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1. Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Author

Trubetskoy, Vassily, Pardiñas, Antonio F., Qi, Ting, Panagiotaropoulou, Georgia, Awasthi, Swapnil, Bigdeli, Tim B., Bryois, Julien, Chen, Chia-Yen, Dennison, Charlotte A., Hall, Lynsey S., Lam, Max, Watanabe, Kyoko, Frei, Oleksandr, Ge, Tian, Harwood, Janet C., Koopmans, Frank, Magnusson, Sigurdur, Richards, Alexander L., Sidorenko, Julia, Wu, Yang, Zeng, Jian, Grove, Jakob, Kim, Minsoo, Li, Zhiqiang, Voloudakis, Georgios, Zhang, Wen, Adams, Mark, Agartz, Ingrid, Atkinson, Elizabeth G., Agerbo, Esben, Al Eissa, Mariam, Albus, Margot, Alexander, Madeline, Alizadeh, Behrooz Z., Alptekin, Köksal, Als, Thomas D., Amin, Farooq, Arolt, Volker, Arrojo, Manuel, Athanasiu, Lavinia, Azevedo, Maria Helena, Bacanu, Silviu A., Bass, Nicholas J., Begemann, Martin, Belliveau, Richard A., Bene, Judit, Benyamin, Beben, Bergen, Sarah E., Blasi, Giuseppe, Bobes, Julio, Bonassi, Stefano, Braun, Alice, Bressan, Rodrigo Affonseca, Bromet, Evelyn J., Bruggeman, Richard, Buckley, Peter F., Buckner, Randy L., Bybjerg-Grauholm, Jonas, Cahn, Wiepke, Cairns, Murray J., Calkins, Monica E., Carr, Vaughan J., Castle, David, Catts, Stanley V., Chambert, Kimberley D., Chan, Raymond C. K., Chaumette, Boris, Cheng, Wei, Cheung, Eric F. C., Chong, Siow Ann, Cohen, David, Consoli, Angèle, Cordeiro, Quirino, Costas, Javier, Curtis, Charles, Davidson, Michael, Davis, Kenneth L., de Haan, Lieuwe, Degenhardt, Franziska, DeLisi, Lynn E., Demontis, Ditte, Dickerson, Faith, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Duan, Jubao, Ducci, Giuseppe, Dudbridge, Frank, Eriksson, Johan G., Fañanás, Lourdes, Faraone, Stephen V., Fiorentino, Alessia, Forstner, Andreas, Frank, Josef, Freimer, Nelson B., Fromer, Menachem, Frustaci, Alessandra, Gadelha, Ary, Genovese, Giulio, Gershon, Elliot S., Giannitelli, Marianna, Giegling, Ina, Giusti-Rodríguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I., González Peñas, Javier, González-Pinto, Ana, Gopal, Srihari, Gratten, Jacob, Green, Michael F., Greenwood, Tiffany A., Guillin, Olivier, Gülöksüz, Sinan, Gur, Raquel E., Gur, Ruben C., Gutiérrez, Blanca, Hahn, Eric, Hakonarson, Hakon, Haroutunian, Vahram, Hartmann, Annette M., Harvey, Carol, Hayward, Caroline, Henskens, Frans A., Herms, Stefan, Hoffmann, Per, Howrigan, Daniel P., Ikeda, Masashi, Iyegbe, Conrad, Joa, Inge, Julià, Antonio, Kähler, Anna K., Kam-Thong, Tony, Kamatani, Yoichiro, Karachanak-Yankova, Sena, Kebir, Oussama, Keller, Matthew C., Kelly, Brian J., Khrunin, Andrey, Kim, Sung-Wan, Klovins, Janis, Kondratiev, Nikolay, Konte, Bettina, Kraft, Julia, Kubo, Michiaki, Kučinskas, Vaidutis, Kučinskiene, Zita Ausrele, Kusumawardhani, Agung, Kuzelova-Ptackova, Hana, Landi, Stefano, Lazzeroni, Laura C., Lee, Phil H., Legge, Sophie E., Lehrer, Douglas S., Lencer, Rebecca, Lerer, Bernard, Li, Miaoxin, Lieberman, Jeffrey, Light, Gregory A., Limborska, Svetlana, Liu, Chih-Min, Lönnqvist, Jouko, Loughland, Carmel M., Lubinski, Jan, Luykx, Jurjen J., Lynham, Amy, Macek, Jr, Milan, Mackinnon, Andrew, Magnusson, Patrik K. E., Maher, Brion S., Maier, Wolfgang, Malaspina, Dolores, Mallet, Jacques, Marder, Stephen R., Marsal, Sara, Martin, Alicia R., Martorell, Lourdes, Mattheisen, Manuel, McCarley, Robert W., McDonald, Colm, McGrath, John J., Medeiros, Helena, Meier, Sandra, Melegh, Bela, Melle, Ingrid, Mesholam-Gately, Raquelle I., Metspalu, Andres, Michie, Patricia T., Milani, Lili, Milanova, Vihra, Mitjans, Marina, Molden, Espen, Molina, Esther, Molto, María Dolores, Mondelli, Valeria, Moreno, Carmen, Morley, Christopher P., Muntané, Gerard, Murphy, Kieran C., Myin-Germeys, Inez, Nenadić, Igor, Nestadt, Gerald, Nikitina-Zake, Liene, Noto, Cristiano, Nuechterlein, Keith H., O’Brien, Niamh Louise, O’Neill, F. Anthony, Oh, Sang-Yun, Olincy, Ann, Ota, Vanessa Kiyomi, Pantelis, Christos, Papadimitriou, George N., Parellada, Mara, Paunio, Tiina, Pellegrino, Renata, Periyasamy, Sathish, Perkins, Diana O., Pfuhlmann, Bruno, Pietiläinen, Olli, Pimm, Jonathan, Porteous, David, Powell, John, Quattrone, Diego, Quested, Digby, Radant, Allen D., Rampino, Antonio, Rapaport, Mark H., Rautanen, Anna, Reichenberg, Abraham, Roe, Cheryl, Roffman, Joshua L., Roth, Julian, Rothermundt, Matthias, Rutten, Bart P. F., Saker-Delye, Safaa, Salomaa, Veikko, Sanjuan, Julio, Santoro, Marcos Leite, Savitz, Adam, Schall, Ulrich, Scott, Rodney J., Seidman, Larry J., Sharp, Sally Isabel, Shi, Jianxin, Siever, Larry J., Sigurdsson, Engilbert, Sim, Kang, Skarabis, Nora, Slominsky, Petr, So, Hon-Cheong, Sobell, Janet L., Söderman, Erik, Stain, Helen J., Steen, Nils Eiel, Steixner-Kumar, Agnes A., Stögmann, Elisabeth, Stone, William S., Straub, Richard E., Streit, Fabian, Strengman, Eric, Stroup, T. Scott, Subramaniam, Mythily, Sugar, Catherine A., Suvisaari, Jaana, Svrakic, Dragan M., Swerdlow, Neal R., Szatkiewicz, Jin P., Ta, Thi Minh Tam, Takahashi, Atsushi, Terao, Chikashi, Thibaut, Florence, Toncheva, Draga, Tooney, Paul A., Torretta, Silvia, Tosato, Sarah, Tura, Gian Battista, Turetsky, Bruce I., Üçok, Alp, Vaaler, Arne, van Amelsvoort, Therese, van Winkel, Ruud, Veijola, Juha, Waddington, John, Walter, Henrik, Waterreus, Anna, Webb, Bradley T., Weiser, Mark, Williams, Nigel M., Witt, Stephanie H., Wormley, Brandon K., Wu, Jing Qin, Xu, Zhida, Yolken, Robert, Zai, Clement C., Zhou, Wei, Zhu, Feng, Zimprich, Fritz, Atbaşoğlu, Eşref Cem, Ayub, Muhammad, Benner, Christian, Bertolino, Alessandro, Black, Donald W., Bray, Nicholas J., Breen, Gerome, Buccola, Nancy G., Byerley, William F., Chen, Wei J., Cloninger, C. Robert, Crespo-Facorro, Benedicto, Donohoe, Gary, Freedman, Robert, Galletly, Cherrie, Gandal, Michael J., Gennarelli, Massimo, Hougaard, David M., Hwu, Hai-Gwo, Jablensky, Assen V., McCarroll, Steven A., Moran, Jennifer L., Mors, Ole, Mortensen, Preben B., Müller-Myhsok, Bertram, Neil, Amanda L., Nordentoft, Merete, Pato, Michele T., Petryshen, Tracey L., Pirinen, Matti, Pulver, Ann E., Schulze, Thomas G., Silverman, Jeremy M., Smoller, Jordan W., Stahl, Eli A., Tsuang, Debby W., Vilella, Elisabet, Wang, Shi-Heng, Xu, Shuhua, Adolfsson, Rolf, Arango, Celso, Baune, Bernhard T., Belangero, Sintia Iole, Børglum, Anders D., Braff, David, Bramon, Elvira, Buxbaum, Joseph D., Campion, Dominique, Cervilla, Jorge A., Cichon, Sven, Collier, David A., Corvin, Aiden, Curtis, David, Forti, Marta Di, Domenici, Enrico, Ehrenreich, Hannelore, Escott-Price, Valentina, Esko, Tõnu, Fanous, Ayman H., Gareeva, Anna, Gawlik, Micha, Gejman, Pablo V., Gill, Michael, Glatt, Stephen J., Golimbet, Vera, Hong, Kyung Sue, Hultman, Christina M., Hyman, Steven E., Iwata, Nakao, Jönsson, Erik G., Kahn, René S., Kennedy, James L., Khusnutdinova, Elza, Kirov, George, Knowles, James A., Krebs, Marie-Odile, Laurent-Levinson, Claudine, Lee, Jimmy, Lencz, Todd, Levinson, Douglas F., Li, Qingqin S., Liu, Jianjun, Malhotra, Anil K., Malhotra, Dheeraj, McIntosh, Andrew, McQuillin, Andrew, Menezes, Paulo R., Morgan, Vera A., Morris, Derek W., Mowry, Bryan J., Murray, Robin M., Nimgaonkar, Vishwajit, Nöthen, Markus M., Ophoff, Roel A., Paciga, Sara A., Palotie, Aarno, Pato, Carlos N., Qin, Shengying, Rietschel, Marcella, Riley, Brien P., Rivera, Margarita, Rujescu, Dan, Saka, Meram C., Sanders, Alan R., Schwab, Sibylle G., Serretti, Alessandro, Sham, Pak C., Shi, Yongyong, St Clair, David, Stefánsson, Hreinn, Stefansson, Kari, Tsuang, Ming T., van Os, Jim, Vawter, Marquis P., Weinberger, Daniel R., Werge, Thomas, Wildenauer, Dieter B., Yu, Xin, Yue, Weihua, Holmans, Peter A., Pocklington, Andrew J., Roussos, Panos, Vassos, Evangelos, Verhage, Matthijs, Visscher, Peter M., Yang, Jian, Posthuma, Danielle, Andreassen, Ole A., Kendler, Kenneth S., Owen, Michael J., Wray, Naomi R., Daly, Mark J., Huang, Hailiang, Neale, Benjamin M., Sullivan, Patrick F., Ripke, Stephan, Walters, James T. R., and O’Donovan, Michael C.

Published
2022
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2. Human CRY1 variants associate with attention deficit/hyperactivity disorder

Author

Onat, O. Emre, Kars, M. Ece, Gul, Seref, Bilguvar, Kaya, Wu, Yiming, Ozhan, Ayse, Aydin, Cihan, Basak, A. Nazli, Trusso, M. Allegra, Goracci, Arianna, Fallerini, Chiara, Renieri, Alessandra, Casanova, Jean-Laurent, Itan, Yuval, Atbasoglu, Cem E., Saka, Meram C., Kavakli, Halil, and Ozcelik, Tayfun

Subjects
France. National Research Agency -- Analysis, Thermo Fisher Scientific Inc., Sleep -- Genetic aspects -- Analysis, Insomnia -- Genetic aspects, Medical schools -- Analysis, Scientific equipment industry -- Genetic aspects -- Analysis, Health care industry, Bilkent University
Abstract

Attention deficit/hyperactivity disorder (ADHD) is a common and heritable phenotype frequently accompanied by insomnia, anxiety, and depression. Here, using a reverse phenotyping approach, we report heterozygous coding variations in the core circadian clock gene cryptochrome 1 in 15 unrelated multigenerational families with combined ADHD and insomnia. The variants led to functional alterations in the circadian molecular rhythms, providing a mechanistic link to the behavioral symptoms. One variant, CRY1[DELTA]11 c.1657+3A>C, is present in approximately 1% of Europeans, therefore standing out as a diagnostic and therapeutic marker. We showed by exome sequencing in an independent cohort of patients with combined ADHD and insomnia that 8 of 62 patients and 0 of 369 controls carried CRY1[DELTA]11. Also, we identified a variant, CRY1[DELTA]6 c.825+1G>A, that shows reduced affinity for BMAL1/CLOCK and causes an arrhythmic phenotype. Genotype-phenotype correlation analysis revealed that this variant segregated with ADHD and delayed sleep phase disorder (DSPD) in the affected family. Finally, we found in a phenome-wide association study involving 9438 unrelated adult Europeans that CRY1[DELTA]11 was associated with major depressive disorder, insomnia, and anxiety. These results defined a distinctive group of circadian psychiatric phenotypes that we propose to designate as 'circiatric' disorders., Introduction Sleep is genetically regulated by the circadian rhythm. Disruption of this rhythm leads to aberrant sleep patterns (1-4). Sleep is also frequently disturbed in individuals with psychiatric disorders. For [...]

Published
2020
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3. Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Author

Medical Research Council (UK), National Natural Science Foundation of China, Royal Society (UK), Chinese Academy of Sciences, Shanghai Science and Technology Committee, Research Council of Norway, European Commission, Fundação de Amparo à Pesquisa do Estado de São Paulo, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Comunidad de Madrid, Fundación Alicia Koplowitz, Fundación Alonso Lozano, Mental Health Research UK, Wellcome Trust, Brain and Behavior Research Foundation, NIHR Biomedical Research Centre (UK), University College London, Generalitat Valenciana, Trubetskoy, Vassily, Pardiñas, Antonio F., Qi, Ting, Panagiotaropoulou, Georgia, Awasthi, Swapnil, Bigdeli, Tim B., Bryois, Julien, Chen, Chia-Yen, Dennison, Charlotte A., Hall, Lynsey S., Lam, Max, Curtis, Charles, Nikitina-Zake, Liene, Davidson, Michael, Joa, Inge, Davis, Kenneth L., Yolken, Robert, Murray, Robin M., de Haan, Lieuwe, Legge, Sophie E., Serretti, Alessandro, van Os, Jim, Smoller, Jordan W., Agartz, Ingrid, Alizadeh, Behrooz Z., Degenhardt, Franziska, DeLisi, Lynn E., Demontis, Ditte, Dickerson, Faith, Zai, Clement C., Dikeos, Dimitris, Dinan, Timothy, Henskens, Frans A., Vaaler, Arne, Noto, Cristiano, Nimgaonkar, Vishwajit, Rautanen, Anna, Lehrer, Douglas S., Djurovic, Srdjan, Duan, Jubao, Julià, Antonio, Stahl, Eli A., Zhou, Wei, Vawter, Marquis P., Toncheva, Draga, Webb, Bradley T., Ducci, Giuseppe, Dudbridge, Frank, Eriksson, Johan G., Fañanas Saura, Lourdes, Goldstein, Jacqueline I., Faraone, Stephen V., Lencer, Rebecca, Moreno, Carmen, Bacanu, Silviu A., Fiorentino, Alessia, Calkins, Monica E., Mitjans, Marina, Forstner, Andreas, Nuechterlein, Keith H., Frank, Josef, Tsuang, Debby W., Freimer, Nelson B., Tooney, Paul A., Belangero, Sintia Iole, Weinberger, Daniel R., Fromer, Menachem, Ge,Tian, Adolfsson, Rolf, Hakonarson, Hakon, Zhu, Feng, Frustaci, Alessandra, Nöthen, Markus M., Gadelha, Ary, Genovese, Giulio, Gershon, Elliot S., Quattrone, Diego, Kähler, Anna K., Kam-Thong, Tony, van Amelsvoort, Therese, Vilella, Elisabet, Molden, Espen, O'Brien, Niamh Louise, Zimprich, Fritz, Kamatani, Yoichiro, Braun, Alice, Melegh, Bela, Pirinen, Matti, Karachanak-Yankova, Sena, Ophoff, Roel A., Kebir, Oussama, Lerer, Bernard, Nordentoft, Merete, Fanous, Ayman H., Reichenberg, Abraham, Li, Miaoxin, Periyasamy, Sathish, Lieberman, Jeffrey, Werge, Thomas, Light, Gregory A., Limborska, Svetlana, Tosato, Sarah, Liu, Chih-Min, Olincy, Ann, Magnusson, Sigurdur, Gareeva, Anna, Bressan, Rodrigo Affonseca, Lönnqvist, Jouko, Roe, Cheryl, Cheng, Wei, Athanasiu, Lavinia, Gutiérrez, Blanca, Harvey, Carol, Loughland, Carmel M., Lubinski, Jan, Luykx, Jurjen J., Lynham, Amy, Gawlik, Micha, Macek, Milan, Mackinnon, Andrew, Buxbaum, Joseph D., Tura, Gian Battista, Bromet, Evelyn J., Atbaşoğlu, Eşref Cem, Roffman, Joshua L., Magnusson, Patrik K. E., Maher, Brion S., Ota, Vanessa Kiyomi, Paciga, Sara A., Gejman, Pablo V., Arango, Celso, Forti, Marta Di, Maier, Wolfgang, Richards, Alexander L., Malaspina, Dolores, Mallet, Jacques, Metspalu, Andres, Marder, Stephen R., Li, Zhiqiang, Takahashi, Atsushi, Marsal, Sara, Kučinskiene, Zita Ausrele, Suvisaari, Jaana, Martin, Alicia R., Turetsky, Bruce I., Martorell, Lourdes, Palotie, Aarno, Mattheisen, Manuel, Baune, Bernhard T., Saka, Meram C., McCarley, Robert W., Giusti-Rodríguez, Paola, Riley, Brien P., Murphy, Kieran C., Gill, Michael, McDonald, Colm, Bruggeman, Richard, McGrath, John J., Sidorenko, Julia, Medeiros, Helena, Pantelis, Christos, Grove, Jakob, Campion, Dominique, Pato, Carlos N., Svrakic, Dragan M., Üçok, Alp, Glatt, Stephen J., Papadimitriou, George N., Khrunin, Andrey, Straub, Richard E., Parellada, Mara, Buckley, Peter F., Paunio, Tiina, Roth, Julian, Morgan, Vera A., Wildenauer, Dieter B., Ayub, Muhammad, Rothermundt, Matthias, Weiser, Mark, Rutten, Bart P. F., Saker-Delye, Safaa, Salomaa, Veikko, Børglum, Anders D., Sanjuán, Julio, van Winkel, Ruud, González Peñas, Javier, Yu, Xin, Kim, Sung-Wan, Santoro, Marcos Leite, Benner, Christian, Ikeda, Masashi, Morley, Christopher P., Zeng, Jian, Savitz, Adam, Schall, Ulrich, Scott, Rodney J., Voloudakis, Georgios, Yue, Weihua, Seidman, Larry J., Sharp, Sally Isabel, Alptekin, Köksal, Klovins, Janis, Amin, Farooq, Bertolino, Alessandro, Shi, Jianxin, Siever, Larry J., Atkinson, Elizabeth G., Buckner, Randy L., Holmans, Peter A., Rivera, Margarita, Sigurdsson, Engilbert, González-Pinto, Ana, Sim, Kang, Skarabis, Nora, Stroup, T Scott, Slominsky, Petr, Guillin, Olivier, Wang, Shi-Heng, So, Hon-Cheong, Quested, Digby, Sobell, Janet L., Braff, David, Zhang, Wen, Bybjerg-Grauholm, Jonas, Söderman, Erik, Rujescu, Dan, Chambert, Kimberley D., Stain, Helen J., Melle, Ingrid, Carr, Vaughan J, Pocklington, Andrew J., Steen, Nils Eiel, Harwood, Janet, Steixner-Kumar, Agnes A., Gopal, Srihari, Stögmann, Elisabeth, Veijola, Juha, Watanabe, Kyoko, Sham, Pak C., Cahn, Wiepke, Bramon, Elvira, Roussos, Panos, Waddington, John, Perkins, Diana O., Pato, Michele T., Walter, Henrik, Kondratiev, Nikolay, Waterreus, Anna, Al Eissa, Mariam, Bobes, Julio, Golimbet, Vera, Black, Donald W., Als, Thomas D., Bray, Nicholas J., Breen, Gerome, Buccola, Nancy G., Sanders, Alan R., Byerley, William F., Cervilla, Jorge A., Michie, Patricia T., Pfuhlmann, Bruno, Chen, Wei J., Hong, Kyung Sue, O'Neill, F Anthony, Terao, Chikashi, Green, Michael F., Cloninger, C. Robert, Crespo-Facorro, Benedicto, Donohoe, Gary, Gülöksüz, Sinan, Freedman, Robert, Albus, Margot, Hayward, Caroline, Pietiläinen, Olli, Herms, Stefan, Hultman, Christina M., Galletly, Cherrie, Gandal, Michael J., Hahn, Eric, Konte, Bettina, Castle, David, Gennarelli, Massimo, Milani, Lili, Hougaard, David M., Hwu, Hai-Gwo, Pulver, Ann E., Jablensky, Assen V., Molina, Esther, Qin, Shengying, McCarroll, Steven A., Moran, Jennifer L., Azevedo, Maria Helena, Gur, Rachel E., Kraft, Julia, Mors, Ole, Catts, Stanley V., Lazzeroni, Laura C., Mortensen, Preben B., Streit, Fabian, Kusumawardhani, Agung, Alexander, Madeline, Godard, Stephanie, Müller-Myhsok, Bertram, Milanova, Vihra, Neil, Amanda L., Cichon, Sven, Giannitelli, Marianna, Cheung, Eric F. C., Kubo, Michiaki, Schwab, Sibylle G., Collier, David A., Williams, Nigel M., Morris, Derek W., Corvin, Aiden, Pimm, Jonathan, Curtis, David, Haroutunian, Vahram, Keller, Matthew C., Vassos, Evangelos, Hyman, Steven E., Iwata, Nakao, Jönsson, Erik G., Kahn, René S., Chan, Raymond C. K., Kennedy, James L., Shi, Yongyong, Adams, Mark, Witt, Stephanie H., Khusnutdinova, Elza, Verhage, Matthijs, Xu, Shuhua, Wu, Yang, Kirov, George, Arolt, Volker, Knowles, James A., Moltó, Maria Dolores, Krebs, Marie-Odile, Hartmann, Annette M., Nestadt, Gerald, Wormley, Brandon K., Bass, Nicholas J., Laurent-Levinson, Claudine, Lee, Jimmy, Muntané, Gerard, Porteous, David, Kuzelova-Ptackova, Hana, Lencz, Todd, Subramaniam, Mythily, Levinson, Douglas F., Li, Qingqin S., Liu, Jianjun, Swerdlow, Neal R., Cairns, Murray J., Malhotra, Anil K., Malhotra, Dheeraj, Iyegbe, Conrad, Mondelli, Valeria, Kim, Minsoo, Arrojo, Manuel, Landi, Stefano, McIntosh, Andrew M., Petryshen, Tracey L., Radant, Allen D., Frei, Oleksandr, Mesholam-Gately, Raquelle I., McQuillin, Andrew, Sugar, Catherine A., Menezes, Paulo Rossi, St Clair, David, Meier, Sandra, Powell, John, Chaumette, Boris, Stefansson, Hreinn, Domenici, Enrico, Bonassi, Stefano, Stefánsson, Kári, Wu, Jing Qin, Tsuang, Ming T., Myin-Germeys, Inez, Pellegrino, Renata, Visscher, Peter M., Yang, Jian, Posthuma, Danielle, Andreassen, Ole A., Koopmans, Frank, Kendler, Kenneth S., Chong, Siow Ann, Gur, Ruben C., Ehrenreich, Hannelore, Owen, Michael J., Rietschel, Marcella, Gratten, Jacob, Wray, Naomi R., Hoffmann, Per, Daly, Mark J., Szatkiewicz, Jin P., Huang, Hailiang, Nenadić, Igor, Torretta, Silvia, Escott-Price, Valentina, Neale, Benjamin M., Begemann, Martin, Thibaut, Florence, Agerbo, Esben, Rampino, Antonio, Sullivan, Patrick F., Schulze, Thomas G., Ripke, Stephan, Walters, James T. R., O'Donovan, Michael C., Kučinskas, Vaidutis, Belliveau, Richard A., Bene, Judit, Oh, Sang-Yun, Ta, Thi Minh Tam, Greenwood, Tiffany A., Howrigan, Daniel P., Rapaport, Mark H., Benyamin, Beben, Mowry, Bryan J., Giegling, Ina, Strengman, Eric, Bergen, Sarah E., Silverman, Jeremy M., Blasi, Giuseppe, Cohen, David, Stone, William S., Xu, Zhida, Lee, Phil H., Consoli, Angèle, Kelly, Brian J.., Cordeiro, Quirino, Esko, Tõnu, Costas, Javier, Medical Research Council (UK), National Natural Science Foundation of China, Royal Society (UK), Chinese Academy of Sciences, Shanghai Science and Technology Committee, Research Council of Norway, European Commission, Fundação de Amparo à Pesquisa do Estado de São Paulo, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Comunidad de Madrid, Fundación Alicia Koplowitz, Fundación Alonso Lozano, Mental Health Research UK, Wellcome Trust, Brain and Behavior Research Foundation, NIHR Biomedical Research Centre (UK), University College London, Generalitat Valenciana, Trubetskoy, Vassily, Pardiñas, Antonio F., Qi, Ting, Panagiotaropoulou, Georgia, Awasthi, Swapnil, Bigdeli, Tim B., Bryois, Julien, Chen, Chia-Yen, Dennison, Charlotte A., Hall, Lynsey S., Lam, Max, Curtis, Charles, Nikitina-Zake, Liene, Davidson, Michael, Joa, Inge, Davis, Kenneth L., Yolken, Robert, Murray, Robin M., de Haan, Lieuwe, Legge, Sophie E., Serretti, Alessandro, van Os, Jim, Smoller, Jordan W., Agartz, Ingrid, Alizadeh, Behrooz Z., Degenhardt, Franziska, DeLisi, Lynn E., Demontis, Ditte, Dickerson, Faith, Zai, Clement C., Dikeos, Dimitris, Dinan, Timothy, Henskens, Frans A., Vaaler, Arne, Noto, Cristiano, Nimgaonkar, Vishwajit, Rautanen, Anna, Lehrer, Douglas S., Djurovic, Srdjan, Duan, Jubao, Julià, Antonio, Stahl, Eli A., Zhou, Wei, Vawter, Marquis P., Toncheva, Draga, Webb, Bradley T., Ducci, Giuseppe, Dudbridge, Frank, Eriksson, Johan G., Fañanas Saura, Lourdes, Goldstein, Jacqueline I., Faraone, Stephen V., Lencer, Rebecca, Moreno, Carmen, Bacanu, Silviu A., Fiorentino, Alessia, Calkins, Monica E., Mitjans, Marina, Forstner, Andreas, Nuechterlein, Keith H., Frank, Josef, Tsuang, Debby W., Freimer, Nelson B., Tooney, Paul A., Belangero, Sintia Iole, Weinberger, Daniel R., Fromer, Menachem, Ge,Tian, Adolfsson, Rolf, Hakonarson, Hakon, Zhu, Feng, Frustaci, Alessandra, Nöthen, Markus M., Gadelha, Ary, Genovese, Giulio, Gershon, Elliot S., Quattrone, Diego, Kähler, Anna K., Kam-Thong, Tony, van Amelsvoort, Therese, Vilella, Elisabet, Molden, Espen, O'Brien, Niamh Louise, Zimprich, Fritz, Kamatani, Yoichiro, Braun, Alice, Melegh, Bela, Pirinen, Matti, Karachanak-Yankova, Sena, Ophoff, Roel A., Kebir, Oussama, Lerer, Bernard, Nordentoft, Merete, Fanous, Ayman H., Reichenberg, Abraham, Li, Miaoxin, Periyasamy, Sathish, Lieberman, Jeffrey, Werge, Thomas, Light, Gregory A., Limborska, Svetlana, Tosato, Sarah, Liu, Chih-Min, Olincy, Ann, Magnusson, Sigurdur, Gareeva, Anna, Bressan, Rodrigo Affonseca, Lönnqvist, Jouko, Roe, Cheryl, Cheng, Wei, Athanasiu, Lavinia, Gutiérrez, Blanca, Harvey, Carol, Loughland, Carmel M., Lubinski, Jan, Luykx, Jurjen J., Lynham, Amy, Gawlik, Micha, Macek, Milan, Mackinnon, Andrew, Buxbaum, Joseph D., Tura, Gian Battista, Bromet, Evelyn J., Atbaşoğlu, Eşref Cem, Roffman, Joshua L., Magnusson, Patrik K. E., Maher, Brion S., Ota, Vanessa Kiyomi, Paciga, Sara A., Gejman, Pablo V., Arango, Celso, Forti, Marta Di, Maier, Wolfgang, Richards, Alexander L., Malaspina, Dolores, Mallet, Jacques, Metspalu, Andres, Marder, Stephen R., Li, Zhiqiang, Takahashi, Atsushi, Marsal, Sara, Kučinskiene, Zita Ausrele, Suvisaari, Jaana, Martin, Alicia R., Turetsky, Bruce I., Martorell, Lourdes, Palotie, Aarno, Mattheisen, Manuel, Baune, Bernhard T., Saka, Meram C., McCarley, Robert W., Giusti-Rodríguez, Paola, Riley, Brien P., Murphy, Kieran C., Gill, Michael, McDonald, Colm, Bruggeman, Richard, McGrath, John J., Sidorenko, Julia, Medeiros, Helena, Pantelis, Christos, Grove, Jakob, Campion, Dominique, Pato, Carlos N., Svrakic, Dragan M., Üçok, Alp, Glatt, Stephen J., Papadimitriou, George N., Khrunin, Andrey, Straub, Richard E., Parellada, Mara, Buckley, Peter F., Paunio, Tiina, Roth, Julian, Morgan, Vera A., Wildenauer, Dieter B., Ayub, Muhammad, Rothermundt, Matthias, Weiser, Mark, Rutten, Bart P. F., Saker-Delye, Safaa, Salomaa, Veikko, Børglum, Anders D., Sanjuán, Julio, van Winkel, Ruud, González Peñas, Javier, Yu, Xin, Kim, Sung-Wan, Santoro, Marcos Leite, Benner, Christian, Ikeda, Masashi, Morley, Christopher P., Zeng, Jian, Savitz, Adam, Schall, Ulrich, Scott, Rodney J., Voloudakis, Georgios, Yue, Weihua, Seidman, Larry J., Sharp, Sally Isabel, Alptekin, Köksal, Klovins, Janis, Amin, Farooq, Bertolino, Alessandro, Shi, Jianxin, Siever, Larry J., Atkinson, Elizabeth G., Buckner, Randy L., Holmans, Peter A., Rivera, Margarita, Sigurdsson, Engilbert, González-Pinto, Ana, Sim, Kang, Skarabis, Nora, Stroup, T Scott, Slominsky, Petr, Guillin, Olivier, Wang, Shi-Heng, So, Hon-Cheong, Quested, Digby, Sobell, Janet L., Braff, David, Zhang, Wen, Bybjerg-Grauholm, Jonas, Söderman, Erik, Rujescu, Dan, Chambert, Kimberley D., Stain, Helen J., Melle, Ingrid, Carr, Vaughan J, Pocklington, Andrew J., Steen, Nils Eiel, Harwood, Janet, Steixner-Kumar, Agnes A., Gopal, Srihari, Stögmann, Elisabeth, Veijola, Juha, Watanabe, Kyoko, Sham, Pak C., Cahn, Wiepke, Bramon, Elvira, Roussos, Panos, Waddington, John, Perkins, Diana O., Pato, Michele T., Walter, Henrik, Kondratiev, Nikolay, Waterreus, Anna, Al Eissa, Mariam, Bobes, Julio, Golimbet, Vera, Black, Donald W., Als, Thomas D., Bray, Nicholas J., Breen, Gerome, Buccola, Nancy G., Sanders, Alan R., Byerley, William F., Cervilla, Jorge A., Michie, Patricia T., Pfuhlmann, Bruno, Chen, Wei J., Hong, Kyung Sue, O'Neill, F Anthony, Terao, Chikashi, Green, Michael F., Cloninger, C. Robert, Crespo-Facorro, Benedicto, Donohoe, Gary, Gülöksüz, Sinan, Freedman, Robert, Albus, Margot, Hayward, Caroline, Pietiläinen, Olli, Herms, Stefan, Hultman, Christina M., Galletly, Cherrie, Gandal, Michael J., Hahn, Eric, Konte, Bettina, Castle, David, Gennarelli, Massimo, Milani, Lili, Hougaard, David M., Hwu, Hai-Gwo, Pulver, Ann E., Jablensky, Assen V., Molina, Esther, Qin, Shengying, McCarroll, Steven A., Moran, Jennifer L., Azevedo, Maria Helena, Gur, Rachel E., Kraft, Julia, Mors, Ole, Catts, Stanley V., Lazzeroni, Laura C., Mortensen, Preben B., Streit, Fabian, Kusumawardhani, Agung, Alexander, Madeline, Godard, Stephanie, Müller-Myhsok, Bertram, Milanova, Vihra, Neil, Amanda L., Cichon, Sven, Giannitelli, Marianna, Cheung, Eric F. C., Kubo, Michiaki, Schwab, Sibylle G., Collier, David A., Williams, Nigel M., Morris, Derek W., Corvin, Aiden, Pimm, Jonathan, Curtis, David, Haroutunian, Vahram, Keller, Matthew C., Vassos, Evangelos, Hyman, Steven E., Iwata, Nakao, Jönsson, Erik G., Kahn, René S., Chan, Raymond C. K., Kennedy, James L., Shi, Yongyong, Adams, Mark, Witt, Stephanie H., Khusnutdinova, Elza, Verhage, Matthijs, Xu, Shuhua, Wu, Yang, Kirov, George, Arolt, Volker, Knowles, James A., Moltó, Maria Dolores, Krebs, Marie-Odile, Hartmann, Annette M., Nestadt, Gerald, Wormley, Brandon K., Bass, Nicholas J., Laurent-Levinson, Claudine, Lee, Jimmy, Muntané, Gerard, Porteous, David, Kuzelova-Ptackova, Hana, Lencz, Todd, Subramaniam, Mythily, Levinson, Douglas F., Li, Qingqin S., Liu, Jianjun, Swerdlow, Neal R., Cairns, Murray J., Malhotra, Anil K., Malhotra, Dheeraj, Iyegbe, Conrad, Mondelli, Valeria, Kim, Minsoo, Arrojo, Manuel, Landi, Stefano, McIntosh, Andrew M., Petryshen, Tracey L., Radant, Allen D., Frei, Oleksandr, Mesholam-Gately, Raquelle I., McQuillin, Andrew, Sugar, Catherine A., Menezes, Paulo Rossi, St Clair, David, Meier, Sandra, Powell, John, Chaumette, Boris, Stefansson, Hreinn, Domenici, Enrico, Bonassi, Stefano, Stefánsson, Kári, Wu, Jing Qin, Tsuang, Ming T., Myin-Germeys, Inez, Pellegrino, Renata, Visscher, Peter M., Yang, Jian, Posthuma, Danielle, Andreassen, Ole A., Koopmans, Frank, Kendler, Kenneth S., Chong, Siow Ann, Gur, Ruben C., Ehrenreich, Hannelore, Owen, Michael J., Rietschel, Marcella, Gratten, Jacob, Wray, Naomi R., Hoffmann, Per, Daly, Mark J., Szatkiewicz, Jin P., Huang, Hailiang, Nenadić, Igor, Torretta, Silvia, Escott-Price, Valentina, Neale, Benjamin M., Begemann, Martin, Thibaut, Florence, Agerbo, Esben, Rampino, Antonio, Sullivan, Patrick F., Schulze, Thomas G., Ripke, Stephan, Walters, James T. R., O'Donovan, Michael C., Kučinskas, Vaidutis, Belliveau, Richard A., Bene, Judit, Oh, Sang-Yun, Ta, Thi Minh Tam, Greenwood, Tiffany A., Howrigan, Daniel P., Rapaport, Mark H., Benyamin, Beben, Mowry, Bryan J., Giegling, Ina, Strengman, Eric, Bergen, Sarah E., Silverman, Jeremy M., Blasi, Giuseppe, Cohen, David, Stone, William S., Xu, Zhida, Lee, Phil H., Consoli, Angèle, Kelly, Brian J.., Cordeiro, Quirino, Esko, Tõnu, and Costas, Javier

Abstract

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.

Published
2022

4. A replication study of JTC bias, genetic liability for psychosis and delusional ideation

Author

Hersenen-Medisch 1, Brain, TN groep Adan, Laboranten CT Radiologie, Henquet, Cécile, van Os, Jim, Pries, Lotta K, Rauschenberg, Christian, Delespaul, Philippe, Kenis, Gunter, Luykx, Jurjen J, Lin, Bochao D, Richards, Alexander L, Akdede, Berna, Binbay, Tolga, Altınyazar, Vesile, Yalınçetin, Berna, Gümüş-Akay, Güvem, Cihan, Burçin, Soygür, Haldun, Ulaş, Halis, Cankurtaran, Eylem S, Kaymak, Semra U, Mihaljevic, Marina M, Petrovic, Sanja S, Mirjanic, Tijana, Bernardo, Miguel, Mezquida, Gisela, Amoretti, Silvia, Bobes, Julio, Saiz, Pilar A, García-Portilla, Maria P, Sanjuan, Julio, Aguilar, Eduardo J, Santos, Jose L, Jiménez-López, Estela, Arrojo, Manuel, Carracedo, Angel, López, Gonzalo, González-Peñas, Javier, Parellada, Mara, Maric, Nadja P, Atbaşoğlu, Cem, Ucok, Alp, Alptekin, Köksal, Saka, Meram C, Arango, Celso, O'Donovan, Michael, Rutten, Bart P F, Gülöksüz, Sinan, Hersenen-Medisch 1, Brain, TN groep Adan, Laboranten CT Radiologie, Henquet, Cécile, van Os, Jim, Pries, Lotta K, Rauschenberg, Christian, Delespaul, Philippe, Kenis, Gunter, Luykx, Jurjen J, Lin, Bochao D, Richards, Alexander L, Akdede, Berna, Binbay, Tolga, Altınyazar, Vesile, Yalınçetin, Berna, Gümüş-Akay, Güvem, Cihan, Burçin, Soygür, Haldun, Ulaş, Halis, Cankurtaran, Eylem S, Kaymak, Semra U, Mihaljevic, Marina M, Petrovic, Sanja S, Mirjanic, Tijana, Bernardo, Miguel, Mezquida, Gisela, Amoretti, Silvia, Bobes, Julio, Saiz, Pilar A, García-Portilla, Maria P, Sanjuan, Julio, Aguilar, Eduardo J, Santos, Jose L, Jiménez-López, Estela, Arrojo, Manuel, Carracedo, Angel, López, Gonzalo, González-Peñas, Javier, Parellada, Mara, Maric, Nadja P, Atbaşoğlu, Cem, Ucok, Alp, Alptekin, Köksal, Saka, Meram C, Arango, Celso, O'Donovan, Michael, Rutten, Bart P F, and Gülöksüz, Sinan

Published
2022

5. Human CRY1 variants associate with attention deficit/hyperactivity disorder

Author

Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics, Gül, Şeref; Aydın, Cihan (ORCID 0000-0003-0560-1895 & YÖK ID 214696); Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512); Kavaklı, İbrahim Halil (ORCID 0000-0001-6624-3505 & YÖK ID 40319), Onat, O. Emre; Kars, M. Ece; Bilguvar, Kaya; Wu, Yiming; Özhan, Ayşe; Trusso, M. Allegra; Goracci, Arianna; Fallerini, Chiara; Renieri, Alessandra; Casanova, Jean Laurent; Itan, Yuval; Atbaşoğlu, Cem E.; Saka, Meram C.; Özçelik, Tayfun, Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics, Gül, Şeref; Aydın, Cihan (ORCID 0000-0003-0560-1895 & YÖK ID 214696); Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512); Kavaklı, İbrahim Halil (ORCID 0000-0001-6624-3505 & YÖK ID 40319), and Onat, O. Emre; Kars, M. Ece; Bilguvar, Kaya; Wu, Yiming; Özhan, Ayşe; Trusso, M. Allegra; Goracci, Arianna; Fallerini, Chiara; Renieri, Alessandra; Casanova, Jean Laurent; Itan, Yuval; Atbaşoğlu, Cem E.; Saka, Meram C.; Özçelik, Tayfun

Abstract

Attention deficit/hyperactivity disorder (ADHD) is a common and heritable phenotype frequently accompanied by insomnia, anxiety, and depression. Here, using a reverse phenotyping approach, we report heterozygous coding variations in the core circadian clock gene cryptochrome 1 in 15 unrelated multigenerational families with combined ADHD and insomnia. The variants led to functional alterations in the circadian molecular rhythms, providing a mechanistic link to the behavioral symptoms. One variant, CRY1Δ11 c.1657+3A>C, is present in approximately 1% of Europeans, therefore standing out as a diagnostic and therapeutic marker. We showed by exome sequencing in an independent cohort of patients with combined ADHD and insomnia that 8 of 62 patients and 0 of 369 controls carried CRY1Δ11. Also, we identified a variant, CRY1Δ6 c.825+1G>A, that shows reduced affinity for BMAL1/CLOCK and causes an arrhythmic phenotype. Genotype-phenotype correlation analysis revealed that this variant segregated with ADHD and delayed sleep phase disorder (DSPD) in the affected family. Finally, we found in a phenome-wide association study involving 9438 unrelated adult Europeans that CRY1Δ11 was associated with major depressive disorder, insomnia, and anxiety. These results defined a distinctive group of circadian psychiatric phenotypes that we propose to designate as "circiatric" disorders.

Published
2020

6. A replication study of JTC bias, genetic liability for psychosis and delusional ideation

Author

Henquet, Cécile, primary, van Os, Jim, additional, Pries, Lotta K., additional, Rauschenberg, Christian, additional, Delespaul, Philippe, additional, Kenis, Gunter, additional, Luykx, Jurjen J., additional, Lin, Bochao D., additional, Richards, Alexander L., additional, Akdede, Berna, additional, Binbay, Tolga, additional, Altınyazar, Vesile, additional, Yalınçetin, Berna, additional, Gümüş-Akay, Güvem, additional, Cihan, Burçin, additional, Soygür, Haldun, additional, Ulaş, Halis, additional, Cankurtaran, Eylem S., additional, Kaymak, Semra U., additional, Mihaljevic, Marina M., additional, Petrovic, Sanja S., additional, Mirjanic, Tijana, additional, Bernardo, Miguel, additional, Mezquida, Gisela, additional, Amoretti, Silvia, additional, Bobes, Julio, additional, Saiz, Pilar A., additional, García-Portilla, Maria P., additional, Sanjuan, Julio, additional, Aguilar, Eduardo J., additional, Santos, Jose L., additional, Jiménez-López, Estela, additional, Arrojo, Manuel, additional, Carracedo, Angel, additional, López, Gonzalo, additional, González-Peñas, Javier, additional, Parellada, Mara, additional, Maric, Nadja P., additional, Atbaşoğlu, Cem, additional, Ucok, Alp, additional, Alptekin, Köksal, additional, Saka, Meram C., additional, Arango, Celso, additional, O'Donovan, Michael, additional, Rutten, Bart P.F., additional, and Gülöksüz, Sinan, additional

Published
2020
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7. The Factor Structure of Schizophrenic Symptoms: Which Model is Supported by Independent Item Analysis?

Author

Kizil, E. Tuğba Özel, Saka, Meram C., Atbaşoğlu, E. Cem, and Gögüs, A. Kemal

Subjects
FACTOR structure, FACTOR analysis, SYMPTOMS, SCHIZOPHRENIA, PEOPLE with schizophrenia
Abstract

Objective: Most studies that have investigated the symptom dimensions of schizophrenia utilizing the Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of Negative Symptoms (SANS), both global rating scales, favored a 3-factor model. Only a few studies have examined the factor structure at the item level and they suggest a wider dimensional structure. The factor structure of schizophrenic symptoms has not been previously studied in Turkey, nor has the construct validity of these scales. The present study sought to determine the factor structure of the independent items and the construct validity of the scales. Method: The study included 180 schizophrenia patients (diagnoses based on DSM-IV criteria). The standard statistical methods of principal component analysis (PCA) and varimax rotation were used to extract factors. Results: PCA of the global items yielded a 3-factor solution, representing positive, negative, and disorganization dimensions. Item-level factor analysis revealed 12 factors: Psychomotor poverty, positive formal thought disorder, auditory/visual hallucinations, social and occupational dysfunction, bizarre delusions, attention/stereotypy, paranoid features, somatic hallucinations/delusions, appearance, grandiose/religious delusions, inappropriate affect, and delusions of jealousy. Conclusion: Consistent with previous studies, neither the global nor the item-level factor structures supported the simple positive-negative dichotomy or the composition of the sub-scales; therefore, future studies should make use of the single items, especially when positive symptoms are being studied. [ABSTRACT FROM AUTHOR]

Published
2008

8. Human CRY1 variants associate with attention deficit/hyperactivity disorder

Author

I Halil Kavaklı, Arianna Goracci, Yuval Itan, Ayse Ozhan, Chiara Fallerini, Jean-Laurent Casanova, Cihan Aydin, M Ece Kars, O Emre Onat, Yiming Wu, Cem Atbaşoğlu, A. Nazli Basak, Kaya Bilguvar, Alessandra Renieri, Tayfun Ozcelik, M Allegra Trusso, Meram Can Saka, Seref Gul, Gül, Şeref, Aydın, Cihan (ORCID 0000-0003-0560-1895 & YÖK ID 214696), Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), Kavaklı, İbrahim Halil (ORCID 0000-0001-6624-3505 & YÖK ID 40319), Onat, O. Emre, Kars, M. Ece, Bilguvar, Kaya, Wu, Yiming, Özhan, Ayşe, Trusso, M. Allegra, Goracci, Arianna, Fallerini, Chiara, Renieri, Alessandra, Casanova, Jean Laurent, Itan, Yuval, Atbaşoğlu, Cem E., Saka, Meram C., Özçelik, Tayfun, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), Graduate School of Sciences and Engineering, College of Engineering, College of Sciences, Department of Chemical and Biological Engineering, Department of Molecular Biology and Genetics, and Başak, A. N.

Subjects
Adult, Male, 0301 basic medicine, Genetic diseases, Genetics, Monogenic diseases, Psychiatric diseases, CLOCK Proteins, Delayed sleep phase, Bioinformatics, ARNTL Transcription Factors, Attention Deficit Disorder with Hyperactivity, Cryptochromes, Female, Genetic Association Studies, HEK293 Cells, Humans, Sleep Disorders, Circadian Rhythm, Mutation, 03 medical and health sciences, 0302 clinical medicine, mental disorders, Insomnia, Medicine, Attention deficit hyperactivity disorder, Circadian rhythm, Exome sequencing, Depression (differential diagnoses), business.industry, General Medicine, medicine.disease, Circadian Rhythm, Biology, 030104 developmental biology, 030220 oncology & carcinogenesis, Anxiety, Major depressive disorder, medicine.symptom, Sleep Disorders, business, Research Article
Abstract

Attention deficit/hyperactivity disorder (ADHD) is a common and heritable phenotype frequently accompanied by insomnia, anxiety, and depression. Here, using a reverse phenotyping approach, we report heterozygous coding variations in the core circadian clock gene cryptochrome 1 in 15 unrelated multigenerational families with combined ADHD and insomnia. The variants led to functional alterations in the circadian molecular rhythms, providing a mechanistic link to the behavioral symptoms. One variant, CRY1Δ11 c.1657+3A>C, is present in approximately 1% of Europeans, therefore standing out as a diagnostic and therapeutic marker. We showed by exome sequencing in an independent cohort of patients with combined ADHD and insomnia that 8 of 62 patients and 0 of 369 controls carried CRY1Δ11. Also, we identified a variant, CRY1Δ6 c.825+1G>A, that shows reduced affinity for BMAL1/CLOCK and causes an arrhythmic phenotype. Genotype-phenotype correlation analysis revealed that this variant segregated with ADHD and delayed sleep phase disorder (DSPD) in the affected family. Finally, we found in a phenome-wide association study involving 9438 unrelated adult Europeans that CRY1Δ11 was associated with major depressive disorder, insomnia, and anxiety. These results defined a distinctive group of circadian psychiatric phenotypes that we propose to designate as "circiatric" disorders., NIH Clinical and Translational Science Award (CTSA) Program; NIH; French National Research Agency (ANR) under the “Investments for the future” Program; Integrative Biology of Emerging Infectious Diseases Laboratoire d’Excellence; IEIHSEER Grant; SEAe-Host Factors Grant; PNEUMOID Project Grant; INCA/Cancéropole Ile-de-France; Turkish Academy of Sciences (TÜBA); National Center for Advancing Translational Sciences (NCAST); Rockefeller University, INSERM; HHMI, University of Paris; St. Giles Foundation; Charles Bronfman Institute for Personalized Medicine at the Icahn School of Medicine at Mount Sinai

Published
2020

9. A replication study of JTC bias, genetic liability for psychosis and delusional ideation.

Author

Henquet C, van Os J, Pries LK, Rauschenberg C, Delespaul P, Kenis G, Luykx JJ, Lin BD, Richards AL, Akdede B, Binbay T, Altınyazar V, Yalınçetin B, Gümüş-Akay G, Cihan B, Soygür H, Ulaş H, Cankurtaran ES, Kaymak SU, Mihaljevic MM, Petrovic SS, Mirjanic T, Bernardo M, Mezquida G, Amoretti S, Bobes J, Saiz PA, García-Portilla MP, Sanjuan J, Aguilar EJ, Santos JL, Jiménez-López E, Arrojo M, Carracedo A, López G, González-Peñas J, Parellada M, Maric NP, Atbaşoğlu C, Ucok A, Alptekin K, Saka MC, Arango C, O'Donovan M, Rutten BPF, and Gülöksüz S

Subjects
Bias, Decision Making, Delusions psychology, Hallucinations, Humans, Psychotic Disorders psychology, Schizophrenia genetics
Abstract

Background: This study attempted to replicate whether a bias in probabilistic reasoning, or 'jumping to conclusions'(JTC) bias is associated with being a sibling of a patient with schizophrenia spectrum disorder; and if so, whether this association is contingent on subthreshold delusional ideation., Methods: Data were derived from the EUGEI project, a 25-centre, 15-country effort to study psychosis spectrum disorder. The current analyses included 1261 patients with schizophrenia spectrum disorder, 1282 siblings of patients and 1525 healthy comparison subjects, recruited in Spain (five centres), Turkey (three centres) and Serbia (one centre). The beads task was used to assess JTC bias. Lifetime experience of delusional ideation and hallucinatory experiences was assessed using the Community Assessment of Psychic Experiences. General cognitive abilities were taken into account in the analyses., Results: JTC bias was positively associated not only with patient status but also with sibling status [adjusted relative risk (aRR) ratio : 4.23 CI 95% 3.46-5.17 for siblings and aRR: 5.07 CI 95% 4.13-6.23 for patients]. The association between JTC bias and sibling status was stronger in those with higher levels of delusional ideation (aRR interaction in siblings: 3.77 CI 95% 1.67-8.51, and in patients: 2.15 CI 95% 0.94-4.92). The association between JTC bias and sibling status was not stronger in those with higher levels of hallucinatory experiences., Conclusions: These findings replicate earlier findings that JTC bias is associated with familial liability for psychosis and that this is contingent on the degree of delusional ideation but not hallucinations.

Published
2022
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