Jens, Lang, Thomas, Wittchen, Hans-Ulrich, Mattheisen, Manuel, Meier, Sandra, Metspalu, Andres, Domschke, Katharina, Reif, Andreas, Hovatta, Iiris, Lindefors, Nils, Andersson, Evelyn, Schalling, Martin, Mbarek, Hamdi, Milaneschi, Yuri, de Geus, Eco J C, Boomsma, Dorret I, Penninx, Brenda W J H, Thorgeirsson, Thorgeir E, Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, Müller-Myhsok, Bertram, Hansen, Thomas Folkmann, Børglum, Anders D, Werge, Thomas, Mortensen, Preben Bo, Nordentoft, Merete, Hougaard, David M, Hultman, Christina M, Sullivan, Patrick F, Nöthen, Markus M, Woldbye, David P D, Mors, Ole, Binder, Elisabeth B, Rück, Christian, Ripke, Stephan, Deckert, Jürgen, and Schumacher, Johannes
Abstract: Panic disorder (PD) has a lifetime prevalence of 2-4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0-34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 × 10-4 were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10 × 10-7). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD.
Published: 2021
Full Text: View/download PDF

40. Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression

Author: Forstner, Andreas J., Awasthi, Swapnil, Wolf, Christiane, Maron, Eduard, Erhardt, Angelika, Czamara, Darina, Eriksson, Elias, Lavebratt, Catharina, Allgulander, Christer, Friedrich, Nina, Becker, Jessica, Hecker, Julian, Rambau, Stefanie, Conrad, Rupert, Geiser, Franziska, McMahon, Francis J., Moebus, Susanne, Hess, Timo, Buerfent, Benedikt C., Hoffmann, Per, Herms, Stefan, Heilmann-Heimbach, Stefanie, Kockum, Ingrid, Olsson, Tomas, Alfredsson, Lars, Weber, Heike, Alpers, Georg W., Arolt, Volker, Fehm, Lydia, Fydrich, Thomas, Gerlach, Alexander L., Hamm, Alfons, Kircher, Tilo, Pane-Farre, Christiane A., Pauli, Paul, Rief, Winfried, Strohle, Andreas, Plag, Jens, Lang, Thomas, Wittchen, Hans-Ulrich, Mattheisen, Manuel, Meier, Sandra, Metspalu, Andres, Domschke, Katharina, Reif, Andreas, Hovatta, Iiris, Lindefors, Nils, Andersson, Evelyn, Schalling, Martin, Mbarek, Hamdi, Milaneschi, Yuri, de Geus, Eco J. C., Boomsma, Dorret, I, Penninx, Brenda W. J. H., Thorgeirsson, Thorgeir E., Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, Muller-Myhsok, Bertram, Hansen, Thomas Folkmann, Borglum, Anders D., Werge, Thomas, Mortensen, Preben Bo, Nordentoft, Merete, Hougaard, David M., Hultman, Christina M., Sullivan, Patrick F., Nothen, Markus M., Woldbye, David P. D., Mors, Ole, Binder, Elisabeth B., Rueck, Christian, Ripke, Stephan, Deckert, Juergen, Schumacher, Johannes, Forstner, Andreas J., Awasthi, Swapnil, Wolf, Christiane, Maron, Eduard, Erhardt, Angelika, Czamara, Darina, Eriksson, Elias, Lavebratt, Catharina, Allgulander, Christer, Friedrich, Nina, Becker, Jessica, Hecker, Julian, Rambau, Stefanie, Conrad, Rupert, Geiser, Franziska, McMahon, Francis J., Moebus, Susanne, Hess, Timo, Buerfent, Benedikt C., Hoffmann, Per, Herms, Stefan, Heilmann-Heimbach, Stefanie, Kockum, Ingrid, Olsson, Tomas, Alfredsson, Lars, Weber, Heike, Alpers, Georg W., Arolt, Volker, Fehm, Lydia, Fydrich, Thomas, Gerlach, Alexander L., Hamm, Alfons, Kircher, Tilo, Pane-Farre, Christiane A., Pauli, Paul, Rief, Winfried, Strohle, Andreas, Plag, Jens, Lang, Thomas, Wittchen, Hans-Ulrich, Mattheisen, Manuel, Meier, Sandra, Metspalu, Andres, Domschke, Katharina, Reif, Andreas, Hovatta, Iiris, Lindefors, Nils, Andersson, Evelyn, Schalling, Martin, Mbarek, Hamdi, Milaneschi, Yuri, de Geus, Eco J. C., Boomsma, Dorret, I, Penninx, Brenda W. J. H., Thorgeirsson, Thorgeir E., Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, Muller-Myhsok, Bertram, Hansen, Thomas Folkmann, Borglum, Anders D., Werge, Thomas, Mortensen, Preben Bo, Nordentoft, Merete, Hougaard, David M., Hultman, Christina M., Sullivan, Patrick F., Nothen, Markus M., Woldbye, David P. D., Mors, Ole, Binder, Elisabeth B., Rueck, Christian, Ripke, Stephan, Deckert, Juergen, and Schumacher, Johannes
Abstract: Panic disorder (PD) has a lifetime prevalence of 2-4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0-34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 x 10(-4) were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10 x 10(-7)). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD.
Published: 2021

41. High Depressive Symptoms in Previously Undetected Diabetes – 10-Year Follow-Up Results of the Heinz Nixdorf Recall Study

Author: Icks,Andrea, Wittgens,Charlotte, Haastert,Burkhard, JÃ¶ckel,Karl-Heinz, Engel,Miriam, Erbel,Raimund, Andrich,Silke, Kruse,Johannes, Kulzer,Bernd, Hermanns,Norbert, Herder,Christian, Moebus,Susanne, Stang,Andreas, Kowall,Bernd, Icks,Andrea, Wittgens,Charlotte, Haastert,Burkhard, JÃ¶ckel,Karl-Heinz, Engel,Miriam, Erbel,Raimund, Andrich,Silke, Kruse,Johannes, Kulzer,Bernd, Hermanns,Norbert, Herder,Christian, Moebus,Susanne, Stang,Andreas, and Kowall,Bernd
Abstract: Andrea Icks,1– 3 Charlotte Wittgens,1 Burkhard Haastert,2,4 Karl-Heinz Jöckel,5 Miriam Engel,5 Raimund Erbel,5 Silke Andrich,1,2 Johannes Kruse,6 Bernd Kulzer,7 Norbert Hermanns,7 Christian Herder,3,8,9 Susanne Moebus,5 Andreas Stang,5 Bernd Kowall5 1Institute for Health Services Research and Health Economics, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; 2Institute for Health Services Research and Health Economics, Centre for Health and Society, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; 3German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany; 4mediStatistica, Neuenrade, Germany; 5Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Essen, Germany; 6Institute for Psychosomatics and Psychotherapy, University Hospital Gießen, Gießen, Germany; 7Research Institute of the Diabetes Academy Mergentheim and Diabetes Centre Mergentheim, Bad Mergentheim, Germany; 8Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; 9Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, GermanyCorrespondence: Andrea IcksInstitute for Health Services Research and Health Economics, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Auf’m Hennekamp 65, Düsseldorf, D-40225, GermanyTel +49 211 33 82 400Fax +49 211 33 82 677Email andrea.icks@uni-duesseldorf.deAim: To determine the 10-year cumulative incidence of high depressive symptoms in people with diagnosed and, in particular, previously undetected diabetes comp
Published: 2021

42. Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression

Author: Forstner, Andreas J., Awasthi, Swapnil, Wolf, Christiane, Maron, Eduard, Erhardt, Angelika, Czamara, Darina, Eriksson, Elias, Lavebratt, Catharina, Allgulander, Christer, Friedrich, Nina, Becker, Jessica, Hecker, Julian, Rambau, Stefanie, Conrad, Rupert, Geiser, Franziska, McMahon, Francis J., Moebus, Susanne, Hess, Timo, Buerfent, Benedikt C., Hoffmann, Per, Herms, Stefan, Heilmann-Heimbach, Stefanie, Kockum, Ingrid, Olsson, Tomas, Alfredsson, Lars, Weber, Heike, Alpers, Georg W., Arolt, Volker, Fehm, Lydia, Fydrich, Thomas, Gerlach, Alexander L., Hamm, Alfons, Kircher, Tilo, Pané-Farré, Christiane A., Pauli, Paul, Rief, Winfried, Ströhle, Andreas, Plag, Jens, Lang, Thomas, Wittchen, Hans-Ulrich, Mattheisen, Manuel, Meier, Sandra, Metspalu, Andres, Domschke, Katharina, Reif, Andreas, Hovatta, Iiris, Lindefors, Nils, Andersson, Evelyn, Schalling, Martin, Mbarek, Hamdi, Milaneschi, Yuri, de Geus, Eco J. C., Boomsma, Dorret I., Penninx, Brenda W. J. H., Thorgeirsson, Thorgeir E., Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, Müller-Myhsok, Bertram, Hansen, Thomas Folkmann, Børglum, Anders D., Werge, Thomas, Mortensen, Preben Bo, Nordentoft, Merete, Hougaard, David M., Hultman, Christina M., Sullivan, Patrick F., Nöthen, Markus M., Woldbye, David P. D., Mors, Ole, Binder, Elisabeth B., Rück, Christian, Ripke, Stephan, Deckert, Jürgen, Schumacher, Johannes, Forstner, Andreas J., Awasthi, Swapnil, Wolf, Christiane, Maron, Eduard, Erhardt, Angelika, Czamara, Darina, Eriksson, Elias, Lavebratt, Catharina, Allgulander, Christer, Friedrich, Nina, Becker, Jessica, Hecker, Julian, Rambau, Stefanie, Conrad, Rupert, Geiser, Franziska, McMahon, Francis J., Moebus, Susanne, Hess, Timo, Buerfent, Benedikt C., Hoffmann, Per, Herms, Stefan, Heilmann-Heimbach, Stefanie, Kockum, Ingrid, Olsson, Tomas, Alfredsson, Lars, Weber, Heike, Alpers, Georg W., Arolt, Volker, Fehm, Lydia, Fydrich, Thomas, Gerlach, Alexander L., Hamm, Alfons, Kircher, Tilo, Pané-Farré, Christiane A., Pauli, Paul, Rief, Winfried, Ströhle, Andreas, Plag, Jens, Lang, Thomas, Wittchen, Hans-Ulrich, Mattheisen, Manuel, Meier, Sandra, Metspalu, Andres, Domschke, Katharina, Reif, Andreas, Hovatta, Iiris, Lindefors, Nils, Andersson, Evelyn, Schalling, Martin, Mbarek, Hamdi, Milaneschi, Yuri, de Geus, Eco J. C., Boomsma, Dorret I., Penninx, Brenda W. J. H., Thorgeirsson, Thorgeir E., Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, Müller-Myhsok, Bertram, Hansen, Thomas Folkmann, Børglum, Anders D., Werge, Thomas, Mortensen, Preben Bo, Nordentoft, Merete, Hougaard, David M., Hultman, Christina M., Sullivan, Patrick F., Nöthen, Markus M., Woldbye, David P. D., Mors, Ole, Binder, Elisabeth B., Rück, Christian, Ripke, Stephan, Deckert, Jürgen, and Schumacher, Johannes
Published: 2021

43. Germline variation in the insulin-like growth factor pathway and risk of Barrett's esophagus and esophageal adenocarcinoma

Author: Dighe, Shruti G., Chen, Jianhong, Yan, Li, He, Qianchuan, Gharahkhani, Puya, Onstad, Lynn, Levine, David M., Palles, Claire, Ye, Weimin, Gammon, Marilie D., Iyer, Prasad G., Anderson, Lesley A., Liu, Geoffrey, Wu, Anna H., Dai, James Y., Chow, Wong-Ho, Risch, Harvey A., Lagergren, Jesper, Shaheen, Nicholas J., Bernstein, Leslie, Corley, Douglas A., Prenen, Hans, DeCaestecker, John, MacDonald, David, Moayyedi, Paul, Barr, Hugh, Love, Sharon B., Chegwidden, Laura, Attwood, Stephen, Watson, Peter, Harrison, Rebecca, Ott, Katja, Moebus, Susanne, Venerito, Marino, Lang, Hauke, Mayershofer, Rupert, Knapp, Michael, Veits, Lothar, Gerges, Christian, Weismueller, Josef, Gockel, Ines, Vashist, Yogesh, Noethen, Markus M., Izbicki, Jakob R., Manner, Hendrik, Neuhaus, Horst, Roesch, Thomas, Boehmer, Anne C., Hoelscher, Arnulf H., Anders, Mario, Pech, Oliver, Schumacher, Brigitte, Schmidt, Claudia, Schmidt, Thomas, Noder, Tania, Lorenz, Dietmar, Vieth, Michael, May, Andrea, Hess, Timo, Kreuser, Nicole, Becker, Jessica, Ell, Christian, Ambrosone, Christine B., Moysich, Kirsten B., MacGregor, Stuart, Tomlinson, Ian, Whiteman, David C., Jankowski, Janusz, Schumacher, Johannes, Vaughan, Thomas L., Madeleine, Margaret M., Hardie, Laura J., Buas, Matthew F., Dighe, Shruti G., Chen, Jianhong, Yan, Li, He, Qianchuan, Gharahkhani, Puya, Onstad, Lynn, Levine, David M., Palles, Claire, Ye, Weimin, Gammon, Marilie D., Iyer, Prasad G., Anderson, Lesley A., Liu, Geoffrey, Wu, Anna H., Dai, James Y., Chow, Wong-Ho, Risch, Harvey A., Lagergren, Jesper, Shaheen, Nicholas J., Bernstein, Leslie, Corley, Douglas A., Prenen, Hans, DeCaestecker, John, MacDonald, David, Moayyedi, Paul, Barr, Hugh, Love, Sharon B., Chegwidden, Laura, Attwood, Stephen, Watson, Peter, Harrison, Rebecca, Ott, Katja, Moebus, Susanne, Venerito, Marino, Lang, Hauke, Mayershofer, Rupert, Knapp, Michael, Veits, Lothar, Gerges, Christian, Weismueller, Josef, Gockel, Ines, Vashist, Yogesh, Noethen, Markus M., Izbicki, Jakob R., Manner, Hendrik, Neuhaus, Horst, Roesch, Thomas, Boehmer, Anne C., Hoelscher, Arnulf H., Anders, Mario, Pech, Oliver, Schumacher, Brigitte, Schmidt, Claudia, Schmidt, Thomas, Noder, Tania, Lorenz, Dietmar, Vieth, Michael, May, Andrea, Hess, Timo, Kreuser, Nicole, Becker, Jessica, Ell, Christian, Ambrosone, Christine B., Moysich, Kirsten B., MacGregor, Stuart, Tomlinson, Ian, Whiteman, David C., Jankowski, Janusz, Schumacher, Johannes, Vaughan, Thomas L., Madeleine, Margaret M., Hardie, Laura J., and Buas, Matthew F.
Abstract: Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS metaanalysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.
Published: 2021

44. Public Health A Public-Health-Strategy of Germany

Author: Altgeld, Thomas, Baernighausen, Till, Boehm, Claudia, Boehm, Katharina, De Bock, Freia, Dierks, Marie-Luise, Dragano, Nico, Geene, Raimund, Geffert, Karin, Geisel, Bertram, Gepp, Sophie, Gerhardus, Ansgar, Hamouda, Osamah, Hoffmann, Wolfgang, Kuhn, Joseph, Kurth, Tobias, Loss, Julika, Moebus, Susanne, Pfaff, Holger, von Philipsborn, Peter, Pospiech, Stefan, Razum, Oliver, Rexroth, Ute, Thaiss, Heidrun M., Thyen, Ute, Tinnemann, Peter, Wieler, Lothar H., Wildner, Manfred, Zeeb, Hajo, Ziese, Thomas, Altgeld, Thomas, Baernighausen, Till, Boehm, Claudia, Boehm, Katharina, De Bock, Freia, Dierks, Marie-Luise, Dragano, Nico, Geene, Raimund, Geffert, Karin, Geisel, Bertram, Gepp, Sophie, Gerhardus, Ansgar, Hamouda, Osamah, Hoffmann, Wolfgang, Kuhn, Joseph, Kurth, Tobias, Loss, Julika, Moebus, Susanne, Pfaff, Holger, von Philipsborn, Peter, Pospiech, Stefan, Razum, Oliver, Rexroth, Ute, Thaiss, Heidrun M., Thyen, Ute, Tinnemann, Peter, Wieler, Lothar H., Wildner, Manfred, Zeeb, Hajo, and Ziese, Thomas
Published: 2021

45. Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression

Author: Forstner, Andreas J, Awasthi, Swapnil, Wolf, Christiane, Maron, Eduard, Erhardt, Angelika, Czamara, Darina, Eriksson, Elias, Lavebratt, Catharina, Allgulander, Christer, Friedrich, Nina, Becker, Jessica, Hecker, Julian, Rambau, Stefanie, Conrad, Rupert, Geiser, Franziska, McMahon, Francis J, Moebus, Susanne, Hess, Timo, Buerfent, Benedikt C, Hoffmann, Per, Herms, Stefan, Heilmann-Heimbach, Stefanie, Kockum, Ingrid, Olsson, Tomas, Alfredsson, Lars, Weber, Heike, Alpers, Georg W, Arolt, Volker, Fehm, Lydia, Fydrich, Thomas, Gerlach, Alexander L, Hamm, Alfons, Kircher, Tilo, Pané-Farré, Christiane A, Pauli, Paul, Rief, Winfried, Ströhle, Andreas, Plag, Jens, Lang, Thomas, Wittchen, Hans-Ulrich, Mattheisen, Manuel, Meier, Sandra, Metspalu, Andres, Domschke, Katharina, Reif, Andreas, Hovatta, Iiris, Lindefors, Nils, Andersson, Evelyn, Schalling, Martin, Mbarek, Hamdi, Milaneschi, Yuri, de Geus, Eco J C, Boomsma, Dorret I, Penninx, Brenda W J H, Thorgeirsson, Thorgeir E, Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, Müller-Myhsok, Bertram, Hansen, Thomas Folkmann, Børglum, Anders D, Werge, Thomas, Mortensen, Preben Bo, Nordentoft, Merete, Hougaard, David M, Hultman, Christina M, Sullivan, Patrick F, Nöthen, Markus M, Woldbye, David P D, Mors, Ole, Binder, Elisabeth B, Rück, Christian, Ripke, Stephan, Deckert, Jürgen, Schumacher, Johannes, Forstner, Andreas J, Awasthi, Swapnil, Wolf, Christiane, Maron, Eduard, Erhardt, Angelika, Czamara, Darina, Eriksson, Elias, Lavebratt, Catharina, Allgulander, Christer, Friedrich, Nina, Becker, Jessica, Hecker, Julian, Rambau, Stefanie, Conrad, Rupert, Geiser, Franziska, McMahon, Francis J, Moebus, Susanne, Hess, Timo, Buerfent, Benedikt C, Hoffmann, Per, Herms, Stefan, Heilmann-Heimbach, Stefanie, Kockum, Ingrid, Olsson, Tomas, Alfredsson, Lars, Weber, Heike, Alpers, Georg W, Arolt, Volker, Fehm, Lydia, Fydrich, Thomas, Gerlach, Alexander L, Hamm, Alfons, Kircher, Tilo, Pané-Farré, Christiane A, Pauli, Paul, Rief, Winfried, Ströhle, Andreas, Plag, Jens, Lang, Thomas, Wittchen, Hans-Ulrich, Mattheisen, Manuel, Meier, Sandra, Metspalu, Andres, Domschke, Katharina, Reif, Andreas, Hovatta, Iiris, Lindefors, Nils, Andersson, Evelyn, Schalling, Martin, Mbarek, Hamdi, Milaneschi, Yuri, de Geus, Eco J C, Boomsma, Dorret I, Penninx, Brenda W J H, Thorgeirsson, Thorgeir E, Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, Müller-Myhsok, Bertram, Hansen, Thomas Folkmann, Børglum, Anders D, Werge, Thomas, Mortensen, Preben Bo, Nordentoft, Merete, Hougaard, David M, Hultman, Christina M, Sullivan, Patrick F, Nöthen, Markus M, Woldbye, David P D, Mors, Ole, Binder, Elisabeth B, Rück, Christian, Ripke, Stephan, Deckert, Jürgen, and Schumacher, Johannes
Abstract: Panic disorder (PD) has a lifetime prevalence of 2-4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0-34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 × 10-4 were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10 × 10-7). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD.
Published: 2021
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46. Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression

Author: Forstner, Andreas J., Awasthi, Swapnil, Wolf, Christiane, Maron, Eduard, Erhardt, Angelika, Czamara, Darina, Eriksson, Elias, Lavebratt, Catharina, Allgulander, Christer, Friedrich, Nina, Becker, Jessica, Hecker, Julian, Rambau, Stefanie, Conrad, Rupert, Geiser, Franziska, Mcmahon, Francis J., Moebus, Susanne, Hess, Timo, Buerfent, Benedikt C., Hoffmann, Per, Herms, Stefan, Heilmann-heimbach, Stefanie, Kockum, Ingrid, Olsson, Tomas, Alfredsson, Lars, Weber, Heike, Alpers, Georg W., Arolt, Volker, Fehm, Lydia, Fydrich, Thomas, Gerlach, Alexander L., Hamm, Alfons, Kircher, Tilo, Pané-farré, Christiane A., Pauli, Paul, Rief, Winfried, Ströhle, Andreas, Plag, Jens, Lang, Thomas, Wittchen, Hans-ulrich, Mattheisen, Manuel, Meier, Sandra, Metspalu, Andres, Domschke, Katharina, Reif, Andreas, Hovatta, Iiris, Lindefors, Nils, Andersson, Evelyn, Schalling, Martin, Mbarek, Hamdi, Milaneschi, Yuri, De Geus, Eco J. C., Boomsma, Dorret I., Penninx, Brenda W. J. H., Thorgeirsson, Thorgeir E., Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, Müller-myhsok, Bertram, Hansen, Thomas Folkmann, Børglum, Anders D., Werge, Thomas, Mortensen, Preben Bo, Nordentoft, Merete, Hougaard, David M., Hultman, Christina M., Sullivan, Patrick F., Nöthen, Markus M., Woldbye, David P. D., Mors, Ole, Binder, Elisabeth B., Rück, Christian, Ripke, Stephan, Deckert, Jürgen, Schumacher, Johannes, Forstner, Andreas J., Awasthi, Swapnil, Wolf, Christiane, Maron, Eduard, Erhardt, Angelika, Czamara, Darina, Eriksson, Elias, Lavebratt, Catharina, Allgulander, Christer, Friedrich, Nina, Becker, Jessica, Hecker, Julian, Rambau, Stefanie, Conrad, Rupert, Geiser, Franziska, Mcmahon, Francis J., Moebus, Susanne, Hess, Timo, Buerfent, Benedikt C., Hoffmann, Per, Herms, Stefan, Heilmann-heimbach, Stefanie, Kockum, Ingrid, Olsson, Tomas, Alfredsson, Lars, Weber, Heike, Alpers, Georg W., Arolt, Volker, Fehm, Lydia, Fydrich, Thomas, Gerlach, Alexander L., Hamm, Alfons, Kircher, Tilo, Pané-farré, Christiane A., Pauli, Paul, Rief, Winfried, Ströhle, Andreas, Plag, Jens, Lang, Thomas, Wittchen, Hans-ulrich, Mattheisen, Manuel, Meier, Sandra, Metspalu, Andres, Domschke, Katharina, Reif, Andreas, Hovatta, Iiris, Lindefors, Nils, Andersson, Evelyn, Schalling, Martin, Mbarek, Hamdi, Milaneschi, Yuri, De Geus, Eco J. C., Boomsma, Dorret I., Penninx, Brenda W. J. H., Thorgeirsson, Thorgeir E., Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, Müller-myhsok, Bertram, Hansen, Thomas Folkmann, Børglum, Anders D., Werge, Thomas, Mortensen, Preben Bo, Nordentoft, Merete, Hougaard, David M., Hultman, Christina M., Sullivan, Patrick F., Nöthen, Markus M., Woldbye, David P. D., Mors, Ole, Binder, Elisabeth B., Rück, Christian, Ripke, Stephan, Deckert, Jürgen, and Schumacher, Johannes
Published: 2021

47. Shared Genetic Etiology of Obesity-Related Traits and Barrett's Esophagus/Adenocarcinoma: Insights from Genome-Wide Association Studies

Author: Boehmer, Anne C., Hecker, Julian, Schroeder, Julia, Gharahkhani, Puya, May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Hess, Timo, Kreuser, Nicole, Thieme, Rene, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Fuchs, Claudia, Izbicki, Jakob R., Hoelscher, Arnulf H., Dietrich, Arne, Moulla, Yusef, Lyros, Orestis, Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Mayershofer, Rupert, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Meismueller, Josef, Moebus, Susanne, Knapp, Michael, Neuhaus, Horst, Roesch, Thomas, Ell, Christian, Noethen, Markus M., Whiteman, David C., Tomlinson, Ian, Jankowski, Janusz, Fitzgerald, Rebecca C., Palles, Claire, Vaughan, Thomas L., Gockel, Ines, Thrift, Aaron P., Fier, Heide, Schumacher, Johannes, Boehmer, Anne C., Hecker, Julian, Schroeder, Julia, Gharahkhani, Puya, May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Hess, Timo, Kreuser, Nicole, Thieme, Rene, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Fuchs, Claudia, Izbicki, Jakob R., Hoelscher, Arnulf H., Dietrich, Arne, Moulla, Yusef, Lyros, Orestis, Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Mayershofer, Rupert, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Meismueller, Josef, Moebus, Susanne, Knapp, Michael, Neuhaus, Horst, Roesch, Thomas, Ell, Christian, Noethen, Markus M., Whiteman, David C., Tomlinson, Ian, Jankowski, Janusz, Fitzgerald, Rebecca C., Palles, Claire, Vaughan, Thomas L., Gockel, Ines, Thrift, Aaron P., Fier, Heide, and Schumacher, Johannes
Abstract: Background: Obesity is a major risk factor for esophageal adenocarcinoma (EA) and its precursor Barrett's esophagus (BE). Research suggests that individuals with high genetic risk to obesity have a higher BE/EA risk. To facilitate understanding of biological factors that lead to progression from BE to EA, the present study investigated the shared genetic background of BE/EA and obesity-related traits. Methods: Cross-trait linkage disequilibrium score regression was applied to summary statistics from genome-wide association metaanalyses on BE/EA and on obesity traits. Body mass index (BMI) was used as a proxy for general obesity, and waist-to-hip ratio (WHR) for abdominal obesity. For single marker analyses, all genome-wide significant risk alleles for BMI and WHR were compared with summary statistics of the BE/EA meta-analyses. Results: Sex-combined analyses revealed a significant genetic correlation between BMI and BE/EA (r(g) = 0.13, P = 2 x 10(-04)) and a r(g) of 0.12 between WHR and BE/EA (P = 1 x 10(-02)). Sexspecific analyses revealed a pronounced genetic correlation between BMI and EA in females (r(g) = 0.17, P = 1.2 x 10(-03)), and WHR and EA in males (r(g) = 0.18, P = 1.51 x 10(-02)). On the single marker level, significant enrichment of concordant effects was observed for BMI and BE/EA risk variants (P = 8.45 x 10(-03)) and WHR and BE/EA risk variants (P = 2 x 10(-02)). Conclusions: Our study provides evidence for sex-specific genetic correlations that might reflect specific biological mechanisms. The data demonstrate that shared genetic factors are particularly relevant in progression from BE to EA. Impact: Our study quantifies the genetic correlation between BE/EA and obesity. Further research is now warranted to elucidate these effects and to understand the shared pathophysiology.
Published: 2020

48. Struktureller und sozio-demographischer Wandel der Arbeitswelt und Änderung der beruflichen Mobilität in Deutschland 1980-2010

Author: Bödeker, Wolfgang, Moebus, Susanne, Bödeker, Wolfgang, and Moebus, Susanne
Abstract: Der Wandel der Arbeitswelt und die Entwicklung der beruflichen Mobilität ist unter gesundheits- und präventionspolitischen Gesichtspunkten wegen einer möglichen Emergenz neuer Belastungsarten und der Einwanderung von Personen in belastungsintensive Berufe von Bedeutung. Bislang fehlt allerdings eine gemeinsame Analyse dieser Einflüsse. Ziel dieses Beitrags ist es, den demographischen und strukturellen Wandel der Arbeitswelt sowie die Änderung der beruflichen Mobilität anhand ausgewählter Indikatoren zu beschreiben. Wir fokussieren dabei auf sozio-demographische Kennzahlen und analysieren die Mobilität interbetrieblich (Wechsel der Arbeitgeber), interberuflich (Wechsel in andere Berufe), intersektoral (Wechsel in andere Branche) sowie interregional (Wechsel in ein anderes Bundesland). Datengrundlage ist die Stichprobe der Integrierten Arbeitsmarktbiografien des Instituts für Arbeits-markt- und Berufsforschung. Bei dem sogenannten Regionalfile handelt sich um eine ca. 2 % Stich-probe aus der Grundgesamtheit der integrierten Erwerbsbiographien. Für den Zeitraum 1980 bis 2010 verdeutlichen die Auswertungen einen durchgreifenden sozio-demographischen und strukturellen Wandel der Arbeitswelt. Während sich in der Mehrzahl der Wirtschaftsgruppen eine Abnahme der Beschäftigung zeigt, gewinnen die ohnehin schon beschäftigungsstarken Branchen wie das Kredit- und Versicherungsgewerbe und die Erziehungs-, Sozial- und Gesundheitseinrichtungen weiter an Bedeutung. Es zeigt sich eine bedeutende Zunahme des Anteils der Frauen, der Teilzeittätigkeit, sowie eine Alterung und Qualifizierung in nahezu allen Wirtschaftsgruppen. Dabei erfasst der Wandel die Wirtschaftsgruppen und besonders die Berufe unterschiedlich stark. Gleichzeitig kann auch 2010 von typischen Frauenberufen mit Beschäftigungsanteilen von über 95 % gesprochen werden, etwa bei KindergärtnerInnen und SprechstundenhelferInnen. Die berufliche Mobilität hat im Hinblick auf alle betrachteten Mobilitätskennziffern zugenommen.
Published: 2020

49. Nächtliche Verkehrslärmbelästigung in Deutschland: individuelle und regionale Unterschiede in der NAKO Gesundheitsstudie

Author: Wolf, Kathrin, Kraus, Ute, Dzolan, Mihovil, Bolte, Gabriele, Lakes, Tobia, Schikowski, Tamara, Greiser, Karin Halina, Kuß, Oliver, Ahrens, Wolfgang, Bamberg, Fabian, Becher, Heiko, Berger, Klaus, Brenner, Hermann, Castell, Stefanie, Damms-Machado, Antje, Fischer, Beate, Franzke, Claus-Werner, Gastell, Sylvia, Günther, Kathrin, Holleczek, Bernd, Jaeschke, Lina, Kaaks, Rudolf, Keil, Thomas, Kemmling, Yvonne, Krist, Lilian, Legath, Nicole, Leitzmann, Michael, Lieb, Wolfgang, Loeffler, Markus, Meinke-Franze, Claudia, Michels, Karin B., Mikolajczyk, Rafael, Moebus, Susanne, Mueller, Ulrich, Obi, Nadia, Pischon, Tobias, Rathmann, Wolfgang, Schipf, Sabine, Schmidt, Börge, Schulze, Matthias, Thiele, Inke, Thierry, Sigrid, Waniek, Sabina, Wigmann, Claudia, Wirkner, Kerstin, Zschocke, Johannes, Peters, Annette, Schneider, Alexandra, Wolf, Kathrin, Kraus, Ute, Dzolan, Mihovil, Bolte, Gabriele, Lakes, Tobia, Schikowski, Tamara, Greiser, Karin Halina, Kuß, Oliver, Ahrens, Wolfgang, Bamberg, Fabian, Becher, Heiko, Berger, Klaus, Brenner, Hermann, Castell, Stefanie, Damms-Machado, Antje, Fischer, Beate, Franzke, Claus-Werner, Gastell, Sylvia, Günther, Kathrin, Holleczek, Bernd, Jaeschke, Lina, Kaaks, Rudolf, Keil, Thomas, Kemmling, Yvonne, Krist, Lilian, Legath, Nicole, Leitzmann, Michael, Lieb, Wolfgang, Loeffler, Markus, Meinke-Franze, Claudia, Michels, Karin B., Mikolajczyk, Rafael, Moebus, Susanne, Mueller, Ulrich, Obi, Nadia, Pischon, Tobias, Rathmann, Wolfgang, Schipf, Sabine, Schmidt, Börge, Schulze, Matthias, Thiele, Inke, Thierry, Sigrid, Waniek, Sabina, Wigmann, Claudia, Wirkner, Kerstin, Zschocke, Johannes, Peters, Annette, and Schneider, Alexandra
Abstract: Hintergrund Lärmbelästigung geht mit gesundheitlicher Beeinträchtigung und reduziertem Wohlbefinden einher. Die subjektive Lärmbelästigung steht im Zusammenhang mit der objektiven Lärmbelastung sowie individuellen und regionalen Faktoren. Fragestellung Wie viele Teilnehmende der NAKO Gesundheitsstudie fühlen sich durch nächtlichen Verkehrslärm belästigt und welche Faktoren stehen damit im Zusammenhang? Material und Methoden Diese Querschnittsanalyse basiert auf Daten von 86.080 NAKO-Teilnehmenden aus 18 Studienzentren, die von 2014 bis 2017 untersucht wurden. Um die Beziehungen zwischen individuellen und regionalen Faktoren und Verkehrslärmbelästigung in den Kategorien nicht belästigt, leicht/mittel und stark/sehr stark belästigt zu untersuchen, wurden multinomiale logistische Regressionsmodelle mit wechselseitiger Adjustierung der Faktoren verwendet. Ergebnisse Zwei Drittel der Teilnehmenden fühlten sich nicht durch Verkehrslärm belästigt; jeder Zehnte berichtete von starker/sehr starker Belästigung, mit den höchsten Anteilen in Berlin-Mitte und Leipzig. Die stärksten Assoziationen mit Lärmbelästigung wurden für Faktoren der individuellen Wohnsituation beobachtet, wie z. B. die Position des Schlafraums zur Hauptstraße (OR für leicht/mittel belästigt: 4,26 [95 % KI: 4,01; 4,52]; OR für stark/sehr stark belästigt: 13,36 [95 % KI: 12,47; 14,32] im Vergleich zu Garten/Innenhof). Teilnehmende im Alter von 40–60 Jahren oder der mittleren und niedrigen Einkommensklasse fühlten sich eher durch Verkehrslärm belästigt als jüngere bzw. ältere Teilnehmende oder solche mit hoher Einkommensklasse. Diskussion Teilnehmende der NAKO Gesundheitsstudie wiesen Unterschiede in der Belästigung durch nächtlichen Verkehrslärm in Bezug auf individuelle und regionale Faktoren auf., Background Noise annoyance is associated with adverse health-related conditions and reduced wellbeing. Thereby, subjective noise annoyance depends on the objective noise exposure and is modified by personal and regional factors. Objective How many participants of the German National Cohort Study (GNC; NAKO Gesundheitsstudie) were annoyed by transportation noise during nighttime and what factors were associated with noise annoyance? Materials and methods This cross-sectional analysis included 86,080 participants from 18 study centers, examined from 2014 to 2017. We used multinomial logistic regression to investigate associations of personal and regional factors to noise annoyance (slightly/moderately or strongly/extremely annoyed vs. not annoyed) mutually adjusting for all factors in the model. Results Two thirds of participants were not annoyed by transportation noise during nighttime and one in ten reported strong/extreme annoyance with highest percentages for the study centers Berlin-Mitte and Leipzig. The strongest associations were seen for factors related to the individual housing situation like the bedroom being positioned towards a major road (OR of being slightly/moderately annoyed: 4.26 [95% CI: 4.01;4.52]; OR of being strongly/extremely annoyed: 13.36 [95% CI: 12.47;14.32]) compared to a garden/inner courtyard. Participants aged 40–60 years and those in low- and medium-income groups reported greater noise annoyance compared to younger or older ones and those in the high-income group. Conclusion In this study from Germany, transportation noise annoyance during nighttime varied by personal and regional factors., Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) (4209), Peer Reviewed
Published: 2020

50. Shared Genetic Etiology of Obesity-Related Traits and Barrett's Esophagus/Adenocarcinoma: Insights from Genome-Wide Association Studies

Author: Boehmer, Anne C., Hecker, Julian, Schroeder, Julia, Gharahkhani, Puya, May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Hess, Timo, Kreuser, Nicole, Thieme, Rene, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Fuchs, Claudia, Izbicki, Jakob R., Hoelscher, Arnulf H., Dietrich, Arne, Moulla, Yusef, Lyros, Orestis, Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Mayershofer, Rupert, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Meismueller, Josef, Moebus, Susanne, Knapp, Michael, Neuhaus, Horst, Roesch, Thomas, Ell, Christian, Noethen, Markus M., Whiteman, David C., Tomlinson, Ian, Jankowski, Janusz, Fitzgerald, Rebecca C., Palles, Claire, Vaughan, Thomas L., Gockel, Ines, Thrift, Aaron P., Fier, Heide, Schumacher, Johannes, Boehmer, Anne C., Hecker, Julian, Schroeder, Julia, Gharahkhani, Puya, May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Hess, Timo, Kreuser, Nicole, Thieme, Rene, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Fuchs, Claudia, Izbicki, Jakob R., Hoelscher, Arnulf H., Dietrich, Arne, Moulla, Yusef, Lyros, Orestis, Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Mayershofer, Rupert, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Meismueller, Josef, Moebus, Susanne, Knapp, Michael, Neuhaus, Horst, Roesch, Thomas, Ell, Christian, Noethen, Markus M., Whiteman, David C., Tomlinson, Ian, Jankowski, Janusz, Fitzgerald, Rebecca C., Palles, Claire, Vaughan, Thomas L., Gockel, Ines, Thrift, Aaron P., Fier, Heide, and Schumacher, Johannes
Abstract: Background: Obesity is a major risk factor for esophageal adenocarcinoma (EA) and its precursor Barrett's esophagus (BE). Research suggests that individuals with high genetic risk to obesity have a higher BE/EA risk. To facilitate understanding of biological factors that lead to progression from BE to EA, the present study investigated the shared genetic background of BE/EA and obesity-related traits. Methods: Cross-trait linkage disequilibrium score regression was applied to summary statistics from genome-wide association metaanalyses on BE/EA and on obesity traits. Body mass index (BMI) was used as a proxy for general obesity, and waist-to-hip ratio (WHR) for abdominal obesity. For single marker analyses, all genome-wide significant risk alleles for BMI and WHR were compared with summary statistics of the BE/EA meta-analyses. Results: Sex-combined analyses revealed a significant genetic correlation between BMI and BE/EA (r(g) = 0.13, P = 2 x 10(-04)) and a r(g) of 0.12 between WHR and BE/EA (P = 1 x 10(-02)). Sexspecific analyses revealed a pronounced genetic correlation between BMI and EA in females (r(g) = 0.17, P = 1.2 x 10(-03)), and WHR and EA in males (r(g) = 0.18, P = 1.51 x 10(-02)). On the single marker level, significant enrichment of concordant effects was observed for BMI and BE/EA risk variants (P = 8.45 x 10(-03)) and WHR and BE/EA risk variants (P = 2 x 10(-02)). Conclusions: Our study provides evidence for sex-specific genetic correlations that might reflect specific biological mechanisms. The data demonstrate that shared genetic factors are particularly relevant in progression from BE to EA. Impact: Our study quantifies the genetic correlation between BE/EA and obesity. Further research is now warranted to elucidate these effects and to understand the shared pathophysiology.
Published: 2020

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