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1. Spliceosome malfunction causes neurodevelopmental disorders with overlapping features

Author: Genetica, Genetica Sectie Research, Cancer, Child Health, Li, Dong, Wang, Qin, Bayat, Allan, Battig, Mark R., Zhou, Yijing, Bosch, Daniëlle G.M., van Haaften, Gijs, Granger, Leslie, Petersen, Andrea K., Pérez-Jurado, Luis A., Aznar-Laín, Gemma, Aneja, Anushree, Hancarova, Miroslava, Bendova, Sarka, Schwarz, Martin, Pourova, Radka Kremlikova, Sedlacek, Zdenek, Keena, Beth A., March, Michael E., Hou, Cuiping, O’Connor, Nora, Bhoj, Elizabeth J., Harr, Margaret H., Lemire, Gabrielle, Boycott, Kym M., Towne, Meghan, Li, Megan, Tarnopolsky, Mark, Brady, Lauren, Parker, Michael J., Faghfoury, Hanna, Parsley, Lea Kristin, Agolini, Emanuele, Dentici, Maria Lisa, Novelli, Antonio, Wright, Meredith, Palmquist, Rachel, Lai, Khanh, Scala, Marcello, Striano, Pasquale, Iacomino, Michele, Zara, Federico, Cooper, Annina, Maarup, Timothy J., Byler, Melissa, Lebel, Robert Roger, Balci, Tugce B., Louie, Raymond, Lyons, Michael, Douglas, Jessica, Nowak, Catherine, Afenjar, Alexandra, Hoyer, Juliane, Keren, Boris, Maas, Saskia M., Motazacker, Mahdi M., Martinez-Agosto, Julian A., Rabani, Ahna M., McCormick, Elizabeth M., Falk, Marni J., Ruggiero, Sarah M., Helbig, Ingo, Møller, Rikke S., Tessarollo, Lino, Ardori, Francesco Tomassoni, Palko, Mary Ellen, Hsieh, Tzung Chien, Krawitz, Peter M., Ganapathi, Mythily, Gelb, Bruce D., Jobanputra, Vaidehi, Wilson, Ashley, Greally, John, Jacquemont, Sébastien, Jizi, Khadijé, Bruel, Ange Line, Quelin, Chloé, Misra, Vinod K., Chick, Erika, Romano, Corrado, Greco, Donatella, Arena, Alessia, Morleo, Manuela, Nigro, Vincenzo, Seyama, Rie, Uchiyama, Yuri, Matsumoto, Naomichi, Taira, Ryoji, Tashiro, Katsuya, Sakai, Yasunari, Yigit, Gökhan, Wollnik, Bernd, Wagner, Michael, Kutsche, Barbara, Hurst, Anna C.E., Thompson, Michelle L., Schmidt, Ryan, Randolph, Linda, Spillmann, Rebecca C., Shashi, Vandana, Higginbotham, Edward J., Cordeiro, Dawn, Carnevale, Amanda, Costain, Gregory, Khan, Tayyaba, Funalot, Benoît, Mau-Them, Frederic Tran, Garcia Moya, Luis Fernandez, García-Miñaúr, Sixto, Osmond, Matthew, Chad, Lauren, Quercia, Nada, Carrasco, Diana, Li, Chumei, Sanchez-Valle, Amarilis, Kelley, Meghan, Nizon, Mathilde, Jensson, Brynjar O., Sulem, Patrick, Stefansson, Kari, Gorokhova, Svetlana, Busa, Tiffany, Rio, Marlène, Habdallah, Hamza Hadj, Lesieur-Sebellin, Marion, Amiel, Jeanne, Pingault, Véronique, Mercier, Sandra, Vincent, Marie, Philippe, Christophe, Fatus-Fauconnier, Clemence, Friend, Kathryn, Halligan, Rebecca K., Biswas, Sunita, Rosser, Jane, Shoubridge, Cheryl, Corbett, Mark, Barnett, Christopher, Gecz, Jozef, Leppig, Kathleen, Slavotinek, Anne, Marcelis, Carlo, Pfundt, Rolph, de Vries, Bert B.A., van Slegtenhorst, Marjon A., Brooks, Alice S., Cogne, Benjamin, Rambaud, Thomas, Tümer, Zeynep, Zackai, Elaine H., Akizu, Naiara, Song, Yuanquan, Hakonarson, Hakon, Genetica, Genetica Sectie Research, Cancer, Child Health, Li, Dong, Wang, Qin, Bayat, Allan, Battig, Mark R., Zhou, Yijing, Bosch, Daniëlle G.M., van Haaften, Gijs, Granger, Leslie, Petersen, Andrea K., Pérez-Jurado, Luis A., Aznar-Laín, Gemma, Aneja, Anushree, Hancarova, Miroslava, Bendova, Sarka, Schwarz, Martin, Pourova, Radka Kremlikova, Sedlacek, Zdenek, Keena, Beth A., March, Michael E., Hou, Cuiping, O’Connor, Nora, Bhoj, Elizabeth J., Harr, Margaret H., Lemire, Gabrielle, Boycott, Kym M., Towne, Meghan, Li, Megan, Tarnopolsky, Mark, Brady, Lauren, Parker, Michael J., Faghfoury, Hanna, Parsley, Lea Kristin, Agolini, Emanuele, Dentici, Maria Lisa, Novelli, Antonio, Wright, Meredith, Palmquist, Rachel, Lai, Khanh, Scala, Marcello, Striano, Pasquale, Iacomino, Michele, Zara, Federico, Cooper, Annina, Maarup, Timothy J., Byler, Melissa, Lebel, Robert Roger, Balci, Tugce B., Louie, Raymond, Lyons, Michael, Douglas, Jessica, Nowak, Catherine, Afenjar, Alexandra, Hoyer, Juliane, Keren, Boris, Maas, Saskia M., Motazacker, Mahdi M., Martinez-Agosto, Julian A., Rabani, Ahna M., McCormick, Elizabeth M., Falk, Marni J., Ruggiero, Sarah M., Helbig, Ingo, Møller, Rikke S., Tessarollo, Lino, Ardori, Francesco Tomassoni, Palko, Mary Ellen, Hsieh, Tzung Chien, Krawitz, Peter M., Ganapathi, Mythily, Gelb, Bruce D., Jobanputra, Vaidehi, Wilson, Ashley, Greally, John, Jacquemont, Sébastien, Jizi, Khadijé, Bruel, Ange Line, Quelin, Chloé, Misra, Vinod K., Chick, Erika, Romano, Corrado, Greco, Donatella, Arena, Alessia, Morleo, Manuela, Nigro, Vincenzo, Seyama, Rie, Uchiyama, Yuri, Matsumoto, Naomichi, Taira, Ryoji, Tashiro, Katsuya, Sakai, Yasunari, Yigit, Gökhan, Wollnik, Bernd, Wagner, Michael, Kutsche, Barbara, Hurst, Anna C.E., Thompson, Michelle L., Schmidt, Ryan, Randolph, Linda, Spillmann, Rebecca C., Shashi, Vandana, Higginbotham, Edward J., Cordeiro, Dawn, Carnevale, Amanda, Costain, Gregory, Khan, Tayyaba, Funalot, Benoît, Mau-Them, Frederic Tran, Garcia Moya, Luis Fernandez, García-Miñaúr, Sixto, Osmond, Matthew, Chad, Lauren, Quercia, Nada, Carrasco, Diana, Li, Chumei, Sanchez-Valle, Amarilis, Kelley, Meghan, Nizon, Mathilde, Jensson, Brynjar O., Sulem, Patrick, Stefansson, Kari, Gorokhova, Svetlana, Busa, Tiffany, Rio, Marlène, Habdallah, Hamza Hadj, Lesieur-Sebellin, Marion, Amiel, Jeanne, Pingault, Véronique, Mercier, Sandra, Vincent, Marie, Philippe, Christophe, Fatus-Fauconnier, Clemence, Friend, Kathryn, Halligan, Rebecca K., Biswas, Sunita, Rosser, Jane, Shoubridge, Cheryl, Corbett, Mark, Barnett, Christopher, Gecz, Jozef, Leppig, Kathleen, Slavotinek, Anne, Marcelis, Carlo, Pfundt, Rolph, de Vries, Bert B.A., van Slegtenhorst, Marjon A., Brooks, Alice S., Cogne, Benjamin, Rambaud, Thomas, Tümer, Zeynep, Zackai, Elaine H., Akizu, Naiara, Song, Yuanquan, and Hakonarson, Hakon
Published: 2024

2. GestaltMatcher Database - A global reference for facial phenotypic variability in rare human diseases

Author: Hsieh, Tzung-Chien, Lesmann, Hellen, Hustinx, Alexander, Moosa, Shahida, Marchi, Elaine, Martin, Maria Del Pilar Caro, Abdelrazek, Ibrahim, Pantel, Jean Tori, Klinkhammer, Hannah, Hagen, Merle Ten, Thong, Meow-Keong, Mazlan, Rifhan Azwani Binti, Tae, Sok Kun, Kamphans, Tom, Meiswinkel, Wolfgang, Javanmardi, Behnam, Knaus, Alexej, Uwineza, Annette, Knopp, Cordula, Tkemaladze, Tinatin, Elbracht, Miriam, Mattern, Larissa, Jamra, Rami Abou, Velmans, Clara, Strehlow, Vincent, Jacob, Maureen, Peron, Angela, Dias, Cristina, Nunes, Beatriz, Vilella, Thainá, Pinheiro, Isabel, Kim, Chong, Melaragno, Maria, Weiland, Hannah, Kaptain, Sophia, Chwiałkowska, Karolina, Kwasniewski, Miroslaw, Saad, Ramy, Wiethoff, Sarah, Goel, Himanshu, Tang, Clara, Hau, Anna, Barakat, Tahsin Stefan, Panek, Przemysław, Nabil, Amira, Suh, Julia, Braun, Frederik, Gomy, Israel, Averdunk, Luisa, Ekure, Ekanem, Bergant, Gaber, Peterlin, Borut, Graziano, Claudio, Gaboon, Nagwa, Fiesco-Roa, Moisés, Spinelli, Alessandro, Wilpert, Nina-Maria, Phowthongkum, Prasit, Güzel, Nergis, Haack, Tobias, Bitar, Rana, Tzschach, Andreas, Rodriguez-Palmero, Agusti, Brunet, Theresa, Rudnik-Schöneborn, Sabine, Contreras-Capetillo, Silvina, Oberlack, Ava, Samango-Sprouse, Carole, Sadeghin, Teresa, Olaya, Margaret, Platzer, Konrad, Borovikov, Artem, Schnabel, Franziska, Heuft, Lara, Herrmann, Vera, Elkhateeb, Nour, Kumar, Sheetal, Komlosi, Katalin, Mohamed, Khoushoua, Kalantari, Silvia, Sirchia, Fabio, Martinez-Monseny, Antonio, Höller, Matthias, Mohamed, Amal, Lasa-Aranzasti, Amaia, Sayer, John, Ehmke, Nadja, Danyel, Magdalena, Sczakiel, Henrike, Schwartzmann, Sarina, Boschann, Felix, Zhao, Max, Adams, Ronja, Einicke, Lara, Chew, Kee Seang, Kam, Choy Chen, Karakoyun, Miray, Pode-Shakked, Ben, Eliyahu, Aviva, Rock, Rachel, Carrion, Teresa, Chorin, Odelia, Zarate, Yuri, Martinez, Marcello, Karakaya, Mert, Tung, Moon Ley, Chandra, Bharatendu, Lumaka, Aimé, Shinawi, Marwan, Blackburn, Patrick, Wang, Tianyun, Niehues, Tim, Hu, Ping, Waikel, Rebekah, Hanchard, Suzanna Ledgister, Elmakkawy, Gehad, Safwat, Sylvia, Ebstein, Frédéric, Krüger, Elke, Küry, Sébastien, Bezieau, Stephane, Arlt, Annabelle, Marbach, Felix, Li, Dong, Dupuis, Lucie, Mendoza-Londono, Roberto, Houge, Sofia Douzgou, Weis, Denisa, Mak, Christopher, Elcioglu, Nursel, Aykut, Ayca, Şimşek-Kiper, Peli, Bögershausen, Nina, Wollnik, Bernd, Bentzen, Heidi Beate, Kurth, Ingo, Netzer, Christian, Jezela-Stanek, Aleksandra, Devriendt, Koen, Gripp, Karen, Mücke, Martin, Verloes, Alain, Schaaf, Christian, Nellåker, Christoffer, Solomon, Benjamin, Nöthen, Markus, Abdalla, Ebtesam, Lyon, Gholson, Krawitz, Peter, Kayserili, Hulya, Toutouna, Louiza, Schmidt, Axel, Roth, Regina, Wieczorek, Dagmar, Olinger, Eric, Hsieh, Tzung-Chien, Lesmann, Hellen, Hustinx, Alexander, Moosa, Shahida, Marchi, Elaine, Martin, Maria Del Pilar Caro, Abdelrazek, Ibrahim, Pantel, Jean Tori, Klinkhammer, Hannah, Hagen, Merle Ten, Thong, Meow-Keong, Mazlan, Rifhan Azwani Binti, Tae, Sok Kun, Kamphans, Tom, Meiswinkel, Wolfgang, Javanmardi, Behnam, Knaus, Alexej, Uwineza, Annette, Knopp, Cordula, Tkemaladze, Tinatin, Elbracht, Miriam, Mattern, Larissa, Jamra, Rami Abou, Velmans, Clara, Strehlow, Vincent, Jacob, Maureen, Peron, Angela, Dias, Cristina, Nunes, Beatriz, Vilella, Thainá, Pinheiro, Isabel, Kim, Chong, Melaragno, Maria, Weiland, Hannah, Kaptain, Sophia, Chwiałkowska, Karolina, Kwasniewski, Miroslaw, Saad, Ramy, Wiethoff, Sarah, Goel, Himanshu, Tang, Clara, Hau, Anna, Barakat, Tahsin Stefan, Panek, Przemysław, Nabil, Amira, Suh, Julia, Braun, Frederik, Gomy, Israel, Averdunk, Luisa, Ekure, Ekanem, Bergant, Gaber, Peterlin, Borut, Graziano, Claudio, Gaboon, Nagwa, Fiesco-Roa, Moisés, Spinelli, Alessandro, Wilpert, Nina-Maria, Phowthongkum, Prasit, Güzel, Nergis, Haack, Tobias, Bitar, Rana, Tzschach, Andreas, Rodriguez-Palmero, Agusti, Brunet, Theresa, Rudnik-Schöneborn, Sabine, Contreras-Capetillo, Silvina, Oberlack, Ava, Samango-Sprouse, Carole, Sadeghin, Teresa, Olaya, Margaret, Platzer, Konrad, Borovikov, Artem, Schnabel, Franziska, Heuft, Lara, Herrmann, Vera, Elkhateeb, Nour, Kumar, Sheetal, Komlosi, Katalin, Mohamed, Khoushoua, Kalantari, Silvia, Sirchia, Fabio, Martinez-Monseny, Antonio, Höller, Matthias, Mohamed, Amal, Lasa-Aranzasti, Amaia, Sayer, John, Ehmke, Nadja, Danyel, Magdalena, Sczakiel, Henrike, Schwartzmann, Sarina, Boschann, Felix, Zhao, Max, Adams, Ronja, Einicke, Lara, Chew, Kee Seang, Kam, Choy Chen, Karakoyun, Miray, Pode-Shakked, Ben, Eliyahu, Aviva, Rock, Rachel, Carrion, Teresa, Chorin, Odelia, Zarate, Yuri, Martinez, Marcello, Karakaya, Mert, Tung, Moon Ley, Chandra, Bharatendu, Lumaka, Aimé, Shinawi, Marwan, Blackburn, Patrick, Wang, Tianyun, Niehues, Tim, Hu, Ping, Waikel, Rebekah, Hanchard, Suzanna Ledgister, Elmakkawy, Gehad, Safwat, Sylvia, Ebstein, Frédéric, Krüger, Elke, Küry, Sébastien, Bezieau, Stephane, Arlt, Annabelle, Marbach, Felix, Li, Dong, Dupuis, Lucie, Mendoza-Londono, Roberto, Houge, Sofia Douzgou, Weis, Denisa, Mak, Christopher, Elcioglu, Nursel, Aykut, Ayca, Şimşek-Kiper, Peli, Bögershausen, Nina, Wollnik, Bernd, Bentzen, Heidi Beate, Kurth, Ingo, Netzer, Christian, Jezela-Stanek, Aleksandra, Devriendt, Koen, Gripp, Karen, Mücke, Martin, Verloes, Alain, Schaaf, Christian, Nellåker, Christoffer, Solomon, Benjamin, Nöthen, Markus, Abdalla, Ebtesam, Lyon, Gholson, Krawitz, Peter, Kayserili, Hulya, Toutouna, Louiza, Schmidt, Axel, Roth, Regina, Wieczorek, Dagmar, and Olinger, Eric
Abstract: The most important factor that complicates the work of dysmorphologists is the significant phenotypic variability of the human face. Next-Generation Phenotyping (NGP) tools that assist clinicians with recognizing characteristic syndromic patterns are particularly challenged when confronted with patients from populations different from their training data. To that end, we systematically analyzed the impact of genetic ancestry on facial dysmorphism. For that purpose, we established the GestaltMatcher Database (GMDB) as a reference dataset for medical images of patients with rare genetic disorders from around the world. We collected 10,980 frontal facial images - more than a quarter previously unpublished - from 8,346 patients, representing 581 rare disorders. Although the predominant ancestry is still European (67%), data from underrepresented populations have been increased considerably via global collaborations (19% Asian and 7% African). This includes previously unpublished reports for more than 40% of the African patients. The NGP analysis on this diverse dataset revealed characteristic performance differences depending on the composition of training and test sets corresponding to genetic relatedness. For clinical use of NGP, incorporating non-European patients resulted in a profound enhancement of GestaltMatcher performance. The top-5 accuracy rate increased by +11.29%. Importantly, this improvement in delineating the correct disorder from a facial portrait was achieved without decreasing the performance on European patients. By design, GMDB complies with the FAIR principles by rendering the curated medical data findable, accessible, interoperable, and reusable. This means GMDB can also serve as data for training and benchmarking. In summary, our study on facial dysmorphism on a global sample revealed a considerable cross ancestral phenotypic variability confounding NGP that should be counteracted by international efforts for increasing data diversity. GMDB wi
Published: 2024

3. Spliceosome malfunction causes neurodevelopmental disorders with overlapping features

Author: Li, Dong, Wang, Qin, Bayat, Allan, Battig, Mark R., Zhou, Yijing, Bosch, Daniëlle G.M., van Haaften, Gijs, Granger, Leslie, Petersen, Andrea K., Pérez-Jurado, Luis A., Aznar-Laín, Gemma, Aneja, Anushree, Hancarova, Miroslava, Bendova, Sarka, Schwarz, Martin, Pourova, Radka Kremlikova, Sedlacek, Zdenek, Keena, Beth A., March, Michael E., Hou, Cuiping, O’Connor, Nora, Bhoj, Elizabeth J., Harr, Margaret H., Lemire, Gabrielle, Boycott, Kym M., Towne, Meghan, Li, Megan, Tarnopolsky, Mark, Brady, Lauren, Parker, Michael J., Faghfoury, Hanna, Parsley, Lea Kristin, Agolini, Emanuele, Dentici, Maria Lisa, Novelli, Antonio, Wright, Meredith, Palmquist, Rachel, Lai, Khanh, Scala, Marcello, Striano, Pasquale, Iacomino, Michele, Zara, Federico, Cooper, Annina, Maarup, Timothy J., Byler, Melissa, Lebel, Robert Roger, Balci, Tugce B., Louie, Raymond, Lyons, Michael, Douglas, Jessica, Nowak, Catherine, Afenjar, Alexandra, Hoyer, Juliane, Keren, Boris, Maas, Saskia M., Motazacker, Mahdi M., Martinez-Agosto, Julian A., Rabani, Ahna M., McCormick, Elizabeth M., Falk, Marni J., Ruggiero, Sarah M., Helbig, Ingo, Møller, Rikke S., Tessarollo, Lino, Ardori, Francesco Tomassoni, Palko, Mary Ellen, Hsieh, Tzung Chien, Krawitz, Peter M., Ganapathi, Mythily, Gelb, Bruce D., Jobanputra, Vaidehi, Wilson, Ashley, Greally, John, Jacquemont, Sébastien, Jizi, Khadijé, Bruel, Ange Line, Quelin, Chloé, Misra, Vinod K., Chick, Erika, Romano, Corrado, Greco, Donatella, Arena, Alessia, Morleo, Manuela, Nigro, Vincenzo, Seyama, Rie, Uchiyama, Yuri, Matsumoto, Naomichi, Taira, Ryoji, Tashiro, Katsuya, Sakai, Yasunari, Yigit, Gökhan, Wollnik, Bernd, Wagner, Michael, Kutsche, Barbara, Hurst, Anna C.E., Thompson, Michelle L., Schmidt, Ryan, Randolph, Linda, Spillmann, Rebecca C., Shashi, Vandana, Higginbotham, Edward J., Cordeiro, Dawn, Carnevale, Amanda, Costain, Gregory, Khan, Tayyaba, Funalot, Benoît, Mau-Them, Frederic Tran, Garcia Moya, Luis Fernandez, García-Miñaúr, Sixto, Osmond, Matthew, Chad, Lauren, Quercia, Nada, Carrasco, Diana, Li, Chumei, Sanchez-Valle, Amarilis, Kelley, Meghan, Nizon, Mathilde, Jensson, Brynjar O., Sulem, Patrick, Stefansson, Kari, Gorokhova, Svetlana, Busa, Tiffany, Rio, Marlène, Habdallah, Hamza Hadj, Lesieur-Sebellin, Marion, Amiel, Jeanne, Pingault, Véronique, Mercier, Sandra, Vincent, Marie, Philippe, Christophe, Fatus-Fauconnier, Clemence, Friend, Kathryn, Halligan, Rebecca K., Biswas, Sunita, Rosser, Jane, Shoubridge, Cheryl, Corbett, Mark, Barnett, Christopher, Gecz, Jozef, Leppig, Kathleen, Slavotinek, Anne, Marcelis, Carlo, Pfundt, Rolph, de Vries, Bert B.A., van Slegtenhorst, Marjon A., Brooks, Alice S., Cogne, Benjamin, Rambaud, Thomas, Tümer, Zeynep, Zackai, Elaine H., Akizu, Naiara, Song, Yuanquan, Hakonarson, Hakon, Li, Dong, Wang, Qin, Bayat, Allan, Battig, Mark R., Zhou, Yijing, Bosch, Daniëlle G.M., van Haaften, Gijs, Granger, Leslie, Petersen, Andrea K., Pérez-Jurado, Luis A., Aznar-Laín, Gemma, Aneja, Anushree, Hancarova, Miroslava, Bendova, Sarka, Schwarz, Martin, Pourova, Radka Kremlikova, Sedlacek, Zdenek, Keena, Beth A., March, Michael E., Hou, Cuiping, O’Connor, Nora, Bhoj, Elizabeth J., Harr, Margaret H., Lemire, Gabrielle, Boycott, Kym M., Towne, Meghan, Li, Megan, Tarnopolsky, Mark, Brady, Lauren, Parker, Michael J., Faghfoury, Hanna, Parsley, Lea Kristin, Agolini, Emanuele, Dentici, Maria Lisa, Novelli, Antonio, Wright, Meredith, Palmquist, Rachel, Lai, Khanh, Scala, Marcello, Striano, Pasquale, Iacomino, Michele, Zara, Federico, Cooper, Annina, Maarup, Timothy J., Byler, Melissa, Lebel, Robert Roger, Balci, Tugce B., Louie, Raymond, Lyons, Michael, Douglas, Jessica, Nowak, Catherine, Afenjar, Alexandra, Hoyer, Juliane, Keren, Boris, Maas, Saskia M., Motazacker, Mahdi M., Martinez-Agosto, Julian A., Rabani, Ahna M., McCormick, Elizabeth M., Falk, Marni J., Ruggiero, Sarah M., Helbig, Ingo, Møller, Rikke S., Tessarollo, Lino, Ardori, Francesco Tomassoni, Palko, Mary Ellen, Hsieh, Tzung Chien, Krawitz, Peter M., Ganapathi, Mythily, Gelb, Bruce D., Jobanputra, Vaidehi, Wilson, Ashley, Greally, John, Jacquemont, Sébastien, Jizi, Khadijé, Bruel, Ange Line, Quelin, Chloé, Misra, Vinod K., Chick, Erika, Romano, Corrado, Greco, Donatella, Arena, Alessia, Morleo, Manuela, Nigro, Vincenzo, Seyama, Rie, Uchiyama, Yuri, Matsumoto, Naomichi, Taira, Ryoji, Tashiro, Katsuya, Sakai, Yasunari, Yigit, Gökhan, Wollnik, Bernd, Wagner, Michael, Kutsche, Barbara, Hurst, Anna C.E., Thompson, Michelle L., Schmidt, Ryan, Randolph, Linda, Spillmann, Rebecca C., Shashi, Vandana, Higginbotham, Edward J., Cordeiro, Dawn, Carnevale, Amanda, Costain, Gregory, Khan, Tayyaba, Funalot, Benoît, Mau-Them, Frederic Tran, Garcia Moya, Luis Fernandez, García-Miñaúr, Sixto, Osmond, Matthew, Chad, Lauren, Quercia, Nada, Carrasco, Diana, Li, Chumei, Sanchez-Valle, Amarilis, Kelley, Meghan, Nizon, Mathilde, Jensson, Brynjar O., Sulem, Patrick, Stefansson, Kari, Gorokhova, Svetlana, Busa, Tiffany, Rio, Marlène, Habdallah, Hamza Hadj, Lesieur-Sebellin, Marion, Amiel, Jeanne, Pingault, Véronique, Mercier, Sandra, Vincent, Marie, Philippe, Christophe, Fatus-Fauconnier, Clemence, Friend, Kathryn, Halligan, Rebecca K., Biswas, Sunita, Rosser, Jane, Shoubridge, Cheryl, Corbett, Mark, Barnett, Christopher, Gecz, Jozef, Leppig, Kathleen, Slavotinek, Anne, Marcelis, Carlo, Pfundt, Rolph, de Vries, Bert B.A., van Slegtenhorst, Marjon A., Brooks, Alice S., Cogne, Benjamin, Rambaud, Thomas, Tümer, Zeynep, Zackai, Elaine H., Akizu, Naiara, Song, Yuanquan, and Hakonarson, Hakon
Abstract: Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.
Published: 2024

4. Impact of Synbiotic Intake on Liver Metabolism in Metabolically Healthy Participants and Its Potential Preventive Effect on Metabolic-Dysfunction-Associated Fatty Liver Disease (MAFLD):A Randomized, Placebo-Controlled, Double-Blinded Clinical Trial

Author: Mantri, Aakash, Köhlmoos, Anika, Schelski, Daniela Stephanie, Seel, Waldemar, Stoffel-Wagner, Birgit, Krawitz, Peter, Stehle, Peter, Holst, Jens Juul, Weber, Bernd, Koban, Leonie, Plassmann, Hilke, Simon, Marie Christine, Mantri, Aakash, Köhlmoos, Anika, Schelski, Daniela Stephanie, Seel, Waldemar, Stoffel-Wagner, Birgit, Krawitz, Peter, Stehle, Peter, Holst, Jens Juul, Weber, Bernd, Koban, Leonie, Plassmann, Hilke, and Simon, Marie Christine
Abstract: Synbiotics modulate the gut microbiome and contribute to the prevention of liver diseases such as metabolic-dysfunction-associated fatty liver disease (MAFLD). This study aimed to evaluate the effect of a randomized, placebo-controlled, double-blinded seven-week intervention trial on the liver metabolism in 117 metabolically healthy male participants. Anthropometric data, blood parameters, and stool samples were analyzed using linear mixed models. After seven weeks of intervention, there was a significant reduction in alanine aminotransferase (ALT) in the synbiotic group compared to the placebo group (-14.92%, CI: -26.60--3.23%, p = 0.013). A stratified analysis according to body fat percentage revealed a significant decrease in ALT (-20.70%, CI: -40.88--0.53%, p = 0.045) in participants with an elevated body fat percentage. Further, a significant change in microbiome composition (1.16, CI: 0.06-2.25, p = 0.039) in this group was found, while the microbial composition remained stable upon intervention in the group with physiological body fat. The 7-week synbiotic intervention reduced ALT levels, especially in participants with an elevated body fat percentage, possibly due to modulation of the gut microbiome. Synbiotic intake may be helpful in delaying the progression of MAFLD and could be used in addition to the recommended lifestyle modification therapy.
Published: 2024

5. Spliceosome malfunction causes neurodevelopmental disorders with overlapping features

Author: Li, Dong, Wang, Qin, Bayat, Allan, Battig, Mark R., Zhou, Yijing, Bosch, Daniëlle G.M., van Haaften, Gijs, Granger, Leslie, Petersen, Andrea K., Pérez-Jurado, Luis A., Aznar-Laín, Gemma, Aneja, Anushree, Hancarova, Miroslava, Bendova, Sarka, Schwarz, Martin, Pourova, Radka Kremlikova, Sedlacek, Zdenek, Keena, Beth A., March, Michael E., Hou, Cuiping, O’Connor, Nora, Bhoj, Elizabeth J., Harr, Margaret H., Lemire, Gabrielle, Boycott, Kym M., Towne, Meghan, Li, Megan, Tarnopolsky, Mark, Brady, Lauren, Parker, Michael J., Faghfoury, Hanna, Parsley, Lea Kristin, Agolini, Emanuele, Dentici, Maria Lisa, Novelli, Antonio, Wright, Meredith, Palmquist, Rachel, Lai, Khanh, Scala, Marcello, Striano, Pasquale, Iacomino, Michele, Zara, Federico, Cooper, Annina, Maarup, Timothy J., Byler, Melissa, Lebel, Robert Roger, Balci, Tugce B., Louie, Raymond, Lyons, Michael, Douglas, Jessica, Nowak, Catherine, Afenjar, Alexandra, Hoyer, Juliane, Keren, Boris, Maas, Saskia M., Motazacker, Mahdi M., Martinez-Agosto, Julian A., Rabani, Ahna M., McCormick, Elizabeth M., Falk, Marni J., Ruggiero, Sarah M., Helbig, Ingo, Møller, Rikke S., Tessarollo, Lino, Ardori, Francesco Tomassoni, Palko, Mary Ellen, Hsieh, Tzung Chien, Krawitz, Peter M., Ganapathi, Mythily, Gelb, Bruce D., Jobanputra, Vaidehi, Wilson, Ashley, Greally, John, Jacquemont, Sébastien, Jizi, Khadijé, Bruel, Ange Line, Quelin, Chloé, Misra, Vinod K., Chick, Erika, Romano, Corrado, Greco, Donatella, Arena, Alessia, Morleo, Manuela, Nigro, Vincenzo, Seyama, Rie, Uchiyama, Yuri, Matsumoto, Naomichi, Taira, Ryoji, Tashiro, Katsuya, Sakai, Yasunari, Yigit, Gökhan, Wollnik, Bernd, Wagner, Michael, Kutsche, Barbara, Hurst, Anna C.E., Thompson, Michelle L., Schmidt, Ryan, Randolph, Linda, Spillmann, Rebecca C., Shashi, Vandana, Higginbotham, Edward J., Cordeiro, Dawn, Carnevale, Amanda, Costain, Gregory, Khan, Tayyaba, Funalot, Benoît, Mau-Them, Frederic Tran, Garcia Moya, Luis Fernandez, García-Miñaúr, Sixto, Osmond, Matthew, Chad, Lauren, Quercia, Nada, Carrasco, Diana, Li, Chumei, Sanchez-Valle, Amarilis, Kelley, Meghan, Nizon, Mathilde, Jensson, Brynjar O., Sulem, Patrick, Stefansson, Kari, Gorokhova, Svetlana, Busa, Tiffany, Rio, Marlène, Habdallah, Hamza Hadj, Lesieur-Sebellin, Marion, Amiel, Jeanne, Pingault, Véronique, Mercier, Sandra, Vincent, Marie, Philippe, Christophe, Fatus-Fauconnier, Clemence, Friend, Kathryn, Halligan, Rebecca K., Biswas, Sunita, Rosser, Jane, Shoubridge, Cheryl, Corbett, Mark, Barnett, Christopher, Gecz, Jozef, Leppig, Kathleen, Slavotinek, Anne, Marcelis, Carlo, Pfundt, Rolph, de Vries, Bert B.A., van Slegtenhorst, Marjon A., Brooks, Alice S., Cogne, Benjamin, Rambaud, Thomas, Tümer, Zeynep, Zackai, Elaine H., Akizu, Naiara, Song, Yuanquan, Hakonarson, Hakon, Li, Dong, Wang, Qin, Bayat, Allan, Battig, Mark R., Zhou, Yijing, Bosch, Daniëlle G.M., van Haaften, Gijs, Granger, Leslie, Petersen, Andrea K., Pérez-Jurado, Luis A., Aznar-Laín, Gemma, Aneja, Anushree, Hancarova, Miroslava, Bendova, Sarka, Schwarz, Martin, Pourova, Radka Kremlikova, Sedlacek, Zdenek, Keena, Beth A., March, Michael E., Hou, Cuiping, O’Connor, Nora, Bhoj, Elizabeth J., Harr, Margaret H., Lemire, Gabrielle, Boycott, Kym M., Towne, Meghan, Li, Megan, Tarnopolsky, Mark, Brady, Lauren, Parker, Michael J., Faghfoury, Hanna, Parsley, Lea Kristin, Agolini, Emanuele, Dentici, Maria Lisa, Novelli, Antonio, Wright, Meredith, Palmquist, Rachel, Lai, Khanh, Scala, Marcello, Striano, Pasquale, Iacomino, Michele, Zara, Federico, Cooper, Annina, Maarup, Timothy J., Byler, Melissa, Lebel, Robert Roger, Balci, Tugce B., Louie, Raymond, Lyons, Michael, Douglas, Jessica, Nowak, Catherine, Afenjar, Alexandra, Hoyer, Juliane, Keren, Boris, Maas, Saskia M., Motazacker, Mahdi M., Martinez-Agosto, Julian A., Rabani, Ahna M., McCormick, Elizabeth M., Falk, Marni J., Ruggiero, Sarah M., Helbig, Ingo, Møller, Rikke S., Tessarollo, Lino, Ardori, Francesco Tomassoni, Palko, Mary Ellen, Hsieh, Tzung Chien, Krawitz, Peter M., Ganapathi, Mythily, Gelb, Bruce D., Jobanputra, Vaidehi, Wilson, Ashley, Greally, John, Jacquemont, Sébastien, Jizi, Khadijé, Bruel, Ange Line, Quelin, Chloé, Misra, Vinod K., Chick, Erika, Romano, Corrado, Greco, Donatella, Arena, Alessia, Morleo, Manuela, Nigro, Vincenzo, Seyama, Rie, Uchiyama, Yuri, Matsumoto, Naomichi, Taira, Ryoji, Tashiro, Katsuya, Sakai, Yasunari, Yigit, Gökhan, Wollnik, Bernd, Wagner, Michael, Kutsche, Barbara, Hurst, Anna C.E., Thompson, Michelle L., Schmidt, Ryan, Randolph, Linda, Spillmann, Rebecca C., Shashi, Vandana, Higginbotham, Edward J., Cordeiro, Dawn, Carnevale, Amanda, Costain, Gregory, Khan, Tayyaba, Funalot, Benoît, Mau-Them, Frederic Tran, Garcia Moya, Luis Fernandez, García-Miñaúr, Sixto, Osmond, Matthew, Chad, Lauren, Quercia, Nada, Carrasco, Diana, Li, Chumei, Sanchez-Valle, Amarilis, Kelley, Meghan, Nizon, Mathilde, Jensson, Brynjar O., Sulem, Patrick, Stefansson, Kari, Gorokhova, Svetlana, Busa, Tiffany, Rio, Marlène, Habdallah, Hamza Hadj, Lesieur-Sebellin, Marion, Amiel, Jeanne, Pingault, Véronique, Mercier, Sandra, Vincent, Marie, Philippe, Christophe, Fatus-Fauconnier, Clemence, Friend, Kathryn, Halligan, Rebecca K., Biswas, Sunita, Rosser, Jane, Shoubridge, Cheryl, Corbett, Mark, Barnett, Christopher, Gecz, Jozef, Leppig, Kathleen, Slavotinek, Anne, Marcelis, Carlo, Pfundt, Rolph, de Vries, Bert B.A., van Slegtenhorst, Marjon A., Brooks, Alice S., Cogne, Benjamin, Rambaud, Thomas, Tümer, Zeynep, Zackai, Elaine H., Akizu, Naiara, Song, Yuanquan, and Hakonarson, Hakon
Abstract: Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50-deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function., Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.
Published: 2024

6. Impact of Synbiotic Intake on Liver Metabolism in Metabolically Healthy Participants and Its Potential Preventive Effect on Metabolic-Dysfunction-Associated Fatty Liver Disease (MAFLD):A Randomized, Placebo-Controlled, Double-Blinded Clinical Trial

Author: Mantri, Aakash, Köhlmoos, Anika, Schelski, Daniela Stephanie, Seel, Waldemar, Stoffel-Wagner, Birgit, Krawitz, Peter, Stehle, Peter, Holst, Jens Juul, Weber, Bernd, Koban, Leonie, Plassmann, Hilke, Simon, Marie Christine, Mantri, Aakash, Köhlmoos, Anika, Schelski, Daniela Stephanie, Seel, Waldemar, Stoffel-Wagner, Birgit, Krawitz, Peter, Stehle, Peter, Holst, Jens Juul, Weber, Bernd, Koban, Leonie, Plassmann, Hilke, and Simon, Marie Christine
Abstract: Synbiotics modulate the gut microbiome and contribute to the prevention of liver diseases such as metabolic-dysfunction-associated fatty liver disease (MAFLD). This study aimed to evaluate the effect of a randomized, placebo-controlled, double-blinded seven-week intervention trial on the liver metabolism in 117 metabolically healthy male participants. Anthropometric data, blood parameters, and stool samples were analyzed using linear mixed models. After seven weeks of intervention, there was a significant reduction in alanine aminotransferase (ALT) in the synbiotic group compared to the placebo group (-14.92%, CI: -26.60--3.23%, p = 0.013). A stratified analysis according to body fat percentage revealed a significant decrease in ALT (-20.70%, CI: -40.88--0.53%, p = 0.045) in participants with an elevated body fat percentage. Further, a significant change in microbiome composition (1.16, CI: 0.06-2.25, p = 0.039) in this group was found, while the microbial composition remained stable upon intervention in the group with physiological body fat. The 7-week synbiotic intervention reduced ALT levels, especially in participants with an elevated body fat percentage, possibly due to modulation of the gut microbiome. Synbiotic intake may be helpful in delaying the progression of MAFLD and could be used in addition to the recommended lifestyle modification therapy.
Published: 2024

7. Spliceosome malfunction causes neurodevelopmental disorders with overlapping features

Author: Li, Dong, Wang, Qin, Bayat, Allan, Battig, Mark R., Zhou, Yijing, Bosch, Daniëlle G.M., van Haaften, Gijs, Granger, Leslie, Petersen, Andrea K., Pérez-Jurado, Luis A., Aznar-Laín, Gemma, Aneja, Anushree, Hancarova, Miroslava, Bendova, Sarka, Schwarz, Martin, Pourova, Radka Kremlikova, Sedlacek, Zdenek, Keena, Beth A., March, Michael E., Hou, Cuiping, O’Connor, Nora, Bhoj, Elizabeth J., Harr, Margaret H., Lemire, Gabrielle, Boycott, Kym M., Towne, Meghan, Li, Megan, Tarnopolsky, Mark, Brady, Lauren, Parker, Michael J., Faghfoury, Hanna, Parsley, Lea Kristin, Agolini, Emanuele, Dentici, Maria Lisa, Novelli, Antonio, Wright, Meredith, Palmquist, Rachel, Lai, Khanh, Scala, Marcello, Striano, Pasquale, Iacomino, Michele, Zara, Federico, Cooper, Annina, Maarup, Timothy J., Byler, Melissa, Lebel, Robert Roger, Balci, Tugce B., Louie, Raymond, Lyons, Michael, Douglas, Jessica, Nowak, Catherine, Afenjar, Alexandra, Hoyer, Juliane, Keren, Boris, Maas, Saskia M., Motazacker, Mahdi M., Martinez-Agosto, Julian A., Rabani, Ahna M., McCormick, Elizabeth M., Falk, Marni J., Ruggiero, Sarah M., Helbig, Ingo, Møller, Rikke S., Tessarollo, Lino, Ardori, Francesco Tomassoni, Palko, Mary Ellen, Hsieh, Tzung Chien, Krawitz, Peter M., Ganapathi, Mythily, Gelb, Bruce D., Jobanputra, Vaidehi, Wilson, Ashley, Greally, John, Jacquemont, Sébastien, Jizi, Khadijé, Bruel, Ange Line, Quelin, Chloé, Misra, Vinod K., Chick, Erika, Romano, Corrado, Greco, Donatella, Arena, Alessia, Morleo, Manuela, Nigro, Vincenzo, Seyama, Rie, Uchiyama, Yuri, Matsumoto, Naomichi, Taira, Ryoji, Tashiro, Katsuya, Sakai, Yasunari, Yigit, Gökhan, Wollnik, Bernd, Wagner, Michael, Kutsche, Barbara, Hurst, Anna C.E., Thompson, Michelle L., Schmidt, Ryan, Randolph, Linda, Spillmann, Rebecca C., Shashi, Vandana, Higginbotham, Edward J., Cordeiro, Dawn, Carnevale, Amanda, Costain, Gregory, Khan, Tayyaba, Funalot, Benoît, Mau-Them, Frederic Tran, Garcia Moya, Luis Fernandez, García-Miñaúr, Sixto, Osmond, Matthew, Chad, Lauren, Quercia, Nada, Carrasco, Diana, Li, Chumei, Sanchez-Valle, Amarilis, Kelley, Meghan, Nizon, Mathilde, Jensson, Brynjar O., Sulem, Patrick, Stefansson, Kari, Gorokhova, Svetlana, Busa, Tiffany, Rio, Marlène, Habdallah, Hamza Hadj, Lesieur-Sebellin, Marion, Amiel, Jeanne, Pingault, Véronique, Mercier, Sandra, Vincent, Marie, Philippe, Christophe, Fatus-Fauconnier, Clemence, Friend, Kathryn, Halligan, Rebecca K., Biswas, Sunita, Rosser, Jane, Shoubridge, Cheryl, Corbett, Mark, Barnett, Christopher, Gecz, Jozef, Leppig, Kathleen, Slavotinek, Anne, Marcelis, Carlo, Pfundt, Rolph, de Vries, Bert B.A., van Slegtenhorst, Marjon A., Brooks, Alice S., Cogne, Benjamin, Rambaud, Thomas, Tümer, Zeynep, Zackai, Elaine H., Akizu, Naiara, Song, Yuanquan, Hakonarson, Hakon, Li, Dong, Wang, Qin, Bayat, Allan, Battig, Mark R., Zhou, Yijing, Bosch, Daniëlle G.M., van Haaften, Gijs, Granger, Leslie, Petersen, Andrea K., Pérez-Jurado, Luis A., Aznar-Laín, Gemma, Aneja, Anushree, Hancarova, Miroslava, Bendova, Sarka, Schwarz, Martin, Pourova, Radka Kremlikova, Sedlacek, Zdenek, Keena, Beth A., March, Michael E., Hou, Cuiping, O’Connor, Nora, Bhoj, Elizabeth J., Harr, Margaret H., Lemire, Gabrielle, Boycott, Kym M., Towne, Meghan, Li, Megan, Tarnopolsky, Mark, Brady, Lauren, Parker, Michael J., Faghfoury, Hanna, Parsley, Lea Kristin, Agolini, Emanuele, Dentici, Maria Lisa, Novelli, Antonio, Wright, Meredith, Palmquist, Rachel, Lai, Khanh, Scala, Marcello, Striano, Pasquale, Iacomino, Michele, Zara, Federico, Cooper, Annina, Maarup, Timothy J., Byler, Melissa, Lebel, Robert Roger, Balci, Tugce B., Louie, Raymond, Lyons, Michael, Douglas, Jessica, Nowak, Catherine, Afenjar, Alexandra, Hoyer, Juliane, Keren, Boris, Maas, Saskia M., Motazacker, Mahdi M., Martinez-Agosto, Julian A., Rabani, Ahna M., McCormick, Elizabeth M., Falk, Marni J., Ruggiero, Sarah M., Helbig, Ingo, Møller, Rikke S., Tessarollo, Lino, Ardori, Francesco Tomassoni, Palko, Mary Ellen, Hsieh, Tzung Chien, Krawitz, Peter M., Ganapathi, Mythily, Gelb, Bruce D., Jobanputra, Vaidehi, Wilson, Ashley, Greally, John, Jacquemont, Sébastien, Jizi, Khadijé, Bruel, Ange Line, Quelin, Chloé, Misra, Vinod K., Chick, Erika, Romano, Corrado, Greco, Donatella, Arena, Alessia, Morleo, Manuela, Nigro, Vincenzo, Seyama, Rie, Uchiyama, Yuri, Matsumoto, Naomichi, Taira, Ryoji, Tashiro, Katsuya, Sakai, Yasunari, Yigit, Gökhan, Wollnik, Bernd, Wagner, Michael, Kutsche, Barbara, Hurst, Anna C.E., Thompson, Michelle L., Schmidt, Ryan, Randolph, Linda, Spillmann, Rebecca C., Shashi, Vandana, Higginbotham, Edward J., Cordeiro, Dawn, Carnevale, Amanda, Costain, Gregory, Khan, Tayyaba, Funalot, Benoît, Mau-Them, Frederic Tran, Garcia Moya, Luis Fernandez, García-Miñaúr, Sixto, Osmond, Matthew, Chad, Lauren, Quercia, Nada, Carrasco, Diana, Li, Chumei, Sanchez-Valle, Amarilis, Kelley, Meghan, Nizon, Mathilde, Jensson, Brynjar O., Sulem, Patrick, Stefansson, Kari, Gorokhova, Svetlana, Busa, Tiffany, Rio, Marlène, Habdallah, Hamza Hadj, Lesieur-Sebellin, Marion, Amiel, Jeanne, Pingault, Véronique, Mercier, Sandra, Vincent, Marie, Philippe, Christophe, Fatus-Fauconnier, Clemence, Friend, Kathryn, Halligan, Rebecca K., Biswas, Sunita, Rosser, Jane, Shoubridge, Cheryl, Corbett, Mark, Barnett, Christopher, Gecz, Jozef, Leppig, Kathleen, Slavotinek, Anne, Marcelis, Carlo, Pfundt, Rolph, de Vries, Bert B.A., van Slegtenhorst, Marjon A., Brooks, Alice S., Cogne, Benjamin, Rambaud, Thomas, Tümer, Zeynep, Zackai, Elaine H., Akizu, Naiara, Song, Yuanquan, and Hakonarson, Hakon
Abstract: Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50-deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function., Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.
Published: 2024

8. Clinically relevant combined effect of polygenic background, rare pathogenic germline variants, and family history on colorectal cancer incidence

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Hassanin, Emadeldin Saeed Fathy Sayed, Spier, Isabel, Bobbili, Dheeraj Reddy, Aldisi, Rana, Klinkhammer, Hannah, David, Friederike, Dueñas, Nuria, Hüneburg, Robert, Perne, Claudia, Brunet, Joan, Capella, Gabriel, Nöthen, Markus M., Forstner, Andreas J., Mayr, Andreas, Krawitz, Peter, May, Patrick, Aretz, Stefan, Maj, Carlo, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Hassanin, Emadeldin Saeed Fathy Sayed, Spier, Isabel, Bobbili, Dheeraj Reddy, Aldisi, Rana, Klinkhammer, Hannah, David, Friederike, Dueñas, Nuria, Hüneburg, Robert, Perne, Claudia, Brunet, Joan, Capella, Gabriel, Nöthen, Markus M., Forstner, Andreas J., Mayr, Andreas, Krawitz, Peter, May, Patrick, Aretz, Stefan, and Maj, Carlo
Abstract: Background and aims: Summarised in polygenic risk scores (PRS), the effect of common, low penetrant genetic variants associated with colorectal cancer (CRC), can be used for risk stratification. Methods: To assess the combined impact of the PRS and other main factors on CRC risk, 163,516 individuals from the UK Biobank were stratified as follows: 1. carriers status for germline pathogenic variants (PV) in CRC susceptibility genes ( APC, MLH1, MSH2, MSH6, PMS2) , 2. low (\textless 20\%), intermediate (20–80\%), or high PRS (\textgreater 80\%), and 3. family history (FH) of CRC. Multivariable logistic regression and Cox proportional hazards models were applied to compare odds ratios and to compute the lifetime incidence, respectively. Results: Depending on the PRS, the CRC lifetime incidence for non-carriers ranges between 6 and 22\%, compared to 40 and 74 for carriers. A suspicious FH is associated with a further increase of the cumulative incidence reaching 26 for non-carriers and 98 for carriers. In non-carriers without FH, but high PRS, the CRC risk is doubled, whereas a low PRS even in the context of a FH results in a decreased risk. The full model including PRS, carrier status, and FH improved the area under the curve in risk prediction (0.704). Conclusion: The findings demonstrate that CRC risks are strongly influenced by the PRS for both a sporadic and monogenic background. FH, PV, and common variants complementary contribute to CRC risk. The implementation of PRS in routine care will likely improve personalized risk stratification, which will in turn guide tailored preventive surveillance strategies in high, intermediate, and low risk groups.
Published: 2023

9. Transferability of European-derived cardiometabolic polygenic risk scores in the South Asians and their interplay with family history 2023.03.20.23287470

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Hassanin, Emadeldin Saeed Fathy Sayed, Maj, Carlo, Krawitz, Peter, May, Patrick, Bobbili, Dheeraj Reddy, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Hassanin, Emadeldin Saeed Fathy Sayed, Maj, Carlo, Krawitz, Peter, May, Patrick, and Bobbili, Dheeraj Reddy
Abstract: Background & Aims We aimed to investigate the effect of polygenic risk scores (PRSs) derived from individuals of European (EUR) ancestry on common diseases among individuals of South Asian (SAS) ancestry in the UK Biobank (UKB). Additionally, we studied the interaction between PRS and family history (FH) in the same population.Methods To calculate the PRS, we used a previously published panel of SNPs derived from the EUR population and applied it to the individuals of SAS ancestry from the UKB study. We applied the PRS using summary statistics from genome-wide association studies (GWAS) for cardiometabolic and lifestyle diseases such as coronary artery disease (CAD), obesity, and type 2 diabetes (T2D). Each PRS was adjusted according to an individual\textquoterights predicted genetic ancestry to derive an adjusted PRS (aPRS). We calculated the percentiles based on aPRS and divided them according to the percentiles into three categories: low, intermediate, and high. Considering the intermediate-aPRS percentile as a reference, we compared the low and high aPRS categories and generated the odds ratio (OR) estimates.Results The risk of developing severe obesity for individuals of SAS ancestry was almost threefold higher for individuals with high aPRS than for those with intermediate aPRS, with an OR of 3.67 (95% CI = 2.47-5.48, P < 0.01). While the risk of severe obesity was lower in the low-aPRS group (OR = 0.19, CI = 0.05\textendash0.52, P < 0.01). Comparable results were found in the EUR data, where the low-PRS group had an OR of 0.26 (95% CI= 0.24-0.3, P < 0.01) and the high-PRS group had an OR of 3.2 (95% CI = 3.1-3.3, P < 0.01). We observed similar results for CAD and T2D. Further, we show that SAS individuals with a familial history of CAD and T2D with high-aPRS exhibit further higher risk to these diseases, thereby implying a greater genetic predisposition to these conditions.Conclusion Our findings suggest that using CAD, obesity, and T2D GWAS summary statistic
Published: 2023

10. Transferability of European-derived cardiometabolic polygenic risk scores in the South Asians and their interplay with family history 2023.03.20.23287470

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Hassanin, Emadeldin Saeed Fathy Sayed, Maj, Carlo, Krawitz, Peter, May, Patrick, Bobbili, Dheeraj Reddy, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Hassanin, Emadeldin Saeed Fathy Sayed, Maj, Carlo, Krawitz, Peter, May, Patrick, and Bobbili, Dheeraj Reddy
Abstract: Background & Aims We aimed to investigate the effect of polygenic risk scores (PRSs) derived from individuals of European (EUR) ancestry on common diseases among individuals of South Asian (SAS) ancestry in the UK Biobank (UKB). Additionally, we studied the interaction between PRS and family history (FH) in the same population.Methods To calculate the PRS, we used a previously published panel of SNPs derived from the EUR population and applied it to the individuals of SAS ancestry from the UKB study. We applied the PRS using summary statistics from genome-wide association studies (GWAS) for cardiometabolic and lifestyle diseases such as coronary artery disease (CAD), obesity, and type 2 diabetes (T2D). Each PRS was adjusted according to an individual\textquoterights predicted genetic ancestry to derive an adjusted PRS (aPRS). We calculated the percentiles based on aPRS and divided them according to the percentiles into three categories: low, intermediate, and high. Considering the intermediate-aPRS percentile as a reference, we compared the low and high aPRS categories and generated the odds ratio (OR) estimates.Results The risk of developing severe obesity for individuals of SAS ancestry was almost threefold higher for individuals with high aPRS than for those with intermediate aPRS, with an OR of 3.67 (95% CI = 2.47-5.48, P < 0.01). While the risk of severe obesity was lower in the low-aPRS group (OR = 0.19, CI = 0.05\textendash0.52, P < 0.01). Comparable results were found in the EUR data, where the low-PRS group had an OR of 0.26 (95% CI= 0.24-0.3, P < 0.01) and the high-PRS group had an OR of 3.2 (95% CI = 3.1-3.3, P < 0.01). We observed similar results for CAD and T2D. Further, we show that SAS individuals with a familial history of CAD and T2D with high-aPRS exhibit further higher risk to these diseases, thereby implying a greater genetic predisposition to these conditions.Conclusion Our findings suggest that using CAD, obesity, and T2D GWAS summary statistic
Published: 2023

11. Transferability of European-derived cardiometabolic polygenic risk scores in the South Asians and their interplay with family history 2023.03.20.23287470

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Hassanin, Emadeldin Saeed Fathy Sayed, Maj, Carlo, Krawitz, Peter, May, Patrick, Bobbili, Dheeraj Reddy, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Hassanin, Emadeldin Saeed Fathy Sayed, Maj, Carlo, Krawitz, Peter, May, Patrick, and Bobbili, Dheeraj Reddy
Abstract: Background & Aims We aimed to investigate the effect of polygenic risk scores (PRSs) derived from individuals of European (EUR) ancestry on common diseases among individuals of South Asian (SAS) ancestry in the UK Biobank (UKB). Additionally, we studied the interaction between PRS and family history (FH) in the same population.Methods To calculate the PRS, we used a previously published panel of SNPs derived from the EUR population and applied it to the individuals of SAS ancestry from the UKB study. We applied the PRS using summary statistics from genome-wide association studies (GWAS) for cardiometabolic and lifestyle diseases such as coronary artery disease (CAD), obesity, and type 2 diabetes (T2D). Each PRS was adjusted according to an individual\textquoterights predicted genetic ancestry to derive an adjusted PRS (aPRS). We calculated the percentiles based on aPRS and divided them according to the percentiles into three categories: low, intermediate, and high. Considering the intermediate-aPRS percentile as a reference, we compared the low and high aPRS categories and generated the odds ratio (OR) estimates.Results The risk of developing severe obesity for individuals of SAS ancestry was almost threefold higher for individuals with high aPRS than for those with intermediate aPRS, with an OR of 3.67 (95% CI = 2.47-5.48, P < 0.01). While the risk of severe obesity was lower in the low-aPRS group (OR = 0.19, CI = 0.05\textendash0.52, P < 0.01). Comparable results were found in the EUR data, where the low-PRS group had an OR of 0.26 (95% CI= 0.24-0.3, P < 0.01) and the high-PRS group had an OR of 3.2 (95% CI = 3.1-3.3, P < 0.01). We observed similar results for CAD and T2D. Further, we show that SAS individuals with a familial history of CAD and T2D with high-aPRS exhibit further higher risk to these diseases, thereby implying a greater genetic predisposition to these conditions.Conclusion Our findings suggest that using CAD, obesity, and T2D GWAS summary statistic
Published: 2023

12. Clinically relevant combined effect of polygenic background, rare pathogenic germline variants, and family history on colorectal cancer incidence

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Hassanin, Emadeldin Saeed Fathy Sayed, Spier, Isabel, Bobbili, Dheeraj Reddy, Aldisi, Rana, Klinkhammer, Hannah, David, Friederike, Dueñas, Nuria, Hüneburg, Robert, Perne, Claudia, Brunet, Joan, Capella, Gabriel, Nöthen, Markus M., Forstner, Andreas J., Mayr, Andreas, Krawitz, Peter, May, Patrick, Aretz, Stefan, Maj, Carlo, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Hassanin, Emadeldin Saeed Fathy Sayed, Spier, Isabel, Bobbili, Dheeraj Reddy, Aldisi, Rana, Klinkhammer, Hannah, David, Friederike, Dueñas, Nuria, Hüneburg, Robert, Perne, Claudia, Brunet, Joan, Capella, Gabriel, Nöthen, Markus M., Forstner, Andreas J., Mayr, Andreas, Krawitz, Peter, May, Patrick, Aretz, Stefan, and Maj, Carlo
Abstract: Background and aims: Summarised in polygenic risk scores (PRS), the effect of common, low penetrant genetic variants associated with colorectal cancer (CRC), can be used for risk stratification. Methods: To assess the combined impact of the PRS and other main factors on CRC risk, 163,516 individuals from the UK Biobank were stratified as follows: 1. carriers status for germline pathogenic variants (PV) in CRC susceptibility genes ( APC, MLH1, MSH2, MSH6, PMS2) , 2. low (\textless 20\%), intermediate (20–80\%), or high PRS (\textgreater 80\%), and 3. family history (FH) of CRC. Multivariable logistic regression and Cox proportional hazards models were applied to compare odds ratios and to compute the lifetime incidence, respectively. Results: Depending on the PRS, the CRC lifetime incidence for non-carriers ranges between 6 and 22\%, compared to 40 and 74 for carriers. A suspicious FH is associated with a further increase of the cumulative incidence reaching 26 for non-carriers and 98 for carriers. In non-carriers without FH, but high PRS, the CRC risk is doubled, whereas a low PRS even in the context of a FH results in a decreased risk. The full model including PRS, carrier status, and FH improved the area under the curve in risk prediction (0.704). Conclusion: The findings demonstrate that CRC risks are strongly influenced by the PRS for both a sporadic and monogenic background. FH, PV, and common variants complementary contribute to CRC risk. The implementation of PRS in routine care will likely improve personalized risk stratification, which will in turn guide tailored preventive surveillance strategies in high, intermediate, and low risk groups.
Published: 2023

13. Dissecting the genetic heterogeneity of gastric cancer

Author: Hess, Timo, Maj, Carlo, Gehlen, Jan, Borisov, Oleg, Haas, Stephan L., Gockel, Ines, Vieth, Michael, Piessen, Guillaume, Alakus, Hakan, Vashist, Yogesh, Pereira, Carina, Knapp, Michael, Schüller, Vitalia, Quaas, Alexander, Grabsch, Heike I., Trautmann, Jessica, Malecka-Wojciesko, Ewa, Mokrowiecka, Anna, Speller, Jan, Mayr, Andreas, Schröder, Julia, Hillmer, Axel M., Heider, Dominik, Lordick, Florian, Pérez-Aísa, Ángeles, Campo, Rafael, Espinel, Jesús, Geijo, Fernando, Thomson, Concha, Bujanda, Luis, Sopeña, Federico, Lanas, Ángel, Pellisé, María, Pauligk, Claudia, Goetze, Thorsten Oliver, Zelck, Carolin, Reingruber, Julian, Hassanin, Emadeldin, Elbe, Peter, Alsabeah, Sandra, Lindblad, Mats, Nilsson, Magnus, Kreuser, Nicole, Thieme, René, Tavano, Francesca, Pastorino, Roberta, Arzani, Dario, Persiani, Roberto, Jung, Jin-On, Nienhüser, Henrik, Ott, Katja, Schumann, Ralf R., Kumpf, Oliver, Burock, Susen, Arndt, Volker, Jakubowska, Anna, Ławniczak, Małgorzta, Moreno, Victor, Martín, Vicente, Kogevinas, Manolis, Pollán, Marina, Dąbrowska, Justyna, Salas, Antonio, Cussenot, Olivier, Boland-Auge, Anne, Daian, Delphine, Deleuze, Jean-Francois, Salvi, Erika, Teder-Laving, Maris, Tomasello, Gianluca, Ratti, Margherita, Senti, Chiara, De Re, Valli, Steffan, Agostino, Hölscher, Arnulf H., Messerle, Katharina, Bruns, Christiane Josephine, Sīviņš, Armands, Bogdanova, Inga, Skieceviciene, Jurgita, Arstikyte, Justina, Moehler, Markus, Lang, Hauke, Grimminger, Peter P., Kruschewski, Martin, Vassos, Nikolaos, Schildberg, Claus, Lingohr, Philipp, Ridwelski, Karsten, Lippert, Hans, Fricker, Nadine, Krawitz, Peter, Hoffmann, Per, Nöthen, Markus M., Veits, Lothar, Izbicki, Jakob R., Mostowska, Adrianna, Martinón-Torres, Federico, Cusi, Daniele, Adolfsson, Rolf, Cancel-Tassin, Geraldine, Höblinger, Aksana, Rodermann, Ernst, Ludwig, Monika, Keller, Gisela, Metspalu, Andres, Brenner, Hermann, Heller, Joerg, Neef, Markus, Schepke, Michael, Dumoulin, Franz Ludwig, Hamann, Lutz, Cannizzaro, Renato, Ghidini, Michele, Plaßmann, Dominik, Geppert, Michael, Malfertheiner, Peter, Gehlen, Olivier, Skoczylas, Tomasz, Majewski, Marek, Lubiński, Jan, Palmieri, Orazio, Boccia, Stefania, Latiano, Anna, Aragones, Nuria, Schmidt, Thomas, Dinis-Ribeiro, Mário, Medeiros, Rui, Al-Batran, Salah-Eddin, Leja, Mārcis, Kupcinskas, Juozas, García-González, María A., Venerito, Marino, Schumacher, Johannes, Hess, Timo, Maj, Carlo, Gehlen, Jan, Borisov, Oleg, Haas, Stephan L., Gockel, Ines, Vieth, Michael, Piessen, Guillaume, Alakus, Hakan, Vashist, Yogesh, Pereira, Carina, Knapp, Michael, Schüller, Vitalia, Quaas, Alexander, Grabsch, Heike I., Trautmann, Jessica, Malecka-Wojciesko, Ewa, Mokrowiecka, Anna, Speller, Jan, Mayr, Andreas, Schröder, Julia, Hillmer, Axel M., Heider, Dominik, Lordick, Florian, Pérez-Aísa, Ángeles, Campo, Rafael, Espinel, Jesús, Geijo, Fernando, Thomson, Concha, Bujanda, Luis, Sopeña, Federico, Lanas, Ángel, Pellisé, María, Pauligk, Claudia, Goetze, Thorsten Oliver, Zelck, Carolin, Reingruber, Julian, Hassanin, Emadeldin, Elbe, Peter, Alsabeah, Sandra, Lindblad, Mats, Nilsson, Magnus, Kreuser, Nicole, Thieme, René, Tavano, Francesca, Pastorino, Roberta, Arzani, Dario, Persiani, Roberto, Jung, Jin-On, Nienhüser, Henrik, Ott, Katja, Schumann, Ralf R., Kumpf, Oliver, Burock, Susen, Arndt, Volker, Jakubowska, Anna, Ławniczak, Małgorzta, Moreno, Victor, Martín, Vicente, Kogevinas, Manolis, Pollán, Marina, Dąbrowska, Justyna, Salas, Antonio, Cussenot, Olivier, Boland-Auge, Anne, Daian, Delphine, Deleuze, Jean-Francois, Salvi, Erika, Teder-Laving, Maris, Tomasello, Gianluca, Ratti, Margherita, Senti, Chiara, De Re, Valli, Steffan, Agostino, Hölscher, Arnulf H., Messerle, Katharina, Bruns, Christiane Josephine, Sīviņš, Armands, Bogdanova, Inga, Skieceviciene, Jurgita, Arstikyte, Justina, Moehler, Markus, Lang, Hauke, Grimminger, Peter P., Kruschewski, Martin, Vassos, Nikolaos, Schildberg, Claus, Lingohr, Philipp, Ridwelski, Karsten, Lippert, Hans, Fricker, Nadine, Krawitz, Peter, Hoffmann, Per, Nöthen, Markus M., Veits, Lothar, Izbicki, Jakob R., Mostowska, Adrianna, Martinón-Torres, Federico, Cusi, Daniele, Adolfsson, Rolf, Cancel-Tassin, Geraldine, Höblinger, Aksana, Rodermann, Ernst, Ludwig, Monika, Keller, Gisela, Metspalu, Andres, Brenner, Hermann, Heller, Joerg, Neef, Markus, Schepke, Michael, Dumoulin, Franz Ludwig, Hamann, Lutz, Cannizzaro, Renato, Ghidini, Michele, Plaßmann, Dominik, Geppert, Michael, Malfertheiner, Peter, Gehlen, Olivier, Skoczylas, Tomasz, Majewski, Marek, Lubiński, Jan, Palmieri, Orazio, Boccia, Stefania, Latiano, Anna, Aragones, Nuria, Schmidt, Thomas, Dinis-Ribeiro, Mário, Medeiros, Rui, Al-Batran, Salah-Eddin, Leja, Mārcis, Kupcinskas, Juozas, García-González, María A., Venerito, Marino, and Schumacher, Johannes
Abstract: Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular me, Errata: Hess, T., Maj, C., Gehlen, J. et. al. Corrigendum to “Dissecting the genetic heterogeneity of gastric cancer”. eBioMedicine. 2023:94:104709. DOI: 10.1016/j.ebiom.2023.104709
Published: 2023
Full Text: View/download PDF

14. Dissecting the genetic heterogeneity of gastric cancer

Author: Hess, Timo, Maj, Carlo, Gehlen, Jan, Borisov, Oleg, Haas, Stephan L., Gockel, Ines, Vieth, Michael, Piessen, Guillaume, Alakus, Hakan, Vashist, Yogesh, Pereira, Carina, Knapp, Michael, Schüller, Vitalia, Quaas, Alexander, Grabsch, Heike I., Trautmann, Jessica, Malecka-Wojciesko, Ewa, Mokrowiecka, Anna, Speller, Jan, Mayr, Andreas, Schröder, Julia, Hillmer, Axel M., Heider, Dominik, Lordick, Florian, Pérez-Aísa, Ángeles, Campo, Rafael, Espinel, Jesús, Geijo, Fernando, Thomson, Concha, Bujanda, Luis, Sopeña, Federico, Lanas, Ángel, Pellisé, María, Pauligk, Claudia, Goetze, Thorsten Oliver, Zelck, Carolin, Reingruber, Julian, Hassanin, Emadeldin, Elbe, Peter, Alsabeah, Sandra, Lindblad, Mats, Nilsson, Magnus, Kreuser, Nicole, Thieme, René, Tavano, Francesca, Pastorino, Roberta, Arzani, Dario, Persiani, Roberto, Jung, Jin-On, Nienhüser, Henrik, Ott, Katja, Schumann, Ralf R., Kumpf, Oliver, Burock, Susen, Arndt, Volker, Jakubowska, Anna, Ławniczak, Małgorzta, Moreno, Victor, Martín, Vicente, Kogevinas, Manolis, Pollán, Marina, Dąbrowska, Justyna, Salas, Antonio, Cussenot, Olivier, Boland-Auge, Anne, Daian, Delphine, Deleuze, Jean-Francois, Salvi, Erika, Teder-Laving, Maris, Tomasello, Gianluca, Ratti, Margherita, Senti, Chiara, De Re, Valli, Steffan, Agostino, Hölscher, Arnulf H., Messerle, Katharina, Bruns, Christiane Josephine, Sīviņš, Armands, Bogdanova, Inga, Skieceviciene, Jurgita, Arstikyte, Justina, Moehler, Markus, Lang, Hauke, Grimminger, Peter P., Kruschewski, Martin, Vassos, Nikolaos, Schildberg, Claus, Lingohr, Philipp, Ridwelski, Karsten, Lippert, Hans, Fricker, Nadine, Krawitz, Peter, Hoffmann, Per, Nöthen, Markus M., Veits, Lothar, Izbicki, Jakob R., Mostowska, Adrianna, Martinón-Torres, Federico, Cusi, Daniele, Adolfsson, Rolf, Cancel-Tassin, Geraldine, Höblinger, Aksana, Rodermann, Ernst, Ludwig, Monika, Keller, Gisela, Metspalu, Andres, Brenner, Hermann, Heller, Joerg, Neef, Markus, Schepke, Michael, Dumoulin, Franz Ludwig, Hamann, Lutz, Cannizzaro, Renato, Ghidini, Michele, Plaßmann, Dominik, Geppert, Michael, Malfertheiner, Peter, Gehlen, Olivier, Skoczylas, Tomasz, Majewski, Marek, Lubiński, Jan, Palmieri, Orazio, Boccia, Stefania, Latiano, Anna, Aragones, Nuria, Schmidt, Thomas, Dinis-Ribeiro, Mário, Medeiros, Rui, Al-Batran, Salah-Eddin, Leja, Mārcis, Kupcinskas, Juozas, García-González, María A., Venerito, Marino, Schumacher, Johannes, Hess, Timo, Maj, Carlo, Gehlen, Jan, Borisov, Oleg, Haas, Stephan L., Gockel, Ines, Vieth, Michael, Piessen, Guillaume, Alakus, Hakan, Vashist, Yogesh, Pereira, Carina, Knapp, Michael, Schüller, Vitalia, Quaas, Alexander, Grabsch, Heike I., Trautmann, Jessica, Malecka-Wojciesko, Ewa, Mokrowiecka, Anna, Speller, Jan, Mayr, Andreas, Schröder, Julia, Hillmer, Axel M., Heider, Dominik, Lordick, Florian, Pérez-Aísa, Ángeles, Campo, Rafael, Espinel, Jesús, Geijo, Fernando, Thomson, Concha, Bujanda, Luis, Sopeña, Federico, Lanas, Ángel, Pellisé, María, Pauligk, Claudia, Goetze, Thorsten Oliver, Zelck, Carolin, Reingruber, Julian, Hassanin, Emadeldin, Elbe, Peter, Alsabeah, Sandra, Lindblad, Mats, Nilsson, Magnus, Kreuser, Nicole, Thieme, René, Tavano, Francesca, Pastorino, Roberta, Arzani, Dario, Persiani, Roberto, Jung, Jin-On, Nienhüser, Henrik, Ott, Katja, Schumann, Ralf R., Kumpf, Oliver, Burock, Susen, Arndt, Volker, Jakubowska, Anna, Ławniczak, Małgorzta, Moreno, Victor, Martín, Vicente, Kogevinas, Manolis, Pollán, Marina, Dąbrowska, Justyna, Salas, Antonio, Cussenot, Olivier, Boland-Auge, Anne, Daian, Delphine, Deleuze, Jean-Francois, Salvi, Erika, Teder-Laving, Maris, Tomasello, Gianluca, Ratti, Margherita, Senti, Chiara, De Re, Valli, Steffan, Agostino, Hölscher, Arnulf H., Messerle, Katharina, Bruns, Christiane Josephine, Sīviņš, Armands, Bogdanova, Inga, Skieceviciene, Jurgita, Arstikyte, Justina, Moehler, Markus, Lang, Hauke, Grimminger, Peter P., Kruschewski, Martin, Vassos, Nikolaos, Schildberg, Claus, Lingohr, Philipp, Ridwelski, Karsten, Lippert, Hans, Fricker, Nadine, Krawitz, Peter, Hoffmann, Per, Nöthen, Markus M., Veits, Lothar, Izbicki, Jakob R., Mostowska, Adrianna, Martinón-Torres, Federico, Cusi, Daniele, Adolfsson, Rolf, Cancel-Tassin, Geraldine, Höblinger, Aksana, Rodermann, Ernst, Ludwig, Monika, Keller, Gisela, Metspalu, Andres, Brenner, Hermann, Heller, Joerg, Neef, Markus, Schepke, Michael, Dumoulin, Franz Ludwig, Hamann, Lutz, Cannizzaro, Renato, Ghidini, Michele, Plaßmann, Dominik, Geppert, Michael, Malfertheiner, Peter, Gehlen, Olivier, Skoczylas, Tomasz, Majewski, Marek, Lubiński, Jan, Palmieri, Orazio, Boccia, Stefania, Latiano, Anna, Aragones, Nuria, Schmidt, Thomas, Dinis-Ribeiro, Mário, Medeiros, Rui, Al-Batran, Salah-Eddin, Leja, Mārcis, Kupcinskas, Juozas, García-González, María A., Venerito, Marino, and Schumacher, Johannes
Abstract: Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular me, Errata: Hess, T., Maj, C., Gehlen, J. et. al. Corrigendum to “Dissecting the genetic heterogeneity of gastric cancer”. eBioMedicine. 2023:94:104709. DOI: 10.1016/j.ebiom.2023.104709
Published: 2023
Full Text: View/download PDF

15. Dissecting the genetic heterogeneity of gastric cancer

Author: Hess, Timo, Maj, Carlo, Gehlen, Jan, Borisov, Oleg, Haas, Stephan L., Gockel, Ines, Vieth, Michael, Piessen, Guillaume, Alakus, Hakan, Vashist, Yogesh, Pereira, Carina, Knapp, Michael, Schüller, Vitalia, Quaas, Alexander, Grabsch, Heike I., Trautmann, Jessica, Malecka-Wojciesko, Ewa, Mokrowiecka, Anna, Speller, Jan, Mayr, Andreas, Schröder, Julia, Hillmer, Axel M., Heider, Dominik, Lordick, Florian, Pérez-Aísa, Ángeles, Campo, Rafael, Espinel, Jesús, Geijo, Fernando, Thomson, Concha, Bujanda, Luis, Sopeña, Federico, Lanas, Ángel, Pellisé, María, Pauligk, Claudia, Goetze, Thorsten Oliver, Zelck, Carolin, Reingruber, Julian, Hassanin, Emadeldin, Elbe, Peter, Alsabeah, Sandra, Lindblad, Mats, Nilsson, Magnus, Kreuser, Nicole, Thieme, René, Tavano, Francesca, Pastorino, Roberta, Arzani, Dario, Persiani, Roberto, Jung, Jin-On, Nienhüser, Henrik, Ott, Katja, Schumann, Ralf R., Kumpf, Oliver, Burock, Susen, Arndt, Volker, Jakubowska, Anna, Ławniczak, Małgorzta, Moreno, Victor, Martín, Vicente, Kogevinas, Manolis, Pollán, Marina, Dąbrowska, Justyna, Salas, Antonio, Cussenot, Olivier, Boland-Auge, Anne, Daian, Delphine, Deleuze, Jean-Francois, Salvi, Erika, Teder-Laving, Maris, Tomasello, Gianluca, Ratti, Margherita, Senti, Chiara, De Re, Valli, Steffan, Agostino, Hölscher, Arnulf H., Messerle, Katharina, Bruns, Christiane Josephine, Sīviņš, Armands, Bogdanova, Inga, Skieceviciene, Jurgita, Arstikyte, Justina, Moehler, Markus, Lang, Hauke, Grimminger, Peter P., Kruschewski, Martin, Vassos, Nikolaos, Schildberg, Claus, Lingohr, Philipp, Ridwelski, Karsten, Lippert, Hans, Fricker, Nadine, Krawitz, Peter, Hoffmann, Per, Nöthen, Markus M., Veits, Lothar, Izbicki, Jakob R., Mostowska, Adrianna, Martinón-Torres, Federico, Cusi, Daniele, Adolfsson, Rolf, Cancel-Tassin, Geraldine, Höblinger, Aksana, Rodermann, Ernst, Ludwig, Monika, Keller, Gisela, Metspalu, Andres, Brenner, Hermann, Heller, Joerg, Neef, Markus, Schepke, Michael, Dumoulin, Franz Ludwig, Hamann, Lutz, Cannizzaro, Renato, Ghidini, Michele, Plaßmann, Dominik, Geppert, Michael, Malfertheiner, Peter, Gehlen, Olivier, Skoczylas, Tomasz, Majewski, Marek, Lubiński, Jan, Palmieri, Orazio, Boccia, Stefania, Latiano, Anna, Aragones, Nuria, Schmidt, Thomas, Dinis-Ribeiro, Mário, Medeiros, Rui, Al-Batran, Salah-Eddin, Leja, Mārcis, Kupcinskas, Juozas, García-González, María A., Venerito, Marino, Schumacher, Johannes, Hess, Timo, Maj, Carlo, Gehlen, Jan, Borisov, Oleg, Haas, Stephan L., Gockel, Ines, Vieth, Michael, Piessen, Guillaume, Alakus, Hakan, Vashist, Yogesh, Pereira, Carina, Knapp, Michael, Schüller, Vitalia, Quaas, Alexander, Grabsch, Heike I., Trautmann, Jessica, Malecka-Wojciesko, Ewa, Mokrowiecka, Anna, Speller, Jan, Mayr, Andreas, Schröder, Julia, Hillmer, Axel M., Heider, Dominik, Lordick, Florian, Pérez-Aísa, Ángeles, Campo, Rafael, Espinel, Jesús, Geijo, Fernando, Thomson, Concha, Bujanda, Luis, Sopeña, Federico, Lanas, Ángel, Pellisé, María, Pauligk, Claudia, Goetze, Thorsten Oliver, Zelck, Carolin, Reingruber, Julian, Hassanin, Emadeldin, Elbe, Peter, Alsabeah, Sandra, Lindblad, Mats, Nilsson, Magnus, Kreuser, Nicole, Thieme, René, Tavano, Francesca, Pastorino, Roberta, Arzani, Dario, Persiani, Roberto, Jung, Jin-On, Nienhüser, Henrik, Ott, Katja, Schumann, Ralf R., Kumpf, Oliver, Burock, Susen, Arndt, Volker, Jakubowska, Anna, Ławniczak, Małgorzta, Moreno, Victor, Martín, Vicente, Kogevinas, Manolis, Pollán, Marina, Dąbrowska, Justyna, Salas, Antonio, Cussenot, Olivier, Boland-Auge, Anne, Daian, Delphine, Deleuze, Jean-Francois, Salvi, Erika, Teder-Laving, Maris, Tomasello, Gianluca, Ratti, Margherita, Senti, Chiara, De Re, Valli, Steffan, Agostino, Hölscher, Arnulf H., Messerle, Katharina, Bruns, Christiane Josephine, Sīviņš, Armands, Bogdanova, Inga, Skieceviciene, Jurgita, Arstikyte, Justina, Moehler, Markus, Lang, Hauke, Grimminger, Peter P., Kruschewski, Martin, Vassos, Nikolaos, Schildberg, Claus, Lingohr, Philipp, Ridwelski, Karsten, Lippert, Hans, Fricker, Nadine, Krawitz, Peter, Hoffmann, Per, Nöthen, Markus M., Veits, Lothar, Izbicki, Jakob R., Mostowska, Adrianna, Martinón-Torres, Federico, Cusi, Daniele, Adolfsson, Rolf, Cancel-Tassin, Geraldine, Höblinger, Aksana, Rodermann, Ernst, Ludwig, Monika, Keller, Gisela, Metspalu, Andres, Brenner, Hermann, Heller, Joerg, Neef, Markus, Schepke, Michael, Dumoulin, Franz Ludwig, Hamann, Lutz, Cannizzaro, Renato, Ghidini, Michele, Plaßmann, Dominik, Geppert, Michael, Malfertheiner, Peter, Gehlen, Olivier, Skoczylas, Tomasz, Majewski, Marek, Lubiński, Jan, Palmieri, Orazio, Boccia, Stefania, Latiano, Anna, Aragones, Nuria, Schmidt, Thomas, Dinis-Ribeiro, Mário, Medeiros, Rui, Al-Batran, Salah-Eddin, Leja, Mārcis, Kupcinskas, Juozas, García-González, María A., Venerito, Marino, and Schumacher, Johannes
Abstract: Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular me, Errata: Hess, T., Maj, C., Gehlen, J. et. al. Corrigendum to “Dissecting the genetic heterogeneity of gastric cancer”. eBioMedicine. 2023:94:104709. DOI: 10.1016/j.ebiom.2023.104709
Published: 2023
Full Text: View/download PDF

16. Identification of de novo variants in nonsyndromic cleft lip with/without cleft palate patients with low polygenic risk scores

Author: German Research Foundation, Ishorst, Nina, Henschel, Leonie, Thieme, Frederic, Drichel, Dmitriy, Sivalingam, Sugirthan, Mehrem, Sarah L., Fechtner, Ariane C., Fazaal, Julia, Welzenbach, Julia, André Heimbach, Maj, Carlo, Hausen, Jonas, Raff, Ruth, Hoischen, Alexander, Dixon, Michael J., Rada-Iglesias, Alvaro, Bartusel, Michaela, Rojas-Martinez, Augusto, Aldhorae, Khalid, Braumann, Bert, Kruse, Teresa, Kirschnech, Christian, Spanier, Gerrit, Reutter, Heiko, Nowak, Stefanie, Gölz, Lina, Knapp, Michael, Buness, Andreas, Krawitz, Peter, Nöthen, Markus M., Nothnagel, Michael, Becker, Tim, Ludwig, Kerstin U., Mangold, Elisabeth, German Research Foundation, Ishorst, Nina, Henschel, Leonie, Thieme, Frederic, Drichel, Dmitriy, Sivalingam, Sugirthan, Mehrem, Sarah L., Fechtner, Ariane C., Fazaal, Julia, Welzenbach, Julia, André Heimbach, Maj, Carlo, Hausen, Jonas, Raff, Ruth, Hoischen, Alexander, Dixon, Michael J., Rada-Iglesias, Alvaro, Bartusel, Michaela, Rojas-Martinez, Augusto, Aldhorae, Khalid, Braumann, Bert, Kruse, Teresa, Kirschnech, Christian, Spanier, Gerrit, Reutter, Heiko, Nowak, Stefanie, Gölz, Lina, Knapp, Michael, Buness, Andreas, Krawitz, Peter, Nöthen, Markus M., Nothnagel, Michael, Becker, Tim, Ludwig, Kerstin U., and Mangold, Elisabeth
Abstract: [Background]: Nonsyndromic cleft lip with/without cleft palate (nsCL/P) is a congenital malformation of multifactorial etiology. Research has identified >40 genome-wide significant risk loci, which explain less than 40% of nsCL/P heritability. Studies show that some of the hidden heritability is explained by rare penetrant variants. [Methods]: To identify new candidate genes, we searched for highly penetrant de novo variants (DNVs) in 50 nsCL/P patient/parent-trios with a low polygenic risk for the phenotype (discovery). We prioritized DNV-carrying candidate genes from the discovery for resequencing in independent cohorts of 1010 nsCL/P patients of diverse ethnicities and 1574 population-matched controls (replication). Segregation analyses and rare variant association in the replication cohort, in combination with additional data (genome-wide association data, expression, protein–protein-interactions), were used for final prioritization. [Conclusion]: In the discovery step, 60 DNVs were identified in 60 genes, including a variant in the established nsCL/P risk gene CDH1. Re-sequencing of 32 prioritized genes led to the identification of 373 rare, likely pathogenic variants. Finally, MDN1 and PAXIP1 were prioritized as top candidates. Our findings demonstrate that DNV detection, including polygenic risk score analysis, is a powerful tool for identifying nsCL/P candidate genes, which can also be applied to other multifactorial congenital malformations.
Published: 2023

17. Dissecting the genetic heterogeneity of gastric cancer

Author: Hess, Timo, Maj, Carlo, Gehlen, Jan, Borisov, Oleg, Haas, Stephan L., Gockel, Ines, Vieth, Michael, Piessen, Guillaume, Alakus, Hakan, Vashist, Yogesh, Pereira, Carina, Knapp, Michael, Schüller, Vitalia, Quaas, Alexander, Grabsch, Heike I., Trautmann, Jessica, Malecka-Wojciesko, Ewa, Mokrowiecka, Anna, Speller, Jan, Mayr, Andreas, Schröder, Julia, Hillmer, Axel M., Heider, Dominik, Lordick, Florian, Pérez-Aísa, Ángeles, Campo, Rafael, Espinel, Jesús, Geijo, Fernando, Thomson, Concha, Bujanda, Luis, Sopeña, Federico, Lanas, Ángel, Pellisé, María, Pauligk, Claudia, Goetze, Thorsten Oliver, Zelck, Carolin, Reingruber, Julian, Hassanin, Emadeldin, Elbe, Peter, Alsabeah, Sandra, Lindblad, Mats, Nilsson, Magnus, Kreuser, Nicole, Thieme, René, Tavano, Francesca, Pastorino, Roberta, Arzani, Dario, Persiani, Roberto, Jung, Jin-On, Nienhüser, Henrik, Ott, Katja, Schumann, Ralf R., Kumpf, Oliver, Burock, Susen, Arndt, Volker, Jakubowska, Anna, Ławniczak, Małgorzta, Moreno, Victor, Martín, Vicente, Kogevinas, Manolis, Pollán, Marina, Dąbrowska, Justyna, Salas, Antonio, Cussenot, Olivier, Boland-Auge, Anne, Daian, Delphine, Deleuze, Jean-Francois, Salvi, Erika, Teder-Laving, Maris, Tomasello, Gianluca, Ratti, Margherita, Senti, Chiara, De Re, Valli, Steffan, Agostino, Hölscher, Arnulf H., Messerle, Katharina, Bruns, Christiane Josephine, Sīviņš, Armands, Bogdanova, Inga, Skieceviciene, Jurgita, Arstikyte, Justina, Moehler, Markus, Lang, Hauke, Grimminger, Peter P., Kruschewski, Martin, Vassos, Nikolaos, Schildberg, Claus, Lingohr, Philipp, Ridwelski, Karsten, Lippert, Hans, Fricker, Nadine, Krawitz, Peter, Hoffmann, Per, Nöthen, Markus M., Veits, Lothar, Izbicki, Jakob R., Mostowska, Adrianna, Martinón-Torres, Federico, Cusi, Daniele, Adolfsson, Rolf, Cancel-Tassin, Geraldine, Höblinger, Aksana, Rodermann, Ernst, Ludwig, Monika, Keller, Gisela, Metspalu, Andres, Brenner, Hermann, Heller, Joerg, Neef, Markus, Schepke, Michael, Dumoulin, Franz Ludwig, Hamann, Lutz, Cannizzaro, Renato, Ghidini, Michele, Plaßmann, Dominik, Geppert, Michael, Malfertheiner, Peter, Gehlen, Olivier, Skoczylas, Tomasz, Majewski, Marek, Lubiński, Jan, Palmieri, Orazio, Boccia, Stefania, Latiano, Anna, Aragones, Nuria, Schmidt, Thomas, Dinis-Ribeiro, Mário, Medeiros, Rui, Al-Batran, Salah-Eddin, Leja, Mārcis, Kupcinskas, Juozas, García-González, María A., Venerito, Marino, Schumacher, Johannes, Hess, Timo, Maj, Carlo, Gehlen, Jan, Borisov, Oleg, Haas, Stephan L., Gockel, Ines, Vieth, Michael, Piessen, Guillaume, Alakus, Hakan, Vashist, Yogesh, Pereira, Carina, Knapp, Michael, Schüller, Vitalia, Quaas, Alexander, Grabsch, Heike I., Trautmann, Jessica, Malecka-Wojciesko, Ewa, Mokrowiecka, Anna, Speller, Jan, Mayr, Andreas, Schröder, Julia, Hillmer, Axel M., Heider, Dominik, Lordick, Florian, Pérez-Aísa, Ángeles, Campo, Rafael, Espinel, Jesús, Geijo, Fernando, Thomson, Concha, Bujanda, Luis, Sopeña, Federico, Lanas, Ángel, Pellisé, María, Pauligk, Claudia, Goetze, Thorsten Oliver, Zelck, Carolin, Reingruber, Julian, Hassanin, Emadeldin, Elbe, Peter, Alsabeah, Sandra, Lindblad, Mats, Nilsson, Magnus, Kreuser, Nicole, Thieme, René, Tavano, Francesca, Pastorino, Roberta, Arzani, Dario, Persiani, Roberto, Jung, Jin-On, Nienhüser, Henrik, Ott, Katja, Schumann, Ralf R., Kumpf, Oliver, Burock, Susen, Arndt, Volker, Jakubowska, Anna, Ławniczak, Małgorzta, Moreno, Victor, Martín, Vicente, Kogevinas, Manolis, Pollán, Marina, Dąbrowska, Justyna, Salas, Antonio, Cussenot, Olivier, Boland-Auge, Anne, Daian, Delphine, Deleuze, Jean-Francois, Salvi, Erika, Teder-Laving, Maris, Tomasello, Gianluca, Ratti, Margherita, Senti, Chiara, De Re, Valli, Steffan, Agostino, Hölscher, Arnulf H., Messerle, Katharina, Bruns, Christiane Josephine, Sīviņš, Armands, Bogdanova, Inga, Skieceviciene, Jurgita, Arstikyte, Justina, Moehler, Markus, Lang, Hauke, Grimminger, Peter P., Kruschewski, Martin, Vassos, Nikolaos, Schildberg, Claus, Lingohr, Philipp, Ridwelski, Karsten, Lippert, Hans, Fricker, Nadine, Krawitz, Peter, Hoffmann, Per, Nöthen, Markus M., Veits, Lothar, Izbicki, Jakob R., Mostowska, Adrianna, Martinón-Torres, Federico, Cusi, Daniele, Adolfsson, Rolf, Cancel-Tassin, Geraldine, Höblinger, Aksana, Rodermann, Ernst, Ludwig, Monika, Keller, Gisela, Metspalu, Andres, Brenner, Hermann, Heller, Joerg, Neef, Markus, Schepke, Michael, Dumoulin, Franz Ludwig, Hamann, Lutz, Cannizzaro, Renato, Ghidini, Michele, Plaßmann, Dominik, Geppert, Michael, Malfertheiner, Peter, Gehlen, Olivier, Skoczylas, Tomasz, Majewski, Marek, Lubiński, Jan, Palmieri, Orazio, Boccia, Stefania, Latiano, Anna, Aragones, Nuria, Schmidt, Thomas, Dinis-Ribeiro, Mário, Medeiros, Rui, Al-Batran, Salah-Eddin, Leja, Mārcis, Kupcinskas, Juozas, García-González, María A., Venerito, Marino, and Schumacher, Johannes
Abstract: Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular me, Errata: Hess, T., Maj, C., Gehlen, J. et. al. Corrigendum to “Dissecting the genetic heterogeneity of gastric cancer”. eBioMedicine. 2023:94:104709. DOI: 10.1016/j.ebiom.2023.104709
Published: 2023
Full Text: View/download PDF

18. Identification of de novo variants in nonsyndromic cleft lip with/without cleft palate patients with low polygenic risk scores

Author: Ishorst, Nina, Henschel, Leonie, Thieme, Frederic, Drichel, Dmitriy, Sivalingam, Sugirthan, Mehrem, Sarah L., Fechtner, Ariane C., Fazaal, Julia, Welzenbach, Julia, Heimbach, Andre, Maj, Carlo, Borisov, Oleg, Hausen, Jonas, Raff, Ruth, Hoischen, Alexander, Dixon, Michael, Rada-Iglesias, Alvaro, Bartusel, Michaela, Rojas-Martinez, Augusto, Aldhorae, Khalid, Braumann, Bert, Kruse, Teresa, Kirschneck, Christian, Spanier, Gerrit, Reutter, Heiko, Nowak, Stefanie, Goelz, Lina, Knapp, Michael, Buness, Andreas, Krawitz, Peter, Noethen, Markus M., Nothnagel, Michael, Becker, Tim, Ludwig, Kerstin U., Mangold, Elisabeth, Ishorst, Nina, Henschel, Leonie, Thieme, Frederic, Drichel, Dmitriy, Sivalingam, Sugirthan, Mehrem, Sarah L., Fechtner, Ariane C., Fazaal, Julia, Welzenbach, Julia, Heimbach, Andre, Maj, Carlo, Borisov, Oleg, Hausen, Jonas, Raff, Ruth, Hoischen, Alexander, Dixon, Michael, Rada-Iglesias, Alvaro, Bartusel, Michaela, Rojas-Martinez, Augusto, Aldhorae, Khalid, Braumann, Bert, Kruse, Teresa, Kirschneck, Christian, Spanier, Gerrit, Reutter, Heiko, Nowak, Stefanie, Goelz, Lina, Knapp, Michael, Buness, Andreas, Krawitz, Peter, Noethen, Markus M., Nothnagel, Michael, Becker, Tim, Ludwig, Kerstin U., and Mangold, Elisabeth
Abstract: BackgroundNonsyndromic cleft lip with/without cleft palate (nsCL/P) is a congenital malformation of multifactorial etiology. Research has identified >40 genome-wide significant risk loci, which explain less than 40% of nsCL/P heritability. Studies show that some of the hidden heritability is explained by rare penetrant variants. MethodsTo identify new candidate genes, we searched for highly penetrant de novo variants (DNVs) in 50 nsCL/P patient/parent-trios with a low polygenic risk for the phenotype (discovery).We prioritized DNV-carrying candidate genes from the discovery for resequencing in independent cohorts of 1010 nsCL/P patients of diverse ethnicities and 1574 population-matched controls (replication). Segregation analyses and rare variant association in the replication cohort, in combination with additional data (genome-wide association data, expression, protein-protein-interactions), were used for final prioritization. ConclusionIn the discovery step, 60 DNVs were identified in 60 genes, including a variant in the established nsCL/P risk gene CDH1. Re-sequencing of 32 prioritized genes led to the identification of 373 rare, likely pathogenic variants. Finally, MDN1 and PAXIP1 were prioritized as top candidates. Our findings demonstrate that DNV detection, including polygenic risk score analysis, is a powerful tool for identifying nsCL/P candidate genes, which can also be applied to other multifactorial congenital malformations.
Published: 2023

19. Dissecting the genetic heterogeneity of gastric cancer

Author: Hess, Timo, Maj, Carlo, Gehlen, Jan, Borisov, Oleg, Haas, Stephan L., Gockel, Ines, Vieth, Michael, Piessen, Guillaume, Alakus, Hakan, Vashist, Yogesh, Pereira, Carina, Knapp, Michael, Schüller, Vitalia, Quaas, Alexander, Grabsch, Heike I., Trautmann, Jessica, Malecka-Wojciesko, Ewa, Mokrowiecka, Anna, Speller, Jan, Mayr, Andreas, Schröder, Julia, Hillmer, Axel M., Heider, Dominik, Lordick, Florian, Pérez-Aísa, Ángeles, Campo, Rafael, Espinel, Jesús, Geijo, Fernando, Thomson, Concha, Bujanda, Luis, Sopeña, Federico, Lanas, Ángel, Pellisé, María, Pauligk, Claudia, Goetze, Thorsten Oliver, Zelck, Carolin, Reingruber, Julian, Hassanin, Emadeldin, Elbe, Peter, Alsabeah, Sandra, Lindblad, Mats, Nilsson, Magnus, Kreuser, Nicole, Thieme, René, Tavano, Francesca, Pastorino, Roberta, Arzani, Dario, Persiani, Roberto, Jung, Jin-On, Nienhüser, Henrik, Ott, Katja, Schumann, Ralf R., Kumpf, Oliver, Burock, Susen, Arndt, Volker, Jakubowska, Anna, Ławniczak, Małgorzta, Moreno, Victor, Martín, Vicente, Kogevinas, Manolis, Pollán, Marina, Dąbrowska, Justyna, Salas, Antonio, Cussenot, Olivier, Boland-Auge, Anne, Daian, Delphine, Deleuze, Jean-Francois, Salvi, Erika, Teder-Laving, Maris, Tomasello, Gianluca, Ratti, Margherita, Senti, Chiara, De Re, Valli, Steffan, Agostino, Hölscher, Arnulf H., Messerle, Katharina, Bruns, Christiane Josephine, Sīviņš, Armands, Bogdanova, Inga, Skieceviciene, Jurgita, Arstikyte, Justina, Moehler, Markus, Lang, Hauke, Grimminger, Peter P., Kruschewski, Martin, Vassos, Nikolaos, Schildberg, Claus, Lingohr, Philipp, Ridwelski, Karsten, Lippert, Hans, Fricker, Nadine, Krawitz, Peter, Hoffmann, Per, Nöthen, Markus M., Veits, Lothar, Izbicki, Jakob R., Mostowska, Adrianna, Martinón-Torres, Federico, Cusi, Daniele, Adolfsson, Rolf, Cancel-Tassin, Geraldine, Höblinger, Aksana, Rodermann, Ernst, Ludwig, Monika, Keller, Gisela, Metspalu, Andres, Brenner, Hermann, Heller, Joerg, Neef, Markus, Schepke, Michael, Dumoulin, Franz Ludwig, Hamann, Lutz, Cannizzaro, Renato, Ghidini, Michele, Plaßmann, Dominik, Geppert, Michael, Malfertheiner, Peter, Gehlen, Olivier, Skoczylas, Tomasz, Majewski, Marek, Lubiński, Jan, Palmieri, Orazio, Boccia, Stefania, Latiano, Anna, Aragones, Nuria, Schmidt, Thomas, Dinis-Ribeiro, Mário, Medeiros, Rui, Al-Batran, Salah-Eddin, Leja, Mārcis, Kupcinskas, Juozas, García-González, María A., Venerito, Marino, Schumacher, Johannes, Hess, Timo, Maj, Carlo, Gehlen, Jan, Borisov, Oleg, Haas, Stephan L., Gockel, Ines, Vieth, Michael, Piessen, Guillaume, Alakus, Hakan, Vashist, Yogesh, Pereira, Carina, Knapp, Michael, Schüller, Vitalia, Quaas, Alexander, Grabsch, Heike I., Trautmann, Jessica, Malecka-Wojciesko, Ewa, Mokrowiecka, Anna, Speller, Jan, Mayr, Andreas, Schröder, Julia, Hillmer, Axel M., Heider, Dominik, Lordick, Florian, Pérez-Aísa, Ángeles, Campo, Rafael, Espinel, Jesús, Geijo, Fernando, Thomson, Concha, Bujanda, Luis, Sopeña, Federico, Lanas, Ángel, Pellisé, María, Pauligk, Claudia, Goetze, Thorsten Oliver, Zelck, Carolin, Reingruber, Julian, Hassanin, Emadeldin, Elbe, Peter, Alsabeah, Sandra, Lindblad, Mats, Nilsson, Magnus, Kreuser, Nicole, Thieme, René, Tavano, Francesca, Pastorino, Roberta, Arzani, Dario, Persiani, Roberto, Jung, Jin-On, Nienhüser, Henrik, Ott, Katja, Schumann, Ralf R., Kumpf, Oliver, Burock, Susen, Arndt, Volker, Jakubowska, Anna, Ławniczak, Małgorzta, Moreno, Victor, Martín, Vicente, Kogevinas, Manolis, Pollán, Marina, Dąbrowska, Justyna, Salas, Antonio, Cussenot, Olivier, Boland-Auge, Anne, Daian, Delphine, Deleuze, Jean-Francois, Salvi, Erika, Teder-Laving, Maris, Tomasello, Gianluca, Ratti, Margherita, Senti, Chiara, De Re, Valli, Steffan, Agostino, Hölscher, Arnulf H., Messerle, Katharina, Bruns, Christiane Josephine, Sīviņš, Armands, Bogdanova, Inga, Skieceviciene, Jurgita, Arstikyte, Justina, Moehler, Markus, Lang, Hauke, Grimminger, Peter P., Kruschewski, Martin, Vassos, Nikolaos, Schildberg, Claus, Lingohr, Philipp, Ridwelski, Karsten, Lippert, Hans, Fricker, Nadine, Krawitz, Peter, Hoffmann, Per, Nöthen, Markus M., Veits, Lothar, Izbicki, Jakob R., Mostowska, Adrianna, Martinón-Torres, Federico, Cusi, Daniele, Adolfsson, Rolf, Cancel-Tassin, Geraldine, Höblinger, Aksana, Rodermann, Ernst, Ludwig, Monika, Keller, Gisela, Metspalu, Andres, Brenner, Hermann, Heller, Joerg, Neef, Markus, Schepke, Michael, Dumoulin, Franz Ludwig, Hamann, Lutz, Cannizzaro, Renato, Ghidini, Michele, Plaßmann, Dominik, Geppert, Michael, Malfertheiner, Peter, Gehlen, Olivier, Skoczylas, Tomasz, Majewski, Marek, Lubiński, Jan, Palmieri, Orazio, Boccia, Stefania, Latiano, Anna, Aragones, Nuria, Schmidt, Thomas, Dinis-Ribeiro, Mário, Medeiros, Rui, Al-Batran, Salah-Eddin, Leja, Mārcis, Kupcinskas, Juozas, García-González, María A., Venerito, Marino, and Schumacher, Johannes
Abstract: Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular me, Errata: Hess, T., Maj, C., Gehlen, J. et. al. Corrigendum to “Dissecting the genetic heterogeneity of gastric cancer”. eBioMedicine. 2023:94:104709. DOI: 10.1016/j.ebiom.2023.104709
Published: 2023
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20. GANonymization: A GAN-based Face Anonymization Framework for Preserving Emotional Expressions

Author: Hellmann, Fabio, Mertes, Silvan, Benouis, Mohamed, Hustinx, Alexander, Hsieh, Tzung-Chien, Conati, Cristina, Krawitz, Peter, André, Elisabeth, Hellmann, Fabio, Mertes, Silvan, Benouis, Mohamed, Hustinx, Alexander, Hsieh, Tzung-Chien, Conati, Cristina, Krawitz, Peter, and André, Elisabeth
Abstract: In recent years, the increasing availability of personal data has raised concerns regarding privacy and security. One of the critical processes to address these concerns is data anonymization, which aims to protect individual privacy and prevent the release of sensitive information. This research focuses on the importance of face anonymization. Therefore, we introduce GANonymization, a novel face anonymization framework with facial expression-preserving abilities. Our approach is based on a high-level representation of a face, which is synthesized into an anonymized version based on a generative adversarial network (GAN). The effectiveness of the approach was assessed by evaluating its performance in removing identifiable facial attributes to increase the anonymity of the given individual face. Additionally, the performance of preserving facial expressions was evaluated on several affect recognition datasets and outperformed the state-of-the-art methods in most categories. Finally, our approach was analyzed for its ability to remove various facial traits, such as jewelry, hair color, and multiple others. Here, it demonstrated reliable performance in removing these attributes. Our results suggest that GANonymization is a promising approach for anonymizing faces while preserving facial expressions., Comment: 26 pages, 11 figures, 6 tables, ACM Transactions on Multimedia Computing, Communications, and Applications
Published: 2023
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21. PSMC3 proteasome subunit variants are associated with neurodevelopmental delay and type I interferon production

Author: Genetica Sectie Genoomdiagnostiek, Genetica Klinische Genetica, Cancer, Child Health, Ebstein, Frédéric, Küry, Sébastien, Most, Victoria, Rosenfelt, Cory, Scott-Boyer, Marie-Pier, van Woerden, Geeske M, Besnard, Thomas, Papendorf, Jonas Johannes, Studencka-Turski, Maja, Wang, Tianyun, Hsieh, Tzung-Chien, Golnik, Richard, Baldridge, Dustin, Forster, Cara, de Konink, Charlotte, Teurlings, Selina M W, Vignard, Virginie, van Jaarsveld, Richard H, Ades, Lesley, Cogné, Benjamin, Mignot, Cyril, Deb, Wallid, Jongmans, Marjolijn C J, Cole, F Sessions, van den Boogaard, Marie-José H, Wambach, Jennifer A, Wegner, Daniel J, Yang, Sandra, Hannig, Vickie, Brault, Jennifer Ann, Zadeh, Neda, Bennetts, Bruce, Keren, Boris, Gélineau, Anne-Claire, Powis, Zöe, Towne, Meghan, Bachman, Kristine, Seeley, Andrea, Beck, Anita E, Morrison, Jennifer, Westman, Rachel, Averill, Kelly, Brunet, Theresa, Haasters, Judith, Carter, Melissa T, Osmond, Matthew, Wheeler, Patricia G, Forzano, Francesca, Mohammed, Shehla, Trakadis, Yannis, Accogli, Andrea, Harrison, Rachel, Guo, Yiran, Hakonarson, Hakon, Rondeau, Sophie, Baujat, Geneviève, Barcia, Giulia, Feichtinger, René Günther, Mayr, Johannes Adalbert, Preisel, Martin, Laumonnier, Frédéric, Kallinich, Tilmann, Knaus, Alexej, Isidor, Bertrand, Krawitz, Peter, Völker, Uwe, Hammer, Elke, Droit, Arnaud, Eichler, Evan E, Elgersma, Ype, Hildebrand, Peter W, Bolduc, François, Krüger, Elke, Bézieau, Stéphane, Genetica Sectie Genoomdiagnostiek, Genetica Klinische Genetica, Cancer, Child Health, Ebstein, Frédéric, Küry, Sébastien, Most, Victoria, Rosenfelt, Cory, Scott-Boyer, Marie-Pier, van Woerden, Geeske M, Besnard, Thomas, Papendorf, Jonas Johannes, Studencka-Turski, Maja, Wang, Tianyun, Hsieh, Tzung-Chien, Golnik, Richard, Baldridge, Dustin, Forster, Cara, de Konink, Charlotte, Teurlings, Selina M W, Vignard, Virginie, van Jaarsveld, Richard H, Ades, Lesley, Cogné, Benjamin, Mignot, Cyril, Deb, Wallid, Jongmans, Marjolijn C J, Cole, F Sessions, van den Boogaard, Marie-José H, Wambach, Jennifer A, Wegner, Daniel J, Yang, Sandra, Hannig, Vickie, Brault, Jennifer Ann, Zadeh, Neda, Bennetts, Bruce, Keren, Boris, Gélineau, Anne-Claire, Powis, Zöe, Towne, Meghan, Bachman, Kristine, Seeley, Andrea, Beck, Anita E, Morrison, Jennifer, Westman, Rachel, Averill, Kelly, Brunet, Theresa, Haasters, Judith, Carter, Melissa T, Osmond, Matthew, Wheeler, Patricia G, Forzano, Francesca, Mohammed, Shehla, Trakadis, Yannis, Accogli, Andrea, Harrison, Rachel, Guo, Yiran, Hakonarson, Hakon, Rondeau, Sophie, Baujat, Geneviève, Barcia, Giulia, Feichtinger, René Günther, Mayr, Johannes Adalbert, Preisel, Martin, Laumonnier, Frédéric, Kallinich, Tilmann, Knaus, Alexej, Isidor, Bertrand, Krawitz, Peter, Völker, Uwe, Hammer, Elke, Droit, Arnaud, Eichler, Evan E, Elgersma, Ype, Hildebrand, Peter W, Bolduc, François, Krüger, Elke, and Bézieau, Stéphane
Published: 2023

22. CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology

Author: Eunice Kennedy Shriver National Institute of Child Health and Human Development (US), National Institutes of Health (US), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Hospital for Sick Children (Canada), University of Toronto, University of Southern Denmark, Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A., Gurnett, Christina A., Jelsig, Anne Marie, Vineke, Susanne H., Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T., Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M., Semina, Elena V., Reuter, Miriam S., Scherer, Stephen W., Iascone, Maria, Weis, Denisa, Fagerberg, Christina R., Brasch-Andersen, Charlotte, Kjaersgaard Hansen, Lars, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B., Pavlidou, Despoina C., Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R., Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M., Lemke, Johannes R., Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, Platzer, Konrad, Eunice Kennedy Shriver National Institute of Child Health and Human Development (US), National Institutes of Health (US), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Hospital for Sick Children (Canada), University of Toronto, University of Southern Denmark, Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A., Gurnett, Christina A., Jelsig, Anne Marie, Vineke, Susanne H., Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T., Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M., Semina, Elena V., Reuter, Miriam S., Scherer, Stephen W., Iascone, Maria, Weis, Denisa, Fagerberg, Christina R., Brasch-Andersen, Charlotte, Kjaersgaard Hansen, Lars, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B., Pavlidou, Despoina C., Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R., Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M., Lemke, Johannes R., Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, and Platzer, Konrad
Abstract: Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1+/− mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1+/− mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/− brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course.
Published: 2023

23. CUX1-related neurodevelopmental disorder:deep insights into phenotype-genotype spectrum and underlying pathology

Author: Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A, Gurnett, Christina A, Jelsig, Anne Marie, Vineke, Susanne H, Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T, Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M, Semina, Elena V, Reuter, Miriam S, Scherer, Stephen W, Iascone, Maria, Weis, Denisa, Fagerberg, Christina R, Brasch-Andersen, Charlotte, Hansen, Lars Kjaersgaard, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B, Pavlidou, Despoina C, Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R, Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M, Lemke, Johannes R, Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, Platzer, Konrad, Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A, Gurnett, Christina A, Jelsig, Anne Marie, Vineke, Susanne H, Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T, Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M, Semina, Elena V, Reuter, Miriam S, Scherer, Stephen W, Iascone, Maria, Weis, Denisa, Fagerberg, Christina R, Brasch-Andersen, Charlotte, Hansen, Lars Kjaersgaard, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B, Pavlidou, Despoina C, Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R, Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M, Lemke, Johannes R, Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, and Platzer, Konrad
Abstract: Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1+/− mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1+/− mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/− brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course., Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/- mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1+/- mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1+/- mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/- brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course.
Published: 2023

24. CUX1-related neurodevelopmental disorder:deep insights into phenotype-genotype spectrum and underlying pathology

Author: Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A, Gurnett, Christina A, Jelsig, Anne Marie, Vineke, Susanne H, Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T, Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M, Semina, Elena V, Reuter, Miriam S, Scherer, Stephen W, Iascone, Maria, Weis, Denisa, Fagerberg, Christina R, Brasch-Andersen, Charlotte, Hansen, Lars Kjaersgaard, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B, Pavlidou, Despoina C, Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R, Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M, Lemke, Johannes R, Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, Platzer, Konrad, Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A, Gurnett, Christina A, Jelsig, Anne Marie, Vineke, Susanne H, Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T, Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M, Semina, Elena V, Reuter, Miriam S, Scherer, Stephen W, Iascone, Maria, Weis, Denisa, Fagerberg, Christina R, Brasch-Andersen, Charlotte, Hansen, Lars Kjaersgaard, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B, Pavlidou, Despoina C, Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R, Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M, Lemke, Johannes R, Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, and Platzer, Konrad
Abstract: Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1+/− mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1+/− mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/− brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course., Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/- mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1+/- mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1+/- mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/- brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course.
Published: 2023

25. GestaltMML: Enhancing Rare Genetic Disease Diagnosis through Multimodal Machine Learning Combining Facial Images and Clinical Texts

Author: Wu, Da, Yang, Jingye, Liu, Cong, Hsieh, Tzung-Chien, Marchi, Elaine, Blair, Justin, Krawitz, Peter, Weng, Chunhua, Chung, Wendy, Lyon, Gholson J., Krantz, Ian D., Kalish, Jennifer M., Wang, Kai, Wu, Da, Yang, Jingye, Liu, Cong, Hsieh, Tzung-Chien, Marchi, Elaine, Blair, Justin, Krawitz, Peter, Weng, Chunhua, Chung, Wendy, Lyon, Gholson J., Krantz, Ian D., Kalish, Jennifer M., and Wang, Kai
Abstract: Individuals with suspected rare genetic disorders often undergo multiple clinical evaluations, imaging studies, laboratory tests and genetic tests, to find a possible answer over a prolonged period of time. Addressing this "diagnostic odyssey" thus has substantial clinical, psychosocial, and economic benefits. Many rare genetic diseases have distinctive facial features, which can be used by artificial intelligence algorithms to facilitate clinical diagnosis, in prioritizing candidate diseases to be further examined by lab tests or genetic assays, or in helping the phenotype-driven reinterpretation of genome/exome sequencing data. Existing methods using frontal facial photos were built on conventional Convolutional Neural Networks (CNNs), rely exclusively on facial images, and cannot capture non-facial phenotypic traits and demographic information essential for guiding accurate diagnoses. Here we introduce GestaltMML, a multimodal machine learning (MML) approach solely based on the Transformer architecture. It integrates facial images, demographic information (age, sex, ethnicity), and clinical notes (optionally, a list of Human Phenotype Ontology terms) to improve prediction accuracy. Furthermore, we also evaluated GestaltMML on a diverse range of datasets, including 528 diseases from the GestaltMatcher Database, several in-house datasets of Beckwith-Wiedemann syndrome (BWS, over-growth syndrome with distinct facial features), Sotos syndrome (overgrowth syndrome with overlapping features with BWS), NAA10-related neurodevelopmental syndrome, Cornelia de Lange syndrome (multiple malformation syndrome), and KBG syndrome (multiple malformation syndrome). Our results suggest that GestaltMML effectively incorporates multiple modalities of data, greatly narrowing candidate genetic diagnoses of rare diseases and may facilitate the reinterpretation of genome/exome sequencing data., Comment: Significant revisions
Published: 2023

26. The GA4GH Phenopacket schema defines a computable representation of clinical data

Author: Jacobsen, Julius OB, Jacobsen, Julius OB, Baudis, Michael, Baynam, Gareth S, Beckmann, Jacques S, Beltran, Sergi, Buske, Orion J, Callahan, Tiffany J, Chute, Christopher G, Courtot, Mélanie, Danis, Daniel, Elemento, Olivier, Essenwanger, Andrea, Freimuth, Robert R, Gargano, Michael A, Groza, Tudor, Hamosh, Ada, Harris, Nomi L, Kaliyaperumal, Rajaram, Lloyd, Kevin C Kent, Khalifa, Aly, Krawitz, Peter M, Köhler, Sebastian, Laraway, Brian J, Lehväslaiho, Heikki, Matalonga, Leslie, McMurry, Julie A, Metke-Jimenez, Alejandro, Mungall, Christopher J, Munoz-Torres, Monica C, Ogishima, Soichi, Papakonstantinou, Anastasios, Piscia, Davide, Pontikos, Nikolas, Queralt-Rosinach, Núria, Roos, Marco, Sass, Julian, Schofield, Paul N, Seelow, Dominik, Siapos, Anastasios, Smedley, Damian, Smith, Lindsay D, Steinhaus, Robin, Sundaramurthi, Jagadish Chandrabose, Swietlik, Emilia M, Thun, Sylvia, Vasilevsky, Nicole A, Wagner, Alex H, Warner, Jeremy L, Weiland, Claus, Haendel, Melissa A, Robinson, Peter N, Jacobsen, Julius OB, Jacobsen, Julius OB, Baudis, Michael, Baynam, Gareth S, Beckmann, Jacques S, Beltran, Sergi, Buske, Orion J, Callahan, Tiffany J, Chute, Christopher G, Courtot, Mélanie, Danis, Daniel, Elemento, Olivier, Essenwanger, Andrea, Freimuth, Robert R, Gargano, Michael A, Groza, Tudor, Hamosh, Ada, Harris, Nomi L, Kaliyaperumal, Rajaram, Lloyd, Kevin C Kent, Khalifa, Aly, Krawitz, Peter M, Köhler, Sebastian, Laraway, Brian J, Lehväslaiho, Heikki, Matalonga, Leslie, McMurry, Julie A, Metke-Jimenez, Alejandro, Mungall, Christopher J, Munoz-Torres, Monica C, Ogishima, Soichi, Papakonstantinou, Anastasios, Piscia, Davide, Pontikos, Nikolas, Queralt-Rosinach, Núria, Roos, Marco, Sass, Julian, Schofield, Paul N, Seelow, Dominik, Siapos, Anastasios, Smedley, Damian, Smith, Lindsay D, Steinhaus, Robin, Sundaramurthi, Jagadish Chandrabose, Swietlik, Emilia M, Thun, Sylvia, Vasilevsky, Nicole A, Wagner, Alex H, Warner, Jeremy L, Weiland, Claus, Haendel, Melissa A, and Robinson, Peter N
Published: 2022

27. Clinically relevant combined effect of polygenic background, rare pathogenic germline variants, and family history on colorectal cancer incidence 2022.01.20.22269585

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], Hassanin, Emadeldin, Spier, Isabel, Bobbili, Dheeraj Reddy, Aldisi, Rana, Klinkhammer, Hannah, David, Friederike, Dueñas, Nuria, Hüneburg, Robert, Perne, Claudia, Brunet, Joan, Capella, Gabriel, Nöthen, Markus M., Forstner, Andreas J., Mayr, Andreas, Krawitz, Peter, May, Patrick, Aretz, Stefan, Maj, Carlo, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], Hassanin, Emadeldin, Spier, Isabel, Bobbili, Dheeraj Reddy, Aldisi, Rana, Klinkhammer, Hannah, David, Friederike, Dueñas, Nuria, Hüneburg, Robert, Perne, Claudia, Brunet, Joan, Capella, Gabriel, Nöthen, Markus M., Forstner, Andreas J., Mayr, Andreas, Krawitz, Peter, May, Patrick, Aretz, Stefan, and Maj, Carlo
Abstract: Background and aims: Summarised in polygenic risk scores (PRS), the effect of common, low penetrant genetic variants associated with colorectal cancer (CRC), can be used for risk stratification.Methods To assess the combined impact of the PRS and other main factors on CRC risk, 163,516 individuals from the UK Biobank were stratified as follows: 1. carriers status for germline pathogenic variants (PV) in CRC susceptibility genes (APC, MLH1, MSH2, MSH6, PMS2), 2. low (<20%), intermediate (20-80%), or high PRS (>80\%), and 3. family history (FH) of CRC. Multivariable logistic regression and Cox proportional hazards models were applied to compare odds ratios (OR) and to compute the lifetime incidence, respectively. Results: Depending on the PRS, the CRC lifetime incidence for non-carriers ranges between 6 and 22\%, compared to 40 and 74 for carriers. A suspicious FH is associated with a further increase of the cumulative incidence reaching 26 for non-carriers and 98 for carriers. In non-carriers without FH, but high PRS, the CRC risk is doubled, whereas a low PRS even in the context of a FH results in a decreased risk. The full model including PRS, carrier status, and FH improved the area under the curve (AUC) in risk prediction (0.704). Conclusion: The findings demonstrate that CRC risks are strongly influenced by the PRS for both a sporadic and monogenic background. FH, PV, and common variants complementary contribute to CRC risk. The implementation of PRS in routine care will likely improve personalized risk stratification, which will in turn guide tailored preventive surveillance strategies in high, intermediate, and low risk groups.
Published: 2022

28. Clinically relevant combined effect of polygenic background, rare pathogenic germline variants, and family history on colorectal cancer incidence 2022.01.20.22269585

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], Hassanin, Emadeldin, Spier, Isabel, Bobbili, Dheeraj Reddy, Aldisi, Rana, Klinkhammer, Hannah, David, Friederike, Dueñas, Nuria, Hüneburg, Robert, Perne, Claudia, Brunet, Joan, Capella, Gabriel, Nöthen, Markus M., Forstner, Andreas J., Mayr, Andreas, Krawitz, Peter, May, Patrick, Aretz, Stefan, Maj, Carlo, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], Hassanin, Emadeldin, Spier, Isabel, Bobbili, Dheeraj Reddy, Aldisi, Rana, Klinkhammer, Hannah, David, Friederike, Dueñas, Nuria, Hüneburg, Robert, Perne, Claudia, Brunet, Joan, Capella, Gabriel, Nöthen, Markus M., Forstner, Andreas J., Mayr, Andreas, Krawitz, Peter, May, Patrick, Aretz, Stefan, and Maj, Carlo
Abstract: Background and aims: Summarised in polygenic risk scores (PRS), the effect of common, low penetrant genetic variants associated with colorectal cancer (CRC), can be used for risk stratification.Methods To assess the combined impact of the PRS and other main factors on CRC risk, 163,516 individuals from the UK Biobank were stratified as follows: 1. carriers status for germline pathogenic variants (PV) in CRC susceptibility genes (APC, MLH1, MSH2, MSH6, PMS2), 2. low (<20%), intermediate (20-80%), or high PRS (>80\%), and 3. family history (FH) of CRC. Multivariable logistic regression and Cox proportional hazards models were applied to compare odds ratios (OR) and to compute the lifetime incidence, respectively. Results: Depending on the PRS, the CRC lifetime incidence for non-carriers ranges between 6 and 22\%, compared to 40 and 74 for carriers. A suspicious FH is associated with a further increase of the cumulative incidence reaching 26 for non-carriers and 98 for carriers. In non-carriers without FH, but high PRS, the CRC risk is doubled, whereas a low PRS even in the context of a FH results in a decreased risk. The full model including PRS, carrier status, and FH improved the area under the curve (AUC) in risk prediction (0.704). Conclusion: The findings demonstrate that CRC risks are strongly influenced by the PRS for both a sporadic and monogenic background. FH, PV, and common variants complementary contribute to CRC risk. The implementation of PRS in routine care will likely improve personalized risk stratification, which will in turn guide tailored preventive surveillance strategies in high, intermediate, and low risk groups.
Published: 2022

29. Clinically relevant combined effect of polygenic background, rare pathogenic germline variants, and family history on colorectal cancer incidence 2022.01.20.22269585

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], Hassanin, Emadeldin, Spier, Isabel, Bobbili, Dheeraj Reddy, Aldisi, Rana, Klinkhammer, Hannah, David, Friederike, Dueñas, Nuria, Hüneburg, Robert, Perne, Claudia, Brunet, Joan, Capella, Gabriel, Nöthen, Markus M., Forstner, Andreas J., Mayr, Andreas, Krawitz, Peter, May, Patrick, Aretz, Stefan, Maj, Carlo, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], Hassanin, Emadeldin, Spier, Isabel, Bobbili, Dheeraj Reddy, Aldisi, Rana, Klinkhammer, Hannah, David, Friederike, Dueñas, Nuria, Hüneburg, Robert, Perne, Claudia, Brunet, Joan, Capella, Gabriel, Nöthen, Markus M., Forstner, Andreas J., Mayr, Andreas, Krawitz, Peter, May, Patrick, Aretz, Stefan, and Maj, Carlo
Abstract: Background and aims: Summarised in polygenic risk scores (PRS), the effect of common, low penetrant genetic variants associated with colorectal cancer (CRC), can be used for risk stratification.Methods To assess the combined impact of the PRS and other main factors on CRC risk, 163,516 individuals from the UK Biobank were stratified as follows: 1. carriers status for germline pathogenic variants (PV) in CRC susceptibility genes (APC, MLH1, MSH2, MSH6, PMS2), 2. low (<20%), intermediate (20-80%), or high PRS (>80\%), and 3. family history (FH) of CRC. Multivariable logistic regression and Cox proportional hazards models were applied to compare odds ratios (OR) and to compute the lifetime incidence, respectively. Results: Depending on the PRS, the CRC lifetime incidence for non-carriers ranges between 6 and 22\%, compared to 40 and 74 for carriers. A suspicious FH is associated with a further increase of the cumulative incidence reaching 26 for non-carriers and 98 for carriers. In non-carriers without FH, but high PRS, the CRC risk is doubled, whereas a low PRS even in the context of a FH results in a decreased risk. The full model including PRS, carrier status, and FH improved the area under the curve (AUC) in risk prediction (0.704). Conclusion: The findings demonstrate that CRC risks are strongly influenced by the PRS for both a sporadic and monogenic background. FH, PV, and common variants complementary contribute to CRC risk. The implementation of PRS in routine care will likely improve personalized risk stratification, which will in turn guide tailored preventive surveillance strategies in high, intermediate, and low risk groups.
Published: 2022

30. Assessment of the Genetic Spectrum of Uncombable Hair Syndrome in a Cohort of 107 Individuals

Author: Basmanav, F. Buket, Cesarato, Nicole, Kumar, Sheetal, Borisov, Oleg, Kokordelis, Pavlos, Ralser, Damian J., Wehner, Maria, Axt, Daisy, Xiong, Xing, Thiele, Holger, Dolgin, Vadim, Gossmann, Yasmina, Fricker, Nadine, Dewenter, Malin Katharina, Weller, Karsten, Suri, Mohnish, Reichenbach, Herbert, Oji, Vinzenz, Addor, Marie-Claude, Ramirez, Karla, Stewart, Helen, Bartels, Natalie Garcia, Weibel, Lisa, Wagner, Nicola, George, Susannah, Kilic, Arzu, Tantcheva-Poor, Iliana, Stewart, Alison, Dikow, Nicola, Blaumeiser, Bettina, Medvecz, Marta, Blume-Peytavi, Ulrike, Farrant, Paul, Grimalt, Ramon, Bertok, Sara, Bradley, Lisa, Eskin-Schwartz, Marina, Birk, Ohad Samuel, Bygum, Anette, Simon, Michel, Krawitz, Peter, Fischer, Christine, Hamm, Henning, Fritz, Gunter, Betz, Regina C., Basmanav, F. Buket, Cesarato, Nicole, Kumar, Sheetal, Borisov, Oleg, Kokordelis, Pavlos, Ralser, Damian J., Wehner, Maria, Axt, Daisy, Xiong, Xing, Thiele, Holger, Dolgin, Vadim, Gossmann, Yasmina, Fricker, Nadine, Dewenter, Malin Katharina, Weller, Karsten, Suri, Mohnish, Reichenbach, Herbert, Oji, Vinzenz, Addor, Marie-Claude, Ramirez, Karla, Stewart, Helen, Bartels, Natalie Garcia, Weibel, Lisa, Wagner, Nicola, George, Susannah, Kilic, Arzu, Tantcheva-Poor, Iliana, Stewart, Alison, Dikow, Nicola, Blaumeiser, Bettina, Medvecz, Marta, Blume-Peytavi, Ulrike, Farrant, Paul, Grimalt, Ramon, Bertok, Sara, Bradley, Lisa, Eskin-Schwartz, Marina, Birk, Ohad Samuel, Bygum, Anette, Simon, Michel, Krawitz, Peter, Fischer, Christine, Hamm, Henning, Fritz, Gunter, and Betz, Regina C.
Abstract: Importance Uncombable hair syndrome (UHS) is a rare hair shaft anomaly that manifests during infancy and is characterized by dry, frizzy, and wiry hair that cannot be combed flat. Only about 100 known cases have been reported so far. Objective To elucidate the genetic spectrum of UHS. Design, Setting, and Participants This cohort study includes 107 unrelated index patients with a suspected diagnosis of UHS and family members who were recruited worldwide from January 2013 to December 2021. Participants of all ages, races, and ethnicities were recruited at referral centers or were enrolled on their own initiative following personal contact with the authors. Genetic analyses were conducted in Germany from January 2014 to December 2021. Main Outcomes and Measures Clinical photographs, Sanger or whole-exome sequencing and array-based genotyping of DNA extracted from blood or saliva samples, and 3-dimensional protein modeling. Descriptive statistics, such as frequency counts, were used to describe the distribution of identified pathogenic variants and genotypes. Results The genetic characteristics of patients with UHS were established in 80 of 107 (74.8%) index patients (82 [76.6%] female) who carried biallelic pathogenic variants in PADI3, TGM3, or TCHH (ie, genes that encode functionally related hair shaft proteins). Molecular genetic findings from 11 of these 80 individuals were previously published. In 76 (71.0%) individuals, the UHS phenotype were associated with pathogenic variants in PADI3. The 2 most commonly observed PADI3 variants account for 73 (48.0%) and 57 (37.5%) of the 152 variant PADI3 alleles in total, respectively. Two individuals carried pathogenic variants in TGM3, and 2 others carried pathogenic variants in TCHH. Haplotype analyses suggested a founder effect for the 4 most commonly observed pathogenic variants in the PADI3 gene. Conclusions and Relevance This cohort study extends and gives an overview of the genetic variant spectrum of UHS based on m
Published: 2022

31. De novo variants of CSNK2B cause a new intellectual disability-craniodigital syndrome by disrupting the canonical Wnt signaling pathway

Author: Asif, Maria, Kaygusuz, Emrah, Shinawi, Marwan, Nickelsen, Anna, Hsieh, Tzung-Chien, Wagle, Prerana, Budde, Birgit S., Hochscherf, Jennifer, Abdullah, Uzma, Honing, Stefan, Nienberg, Christian, Lindenblatt, Dirk, Noegel, Angelika A., Altmuller, Janine, Thiele, Holger, Motameny, Susanne, Fleischer, Nicole, Segal, Idan, Pais, Lynn, Tinschert, Sigrid, Samra, Nadra Nasser, Savatt, Juliann M., Rudy, Natasha L., De Luca, Chiara, Fortugno, Paola, White, Susan M., Krawitz, Peter, Hurst, Anna C. E., Niefind, Karsten, Jose, Joachim, Brancati, Francesco, Nurnberg, Peter, Hussain, Muhammad Sajid, Asif, Maria, Kaygusuz, Emrah, Shinawi, Marwan, Nickelsen, Anna, Hsieh, Tzung-Chien, Wagle, Prerana, Budde, Birgit S., Hochscherf, Jennifer, Abdullah, Uzma, Honing, Stefan, Nienberg, Christian, Lindenblatt, Dirk, Noegel, Angelika A., Altmuller, Janine, Thiele, Holger, Motameny, Susanne, Fleischer, Nicole, Segal, Idan, Pais, Lynn, Tinschert, Sigrid, Samra, Nadra Nasser, Savatt, Juliann M., Rudy, Natasha L., De Luca, Chiara, Fortugno, Paola, White, Susan M., Krawitz, Peter, Hurst, Anna C. E., Niefind, Karsten, Jose, Joachim, Brancati, Francesco, Nurnberg, Peter, and Hussain, Muhammad Sajid
Abstract: CSNK2B encodes for casein kinase II subunit beta (CK2 beta), the regulatory subunit of casein kinase II (CK2), which is known to mediate diverse cellular pathways. Variants in this gene have been recently identified as a cause of Poirier-Bienvenu neurodevelopmental syndrome (POBINDS), but functional evidence is sparse. Here, we report five unrelated individuals: two of them manifesting POBINDS, while three are identified to segregate a new intellectual disability-craniodigital syndrome (IDCS), distinct from POBINDS. The three IDCS individuals carried two different de novo missense variants affecting the same codon of CSNK2B. Both variants, NP_001311.3; p.Asp32His and NP_001311.3; p.Asp32Asn, lead to an upregulation of CSNK2B expression at transcript and protein level, along with global dysregulation of canonical Wnt signaling. We found impaired interaction of the two key players DVL3 and beta-catenin with mutated CK2f3. The variants compromise the kinase activity of CK2 as evident by a marked reduction of phosphorylated beta-catenin and consequent absence of active beta-catenin inside nuclei of the patient-derived lymphoblastoid cell lines (LCLs). In line with these findings, whole-transcriptome profiling of patient-derived LCLs harboring the NP_001311.3; p.Asp32His variant confirmed a marked difference in expression of genes involved in the Wnt signaling pathway. In addition, whole-phosphoproteome analysis of the LCLs of the same subject showed absence of phosphorylation for 313 putative CK2 substrates, enriched in the regulation of nuclear beta-catenin and transcription of the target genes. Our findings suggest that discrete variants in CSNK2B cause dominant-negative perturbation of the canonical Wnt signaling pathway, leading to a new craniodigital syndrome distinguishable from POBINDS.
Published: 2022

32. Clinical, Brain, and Multilevel Clustering in Early Psychosis and Affective Stages

Author: Dwyer, Dominic B., Buciuman, Madalina-Octavia, Ruef, Anne, Kambeitz, Joseph, Sen Dong, Mark, Stinson, Caedyn, Kambeitz-Ilankovic, Lana, Degenhardt, Franziska, Sanfelici, Rachele, Antonucci, Linda A., Lalousis, Paris Alexandros, Wenzel, Julian, Urquijo-Castro, Maria Fernanda, Popovic, David, Oeztuerk, Oemer Faruk, Haas, Shalaila S., Weiske, Johanna, Hauke, Daniel, Neufang, Susanne, Schmidt-Kraepelin, Christian, Ruhrmann, Stephan, Penzel, Nora, Lichtenstein, Theresa, Rosen, Marlene, Chisholm, Katharine, Riecher-Roessler, Anita, Egloff, Laura, Schmidt, Andre, Andreou, Christina, Hietala, Jarmo, Schirmer, Timo, Romer, Georg, Michel, Chantal, Rossler, Wulf, Maj, Carlo, Borisov, Oleg, Krawitz, Peter M., Falkai, Peter, Pantelis, Christos, Lencer, Rebekka, Bertolino, Alessandro, Borgwardt, Stefan, Noethen, Markus, Brambilla, Paolo, Schultze-Lutter, Frauke, Meisenzahl, Eva, Wood, Stephen J., Davatzikos, Christos, Upthegrove, Rachel, Salokangas, Raimo K. R., Koutsouleris, Nikolaos, Dwyer, Dominic B., Buciuman, Madalina-Octavia, Ruef, Anne, Kambeitz, Joseph, Sen Dong, Mark, Stinson, Caedyn, Kambeitz-Ilankovic, Lana, Degenhardt, Franziska, Sanfelici, Rachele, Antonucci, Linda A., Lalousis, Paris Alexandros, Wenzel, Julian, Urquijo-Castro, Maria Fernanda, Popovic, David, Oeztuerk, Oemer Faruk, Haas, Shalaila S., Weiske, Johanna, Hauke, Daniel, Neufang, Susanne, Schmidt-Kraepelin, Christian, Ruhrmann, Stephan, Penzel, Nora, Lichtenstein, Theresa, Rosen, Marlene, Chisholm, Katharine, Riecher-Roessler, Anita, Egloff, Laura, Schmidt, Andre, Andreou, Christina, Hietala, Jarmo, Schirmer, Timo, Romer, Georg, Michel, Chantal, Rossler, Wulf, Maj, Carlo, Borisov, Oleg, Krawitz, Peter M., Falkai, Peter, Pantelis, Christos, Lencer, Rebekka, Bertolino, Alessandro, Borgwardt, Stefan, Noethen, Markus, Brambilla, Paolo, Schultze-Lutter, Frauke, Meisenzahl, Eva, Wood, Stephen J., Davatzikos, Christos, Upthegrove, Rachel, Salokangas, Raimo K. R., and Koutsouleris, Nikolaos
Abstract: IMPORTANCE Approaches are needed to stratify individuals in early psychosis stages beyond positive symptom severity to investigate specificity related to affective and normative variation and to validate solutions with premorbid, longitudinal, and genetic risk measures. OBJECTIVE To use machine learning techniques to cluster, compare, and combine subgroup solutions using clinical and brain structural imaging data from early psychosis and depression stages. DESIGN, SETTING, AND PARTICIPANTS A multisite, naturalistic, longitudinal cohort study (10 sites in 5 European countries; including major follow-up intervals at 9 and 18 months) with a referred patient sample of those with clinical high risk for psychosis (CHR-P), recent-onset psychosis (ROP), recent-onset depression (ROD), and healthy controls were recruited between February 1, 2014, to July 1, 2019. Data were analyzed between January 2020 and January 2022. MAIN OUTCOMES AND MEASURES A nonnegative matrix factorization technique separately decomposed clinical (287 variables) and parcellated brain structural volume (204 gray, white, and cerebrospinal fluid regions) data across CHR-P, ROP, ROD, and healthy controls study groups. Stability criteria determined cluster number using nested cross-validation. Validation targets were compared across subgroup solutions (premorbid, longitudinal, and schizophrenia polygenic risk scores). Multiclass supervised machine learning produced a transferable solution to the validation sample. RESULTS There were a total of 749 individuals in the discovery group and 610 individuals in the validation group. Individuals included those with CHR-P (n = 287), ROP (n = 323), ROD (n = 285), and healthy controls (n = 464), The mean (SD) age was 25.1 (5.9) years, and 702 (51.7%) were female. A clinical 4-dimensional solution separated individuals based on positive symptoms, negative symptoms, depression, and functioning, demonstrating associations with all validation targets. Brain clustering re
Published: 2022

33. Improving Deep Facial Phenotyping for Ultra-rare Disorder Verification Using Model Ensembles

Author: Hustinx, Alexander, Hellmann, Fabio, Sümer, Ömer, Javanmardi, Behnam, André, Elisabeth, Krawitz, Peter, Hsieh, Tzung-Chien, Hustinx, Alexander, Hellmann, Fabio, Sümer, Ömer, Javanmardi, Behnam, André, Elisabeth, Krawitz, Peter, and Hsieh, Tzung-Chien
Abstract: Rare genetic disorders affect more than 6% of the global population. Reaching a diagnosis is challenging because rare disorders are very diverse. Many disorders have recognizable facial features that are hints for clinicians to diagnose patients. Previous work, such as GestaltMatcher, utilized representation vectors produced by a DCNN similar to AlexNet to match patients in high-dimensional feature space to support "unseen" ultra-rare disorders. However, the architecture and dataset used for transfer learning in GestaltMatcher have become outdated. Moreover, a way to train the model for generating better representation vectors for unseen ultra-rare disorders has not yet been studied. Because of the overall scarcity of patients with ultra-rare disorders, it is infeasible to directly train a model on them. Therefore, we first analyzed the influence of replacing GestaltMatcher DCNN with a state-of-the-art face recognition approach, iResNet with ArcFace. Additionally, we experimented with different face recognition datasets for transfer learning. Furthermore, we proposed test-time augmentation, and model ensembles that mix general face verification models and models specific for verifying disorders to improve the disorder verification accuracy of unseen ultra-rare disorders. Our proposed ensemble model achieves state-of-the-art performance on both seen and unseen disorders.
Published: 2022
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34. Few-Shot Meta Learning for Recognizing Facial Phenotypes of Genetic Disorders

Author: Sümer, Ömer, Hellmann, Fabio, Hustinx, Alexander, Hsieh, Tzung-Chien, André, Elisabeth, Krawitz, Peter, Sümer, Ömer, Hellmann, Fabio, Hustinx, Alexander, Hsieh, Tzung-Chien, André, Elisabeth, and Krawitz, Peter
Abstract: Computer vision-based methods have valuable use cases in precision medicine, and recognizing facial phenotypes of genetic disorders is one of them. Many genetic disorders are known to affect faces' visual appearance and geometry. Automated classification and similarity retrieval aid physicians in decision-making to diagnose possible genetic conditions as early as possible. Previous work has addressed the problem as a classification problem and used deep learning methods. The challenging issue in practice is the sparse label distribution and huge class imbalances across categories. Furthermore, most disorders have few labeled samples in training sets, making representation learning and generalization essential to acquiring a reliable feature descriptor. In this study, we used a facial recognition model trained on a large corpus of healthy individuals as a pre-task and transferred it to facial phenotype recognition. Furthermore, we created simple baselines of few-shot meta-learning methods to improve our base feature descriptor. Our quantitative results on GestaltMatcher Database show that our CNN baseline surpasses previous works, including GestaltMatcher, and few-shot meta-learning strategies improve retrieval performance in frequent and rare classes., Comment: This paper is accepted for publication at MIE 2023 Conference
Published: 2022
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35. Cross-tissue transcriptome-wide association studies identify susceptibility genes shared between schizophrenia and inflammatory bowel disease

Author: Uellendahl-Werth, Florian, Maj, Carlo, Borisov, Oleg, Juzenas, Simonas, Wacker, Eike Matthias, Jorgensen, Isabella Friis, Steiert, Tim Alexander, Bej, Saptarshi, Krawitz, Peter, Hoffmann, Per, Schramm, Christoph, Wolkenhauer, Olaf, Banasik, Karina, Brunak, Søren, Schreiber, Stefan, Karlsen, Tom Hemming, Degenhardt, Franziska, Noethen, Markus, Franke, Andre, Folseraas, Trine, Ellinghaus, David, Uellendahl-Werth, Florian, Maj, Carlo, Borisov, Oleg, Juzenas, Simonas, Wacker, Eike Matthias, Jorgensen, Isabella Friis, Steiert, Tim Alexander, Bej, Saptarshi, Krawitz, Peter, Hoffmann, Per, Schramm, Christoph, Wolkenhauer, Olaf, Banasik, Karina, Brunak, Søren, Schreiber, Stefan, Karlsen, Tom Hemming, Degenhardt, Franziska, Noethen, Markus, Franke, Andre, Folseraas, Trine, and Ellinghaus, David
Published: 2022

36. Cross-tissue transcriptome-wide association studies identify susceptibility genes shared between schizophrenia and inflammatory bowel disease

Author: Uellendahl-Werth, Florian, Maj, Carlo, Borisov, Oleg, Juzenas, Simonas, Wacker, Eike Matthias, Jorgensen, Isabella Friis, Steiert, Tim Alexander, Bej, Saptarshi, Krawitz, Peter, Hoffmann, Per, Schramm, Christoph, Wolkenhauer, Olaf, Banasik, Karina, Brunak, Søren, Schreiber, Stefan, Karlsen, Tom Hemming, Degenhardt, Franziska, Noethen, Markus, Franke, Andre, Folseraas, Trine, Ellinghaus, David, Uellendahl-Werth, Florian, Maj, Carlo, Borisov, Oleg, Juzenas, Simonas, Wacker, Eike Matthias, Jorgensen, Isabella Friis, Steiert, Tim Alexander, Bej, Saptarshi, Krawitz, Peter, Hoffmann, Per, Schramm, Christoph, Wolkenhauer, Olaf, Banasik, Karina, Brunak, Søren, Schreiber, Stefan, Karlsen, Tom Hemming, Degenhardt, Franziska, Noethen, Markus, Franke, Andre, Folseraas, Trine, and Ellinghaus, David
Published: 2022

37. Extending the allelic spectrum at noncoding risk loci of orofacial clefting

Author: Thieme, Frederic, Henschel, Leonie, Hammond, Nigel L., Ishorst, Nina, Hausen, Jonas, Adamson, Antony D., Biedermann, Angelika, Bowes, John, Zieger, Hanna K., Maj, Carlo, Kruse, Teresa, Buness, Andreas, Hoischen, Alexander, Gilissen, Christian, Kreusch, Thomas, Jaeger, Andreas, Goelz, Lina, Braumann, Bert, Aldhorae, Khalid, Rojas-Martinez, Augusto, Krawitz, Peter M., Mangold, Elisabeth, Dixon, Michael J., Ludwig, Kerstin U., Thieme, Frederic, Henschel, Leonie, Hammond, Nigel L., Ishorst, Nina, Hausen, Jonas, Adamson, Antony D., Biedermann, Angelika, Bowes, John, Zieger, Hanna K., Maj, Carlo, Kruse, Teresa, Buness, Andreas, Hoischen, Alexander, Gilissen, Christian, Kreusch, Thomas, Jaeger, Andreas, Goelz, Lina, Braumann, Bert, Aldhorae, Khalid, Rojas-Martinez, Augusto, Krawitz, Peter M., Mangold, Elisabeth, Dixon, Michael J., and Ludwig, Kerstin U.
Abstract: Genome-wide association studies (GWAS) have generated unprecedented insights into the genetic etiology of orofacial clefting (OFC). The moderate effect sizes of associated noncoding risk variants and limited access to disease-relevant tissue represent considerable challenges for biological interpretation of genetic findings. As rare variants with stronger effect sizes are likely to also contribute to OFC, an alternative approach to delineate pathogenic mechanisms is to identify private mutations and/or an increased burden of rare variants in associated regions. This report describes a framework for targeted resequencing at selected noncoding risk loci contributing to nonsyndromic cleft lip with/without cleft palate (nsCL/P), the most frequent OFC subtype. Based on GWAS data, we selected three risk loci and identified candidate regulatory regions (CRRs) through the integration of credible SNP information, epigenetic data from relevant cells/tissues, and conservation scores. The CRRs (total 57 kb) were resequenced in a multiethnic study population (1061 patients; 1591 controls), using single-molecule molecular inversion probe technology. Combining evidence from in silico variant annotation, pedigree- and burden analyses, we identified 16 likely deleterious rare variants that represent new candidates for functional studies in nsCL/P. Our framework is scalable and represents a promising approach to the investigation of additional congenital malformations with multifactorial etiology.
Published: 2021

38. Assessing the role of polygenic background on the penetrance of monogenic forms in Parkinson\textquoterights disease. 2021.06.06.21253270

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], The FNR supported P.M. as part of the National Centre of Excellence in Research on Parkinson's disease (NCER-PD, FNR11264123) and the DFG Research Units FOR2715 (INTER/DFG/17/11583046) and FOR2488 (INTER/DFG/19/14429377) [sponsor], Hassanin, Emadeldin, May, Patrick, Aldisi, Rana, Krawitz, Peter, Maj, Carlo, Bobbili, Dheeraj Reddy, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], The FNR supported P.M. as part of the National Centre of Excellence in Research on Parkinson's disease (NCER-PD, FNR11264123) and the DFG Research Units FOR2715 (INTER/DFG/17/11583046) and FOR2488 (INTER/DFG/19/14429377) [sponsor], Hassanin, Emadeldin, May, Patrick, Aldisi, Rana, Krawitz, Peter, Maj, Carlo, and Bobbili, Dheeraj Reddy
Abstract: Background: Several rare and common variants are associated with Parkinson's disease. However, there is still an incomplete penetrance in the carriers of rare variants associated with Parkinson's disease. To address this issue, we investigated whether a PRS calculated from significant GWAS SNPs affects the penetrance of Parkinson's disease among carriers of rare monogenic variants in known Parkinson's disease genes and those with a family history. Methods: We calculated the PRS based on common variants and selected the carriers of rare monogenic variants by using the exome data from UK Biobank. Individuals were divided into three risk categories based on PRS: low (<10%), intermediate (10%-90%), and high (>90%) risk groups. We then compared how PRS affects Parkinson\textquoterights disease risk among carriers of rare monogenic variants and those with family-history. Results: We observed a two-fold higher odds ratio for a carrier of a monogenic variant that had a high PRS (OR 4.07,95\% CI, 1.72-8.08) compared to carriers with a low PRS (OR 1.91, 95\% CI, 0.31-6.05). In the same line, carriers with a first-degree family history and with \>90\% PRS have even a higher risk of developing PD (OR 23.53, 95\%CI 5.39-71.54) compared to those with \<90\% PRS (OR 9.54, 95\% CI 3.32-21.65). Conclusions: Our results show that PRS, carrier status, and family history contribute independently and additively to the Parkinson's disease risk.
Published: 2021

39. Breast and prostate cancer risk: the interplay of polygenic risk, high-impact monogenic variants, and family history 2021.06.04.21258277

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], The FNR supported P.M. as part of the National Centre of Excellence in Research on Parkinson's disease (NCER-PD, FNR11264123) and the DFG Research Units FOR2715 (INTER/DFG/17/11583046) and FOR2488 (INTER/DFG/19/14429377) [sponsor], Hassanin, Emadeldin, May, Patrick, Aldisi, Rana, Spier, Isabel, Forstner, Andreas J., Nothen, Markus M., Aretz, Stefan, Krawitz, Peter, Bobbili, Dheeraj Reddy, Maj, Carlo, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], The FNR supported P.M. as part of the National Centre of Excellence in Research on Parkinson's disease (NCER-PD, FNR11264123) and the DFG Research Units FOR2715 (INTER/DFG/17/11583046) and FOR2488 (INTER/DFG/19/14429377) [sponsor], Hassanin, Emadeldin, May, Patrick, Aldisi, Rana, Spier, Isabel, Forstner, Andreas J., Nothen, Markus M., Aretz, Stefan, Krawitz, Peter, Bobbili, Dheeraj Reddy, and Maj, Carlo
Abstract: Purpose: Investigate to which extent polygenic risk scores (PRS), high-impact monogenic variants, and family history affect breast and prostate cancer risk by assessing cancer prevalence and cancer cumulative lifetime incidence. Methods 200,643 individuals from the UK Biobank were stratified as follows: 1. carriers or non-carriers of high impact constitutive, monogenic variants in cancer susceptibility genes, 2. high or non-high PRS (90th percentile threshold), 3. with or without a family history of cancer. Multivariable logistic regression was used to compare the odds ratio (OR) across the different groups while Cox proportional hazards models were used to compute the cumulative incidence through life. Results Breast and prostate cancer cumulative incidence by age 70 is 7 and 5 for non-carriers with non-high PRS and reaches 37 and 32 among carriers of high-impact variants in cancer susceptibility genes with high PRS. The additional presence of family history is associated with a further increase of the risk of developing cancer reaching an OR of 14 and 21 for breast and prostate cancer, respectively. Conclusion: High PRS confers a cancer risk comparable to high-impact monogenic variants. Family history, monogenic variants, and PRS contribute additively to breast and prostate cancer risk.
Published: 2021

40. Assessing the role of polygenic background on the penetrance of monogenic forms in Parkinson\textquoterights disease. 2021.06.06.21253270

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], The FNR supported P.M. as part of the National Centre of Excellence in Research on Parkinson's disease (NCER-PD, FNR11264123) and the DFG Research Units FOR2715 (INTER/DFG/17/11583046) and FOR2488 (INTER/DFG/19/14429377) [sponsor], Hassanin, Emadeldin, May, Patrick, Aldisi, Rana, Krawitz, Peter, Maj, Carlo, Bobbili, Dheeraj Reddy, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], The FNR supported P.M. as part of the National Centre of Excellence in Research on Parkinson's disease (NCER-PD, FNR11264123) and the DFG Research Units FOR2715 (INTER/DFG/17/11583046) and FOR2488 (INTER/DFG/19/14429377) [sponsor], Hassanin, Emadeldin, May, Patrick, Aldisi, Rana, Krawitz, Peter, Maj, Carlo, and Bobbili, Dheeraj Reddy
Abstract: Background: Several rare and common variants are associated with Parkinson's disease. However, there is still an incomplete penetrance in the carriers of rare variants associated with Parkinson's disease. To address this issue, we investigated whether a PRS calculated from significant GWAS SNPs affects the penetrance of Parkinson's disease among carriers of rare monogenic variants in known Parkinson's disease genes and those with a family history. Methods: We calculated the PRS based on common variants and selected the carriers of rare monogenic variants by using the exome data from UK Biobank. Individuals were divided into three risk categories based on PRS: low (<10%), intermediate (10%-90%), and high (>90%) risk groups. We then compared how PRS affects Parkinson\textquoterights disease risk among carriers of rare monogenic variants and those with family-history. Results: We observed a two-fold higher odds ratio for a carrier of a monogenic variant that had a high PRS (OR 4.07,95\% CI, 1.72-8.08) compared to carriers with a low PRS (OR 1.91, 95\% CI, 0.31-6.05). In the same line, carriers with a first-degree family history and with \>90\% PRS have even a higher risk of developing PD (OR 23.53, 95\%CI 5.39-71.54) compared to those with \<90\% PRS (OR 9.54, 95\% CI 3.32-21.65). Conclusions: Our results show that PRS, carrier status, and family history contribute independently and additively to the Parkinson's disease risk.
Published: 2021

41. Breast and prostate cancer risk: the interplay of polygenic risk, rare pathogenic germline variants, and family history

Author: Fonds National de la Recherche - FnR [sponsor], Hassanin, Emadeldin, May, Patrick, Aldisi, Rana, Spier, Isabel, Forstner, Andreas J., Nöthen, Markus M., Aretz, Stefan, Krawitz, Peter, Bobbili, Dheeraj Reddy, Maj, Carlo, Fonds National de la Recherche - FnR [sponsor], Hassanin, Emadeldin, May, Patrick, Aldisi, Rana, Spier, Isabel, Forstner, Andreas J., Nöthen, Markus M., Aretz, Stefan, Krawitz, Peter, Bobbili, Dheeraj Reddy, and Maj, Carlo
Abstract: Purpose Investigate to which extent polygenic risk scores (PRS), pathogenic or likely rare pathogenic germline variants (PV), and family history jointly influence breast and prostate cancer risk. Methods 200,643 individuals from the UK Biobank were stratified as follows: 1. Heterozygotes or non-heterozygotes of PV in moderate to high cancer risk genes, 2. PRS strata, 3. with or without a family history of cancer. Multivariable logistic regression and Cox proportional hazards models were used to compute the odds ratio (OR) across groups and the cumulative incidence through life. Results Cumulative incidence by age 70 among non-heterozygotes across PRS strata ranged from 9% to 32% and from 9% to 35% for breast and prostate cancer, respectively. Among PV heterozygotes it ranged from 20% to 48% in moderate-risk genes and from 51% to 74% in high-risk genes for breast cancer, and it ranged from 30% to 59% in prostate cancer risk genes. Family history is always associated with an increased cancer OR. Conclusion PRS provides a meaningful risk gradient leading alone to a cancer risk comparable to PV in moderate risk genes while acting as risk modifier for high-risk genes. Including family history beside PV and PRS further improves cancer risk stratification.
Published: 2021

42. Breast and prostate cancer risk: the interplay of polygenic risk, rare pathogenic germline variants, and family history

Author: Fonds National de la Recherche - FnR [sponsor], Hassanin, Emadeldin, May, Patrick, Aldisi, Rana, Spier, Isabel, Forstner, Andreas J., Nöthen, Markus M., Aretz, Stefan, Krawitz, Peter, Bobbili, Dheeraj Reddy, Maj, Carlo, Fonds National de la Recherche - FnR [sponsor], Hassanin, Emadeldin, May, Patrick, Aldisi, Rana, Spier, Isabel, Forstner, Andreas J., Nöthen, Markus M., Aretz, Stefan, Krawitz, Peter, Bobbili, Dheeraj Reddy, and Maj, Carlo
Abstract: Purpose Investigate to which extent polygenic risk scores (PRS), pathogenic or likely rare pathogenic germline variants (PV), and family history jointly influence breast and prostate cancer risk. Methods 200,643 individuals from the UK Biobank were stratified as follows: 1. Heterozygotes or non-heterozygotes of PV in moderate to high cancer risk genes, 2. PRS strata, 3. with or without a family history of cancer. Multivariable logistic regression and Cox proportional hazards models were used to compute the odds ratio (OR) across groups and the cumulative incidence through life. Results Cumulative incidence by age 70 among non-heterozygotes across PRS strata ranged from 9% to 32% and from 9% to 35% for breast and prostate cancer, respectively. Among PV heterozygotes it ranged from 20% to 48% in moderate-risk genes and from 51% to 74% in high-risk genes for breast cancer, and it ranged from 30% to 59% in prostate cancer risk genes. Family history is always associated with an increased cancer OR. Conclusion PRS provides a meaningful risk gradient leading alone to a cancer risk comparable to PV in moderate risk genes while acting as risk modifier for high-risk genes. Including family history beside PV and PRS further improves cancer risk stratification.
Published: 2021

43. Breast and prostate cancer risk: the interplay of polygenic risk, rare pathogenic germline variants, and family history

Author: Fonds National de la Recherche - FnR [sponsor], Hassanin, Emadeldin, May, Patrick, Aldisi, Rana, Spier, Isabel, Forstner, Andreas J., Nöthen, Markus M., Aretz, Stefan, Krawitz, Peter, Bobbili, Dheeraj Reddy, Maj, Carlo, Fonds National de la Recherche - FnR [sponsor], Hassanin, Emadeldin, May, Patrick, Aldisi, Rana, Spier, Isabel, Forstner, Andreas J., Nöthen, Markus M., Aretz, Stefan, Krawitz, Peter, Bobbili, Dheeraj Reddy, and Maj, Carlo
Abstract: Purpose Investigate to which extent polygenic risk scores (PRS), pathogenic or likely rare pathogenic germline variants (PV), and family history jointly influence breast and prostate cancer risk. Methods 200,643 individuals from the UK Biobank were stratified as follows: 1. Heterozygotes or non-heterozygotes of PV in moderate to high cancer risk genes, 2. PRS strata, 3. with or without a family history of cancer. Multivariable logistic regression and Cox proportional hazards models were used to compute the odds ratio (OR) across groups and the cumulative incidence through life. Results Cumulative incidence by age 70 among non-heterozygotes across PRS strata ranged from 9% to 32% and from 9% to 35% for breast and prostate cancer, respectively. Among PV heterozygotes it ranged from 20% to 48% in moderate-risk genes and from 51% to 74% in high-risk genes for breast cancer, and it ranged from 30% to 59% in prostate cancer risk genes. Family history is always associated with an increased cancer OR. Conclusion PRS provides a meaningful risk gradient leading alone to a cancer risk comparable to PV in moderate risk genes while acting as risk modifier for high-risk genes. Including family history beside PV and PRS further improves cancer risk stratification.
Published: 2021

44. Breast and prostate cancer risk: the interplay of polygenic risk, rare pathogenic germline variants, and family history

Author: Fonds National de la Recherche - FnR [sponsor], Hassanin, Emadeldin, May, Patrick, Aldisi, Rana, Spier, Isabel, Forstner, Andreas J., Nöthen, Markus M., Aretz, Stefan, Krawitz, Peter, Bobbili, Dheeraj Reddy, Maj, Carlo, Fonds National de la Recherche - FnR [sponsor], Hassanin, Emadeldin, May, Patrick, Aldisi, Rana, Spier, Isabel, Forstner, Andreas J., Nöthen, Markus M., Aretz, Stefan, Krawitz, Peter, Bobbili, Dheeraj Reddy, and Maj, Carlo
Abstract: Purpose Investigate to which extent polygenic risk scores (PRS), pathogenic or likely rare pathogenic germline variants (PV), and family history jointly influence breast and prostate cancer risk. Methods 200,643 individuals from the UK Biobank were stratified as follows: 1. Heterozygotes or non-heterozygotes of PV in moderate to high cancer risk genes, 2. PRS strata, 3. with or without a family history of cancer. Multivariable logistic regression and Cox proportional hazards models were used to compute the odds ratio (OR) across groups and the cumulative incidence through life. Results Cumulative incidence by age 70 among non-heterozygotes across PRS strata ranged from 9% to 32% and from 9% to 35% for breast and prostate cancer, respectively. Among PV heterozygotes it ranged from 20% to 48% in moderate-risk genes and from 51% to 74% in high-risk genes for breast cancer, and it ranged from 30% to 59% in prostate cancer risk genes. Family history is always associated with an increased cancer OR. Conclusion PRS provides a meaningful risk gradient leading alone to a cancer risk comparable to PV in moderate risk genes while acting as risk modifier for high-risk genes. Including family history beside PV and PRS further improves cancer risk stratification.
Published: 2021

45. Breast and prostate cancer risk: the interplay of polygenic risk, high-impact monogenic variants, and family history 2021.06.04.21258277

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], The FNR supported P.M. as part of the National Centre of Excellence in Research on Parkinson's disease (NCER-PD, FNR11264123) and the DFG Research Units FOR2715 (INTER/DFG/17/11583046) and FOR2488 (INTER/DFG/19/14429377) [sponsor], Hassanin, Emadeldin, May, Patrick, Aldisi, Rana, Spier, Isabel, Forstner, Andreas J., Nothen, Markus M., Aretz, Stefan, Krawitz, Peter, Bobbili, Dheeraj Reddy, Maj, Carlo, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], The FNR supported P.M. as part of the National Centre of Excellence in Research on Parkinson's disease (NCER-PD, FNR11264123) and the DFG Research Units FOR2715 (INTER/DFG/17/11583046) and FOR2488 (INTER/DFG/19/14429377) [sponsor], Hassanin, Emadeldin, May, Patrick, Aldisi, Rana, Spier, Isabel, Forstner, Andreas J., Nothen, Markus M., Aretz, Stefan, Krawitz, Peter, Bobbili, Dheeraj Reddy, and Maj, Carlo
Abstract: Purpose: Investigate to which extent polygenic risk scores (PRS), high-impact monogenic variants, and family history affect breast and prostate cancer risk by assessing cancer prevalence and cancer cumulative lifetime incidence. Methods 200,643 individuals from the UK Biobank were stratified as follows: 1. carriers or non-carriers of high impact constitutive, monogenic variants in cancer susceptibility genes, 2. high or non-high PRS (90th percentile threshold), 3. with or without a family history of cancer. Multivariable logistic regression was used to compare the odds ratio (OR) across the different groups while Cox proportional hazards models were used to compute the cumulative incidence through life. Results Breast and prostate cancer cumulative incidence by age 70 is 7 and 5 for non-carriers with non-high PRS and reaches 37 and 32 among carriers of high-impact variants in cancer susceptibility genes with high PRS. The additional presence of family history is associated with a further increase of the risk of developing cancer reaching an OR of 14 and 21 for breast and prostate cancer, respectively. Conclusion: High PRS confers a cancer risk comparable to high-impact monogenic variants. Family history, monogenic variants, and PRS contribute additively to breast and prostate cancer risk.
Published: 2021

46. Extending the allelic spectrum at noncoding risk loci of orofacial clefting

Author: Thieme, Frederic, Henschel, Leonie, Hammond, Nigel L., Ishorst, Nina, Hausen, Jonas, Adamson, Antony D., Biedermann, Angelika, Bowes, John, Zieger, Hanna K., Maj, Carlo, Kruse, Teresa, Buness, Andreas, Hoischen, Alexander, Gilissen, Christian, Kreusch, Thomas, Jaeger, Andreas, Goelz, Lina, Braumann, Bert, Aldhorae, Khalid, Rojas-Martinez, Augusto, Krawitz, Peter M., Mangold, Elisabeth, Dixon, Michael J., Ludwig, Kerstin U., Thieme, Frederic, Henschel, Leonie, Hammond, Nigel L., Ishorst, Nina, Hausen, Jonas, Adamson, Antony D., Biedermann, Angelika, Bowes, John, Zieger, Hanna K., Maj, Carlo, Kruse, Teresa, Buness, Andreas, Hoischen, Alexander, Gilissen, Christian, Kreusch, Thomas, Jaeger, Andreas, Goelz, Lina, Braumann, Bert, Aldhorae, Khalid, Rojas-Martinez, Augusto, Krawitz, Peter M., Mangold, Elisabeth, Dixon, Michael J., and Ludwig, Kerstin U.
Abstract: Genome-wide association studies (GWAS) have generated unprecedented insights into the genetic etiology of orofacial clefting (OFC). The moderate effect sizes of associated noncoding risk variants and limited access to disease-relevant tissue represent considerable challenges for biological interpretation of genetic findings. As rare variants with stronger effect sizes are likely to also contribute to OFC, an alternative approach to delineate pathogenic mechanisms is to identify private mutations and/or an increased burden of rare variants in associated regions. This report describes a framework for targeted resequencing at selected noncoding risk loci contributing to nonsyndromic cleft lip with/without cleft palate (nsCL/P), the most frequent OFC subtype. Based on GWAS data, we selected three risk loci and identified candidate regulatory regions (CRRs) through the integration of credible SNP information, epigenetic data from relevant cells/tissues, and conservation scores. The CRRs (total 57 kb) were resequenced in a multiethnic study population (1061 patients; 1591 controls), using single-molecule molecular inversion probe technology. Combining evidence from in silico variant annotation, pedigree- and burden analyses, we identified 16 likely deleterious rare variants that represent new candidates for functional studies in nsCL/P. Our framework is scalable and represents a promising approach to the investigation of additional congenital malformations with multifactorial etiology.
Published: 2021

47. Lessons learned from 40 novel PIGA patients and a review of the literature

Author: Bayat, Allan, Knaus, Alexej, Pendziwiat, Manuela, Afenjar, Alexandra, Barakat, Tahsin Stefan, Bosch, Friedrich, Callewaert, Bert, Calvas, Patrick, Ceulemans, Berten, Chassaing, Nicolas, Depienne, Christel, Endziniene, Milda, Ferreira, Carlos R., Moura de Souza, Carolina Fischinger, Freihuber, Cecile, Ganesan, Shiva, Gataullina, Svetlana, Guerrini, Renzo, Guerrot, Anne-Marie, Hansen, Lars, Jezela-Stanek, Aleksandra, Karsenty, Caroline, Kievit, Anneke, Kooy, Frank R., Korff, Christian M., Hansen, Johanne Kragh, Larsen, Martin, Layet, Valerie, Lesca, Gaetan, McBride, Kim L., Meuwissen, Marije, Mignot, Cyril, Montomoli, Martino, Moore, Hannah, Naudion, Sophie, Nava, Caroline, Nougues, Marie-Christine, Parrini, Elena, Pastore, Matthew, Schelhaas, Jurgen H., Skinner, Steven, Szczaluba, Krzysztol, Thomas, Ashley, Thomassen, Mads, Tranebjaerg, Lisbeth, van Slegtenhorst, Marjon, Wolfe, Lynne A., Lal, Dennis, Gardella, Elena, Ousager, Lilian Bomme, Bruenger, Tobias, Helbig, Ingo, Krawitz, Peter, Moller, Rikke S., Bayat, Allan, Knaus, Alexej, Pendziwiat, Manuela, Afenjar, Alexandra, Barakat, Tahsin Stefan, Bosch, Friedrich, Callewaert, Bert, Calvas, Patrick, Ceulemans, Berten, Chassaing, Nicolas, Depienne, Christel, Endziniene, Milda, Ferreira, Carlos R., Moura de Souza, Carolina Fischinger, Freihuber, Cecile, Ganesan, Shiva, Gataullina, Svetlana, Guerrini, Renzo, Guerrot, Anne-Marie, Hansen, Lars, Jezela-Stanek, Aleksandra, Karsenty, Caroline, Kievit, Anneke, Kooy, Frank R., Korff, Christian M., Hansen, Johanne Kragh, Larsen, Martin, Layet, Valerie, Lesca, Gaetan, McBride, Kim L., Meuwissen, Marije, Mignot, Cyril, Montomoli, Martino, Moore, Hannah, Naudion, Sophie, Nava, Caroline, Nougues, Marie-Christine, Parrini, Elena, Pastore, Matthew, Schelhaas, Jurgen H., Skinner, Steven, Szczaluba, Krzysztol, Thomas, Ashley, Thomassen, Mads, Tranebjaerg, Lisbeth, van Slegtenhorst, Marjon, Wolfe, Lynne A., Lal, Dennis, Gardella, Elena, Ousager, Lilian Bomme, Bruenger, Tobias, Helbig, Ingo, Krawitz, Peter, and Moller, Rikke S.
Abstract: Objective To define the phenotypic spectrum of phosphatidylinositol glycan class A protein (PIGA)-related congenital disorder of glycosylation (PIGA-CDG) and evaluate genotype-phenotype correlations. Methods Our cohort encompasses 40 affected males with a pathogenic PIGA variant. We performed a detailed phenotypic assessment, and in addition, we reviewed the available clinical data of 36 previously published cases and assessed the variant pathogenicity using bioinformatical approaches. Results Most individuals had hypotonia, moderate to profound global developmental delay, and intractable seizures. We found that PIGA-CDG spans from a pure neurological phenotype at the mild end to a Fryns syndrome-like phenotype. We found a high frequency of cardiac anomalies including structural anomalies and cardiomyopathy, and a high frequency of spontaneous death, especially in childhood. Comparative bioinformatical analysis of common variants, found in the healthy population, and pathogenic variants, identified in affected individuals, revealed a profound physiochemical dissimilarity of the substituted amino acids in variant constrained regions of the protein. Significance Our comprehensive analysis of the largest cohort of published and novel PIGA patients broadens the spectrum of PIGA-CDG. Our genotype-phenotype correlation facilitates the estimation on pathogenicity of variants with unknown clinical significance and prognosis for individuals with pathogenic variants in PIGA.
Published: 2020

48. Sex-Specific Genetic Associations for Barrett's Esophagus and Esophageal Adenocarcinoma

Author: Dong, Jing, Maj, Carlo, Tsavachidis, Spiridon, Ostrom, Quinn T., Gharahkhani, Puya, Anderson, Lesley A., Wu, Anna H., Ye, Weimin, Bernstein, Leslie, Borisov, Oleg, Schroeder, Julia, Chow, Wong-Ho, Gammon, Marilie D., Liu, Geoffrey, Caldas, Carlos, Pharoah, Paul D., Risch, Harvey A., May, Andrea, Gerges, Christian, Anders, Mario, Venerito, Marino, Schmidt, Thomas, Izbicki, Jakob R., Hoelscher, Arnulf H., Schumacher, Brigitte, Vashist, Yogesh, Neuhaus, Horst, Roesch, Thomas, Knapp, Michael, Krawitz, Peter, Boehmer, Anne, Iyer, Prasad G., Reid, Brian J., Lagergren, Jesper, Shaheen, Nicholas J., Corley, Douglas A., Gockel, Ines, Fitzgerald, Rebecca C., Cook, Michael B., Whiteman, David C., Vaughan, Thomas L., Schumacher, Johannes, Thrift, Aaron P., Dong, Jing, Maj, Carlo, Tsavachidis, Spiridon, Ostrom, Quinn T., Gharahkhani, Puya, Anderson, Lesley A., Wu, Anna H., Ye, Weimin, Bernstein, Leslie, Borisov, Oleg, Schroeder, Julia, Chow, Wong-Ho, Gammon, Marilie D., Liu, Geoffrey, Caldas, Carlos, Pharoah, Paul D., Risch, Harvey A., May, Andrea, Gerges, Christian, Anders, Mario, Venerito, Marino, Schmidt, Thomas, Izbicki, Jakob R., Hoelscher, Arnulf H., Schumacher, Brigitte, Vashist, Yogesh, Neuhaus, Horst, Roesch, Thomas, Knapp, Michael, Krawitz, Peter, Boehmer, Anne, Iyer, Prasad G., Reid, Brian J., Lagergren, Jesper, Shaheen, Nicholas J., Corley, Douglas A., Gockel, Ines, Fitzgerald, Rebecca C., Cook, Michael B., Whiteman, David C., Vaughan, Thomas L., Schumacher, Johannes, and Thrift, Aaron P.
Abstract: BACKGROUND & AIMS: Esophageal adenocarcinoma (EA) and its premalignant lesion, Barrett's esophagus (BE), are characterized by a strong and yet unexplained male predominance (with a male-to-female ratio in EA incidence of up to 6:1). Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for these conditions. However, potential sex differences in genetic associations with BE/EA remain largely unexplored. METHODS: Given strong genetic overlap, BE and EA cases were combined into a single case group for analysis. These were compared with population based controls. We performed sex-specific GWAS of BE/EA in 3 separate studies and then used fixed-effects meta-analysis to provide summary estimates for >9 million variants for male and female individuals. A series of downstream analyses were conducted separately in male and female individuals to identify genes associated with BE/EA and the genetic correlations between BE/EA and other traits. RESULTS: We included 6758 male BE/EA cases, 7489 male controls, 1670 female BE/EA cases, and 6174 female controls. After Bonferroni correction, our meta-analysis of sex-specific GWAS identified 1 variant at chromosome 6q11.1 (rs112894788, KHDRBS2-MTRNR2L9, PBONF = .039) that was statistically significantly associated with BE/EA risk in male individuals only, and 1 variant at chromosome 8p23.1 (rs13259457, PRSS55-RP1L1, PBONF = 0.057) associated, at borderline significance, with BE/EA risk in female individuals only. We also observed strong genetic correlations of BE/EA with gastroesophageal reflux disease in male individuals and obesity in female individuals. CONCLUSIONS: The identified novel sex-specific variants associated with BE/ EA could improve the understanding of the genetic architecture of the disease and the reasons for the male predominance.
Published: 2020

49. Lessons learned from 40 novel PIGA patients and a review of the literature

Author: Bayat, Allan, Knaus, Alexej, Pendziwiat, Manuela, Afenjar, Alexandra, Barakat, Tahsin Stefan, Bosch, Friedrich, Callewaert, Bert, Calvas, Patrick, Ceulemans, Berten, Chassaing, Nicolas, Depienne, Christel, Endziniene, Milda, Ferreira, Carlos R., Moura de Souza, Carolina Fischinger, Freihuber, Cecile, Ganesan, Shiva, Gataullina, Svetlana, Guerrini, Renzo, Guerrot, Anne-Marie, Hansen, Lars, Jezela-Stanek, Aleksandra, Karsenty, Caroline, Kievit, Anneke, Kooy, Frank R., Korff, Christian M., Hansen, Johanne Kragh, Larsen, Martin, Layet, Valerie, Lesca, Gaetan, McBride, Kim L., Meuwissen, Marije, Mignot, Cyril, Montomoli, Martino, Moore, Hannah, Naudion, Sophie, Nava, Caroline, Nougues, Marie-Christine, Parrini, Elena, Pastore, Matthew, Schelhaas, Jurgen H., Skinner, Steven, Szczaluba, Krzysztol, Thomas, Ashley, Thomassen, Mads, Tranebjaerg, Lisbeth, van Slegtenhorst, Marjon, Wolfe, Lynne A., Lal, Dennis, Gardella, Elena, Ousager, Lilian Bomme, Bruenger, Tobias, Helbig, Ingo, Krawitz, Peter, Moller, Rikke S., Bayat, Allan, Knaus, Alexej, Pendziwiat, Manuela, Afenjar, Alexandra, Barakat, Tahsin Stefan, Bosch, Friedrich, Callewaert, Bert, Calvas, Patrick, Ceulemans, Berten, Chassaing, Nicolas, Depienne, Christel, Endziniene, Milda, Ferreira, Carlos R., Moura de Souza, Carolina Fischinger, Freihuber, Cecile, Ganesan, Shiva, Gataullina, Svetlana, Guerrini, Renzo, Guerrot, Anne-Marie, Hansen, Lars, Jezela-Stanek, Aleksandra, Karsenty, Caroline, Kievit, Anneke, Kooy, Frank R., Korff, Christian M., Hansen, Johanne Kragh, Larsen, Martin, Layet, Valerie, Lesca, Gaetan, McBride, Kim L., Meuwissen, Marije, Mignot, Cyril, Montomoli, Martino, Moore, Hannah, Naudion, Sophie, Nava, Caroline, Nougues, Marie-Christine, Parrini, Elena, Pastore, Matthew, Schelhaas, Jurgen H., Skinner, Steven, Szczaluba, Krzysztol, Thomas, Ashley, Thomassen, Mads, Tranebjaerg, Lisbeth, van Slegtenhorst, Marjon, Wolfe, Lynne A., Lal, Dennis, Gardella, Elena, Ousager, Lilian Bomme, Bruenger, Tobias, Helbig, Ingo, Krawitz, Peter, and Moller, Rikke S.
Abstract: Objective To define the phenotypic spectrum of phosphatidylinositol glycan class A protein (PIGA)-related congenital disorder of glycosylation (PIGA-CDG) and evaluate genotype-phenotype correlations. Methods Our cohort encompasses 40 affected males with a pathogenic PIGA variant. We performed a detailed phenotypic assessment, and in addition, we reviewed the available clinical data of 36 previously published cases and assessed the variant pathogenicity using bioinformatical approaches. Results Most individuals had hypotonia, moderate to profound global developmental delay, and intractable seizures. We found that PIGA-CDG spans from a pure neurological phenotype at the mild end to a Fryns syndrome-like phenotype. We found a high frequency of cardiac anomalies including structural anomalies and cardiomyopathy, and a high frequency of spontaneous death, especially in childhood. Comparative bioinformatical analysis of common variants, found in the healthy population, and pathogenic variants, identified in affected individuals, revealed a profound physiochemical dissimilarity of the substituted amino acids in variant constrained regions of the protein. Significance Our comprehensive analysis of the largest cohort of published and novel PIGA patients broadens the spectrum of PIGA-CDG. Our genotype-phenotype correlation facilitates the estimation on pathogenicity of variants with unknown clinical significance and prognosis for individuals with pathogenic variants in PIGA.
Published: 2020

50. Sex-Specific Genetic Associations for Barrett's Esophagus and Esophageal Adenocarcinoma

Author: Dong, Jing, Maj, Carlo, Tsavachidis, Spiridon, Ostrom, Quinn T., Gharahkhani, Puya, Anderson, Lesley A., Wu, Anna H., Ye, Weimin, Bernstein, Leslie, Borisov, Oleg, Schroeder, Julia, Chow, Wong-Ho, Gammon, Marilie D., Liu, Geoffrey, Caldas, Carlos, Pharoah, Paul D., Risch, Harvey A., May, Andrea, Gerges, Christian, Anders, Mario, Venerito, Marino, Schmidt, Thomas, Izbicki, Jakob R., Hoelscher, Arnulf H., Schumacher, Brigitte, Vashist, Yogesh, Neuhaus, Horst, Roesch, Thomas, Knapp, Michael, Krawitz, Peter, Boehmer, Anne, Iyer, Prasad G., Reid, Brian J., Lagergren, Jesper, Shaheen, Nicholas J., Corley, Douglas A., Gockel, Ines, Fitzgerald, Rebecca C., Cook, Michael B., Whiteman, David C., Vaughan, Thomas L., Schumacher, Johannes, Thrift, Aaron P., Dong, Jing, Maj, Carlo, Tsavachidis, Spiridon, Ostrom, Quinn T., Gharahkhani, Puya, Anderson, Lesley A., Wu, Anna H., Ye, Weimin, Bernstein, Leslie, Borisov, Oleg, Schroeder, Julia, Chow, Wong-Ho, Gammon, Marilie D., Liu, Geoffrey, Caldas, Carlos, Pharoah, Paul D., Risch, Harvey A., May, Andrea, Gerges, Christian, Anders, Mario, Venerito, Marino, Schmidt, Thomas, Izbicki, Jakob R., Hoelscher, Arnulf H., Schumacher, Brigitte, Vashist, Yogesh, Neuhaus, Horst, Roesch, Thomas, Knapp, Michael, Krawitz, Peter, Boehmer, Anne, Iyer, Prasad G., Reid, Brian J., Lagergren, Jesper, Shaheen, Nicholas J., Corley, Douglas A., Gockel, Ines, Fitzgerald, Rebecca C., Cook, Michael B., Whiteman, David C., Vaughan, Thomas L., Schumacher, Johannes, and Thrift, Aaron P.
Abstract: BACKGROUND & AIMS: Esophageal adenocarcinoma (EA) and its premalignant lesion, Barrett's esophagus (BE), are characterized by a strong and yet unexplained male predominance (with a male-to-female ratio in EA incidence of up to 6:1). Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for these conditions. However, potential sex differences in genetic associations with BE/EA remain largely unexplored. METHODS: Given strong genetic overlap, BE and EA cases were combined into a single case group for analysis. These were compared with population based controls. We performed sex-specific GWAS of BE/EA in 3 separate studies and then used fixed-effects meta-analysis to provide summary estimates for >9 million variants for male and female individuals. A series of downstream analyses were conducted separately in male and female individuals to identify genes associated with BE/EA and the genetic correlations between BE/EA and other traits. RESULTS: We included 6758 male BE/EA cases, 7489 male controls, 1670 female BE/EA cases, and 6174 female controls. After Bonferroni correction, our meta-analysis of sex-specific GWAS identified 1 variant at chromosome 6q11.1 (rs112894788, KHDRBS2-MTRNR2L9, PBONF = .039) that was statistically significantly associated with BE/EA risk in male individuals only, and 1 variant at chromosome 8p23.1 (rs13259457, PRSS55-RP1L1, PBONF = 0.057) associated, at borderline significance, with BE/EA risk in female individuals only. We also observed strong genetic correlations of BE/EA with gastroesophageal reflux disease in male individuals and obesity in female individuals. CONCLUSIONS: The identified novel sex-specific variants associated with BE/ EA could improve the understanding of the genetic architecture of the disease and the reasons for the male predominance.
Published: 2020

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