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1. Cognition and Educational Achievement in the Toronto Adolescent and Youth Cohort Study:Rationale, Methods, and Early Data

Author: Quilty, Lena C, Tempelaar, Wanda, Andrade, Brendan F, Kidd, Sean A, Lunsky, Yona, Chen, Sheng, Wang, Wei, Wong, Jimmy K Y, Lau, Chloe, Sedrak, Andrew B, Kelly, Rachel, Sivakumar, Harijah, Jani, Melanie, Ameis, Stephanie H, Cleverley, Kristin, Goldstein, Benjamin I, Felsky, Daniel, Dickie, Erin W, Foussias, George, Kozloff, Nicole, Nikolova, Yuliya S, Polillo, Alexia, Diaconescu, Andreea O, Wheeler, Anne L, Courtney, Darren B, Hawke, Lisa D, Rotenberg, Martin, Voineskos, Aristotle N, Quilty, Lena C, Tempelaar, Wanda, Andrade, Brendan F, Kidd, Sean A, Lunsky, Yona, Chen, Sheng, Wang, Wei, Wong, Jimmy K Y, Lau, Chloe, Sedrak, Andrew B, Kelly, Rachel, Sivakumar, Harijah, Jani, Melanie, Ameis, Stephanie H, Cleverley, Kristin, Goldstein, Benjamin I, Felsky, Daniel, Dickie, Erin W, Foussias, George, Kozloff, Nicole, Nikolova, Yuliya S, Polillo, Alexia, Diaconescu, Andreea O, Wheeler, Anne L, Courtney, Darren B, Hawke, Lisa D, Rotenberg, Martin, and Voineskos, Aristotle N
Abstract: Background: Both cognition and educational achievement in youths are linked to psychosis risk. One major aim of the Toronto Adolescent and Youth (TAY) Cohort Study is to characterize how cognitive and educational achievement trajectories inform the course of psychosis spectrum symptoms (PSSs), functioning, and suicidality. Here, we describe the protocol for the cognitive and educational data and early baseline data. Methods: The cognitive assessment design is consistent with youth population cohort studies, including the NIH Toolbox, Rey Auditory Verbal Learning Test, Wechsler Matrix Reasoning Task, and Little Man Task. Participants complete an educational achievement questionnaire, and report cards are requested. Completion rates, descriptive data, and differences across PSS status are reported for the first participants (N = 417) ages 11 to 24 years, who were recruited between May 4, 2021, and February 2, 2023. Results: Nearly 84% of the sample completed cognitive testing, and 88.2% completed the educational questionnaire, whereas report cards were collected for only 40.3%. Modifications to workflows were implemented to improve data collection. Participants who met criteria for PSSs demonstrated lower performance than those who did not on numerous key cognitive indices (p < .05) and also had more academic/educational problems. Conclusions: Following youths longitudinally enabled trajectory mapping and prediction based on cognitive and educational performance in relation to PSSs in treatment-seeking youths. Youths with PSSs had lower cognitive performance and worse educational outcomes than youths without PSSs. Results show the feasibility of collecting data on cognitive and educational outcomes in a cohort of youths seeking treatment related to mental illness and substance use.
Published: 2024

2. The Toronto Adolescent and Youth Cohort Study:Study Design and Early Data Related to Psychosis Spectrum Symptoms, Functioning, and Suicidality

Author: Cleverley, Kristin, Foussias, George, Ameis, Stephanie H, Courtney, Darren B, Goldstein, Benjamin I, Hawke, Lisa D, Kozloff, Nicole, Quilty, Lena C, Rotenberg, Martin, Wheeler, Anne L, Andrade, Brendan F, Aitken, Madison, Mahleka, Don, Jani, Melanie, Frayne, Margot, Wong, Jimmy K Y, Kelly, Rachel, Dickie, Erin W, Felsky, Daniel, Haltigan, John D, Lai, Meng-Chuan, Nikolova, Yuliya S, Tempelaar, Wanda, Wang, Wei, Battaglia, Marco, Husain, Muhammad Omair, Kidd, Sean, Kurdyak, Paul, Levitan, Robert D, Lewis, Stephen P, Polillo, Alexia, Szatmari, Peter, van der Miesen, Anna I R, Ahmadzadasl, Masoud, Voineskos, Aristotle N, Cleverley, Kristin, Foussias, George, Ameis, Stephanie H, Courtney, Darren B, Goldstein, Benjamin I, Hawke, Lisa D, Kozloff, Nicole, Quilty, Lena C, Rotenberg, Martin, Wheeler, Anne L, Andrade, Brendan F, Aitken, Madison, Mahleka, Don, Jani, Melanie, Frayne, Margot, Wong, Jimmy K Y, Kelly, Rachel, Dickie, Erin W, Felsky, Daniel, Haltigan, John D, Lai, Meng-Chuan, Nikolova, Yuliya S, Tempelaar, Wanda, Wang, Wei, Battaglia, Marco, Husain, Muhammad Omair, Kidd, Sean, Kurdyak, Paul, Levitan, Robert D, Lewis, Stephen P, Polillo, Alexia, Szatmari, Peter, van der Miesen, Anna I R, Ahmadzadasl, Masoud, and Voineskos, Aristotle N
Abstract: BACKGROUND: Psychosis spectrum symptoms (PSSs) occur in a sizable percentage of youth and are associated with poorer cognitive performance, poorer functioning, and suicidality (i.e., suicidal thoughts and behaviors). PSSs may occur more frequently in youths already experiencing another mental illness, but the antecedents are not well known. The Toronto Adolescent and Youth (TAY) Cohort Study aims to characterize developmental trajectories in youths with mental illness and understand associations with PSSs, functioning, and suicidality.METHODS: The TAY Cohort Study is a longitudinal cohort study that aims to assess 1500 youths (age 11-24 years) presenting to tertiary care. In this article, we describe the extensive diagnostic and clinical characterization of psychopathology, substance use, functioning, suicidality, and health service utilization in these youths, with follow-up every 6 months over 5 years, including early baseline data.RESULTS: A total of 417 participants were enrolled between May 4, 2021, and February 2, 2023. Participants met diagnostic criteria for an average of 3.5 psychiatric diagnoses, most frequently anxiety and depressive disorders. Forty-nine percent of participants met a pre-established threshold for PSSs and exhibited higher rates of functional impairment, internalizing and externalizing symptoms, and suicidality than participants without PSSs.CONCLUSIONS: Initial findings from the TAY Cohort Study demonstrate the feasibility of extensive clinical phenotyping in youths who are seeking help for mental health problems. PSS prevalence is much higher than in community-based studies. Our early data support the critical need to better understand longitudinal trajectories of clinical youth cohorts in relation to psychosis risk, functioning, and suicidality.
Published: 2024

3. Neuroimaging and Biosample Collection in the Toronto Adolescent and Youth Cohort Study:Rationale, Methods, and Early Data

Author: Dickie, Erin W, Ameis, Stephanie H, Boileau, Isabelle, Diaconescu, Andreea O, Felsky, Daniel, Goldstein, Benjamin I, Gonçalves, Vanessa, Griffiths, John D, Haltigan, John D, Husain, Muhammad O, Rubin-Kahana, Dafna S, Iftikhar, Myera, Jani, Melanie, Lai, Meng-Chuan, Lin, Hsiang-Yuan, MacIntosh, Bradley J, Wheeler, Anne L, Vasdev, Neil, Vieira, Erica, Ahmadzadeh, Ghazaleh, Heyland, Lindsay, Mohan, Akshay, Ogunsanya, Feyi, Oliver, Lindsay D, Zhu, Cherrie, Wong, Jimmy K Y, Charlton, Colleen, Truong, Jennifer, Yu, Lujia, Kelly, Rachel, Cleverley, Kristin, Courtney, Darren B, Foussias, George, Hawke, Lisa D, Hill, Sean, Kozloff, Nicole, Polillo, Alexia, Rotenberg, Martin, Quilty, Lena C, Tempelaar, Wanda, Wang, Wei, Nikolova, Yuliya S, Voineskos, Aristotle N, Dickie, Erin W, Ameis, Stephanie H, Boileau, Isabelle, Diaconescu, Andreea O, Felsky, Daniel, Goldstein, Benjamin I, Gonçalves, Vanessa, Griffiths, John D, Haltigan, John D, Husain, Muhammad O, Rubin-Kahana, Dafna S, Iftikhar, Myera, Jani, Melanie, Lai, Meng-Chuan, Lin, Hsiang-Yuan, MacIntosh, Bradley J, Wheeler, Anne L, Vasdev, Neil, Vieira, Erica, Ahmadzadeh, Ghazaleh, Heyland, Lindsay, Mohan, Akshay, Ogunsanya, Feyi, Oliver, Lindsay D, Zhu, Cherrie, Wong, Jimmy K Y, Charlton, Colleen, Truong, Jennifer, Yu, Lujia, Kelly, Rachel, Cleverley, Kristin, Courtney, Darren B, Foussias, George, Hawke, Lisa D, Hill, Sean, Kozloff, Nicole, Polillo, Alexia, Rotenberg, Martin, Quilty, Lena C, Tempelaar, Wanda, Wang, Wei, Nikolova, Yuliya S, and Voineskos, Aristotle N
Abstract: BACKGROUND: The Toronto Adolescent and Youth (TAY) Cohort Study will characterize the neurobiological trajectories of psychosis spectrum symptoms, functioning, and suicidality (i.e., suicidal thoughts and behaviors) in youth seeking mental health care. Here, we present the neuroimaging and biosample component of the protocol. We also present feasibility and quality control metrics for the baseline sample collected thus far.METHODS: The current study includes youths (ages 11-24 years) who were referred to child and youth mental health services within a large tertiary care center in Toronto, Ontario, Canada, with target recruitment of 1500 participants. Participants were offered the opportunity to provide any or all of the following: 1) 1-hour magnetic resonance imaging (MRI) scan (electroencephalography if ineligible for or declined MRI), 2) blood sample for genomic and proteomic data (or saliva if blood collection was declined or not feasible) and urine sample, and 3) heart rate recording to assess respiratory sinus arrhythmia.RESULTS: Of the first 417 participants who consented to participate between May 4, 2021, and February 2, 2023, 412 agreed to participate in the imaging and biosample protocol. Of these, 334 completed imaging, 341 provided a biosample, 338 completed respiratory sinus arrhythmia, and 316 completed all 3. Following quality control, data usability was high (MRI: T1-weighted 99%, diffusion-weighted imaging 99%, arterial spin labeling 90%, resting-state functional MRI 95%, task functional MRI 90%; electroencephalography: 83%; respiratory sinus arrhythmia: 99%).CONCLUSIONS: The high consent rates, good completion rates, and high data usability reported here demonstrate the feasibility of collecting and using brain imaging and biosamples in a large clinical cohort of youths seeking mental health care.
Published: 2024

4. Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium

Author: Schijven, Dick, Postema, Merel C., Fukunaga, Masaki, Matsumoto, Junya, Miura, Kenichiro, de Zwarte, Sonja M. C., van Haren, Neeltje E. M., Cahn, Wiepke, Hulshoff Pol, Hilleke E., Kahn, René S., Ayesa-Arriola, Rosa, Ortiz-García de la Foz, Víctor, Tordesillas-Gutierrez, Diana, Vázquez-Bourgon, Javier, Crespo-Facorro, Benedicto, Alnæs, Dag, Dahl, Andreas, Westlye, Lars T., Agartz, Ingrid, Andreassen, Ole A., Jönsson, Erik G., Kochunov, Peter, Bruggemann, Jason M., Catts, Stanley V., Michie, Patricia T., Mowry, Bryan J., Quidé, Yann, Rasser, Paul E., Schall, Ulrich, Scott, Rodney J., Carr, Vaughan J., Green, Melissa J., Henskens, Frans A., Loughland, Carmel M., Pantelis, Christos, Weickert, Cynthia Shannon, Weickert, Thomas W., de Haan, Lieuwe, Brosch, Katharina, Pfarr, Julia-Katharina, Ringwald, Kai G., Stein, Frederike, Jansen, Andreas, Kircher, Tilo T. J., Nenadić, Igor, Krämer, Bernd, Gruber, Oliver, Satterthwaite, Theodore D., Bustillo, Juan, Mathalon, Daniel H., Preda, Adrian, Calhoun, Vince D., Ford, Judith M., Potkin, Steven G., Chen, Jingxu, Tan, Yunlong, Wang, Zhiren, Xiang, Hong, Fan, Fengmei, Bernardoni, Fabio, Ehrlich, Stefan, Fuentes-Claramonte, Paola, Garcia-Leon, Maria Angeles, Guerrero-Pedraza, Amalia, Salvador, Raymond, Sarró, Salvador, Pomarol-Clotet, Edith, Ciullo, Valentina, Piras, Fabrizio, Vecchio, Daniela, Banaj, Nerisa, Spalletta, Gianfranco, Michielse, Stijn, van Amelsvoort, Therese, Dickie, Erin W., Voineskos, Aristotle N., Sim, Kang, Ciufolini, Simone, Dazzan, Paola, Murray, Robin M., Kim, Woo-Sung, Chung, Young-Chul, Andreou, Christina, Schmidt, André, Borgwardt, Stefan, McIntosh, Andrew M., Whalley, Heather C., Lawrie, Stephen M., du Plessis, Stefan, Luckhoff, Hilmar K., Scheffler, Freda, Emsley, Robin, Grotegerd, Dominik, Lencer, Rebekka, Dannlowski, Udo, Edmond, Jesse T., Rootes-Murdy, Kelly, Stephen, Julia M., Mayer, Andrew R., Antonucci, Linda A., Fazio, Leonardo, Pergola, Giulio, Bertolino, Alessandro, Díaz-Caneja, Covadonga M., Janssen, Joost, Lois, Noemi G., Arango, Celso, Tomyshev, Alexander S., Lebedeva, Irina, Cervenka, Simon, Sellgren, Carl M., Georgiadis, Foivos, Kirschner, Matthias, Kaiser, Stefan, Hajek, Tomas, Skoch, Antonin, Spaniel, Filip, Kim, Minah, Kwak, Yoo Bin, Oh, Sanghoon, Kwon, Jun Soo, James, Anthony, Bakker, Geor, Knöchel, Christian, Stäblein, Michael, Oertel, Viola, Uhlmann, Anne, Howells, Fleur M., Stein, Dan J., Temmingh, Henk S., Diaz-Zuluaga, Ana M., Pineda-Zapata, Julian A., López-Jaramillo, Carlos, Homan, Stephanie, Ji, Ellen, Surbeck, Werner, Homan, Philipp, Fisher, Simon E., Franke, Barbara, Glahn, David C., Gur, Ruben C., Hashimoto, Ryota, Jahanshad, Neda, Lueders, Eileen, Medland, Sarah E., Thompson, Paul M., Turner, Jessica A., van Erp, Theo G. M., Francks, Clyde, Schijven, Dick, Postema, Merel C., Fukunaga, Masaki, Matsumoto, Junya, Miura, Kenichiro, de Zwarte, Sonja M. C., van Haren, Neeltje E. M., Cahn, Wiepke, Hulshoff Pol, Hilleke E., Kahn, René S., Ayesa-Arriola, Rosa, Ortiz-García de la Foz, Víctor, Tordesillas-Gutierrez, Diana, Vázquez-Bourgon, Javier, Crespo-Facorro, Benedicto, Alnæs, Dag, Dahl, Andreas, Westlye, Lars T., Agartz, Ingrid, Andreassen, Ole A., Jönsson, Erik G., Kochunov, Peter, Bruggemann, Jason M., Catts, Stanley V., Michie, Patricia T., Mowry, Bryan J., Quidé, Yann, Rasser, Paul E., Schall, Ulrich, Scott, Rodney J., Carr, Vaughan J., Green, Melissa J., Henskens, Frans A., Loughland, Carmel M., Pantelis, Christos, Weickert, Cynthia Shannon, Weickert, Thomas W., de Haan, Lieuwe, Brosch, Katharina, Pfarr, Julia-Katharina, Ringwald, Kai G., Stein, Frederike, Jansen, Andreas, Kircher, Tilo T. J., Nenadić, Igor, Krämer, Bernd, Gruber, Oliver, Satterthwaite, Theodore D., Bustillo, Juan, Mathalon, Daniel H., Preda, Adrian, Calhoun, Vince D., Ford, Judith M., Potkin, Steven G., Chen, Jingxu, Tan, Yunlong, Wang, Zhiren, Xiang, Hong, Fan, Fengmei, Bernardoni, Fabio, Ehrlich, Stefan, Fuentes-Claramonte, Paola, Garcia-Leon, Maria Angeles, Guerrero-Pedraza, Amalia, Salvador, Raymond, Sarró, Salvador, Pomarol-Clotet, Edith, Ciullo, Valentina, Piras, Fabrizio, Vecchio, Daniela, Banaj, Nerisa, Spalletta, Gianfranco, Michielse, Stijn, van Amelsvoort, Therese, Dickie, Erin W., Voineskos, Aristotle N., Sim, Kang, Ciufolini, Simone, Dazzan, Paola, Murray, Robin M., Kim, Woo-Sung, Chung, Young-Chul, Andreou, Christina, Schmidt, André, Borgwardt, Stefan, McIntosh, Andrew M., Whalley, Heather C., Lawrie, Stephen M., du Plessis, Stefan, Luckhoff, Hilmar K., Scheffler, Freda, Emsley, Robin, Grotegerd, Dominik, Lencer, Rebekka, Dannlowski, Udo, Edmond, Jesse T., Rootes-Murdy, Kelly, Stephen, Julia M., Mayer, Andrew R., Antonucci, Linda A., Fazio, Leonardo, Pergola, Giulio, Bertolino, Alessandro, Díaz-Caneja, Covadonga M., Janssen, Joost, Lois, Noemi G., Arango, Celso, Tomyshev, Alexander S., Lebedeva, Irina, Cervenka, Simon, Sellgren, Carl M., Georgiadis, Foivos, Kirschner, Matthias, Kaiser, Stefan, Hajek, Tomas, Skoch, Antonin, Spaniel, Filip, Kim, Minah, Kwak, Yoo Bin, Oh, Sanghoon, Kwon, Jun Soo, James, Anthony, Bakker, Geor, Knöchel, Christian, Stäblein, Michael, Oertel, Viola, Uhlmann, Anne, Howells, Fleur M., Stein, Dan J., Temmingh, Henk S., Diaz-Zuluaga, Ana M., Pineda-Zapata, Julian A., López-Jaramillo, Carlos, Homan, Stephanie, Ji, Ellen, Surbeck, Werner, Homan, Philipp, Fisher, Simon E., Franke, Barbara, Glahn, David C., Gur, Ruben C., Hashimoto, Ryota, Jahanshad, Neda, Lueders, Eileen, Medland, Sarah E., Thompson, Paul M., Turner, Jessica A., van Erp, Theo G. M., and Francks, Clyde
Abstract: Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.
Published: 2023
Full Text: View/download PDF

5. Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium

Author: Schijven, Dick, Postema, Merel C., Fukunaga, Masaki, Matsumoto, Junya, Miura, Kenichiro, de Zwarte, Sonja M. C., van Haren, Neeltje E. M., Cahn, Wiepke, Hulshoff Pol, Hilleke E., Kahn, René S., Ayesa-Arriola, Rosa, Ortiz-García de la Foz, Víctor, Tordesillas-Gutierrez, Diana, Vázquez-Bourgon, Javier, Crespo-Facorro, Benedicto, Alnæs, Dag, Dahl, Andreas, Westlye, Lars T., Agartz, Ingrid, Andreassen, Ole A., Jönsson, Erik G., Kochunov, Peter, Bruggemann, Jason M., Catts, Stanley V., Michie, Patricia T., Mowry, Bryan J., Quidé, Yann, Rasser, Paul E., Schall, Ulrich, Scott, Rodney J., Carr, Vaughan J., Green, Melissa J., Henskens, Frans A., Loughland, Carmel M., Pantelis, Christos, Weickert, Cynthia Shannon, Weickert, Thomas W., de Haan, Lieuwe, Brosch, Katharina, Pfarr, Julia-Katharina, Ringwald, Kai G., Stein, Frederike, Jansen, Andreas, Kircher, Tilo T. J., Nenadić, Igor, Krämer, Bernd, Gruber, Oliver, Satterthwaite, Theodore D., Bustillo, Juan, Mathalon, Daniel H., Preda, Adrian, Calhoun, Vince D., Ford, Judith M., Potkin, Steven G., Chen, Jingxu, Tan, Yunlong, Wang, Zhiren, Xiang, Hong, Fan, Fengmei, Bernardoni, Fabio, Ehrlich, Stefan, Fuentes-Claramonte, Paola, Garcia-Leon, Maria Angeles, Guerrero-Pedraza, Amalia, Salvador, Raymond, Sarró, Salvador, Pomarol-Clotet, Edith, Ciullo, Valentina, Piras, Fabrizio, Vecchio, Daniela, Banaj, Nerisa, Spalletta, Gianfranco, Michielse, Stijn, van Amelsvoort, Therese, Dickie, Erin W., Voineskos, Aristotle N., Sim, Kang, Ciufolini, Simone, Dazzan, Paola, Murray, Robin M., Kim, Woo-Sung, Chung, Young-Chul, Andreou, Christina, Schmidt, André, Borgwardt, Stefan, McIntosh, Andrew M., Whalley, Heather C., Lawrie, Stephen M., du Plessis, Stefan, Luckhoff, Hilmar K., Scheffler, Freda, Emsley, Robin, Grotegerd, Dominik, Lencer, Rebekka, Dannlowski, Udo, Edmond, Jesse T., Rootes-Murdy, Kelly, Stephen, Julia M., Mayer, Andrew R., Antonucci, Linda A., Fazio, Leonardo, Pergola, Giulio, Bertolino, Alessandro, Díaz-Caneja, Covadonga M., Janssen, Joost, Lois, Noemi G., Arango, Celso, Tomyshev, Alexander S., Lebedeva, Irina, Cervenka, Simon, Sellgren, Carl M., Georgiadis, Foivos, Kirschner, Matthias, Kaiser, Stefan, Hajek, Tomas, Skoch, Antonin, Spaniel, Filip, Kim, Minah, Kwak, Yoo Bin, Oh, Sanghoon, Kwon, Jun Soo, James, Anthony, Bakker, Geor, Knöchel, Christian, Stäblein, Michael, Oertel, Viola, Uhlmann, Anne, Howells, Fleur M., Stein, Dan J., Temmingh, Henk S., Diaz-Zuluaga, Ana M., Pineda-Zapata, Julian A., López-Jaramillo, Carlos, Homan, Stephanie, Ji, Ellen, Surbeck, Werner, Homan, Philipp, Fisher, Simon E., Franke, Barbara, Glahn, David C., Gur, Ruben C., Hashimoto, Ryota, Jahanshad, Neda, Lueders, Eileen, Medland, Sarah E., Thompson, Paul M., Turner, Jessica A., van Erp, Theo G. M., Francks, Clyde, Schijven, Dick, Postema, Merel C., Fukunaga, Masaki, Matsumoto, Junya, Miura, Kenichiro, de Zwarte, Sonja M. C., van Haren, Neeltje E. M., Cahn, Wiepke, Hulshoff Pol, Hilleke E., Kahn, René S., Ayesa-Arriola, Rosa, Ortiz-García de la Foz, Víctor, Tordesillas-Gutierrez, Diana, Vázquez-Bourgon, Javier, Crespo-Facorro, Benedicto, Alnæs, Dag, Dahl, Andreas, Westlye, Lars T., Agartz, Ingrid, Andreassen, Ole A., Jönsson, Erik G., Kochunov, Peter, Bruggemann, Jason M., Catts, Stanley V., Michie, Patricia T., Mowry, Bryan J., Quidé, Yann, Rasser, Paul E., Schall, Ulrich, Scott, Rodney J., Carr, Vaughan J., Green, Melissa J., Henskens, Frans A., Loughland, Carmel M., Pantelis, Christos, Weickert, Cynthia Shannon, Weickert, Thomas W., de Haan, Lieuwe, Brosch, Katharina, Pfarr, Julia-Katharina, Ringwald, Kai G., Stein, Frederike, Jansen, Andreas, Kircher, Tilo T. J., Nenadić, Igor, Krämer, Bernd, Gruber, Oliver, Satterthwaite, Theodore D., Bustillo, Juan, Mathalon, Daniel H., Preda, Adrian, Calhoun, Vince D., Ford, Judith M., Potkin, Steven G., Chen, Jingxu, Tan, Yunlong, Wang, Zhiren, Xiang, Hong, Fan, Fengmei, Bernardoni, Fabio, Ehrlich, Stefan, Fuentes-Claramonte, Paola, Garcia-Leon, Maria Angeles, Guerrero-Pedraza, Amalia, Salvador, Raymond, Sarró, Salvador, Pomarol-Clotet, Edith, Ciullo, Valentina, Piras, Fabrizio, Vecchio, Daniela, Banaj, Nerisa, Spalletta, Gianfranco, Michielse, Stijn, van Amelsvoort, Therese, Dickie, Erin W., Voineskos, Aristotle N., Sim, Kang, Ciufolini, Simone, Dazzan, Paola, Murray, Robin M., Kim, Woo-Sung, Chung, Young-Chul, Andreou, Christina, Schmidt, André, Borgwardt, Stefan, McIntosh, Andrew M., Whalley, Heather C., Lawrie, Stephen M., du Plessis, Stefan, Luckhoff, Hilmar K., Scheffler, Freda, Emsley, Robin, Grotegerd, Dominik, Lencer, Rebekka, Dannlowski, Udo, Edmond, Jesse T., Rootes-Murdy, Kelly, Stephen, Julia M., Mayer, Andrew R., Antonucci, Linda A., Fazio, Leonardo, Pergola, Giulio, Bertolino, Alessandro, Díaz-Caneja, Covadonga M., Janssen, Joost, Lois, Noemi G., Arango, Celso, Tomyshev, Alexander S., Lebedeva, Irina, Cervenka, Simon, Sellgren, Carl M., Georgiadis, Foivos, Kirschner, Matthias, Kaiser, Stefan, Hajek, Tomas, Skoch, Antonin, Spaniel, Filip, Kim, Minah, Kwak, Yoo Bin, Oh, Sanghoon, Kwon, Jun Soo, James, Anthony, Bakker, Geor, Knöchel, Christian, Stäblein, Michael, Oertel, Viola, Uhlmann, Anne, Howells, Fleur M., Stein, Dan J., Temmingh, Henk S., Diaz-Zuluaga, Ana M., Pineda-Zapata, Julian A., López-Jaramillo, Carlos, Homan, Stephanie, Ji, Ellen, Surbeck, Werner, Homan, Philipp, Fisher, Simon E., Franke, Barbara, Glahn, David C., Gur, Ruben C., Hashimoto, Ryota, Jahanshad, Neda, Lueders, Eileen, Medland, Sarah E., Thompson, Paul M., Turner, Jessica A., van Erp, Theo G. M., and Francks, Clyde
Abstract: Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.
Published: 2023
Full Text: View/download PDF

6. Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium

Author: Schijven, Dick, Postema, Merel C., Fukunaga, Masaki, Matsumoto, Junya, Miura, Kenichiro, de Zwarte, Sonja M. C., van Haren, Neeltje E. M., Cahn, Wiepke, Hulshoff Pol, Hilleke E., Kahn, René S., Ayesa-Arriola, Rosa, Ortiz-García de la Foz, Víctor, Tordesillas-Gutierrez, Diana, Vázquez-Bourgon, Javier, Crespo-Facorro, Benedicto, Alnæs, Dag, Dahl, Andreas, Westlye, Lars T., Agartz, Ingrid, Andreassen, Ole A., Jönsson, Erik G., Kochunov, Peter, Bruggemann, Jason M., Catts, Stanley V., Michie, Patricia T., Mowry, Bryan J., Quidé, Yann, Rasser, Paul E., Schall, Ulrich, Scott, Rodney J., Carr, Vaughan J., Green, Melissa J., Henskens, Frans A., Loughland, Carmel M., Pantelis, Christos, Weickert, Cynthia Shannon, Weickert, Thomas W., de Haan, Lieuwe, Brosch, Katharina, Pfarr, Julia-Katharina, Ringwald, Kai G., Stein, Frederike, Jansen, Andreas, Kircher, Tilo T. J., Nenadić, Igor, Krämer, Bernd, Gruber, Oliver, Satterthwaite, Theodore D., Bustillo, Juan, Mathalon, Daniel H., Preda, Adrian, Calhoun, Vince D., Ford, Judith M., Potkin, Steven G., Chen, Jingxu, Tan, Yunlong, Wang, Zhiren, Xiang, Hong, Fan, Fengmei, Bernardoni, Fabio, Ehrlich, Stefan, Fuentes-Claramonte, Paola, Garcia-Leon, Maria Angeles, Guerrero-Pedraza, Amalia, Salvador, Raymond, Sarró, Salvador, Pomarol-Clotet, Edith, Ciullo, Valentina, Piras, Fabrizio, Vecchio, Daniela, Banaj, Nerisa, Spalletta, Gianfranco, Michielse, Stijn, van Amelsvoort, Therese, Dickie, Erin W., Voineskos, Aristotle N., Sim, Kang, Ciufolini, Simone, Dazzan, Paola, Murray, Robin M., Kim, Woo-Sung, Chung, Young-Chul, Andreou, Christina, Schmidt, André, Borgwardt, Stefan, McIntosh, Andrew M., Whalley, Heather C., Lawrie, Stephen M., du Plessis, Stefan, Luckhoff, Hilmar K., Scheffler, Freda, Emsley, Robin, Grotegerd, Dominik, Lencer, Rebekka, Dannlowski, Udo, Edmond, Jesse T., Rootes-Murdy, Kelly, Stephen, Julia M., Mayer, Andrew R., Antonucci, Linda A., Fazio, Leonardo, Pergola, Giulio, Bertolino, Alessandro, Díaz-Caneja, Covadonga M., Janssen, Joost, Lois, Noemi G., Arango, Celso, Tomyshev, Alexander S., Lebedeva, Irina, Cervenka, Simon, Sellgren, Carl M., Georgiadis, Foivos, Kirschner, Matthias, Kaiser, Stefan, Hajek, Tomas, Skoch, Antonin, Spaniel, Filip, Kim, Minah, Kwak, Yoo Bin, Oh, Sanghoon, Kwon, Jun Soo, James, Anthony, Bakker, Geor, Knöchel, Christian, Stäblein, Michael, Oertel, Viola, Uhlmann, Anne, Howells, Fleur M., Stein, Dan J., Temmingh, Henk S., Diaz-Zuluaga, Ana M., Pineda-Zapata, Julian A., López-Jaramillo, Carlos, Homan, Stephanie, Ji, Ellen, Surbeck, Werner, Homan, Philipp, Fisher, Simon E., Franke, Barbara, Glahn, David C., Gur, Ruben C., Hashimoto, Ryota, Jahanshad, Neda, Lueders, Eileen, Medland, Sarah E., Thompson, Paul M., Turner, Jessica A., van Erp, Theo G. M., Francks, Clyde, Schijven, Dick, Postema, Merel C., Fukunaga, Masaki, Matsumoto, Junya, Miura, Kenichiro, de Zwarte, Sonja M. C., van Haren, Neeltje E. M., Cahn, Wiepke, Hulshoff Pol, Hilleke E., Kahn, René S., Ayesa-Arriola, Rosa, Ortiz-García de la Foz, Víctor, Tordesillas-Gutierrez, Diana, Vázquez-Bourgon, Javier, Crespo-Facorro, Benedicto, Alnæs, Dag, Dahl, Andreas, Westlye, Lars T., Agartz, Ingrid, Andreassen, Ole A., Jönsson, Erik G., Kochunov, Peter, Bruggemann, Jason M., Catts, Stanley V., Michie, Patricia T., Mowry, Bryan J., Quidé, Yann, Rasser, Paul E., Schall, Ulrich, Scott, Rodney J., Carr, Vaughan J., Green, Melissa J., Henskens, Frans A., Loughland, Carmel M., Pantelis, Christos, Weickert, Cynthia Shannon, Weickert, Thomas W., de Haan, Lieuwe, Brosch, Katharina, Pfarr, Julia-Katharina, Ringwald, Kai G., Stein, Frederike, Jansen, Andreas, Kircher, Tilo T. J., Nenadić, Igor, Krämer, Bernd, Gruber, Oliver, Satterthwaite, Theodore D., Bustillo, Juan, Mathalon, Daniel H., Preda, Adrian, Calhoun, Vince D., Ford, Judith M., Potkin, Steven G., Chen, Jingxu, Tan, Yunlong, Wang, Zhiren, Xiang, Hong, Fan, Fengmei, Bernardoni, Fabio, Ehrlich, Stefan, Fuentes-Claramonte, Paola, Garcia-Leon, Maria Angeles, Guerrero-Pedraza, Amalia, Salvador, Raymond, Sarró, Salvador, Pomarol-Clotet, Edith, Ciullo, Valentina, Piras, Fabrizio, Vecchio, Daniela, Banaj, Nerisa, Spalletta, Gianfranco, Michielse, Stijn, van Amelsvoort, Therese, Dickie, Erin W., Voineskos, Aristotle N., Sim, Kang, Ciufolini, Simone, Dazzan, Paola, Murray, Robin M., Kim, Woo-Sung, Chung, Young-Chul, Andreou, Christina, Schmidt, André, Borgwardt, Stefan, McIntosh, Andrew M., Whalley, Heather C., Lawrie, Stephen M., du Plessis, Stefan, Luckhoff, Hilmar K., Scheffler, Freda, Emsley, Robin, Grotegerd, Dominik, Lencer, Rebekka, Dannlowski, Udo, Edmond, Jesse T., Rootes-Murdy, Kelly, Stephen, Julia M., Mayer, Andrew R., Antonucci, Linda A., Fazio, Leonardo, Pergola, Giulio, Bertolino, Alessandro, Díaz-Caneja, Covadonga M., Janssen, Joost, Lois, Noemi G., Arango, Celso, Tomyshev, Alexander S., Lebedeva, Irina, Cervenka, Simon, Sellgren, Carl M., Georgiadis, Foivos, Kirschner, Matthias, Kaiser, Stefan, Hajek, Tomas, Skoch, Antonin, Spaniel, Filip, Kim, Minah, Kwak, Yoo Bin, Oh, Sanghoon, Kwon, Jun Soo, James, Anthony, Bakker, Geor, Knöchel, Christian, Stäblein, Michael, Oertel, Viola, Uhlmann, Anne, Howells, Fleur M., Stein, Dan J., Temmingh, Henk S., Diaz-Zuluaga, Ana M., Pineda-Zapata, Julian A., López-Jaramillo, Carlos, Homan, Stephanie, Ji, Ellen, Surbeck, Werner, Homan, Philipp, Fisher, Simon E., Franke, Barbara, Glahn, David C., Gur, Ruben C., Hashimoto, Ryota, Jahanshad, Neda, Lueders, Eileen, Medland, Sarah E., Thompson, Paul M., Turner, Jessica A., van Erp, Theo G. M., and Francks, Clyde
Abstract: Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.
Published: 2023
Full Text: View/download PDF

7. Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium.

Author: Schijven, Dick, Schijven, Dick, Postema, Merel C, Fukunaga, Masaki, Matsumoto, Junya, Miura, Kenichiro, de Zwarte, Sonja MC, van Haren, Neeltje EM, Cahn, Wiepke, Hulshoff Pol, Hilleke E, Kahn, René S, Ayesa-Arriola, Rosa, Ortiz-García de la Foz, Víctor, Tordesillas-Gutierrez, Diana, Vázquez-Bourgon, Javier, Crespo-Facorro, Benedicto, Alnæs, Dag, Dahl, Andreas, Westlye, Lars T, Agartz, Ingrid, Andreassen, Ole A, Jönsson, Erik G, Kochunov, Peter, Bruggemann, Jason M, Catts, Stanley V, Michie, Patricia T, Mowry, Bryan J, Quidé, Yann, Rasser, Paul E, Schall, Ulrich, Scott, Rodney J, Carr, Vaughan J, Green, Melissa J, Henskens, Frans A, Loughland, Carmel M, Pantelis, Christos, Weickert, Cynthia Shannon, Weickert, Thomas W, de Haan, Lieuwe, Brosch, Katharina, Pfarr, Julia-Katharina, Ringwald, Kai G, Stein, Frederike, Jansen, Andreas, Kircher, Tilo TJ, Nenadić, Igor, Krämer, Bernd, Gruber, Oliver, Satterthwaite, Theodore D, Bustillo, Juan, Mathalon, Daniel H, Preda, Adrian, Calhoun, Vince D, Ford, Judith M, Potkin, Steven G, Chen, Jingxu, Tan, Yunlong, Wang, Zhiren, Xiang, Hong, Fan, Fengmei, Bernardoni, Fabio, Ehrlich, Stefan, Fuentes-Claramonte, Paola, Garcia-Leon, Maria Angeles, Guerrero-Pedraza, Amalia, Salvador, Raymond, Sarró, Salvador, Pomarol-Clotet, Edith, Ciullo, Valentina, Piras, Fabrizio, Vecchio, Daniela, Banaj, Nerisa, Spalletta, Gianfranco, Michielse, Stijn, van Amelsvoort, Therese, Dickie, Erin W, Voineskos, Aristotle N, Sim, Kang, Ciufolini, Simone, Dazzan, Paola, Murray, Robin M, Kim, Woo-Sung, Chung, Young-Chul, Andreou, Christina, Schmidt, André, Borgwardt, Stefan, McIntosh, Andrew M, Whalley, Heather C, Lawrie, Stephen M, du Plessis, Stefan, Luckhoff, Hilmar K, Scheffler, Freda, Emsley, Robin, Grotegerd, Dominik, Lencer, Rebekka, Dannlowski, Udo, Edmond, Jesse T, Rootes-Murdy, Kelly, Stephen, Julia M, Mayer, Andrew R, Antonucci, Linda A, Schijven, Dick, Schijven, Dick, Postema, Merel C, Fukunaga, Masaki, Matsumoto, Junya, Miura, Kenichiro, de Zwarte, Sonja MC, van Haren, Neeltje EM, Cahn, Wiepke, Hulshoff Pol, Hilleke E, Kahn, René S, Ayesa-Arriola, Rosa, Ortiz-García de la Foz, Víctor, Tordesillas-Gutierrez, Diana, Vázquez-Bourgon, Javier, Crespo-Facorro, Benedicto, Alnæs, Dag, Dahl, Andreas, Westlye, Lars T, Agartz, Ingrid, Andreassen, Ole A, Jönsson, Erik G, Kochunov, Peter, Bruggemann, Jason M, Catts, Stanley V, Michie, Patricia T, Mowry, Bryan J, Quidé, Yann, Rasser, Paul E, Schall, Ulrich, Scott, Rodney J, Carr, Vaughan J, Green, Melissa J, Henskens, Frans A, Loughland, Carmel M, Pantelis, Christos, Weickert, Cynthia Shannon, Weickert, Thomas W, de Haan, Lieuwe, Brosch, Katharina, Pfarr, Julia-Katharina, Ringwald, Kai G, Stein, Frederike, Jansen, Andreas, Kircher, Tilo TJ, Nenadić, Igor, Krämer, Bernd, Gruber, Oliver, Satterthwaite, Theodore D, Bustillo, Juan, Mathalon, Daniel H, Preda, Adrian, Calhoun, Vince D, Ford, Judith M, Potkin, Steven G, Chen, Jingxu, Tan, Yunlong, Wang, Zhiren, Xiang, Hong, Fan, Fengmei, Bernardoni, Fabio, Ehrlich, Stefan, Fuentes-Claramonte, Paola, Garcia-Leon, Maria Angeles, Guerrero-Pedraza, Amalia, Salvador, Raymond, Sarró, Salvador, Pomarol-Clotet, Edith, Ciullo, Valentina, Piras, Fabrizio, Vecchio, Daniela, Banaj, Nerisa, Spalletta, Gianfranco, Michielse, Stijn, van Amelsvoort, Therese, Dickie, Erin W, Voineskos, Aristotle N, Sim, Kang, Ciufolini, Simone, Dazzan, Paola, Murray, Robin M, Kim, Woo-Sung, Chung, Young-Chul, Andreou, Christina, Schmidt, André, Borgwardt, Stefan, McIntosh, Andrew M, Whalley, Heather C, Lawrie, Stephen M, du Plessis, Stefan, Luckhoff, Hilmar K, Scheffler, Freda, Emsley, Robin, Grotegerd, Dominik, Lencer, Rebekka, Dannlowski, Udo, Edmond, Jesse T, Rootes-Murdy, Kelly, Stephen, Julia M, Mayer, Andrew R, and Antonucci, Linda A
Abstract: Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.
Published: 2023

8. Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium

Author: Schijven, Dick, Postema, Merel C., Fukunaga, Masaki, Matsumoto, Junya, Miura, Kenichiro, de Zwarte, Sonja M. C., van Haren, Neeltje E. M., Cahn, Wiepke, Hulshoff Pol, Hilleke E., Kahn, René S., Ayesa-Arriola, Rosa, Ortiz-García de la Foz, Víctor, Tordesillas-Gutierrez, Diana, Vázquez-Bourgon, Javier, Crespo-Facorro, Benedicto, Alnæs, Dag, Dahl, Andreas, Westlye, Lars T., Agartz, Ingrid, Andreassen, Ole A., Jönsson, Erik G., Kochunov, Peter, Bruggemann, Jason M., Catts, Stanley V., Michie, Patricia T., Mowry, Bryan J., Quidé, Yann, Rasser, Paul E., Schall, Ulrich, Scott, Rodney J., Carr, Vaughan J., Green, Melissa J., Henskens, Frans A., Loughland, Carmel M., Pantelis, Christos, Weickert, Cynthia Shannon, Weickert, Thomas W., de Haan, Lieuwe, Brosch, Katharina, Pfarr, Julia-Katharina, Ringwald, Kai G., Stein, Frederike, Jansen, Andreas, Kircher, Tilo T. J., Nenadić, Igor, Krämer, Bernd, Gruber, Oliver, Satterthwaite, Theodore D., Bustillo, Juan, Mathalon, Daniel H., Preda, Adrian, Calhoun, Vince D., Ford, Judith M., Potkin, Steven G., Chen, Jingxu, Tan, Yunlong, Wang, Zhiren, Xiang, Hong, Fan, Fengmei, Bernardoni, Fabio, Ehrlich, Stefan, Fuentes-Claramonte, Paola, Garcia-Leon, Maria Angeles, Guerrero-Pedraza, Amalia, Salvador, Raymond, Sarró, Salvador, Pomarol-Clotet, Edith, Ciullo, Valentina, Piras, Fabrizio, Vecchio, Daniela, Banaj, Nerisa, Spalletta, Gianfranco, Michielse, Stijn, van Amelsvoort, Therese, Dickie, Erin W., Voineskos, Aristotle N., Sim, Kang, Ciufolini, Simone, Dazzan, Paola, Murray, Robin M., Kim, Woo-Sung, Chung, Young-Chul, Andreou, Christina, Schmidt, André, Borgwardt, Stefan, McIntosh, Andrew M., Whalley, Heather C., Lawrie, Stephen M., du Plessis, Stefan, Luckhoff, Hilmar K., Scheffler, Freda, Emsley, Robin, Grotegerd, Dominik, Lencer, Rebekka, Dannlowski, Udo, Edmond, Jesse T., Rootes-Murdy, Kelly, Stephen, Julia M., Mayer, Andrew R., Antonucci, Linda A., Fazio, Leonardo, Pergola, Giulio, Bertolino, Alessandro, Díaz-Caneja, Covadonga M., Janssen, Joost, Lois, Noemi G., Arango, Celso, Tomyshev, Alexander S., Lebedeva, Irina, Cervenka, Simon, Sellgren, Carl M., Georgiadis, Foivos, Kirschner, Matthias, Kaiser, Stefan, Hajek, Tomas, Skoch, Antonin, Spaniel, Filip, Kim, Minah, Kwak, Yoo Bin, Oh, Sanghoon, Kwon, Jun Soo, James, Anthony, Bakker, Geor, Knöchel, Christian, Stäblein, Michael, Oertel, Viola, Uhlmann, Anne, Howells, Fleur M., Stein, Dan J., Temmingh, Henk S., Diaz-Zuluaga, Ana M., Pineda-Zapata, Julian A., López-Jaramillo, Carlos, Homan, Stephanie, Ji, Ellen, Surbeck, Werner, Homan, Philipp, Fisher, Simon E., Franke, Barbara, Glahn, David C., Gur, Ruben C., Hashimoto, Ryota, Jahanshad, Neda, Lueders, Eileen, Medland, Sarah E., Thompson, Paul M., Turner, Jessica A., van Erp, Theo G. M., Francks, Clyde, Schijven, Dick, Postema, Merel C., Fukunaga, Masaki, Matsumoto, Junya, Miura, Kenichiro, de Zwarte, Sonja M. C., van Haren, Neeltje E. M., Cahn, Wiepke, Hulshoff Pol, Hilleke E., Kahn, René S., Ayesa-Arriola, Rosa, Ortiz-García de la Foz, Víctor, Tordesillas-Gutierrez, Diana, Vázquez-Bourgon, Javier, Crespo-Facorro, Benedicto, Alnæs, Dag, Dahl, Andreas, Westlye, Lars T., Agartz, Ingrid, Andreassen, Ole A., Jönsson, Erik G., Kochunov, Peter, Bruggemann, Jason M., Catts, Stanley V., Michie, Patricia T., Mowry, Bryan J., Quidé, Yann, Rasser, Paul E., Schall, Ulrich, Scott, Rodney J., Carr, Vaughan J., Green, Melissa J., Henskens, Frans A., Loughland, Carmel M., Pantelis, Christos, Weickert, Cynthia Shannon, Weickert, Thomas W., de Haan, Lieuwe, Brosch, Katharina, Pfarr, Julia-Katharina, Ringwald, Kai G., Stein, Frederike, Jansen, Andreas, Kircher, Tilo T. J., Nenadić, Igor, Krämer, Bernd, Gruber, Oliver, Satterthwaite, Theodore D., Bustillo, Juan, Mathalon, Daniel H., Preda, Adrian, Calhoun, Vince D., Ford, Judith M., Potkin, Steven G., Chen, Jingxu, Tan, Yunlong, Wang, Zhiren, Xiang, Hong, Fan, Fengmei, Bernardoni, Fabio, Ehrlich, Stefan, Fuentes-Claramonte, Paola, Garcia-Leon, Maria Angeles, Guerrero-Pedraza, Amalia, Salvador, Raymond, Sarró, Salvador, Pomarol-Clotet, Edith, Ciullo, Valentina, Piras, Fabrizio, Vecchio, Daniela, Banaj, Nerisa, Spalletta, Gianfranco, Michielse, Stijn, van Amelsvoort, Therese, Dickie, Erin W., Voineskos, Aristotle N., Sim, Kang, Ciufolini, Simone, Dazzan, Paola, Murray, Robin M., Kim, Woo-Sung, Chung, Young-Chul, Andreou, Christina, Schmidt, André, Borgwardt, Stefan, McIntosh, Andrew M., Whalley, Heather C., Lawrie, Stephen M., du Plessis, Stefan, Luckhoff, Hilmar K., Scheffler, Freda, Emsley, Robin, Grotegerd, Dominik, Lencer, Rebekka, Dannlowski, Udo, Edmond, Jesse T., Rootes-Murdy, Kelly, Stephen, Julia M., Mayer, Andrew R., Antonucci, Linda A., Fazio, Leonardo, Pergola, Giulio, Bertolino, Alessandro, Díaz-Caneja, Covadonga M., Janssen, Joost, Lois, Noemi G., Arango, Celso, Tomyshev, Alexander S., Lebedeva, Irina, Cervenka, Simon, Sellgren, Carl M., Georgiadis, Foivos, Kirschner, Matthias, Kaiser, Stefan, Hajek, Tomas, Skoch, Antonin, Spaniel, Filip, Kim, Minah, Kwak, Yoo Bin, Oh, Sanghoon, Kwon, Jun Soo, James, Anthony, Bakker, Geor, Knöchel, Christian, Stäblein, Michael, Oertel, Viola, Uhlmann, Anne, Howells, Fleur M., Stein, Dan J., Temmingh, Henk S., Diaz-Zuluaga, Ana M., Pineda-Zapata, Julian A., López-Jaramillo, Carlos, Homan, Stephanie, Ji, Ellen, Surbeck, Werner, Homan, Philipp, Fisher, Simon E., Franke, Barbara, Glahn, David C., Gur, Ruben C., Hashimoto, Ryota, Jahanshad, Neda, Lueders, Eileen, Medland, Sarah E., Thompson, Paul M., Turner, Jessica A., van Erp, Theo G. M., and Francks, Clyde
Abstract: Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.
Published: 2023
Full Text: View/download PDF

9. Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium

Author: Schijven, Dick, Postema, Merel C., Fukunaga, Masaki, Matsumoto, Junya, Miura, Kenichiro, de Zwarte, Sonja M. C., van Haren, Neeltje E. M., Cahn, Wiepke, Hulshoff Pol, Hilleke E., Kahn, René S., Ayesa-Arriola, Rosa, Ortiz-García de la Foz, Víctor, Tordesillas-Gutierrez, Diana, Vázquez-Bourgon, Javier, Crespo-Facorro, Benedicto, Alnæs, Dag, Dahl, Andreas, Westlye, Lars T., Agartz, Ingrid, Andreassen, Ole A., Jönsson, Erik G., Kochunov, Peter, Bruggemann, Jason M., Catts, Stanley V., Michie, Patricia T., Mowry, Bryan J., Quidé, Yann, Rasser, Paul E., Schall, Ulrich, Scott, Rodney J., Carr, Vaughan J., Green, Melissa J., Henskens, Frans A., Loughland, Carmel M., Pantelis, Christos, Weickert, Cynthia Shannon, Weickert, Thomas W., de Haan, Lieuwe, Brosch, Katharina, Pfarr, Julia-Katharina, Ringwald, Kai G., Stein, Frederike, Jansen, Andreas, Kircher, Tilo T. J., Nenadić, Igor, Krämer, Bernd, Gruber, Oliver, Satterthwaite, Theodore D., Bustillo, Juan, Mathalon, Daniel H., Preda, Adrian, Calhoun, Vince D., Ford, Judith M., Potkin, Steven G., Chen, Jingxu, Tan, Yunlong, Wang, Zhiren, Xiang, Hong, Fan, Fengmei, Bernardoni, Fabio, Ehrlich, Stefan, Fuentes-Claramonte, Paola, Garcia-Leon, Maria Angeles, Guerrero-Pedraza, Amalia, Salvador, Raymond, Sarró, Salvador, Pomarol-Clotet, Edith, Ciullo, Valentina, Piras, Fabrizio, Vecchio, Daniela, Banaj, Nerisa, Spalletta, Gianfranco, Michielse, Stijn, van Amelsvoort, Therese, Dickie, Erin W., Voineskos, Aristotle N., Sim, Kang, Ciufolini, Simone, Dazzan, Paola, Murray, Robin M., Kim, Woo-Sung, Chung, Young-Chul, Andreou, Christina, Schmidt, André, Borgwardt, Stefan, McIntosh, Andrew M., Whalley, Heather C., Lawrie, Stephen M., du Plessis, Stefan, Luckhoff, Hilmar K., Scheffler, Freda, Emsley, Robin, Grotegerd, Dominik, Lencer, Rebekka, Dannlowski, Udo, Edmond, Jesse T., Rootes-Murdy, Kelly, Stephen, Julia M., Mayer, Andrew R., Antonucci, Linda A., Fazio, Leonardo, Pergola, Giulio, Bertolino, Alessandro, Díaz-Caneja, Covadonga M., Janssen, Joost, Lois, Noemi G., Arango, Celso, Tomyshev, Alexander S., Lebedeva, Irina, Cervenka, Simon, Sellgren, Carl M., Georgiadis, Foivos, Kirschner, Matthias, Kaiser, Stefan, Hajek, Tomas, Skoch, Antonin, Spaniel, Filip, Kim, Minah, Kwak, Yoo Bin, Oh, Sanghoon, Kwon, Jun Soo, James, Anthony, Bakker, Geor, Knöchel, Christian, Stäblein, Michael, Oertel, Viola, Uhlmann, Anne, Howells, Fleur M., Stein, Dan J., Temmingh, Henk S., Diaz-Zuluaga, Ana M., Pineda-Zapata, Julian A., López-Jaramillo, Carlos, Homan, Stephanie, Ji, Ellen, Surbeck, Werner, Homan, Philipp, Fisher, Simon E., Franke, Barbara, Glahn, David C., Gur, Ruben C., Hashimoto, Ryota, Jahanshad, Neda, Lueders, Eileen, Medland, Sarah E., Thompson, Paul M., Turner, Jessica A., van Erp, Theo G. M., Francks, Clyde, Schijven, Dick, Postema, Merel C., Fukunaga, Masaki, Matsumoto, Junya, Miura, Kenichiro, de Zwarte, Sonja M. C., van Haren, Neeltje E. M., Cahn, Wiepke, Hulshoff Pol, Hilleke E., Kahn, René S., Ayesa-Arriola, Rosa, Ortiz-García de la Foz, Víctor, Tordesillas-Gutierrez, Diana, Vázquez-Bourgon, Javier, Crespo-Facorro, Benedicto, Alnæs, Dag, Dahl, Andreas, Westlye, Lars T., Agartz, Ingrid, Andreassen, Ole A., Jönsson, Erik G., Kochunov, Peter, Bruggemann, Jason M., Catts, Stanley V., Michie, Patricia T., Mowry, Bryan J., Quidé, Yann, Rasser, Paul E., Schall, Ulrich, Scott, Rodney J., Carr, Vaughan J., Green, Melissa J., Henskens, Frans A., Loughland, Carmel M., Pantelis, Christos, Weickert, Cynthia Shannon, Weickert, Thomas W., de Haan, Lieuwe, Brosch, Katharina, Pfarr, Julia-Katharina, Ringwald, Kai G., Stein, Frederike, Jansen, Andreas, Kircher, Tilo T. J., Nenadić, Igor, Krämer, Bernd, Gruber, Oliver, Satterthwaite, Theodore D., Bustillo, Juan, Mathalon, Daniel H., Preda, Adrian, Calhoun, Vince D., Ford, Judith M., Potkin, Steven G., Chen, Jingxu, Tan, Yunlong, Wang, Zhiren, Xiang, Hong, Fan, Fengmei, Bernardoni, Fabio, Ehrlich, Stefan, Fuentes-Claramonte, Paola, Garcia-Leon, Maria Angeles, Guerrero-Pedraza, Amalia, Salvador, Raymond, Sarró, Salvador, Pomarol-Clotet, Edith, Ciullo, Valentina, Piras, Fabrizio, Vecchio, Daniela, Banaj, Nerisa, Spalletta, Gianfranco, Michielse, Stijn, van Amelsvoort, Therese, Dickie, Erin W., Voineskos, Aristotle N., Sim, Kang, Ciufolini, Simone, Dazzan, Paola, Murray, Robin M., Kim, Woo-Sung, Chung, Young-Chul, Andreou, Christina, Schmidt, André, Borgwardt, Stefan, McIntosh, Andrew M., Whalley, Heather C., Lawrie, Stephen M., du Plessis, Stefan, Luckhoff, Hilmar K., Scheffler, Freda, Emsley, Robin, Grotegerd, Dominik, Lencer, Rebekka, Dannlowski, Udo, Edmond, Jesse T., Rootes-Murdy, Kelly, Stephen, Julia M., Mayer, Andrew R., Antonucci, Linda A., Fazio, Leonardo, Pergola, Giulio, Bertolino, Alessandro, Díaz-Caneja, Covadonga M., Janssen, Joost, Lois, Noemi G., Arango, Celso, Tomyshev, Alexander S., Lebedeva, Irina, Cervenka, Simon, Sellgren, Carl M., Georgiadis, Foivos, Kirschner, Matthias, Kaiser, Stefan, Hajek, Tomas, Skoch, Antonin, Spaniel, Filip, Kim, Minah, Kwak, Yoo Bin, Oh, Sanghoon, Kwon, Jun Soo, James, Anthony, Bakker, Geor, Knöchel, Christian, Stäblein, Michael, Oertel, Viola, Uhlmann, Anne, Howells, Fleur M., Stein, Dan J., Temmingh, Henk S., Diaz-Zuluaga, Ana M., Pineda-Zapata, Julian A., López-Jaramillo, Carlos, Homan, Stephanie, Ji, Ellen, Surbeck, Werner, Homan, Philipp, Fisher, Simon E., Franke, Barbara, Glahn, David C., Gur, Ruben C., Hashimoto, Ryota, Jahanshad, Neda, Lueders, Eileen, Medland, Sarah E., Thompson, Paul M., Turner, Jessica A., van Erp, Theo G. M., and Francks, Clyde
Abstract: Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.
Published: 2023
Full Text: View/download PDF

10. Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium

Author: Schijven, Dick, Postema, Merel C., Fukunaga, Masaki, Matsumoto, Junya, Miura, Kenichiro, de Zwarte, Sonja M.C., van Haren, Neeltje E.M., Cahn, Wiepke, Hulshoff Pol, Hilleke E., Kahn, René S., Ayesa-Arriola, Rosa, Ortiz-García de la Foz, Víctor, Tordesillas-Gutierrez, Diana, Vázquez-Bourgon, Javier, Crespo-Facorro, Benedicto, Alnæs, Dag, Dahl, Andreas, Westlye, Lars T., Agartz, Ingrid, Andreassen, Ole A., Jönsson, Erik G., Kochunov, Peter, Bruggemann, Jason M., Catts, Stanley V., Michie, Patricia T., Mowry, Bryan J., Quidé, Yann, Rasser, Paul E., Schall, Ulrich, Scott, Rodney J., Carr, Vaughan J., Green, Melissa J., Henskens, Frans A., Loughland, Carmel M., Pantelis, Christos, Weickert, Cynthia Shannon, Weickert, Thomas W., de Haan, Lieuwe, Brosch, Katharina, Pfarr, Julia Katharina, Ringwald, Kai G., Stein, Frederike, Jansen, Andreas, Kircher, Tilo T.J., Nenadić, Igor, Krämer, Bernd, Gruber, Oliver, Satterthwaite, Theodore D., Bustillo, Juan, Mathalon, Daniel H., Preda, Adrian, Calhoun, Vince D., Ford, Judith M., Potkin, Steven G., Chen, Jingxu, Tan, Yunlong, Wang, Zhiren, Xiang, Hong, Fan, Fengmei, Bernardoni, Fabio, Ehrlich, Stefan, Fuentes-Claramonte, Paola, Garcia-Leon, Maria Angeles, Guerrero-Pedraza, Amalia, Salvador, Raymond, Sarró, Salvador, Pomarol-Clotet, Edith, Ciullo, Valentina, Piras, Fabrizio, Vecchio, Daniela, Banaj, Nerisa, Spalletta, Gianfranco, Michielse, Stijn, van Amelsvoort, Therese, Dickie, Erin W., Voineskos, Aristotle N., Sim, Kang, Ciufolini, Simone, Dazzan, Paola, Murray, Robin M., Kim, Woo Sung, Chung, Young Chul, Andreou, Christina, Schmidt, André, Borgwardt, Stefan, McIntosh, Andrew M., Whalley, Heather C., Lawrie, Stephen M., du Plessis, Stefan, Luckhoff, Hilmar K., Scheffler, Freda, Emsley, Robin, Grotegerd, Dominik, Lencer, Rebekka, Dannlowski, Udo, Edmond, Jesse T., Rootes-Murdy, Kelly, Stephen, Julia M., Mayer, Andrew R., Antonucci, Linda A., Fazio, Leonardo, Pergola, Giulio, Bertolino, Alessandro, Díaz-Caneja, Covadonga M., Janssen, Joost, Lois, Noemi G., Arango, Celso, Tomyshev, Alexander S., Lebedeva, Irina, Cervenka, Simon, Sellgren, Carl M., Georgiadis, Foivos, Kirschner, Matthias, Kaiser, Stefan, Hajek, Tomas, Skoch, Antonin, Spaniel, Filip, Kim, Minah, Kwak, Yoo Bin, Oh, Sanghoon, Kwon, Jun Soo, James, Anthony, Bakker, Geor, Knöchel, Christian, Stäblein, Michael, Oertel, Viola, Uhlmann, Anne, Howells, Fleur M., Stein, Dan J., Temmingh, Henk S., Diaz-Zuluaga, Ana M., Pineda-Zapata, Julian A., López-Jaramillo, Carlos, Homan, Stephanie, Ji, Ellen, Surbeck, Werner, Homan, Philipp, Fisher, Simon E., Franke, Barbara, Glahn, David C., Gur, Ruben C., Hashimoto, Ryota, Jahanshad, Neda, Luders, Eileen, Medland, Sarah E., Thompson, Paul M., Turner, Jessica A., van Erp, Theo G.M., Francks, Clyde, Schijven, Dick, Postema, Merel C., Fukunaga, Masaki, Matsumoto, Junya, Miura, Kenichiro, de Zwarte, Sonja M.C., van Haren, Neeltje E.M., Cahn, Wiepke, Hulshoff Pol, Hilleke E., Kahn, René S., Ayesa-Arriola, Rosa, Ortiz-García de la Foz, Víctor, Tordesillas-Gutierrez, Diana, Vázquez-Bourgon, Javier, Crespo-Facorro, Benedicto, Alnæs, Dag, Dahl, Andreas, Westlye, Lars T., Agartz, Ingrid, Andreassen, Ole A., Jönsson, Erik G., Kochunov, Peter, Bruggemann, Jason M., Catts, Stanley V., Michie, Patricia T., Mowry, Bryan J., Quidé, Yann, Rasser, Paul E., Schall, Ulrich, Scott, Rodney J., Carr, Vaughan J., Green, Melissa J., Henskens, Frans A., Loughland, Carmel M., Pantelis, Christos, Weickert, Cynthia Shannon, Weickert, Thomas W., de Haan, Lieuwe, Brosch, Katharina, Pfarr, Julia Katharina, Ringwald, Kai G., Stein, Frederike, Jansen, Andreas, Kircher, Tilo T.J., Nenadić, Igor, Krämer, Bernd, Gruber, Oliver, Satterthwaite, Theodore D., Bustillo, Juan, Mathalon, Daniel H., Preda, Adrian, Calhoun, Vince D., Ford, Judith M., Potkin, Steven G., Chen, Jingxu, Tan, Yunlong, Wang, Zhiren, Xiang, Hong, Fan, Fengmei, Bernardoni, Fabio, Ehrlich, Stefan, Fuentes-Claramonte, Paola, Garcia-Leon, Maria Angeles, Guerrero-Pedraza, Amalia, Salvador, Raymond, Sarró, Salvador, Pomarol-Clotet, Edith, Ciullo, Valentina, Piras, Fabrizio, Vecchio, Daniela, Banaj, Nerisa, Spalletta, Gianfranco, Michielse, Stijn, van Amelsvoort, Therese, Dickie, Erin W., Voineskos, Aristotle N., Sim, Kang, Ciufolini, Simone, Dazzan, Paola, Murray, Robin M., Kim, Woo Sung, Chung, Young Chul, Andreou, Christina, Schmidt, André, Borgwardt, Stefan, McIntosh, Andrew M., Whalley, Heather C., Lawrie, Stephen M., du Plessis, Stefan, Luckhoff, Hilmar K., Scheffler, Freda, Emsley, Robin, Grotegerd, Dominik, Lencer, Rebekka, Dannlowski, Udo, Edmond, Jesse T., Rootes-Murdy, Kelly, Stephen, Julia M., Mayer, Andrew R., Antonucci, Linda A., Fazio, Leonardo, Pergola, Giulio, Bertolino, Alessandro, Díaz-Caneja, Covadonga M., Janssen, Joost, Lois, Noemi G., Arango, Celso, Tomyshev, Alexander S., Lebedeva, Irina, Cervenka, Simon, Sellgren, Carl M., Georgiadis, Foivos, Kirschner, Matthias, Kaiser, Stefan, Hajek, Tomas, Skoch, Antonin, Spaniel, Filip, Kim, Minah, Kwak, Yoo Bin, Oh, Sanghoon, Kwon, Jun Soo, James, Anthony, Bakker, Geor, Knöchel, Christian, Stäblein, Michael, Oertel, Viola, Uhlmann, Anne, Howells, Fleur M., Stein, Dan J., Temmingh, Henk S., Diaz-Zuluaga, Ana M., Pineda-Zapata, Julian A., López-Jaramillo, Carlos, Homan, Stephanie, Ji, Ellen, Surbeck, Werner, Homan, Philipp, Fisher, Simon E., Franke, Barbara, Glahn, David C., Gur, Ruben C., Hashimoto, Ryota, Jahanshad, Neda, Luders, Eileen, Medland, Sarah E., Thompson, Paul M., Turner, Jessica A., van Erp, Theo G.M., and Francks, Clyde
Abstract: Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.
Published: 2023

11. Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium

Author: Schijven, Dick; https://orcid.org/0000-0001-5190-7241, Postema, Merel C; https://orcid.org/0000-0002-1536-7062, Fukunaga, Masaki; https://orcid.org/0000-0003-1010-2644, Matsumoto, Junya; https://orcid.org/0000-0003-4228-3208, Miura, Kenichiro, de Zwarte, Sonja M C, van Haren, Neeltje E M, Cahn, Wiepke, Hulshoff Pol, Hilleke E, Kahn, René S, Ayesa-Arriola, Rosa; https://orcid.org/0000-0003-0570-5352, de la Foz, Víctor Ortiz-García; https://orcid.org/0000-0002-0627-1827, Tordesillas-Gutierrez, Diana; https://orcid.org/0000-0003-1458-3932, Vázquez-Bourgon, Javier; https://orcid.org/0000-0002-5478-3376, Crespo-Facorro, Benedicto, Alnæs, Dag; https://orcid.org/0000-0001-7361-5418, Dahl, Andreas; https://orcid.org/0000-0002-2668-8371, Westlye, Lars T; https://orcid.org/0000-0001-8644-956X, Agartz, Ingrid, Andreassen, Ole A; https://orcid.org/0000-0002-4461-3568, Jönsson, Erik G, Kochunov, Peter, Bruggemann, Jason M, Catts, Stanley V, Michie, Patricia T, Mowry, Bryan J, Quidé, Yann, Rasser, Paul E; https://orcid.org/0000-0003-3482-721X, Schall, Ulrich; https://orcid.org/0000-0001-9041-4562, Scott, Rodney J; https://orcid.org/0000-0001-7724-3404, Carr, Vaughan J; https://orcid.org/0000-0002-8907-5804, Green, Melissa J; https://orcid.org/0000-0002-9361-4874, Henskens, Frans A; https://orcid.org/0000-0003-2358-5630, Loughland, Carmel M, Pantelis, Christos; https://orcid.org/0000-0002-9565-0238, Weickert, Cynthia Shannon, Weickert, Thomas W, de Haan, Lieuwe, Brosch, Katharina; https://orcid.org/0000-0002-0526-8095, Pfarr, Julia-Katharina, Ringwald, Kai G, Stein, Frederike, Jansen, Andreas, Kircher, Tilo T J, Nenadić, Igor, Krämer, Bernd; https://orcid.org/0000-0002-1145-9103, Gruber, Oliver; https://orcid.org/0000-0003-1841-7413, Satterthwaite, Theodore D; https://orcid.org/0000-0001-7072-9399, Bustillo, Juan; https://orcid.org/0000-0001-8730-8152, Mathalon, Daniel H, Preda, Adrian, Calhoun, Vince D; https://orcid.org/0000-0001-9058-0747, Ford, Judith M; https://orcid.org/0000-0002-6500-6548, Potkin, Steven G, Chen, Jingxu, Tan, Yunlong; https://orcid.org/0000-0002-3522-3912, Wang, Zhiren, Xiang, Hong, Fan, Fengmei, Bernardoni, Fabio, Ehrlich, Stefan; https://orcid.org/0000-0003-2132-4445, Fuentes-Claramonte, Paola; https://orcid.org/0000-0002-1428-7976, Garcia-Leon, Maria Angeles, Guerrero-Pedraza, Amalia, Salvador, Raymond; https://orcid.org/0000-0001-5557-1562, Sarró, Salvador; https://orcid.org/0000-0003-1835-2189, Pomarol-Clotet, Edith, Ciullo, Valentina; https://orcid.org/0000-0002-6870-6259, Piras, Fabrizio; https://orcid.org/0000-0003-3566-5494, Vecchio, Daniela, Banaj, Nerisa, Spalletta, Gianfranco; https://orcid.org/0000-0002-7432-4249, Michielse, Stijn, van Amelsvoort, Therese, Dickie, Erin W, Voineskos, Aristotle N; https://orcid.org/0000-0003-0156-0395, Sim, Kang; https://orcid.org/0000-0003-3209-9626, Ciufolini, Simone, Dazzan, Paola, Murray, Robin M; https://orcid.org/0000-0003-0829-0519, Kim, Woo-Sung, Chung, Young-Chul, Andreou, Christina, Schmidt, André; https://orcid.org/0000-0001-6055-8397, Borgwardt, Stefan; https://orcid.org/0000-0002-5792-3987, McIntosh, Andrew M, Whalley, Heather C, Lawrie, Stephen M; https://orcid.org/0000-0002-2444-5675, du Plessis, Stefan, Luckhoff, Hilmar K, Scheffler, Freda; https://orcid.org/0000-0002-8898-8599, Emsley, Robin, Grotegerd, Dominik, Lencer, Rebekka, Dannlowski, Udo; https://orcid.org/0000-0002-0623-3759, Edmond, Jesse T, Rootes-Murdy, Kelly, Stephen, Julia M, Mayer, Andrew R, Antonucci, Linda A, Fazio, Leonardo; https://orcid.org/0000-0003-4000-974X, Pergola, Giulio; https://orcid.org/0000-0002-9193-1841, Bertolino, Alessandro, Díaz-Caneja, Covadonga M; https://orcid.org/0000-0001-8538-3175, Janssen, Joost, Lois, Noemi G; https://orcid.org/0000-0002-6600-072X, Arango, Celso; https://orcid.org/0000-0003-3382-4754, Tomyshev, Alexander S, Lebedeva, Irina, Cervenka, Simon, Sellgren, Carl M, Georgiadis, Foivos, Kirschner, Matthias; https://orcid.org/0000-0002-9486-1439, Kaiser, Stefan, Hajek, Tomas, Skoch, Antonin; https://orcid.org/0000-0002-1739-3256, Spaniel, Filip, Kim, Minah; https://orcid.org/0000-0001-8668-0817, Kwak, Yoo Bin, Oh, Sanghoon; https://orcid.org/0000-0002-7394-5211, Kwon, Jun Soo; https://orcid.org/0000-0002-1060-1462, James, Anthony; https://orcid.org/0000-0002-2742-8328, Bakker, Geor, Knöchel, Christian, Stäblein, Michael, Oertel, Viola, Uhlmann, Anne; https://orcid.org/0000-0002-1753-7811, Howells, Fleur M, Stein, Dan J; https://orcid.org/0000-0001-7218-7810, Temmingh, Henk S; https://orcid.org/0000-0002-7688-0759, Diaz-Zuluaga, Ana M, Pineda-Zapata, Julian A, López-Jaramillo, Carlos, Homan, Stephanie; https://orcid.org/0000-0003-1449-7508, Ji, Ellen; https://orcid.org/0000-0003-1527-8868, Surbeck, Werner; https://orcid.org/0000-0002-4733-795X, Homan, Philipp; https://orcid.org/0000-0001-9034-148X, Fisher, Simon E; https://orcid.org/0000-0002-3132-1996, Franke, Barbara; https://orcid.org/0000-0003-4375-6572, Glahn, David C; https://orcid.org/0000-0002-4749-6977, Gur, Ruben C; https://orcid.org/0000-0002-9657-1996, Hashimoto, Ryota, Jahanshad, Neda, Luders, Eileen; https://orcid.org/0000-0001-5659-992X, Medland, Sarah E, Thompson, Paul M; https://orcid.org/0000-0002-4720-8867, Turner, Jessica A, van Erp, Theo G M, Francks, Clyde; https://orcid.org/0000-0002-9098-890X, Schijven, Dick; https://orcid.org/0000-0001-5190-7241, Postema, Merel C; https://orcid.org/0000-0002-1536-7062, Fukunaga, Masaki; https://orcid.org/0000-0003-1010-2644, Matsumoto, Junya; https://orcid.org/0000-0003-4228-3208, Miura, Kenichiro, de Zwarte, Sonja M C, van Haren, Neeltje E M, Cahn, Wiepke, Hulshoff Pol, Hilleke E, Kahn, René S, Ayesa-Arriola, Rosa; https://orcid.org/0000-0003-0570-5352, de la Foz, Víctor Ortiz-García; https://orcid.org/0000-0002-0627-1827, Tordesillas-Gutierrez, Diana; https://orcid.org/0000-0003-1458-3932, Vázquez-Bourgon, Javier; https://orcid.org/0000-0002-5478-3376, Crespo-Facorro, Benedicto, Alnæs, Dag; https://orcid.org/0000-0001-7361-5418, Dahl, Andreas; https://orcid.org/0000-0002-2668-8371, Westlye, Lars T; https://orcid.org/0000-0001-8644-956X, Agartz, Ingrid, Andreassen, Ole A; https://orcid.org/0000-0002-4461-3568, Jönsson, Erik G, Kochunov, Peter, Bruggemann, Jason M, Catts, Stanley V, Michie, Patricia T, Mowry, Bryan J, Quidé, Yann, Rasser, Paul E; https://orcid.org/0000-0003-3482-721X, Schall, Ulrich; https://orcid.org/0000-0001-9041-4562, Scott, Rodney J; https://orcid.org/0000-0001-7724-3404, Carr, Vaughan J; https://orcid.org/0000-0002-8907-5804, Green, Melissa J; https://orcid.org/0000-0002-9361-4874, Henskens, Frans A; https://orcid.org/0000-0003-2358-5630, Loughland, Carmel M, Pantelis, Christos; https://orcid.org/0000-0002-9565-0238, Weickert, Cynthia Shannon, Weickert, Thomas W, de Haan, Lieuwe, Brosch, Katharina; https://orcid.org/0000-0002-0526-8095, Pfarr, Julia-Katharina, Ringwald, Kai G, Stein, Frederike, Jansen, Andreas, Kircher, Tilo T J, Nenadić, Igor, Krämer, Bernd; https://orcid.org/0000-0002-1145-9103, Gruber, Oliver; https://orcid.org/0000-0003-1841-7413, Satterthwaite, Theodore D; https://orcid.org/0000-0001-7072-9399, Bustillo, Juan; https://orcid.org/0000-0001-8730-8152, Mathalon, Daniel H, Preda, Adrian, Calhoun, Vince D; https://orcid.org/0000-0001-9058-0747, Ford, Judith M; https://orcid.org/0000-0002-6500-6548, Potkin, Steven G, Chen, Jingxu, Tan, Yunlong; https://orcid.org/0000-0002-3522-3912, Wang, Zhiren, Xiang, Hong, Fan, Fengmei, Bernardoni, Fabio, Ehrlich, Stefan; https://orcid.org/0000-0003-2132-4445, Fuentes-Claramonte, Paola; https://orcid.org/0000-0002-1428-7976, Garcia-Leon, Maria Angeles, Guerrero-Pedraza, Amalia, Salvador, Raymond; https://orcid.org/0000-0001-5557-1562, Sarró, Salvador; https://orcid.org/0000-0003-1835-2189, Pomarol-Clotet, Edith, Ciullo, Valentina; https://orcid.org/0000-0002-6870-6259, Piras, Fabrizio; https://orcid.org/0000-0003-3566-5494, Vecchio, Daniela, Banaj, Nerisa, Spalletta, Gianfranco; https://orcid.org/0000-0002-7432-4249, Michielse, Stijn, van Amelsvoort, Therese, Dickie, Erin W, Voineskos, Aristotle N; https://orcid.org/0000-0003-0156-0395, Sim, Kang; https://orcid.org/0000-0003-3209-9626, Ciufolini, Simone, Dazzan, Paola, Murray, Robin M; https://orcid.org/0000-0003-0829-0519, Kim, Woo-Sung, Chung, Young-Chul, Andreou, Christina, Schmidt, André; https://orcid.org/0000-0001-6055-8397, Borgwardt, Stefan; https://orcid.org/0000-0002-5792-3987, McIntosh, Andrew M, Whalley, Heather C, Lawrie, Stephen M; https://orcid.org/0000-0002-2444-5675, du Plessis, Stefan, Luckhoff, Hilmar K, Scheffler, Freda; https://orcid.org/0000-0002-8898-8599, Emsley, Robin, Grotegerd, Dominik, Lencer, Rebekka, Dannlowski, Udo; https://orcid.org/0000-0002-0623-3759, Edmond, Jesse T, Rootes-Murdy, Kelly, Stephen, Julia M, Mayer, Andrew R, Antonucci, Linda A, Fazio, Leonardo; https://orcid.org/0000-0003-4000-974X, Pergola, Giulio; https://orcid.org/0000-0002-9193-1841, Bertolino, Alessandro, Díaz-Caneja, Covadonga M; https://orcid.org/0000-0001-8538-3175, Janssen, Joost, Lois, Noemi G; https://orcid.org/0000-0002-6600-072X, Arango, Celso; https://orcid.org/0000-0003-3382-4754, Tomyshev, Alexander S, Lebedeva, Irina, Cervenka, Simon, Sellgren, Carl M, Georgiadis, Foivos, Kirschner, Matthias; https://orcid.org/0000-0002-9486-1439, Kaiser, Stefan, Hajek, Tomas, Skoch, Antonin; https://orcid.org/0000-0002-1739-3256, Spaniel, Filip, Kim, Minah; https://orcid.org/0000-0001-8668-0817, Kwak, Yoo Bin, Oh, Sanghoon; https://orcid.org/0000-0002-7394-5211, Kwon, Jun Soo; https://orcid.org/0000-0002-1060-1462, James, Anthony; https://orcid.org/0000-0002-2742-8328, Bakker, Geor, Knöchel, Christian, Stäblein, Michael, Oertel, Viola, Uhlmann, Anne; https://orcid.org/0000-0002-1753-7811, Howells, Fleur M, Stein, Dan J; https://orcid.org/0000-0001-7218-7810, Temmingh, Henk S; https://orcid.org/0000-0002-7688-0759, Diaz-Zuluaga, Ana M, Pineda-Zapata, Julian A, López-Jaramillo, Carlos, Homan, Stephanie; https://orcid.org/0000-0003-1449-7508, Ji, Ellen; https://orcid.org/0000-0003-1527-8868, Surbeck, Werner; https://orcid.org/0000-0002-4733-795X, Homan, Philipp; https://orcid.org/0000-0001-9034-148X, Fisher, Simon E; https://orcid.org/0000-0002-3132-1996, Franke, Barbara; https://orcid.org/0000-0003-4375-6572, Glahn, David C; https://orcid.org/0000-0002-4749-6977, Gur, Ruben C; https://orcid.org/0000-0002-9657-1996, Hashimoto, Ryota, Jahanshad, Neda, Luders, Eileen; https://orcid.org/0000-0001-5659-992X, Medland, Sarah E, Thompson, Paul M; https://orcid.org/0000-0002-4720-8867, Turner, Jessica A, van Erp, Theo G M, and Francks, Clyde; https://orcid.org/0000-0002-9098-890X
Abstract: Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, using MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets in the ENIGMA consortium, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macro-structural asymmetry may reflect differences at the molecular, cytoarchitectonic or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.
Published: 2023

12. Brain Structure in Acutely Underweight and Partially Weight-Restored Individuals With Anorexia Nervosa : A Coordinated Analysis by the ENIGMA Eating Disorders Working Group

Author: Walton, Esther, Bernardoni, Fabio, Batury, Victoria-Luise, Bahnsen, Klaas, Lariviere, Sara, Abbate-Daga, Giovanni, Andres-Perpina, Susana, Bang, Lasse, Bischoff-Grethe, Amanda, Brooks, Samantha, Campbell, Iain C., Cascino, Giammarco, Castro-Fornieles, Josefina, Collantoni, Enrico, D'Agata, Federico, Dahmen, Brigitte, Danner, Unna N., Favaro, Angela, Feusner, Jamie D., Frank, Guido K. W., Friederich, Hans-Christoph, Graner, John L., Herpertz-Dahlmann, Beate, Hess, Andreas, Horndasch, Stefanie, Kaplan, Allan S., Kaufmann, Lisa-Katrin, Kaye, Walter H., Khalsa, Sahib S., LaBar, Kevin S., Lavagnino, Luca, Lazaro, Luisa, Manara, Renzo, Miles, Amy E., Milos, Gabriella F., Monteleone, Alessio Maria, Monteleone, Palmiero, Mwangi, Benson, O'Daly, Owen, Pariente, Jose, Roesch, Julie, Schmidt, Ulrike H., Seitz, Jochen, Shott, Megan E., Simon, Joe J., Smeets, Paul A. M., Tamnes, Christian K., Tenconi, Elena, Thomopoulos, Sophia, I, van Elburg, Annemarie A., Voineskos, Aristotle N., von Polier, Georg G., Wierenga, Christina E., Zucker, Nancy L., Jahanshad, Neda, King, Joseph A., Thompson, Paul M., Berner, Laura A., Ehrlich, Stefan, Walton, Esther, Bernardoni, Fabio, Batury, Victoria-Luise, Bahnsen, Klaas, Lariviere, Sara, Abbate-Daga, Giovanni, Andres-Perpina, Susana, Bang, Lasse, Bischoff-Grethe, Amanda, Brooks, Samantha, Campbell, Iain C., Cascino, Giammarco, Castro-Fornieles, Josefina, Collantoni, Enrico, D'Agata, Federico, Dahmen, Brigitte, Danner, Unna N., Favaro, Angela, Feusner, Jamie D., Frank, Guido K. W., Friederich, Hans-Christoph, Graner, John L., Herpertz-Dahlmann, Beate, Hess, Andreas, Horndasch, Stefanie, Kaplan, Allan S., Kaufmann, Lisa-Katrin, Kaye, Walter H., Khalsa, Sahib S., LaBar, Kevin S., Lavagnino, Luca, Lazaro, Luisa, Manara, Renzo, Miles, Amy E., Milos, Gabriella F., Monteleone, Alessio Maria, Monteleone, Palmiero, Mwangi, Benson, O'Daly, Owen, Pariente, Jose, Roesch, Julie, Schmidt, Ulrike H., Seitz, Jochen, Shott, Megan E., Simon, Joe J., Smeets, Paul A. M., Tamnes, Christian K., Tenconi, Elena, Thomopoulos, Sophia, I, van Elburg, Annemarie A., Voineskos, Aristotle N., von Polier, Georg G., Wierenga, Christina E., Zucker, Nancy L., Jahanshad, Neda, King, Joseph A., Thompson, Paul M., Berner, Laura A., and Ehrlich, Stefan
Abstract: BACKGROUND: The pattern of structural brain abnormalities in anorexia nervosa (AN) is still not well understood. While several studies report substantial deficits in gray matter volume and cortical thickness in acutely underweight patients, others find no differences, or even increases in patients compared with healthy control subjects. Recent weight regain before scanning may explain some of this heterogeneity. To clarify the extent, magnitude, and de-pendencies of gray matter changes in AN, we conducted a prospective, coordinated meta-analysis of multicenter neuroimaging data. METHODS: We analyzed T1-weighted structural magnetic resonance imaging scans assessed with standardized methods from 685 female patients with AN and 963 female healthy control subjects across 22 sites worldwide. In addition to a case-control comparison, we conducted a 3-group analysis comparing healthy control subjects with acutely underweight AN patients (n = 466) and partially weight-restored patients in treatment (n = 251). RESULTS: In AN, reductions in cortical thickness, subcortical volumes, and, to a lesser extent, cortical surface area were sizable (Cohen's d up to 0.95), widespread, and colocalized with hub regions. Highlighting the effects of un-dernutrition, these deficits were associated with lower body mass index in the AN sample and were less pronounced in partially weight-restored patients. CONCLUSIONS: The effect sizes observed for cortical thickness deficits in acute AN are the largest of any psychiatric disorder investigated in the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium to date. These results confirm the importance of considering weight loss and renutrition in biomedical research on AN and underscore the importance of treatment engagement to prevent potentially long-lasting structural brain changes in this population.
Published: 2022
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13. Tractography dissection variability: What happens when 42 groups dissect 14 white matter bundles on the same dataset?

Author: Schilling, Kurt G., Rheault, François, Petit, Laurent, Hansen, Colin B., Nath, Vishwesh, Yeh, Fang-Cheng, Girard, Gabriel, Barakovic, Muhamed, Rafael-Patino, Jonathan, Yu, Thomas, Fischi-Gomez, Elda, Pizzolato, Marco, Ocampo-Pineda, Mario, Schiavi, Simona, Canales-Rodríguez, Erick J., Daducci, Alessandro, Granziera, Cristina, Innocenti, Giorgio, Thiran, Jean-Philippe, Mancini, Laura, Wastling, Stephen, Cocozza, Sirio, Petracca, Maria, Pontillo, Giuseppe, Mancini, Matteo, Vos, Sjoerd B., Vakharia, Vejay N., Duncan, John S., Melero Carrasco, Helena, Manzanedo, Lidia, Sanz-Morales, Emilio, Peña-Melián, Ángel, Calamante, Fernando, Attyé, Arnaud, Cabeen, Ryan P., Korobova, Laura, Toga, Arthur W., Vijayakumari, Anupa Ambili, Parker, Drew, Verma, Ragini, Radwan, Ahmed, Sunaert, Stefan, Emsell, Louise, De Luca, Alberto, Leemans, Alexander, Bajada, Claude J., Haroon, Hamied, Azadbakht, Hojjatollah, Chamberland, Maxime, Genc, Sila, Tax, Chantal M.W., Yeh, Ping-Hong, Srikanchana, Rujirutana, Mcknight, Colin D., Yang, Joseph Yuan-Mou, Chen, Jian, Kelly, Claire E., Yeh, Chun-Hung, Cochereau, Jerome, Maller, Jerome J., Welton, Thomas, Almairac, Fabien, Seunarine, Kiran K, Clark, Chris A., Zhang, Fan, Makris, Nikos, Golby, Alexandra, Rathi, Yogesh, O'Donnell, Lauren J., Xia, Yihao, Aydogan, Dogu Baran, Shi, Yonggang, Guerreiro Fernandes, Francisco, Raemaekers, Mathijs, Warrington, Shaun, Michielse, Stijn, Ramírez-Manzanares, Alonso, Concha, Luis, Aranda, Ramón, Rivera Meraz, Mariano, Lerma-Usabiaga, Garikoitz, Roitman, Lucas, Fekonja, Lucius S., Calarco, Navona, Joseph, Michael, Nakua, Hajer, Voineskos, Aristotle N., Karan, Philippe, Grenier, Gabrielle, Legarreta, Jon Haitz, Adluru, Nagesh, Nair, Veena A., Prabhakaran, Vivek, Alexander, Andrew L., Kamagata, Koji, Saito, Yuya, Uchida, Wataru, Andica, Christina, Abe, Masahiro, Bayrak, Roza G., Gandini Wheeler-Kingshott, Claudia A.M., D'Angelo, Egidio, Palesi, Fulvia, Savini, Giovanni, Rolandi, Nicolò, Guevara, Pamela, Houenou, Josselin, López-López, Narciso, Mangin, Jean-François, Poupon, Cyril, Claudio Román, Claudio, Vázquez, Andrea, Maffei, Chiara, Arantes, Mavilde, Andrade, José Paulo, Silva, Susana Maria, Calhoun, Vince D., Caverzasi, Eduardo, Sacco, Simone, Lauricella, Michael, Pestilli, Franco, Daniel Bullock, Daniel, Zhan, Yang, Brignoni-Perez, Edith, Lebel, Catherine, Reynolds, Jess E, Nestrasil, Igor, Labounek, René, Lenglet, Christophe, Paulson, Amy, Aulicka, Stefania, Heilbronner, Sarah R., Heuer, Katja, Chandio, Bramsh Qamar, Guaje, Javier, Tang, Wei, Garyfallidis, Eleftherios, Raja, Rajikha, Anderson, Adam W., Landman, Bennett A., Descoteaux, Maxime, Schilling, Kurt G., Rheault, François, Petit, Laurent, Hansen, Colin B., Nath, Vishwesh, Yeh, Fang-Cheng, Girard, Gabriel, Barakovic, Muhamed, Rafael-Patino, Jonathan, Yu, Thomas, Fischi-Gomez, Elda, Pizzolato, Marco, Ocampo-Pineda, Mario, Schiavi, Simona, Canales-Rodríguez, Erick J., Daducci, Alessandro, Granziera, Cristina, Innocenti, Giorgio, Thiran, Jean-Philippe, Mancini, Laura, Wastling, Stephen, Cocozza, Sirio, Petracca, Maria, Pontillo, Giuseppe, Mancini, Matteo, Vos, Sjoerd B., Vakharia, Vejay N., Duncan, John S., Melero Carrasco, Helena, Manzanedo, Lidia, Sanz-Morales, Emilio, Peña-Melián, Ángel, Calamante, Fernando, Attyé, Arnaud, Cabeen, Ryan P., Korobova, Laura, Toga, Arthur W., Vijayakumari, Anupa Ambili, Parker, Drew, Verma, Ragini, Radwan, Ahmed, Sunaert, Stefan, Emsell, Louise, De Luca, Alberto, Leemans, Alexander, Bajada, Claude J., Haroon, Hamied, Azadbakht, Hojjatollah, Chamberland, Maxime, Genc, Sila, Tax, Chantal M.W., Yeh, Ping-Hong, Srikanchana, Rujirutana, Mcknight, Colin D., Yang, Joseph Yuan-Mou, Chen, Jian, Kelly, Claire E., Yeh, Chun-Hung, Cochereau, Jerome, Maller, Jerome J., Welton, Thomas, Almairac, Fabien, Seunarine, Kiran K, Clark, Chris A., Zhang, Fan, Makris, Nikos, Golby, Alexandra, Rathi, Yogesh, O'Donnell, Lauren J., Xia, Yihao, Aydogan, Dogu Baran, Shi, Yonggang, Guerreiro Fernandes, Francisco, Raemaekers, Mathijs, Warrington, Shaun, Michielse, Stijn, Ramírez-Manzanares, Alonso, Concha, Luis, Aranda, Ramón, Rivera Meraz, Mariano, Lerma-Usabiaga, Garikoitz, Roitman, Lucas, Fekonja, Lucius S., Calarco, Navona, Joseph, Michael, Nakua, Hajer, Voineskos, Aristotle N., Karan, Philippe, Grenier, Gabrielle, Legarreta, Jon Haitz, Adluru, Nagesh, Nair, Veena A., Prabhakaran, Vivek, Alexander, Andrew L., Kamagata, Koji, Saito, Yuya, Uchida, Wataru, Andica, Christina, Abe, Masahiro, Bayrak, Roza G., Gandini Wheeler-Kingshott, Claudia A.M., D'Angelo, Egidio, Palesi, Fulvia, Savini, Giovanni, Rolandi, Nicolò, Guevara, Pamela, Houenou, Josselin, López-López, Narciso, Mangin, Jean-François, Poupon, Cyril, Claudio Román, Claudio, Vázquez, Andrea, Maffei, Chiara, Arantes, Mavilde, Andrade, José Paulo, Silva, Susana Maria, Calhoun, Vince D., Caverzasi, Eduardo, Sacco, Simone, Lauricella, Michael, Pestilli, Franco, Daniel Bullock, Daniel, Zhan, Yang, Brignoni-Perez, Edith, Lebel, Catherine, Reynolds, Jess E, Nestrasil, Igor, Labounek, René, Lenglet, Christophe, Paulson, Amy, Aulicka, Stefania, Heilbronner, Sarah R., Heuer, Katja, Chandio, Bramsh Qamar, Guaje, Javier, Tang, Wei, Garyfallidis, Eleftherios, Raja, Rajikha, Anderson, Adam W., Landman, Bennett A., and Descoteaux, Maxime
Abstract: White matter bundle segmentation using diffusion MRI fiber tractography has become the method of choice to identify white matter fiber pathways in vivo in human brains. However, like other analyses of complex data, there is considerable variability in segmentation protocols and techniques. This can result in different reconstructions of the same intended white matter pathways, which directly affects tractography results, quantification, and interpretation. In this study, we aim to evaluate and quantify the variability that arises from different protocols for bundle segmentation. Through an open call to users of fiber tractography, including anatomists, clinicians, and algorithm developers, 42 independent teams were given processed sets of human whole-brain streamlines and asked to segment 14 white matter fascicles on six subjects. In total, we received 57 different bundle segmentation protocols, which enabled detailed volume-based and streamline-based analyses of agreement and disagreement among protocols for each fiber pathway. Results show that even when given the exact same sets of underlying streamlines, the variability across protocols for bundle segmentation is greater than all other sources of variability in the virtual dissection process, including variability within protocols and variability across subjects. In order to foster the use of tractography bundle dissection in routine clinical settings, and as a fundamental analytical tool, future endeavors must aim to resolve and reduce this heterogeneity. Although external validation is needed to verify the anatomical accuracy of bundle dissections, reducing heterogeneity is a step towards reproducible research and may be achieved through the use of standard nomenclature and definitions of white matter bundles and well-chosen constraints and decisions in the dissection process, Depto. de Psicobiología y Metodología en Ciencias del Comportamiento, Fac. de Psicología, TRUE, pub
Published: 2021

14. Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics.

Author: Lam, Max, Lam, Max, Chen, Chia-Yen, Ge, Tian, Xia, Yan, Hill, David W, Trampush, Joey W, Yu, Jin, Knowles, Emma, Davies, Gail, Stahl, Eli A, Huckins, Laura, Liewald, David C, Djurovic, Srdjan, Melle, Ingrid, Christoforou, Andrea, Reinvang, Ivar, DeRosse, Pamela, Lundervold, Astri J, Steen, Vidar M, Espeseth, Thomas, Räikkönen, Katri, Widen, Elisabeth, Palotie, Aarno, Eriksson, Johan G, Giegling, Ina, Konte, Bettina, Hartmann, Annette M, Roussos, Panos, Giakoumaki, Stella, Burdick, Katherine E, Payton, Antony, Ollier, William, Chiba-Falek, Ornit, Koltai, Deborah C, Need, Anna C, Cirulli, Elizabeth T, Voineskos, Aristotle N, Stefanis, Nikos C, Avramopoulos, Dimitrios, Hatzimanolis, Alex, Smyrnis, Nikolaos, Bilder, Robert M, Freimer, Nelson B, Cannon, Tyrone D, London, Edythe, Poldrack, Russell A, Sabb, Fred W, Congdon, Eliza, Conley, Emily Drabant, Scult, Matthew A, Dickinson, Dwight, Straub, Richard E, Donohoe, Gary, Morris, Derek, Corvin, Aiden, Gill, Michael, Hariri, Ahmad R, Weinberger, Daniel R, Pendleton, Neil, Bitsios, Panos, Rujescu, Dan, Lahti, Jari, Le Hellard, Stephanie, Keller, Matthew C, Andreassen, Ole A, Deary, Ian J, Glahn, David C, Huang, Hailiang, Liu, Chunyu, Malhotra, Anil K, Lencz, Todd, Lam, Max, Lam, Max, Chen, Chia-Yen, Ge, Tian, Xia, Yan, Hill, David W, Trampush, Joey W, Yu, Jin, Knowles, Emma, Davies, Gail, Stahl, Eli A, Huckins, Laura, Liewald, David C, Djurovic, Srdjan, Melle, Ingrid, Christoforou, Andrea, Reinvang, Ivar, DeRosse, Pamela, Lundervold, Astri J, Steen, Vidar M, Espeseth, Thomas, Räikkönen, Katri, Widen, Elisabeth, Palotie, Aarno, Eriksson, Johan G, Giegling, Ina, Konte, Bettina, Hartmann, Annette M, Roussos, Panos, Giakoumaki, Stella, Burdick, Katherine E, Payton, Antony, Ollier, William, Chiba-Falek, Ornit, Koltai, Deborah C, Need, Anna C, Cirulli, Elizabeth T, Voineskos, Aristotle N, Stefanis, Nikos C, Avramopoulos, Dimitrios, Hatzimanolis, Alex, Smyrnis, Nikolaos, Bilder, Robert M, Freimer, Nelson B, Cannon, Tyrone D, London, Edythe, Poldrack, Russell A, Sabb, Fred W, Congdon, Eliza, Conley, Emily Drabant, Scult, Matthew A, Dickinson, Dwight, Straub, Richard E, Donohoe, Gary, Morris, Derek, Corvin, Aiden, Gill, Michael, Hariri, Ahmad R, Weinberger, Daniel R, Pendleton, Neil, Bitsios, Panos, Rujescu, Dan, Lahti, Jari, Le Hellard, Stephanie, Keller, Matthew C, Andreassen, Ole A, Deary, Ian J, Glahn, David C, Huang, Hailiang, Liu, Chunyu, Malhotra, Anil K, and Lencz, Todd
Abstract: Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.
Published: 2021

15. Tractography dissection variability: What happens when 42 groups dissect 14 white matter bundles on the same dataset?

Author: Schilling, Kurt G., Rheault, François, Petit, Laurent, Hansen, Colin B., Nath, Vishwesh, Yeh, Fang-Cheng, Girard, Gabriel, Barakovic, Muhamed, Rafael-Patino, Jonathan, Yu, Thomas, Fischi-Gomez, Elda, Pizzolato, Marco, Ocampo-Pineda, Mario, Schiavi, Simona, Canales-Rodríguez, Erick J., Daducci, Alessandro, Granziera, Cristina, Innocenti, Giorgio, Thiran, Jean-Philippe, Mancini, Laura, Wastling, Stephen, Cocozza, Sirio, Petracca, Maria, Pontillo, Giuseppe, Mancini, Matteo, Vos, Sjoerd B., Vakharia, Vejay N., Duncan, John S., Melero, Helena, Manzanedo, Lidia, Sanz-Morales, Emilio, Peña-Melián, Ángel, Calamante, Fernando, Attyé, Arnaud, Cabeen, Ryan P., Korobova, Laura, Toga, Arthur W., Vijayakumari, Anupa Ambili, Parker, Drew, Verma, Ragini, Radwan, Ahmed, Sunaert, Stefan, Emsell, Louise, De Luca, Alberto, Leemans, Alexander, Bajada, Claude J., Haroon, Hamied, Azadbakht, Hojjatollah, Chamberland, Maxime, Genc, Sila, Tax, Chantal M.W., Yeh, Ping-Hong, Srikanchana, Rujirutana, Mcknight, Colin D., Yang, Joseph Yuan-Mou, Chen, Jian, Kelly, Claire E., Yeh, Chun-Hung, Cochereau, Jerome, Maller, Jerome J., Welton, Thomas, Almairac, Fabien, Seunarine, Kiran K, Clark, Chris A., Zhang, Fan, Makris, Nikos, Golby, Alexandra, Rathi, Yogesh, O'Donnell, Lauren J., Xia, Yihao, Aydogan, Dogu Baran, Shi, Yonggang, Guerreiro Fernandes, Francisco, Raemaekers, Mathijs, Warrington, Shaun, Michielse, Stijn, Ramírez-Manzanares, Alonso, Concha, Luis, Aranda, Ramón, Rivera Meraz, Mariano, Lerma-Usabiaga, Garikoitz, Roitman, Lucas, Fekonja, Lucius S., Calarco, Navona, Joseph, Michael, Nakua, Hajer, Voineskos, Aristotle N., Karan, Philippe, Grenier, Gabrielle, Legarreta, Jon Haitz, Adluru, Nagesh, Nair, Veena A., Prabhakaran, Vivek, Alexander, Andrew L., Kamagata, Koji, Saito, Yuya, Uchida, Wataru, Andica, Christina, Abe, Masahiro, Bayrak, Roza G., Gandini Wheeler-Kingshott, Claudia A.M., D'Angelo, Egidio, Palesi, Fulvia, Savini, Giovanni, Rolandi, Nicolò, Guevara, Pamela, Houenou, Josselin, López-López, Narciso, Mangin, Jean-François, Poupon, Cyril, Román, Claudio, Vázquez, Andrea, Maffei, Chiara, Arantes, Mavilde, Andrade, José Paulo, Silva, Susana Maria, Calhoun, Vince D., Caverzasi, Eduardo, Sacco, Simone, Lauricella, Michael, Pestilli, Franco, Bullock, Daniel, Zhan, Yang, Brignoni-Perez, Edith, Lebel, Catherine, Reynolds, Jess E, Nestrasil, Igor, Labounek, René, Lenglet, Christophe, Paulson, Amy, Aulicka, Stefania, Heilbronner, Sarah R., Heuer, Katja, Chandio, Bramsh Qamar, Guaje, Javier, Tang, Wei, Garyfallidis, Eleftherios, Raja, Rajikha, Anderson, Adam W., Landman, Bennett A., Descoteaux, Maxime, Schilling, Kurt G., Rheault, François, Petit, Laurent, Hansen, Colin B., Nath, Vishwesh, Yeh, Fang-Cheng, Girard, Gabriel, Barakovic, Muhamed, Rafael-Patino, Jonathan, Yu, Thomas, Fischi-Gomez, Elda, Pizzolato, Marco, Ocampo-Pineda, Mario, Schiavi, Simona, Canales-Rodríguez, Erick J., Daducci, Alessandro, Granziera, Cristina, Innocenti, Giorgio, Thiran, Jean-Philippe, Mancini, Laura, Wastling, Stephen, Cocozza, Sirio, Petracca, Maria, Pontillo, Giuseppe, Mancini, Matteo, Vos, Sjoerd B., Vakharia, Vejay N., Duncan, John S., Melero, Helena, Manzanedo, Lidia, Sanz-Morales, Emilio, Peña-Melián, Ángel, Calamante, Fernando, Attyé, Arnaud, Cabeen, Ryan P., Korobova, Laura, Toga, Arthur W., Vijayakumari, Anupa Ambili, Parker, Drew, Verma, Ragini, Radwan, Ahmed, Sunaert, Stefan, Emsell, Louise, De Luca, Alberto, Leemans, Alexander, Bajada, Claude J., Haroon, Hamied, Azadbakht, Hojjatollah, Chamberland, Maxime, Genc, Sila, Tax, Chantal M.W., Yeh, Ping-Hong, Srikanchana, Rujirutana, Mcknight, Colin D., Yang, Joseph Yuan-Mou, Chen, Jian, Kelly, Claire E., Yeh, Chun-Hung, Cochereau, Jerome, Maller, Jerome J., Welton, Thomas, Almairac, Fabien, Seunarine, Kiran K, Clark, Chris A., Zhang, Fan, Makris, Nikos, Golby, Alexandra, Rathi, Yogesh, O'Donnell, Lauren J., Xia, Yihao, Aydogan, Dogu Baran, Shi, Yonggang, Guerreiro Fernandes, Francisco, Raemaekers, Mathijs, Warrington, Shaun, Michielse, Stijn, Ramírez-Manzanares, Alonso, Concha, Luis, Aranda, Ramón, Rivera Meraz, Mariano, Lerma-Usabiaga, Garikoitz, Roitman, Lucas, Fekonja, Lucius S., Calarco, Navona, Joseph, Michael, Nakua, Hajer, Voineskos, Aristotle N., Karan, Philippe, Grenier, Gabrielle, Legarreta, Jon Haitz, Adluru, Nagesh, Nair, Veena A., Prabhakaran, Vivek, Alexander, Andrew L., Kamagata, Koji, Saito, Yuya, Uchida, Wataru, Andica, Christina, Abe, Masahiro, Bayrak, Roza G., Gandini Wheeler-Kingshott, Claudia A.M., D'Angelo, Egidio, Palesi, Fulvia, Savini, Giovanni, Rolandi, Nicolò, Guevara, Pamela, Houenou, Josselin, López-López, Narciso, Mangin, Jean-François, Poupon, Cyril, Román, Claudio, Vázquez, Andrea, Maffei, Chiara, Arantes, Mavilde, Andrade, José Paulo, Silva, Susana Maria, Calhoun, Vince D., Caverzasi, Eduardo, Sacco, Simone, Lauricella, Michael, Pestilli, Franco, Bullock, Daniel, Zhan, Yang, Brignoni-Perez, Edith, Lebel, Catherine, Reynolds, Jess E, Nestrasil, Igor, Labounek, René, Lenglet, Christophe, Paulson, Amy, Aulicka, Stefania, Heilbronner, Sarah R., Heuer, Katja, Chandio, Bramsh Qamar, Guaje, Javier, Tang, Wei, Garyfallidis, Eleftherios, Raja, Rajikha, Anderson, Adam W., Landman, Bennett A., and Descoteaux, Maxime
Abstract: Available online 22 August 2021., White matter bundle segmentation using diffusion MRI fiber tractography has become the method of choice to identify white matter fiber pathways in vivo in human brains. However, like other analyses of complex data, there is considerable variability in segmentation protocols and techniques. This can result in different reconstructions of the same intended white matter pathways, which directly affects tractography results, quantification, and interpretation. In this study, we aim to evaluate and quantify the variability that arises from different protocols for bundle segmentation. Through an open call to users of fiber tractography, including anatomists, clinicians, and algorithm developers, 42 independent teams were given processed sets of human whole-brain streamlines and asked to segment 14 white matter fascicles on six subjects. In total, we received 57 different bundle segmentation protocols, which enabled detailed volume-based and streamline-based analyses of agreement and disagreement among protocols for each fiber pathway. Results show that even when given the exact same sets of underlying streamlines, the variability across protocols for bundle segmentation is greater than all other sources of variability in the virtual dissection process, including variability within protocols and variability across subjects. In order to foster the use of tractography bundle dissection in routine clinical settings, and as a fundamental analytical tool, future endeavors must aim to resolve and reduce this heterogeneity. Although external validation is needed to verify the anatomical accuracy of bundle dissections, reducing heterogeneity is a step towards reproducible research and may be achieved through the use of standard nomenclature and definitions of white matter bundles and well-chosen constraints and decisions in the dissection process.
Published: 2021

16. Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics.

Author: Lam, Max, Lam, Max, Chen, Chia-Yen, Ge, Tian, Xia, Yan, Hill, David W, Trampush, Joey W, Yu, Jin, Knowles, Emma, Davies, Gail, Stahl, Eli A, Huckins, Laura, Liewald, David C, Djurovic, Srdjan, Melle, Ingrid, Christoforou, Andrea, Reinvang, Ivar, DeRosse, Pamela, Lundervold, Astri J, Steen, Vidar M, Espeseth, Thomas, Räikkönen, Katri, Widen, Elisabeth, Palotie, Aarno, Eriksson, Johan G, Giegling, Ina, Konte, Bettina, Hartmann, Annette M, Roussos, Panos, Giakoumaki, Stella, Burdick, Katherine E, Payton, Antony, Ollier, William, Chiba-Falek, Ornit, Koltai, Deborah C, Need, Anna C, Cirulli, Elizabeth T, Voineskos, Aristotle N, Stefanis, Nikos C, Avramopoulos, Dimitrios, Hatzimanolis, Alex, Smyrnis, Nikolaos, Bilder, Robert M, Freimer, Nelson B, Cannon, Tyrone D, London, Edythe, Poldrack, Russell A, Sabb, Fred W, Congdon, Eliza, Conley, Emily Drabant, Scult, Matthew A, Dickinson, Dwight, Straub, Richard E, Donohoe, Gary, Morris, Derek, Corvin, Aiden, Gill, Michael, Hariri, Ahmad R, Weinberger, Daniel R, Pendleton, Neil, Bitsios, Panos, Rujescu, Dan, Lahti, Jari, Le Hellard, Stephanie, Keller, Matthew C, Andreassen, Ole A, Deary, Ian J, Glahn, David C, Huang, Hailiang, Liu, Chunyu, Malhotra, Anil K, Lencz, Todd, Lam, Max, Lam, Max, Chen, Chia-Yen, Ge, Tian, Xia, Yan, Hill, David W, Trampush, Joey W, Yu, Jin, Knowles, Emma, Davies, Gail, Stahl, Eli A, Huckins, Laura, Liewald, David C, Djurovic, Srdjan, Melle, Ingrid, Christoforou, Andrea, Reinvang, Ivar, DeRosse, Pamela, Lundervold, Astri J, Steen, Vidar M, Espeseth, Thomas, Räikkönen, Katri, Widen, Elisabeth, Palotie, Aarno, Eriksson, Johan G, Giegling, Ina, Konte, Bettina, Hartmann, Annette M, Roussos, Panos, Giakoumaki, Stella, Burdick, Katherine E, Payton, Antony, Ollier, William, Chiba-Falek, Ornit, Koltai, Deborah C, Need, Anna C, Cirulli, Elizabeth T, Voineskos, Aristotle N, Stefanis, Nikos C, Avramopoulos, Dimitrios, Hatzimanolis, Alex, Smyrnis, Nikolaos, Bilder, Robert M, Freimer, Nelson B, Cannon, Tyrone D, London, Edythe, Poldrack, Russell A, Sabb, Fred W, Congdon, Eliza, Conley, Emily Drabant, Scult, Matthew A, Dickinson, Dwight, Straub, Richard E, Donohoe, Gary, Morris, Derek, Corvin, Aiden, Gill, Michael, Hariri, Ahmad R, Weinberger, Daniel R, Pendleton, Neil, Bitsios, Panos, Rujescu, Dan, Lahti, Jari, Le Hellard, Stephanie, Keller, Matthew C, Andreassen, Ole A, Deary, Ian J, Glahn, David C, Huang, Hailiang, Liu, Chunyu, Malhotra, Anil K, and Lencz, Todd
Abstract: Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.
Published: 2021

17. Tractography dissection variability: What happens when 42 groups dissect 14 white matter bundles on the same dataset?

Author: Schilling, Kurt G, Schilling, Kurt G, Rheault, François, Petit, Laurent, Hansen, Colin B, Nath, Vishwesh, Yeh, Fang-Cheng, Girard, Gabriel, Barakovic, Muhamed, Rafael-Patino, Jonathan, Yu, Thomas, Fischi-Gomez, Elda, Pizzolato, Marco, Ocampo-Pineda, Mario, Schiavi, Simona, Canales-Rodríguez, Erick J, Daducci, Alessandro, Granziera, Cristina, Innocenti, Giorgio, Thiran, Jean-Philippe, Mancini, Laura, Wastling, Stephen, Cocozza, Sirio, Petracca, Maria, Pontillo, Giuseppe, Mancini, Matteo, Vos, Sjoerd B, Vakharia, Vejay N, Duncan, John S, Melero, Helena, Manzanedo, Lidia, Sanz-Morales, Emilio, Peña-Melián, Ángel, Calamante, Fernando, Attyé, Arnaud, Cabeen, Ryan P, Korobova, Laura, Toga, Arthur W, Vijayakumari, Anupa Ambili, Parker, Drew, Verma, Ragini, Radwan, Ahmed, Sunaert, Stefan, Emsell, Louise, De Luca, Alberto, Leemans, Alexander, Bajada, Claude J, Haroon, Hamied, Azadbakht, Hojjatollah, Chamberland, Maxime, Genc, Sila, Tax, Chantal MW, Yeh, Ping-Hong, Srikanchana, Rujirutana, Mcknight, Colin D, Yang, Joseph Yuan-Mou, Chen, Jian, Kelly, Claire E, Yeh, Chun-Hung, Cochereau, Jerome, Maller, Jerome J, Welton, Thomas, Almairac, Fabien, Seunarine, Kiran K, Clark, Chris A, Zhang, Fan, Makris, Nikos, Golby, Alexandra, Rathi, Yogesh, O'Donnell, Lauren J, Xia, Yihao, Aydogan, Dogu Baran, Shi, Yonggang, Fernandes, Francisco Guerreiro, Raemaekers, Mathijs, Warrington, Shaun, Michielse, Stijn, Ramírez-Manzanares, Alonso, Concha, Luis, Aranda, Ramón, Meraz, Mariano Rivera, Lerma-Usabiaga, Garikoitz, Roitman, Lucas, Fekonja, Lucius S, Calarco, Navona, Joseph, Michael, Nakua, Hajer, Voineskos, Aristotle N, Karan, Philippe, Grenier, Gabrielle, Legarreta, Jon Haitz, Adluru, Nagesh, Nair, Veena A, Prabhakaran, Vivek, Alexander, Andrew L, Kamagata, Koji, Saito, Yuya, Uchida, Wataru, Andica, Christina, Abe, Masahiro, Bayrak, Roza G, Schilling, Kurt G, Schilling, Kurt G, Rheault, François, Petit, Laurent, Hansen, Colin B, Nath, Vishwesh, Yeh, Fang-Cheng, Girard, Gabriel, Barakovic, Muhamed, Rafael-Patino, Jonathan, Yu, Thomas, Fischi-Gomez, Elda, Pizzolato, Marco, Ocampo-Pineda, Mario, Schiavi, Simona, Canales-Rodríguez, Erick J, Daducci, Alessandro, Granziera, Cristina, Innocenti, Giorgio, Thiran, Jean-Philippe, Mancini, Laura, Wastling, Stephen, Cocozza, Sirio, Petracca, Maria, Pontillo, Giuseppe, Mancini, Matteo, Vos, Sjoerd B, Vakharia, Vejay N, Duncan, John S, Melero, Helena, Manzanedo, Lidia, Sanz-Morales, Emilio, Peña-Melián, Ángel, Calamante, Fernando, Attyé, Arnaud, Cabeen, Ryan P, Korobova, Laura, Toga, Arthur W, Vijayakumari, Anupa Ambili, Parker, Drew, Verma, Ragini, Radwan, Ahmed, Sunaert, Stefan, Emsell, Louise, De Luca, Alberto, Leemans, Alexander, Bajada, Claude J, Haroon, Hamied, Azadbakht, Hojjatollah, Chamberland, Maxime, Genc, Sila, Tax, Chantal MW, Yeh, Ping-Hong, Srikanchana, Rujirutana, Mcknight, Colin D, Yang, Joseph Yuan-Mou, Chen, Jian, Kelly, Claire E, Yeh, Chun-Hung, Cochereau, Jerome, Maller, Jerome J, Welton, Thomas, Almairac, Fabien, Seunarine, Kiran K, Clark, Chris A, Zhang, Fan, Makris, Nikos, Golby, Alexandra, Rathi, Yogesh, O'Donnell, Lauren J, Xia, Yihao, Aydogan, Dogu Baran, Shi, Yonggang, Fernandes, Francisco Guerreiro, Raemaekers, Mathijs, Warrington, Shaun, Michielse, Stijn, Ramírez-Manzanares, Alonso, Concha, Luis, Aranda, Ramón, Meraz, Mariano Rivera, Lerma-Usabiaga, Garikoitz, Roitman, Lucas, Fekonja, Lucius S, Calarco, Navona, Joseph, Michael, Nakua, Hajer, Voineskos, Aristotle N, Karan, Philippe, Grenier, Gabrielle, Legarreta, Jon Haitz, Adluru, Nagesh, Nair, Veena A, Prabhakaran, Vivek, Alexander, Andrew L, Kamagata, Koji, Saito, Yuya, Uchida, Wataru, Andica, Christina, Abe, Masahiro, and Bayrak, Roza G
Abstract: White matter bundle segmentation using diffusion MRI fiber tractography has become the method of choice to identify white matter fiber pathways in vivo in human brains. However, like other analyses of complex data, there is considerable variability in segmentation protocols and techniques. This can result in different reconstructions of the same intended white matter pathways, which directly affects tractography results, quantification, and interpretation. In this study, we aim to evaluate and quantify the variability that arises from different protocols for bundle segmentation. Through an open call to users of fiber tractography, including anatomists, clinicians, and algorithm developers, 42 independent teams were given processed sets of human whole-brain streamlines and asked to segment 14 white matter fascicles on six subjects. In total, we received 57 different bundle segmentation protocols, which enabled detailed volume-based and streamline-based analyses of agreement and disagreement among protocols for each fiber pathway. Results show that even when given the exact same sets of underlying streamlines, the variability across protocols for bundle segmentation is greater than all other sources of variability in the virtual dissection process, including variability within protocols and variability across subjects. In order to foster the use of tractography bundle dissection in routine clinical settings, and as a fundamental analytical tool, future endeavors must aim to resolve and reduce this heterogeneity. Although external validation is needed to verify the anatomical accuracy of bundle dissections, reducing heterogeneity is a step towards reproducible research and may be achieved through the use of standard nomenclature and definitions of white matter bundles and well-chosen constraints and decisions in the dissection process.
Published: 2021

18. Tractography dissection variability: What happens when 42 groups dissect 14 white matter bundles on the same dataset?

Author: Schilling, Kurt G., Rheault, François, Petit, Laurent, Hansen, Colin B., Nath, Vishwesh, Yeh, Fang Cheng, Girard, Gabriel, Barakovic, Muhamed, Rafael-Patino, Jonathan, Yu, Thomas, Fischi-Gomez, Elda, Pizzolato, Marco, Ocampo-Pineda, Mario, Schiavi, Simona, Canales-Rodríguez, Erick J., Daducci, Alessandro, Granziera, Cristina, Innocenti, Giorgio, Thiran, Jean Philippe, Mancini, Laura, Wastling, Stephen, Cocozza, Sirio, Petracca, Maria, Pontillo, Giuseppe, Mancini, Matteo, Vos, Sjoerd B., Vakharia, Vejay N., Duncan, John S., Melero, Helena, Manzanedo, Lidia, Sanz-Morales, Emilio, Peña-Melián, Ángel, Calamante, Fernando, Attyé, Arnaud, Cabeen, Ryan P., Korobova, Laura, Toga, Arthur W., Vijayakumari, Anupa Ambili, Parker, Drew, Verma, Ragini, Radwan, Ahmed, Sunaert, Stefan, Emsell, Louise, De Luca, Alberto, Leemans, Alexander, Bajada, Claude J., Haroon, Hamied, Azadbakht, Hojjatollah, Chamberland, Maxime, Genc, Sila, Tax, Chantal M.W., Yeh, Ping Hong, Srikanchana, Rujirutana, Mcknight, Colin D., Yang, Joseph Yuan Mou, Chen, Jian, Kelly, Claire E., Yeh, Chun Hung, Cochereau, Jerome, Maller, Jerome J., Welton, Thomas, Almairac, Fabien, Seunarine, Kiran K., Clark, Chris A., Zhang, Fan, Makris, Nikos, Golby, Alexandra, Rathi, Yogesh, O'Donnell, Lauren J., Xia, Yihao, Aydogan, Dogu Baran, Shi, Yonggang, Fernandes, Francisco Guerreiro, Raemaekers, Mathijs, Warrington, Shaun, Michielse, Stijn, Ramírez-Manzanares, Alonso, Concha, Luis, Aranda, Ramón, Meraz, Mariano Rivera, Lerma-Usabiaga, Garikoitz, Roitman, Lucas, Fekonja, Lucius S., Calarco, Navona, Joseph, Michael, Nakua, Hajer, Voineskos, Aristotle N., Karan, Philippe, Grenier, Gabrielle, Legarreta, Jon Haitz, Adluru, Nagesh, Nair, Veena A., Prabhakaran, Vivek, Alexander, Andrew L., Kamagata, Koji, Saito, Yuya, Uchida, Wataru, Andica, Christina, Abe, Masahiro, Bayrak, Roza G., Wheeler-Kingshott, Claudia A.M.Gandini, D'Angelo, Egidio, Palesi, Fulvia, Savini, Giovanni, Rolandi, Nicolò, Guevara, Pamela, Houenou, Josselin, López-López, Narciso, Mangin, Jean François, Poupon, Cyril, Román, Claudio, Vázquez, Andrea, Maffei, Chiara, Arantes, Mavilde, Andrade, José Paulo, Silva, Susana Maria, Calhoun, Vince D., Caverzasi, Eduardo, Sacco, Simone, Lauricella, Michael, Pestilli, Franco, Bullock, Daniel, Zhan, Yang, Brignoni-Perez, Edith, Lebel, Catherine, Reynolds, Jess E., Nestrasil, Igor, Labounek, René, Lenglet, Christophe, Paulson, Amy, Aulicka, Stefania, Heilbronner, Sarah R., Heuer, Katja, Chandio, Bramsh Qamar, Guaje, Javier, Tang, Wei, Garyfallidis, Eleftherios, Raja, Rajikha, Anderson, Adam W., Landman, Bennett A., Descoteaux, Maxime, Schilling, Kurt G., Rheault, François, Petit, Laurent, Hansen, Colin B., Nath, Vishwesh, Yeh, Fang Cheng, Girard, Gabriel, Barakovic, Muhamed, Rafael-Patino, Jonathan, Yu, Thomas, Fischi-Gomez, Elda, Pizzolato, Marco, Ocampo-Pineda, Mario, Schiavi, Simona, Canales-Rodríguez, Erick J., Daducci, Alessandro, Granziera, Cristina, Innocenti, Giorgio, Thiran, Jean Philippe, Mancini, Laura, Wastling, Stephen, Cocozza, Sirio, Petracca, Maria, Pontillo, Giuseppe, Mancini, Matteo, Vos, Sjoerd B., Vakharia, Vejay N., Duncan, John S., Melero, Helena, Manzanedo, Lidia, Sanz-Morales, Emilio, Peña-Melián, Ángel, Calamante, Fernando, Attyé, Arnaud, Cabeen, Ryan P., Korobova, Laura, Toga, Arthur W., Vijayakumari, Anupa Ambili, Parker, Drew, Verma, Ragini, Radwan, Ahmed, Sunaert, Stefan, Emsell, Louise, De Luca, Alberto, Leemans, Alexander, Bajada, Claude J., Haroon, Hamied, Azadbakht, Hojjatollah, Chamberland, Maxime, Genc, Sila, Tax, Chantal M.W., Yeh, Ping Hong, Srikanchana, Rujirutana, Mcknight, Colin D., Yang, Joseph Yuan Mou, Chen, Jian, Kelly, Claire E., Yeh, Chun Hung, Cochereau, Jerome, Maller, Jerome J., Welton, Thomas, Almairac, Fabien, Seunarine, Kiran K., Clark, Chris A., Zhang, Fan, Makris, Nikos, Golby, Alexandra, Rathi, Yogesh, O'Donnell, Lauren J., Xia, Yihao, Aydogan, Dogu Baran, Shi, Yonggang, Fernandes, Francisco Guerreiro, Raemaekers, Mathijs, Warrington, Shaun, Michielse, Stijn, Ramírez-Manzanares, Alonso, Concha, Luis, Aranda, Ramón, Meraz, Mariano Rivera, Lerma-Usabiaga, Garikoitz, Roitman, Lucas, Fekonja, Lucius S., Calarco, Navona, Joseph, Michael, Nakua, Hajer, Voineskos, Aristotle N., Karan, Philippe, Grenier, Gabrielle, Legarreta, Jon Haitz, Adluru, Nagesh, Nair, Veena A., Prabhakaran, Vivek, Alexander, Andrew L., Kamagata, Koji, Saito, Yuya, Uchida, Wataru, Andica, Christina, Abe, Masahiro, Bayrak, Roza G., Wheeler-Kingshott, Claudia A.M.Gandini, D'Angelo, Egidio, Palesi, Fulvia, Savini, Giovanni, Rolandi, Nicolò, Guevara, Pamela, Houenou, Josselin, López-López, Narciso, Mangin, Jean François, Poupon, Cyril, Román, Claudio, Vázquez, Andrea, Maffei, Chiara, Arantes, Mavilde, Andrade, José Paulo, Silva, Susana Maria, Calhoun, Vince D., Caverzasi, Eduardo, Sacco, Simone, Lauricella, Michael, Pestilli, Franco, Bullock, Daniel, Zhan, Yang, Brignoni-Perez, Edith, Lebel, Catherine, Reynolds, Jess E., Nestrasil, Igor, Labounek, René, Lenglet, Christophe, Paulson, Amy, Aulicka, Stefania, Heilbronner, Sarah R., Heuer, Katja, Chandio, Bramsh Qamar, Guaje, Javier, Tang, Wei, Garyfallidis, Eleftherios, Raja, Rajikha, Anderson, Adam W., Landman, Bennett A., and Descoteaux, Maxime
Abstract: White matter bundle segmentation using diffusion MRI fiber tractography has become the method of choice to identify white matter fiber pathways in vivo in human brains. However, like other analyses of complex data, there is considerable variability in segmentation protocols and techniques. This can result in different reconstructions of the same intended white matter pathways, which directly affects tractography results, quantification, and interpretation. In this study, we aim to evaluate and quantify the variability that arises from different protocols for bundle segmentation. Through an open call to users of fiber tractography, including anatomists, clinicians, and algorithm developers, 42 independent teams were given processed sets of human whole-brain streamlines and asked to segment 14 white matter fascicles on six subjects. In total, we received 57 different bundle segmentation protocols, which enabled detailed volume-based and streamline-based analyses of agreement and disagreement among protocols for each fiber pathway. Results show that even when given the exact same sets of underlying streamlines, the variability across protocols for bundle segmentation is greater than all other sources of variability in the virtual dissection process, including variability within protocols and variability across subjects. In order to foster the use of tractography bundle dissection in routine clinical settings, and as a fundamental analytical tool, future endeavors must aim to resolve and reduce this heterogeneity. Although external validation is needed to verify the anatomical accuracy of bundle dissections, reducing heterogeneity is a step towards reproducible research and may be achieved through the use of standard nomenclature and definitions of white matter bundles and well-chosen constraints and decisions in the dissection process.
Published: 2021

19. Molecular neuroanatomy of anorexia nervosa.

Author: Howard, Derek, Howard, Derek, Negraes, Priscilla, Voineskos, Aristotle N, Kaplan, Allan S, Muotri, Alysson R, Duvvuri, Vikas, French, Leon, Howard, Derek, Howard, Derek, Negraes, Priscilla, Voineskos, Aristotle N, Kaplan, Allan S, Muotri, Alysson R, Duvvuri, Vikas, and French, Leon
Abstract: Anorexia nervosa is a complex eating disorder with genetic, metabolic, and psychosocial underpinnings. Using genome-wide methods, recent studies have associated many genes with the disorder. We characterized these genes by projecting them into reference transcriptomic atlases of the prenatal and adult human brain to determine where these genes are expressed in fine detail. We found that genes from an induced stem cell study of anorexia nervosa cases are expressed at higher levels in the lateral parabrachial nucleus. Although weaker, expression enrichment of the adult lateral parabrachial is also found with genes from independent genetic studies. Candidate causal genes from the largest genetic study of anorexia nervosa to date were enriched for expression in the arcuate nucleus of the hypothalamus. We also found an enrichment of anorexia nervosa associated genes in the adult and fetal raphe and ventral tegmental areas. Motivated by enrichment of these feeding circuits, we tested if these genes respond to fasting in mice hypothalami, which highlighted the differential expression of Rps26 and Dalrd3. This work improves our understanding of the neurobiology of anorexia nervosa by suggesting disturbances in subcortical appetitive circuits.
Published: 2020

20. Molecular neuroanatomy of anorexia nervosa.

Author: Howard, Derek, Howard, Derek, Negraes, Priscilla, Voineskos, Aristotle N, Kaplan, Allan S, Muotri, Alysson R, Duvvuri, Vikas, French, Leon, Howard, Derek, Howard, Derek, Negraes, Priscilla, Voineskos, Aristotle N, Kaplan, Allan S, Muotri, Alysson R, Duvvuri, Vikas, and French, Leon
Abstract: Anorexia nervosa is a complex eating disorder with genetic, metabolic, and psychosocial underpinnings. Using genome-wide methods, recent studies have associated many genes with the disorder. We characterized these genes by projecting them into reference transcriptomic atlases of the prenatal and adult human brain to determine where these genes are expressed in fine detail. We found that genes from an induced stem cell study of anorexia nervosa cases are expressed at higher levels in the lateral parabrachial nucleus. Although weaker, expression enrichment of the adult lateral parabrachial is also found with genes from independent genetic studies. Candidate causal genes from the largest genetic study of anorexia nervosa to date were enriched for expression in the arcuate nucleus of the hypothalamus. We also found an enrichment of anorexia nervosa associated genes in the adult and fetal raphe and ventral tegmental areas. Motivated by enrichment of these feeding circuits, we tested if these genes respond to fasting in mice hypothalami, which highlighted the differential expression of Rps26 and Dalrd3. This work improves our understanding of the neurobiology of anorexia nervosa by suggesting disturbances in subcortical appetitive circuits.
Published: 2020

21. Can we accurately classify schizophrenia patients from healthy controls using magnetic resonance imaging and machine learning?:A multi-method and multi-dataset study

Author: Winterburn, Julie L, Voineskos, Aristotle N, Devenyi, Gabriel A, Plitman, Eric, de la Fuente-Sandoval, Camilo, Bhagwat, Nikhil, Graff-Guerrero, Ariel, Knight, Jo, Chakravarty, M Mallar, Winterburn, Julie L, Voineskos, Aristotle N, Devenyi, Gabriel A, Plitman, Eric, de la Fuente-Sandoval, Camilo, Bhagwat, Nikhil, Graff-Guerrero, Ariel, Knight, Jo, and Chakravarty, M Mallar
Abstract: Machine learning is a powerful tool that has previously been used to classify schizophrenia (SZ) patients from healthy controls (HC) using magnetic resonance images. Each study, however, uses different datasets, classification algorithms, and validation techniques. Here, we perform a critical appraisal of the accuracy of machine learning methodologies used in SZ/HC classifications studies by comparing three machine learning algorithms (logistic regression [LR], support vector machines [SVMs], and linear discriminant analysis [LDA]) on three independent datasets (435 subjects total) using two tissue density estimates and cortical thickness (CT). Performance is assessed using 10-fold cross-validation, as well as a held-out validation set. Classification using CT outperformed tissue densities, but there was no clear effect of dataset. LR, SVMs, and LDA each yielded the highest accuracies for a different feature set and validation paradigm, but most accuracies were between 55 and 70%, well below previously reported values. The highest accuracy achieved was 73.5% using CT data and an SVM. Taken together, these results illustrate some of the obstacles to constructing effective disease classifiers, and suggest that tissue densities and CT may not be sufficiently sensitive for SZ/HC classification given current available methodologies and sample sizes.
Published: 2019

22. Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.

Author: Lam, Max, Lam, Max, Hill, W David, Trampush, Joey W, Yu, Jin, Knowles, Emma, Davies, Gail, Stahl, Eli, Huckins, Laura, Liewald, David C, Djurovic, Srdjan, Melle, Ingrid, Sundet, Kjetil, Christoforou, Andrea, Reinvang, Ivar, DeRosse, Pamela, Lundervold, Astri J, Steen, Vidar M, Espeseth, Thomas, Räikkönen, Katri, Widen, Elisabeth, Palotie, Aarno, Eriksson, Johan G, Giegling, Ina, Konte, Bettina, Hartmann, Annette M, Roussos, Panos, Giakoumaki, Stella, Burdick, Katherine E, Payton, Antony, Ollier, William, Chiba-Falek, Ornit, Attix, Deborah K, Need, Anna C, Cirulli, Elizabeth T, Voineskos, Aristotle N, Stefanis, Nikos C, Avramopoulos, Dimitrios, Hatzimanolis, Alex, Arking, Dan E, Smyrnis, Nikolaos, Bilder, Robert M, Freimer, Nelson A, Cannon, Tyrone D, London, Edythe, Poldrack, Russell A, Sabb, Fred W, Congdon, Eliza, Conley, Emily Drabant, Scult, Matthew A, Dickinson, Dwight, Straub, Richard E, Donohoe, Gary, Morris, Derek, Corvin, Aiden, Gill, Michael, Hariri, Ahmad R, Weinberger, Daniel R, Pendleton, Neil, Bitsios, Panos, Rujescu, Dan, Lahti, Jari, Le Hellard, Stephanie, Keller, Matthew C, Andreassen, Ole A, Deary, Ian J, Glahn, David C, Malhotra, Anil K, Lencz, Todd, Lam, Max, Lam, Max, Hill, W David, Trampush, Joey W, Yu, Jin, Knowles, Emma, Davies, Gail, Stahl, Eli, Huckins, Laura, Liewald, David C, Djurovic, Srdjan, Melle, Ingrid, Sundet, Kjetil, Christoforou, Andrea, Reinvang, Ivar, DeRosse, Pamela, Lundervold, Astri J, Steen, Vidar M, Espeseth, Thomas, Räikkönen, Katri, Widen, Elisabeth, Palotie, Aarno, Eriksson, Johan G, Giegling, Ina, Konte, Bettina, Hartmann, Annette M, Roussos, Panos, Giakoumaki, Stella, Burdick, Katherine E, Payton, Antony, Ollier, William, Chiba-Falek, Ornit, Attix, Deborah K, Need, Anna C, Cirulli, Elizabeth T, Voineskos, Aristotle N, Stefanis, Nikos C, Avramopoulos, Dimitrios, Hatzimanolis, Alex, Arking, Dan E, Smyrnis, Nikolaos, Bilder, Robert M, Freimer, Nelson A, Cannon, Tyrone D, London, Edythe, Poldrack, Russell A, Sabb, Fred W, Congdon, Eliza, Conley, Emily Drabant, Scult, Matthew A, Dickinson, Dwight, Straub, Richard E, Donohoe, Gary, Morris, Derek, Corvin, Aiden, Gill, Michael, Hariri, Ahmad R, Weinberger, Daniel R, Pendleton, Neil, Bitsios, Panos, Rujescu, Dan, Lahti, Jari, Le Hellard, Stephanie, Keller, Matthew C, Andreassen, Ole A, Deary, Ian J, Glahn, David C, Malhotra, Anil K, and Lencz, Todd
Abstract: Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected ("concordant") direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive ("discordant") relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10-8. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms-early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways-that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the bro
Published: 2019

23. Can we accurately classify schizophrenia patients from healthy controls using magnetic resonance imaging and machine learning? : A multi-method and multi-dataset study

Author: Winterburn, Julie L, Voineskos, Aristotle N, Devenyi, Gabriel A, Plitman, Eric, de la Fuente-Sandoval, Camilo, Bhagwat, Nikhil, Graff-Guerrero, Ariel, Knight, Jo, Chakravarty, M Mallar, Winterburn, Julie L, Voineskos, Aristotle N, Devenyi, Gabriel A, Plitman, Eric, de la Fuente-Sandoval, Camilo, Bhagwat, Nikhil, Graff-Guerrero, Ariel, Knight, Jo, and Chakravarty, M Mallar
Abstract: Machine learning is a powerful tool that has previously been used to classify schizophrenia (SZ) patients from healthy controls (HC) using magnetic resonance images. Each study, however, uses different datasets, classification algorithms, and validation techniques. Here, we perform a critical appraisal of the accuracy of machine learning methodologies used in SZ/HC classifications studies by comparing three machine learning algorithms (logistic regression [LR], support vector machines [SVMs], and linear discriminant analysis [LDA]) on three independent datasets (435 subjects total) using two tissue density estimates and cortical thickness (CT). Performance is assessed using 10-fold cross-validation, as well as a held-out validation set. Classification using CT outperformed tissue densities, but there was no clear effect of dataset. LR, SVMs, and LDA each yielded the highest accuracies for a different feature set and validation paradigm, but most accuracies were between 55 and 70%, well below previously reported values. The highest accuracy achieved was 73.5% using CT data and an SVM. Taken together, these results illustrate some of the obstacles to constructing effective disease classifiers, and suggest that tissue densities and CT may not be sufficiently sensitive for SZ/HC classification given current available methodologies and sample sizes.
Published: 2019

24. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Author: Davies, Gail, Lam, Max, Harris, Sarah E., Trampush, Joey W., Luciano, Michelle, Hill, W. David, Hagenaars, Saskia P., Ritchie, Stuart J., Marioni, Riccardo E., Fawns-Ritchie, Chloe, Liewald, David C. M., Okely, Judith A., Ahola-Olli, Ari V., Barnes, Catriona L. K., Bertram, Lars, Bis, Joshua C., Burdick, Katherine E., Christoforou, Andrea, DeRosse, Pamela, Djurovic, Srdjan, Espeseth, Thomas, Giakoumaki, Stella, Giddaluru, Sudheer, Gustavson, Daniel E., Hayward, Caroline, Hofer, Edith, Ikram, M. Arfan, Karlsson, Robert, Knowles, Emma, Lahti, Jari, Leber, Markus, Li, Shuo, Mather, Karen A., Melle, Ingrid, Morris, Derek, Oldmeadow, Christopher, Palviainen, Teemu, Payton, Antony, Pazoki, Raha, Petrovic, Katja, Reynolds, Chandra A., Sargurupremraj, Muralidharan, Scholz, Markus, Smith, Jennifer A., Smith, Albert V., Terzikhan, Natalie, Thalamuthu, Anbupalam, Trompet, Stella, van der Lee, Sven J., Ware, Erin B., Windham, B. Gwen, Wright, Margaret J., Yang, Jingyun, Yu, Jin, Ames, David, Amin, Najaf, Amouyel, Philippe, Andreassen, Ole A., Armstrong, Nicola J., Assareh, Amelia A., Attia, John R., Attix, Deborah, Avramopoulos, Dimitrios, Bennett, David A., Boehmer, Anne C., Boyle, Patricia A., Brodaty, Henry, Campbell, Harry, Cannon, Tyrone D., Cirulli, Elizabeth T., Congdon, Eliza, Conley, Emily Drabant, Corley, Janie, Cox, Simon R., Dale, Anders M., Dehghan, Abbas, Dick, Danielle, Dickinson, Dwight, Eriksson, Johan G., Evangelou, Evangelos, Faul, Jessica D., Ford, Ian, Freimer, Nelson A., Gao, He, Giegling, Ina, Gillespie, Nathan A., Gordon, Scott D., Gottesman, Rebecca F., Griswold, Michael E., Gudnason, Vilmundur, Harris, Tamara B., Hartmann, Annette M., Hatzimanolis, Alex, Heiss, Gerardo, Holliday, Elizabeth G., Joshi, Peter K., Kahonen, Mika, Kardia, Sharon L. R., Karlsson, Ida, Kleineidam, Luca, Knopman, David S., Kochan, Nicole A., Konte, Bettina, Kwok, John B., Le Hellard, Stephanie, Lee, Teresa, Lehtimaki, Terho, Li, Shu-Chen, Liu, Tian, Koini, Marisa, London, Edythe, Longstreth, Will T., Jr., Lopez, Oscar L., Loukola, Anu, Luck, Tobias, Lundervold, Astri J., Lundquist, Anders, Lyytikainen, Leo-Pekka, Martin, Nicholas G., Montgomery, Grant W., Murray, Alison D., Need, Anna C., Noordam, Raymond, Nyberg, Lars, Ollier, William, Papenberg, Goran, Pattie, Alison, Polasek, Ozren, Poldrack, Russell A., Psaty, Bruce M., Reppermund, Simone, Riedel-Heller, Steffi G., Rose, Richard J., Rotter, Jerome I., Roussos, Panos, Rovio, Suvi P., Saba, Yasaman, Sabb, Fred W., Sachdev, Perminder S., Satizabal, Claudia L., Schmid, Matthias, Scott, Rodney J., Scult, Matthew A., Simino, Jeannette, Slagboom, P. Eline, Smyrnis, Nikolaos, Soumare, Aicha, Stefanis, Nikos C., Stott, David J., Straub, Richard E., Sundet, Kjetil, Taylor, Adele M., Taylor, Kent D., Tzoulaki, Ioanna, Tzourio, Christophe, Uitterlinden, Andre, Vitart, Veronique, Voineskos, Aristotle N., Kaprio, Jaakko, Wagner, Michael, Wagner, Holger, Weinhold, Leonie, Wen, K. Hoyan, Widen, Elisabeth, Yang, Qiong, Zhao, Wei, Adams, Hieab H. H., Arking, Dan E., Bilder, Robert M., Bitsios, Panos, Boerwinkle, Eric, Chiba-Falek, Ornit, Corvin, Aiden, De Jager, Philip L., Debette, Stephanie, Donohoe, Gary, Elliott, Paul, Fitzpatrick, Annette L., Gill, Michael, Glahn, David C., Hagg, Sara, Hansell, Narelle K., Hariri, Ahmad R., Ikram, M. Kamran, Jukema, J. Wouter, Vuoksimaa, Eero, Keller, Matthew C., Kremen, William S., Launer, Lenore, Lindenberger, Ulman, Palotie, Aarno, Pedersen, Nancy L., Pendleton, Neil, Porteous, David J., Raikkonen, Katri, Raitakari, Olli T., Ramirez, Alfredo, Reinvang, Ivar, Rudan, Igor, Rujescu, Dan, Schmidt, Reinhold, Schmidt, Helena, Schofield, Peter W., Schofield, Peter R., Starr, John M., Steen, Vidar M., Trollor, Julian N., Turner, Steven T., Van Duijn, Cornelia M., Villringer, Arno, Weinberger, Daniel R., Weir, David R., Wilson, James F., Malhotra, Anil, McIntosh, Andrew M., Gale, Catharine R., Seshadri, Sudha, Mosley, Thomas H., Jr., Bressler, Jan, Lencz, Todd, Deary, Ian J., Davies, Gail, Lam, Max, Harris, Sarah E., Trampush, Joey W., Luciano, Michelle, Hill, W. David, Hagenaars, Saskia P., Ritchie, Stuart J., Marioni, Riccardo E., Fawns-Ritchie, Chloe, Liewald, David C. M., Okely, Judith A., Ahola-Olli, Ari V., Barnes, Catriona L. K., Bertram, Lars, Bis, Joshua C., Burdick, Katherine E., Christoforou, Andrea, DeRosse, Pamela, Djurovic, Srdjan, Espeseth, Thomas, Giakoumaki, Stella, Giddaluru, Sudheer, Gustavson, Daniel E., Hayward, Caroline, Hofer, Edith, Ikram, M. Arfan, Karlsson, Robert, Knowles, Emma, Lahti, Jari, Leber, Markus, Li, Shuo, Mather, Karen A., Melle, Ingrid, Morris, Derek, Oldmeadow, Christopher, Palviainen, Teemu, Payton, Antony, Pazoki, Raha, Petrovic, Katja, Reynolds, Chandra A., Sargurupremraj, Muralidharan, Scholz, Markus, Smith, Jennifer A., Smith, Albert V., Terzikhan, Natalie, Thalamuthu, Anbupalam, Trompet, Stella, van der Lee, Sven J., Ware, Erin B., Windham, B. Gwen, Wright, Margaret J., Yang, Jingyun, Yu, Jin, Ames, David, Amin, Najaf, Amouyel, Philippe, Andreassen, Ole A., Armstrong, Nicola J., Assareh, Amelia A., Attia, John R., Attix, Deborah, Avramopoulos, Dimitrios, Bennett, David A., Boehmer, Anne C., Boyle, Patricia A., Brodaty, Henry, Campbell, Harry, Cannon, Tyrone D., Cirulli, Elizabeth T., Congdon, Eliza, Conley, Emily Drabant, Corley, Janie, Cox, Simon R., Dale, Anders M., Dehghan, Abbas, Dick, Danielle, Dickinson, Dwight, Eriksson, Johan G., Evangelou, Evangelos, Faul, Jessica D., Ford, Ian, Freimer, Nelson A., Gao, He, Giegling, Ina, Gillespie, Nathan A., Gordon, Scott D., Gottesman, Rebecca F., Griswold, Michael E., Gudnason, Vilmundur, Harris, Tamara B., Hartmann, Annette M., Hatzimanolis, Alex, Heiss, Gerardo, Holliday, Elizabeth G., Joshi, Peter K., Kahonen, Mika, Kardia, Sharon L. R., Karlsson, Ida, Kleineidam, Luca, Knopman, David S., Kochan, Nicole A., Konte, Bettina, Kwok, John B., Le Hellard, Stephanie, Lee, Teresa, Lehtimaki, Terho, Li, Shu-Chen, Liu, Tian, Koini, Marisa, London, Edythe, Longstreth, Will T., Jr., Lopez, Oscar L., Loukola, Anu, Luck, Tobias, Lundervold, Astri J., Lundquist, Anders, Lyytikainen, Leo-Pekka, Martin, Nicholas G., Montgomery, Grant W., Murray, Alison D., Need, Anna C., Noordam, Raymond, Nyberg, Lars, Ollier, William, Papenberg, Goran, Pattie, Alison, Polasek, Ozren, Poldrack, Russell A., Psaty, Bruce M., Reppermund, Simone, Riedel-Heller, Steffi G., Rose, Richard J., Rotter, Jerome I., Roussos, Panos, Rovio, Suvi P., Saba, Yasaman, Sabb, Fred W., Sachdev, Perminder S., Satizabal, Claudia L., Schmid, Matthias, Scott, Rodney J., Scult, Matthew A., Simino, Jeannette, Slagboom, P. Eline, Smyrnis, Nikolaos, Soumare, Aicha, Stefanis, Nikos C., Stott, David J., Straub, Richard E., Sundet, Kjetil, Taylor, Adele M., Taylor, Kent D., Tzoulaki, Ioanna, Tzourio, Christophe, Uitterlinden, Andre, Vitart, Veronique, Voineskos, Aristotle N., Kaprio, Jaakko, Wagner, Michael, Wagner, Holger, Weinhold, Leonie, Wen, K. Hoyan, Widen, Elisabeth, Yang, Qiong, Zhao, Wei, Adams, Hieab H. H., Arking, Dan E., Bilder, Robert M., Bitsios, Panos, Boerwinkle, Eric, Chiba-Falek, Ornit, Corvin, Aiden, De Jager, Philip L., Debette, Stephanie, Donohoe, Gary, Elliott, Paul, Fitzpatrick, Annette L., Gill, Michael, Glahn, David C., Hagg, Sara, Hansell, Narelle K., Hariri, Ahmad R., Ikram, M. Kamran, Jukema, J. Wouter, Vuoksimaa, Eero, Keller, Matthew C., Kremen, William S., Launer, Lenore, Lindenberger, Ulman, Palotie, Aarno, Pedersen, Nancy L., Pendleton, Neil, Porteous, David J., Raikkonen, Katri, Raitakari, Olli T., Ramirez, Alfredo, Reinvang, Ivar, Rudan, Igor, Rujescu, Dan, Schmidt, Reinhold, Schmidt, Helena, Schofield, Peter W., Schofield, Peter R., Starr, John M., Steen, Vidar M., Trollor, Julian N., Turner, Steven T., Van Duijn, Cornelia M., Villringer, Arno, Weinberger, Daniel R., Weir, David R., Wilson, James F., Malhotra, Anil, McIntosh, Andrew M., Gale, Catharine R., Seshadri, Sudha, Mosley, Thomas H., Jr., Bressler, Jan, Lencz, Todd, and Deary, Ian J.
Abstract: General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 x 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function., Errata: Davies, G., Lam, M., Harris, S. E., Trampush, J. W., Luciano, M., Hill, W. D., … Deary, I. J. (2019). Author correction to Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. [Nature Communications (2018), 9, Article number 2098]. Nature Communications, 10, Article number: 2068. DOI: 10.1038/s41467-019-10160-w
Published: 2018
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25. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Author: Davies, Gail, Lam, Max, Harris, Sarah E., Trampush, Joey W., Luciano, Michelle, Hill, W. David, Hagenaars, Saskia P., Ritchie, Stuart J., Marioni, Riccardo E., Fawns-Ritchie, Chloe, Liewald, David C. M., Okely, Judith A., Ahola-Olli, Ari V., Barnes, Catriona L. K., Bertram, Lars, Bis, Joshua C., Burdick, Katherine E., Christoforou, Andrea, DeRosse, Pamela, Djurovic, Srdjan, Espeseth, Thomas, Giakoumaki, Stella, Giddaluru, Sudheer, Gustavson, Daniel E., Hayward, Caroline, Hofer, Edith, Ikram, M. Arfan, Karlsson, Robert, Knowles, Emma, Lahti, Jari, Leber, Markus, Li, Shuo, Mather, Karen A., Melle, Ingrid, Morris, Derek, Oldmeadow, Christopher, Palviainen, Teemu, Payton, Antony, Pazoki, Raha, Petrovic, Katja, Reynolds, Chandra A., Sargurupremraj, Muralidharan, Scholz, Markus, Smith, Jennifer A., Smith, Albert V., Terzikhan, Natalie, Thalamuthu, Anbupalam, Trompet, Stella, van der Lee, Sven J., Ware, Erin B., Windham, B. Gwen, Wright, Margaret J., Yang, Jingyun, Yu, Jin, Ames, David, Amin, Najaf, Amouyel, Philippe, Andreassen, Ole A., Armstrong, Nicola J., Assareh, Amelia A., Attia, John R., Attix, Deborah, Avramopoulos, Dimitrios, Bennett, David A., Boehmer, Anne C., Boyle, Patricia A., Brodaty, Henry, Campbell, Harry, Cannon, Tyrone D., Cirulli, Elizabeth T., Congdon, Eliza, Conley, Emily Drabant, Corley, Janie, Cox, Simon R., Dale, Anders M., Dehghan, Abbas, Dick, Danielle, Dickinson, Dwight, Eriksson, Johan G., Evangelou, Evangelos, Faul, Jessica D., Ford, Ian, Freimer, Nelson A., Gao, He, Giegling, Ina, Gillespie, Nathan A., Gordon, Scott D., Gottesman, Rebecca F., Griswold, Michael E., Gudnason, Vilmundur, Harris, Tamara B., Hartmann, Annette M., Hatzimanolis, Alex, Heiss, Gerardo, Holliday, Elizabeth G., Joshi, Peter K., Kahonen, Mika, Kardia, Sharon L. R., Karlsson, Ida, Kleineidam, Luca, Knopman, David S., Kochan, Nicole A., Konte, Bettina, Kwok, John B., Le Hellard, Stephanie, Lee, Teresa, Lehtimaki, Terho, Li, Shu-Chen, Liu, Tian, Koini, Marisa, London, Edythe, Longstreth, Will T., Jr., Lopez, Oscar L., Loukola, Anu, Luck, Tobias, Lundervold, Astri J., Lundquist, Anders, Lyytikainen, Leo-Pekka, Martin, Nicholas G., Montgomery, Grant W., Murray, Alison D., Need, Anna C., Noordam, Raymond, Nyberg, Lars, Ollier, William, Papenberg, Goran, Pattie, Alison, Polasek, Ozren, Poldrack, Russell A., Psaty, Bruce M., Reppermund, Simone, Riedel-Heller, Steffi G., Rose, Richard J., Rotter, Jerome I., Roussos, Panos, Rovio, Suvi P., Saba, Yasaman, Sabb, Fred W., Sachdev, Perminder S., Satizabal, Claudia L., Schmid, Matthias, Scott, Rodney J., Scult, Matthew A., Simino, Jeannette, Slagboom, P. Eline, Smyrnis, Nikolaos, Soumare, Aicha, Stefanis, Nikos C., Stott, David J., Straub, Richard E., Sundet, Kjetil, Taylor, Adele M., Taylor, Kent D., Tzoulaki, Ioanna, Tzourio, Christophe, Uitterlinden, Andre, Vitart, Veronique, Voineskos, Aristotle N., Kaprio, Jaakko, Wagner, Michael, Wagner, Holger, Weinhold, Leonie, Wen, K. Hoyan, Widen, Elisabeth, Yang, Qiong, Zhao, Wei, Adams, Hieab H. H., Arking, Dan E., Bilder, Robert M., Bitsios, Panos, Boerwinkle, Eric, Chiba-Falek, Ornit, Corvin, Aiden, De Jager, Philip L., Debette, Stephanie, Donohoe, Gary, Elliott, Paul, Fitzpatrick, Annette L., Gill, Michael, Glahn, David C., Hagg, Sara, Hansell, Narelle K., Hariri, Ahmad R., Ikram, M. Kamran, Jukema, J. Wouter, Vuoksimaa, Eero, Keller, Matthew C., Kremen, William S., Launer, Lenore, Lindenberger, Ulman, Palotie, Aarno, Pedersen, Nancy L., Pendleton, Neil, Porteous, David J., Raikkonen, Katri, Raitakari, Olli T., Ramirez, Alfredo, Reinvang, Ivar, Rudan, Igor, Rujescu, Dan, Schmidt, Reinhold, Schmidt, Helena, Schofield, Peter W., Schofield, Peter R., Starr, John M., Steen, Vidar M., Trollor, Julian N., Turner, Steven T., Van Duijn, Cornelia M., Villringer, Arno, Weinberger, Daniel R., Weir, David R., Wilson, James F., Malhotra, Anil, McIntosh, Andrew M., Gale, Catharine R., Seshadri, Sudha, Mosley, Thomas H., Jr., Bressler, Jan, Lencz, Todd, Deary, Ian J., Davies, Gail, Lam, Max, Harris, Sarah E., Trampush, Joey W., Luciano, Michelle, Hill, W. David, Hagenaars, Saskia P., Ritchie, Stuart J., Marioni, Riccardo E., Fawns-Ritchie, Chloe, Liewald, David C. M., Okely, Judith A., Ahola-Olli, Ari V., Barnes, Catriona L. K., Bertram, Lars, Bis, Joshua C., Burdick, Katherine E., Christoforou, Andrea, DeRosse, Pamela, Djurovic, Srdjan, Espeseth, Thomas, Giakoumaki, Stella, Giddaluru, Sudheer, Gustavson, Daniel E., Hayward, Caroline, Hofer, Edith, Ikram, M. Arfan, Karlsson, Robert, Knowles, Emma, Lahti, Jari, Leber, Markus, Li, Shuo, Mather, Karen A., Melle, Ingrid, Morris, Derek, Oldmeadow, Christopher, Palviainen, Teemu, Payton, Antony, Pazoki, Raha, Petrovic, Katja, Reynolds, Chandra A., Sargurupremraj, Muralidharan, Scholz, Markus, Smith, Jennifer A., Smith, Albert V., Terzikhan, Natalie, Thalamuthu, Anbupalam, Trompet, Stella, van der Lee, Sven J., Ware, Erin B., Windham, B. Gwen, Wright, Margaret J., Yang, Jingyun, Yu, Jin, Ames, David, Amin, Najaf, Amouyel, Philippe, Andreassen, Ole A., Armstrong, Nicola J., Assareh, Amelia A., Attia, John R., Attix, Deborah, Avramopoulos, Dimitrios, Bennett, David A., Boehmer, Anne C., Boyle, Patricia A., Brodaty, Henry, Campbell, Harry, Cannon, Tyrone D., Cirulli, Elizabeth T., Congdon, Eliza, Conley, Emily Drabant, Corley, Janie, Cox, Simon R., Dale, Anders M., Dehghan, Abbas, Dick, Danielle, Dickinson, Dwight, Eriksson, Johan G., Evangelou, Evangelos, Faul, Jessica D., Ford, Ian, Freimer, Nelson A., Gao, He, Giegling, Ina, Gillespie, Nathan A., Gordon, Scott D., Gottesman, Rebecca F., Griswold, Michael E., Gudnason, Vilmundur, Harris, Tamara B., Hartmann, Annette M., Hatzimanolis, Alex, Heiss, Gerardo, Holliday, Elizabeth G., Joshi, Peter K., Kahonen, Mika, Kardia, Sharon L. R., Karlsson, Ida, Kleineidam, Luca, Knopman, David S., Kochan, Nicole A., Konte, Bettina, Kwok, John B., Le Hellard, Stephanie, Lee, Teresa, Lehtimaki, Terho, Li, Shu-Chen, Liu, Tian, Koini, Marisa, London, Edythe, Longstreth, Will T., Jr., Lopez, Oscar L., Loukola, Anu, Luck, Tobias, Lundervold, Astri J., Lundquist, Anders, Lyytikainen, Leo-Pekka, Martin, Nicholas G., Montgomery, Grant W., Murray, Alison D., Need, Anna C., Noordam, Raymond, Nyberg, Lars, Ollier, William, Papenberg, Goran, Pattie, Alison, Polasek, Ozren, Poldrack, Russell A., Psaty, Bruce M., Reppermund, Simone, Riedel-Heller, Steffi G., Rose, Richard J., Rotter, Jerome I., Roussos, Panos, Rovio, Suvi P., Saba, Yasaman, Sabb, Fred W., Sachdev, Perminder S., Satizabal, Claudia L., Schmid, Matthias, Scott, Rodney J., Scult, Matthew A., Simino, Jeannette, Slagboom, P. Eline, Smyrnis, Nikolaos, Soumare, Aicha, Stefanis, Nikos C., Stott, David J., Straub, Richard E., Sundet, Kjetil, Taylor, Adele M., Taylor, Kent D., Tzoulaki, Ioanna, Tzourio, Christophe, Uitterlinden, Andre, Vitart, Veronique, Voineskos, Aristotle N., Kaprio, Jaakko, Wagner, Michael, Wagner, Holger, Weinhold, Leonie, Wen, K. Hoyan, Widen, Elisabeth, Yang, Qiong, Zhao, Wei, Adams, Hieab H. H., Arking, Dan E., Bilder, Robert M., Bitsios, Panos, Boerwinkle, Eric, Chiba-Falek, Ornit, Corvin, Aiden, De Jager, Philip L., Debette, Stephanie, Donohoe, Gary, Elliott, Paul, Fitzpatrick, Annette L., Gill, Michael, Glahn, David C., Hagg, Sara, Hansell, Narelle K., Hariri, Ahmad R., Ikram, M. Kamran, Jukema, J. Wouter, Vuoksimaa, Eero, Keller, Matthew C., Kremen, William S., Launer, Lenore, Lindenberger, Ulman, Palotie, Aarno, Pedersen, Nancy L., Pendleton, Neil, Porteous, David J., Raikkonen, Katri, Raitakari, Olli T., Ramirez, Alfredo, Reinvang, Ivar, Rudan, Igor, Rujescu, Dan, Schmidt, Reinhold, Schmidt, Helena, Schofield, Peter W., Schofield, Peter R., Starr, John M., Steen, Vidar M., Trollor, Julian N., Turner, Steven T., Van Duijn, Cornelia M., Villringer, Arno, Weinberger, Daniel R., Weir, David R., Wilson, James F., Malhotra, Anil, McIntosh, Andrew M., Gale, Catharine R., Seshadri, Sudha, Mosley, Thomas H., Jr., Bressler, Jan, Lencz, Todd, and Deary, Ian J.
Abstract: General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 x 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function., Errata: Davies, G., Lam, M., Harris, S. E., Trampush, J. W., Luciano, M., Hill, W. D., … Deary, I. J. (2019). Author correction to Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. [Nature Communications (2018), 9, Article number 2098]. Nature Communications, 10, Article number: 2068. DOI: 10.1038/s41467-019-10160-w
Published: 2018
Full Text: View/download PDF

26. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Author: Davies, Gail, Lam, Max, Harris, Sarah E., Trampush, Joey W., Luciano, Michelle, Hill, W. David, Hagenaars, Saskia P., Ritchie, Stuart J., Marioni, Riccardo E., Fawns-Ritchie, Chloe, Liewald, David C. M., Okely, Judith A., Ahola-Olli, Ari V., Barnes, Catriona L. K., Bertram, Lars, Bis, Joshua C., Burdick, Katherine E., Christoforou, Andrea, DeRosse, Pamela, Djurovic, Srdjan, Espeseth, Thomas, Giakoumaki, Stella, Giddaluru, Sudheer, Gustavson, Daniel E., Hayward, Caroline, Hofer, Edith, Ikram, M. Arfan, Karlsson, Robert, Knowles, Emma, Lahti, Jari, Leber, Markus, Li, Shuo, Mather, Karen A., Melle, Ingrid, Morris, Derek, Oldmeadow, Christopher, Palviainen, Teemu, Payton, Antony, Pazoki, Raha, Petrovic, Katja, Reynolds, Chandra A., Sargurupremraj, Muralidharan, Scholz, Markus, Smith, Jennifer A., Smith, Albert V., Terzikhan, Natalie, Thalamuthu, Anbupalam, Trompet, Stella, van der Lee, Sven J., Ware, Erin B., Windham, B. Gwen, Wright, Margaret J., Yang, Jingyun, Yu, Jin, Ames, David, Amin, Najaf, Amouyel, Philippe, Andreassen, Ole A., Armstrong, Nicola J., Assareh, Amelia A., Attia, John R., Attix, Deborah, Avramopoulos, Dimitrios, Bennett, David A., Boehmer, Anne C., Boyle, Patricia A., Brodaty, Henry, Campbell, Harry, Cannon, Tyrone D., Cirulli, Elizabeth T., Congdon, Eliza, Conley, Emily Drabant, Corley, Janie, Cox, Simon R., Dale, Anders M., Dehghan, Abbas, Dick, Danielle, Dickinson, Dwight, Eriksson, Johan G., Evangelou, Evangelos, Faul, Jessica D., Ford, Ian, Freimer, Nelson A., Gao, He, Giegling, Ina, Gillespie, Nathan A., Gordon, Scott D., Gottesman, Rebecca F., Griswold, Michael E., Gudnason, Vilmundur, Harris, Tamara B., Hartmann, Annette M., Hatzimanolis, Alex, Heiss, Gerardo, Holliday, Elizabeth G., Joshi, Peter K., Kahonen, Mika, Kardia, Sharon L. R., Karlsson, Ida, Kleineidam, Luca, Knopman, David S., Kochan, Nicole A., Konte, Bettina, Kwok, John B., Le Hellard, Stephanie, Lee, Teresa, Lehtimaki, Terho, Li, Shu-Chen, Liu, Tian, Koini, Marisa, London, Edythe, Longstreth, Will T., Jr., Lopez, Oscar L., Loukola, Anu, Luck, Tobias, Lundervold, Astri J., Lundquist, Anders, Lyytikainen, Leo-Pekka, Martin, Nicholas G., Montgomery, Grant W., Murray, Alison D., Need, Anna C., Noordam, Raymond, Nyberg, Lars, Ollier, William, Papenberg, Goran, Pattie, Alison, Polasek, Ozren, Poldrack, Russell A., Psaty, Bruce M., Reppermund, Simone, Riedel-Heller, Steffi G., Rose, Richard J., Rotter, Jerome I., Roussos, Panos, Rovio, Suvi P., Saba, Yasaman, Sabb, Fred W., Sachdev, Perminder S., Satizabal, Claudia L., Schmid, Matthias, Scott, Rodney J., Scult, Matthew A., Simino, Jeannette, Slagboom, P. Eline, Smyrnis, Nikolaos, Soumare, Aicha, Stefanis, Nikos C., Stott, David J., Straub, Richard E., Sundet, Kjetil, Taylor, Adele M., Taylor, Kent D., Tzoulaki, Ioanna, Tzourio, Christophe, Uitterlinden, Andre, Vitart, Veronique, Voineskos, Aristotle N., Kaprio, Jaakko, Wagner, Michael, Wagner, Holger, Weinhold, Leonie, Wen, K. Hoyan, Widen, Elisabeth, Yang, Qiong, Zhao, Wei, Adams, Hieab H. H., Arking, Dan E., Bilder, Robert M., Bitsios, Panos, Boerwinkle, Eric, Chiba-Falek, Ornit, Corvin, Aiden, De Jager, Philip L., Debette, Stephanie, Donohoe, Gary, Elliott, Paul, Fitzpatrick, Annette L., Gill, Michael, Glahn, David C., Hagg, Sara, Hansell, Narelle K., Hariri, Ahmad R., Ikram, M. Kamran, Jukema, J. Wouter, Vuoksimaa, Eero, Keller, Matthew C., Kremen, William S., Launer, Lenore, Lindenberger, Ulman, Palotie, Aarno, Pedersen, Nancy L., Pendleton, Neil, Porteous, David J., Raikkonen, Katri, Raitakari, Olli T., Ramirez, Alfredo, Reinvang, Ivar, Rudan, Igor, Rujescu, Dan, Schmidt, Reinhold, Schmidt, Helena, Schofield, Peter W., Schofield, Peter R., Starr, John M., Steen, Vidar M., Trollor, Julian N., Turner, Steven T., Van Duijn, Cornelia M., Villringer, Arno, Weinberger, Daniel R., Weir, David R., Wilson, James F., Malhotra, Anil, McIntosh, Andrew M., Gale, Catharine R., Seshadri, Sudha, Mosley, Thomas H., Jr., Bressler, Jan, Lencz, Todd, Deary, Ian J., Davies, Gail, Lam, Max, Harris, Sarah E., Trampush, Joey W., Luciano, Michelle, Hill, W. David, Hagenaars, Saskia P., Ritchie, Stuart J., Marioni, Riccardo E., Fawns-Ritchie, Chloe, Liewald, David C. M., Okely, Judith A., Ahola-Olli, Ari V., Barnes, Catriona L. K., Bertram, Lars, Bis, Joshua C., Burdick, Katherine E., Christoforou, Andrea, DeRosse, Pamela, Djurovic, Srdjan, Espeseth, Thomas, Giakoumaki, Stella, Giddaluru, Sudheer, Gustavson, Daniel E., Hayward, Caroline, Hofer, Edith, Ikram, M. Arfan, Karlsson, Robert, Knowles, Emma, Lahti, Jari, Leber, Markus, Li, Shuo, Mather, Karen A., Melle, Ingrid, Morris, Derek, Oldmeadow, Christopher, Palviainen, Teemu, Payton, Antony, Pazoki, Raha, Petrovic, Katja, Reynolds, Chandra A., Sargurupremraj, Muralidharan, Scholz, Markus, Smith, Jennifer A., Smith, Albert V., Terzikhan, Natalie, Thalamuthu, Anbupalam, Trompet, Stella, van der Lee, Sven J., Ware, Erin B., Windham, B. Gwen, Wright, Margaret J., Yang, Jingyun, Yu, Jin, Ames, David, Amin, Najaf, Amouyel, Philippe, Andreassen, Ole A., Armstrong, Nicola J., Assareh, Amelia A., Attia, John R., Attix, Deborah, Avramopoulos, Dimitrios, Bennett, David A., Boehmer, Anne C., Boyle, Patricia A., Brodaty, Henry, Campbell, Harry, Cannon, Tyrone D., Cirulli, Elizabeth T., Congdon, Eliza, Conley, Emily Drabant, Corley, Janie, Cox, Simon R., Dale, Anders M., Dehghan, Abbas, Dick, Danielle, Dickinson, Dwight, Eriksson, Johan G., Evangelou, Evangelos, Faul, Jessica D., Ford, Ian, Freimer, Nelson A., Gao, He, Giegling, Ina, Gillespie, Nathan A., Gordon, Scott D., Gottesman, Rebecca F., Griswold, Michael E., Gudnason, Vilmundur, Harris, Tamara B., Hartmann, Annette M., Hatzimanolis, Alex, Heiss, Gerardo, Holliday, Elizabeth G., Joshi, Peter K., Kahonen, Mika, Kardia, Sharon L. R., Karlsson, Ida, Kleineidam, Luca, Knopman, David S., Kochan, Nicole A., Konte, Bettina, Kwok, John B., Le Hellard, Stephanie, Lee, Teresa, Lehtimaki, Terho, Li, Shu-Chen, Liu, Tian, Koini, Marisa, London, Edythe, Longstreth, Will T., Jr., Lopez, Oscar L., Loukola, Anu, Luck, Tobias, Lundervold, Astri J., Lundquist, Anders, Lyytikainen, Leo-Pekka, Martin, Nicholas G., Montgomery, Grant W., Murray, Alison D., Need, Anna C., Noordam, Raymond, Nyberg, Lars, Ollier, William, Papenberg, Goran, Pattie, Alison, Polasek, Ozren, Poldrack, Russell A., Psaty, Bruce M., Reppermund, Simone, Riedel-Heller, Steffi G., Rose, Richard J., Rotter, Jerome I., Roussos, Panos, Rovio, Suvi P., Saba, Yasaman, Sabb, Fred W., Sachdev, Perminder S., Satizabal, Claudia L., Schmid, Matthias, Scott, Rodney J., Scult, Matthew A., Simino, Jeannette, Slagboom, P. Eline, Smyrnis, Nikolaos, Soumare, Aicha, Stefanis, Nikos C., Stott, David J., Straub, Richard E., Sundet, Kjetil, Taylor, Adele M., Taylor, Kent D., Tzoulaki, Ioanna, Tzourio, Christophe, Uitterlinden, Andre, Vitart, Veronique, Voineskos, Aristotle N., Kaprio, Jaakko, Wagner, Michael, Wagner, Holger, Weinhold, Leonie, Wen, K. Hoyan, Widen, Elisabeth, Yang, Qiong, Zhao, Wei, Adams, Hieab H. H., Arking, Dan E., Bilder, Robert M., Bitsios, Panos, Boerwinkle, Eric, Chiba-Falek, Ornit, Corvin, Aiden, De Jager, Philip L., Debette, Stephanie, Donohoe, Gary, Elliott, Paul, Fitzpatrick, Annette L., Gill, Michael, Glahn, David C., Hagg, Sara, Hansell, Narelle K., Hariri, Ahmad R., Ikram, M. Kamran, Jukema, J. Wouter, Vuoksimaa, Eero, Keller, Matthew C., Kremen, William S., Launer, Lenore, Lindenberger, Ulman, Palotie, Aarno, Pedersen, Nancy L., Pendleton, Neil, Porteous, David J., Raikkonen, Katri, Raitakari, Olli T., Ramirez, Alfredo, Reinvang, Ivar, Rudan, Igor, Rujescu, Dan, Schmidt, Reinhold, Schmidt, Helena, Schofield, Peter W., Schofield, Peter R., Starr, John M., Steen, Vidar M., Trollor, Julian N., Turner, Steven T., Van Duijn, Cornelia M., Villringer, Arno, Weinberger, Daniel R., Weir, David R., Wilson, James F., Malhotra, Anil, McIntosh, Andrew M., Gale, Catharine R., Seshadri, Sudha, Mosley, Thomas H., Jr., Bressler, Jan, Lencz, Todd, and Deary, Ian J.
Abstract: General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 x 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function., Errata: Davies, G., Lam, M., Harris, S. E., Trampush, J. W., Luciano, M., Hill, W. D., … Deary, I. J. (2019). Author correction to Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. [Nature Communications (2018), 9, Article number 2098]. Nature Communications, 10, Article number: 2068. DOI: 10.1038/s41467-019-10160-w
Published: 2018
Full Text: View/download PDF

27. Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence.

Author: Savage, Jeanne E, Savage, Jeanne E, Jansen, Philip R, Stringer, Sven, Watanabe, Kyoko, Bryois, Julien, de Leeuw, Christiaan A, Nagel, Mats, Awasthi, Swapnil, Barr, Peter B, Coleman, Jonathan RI, Grasby, Katrina L, Hammerschlag, Anke R, Kaminski, Jakob A, Karlsson, Robert, Krapohl, Eva, Lam, Max, Nygaard, Marianne, Reynolds, Chandra A, Trampush, Joey W, Young, Hannah, Zabaneh, Delilah, Hägg, Sara, Hansell, Narelle K, Karlsson, Ida K, Linnarsson, Sten, Montgomery, Grant W, Muñoz-Manchado, Ana B, Quinlan, Erin B, Schumann, Gunter, Skene, Nathan G, Webb, Bradley T, White, Tonya, Arking, Dan E, Avramopoulos, Dimitrios, Bilder, Robert M, Bitsios, Panos, Burdick, Katherine E, Cannon, Tyrone D, Chiba-Falek, Ornit, Christoforou, Andrea, Cirulli, Elizabeth T, Congdon, Eliza, Corvin, Aiden, Davies, Gail, Deary, Ian J, DeRosse, Pamela, Dickinson, Dwight, Djurovic, Srdjan, Donohoe, Gary, Conley, Emily Drabant, Eriksson, Johan G, Espeseth, Thomas, Freimer, Nelson A, Giakoumaki, Stella, Giegling, Ina, Gill, Michael, Glahn, David C, Hariri, Ahmad R, Hatzimanolis, Alex, Keller, Matthew C, Knowles, Emma, Koltai, Deborah, Konte, Bettina, Lahti, Jari, Le Hellard, Stephanie, Lencz, Todd, Liewald, David C, London, Edythe, Lundervold, Astri J, Malhotra, Anil K, Melle, Ingrid, Morris, Derek, Need, Anna C, Ollier, William, Palotie, Aarno, Payton, Antony, Pendleton, Neil, Poldrack, Russell A, Räikkönen, Katri, Reinvang, Ivar, Roussos, Panos, Rujescu, Dan, Sabb, Fred W, Scult, Matthew A, Smeland, Olav B, Smyrnis, Nikolaos, Starr, John M, Steen, Vidar M, Stefanis, Nikos C, Straub, Richard E, Sundet, Kjetil, Tiemeier, Henning, Voineskos, Aristotle N, Weinberger, Daniel R, Widen, Elisabeth, Yu, Jin, Abecasis, Goncalo, Andreassen, Ole A, Breen, Gerome, Christiansen, Lene, Savage, Jeanne E, Savage, Jeanne E, Jansen, Philip R, Stringer, Sven, Watanabe, Kyoko, Bryois, Julien, de Leeuw, Christiaan A, Nagel, Mats, Awasthi, Swapnil, Barr, Peter B, Coleman, Jonathan RI, Grasby, Katrina L, Hammerschlag, Anke R, Kaminski, Jakob A, Karlsson, Robert, Krapohl, Eva, Lam, Max, Nygaard, Marianne, Reynolds, Chandra A, Trampush, Joey W, Young, Hannah, Zabaneh, Delilah, Hägg, Sara, Hansell, Narelle K, Karlsson, Ida K, Linnarsson, Sten, Montgomery, Grant W, Muñoz-Manchado, Ana B, Quinlan, Erin B, Schumann, Gunter, Skene, Nathan G, Webb, Bradley T, White, Tonya, Arking, Dan E, Avramopoulos, Dimitrios, Bilder, Robert M, Bitsios, Panos, Burdick, Katherine E, Cannon, Tyrone D, Chiba-Falek, Ornit, Christoforou, Andrea, Cirulli, Elizabeth T, Congdon, Eliza, Corvin, Aiden, Davies, Gail, Deary, Ian J, DeRosse, Pamela, Dickinson, Dwight, Djurovic, Srdjan, Donohoe, Gary, Conley, Emily Drabant, Eriksson, Johan G, Espeseth, Thomas, Freimer, Nelson A, Giakoumaki, Stella, Giegling, Ina, Gill, Michael, Glahn, David C, Hariri, Ahmad R, Hatzimanolis, Alex, Keller, Matthew C, Knowles, Emma, Koltai, Deborah, Konte, Bettina, Lahti, Jari, Le Hellard, Stephanie, Lencz, Todd, Liewald, David C, London, Edythe, Lundervold, Astri J, Malhotra, Anil K, Melle, Ingrid, Morris, Derek, Need, Anna C, Ollier, William, Palotie, Aarno, Payton, Antony, Pendleton, Neil, Poldrack, Russell A, Räikkönen, Katri, Reinvang, Ivar, Roussos, Panos, Rujescu, Dan, Sabb, Fred W, Scult, Matthew A, Smeland, Olav B, Smyrnis, Nikolaos, Starr, John M, Steen, Vidar M, Stefanis, Nikos C, Straub, Richard E, Sundet, Kjetil, Tiemeier, Henning, Voineskos, Aristotle N, Weinberger, Daniel R, Widen, Elisabeth, Yu, Jin, Abecasis, Goncalo, Andreassen, Ole A, Breen, Gerome, and Christiansen, Lene
Abstract: Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.
Published: 2018

28. Multi-Trait Analysis of GWAS and Biological Insights Into Cognition: A Response to Hill (2018).

Author: Lam, Max, Lam, Max, Trampush, Joey W, Yu, Jin, Knowles, Emma, Djurovic, Srdjan, Melle, Ingrid, Sundet, Kjetil, Christoforou, Andrea, Reinvang, Ivar, DeRosse, Pamela, Lundervold, Astri J, Steen, Vidar M, Espeseth, Thomas, Räikkönen, Katri, Widen, Elisabeth, Palotie, Aarno, Eriksson, Johan G, Giegling, Ina, Konte, Bettina, Roussos, Panos, Giakoumaki, Stella, Burdick, Katherine E, Payton, Antony, Ollier, William, Chiba-Falek, Ornit, Attix, Deborah K, Need, Anna C, Cirulli, Elizabeth T, Voineskos, Aristotle N, Stefanis, Nikos C, Avramopoulos, Dimitrios, Hatzimanolis, Alex, Arking, Dan E, Smyrnis, Nikolaos, Bilder, Robert M, Freimer, Nelson A, Cannon, Tyrone D, London, Edythe, Poldrack, Russell A, Sabb, Fred W, Congdon, Eliza, Conley, Emily Drabant, Scult, Matthew A, Dickinson, Dwight, Straub, Richard E, Donohoe, Gary, Morris, Derek, Corvin, Aiden, Gill, Michael, Hariri, Ahmad R, Weinberger, Daniel R, Pendleton, Neil, Bitsios, Panos, Rujescu, Dan, Lahti, Jari, Hellard, Stephanie Le, Keller, Matthew C, Andreassen, Ole A, Glahn, David C, Malhotra, Anil K, Lencz, Todd, Lam, Max, Lam, Max, Trampush, Joey W, Yu, Jin, Knowles, Emma, Djurovic, Srdjan, Melle, Ingrid, Sundet, Kjetil, Christoforou, Andrea, Reinvang, Ivar, DeRosse, Pamela, Lundervold, Astri J, Steen, Vidar M, Espeseth, Thomas, Räikkönen, Katri, Widen, Elisabeth, Palotie, Aarno, Eriksson, Johan G, Giegling, Ina, Konte, Bettina, Roussos, Panos, Giakoumaki, Stella, Burdick, Katherine E, Payton, Antony, Ollier, William, Chiba-Falek, Ornit, Attix, Deborah K, Need, Anna C, Cirulli, Elizabeth T, Voineskos, Aristotle N, Stefanis, Nikos C, Avramopoulos, Dimitrios, Hatzimanolis, Alex, Arking, Dan E, Smyrnis, Nikolaos, Bilder, Robert M, Freimer, Nelson A, Cannon, Tyrone D, London, Edythe, Poldrack, Russell A, Sabb, Fred W, Congdon, Eliza, Conley, Emily Drabant, Scult, Matthew A, Dickinson, Dwight, Straub, Richard E, Donohoe, Gary, Morris, Derek, Corvin, Aiden, Gill, Michael, Hariri, Ahmad R, Weinberger, Daniel R, Pendleton, Neil, Bitsios, Panos, Rujescu, Dan, Lahti, Jari, Hellard, Stephanie Le, Keller, Matthew C, Andreassen, Ole A, Glahn, David C, Malhotra, Anil K, and Lencz, Todd
Abstract: Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88) presented a critique of our recently published paper in Cell Reports entitled 'Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets' (Lam et al., Cell Reports, Vol. 21, 2017, 2597-2613). Specifically, Hill offered several interrelated comments suggesting potential problems with our use of a new analytic method called Multi-Trait Analysis of GWAS (MTAG) (Turley et al., Nature Genetics, Vol. 50, 2018, 229-237). In this brief article, we respond to each of these concerns. Using empirical data, we conclude that our MTAG results do not suffer from 'inflation in the FDR [false discovery rate]', as suggested by Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88), and are not 'more relevant to the genetic contributions to education than they are to the genetic contributions to intelligence'.
Published: 2018

29. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Author: Davies, Gail, Lam, Max, Harris, Sarah E., Trampush, Joey W., Luciano, Michelle, Hill, W. David, Hagenaars, Saskia P., Ritchie, Stuart J., Marioni, Riccardo E., Fawns-Ritchie, Chloe, Liewald, David C. M., Okely, Judith A., Ahola-Olli, Ari V., Barnes, Catriona L. K., Bertram, Lars, Bis, Joshua C., Burdick, Katherine E., Christoforou, Andrea, DeRosse, Pamela, Djurovic, Srdjan, Espeseth, Thomas, Giakoumaki, Stella, Giddaluru, Sudheer, Gustavson, Daniel E., Hayward, Caroline, Hofer, Edith, Ikram, M. Arfan, Karlsson, Robert, Knowles, Emma, Lahti, Jari, Leber, Markus, Li, Shuo, Mather, Karen A., Melle, Ingrid, Morris, Derek, Oldmeadow, Christopher, Palviainen, Teemu, Payton, Antony, Pazoki, Raha, Petrovic, Katja, Reynolds, Chandra A., Sargurupremraj, Muralidharan, Scholz, Markus, Smith, Jennifer A., Smith, Albert V., Terzikhan, Natalie, Thalamuthu, Anbupalam, Trompet, Stella, van der Lee, Sven J., Ware, Erin B., Windham, B. Gwen, Wright, Margaret J., Yang, Jingyun, Yu, Jin, Ames, David, Amin, Najaf, Amouyel, Philippe, Andreassen, Ole A., Armstrong, Nicola J., Assareh, Amelia A., Attia, John R., Attix, Deborah, Avramopoulos, Dimitrios, Bennett, David A., Boehmer, Anne C., Boyle, Patricia A., Brodaty, Henry, Campbell, Harry, Cannon, Tyrone D., Cirulli, Elizabeth T., Congdon, Eliza, Conley, Emily Drabant, Corley, Janie, Cox, Simon R., Dale, Anders M., Dehghan, Abbas, Dick, Danielle, Dickinson, Dwight, Eriksson, Johan G., Evangelou, Evangelos, Faul, Jessica D., Ford, Ian, Freimer, Nelson A., Gao, He, Giegling, Ina, Gillespie, Nathan A., Gordon, Scott D., Gottesman, Rebecca F., Griswold, Michael E., Gudnason, Vilmundur, Harris, Tamara B., Hartmann, Annette M., Hatzimanolis, Alex, Heiss, Gerardo, Holliday, Elizabeth G., Joshi, Peter K., Kahonen, Mika, Kardia, Sharon L. R., Karlsson, Ida, Kleineidam, Luca, Knopman, David S., Kochan, Nicole A., Konte, Bettina, Kwok, John B., Le Hellard, Stephanie, Lee, Teresa, Lehtimaki, Terho, Li, Shu-Chen, Liu, Tian, Koini, Marisa, London, Edythe, Longstreth, Will T., Lopez, Oscar L., Loukola, Anu, Luck, Tobias, Lundervold, Astri J., Lundquist, Anders, Lyytikainen, Leo-Pekka, Martin, Nicholas G., Montgomery, Grant W., Murray, Alison D., Need, Anna C., Noordam, Raymond, Nyberg, Lars, Ollier, William, Papenberg, Göran, Pattie, Alison, Polasek, Ozren, Poldrack, Russell A., Psaty, Bruce M., Reppermund, Simone, Riedel-Heller, Steffi G., Rose, Richard J., Rotter, Jerome I., Roussos, Panos, Rovio, Suvi P., Saba, Yasaman, Sabb, Fred W., Sachdev, Perminder S., Satizabal, Claudia L., Schmid, Matthias, Scott, Rodney J., Scult, Matthew A., Simino, Jeannette, Slagboom, P. Eline, Smyrnis, Nikolaos, Soumare, Aicha, Stefanis, Nikos C., Stott, David J., Straub, Richard E., Sundet, Kjetil, Taylor, Adele M., Taylor, Kent D., Tzoulaki, Ioanna, Tzourio, Christophe, Uitterlinden, Andre, Vitart, Veronique, Voineskos, Aristotle N., Kaprio, Jaakko, Wagner, Michael, Wagner, Holger, Weinhold, Leonie, Wen, K. Hoyan, Widen, Elisabeth, Yang, Qiong, Zhao, Wei, Adams, Hieab H. H., Arking, Dan E., Bilder, Robert M., Bitsios, Panos, Boerwinkle, Eric, Chiba-Falek, Ornit, Corvin, Aiden, De Jager, Philip L., Debette, Stephanie, Donohoe, Gary, Elliott, Paul, Fitzpatrick, Annette L., Gill, Michael, Glahn, David C., Hagg, Sara, Hansell, Narelle K., Hariri, Ahmad R., Ikram, M. Kamran, Jukema, J. Wouter, Vuoksimaa, Eero, Keller, Matthew C., Kremen, William S., Launer, Lenore, Lindenberger, Ulman, Palotie, Aarno, Pedersen, Nancy L., Pendleton, Neil, Porteous, David J., Raikkonen, Katri, Raitakari, Olli T., Ramirez, Alfredo, Reinvang, Ivar, Rudan, Igor, Rujescu, Dan, Schmidt, Reinhold, Schmidt, Helena, Schofield, Peter W., Schofield, Peter R., Starr, John M., Steen, Vidar M., Trollor, Julian N., Turner, Steven T., Van Duijn, Cornelia M., Villringer, Arno, Weinberger, Daniel R., Weir, David R., Wilson, James F., Malhotra, Anil, McIntosh, Andrew M., Gale, Catharine R., Seshadri, Sudha, Mosley, Thomas H., Bressler, Jan, Lencz, Todd, Deary, Ian J., Davies, Gail, Lam, Max, Harris, Sarah E., Trampush, Joey W., Luciano, Michelle, Hill, W. David, Hagenaars, Saskia P., Ritchie, Stuart J., Marioni, Riccardo E., Fawns-Ritchie, Chloe, Liewald, David C. M., Okely, Judith A., Ahola-Olli, Ari V., Barnes, Catriona L. K., Bertram, Lars, Bis, Joshua C., Burdick, Katherine E., Christoforou, Andrea, DeRosse, Pamela, Djurovic, Srdjan, Espeseth, Thomas, Giakoumaki, Stella, Giddaluru, Sudheer, Gustavson, Daniel E., Hayward, Caroline, Hofer, Edith, Ikram, M. Arfan, Karlsson, Robert, Knowles, Emma, Lahti, Jari, Leber, Markus, Li, Shuo, Mather, Karen A., Melle, Ingrid, Morris, Derek, Oldmeadow, Christopher, Palviainen, Teemu, Payton, Antony, Pazoki, Raha, Petrovic, Katja, Reynolds, Chandra A., Sargurupremraj, Muralidharan, Scholz, Markus, Smith, Jennifer A., Smith, Albert V., Terzikhan, Natalie, Thalamuthu, Anbupalam, Trompet, Stella, van der Lee, Sven J., Ware, Erin B., Windham, B. Gwen, Wright, Margaret J., Yang, Jingyun, Yu, Jin, Ames, David, Amin, Najaf, Amouyel, Philippe, Andreassen, Ole A., Armstrong, Nicola J., Assareh, Amelia A., Attia, John R., Attix, Deborah, Avramopoulos, Dimitrios, Bennett, David A., Boehmer, Anne C., Boyle, Patricia A., Brodaty, Henry, Campbell, Harry, Cannon, Tyrone D., Cirulli, Elizabeth T., Congdon, Eliza, Conley, Emily Drabant, Corley, Janie, Cox, Simon R., Dale, Anders M., Dehghan, Abbas, Dick, Danielle, Dickinson, Dwight, Eriksson, Johan G., Evangelou, Evangelos, Faul, Jessica D., Ford, Ian, Freimer, Nelson A., Gao, He, Giegling, Ina, Gillespie, Nathan A., Gordon, Scott D., Gottesman, Rebecca F., Griswold, Michael E., Gudnason, Vilmundur, Harris, Tamara B., Hartmann, Annette M., Hatzimanolis, Alex, Heiss, Gerardo, Holliday, Elizabeth G., Joshi, Peter K., Kahonen, Mika, Kardia, Sharon L. R., Karlsson, Ida, Kleineidam, Luca, Knopman, David S., Kochan, Nicole A., Konte, Bettina, Kwok, John B., Le Hellard, Stephanie, Lee, Teresa, Lehtimaki, Terho, Li, Shu-Chen, Liu, Tian, Koini, Marisa, London, Edythe, Longstreth, Will T., Lopez, Oscar L., Loukola, Anu, Luck, Tobias, Lundervold, Astri J., Lundquist, Anders, Lyytikainen, Leo-Pekka, Martin, Nicholas G., Montgomery, Grant W., Murray, Alison D., Need, Anna C., Noordam, Raymond, Nyberg, Lars, Ollier, William, Papenberg, Göran, Pattie, Alison, Polasek, Ozren, Poldrack, Russell A., Psaty, Bruce M., Reppermund, Simone, Riedel-Heller, Steffi G., Rose, Richard J., Rotter, Jerome I., Roussos, Panos, Rovio, Suvi P., Saba, Yasaman, Sabb, Fred W., Sachdev, Perminder S., Satizabal, Claudia L., Schmid, Matthias, Scott, Rodney J., Scult, Matthew A., Simino, Jeannette, Slagboom, P. Eline, Smyrnis, Nikolaos, Soumare, Aicha, Stefanis, Nikos C., Stott, David J., Straub, Richard E., Sundet, Kjetil, Taylor, Adele M., Taylor, Kent D., Tzoulaki, Ioanna, Tzourio, Christophe, Uitterlinden, Andre, Vitart, Veronique, Voineskos, Aristotle N., Kaprio, Jaakko, Wagner, Michael, Wagner, Holger, Weinhold, Leonie, Wen, K. Hoyan, Widen, Elisabeth, Yang, Qiong, Zhao, Wei, Adams, Hieab H. H., Arking, Dan E., Bilder, Robert M., Bitsios, Panos, Boerwinkle, Eric, Chiba-Falek, Ornit, Corvin, Aiden, De Jager, Philip L., Debette, Stephanie, Donohoe, Gary, Elliott, Paul, Fitzpatrick, Annette L., Gill, Michael, Glahn, David C., Hagg, Sara, Hansell, Narelle K., Hariri, Ahmad R., Ikram, M. Kamran, Jukema, J. Wouter, Vuoksimaa, Eero, Keller, Matthew C., Kremen, William S., Launer, Lenore, Lindenberger, Ulman, Palotie, Aarno, Pedersen, Nancy L., Pendleton, Neil, Porteous, David J., Raikkonen, Katri, Raitakari, Olli T., Ramirez, Alfredo, Reinvang, Ivar, Rudan, Igor, Rujescu, Dan, Schmidt, Reinhold, Schmidt, Helena, Schofield, Peter W., Schofield, Peter R., Starr, John M., Steen, Vidar M., Trollor, Julian N., Turner, Steven T., Van Duijn, Cornelia M., Villringer, Arno, Weinberger, Daniel R., Weir, David R., Wilson, James F., Malhotra, Anil, McIntosh, Andrew M., Gale, Catharine R., Seshadri, Sudha, Mosley, Thomas H., Bressler, Jan, Lencz, Todd, and Deary, Ian J.
Abstract: General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 x 10(-8)) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.
Published: 2018
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30. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Author: Davies, Gail, Lam, Max, Harris, Sarah E, Trampush, Joey W, Luciano, Michelle, Hill, W David, Hagenaars, Saskia P, Ritchie, Stuart J, Marioni, Riccardo E, Fawns-Ritchie, Chloe, Liewald, David CM, Okely, Judith A, Ahola-Olli, Ari V, Barnes, Catriona LK, Bertram, Lars, Bis, Joshua C, Burdick, Katherine E, Christoforou, Andrea, DeRosse, Pamela, Djurovic, Srdjan, Espeseth, Thomas, Giakoumaki, Stella, Giddaluru, Sudheer, Gustavson, Daniel E, Hayward, Caroline, Hofer, Edith, Ikram, M Arfan, Karlsson, Robert, Knowles, Emma, Lahti, Jari, Leber, Markus, Li, Shuo, Mather, Karen A, Melle, Ingrid, Morris, Derek, Oldmeadow, Christopher, Palviainen, Teemu, Payton, Antony, Pazoki, Raha, Petrovic, Katja, Reynolds, Chandra A, Sargurupremraj, Muralidharan, Scholz, Markus, Smith, Jennifer A, Smith, Albert V, Terzikhan, Natalie, Thalamuthu, Anbupalam, Trompet, Stella, van der Lee, Sven J, Ware, Erin B, Windham, B Gwen, Wright, Margaret J, Yang, Jingyun, Yu, Jin, Ames, David, Amin, Najaf, Amouyel, Philippe, Andreassen, Ole A, Armstrong, Nicola J, Assareh, Amelia A, Attia, John R, Attix, Deborah, Avramopoulos, Dimitrios, Bennett, David A, Böhmer, Anne C, Boyle, Patricia A, Brodaty, Henry, Campbell, Harry, Cannon, Tyrone D, Cirulli, Elizabeth T, Congdon, Eliza, Conley, Emily Drabant, Corley, Janie, Cox, Simon R, Dale, Anders M, Dehghan, Abbas, Dick, Danielle, Dickinson, Dwight, Eriksson, Johan G, Evangelou, Evangelos, Faul, Jessica D, Ford, Ian, Freimer, Nelson A, Gao, He, Giegling, Ina, Gillespie, Nathan A, Gordon, Scott D, Gottesman, Rebecca F, Griswold, Michael E, Gudnason, Vilmundur, Harris, Tamara B, Hartmann, Annette M, Hatzimanolis, Alex, Heiss, Gerardo, Holliday, Elizabeth G, Joshi, Peter K, Kähönen, Mika, Kardia, Sharon LR, Karlsson, Ida, Kleineidam, Luca, Knopman, David S, Kochan, Nicole A, Konte, Bettina, Kwok, John B, Le Hellard, Stephanie, Lee, Teresa, Lehtimäki, Terho, Li, Shu-Chen, Lill, Christina M, Liu, Tian, Koini, Marisa, London, Edythe, Longstreth, Will T, Lopez, Oscar L, Loukola, Anu, Luck, Tobias, Lundervold, Astri J, Lundquist, Anders, Lyytikäinen, Leo-Pekka, Martin, Nicholas G, Montgomery, Grant W, Murray, Alison D, Need, Anna C, Noordam, Raymond, Nyberg, Lars, Ollier, William, Papenberg, Goran, Pattie, Alison, Polasek, Ozren, Poldrack, Russell A, Psaty, Bruce M, Reppermund, Simone, Riedel-Heller, Steffi G, Rose, Richard J, Rotter, Jerome I, Roussos, Panos, Rovio, Suvi P, Saba, Yasaman, Sabb, Fred W, Sachdev, Perminder S, Satizabal, Claudia L, Schmid, Matthias, Scott, Rodney J, Scult, Matthew A, Simino, Jeannette, Slagboom, P Eline, Smyrnis, Nikolaos, Soumaré, Aïcha, Stefanis, Nikos C, Stott, David J, Straub, Richard E, Sundet, Kjetil, Taylor, Adele M, Taylor, Kent D, Tzoulaki, Ioanna, Tzourio, Christophe, Uitterlinden, André, Vitart, Veronique, Voineskos, Aristotle N, Kaprio, Jaakko, Wagner, Michael, Wagner, Holger, Weinhold, Leonie, Wen, K Hoyan, Widen, Elisabeth, Yang, Qiong, Zhao, Wei, Adams, Hieab HH, Arking, Dan E, Bilder, Robert M, Bitsios, Panos, Boerwinkle, Eric, Chiba-Falek, Ornit, Corvin, Aiden, De Jager, Philip L, Debette, Stéphanie, Donohoe, Gary, Elliott, Paul, Fitzpatrick, Annette L, Gill, Michael, Glahn, David C, Hägg, Sara, Hansell, Narelle K, Hariri, Ahmad R, Ikram, M Kamran, Jukema, J Wouter, Vuoksimaa, Eero, Keller, Matthew C, Kremen, William S, Launer, Lenore, Lindenberger, Ulman, Palotie, Aarno, Pedersen, Nancy L, Pendleton, Neil, Porteous, David J, Räikkönen, Katri, Raitakari, Olli T, Ramirez, Alfredo, Reinvang, Ivar, Rudan, Igor, Dan Rujescu, Schmidt, Reinhold, Schmidt, Helena, Schofield, Peter W, Schofield, Peter R, Starr, John M, Steen, Vidar M, Trollor, Julian N, Turner, Steven T, Van Duijn, Cornelia M, Villringer, Arno, Weinberger, Daniel R, Weir, David R, Wilson, James F, Malhotra, Anil, McIntosh, Andrew M, Gale, Catharine R, Seshadri, Sudha, Mosley, Thomas H, Bressler, Jan, Lencz, Todd, Deary, Ian J, Davies, Gail, Lam, Max, Harris, Sarah E, Trampush, Joey W, Luciano, Michelle, Hill, W David, Hagenaars, Saskia P, Ritchie, Stuart J, Marioni, Riccardo E, Fawns-Ritchie, Chloe, Liewald, David CM, Okely, Judith A, Ahola-Olli, Ari V, Barnes, Catriona LK, Bertram, Lars, Bis, Joshua C, Burdick, Katherine E, Christoforou, Andrea, DeRosse, Pamela, Djurovic, Srdjan, Espeseth, Thomas, Giakoumaki, Stella, Giddaluru, Sudheer, Gustavson, Daniel E, Hayward, Caroline, Hofer, Edith, Ikram, M Arfan, Karlsson, Robert, Knowles, Emma, Lahti, Jari, Leber, Markus, Li, Shuo, Mather, Karen A, Melle, Ingrid, Morris, Derek, Oldmeadow, Christopher, Palviainen, Teemu, Payton, Antony, Pazoki, Raha, Petrovic, Katja, Reynolds, Chandra A, Sargurupremraj, Muralidharan, Scholz, Markus, Smith, Jennifer A, Smith, Albert V, Terzikhan, Natalie, Thalamuthu, Anbupalam, Trompet, Stella, van der Lee, Sven J, Ware, Erin B, Windham, B Gwen, Wright, Margaret J, Yang, Jingyun, Yu, Jin, Ames, David, Amin, Najaf, Amouyel, Philippe, Andreassen, Ole A, Armstrong, Nicola J, Assareh, Amelia A, Attia, John R, Attix, Deborah, Avramopoulos, Dimitrios, Bennett, David A, Böhmer, Anne C, Boyle, Patricia A, Brodaty, Henry, Campbell, Harry, Cannon, Tyrone D, Cirulli, Elizabeth T, Congdon, Eliza, Conley, Emily Drabant, Corley, Janie, Cox, Simon R, Dale, Anders M, Dehghan, Abbas, Dick, Danielle, Dickinson, Dwight, Eriksson, Johan G, Evangelou, Evangelos, Faul, Jessica D, Ford, Ian, Freimer, Nelson A, Gao, He, Giegling, Ina, Gillespie, Nathan A, Gordon, Scott D, Gottesman, Rebecca F, Griswold, Michael E, Gudnason, Vilmundur, Harris, Tamara B, Hartmann, Annette M, Hatzimanolis, Alex, Heiss, Gerardo, Holliday, Elizabeth G, Joshi, Peter K, Kähönen, Mika, Kardia, Sharon LR, Karlsson, Ida, Kleineidam, Luca, Knopman, David S, Kochan, Nicole A, Konte, Bettina, Kwok, John B, Le Hellard, Stephanie, Lee, Teresa, Lehtimäki, Terho, Li, Shu-Chen, Lill, Christina M, Liu, Tian, Koini, Marisa, London, Edythe, Longstreth, Will T, Lopez, Oscar L, Loukola, Anu, Luck, Tobias, Lundervold, Astri J, Lundquist, Anders, Lyytikäinen, Leo-Pekka, Martin, Nicholas G, Montgomery, Grant W, Murray, Alison D, Need, Anna C, Noordam, Raymond, Nyberg, Lars, Ollier, William, Papenberg, Goran, Pattie, Alison, Polasek, Ozren, Poldrack, Russell A, Psaty, Bruce M, Reppermund, Simone, Riedel-Heller, Steffi G, Rose, Richard J, Rotter, Jerome I, Roussos, Panos, Rovio, Suvi P, Saba, Yasaman, Sabb, Fred W, Sachdev, Perminder S, Satizabal, Claudia L, Schmid, Matthias, Scott, Rodney J, Scult, Matthew A, Simino, Jeannette, Slagboom, P Eline, Smyrnis, Nikolaos, Soumaré, Aïcha, Stefanis, Nikos C, Stott, David J, Straub, Richard E, Sundet, Kjetil, Taylor, Adele M, Taylor, Kent D, Tzoulaki, Ioanna, Tzourio, Christophe, Uitterlinden, André, Vitart, Veronique, Voineskos, Aristotle N, Kaprio, Jaakko, Wagner, Michael, Wagner, Holger, Weinhold, Leonie, Wen, K Hoyan, Widen, Elisabeth, Yang, Qiong, Zhao, Wei, Adams, Hieab HH, Arking, Dan E, Bilder, Robert M, Bitsios, Panos, Boerwinkle, Eric, Chiba-Falek, Ornit, Corvin, Aiden, De Jager, Philip L, Debette, Stéphanie, Donohoe, Gary, Elliott, Paul, Fitzpatrick, Annette L, Gill, Michael, Glahn, David C, Hägg, Sara, Hansell, Narelle K, Hariri, Ahmad R, Ikram, M Kamran, Jukema, J Wouter, Vuoksimaa, Eero, Keller, Matthew C, Kremen, William S, Launer, Lenore, Lindenberger, Ulman, Palotie, Aarno, Pedersen, Nancy L, Pendleton, Neil, Porteous, David J, Räikkönen, Katri, Raitakari, Olli T, Ramirez, Alfredo, Reinvang, Ivar, Rudan, Igor, Dan Rujescu, Schmidt, Reinhold, Schmidt, Helena, Schofield, Peter W, Schofield, Peter R, Starr, John M, Steen, Vidar M, Trollor, Julian N, Turner, Steven T, Van Duijn, Cornelia M, Villringer, Arno, Weinberger, Daniel R, Weir, David R, Wilson, James F, Malhotra, Anil, McIntosh, Andrew M, Gale, Catharine R, Seshadri, Sudha, Mosley, Thomas H, Bressler, Jan, Lencz, Todd, and Deary, Ian J
Abstract: General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.
Published: 2018

31. Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence

Author: Savage, Jeanne E, Jansen, Philip R, Stringer, Sven, Watanabe, Kyoko, Bryois, Julien, de Leeuw, Christiaan A, Nagel, Mats, Awasthi, Swapnil, Barr, Peter B, Coleman, Jonathan RI, Grasby, Katrina L, Hammerschlag, Anke R, Kaminski, Jakob A, Karlsson, Robert, Krapohl, Eva, Lam, Max, Nygaard, Marianne, Reynolds, Chandra A, Trampush, Joey W, Young, Hannah, Zabaneh, Delilah, Hägg, Sara, Hansell, Narelle K, Karlsson, Ida K, Linnarsson, Sten, Montgomery, Grant W, Muñoz-Manchado, Ana B, Quinlan, Erin B, Schumann, Gunter, Skene, Nathan G, Webb, Bradley T, White, Tonya, Arking, Dan E, Avramopoulos, Dimitrios, Bilder, Robert M, Bitsios, Panos, Burdick, Katherine E, Cannon, Tyrone D, Chiba-Falek, Ornit, Christoforou, Andrea, Cirulli, Elizabeth T, Congdon, Eliza, Corvin, Aiden, Davies, Gail, Deary, Ian J, DeRosse, Pamela, Dickinson, Dwight, Djurovic, Srdjan, Donohoe, Gary, Conley, Emily Drabant, Eriksson, Johan G, Espeseth, Thomas, Freimer, Nelson A, Giakoumaki, Stella, Giegling, Ina, Gill, Michael, Glahn, David C, Hariri, Ahmad R, Hatzimanolis, Alex, Keller, Matthew C, Knowles, Emma, Koltai, Deborah, Konte, Bettina, Lahti, Jari, Le Hellard, Stephanie, Lencz, Todd, Liewald, David C, London, Edythe, Lundervold, Astri J, Malhotra, Anil K, Melle, Ingrid, Morris, Derek, Need, Anna C, Ollier, William, Palotie, Aarno, Payton, Antony, Pendleton, Neil, Poldrack, Russell A, Räikkönen, Katri, Reinvang, Ivar, Roussos, Panos, Rujescu, Dan, Sabb, Fred W, Scult, Matthew A, Smeland, Olav B, Smyrnis, Nikolaos, Starr, John M, Steen, Vidar M, Stefanis, Nikos C, Straub, Richard E, Sundet, Kjetil, Tiemeier, Henning, Voineskos, Aristotle N, Weinberger, Daniel R, Widen, Elisabeth, Yu, Jin, Abecasis, Goncalo, Andreassen, Ole A, Breen, Gerome, Christiansen, Lene, Debrabant, Birgit, Dick, Danielle M, Heinz, Andreas, Hjerling-Leffler, Jens, Ikram, M Arfan, Kendler, Kenneth S, Martin, Nicholas G, Medland, Sarah E, Pedersen, Nancy L, Plomin, Robert, Polderman, Tinca JC, Ripke, Stephan, van der Sluis, Sophie, Sullivan, Patrick F, Vrieze, Scott I, Wright, Margaret J, Posthuma, Danielle, Savage, Jeanne E, Jansen, Philip R, Stringer, Sven, Watanabe, Kyoko, Bryois, Julien, de Leeuw, Christiaan A, Nagel, Mats, Awasthi, Swapnil, Barr, Peter B, Coleman, Jonathan RI, Grasby, Katrina L, Hammerschlag, Anke R, Kaminski, Jakob A, Karlsson, Robert, Krapohl, Eva, Lam, Max, Nygaard, Marianne, Reynolds, Chandra A, Trampush, Joey W, Young, Hannah, Zabaneh, Delilah, Hägg, Sara, Hansell, Narelle K, Karlsson, Ida K, Linnarsson, Sten, Montgomery, Grant W, Muñoz-Manchado, Ana B, Quinlan, Erin B, Schumann, Gunter, Skene, Nathan G, Webb, Bradley T, White, Tonya, Arking, Dan E, Avramopoulos, Dimitrios, Bilder, Robert M, Bitsios, Panos, Burdick, Katherine E, Cannon, Tyrone D, Chiba-Falek, Ornit, Christoforou, Andrea, Cirulli, Elizabeth T, Congdon, Eliza, Corvin, Aiden, Davies, Gail, Deary, Ian J, DeRosse, Pamela, Dickinson, Dwight, Djurovic, Srdjan, Donohoe, Gary, Conley, Emily Drabant, Eriksson, Johan G, Espeseth, Thomas, Freimer, Nelson A, Giakoumaki, Stella, Giegling, Ina, Gill, Michael, Glahn, David C, Hariri, Ahmad R, Hatzimanolis, Alex, Keller, Matthew C, Knowles, Emma, Koltai, Deborah, Konte, Bettina, Lahti, Jari, Le Hellard, Stephanie, Lencz, Todd, Liewald, David C, London, Edythe, Lundervold, Astri J, Malhotra, Anil K, Melle, Ingrid, Morris, Derek, Need, Anna C, Ollier, William, Palotie, Aarno, Payton, Antony, Pendleton, Neil, Poldrack, Russell A, Räikkönen, Katri, Reinvang, Ivar, Roussos, Panos, Rujescu, Dan, Sabb, Fred W, Scult, Matthew A, Smeland, Olav B, Smyrnis, Nikolaos, Starr, John M, Steen, Vidar M, Stefanis, Nikos C, Straub, Richard E, Sundet, Kjetil, Tiemeier, Henning, Voineskos, Aristotle N, Weinberger, Daniel R, Widen, Elisabeth, Yu, Jin, Abecasis, Goncalo, Andreassen, Ole A, Breen, Gerome, Christiansen, Lene, Debrabant, Birgit, Dick, Danielle M, Heinz, Andreas, Hjerling-Leffler, Jens, Ikram, M Arfan, Kendler, Kenneth S, Martin, Nicholas G, Medland, Sarah E, Pedersen, Nancy L, Plomin, Robert, Polderman, Tinca JC, Ripke, Stephan, van der Sluis, Sophie, Sullivan, Patrick F, Vrieze, Scott I, Wright, Margaret J, and Posthuma, Danielle
Abstract: Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3,4,5,6,7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer’s disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.
Published: 2018

32. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Author: Davies, Gail, Lam, Max, Harris, Sarah E., Trampush, Joey W., Luciano, Michelle, Hill, W. David, Hagenaars, Saskia P., Ritchie, Stuart J., Marioni, Riccardo E., Fawns-Ritchie, Chloe, Liewald, David C. M., Okely, Judith A., Ahola-Olli, Ari V., Barnes, Catriona L. K., Bertram, Lars, Bis, Joshua C., Burdick, Katherine E., Christoforou, Andrea, DeRosse, Pamela, Djurovic, Srdjan, Espeseth, Thomas, Giakoumaki, Stella, Giddaluru, Sudheer, Gustavson, Daniel E., Hayward, Caroline, Hofer, Edith, Ikram, M. Arfan, Karlsson, Robert, Knowles, Emma, Lahti, Jari, Leber, Markus, Li, Shuo, Mather, Karen A., Melle, Ingrid, Morris, Derek, Oldmeadow, Christopher, Palviainen, Teemu, Payton, Antony, Pazoki, Raha, Petrovic, Katja, Reynolds, Chandra A., Sargurupremraj, Muralidharan, Scholz, Markus, Smith, Jennifer A., Smith, Albert V., Terzikhan, Natalie, Thalamuthu, Anbupalam, Trompet, Stella, van der Lee, Sven J., Ware, Erin B., Windham, B. Gwen, Wright, Margaret J., Yang, Jingyun, Yu, Jin, Ames, David, Amin, Najaf, Amouyel, Philippe, Andreassen, Ole A., Armstrong, Nicola J., Assareh, Amelia A., Attia, John R., Attix, Deborah, Avramopoulos, Dimitrios, Bennett, David A., Boehmer, Anne C., Boyle, Patricia A., Brodaty, Henry, Campbell, Harry, Cannon, Tyrone D., Cirulli, Elizabeth T., Congdon, Eliza, Conley, Emily Drabant, Corley, Janie, Cox, Simon R., Dale, Anders M., Dehghan, Abbas, Dick, Danielle, Dickinson, Dwight, Eriksson, Johan G., Evangelou, Evangelos, Faul, Jessica D., Ford, Ian, Freimer, Nelson A., Gao, He, Giegling, Ina, Gillespie, Nathan A., Gordon, Scott D., Gottesman, Rebecca F., Griswold, Michael E., Gudnason, Vilmundur, Harris, Tamara B., Hartmann, Annette M., Hatzimanolis, Alex, Heiss, Gerardo, Holliday, Elizabeth G., Joshi, Peter K., Kahonen, Mika, Kardia, Sharon L. R., Karlsson, Ida, Kleineidam, Luca, Knopman, David S., Kochan, Nicole A., Konte, Bettina, Kwok, John B., Le Hellard, Stephanie, Lee, Teresa, Lehtimaki, Terho, Li, Shu-Chen, Liu, Tian, Koini, Marisa, London, Edythe, Longstreth, Will T., Jr., Lopez, Oscar L., Loukola, Anu, Luck, Tobias, Lundervold, Astri J., Lundquist, Anders, Lyytikainen, Leo-Pekka, Martin, Nicholas G., Montgomery, Grant W., Murray, Alison D., Need, Anna C., Noordam, Raymond, Nyberg, Lars, Ollier, William, Papenberg, Goran, Pattie, Alison, Polasek, Ozren, Poldrack, Russell A., Psaty, Bruce M., Reppermund, Simone, Riedel-Heller, Steffi G., Rose, Richard J., Rotter, Jerome I., Roussos, Panos, Rovio, Suvi P., Saba, Yasaman, Sabb, Fred W., Sachdev, Perminder S., Satizabal, Claudia L., Schmid, Matthias, Scott, Rodney J., Scult, Matthew A., Simino, Jeannette, Slagboom, P. Eline, Smyrnis, Nikolaos, Soumare, Aicha, Stefanis, Nikos C., Stott, David J., Straub, Richard E., Sundet, Kjetil, Taylor, Adele M., Taylor, Kent D., Tzoulaki, Ioanna, Tzourio, Christophe, Uitterlinden, Andre, Vitart, Veronique, Voineskos, Aristotle N., Kaprio, Jaakko, Wagner, Michael, Wagner, Holger, Weinhold, Leonie, Wen, K. Hoyan, Widen, Elisabeth, Yang, Qiong, Zhao, Wei, Adams, Hieab H. H., Arking, Dan E., Bilder, Robert M., Bitsios, Panos, Boerwinkle, Eric, Chiba-Falek, Ornit, Corvin, Aiden, De Jager, Philip L., Debette, Stephanie, Donohoe, Gary, Elliott, Paul, Fitzpatrick, Annette L., Gill, Michael, Glahn, David C., Hagg, Sara, Hansell, Narelle K., Hariri, Ahmad R., Ikram, M. Kamran, Jukema, J. Wouter, Vuoksimaa, Eero, Keller, Matthew C., Kremen, William S., Launer, Lenore, Lindenberger, Ulman, Palotie, Aarno, Pedersen, Nancy L., Pendleton, Neil, Porteous, David J., Raikkonen, Katri, Raitakari, Olli T., Ramirez, Alfredo, Reinvang, Ivar, Rudan, Igor, Rujescu, Dan, Schmidt, Reinhold, Schmidt, Helena, Schofield, Peter W., Schofield, Peter R., Starr, John M., Steen, Vidar M., Trollor, Julian N., Turner, Steven T., Van Duijn, Cornelia M., Villringer, Arno, Weinberger, Daniel R., Weir, David R., Wilson, James F., Malhotra, Anil, McIntosh, Andrew M., Gale, Catharine R., Seshadri, Sudha, Mosley, Thomas H., Jr., Bressler, Jan, Lencz, Todd, Deary, Ian J., Davies, Gail, Lam, Max, Harris, Sarah E., Trampush, Joey W., Luciano, Michelle, Hill, W. David, Hagenaars, Saskia P., Ritchie, Stuart J., Marioni, Riccardo E., Fawns-Ritchie, Chloe, Liewald, David C. M., Okely, Judith A., Ahola-Olli, Ari V., Barnes, Catriona L. K., Bertram, Lars, Bis, Joshua C., Burdick, Katherine E., Christoforou, Andrea, DeRosse, Pamela, Djurovic, Srdjan, Espeseth, Thomas, Giakoumaki, Stella, Giddaluru, Sudheer, Gustavson, Daniel E., Hayward, Caroline, Hofer, Edith, Ikram, M. Arfan, Karlsson, Robert, Knowles, Emma, Lahti, Jari, Leber, Markus, Li, Shuo, Mather, Karen A., Melle, Ingrid, Morris, Derek, Oldmeadow, Christopher, Palviainen, Teemu, Payton, Antony, Pazoki, Raha, Petrovic, Katja, Reynolds, Chandra A., Sargurupremraj, Muralidharan, Scholz, Markus, Smith, Jennifer A., Smith, Albert V., Terzikhan, Natalie, Thalamuthu, Anbupalam, Trompet, Stella, van der Lee, Sven J., Ware, Erin B., Windham, B. Gwen, Wright, Margaret J., Yang, Jingyun, Yu, Jin, Ames, David, Amin, Najaf, Amouyel, Philippe, Andreassen, Ole A., Armstrong, Nicola J., Assareh, Amelia A., Attia, John R., Attix, Deborah, Avramopoulos, Dimitrios, Bennett, David A., Boehmer, Anne C., Boyle, Patricia A., Brodaty, Henry, Campbell, Harry, Cannon, Tyrone D., Cirulli, Elizabeth T., Congdon, Eliza, Conley, Emily Drabant, Corley, Janie, Cox, Simon R., Dale, Anders M., Dehghan, Abbas, Dick, Danielle, Dickinson, Dwight, Eriksson, Johan G., Evangelou, Evangelos, Faul, Jessica D., Ford, Ian, Freimer, Nelson A., Gao, He, Giegling, Ina, Gillespie, Nathan A., Gordon, Scott D., Gottesman, Rebecca F., Griswold, Michael E., Gudnason, Vilmundur, Harris, Tamara B., Hartmann, Annette M., Hatzimanolis, Alex, Heiss, Gerardo, Holliday, Elizabeth G., Joshi, Peter K., Kahonen, Mika, Kardia, Sharon L. R., Karlsson, Ida, Kleineidam, Luca, Knopman, David S., Kochan, Nicole A., Konte, Bettina, Kwok, John B., Le Hellard, Stephanie, Lee, Teresa, Lehtimaki, Terho, Li, Shu-Chen, Liu, Tian, Koini, Marisa, London, Edythe, Longstreth, Will T., Jr., Lopez, Oscar L., Loukola, Anu, Luck, Tobias, Lundervold, Astri J., Lundquist, Anders, Lyytikainen, Leo-Pekka, Martin, Nicholas G., Montgomery, Grant W., Murray, Alison D., Need, Anna C., Noordam, Raymond, Nyberg, Lars, Ollier, William, Papenberg, Goran, Pattie, Alison, Polasek, Ozren, Poldrack, Russell A., Psaty, Bruce M., Reppermund, Simone, Riedel-Heller, Steffi G., Rose, Richard J., Rotter, Jerome I., Roussos, Panos, Rovio, Suvi P., Saba, Yasaman, Sabb, Fred W., Sachdev, Perminder S., Satizabal, Claudia L., Schmid, Matthias, Scott, Rodney J., Scult, Matthew A., Simino, Jeannette, Slagboom, P. Eline, Smyrnis, Nikolaos, Soumare, Aicha, Stefanis, Nikos C., Stott, David J., Straub, Richard E., Sundet, Kjetil, Taylor, Adele M., Taylor, Kent D., Tzoulaki, Ioanna, Tzourio, Christophe, Uitterlinden, Andre, Vitart, Veronique, Voineskos, Aristotle N., Kaprio, Jaakko, Wagner, Michael, Wagner, Holger, Weinhold, Leonie, Wen, K. Hoyan, Widen, Elisabeth, Yang, Qiong, Zhao, Wei, Adams, Hieab H. H., Arking, Dan E., Bilder, Robert M., Bitsios, Panos, Boerwinkle, Eric, Chiba-Falek, Ornit, Corvin, Aiden, De Jager, Philip L., Debette, Stephanie, Donohoe, Gary, Elliott, Paul, Fitzpatrick, Annette L., Gill, Michael, Glahn, David C., Hagg, Sara, Hansell, Narelle K., Hariri, Ahmad R., Ikram, M. Kamran, Jukema, J. Wouter, Vuoksimaa, Eero, Keller, Matthew C., Kremen, William S., Launer, Lenore, Lindenberger, Ulman, Palotie, Aarno, Pedersen, Nancy L., Pendleton, Neil, Porteous, David J., Raikkonen, Katri, Raitakari, Olli T., Ramirez, Alfredo, Reinvang, Ivar, Rudan, Igor, Rujescu, Dan, Schmidt, Reinhold, Schmidt, Helena, Schofield, Peter W., Schofield, Peter R., Starr, John M., Steen, Vidar M., Trollor, Julian N., Turner, Steven T., Van Duijn, Cornelia M., Villringer, Arno, Weinberger, Daniel R., Weir, David R., Wilson, James F., Malhotra, Anil, McIntosh, Andrew M., Gale, Catharine R., Seshadri, Sudha, Mosley, Thomas H., Jr., Bressler, Jan, Lencz, Todd, and Deary, Ian J.
Abstract: General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 x 10(-8)) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.
Published: 2018

33. Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence

Author: Savage, Jeanne E, Jansen, Philip R, Stringer, Sven, Watanabe, Kyoko, Bryois, Julien, de Leeuw, Christiaan A, Nagel, Mats, Awasthi, Swapnil, Barr, Peter B, Coleman, Jonathan R I, Grasby, Katrina L, Hammerschlag, Anke R, Kaminski, Jakob A, Karlsson, Robert, Krapohl, Eva, Lam, Max, Nygaard, Marianne, Reynolds, Chandra A, Trampush, Joey W, Young, Hannah, Zabaneh, Delilah, Hägg, Sara, Hansell, Narelle K, Karlsson, Ida K, Linnarsson, Sten, Montgomery, Grant W, Muñoz-Manchado, Ana B, Quinlan, Erin B, Schumann, Gunter, Skene, Nathan G, Webb, Bradley T, White, Tonya, Arking, Dan E, Avramopoulos, Dimitrios, Bilder, Robert M, Bitsios, Panos, Burdick, Katherine E, Cannon, Tyrone D, Chiba-Falek, Ornit, Christoforou, Andrea, Cirulli, Elizabeth T, Congdon, Eliza, Corvin, Aiden, Davies, Gail, Deary, Ian J, DeRosse, Pamela, Dickinson, Dwight, Djurovic, Srdjan, Donohoe, Gary, Conley, Emily Drabant, Eriksson, Johan G, Espeseth, Thomas, Freimer, Nelson A, Giakoumaki, Stella, Giegling, Ina, Gill, Michael, Glahn, David C, Hariri, Ahmad R, Hatzimanolis, Alex, Keller, Matthew C, Knowles, Emma, Koltai, Deborah, Konte, Bettina, Lahti, Jari, Le Hellard, Stephanie, Lencz, Todd, Liewald, David C, London, Edythe, Lundervold, Astri J, Malhotra, Anil K, Melle, Ingrid, Morris, Derek, Need, Anna C, Ollier, William, Palotie, Aarno, Payton, Antony, Pendleton, Neil, Poldrack, Russell A, Räikkönen, Katri, Reinvang, Ivar, Roussos, Panos, Rujescu, Dan, Sabb, Fred W, Scult, Matthew A, Smeland, Olav B, Smyrnis, Nikolaos, Starr, John M, Steen, Vidar M, Stefanis, Nikos C, Straub, Richard E, Sundet, Kjetil, Tiemeier, Henning, Voineskos, Aristotle N, Weinberger, Daniel R, Widen, Elisabeth, Yu, Jin, Abecasis, Goncalo, Andreassen, Ole A, Breen, Gerome, Christiansen, Lene, Debrabant, Birgit, Dick, Danielle M, Heinz, Andreas, Hjerling-Leffler, Jens, Ikram, M Arfan, Kendler, Kenneth S, Martin, Nicholas G, Medland, Sarah E, Pedersen, Nancy L, Plomin, Robert, Polderman, Tinca J C, Ripke, Stephan, van der Sluis, Sophie, Sullivan, Patrick F, Vrieze, Scott I, Wright, Margaret J, Posthuma, Danielle, Savage, Jeanne E, Jansen, Philip R, Stringer, Sven, Watanabe, Kyoko, Bryois, Julien, de Leeuw, Christiaan A, Nagel, Mats, Awasthi, Swapnil, Barr, Peter B, Coleman, Jonathan R I, Grasby, Katrina L, Hammerschlag, Anke R, Kaminski, Jakob A, Karlsson, Robert, Krapohl, Eva, Lam, Max, Nygaard, Marianne, Reynolds, Chandra A, Trampush, Joey W, Young, Hannah, Zabaneh, Delilah, Hägg, Sara, Hansell, Narelle K, Karlsson, Ida K, Linnarsson, Sten, Montgomery, Grant W, Muñoz-Manchado, Ana B, Quinlan, Erin B, Schumann, Gunter, Skene, Nathan G, Webb, Bradley T, White, Tonya, Arking, Dan E, Avramopoulos, Dimitrios, Bilder, Robert M, Bitsios, Panos, Burdick, Katherine E, Cannon, Tyrone D, Chiba-Falek, Ornit, Christoforou, Andrea, Cirulli, Elizabeth T, Congdon, Eliza, Corvin, Aiden, Davies, Gail, Deary, Ian J, DeRosse, Pamela, Dickinson, Dwight, Djurovic, Srdjan, Donohoe, Gary, Conley, Emily Drabant, Eriksson, Johan G, Espeseth, Thomas, Freimer, Nelson A, Giakoumaki, Stella, Giegling, Ina, Gill, Michael, Glahn, David C, Hariri, Ahmad R, Hatzimanolis, Alex, Keller, Matthew C, Knowles, Emma, Koltai, Deborah, Konte, Bettina, Lahti, Jari, Le Hellard, Stephanie, Lencz, Todd, Liewald, David C, London, Edythe, Lundervold, Astri J, Malhotra, Anil K, Melle, Ingrid, Morris, Derek, Need, Anna C, Ollier, William, Palotie, Aarno, Payton, Antony, Pendleton, Neil, Poldrack, Russell A, Räikkönen, Katri, Reinvang, Ivar, Roussos, Panos, Rujescu, Dan, Sabb, Fred W, Scult, Matthew A, Smeland, Olav B, Smyrnis, Nikolaos, Starr, John M, Steen, Vidar M, Stefanis, Nikos C, Straub, Richard E, Sundet, Kjetil, Tiemeier, Henning, Voineskos, Aristotle N, Weinberger, Daniel R, Widen, Elisabeth, Yu, Jin, Abecasis, Goncalo, Andreassen, Ole A, Breen, Gerome, Christiansen, Lene, Debrabant, Birgit, Dick, Danielle M, Heinz, Andreas, Hjerling-Leffler, Jens, Ikram, M Arfan, Kendler, Kenneth S, Martin, Nicholas G, Medland, Sarah E, Pedersen, Nancy L, Plomin, Robert, Polderman, Tinca J C, Ripke, Stephan, van der Sluis, Sophie, Sullivan, Patrick F, Vrieze, Scott I, Wright, Margaret J, and Posthuma, Danielle
Abstract: Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.
Published: 2018
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34. Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence.

Author: Savage, Jeanne E, Savage, Jeanne E, Jansen, Philip R, Stringer, Sven, Watanabe, Kyoko, Bryois, Julien, de Leeuw, Christiaan A, Nagel, Mats, Awasthi, Swapnil, Barr, Peter B, Coleman, Jonathan RI, Grasby, Katrina L, Hammerschlag, Anke R, Kaminski, Jakob A, Karlsson, Robert, Krapohl, Eva, Lam, Max, Nygaard, Marianne, Reynolds, Chandra A, Trampush, Joey W, Young, Hannah, Zabaneh, Delilah, Hägg, Sara, Hansell, Narelle K, Karlsson, Ida K, Linnarsson, Sten, Montgomery, Grant W, Muñoz-Manchado, Ana B, Quinlan, Erin B, Schumann, Gunter, Skene, Nathan G, Webb, Bradley T, White, Tonya, Arking, Dan E, Avramopoulos, Dimitrios, Bilder, Robert M, Bitsios, Panos, Burdick, Katherine E, Cannon, Tyrone D, Chiba-Falek, Ornit, Christoforou, Andrea, Cirulli, Elizabeth T, Congdon, Eliza, Corvin, Aiden, Davies, Gail, Deary, Ian J, DeRosse, Pamela, Dickinson, Dwight, Djurovic, Srdjan, Donohoe, Gary, Conley, Emily Drabant, Eriksson, Johan G, Espeseth, Thomas, Freimer, Nelson A, Giakoumaki, Stella, Giegling, Ina, Gill, Michael, Glahn, David C, Hariri, Ahmad R, Hatzimanolis, Alex, Keller, Matthew C, Knowles, Emma, Koltai, Deborah, Konte, Bettina, Lahti, Jari, Le Hellard, Stephanie, Lencz, Todd, Liewald, David C, London, Edythe, Lundervold, Astri J, Malhotra, Anil K, Melle, Ingrid, Morris, Derek, Need, Anna C, Ollier, William, Palotie, Aarno, Payton, Antony, Pendleton, Neil, Poldrack, Russell A, Räikkönen, Katri, Reinvang, Ivar, Roussos, Panos, Rujescu, Dan, Sabb, Fred W, Scult, Matthew A, Smeland, Olav B, Smyrnis, Nikolaos, Starr, John M, Steen, Vidar M, Stefanis, Nikos C, Straub, Richard E, Sundet, Kjetil, Tiemeier, Henning, Voineskos, Aristotle N, Weinberger, Daniel R, Widen, Elisabeth, Yu, Jin, Abecasis, Goncalo, Andreassen, Ole A, Breen, Gerome, Christiansen, Lene, Savage, Jeanne E, Savage, Jeanne E, Jansen, Philip R, Stringer, Sven, Watanabe, Kyoko, Bryois, Julien, de Leeuw, Christiaan A, Nagel, Mats, Awasthi, Swapnil, Barr, Peter B, Coleman, Jonathan RI, Grasby, Katrina L, Hammerschlag, Anke R, Kaminski, Jakob A, Karlsson, Robert, Krapohl, Eva, Lam, Max, Nygaard, Marianne, Reynolds, Chandra A, Trampush, Joey W, Young, Hannah, Zabaneh, Delilah, Hägg, Sara, Hansell, Narelle K, Karlsson, Ida K, Linnarsson, Sten, Montgomery, Grant W, Muñoz-Manchado, Ana B, Quinlan, Erin B, Schumann, Gunter, Skene, Nathan G, Webb, Bradley T, White, Tonya, Arking, Dan E, Avramopoulos, Dimitrios, Bilder, Robert M, Bitsios, Panos, Burdick, Katherine E, Cannon, Tyrone D, Chiba-Falek, Ornit, Christoforou, Andrea, Cirulli, Elizabeth T, Congdon, Eliza, Corvin, Aiden, Davies, Gail, Deary, Ian J, DeRosse, Pamela, Dickinson, Dwight, Djurovic, Srdjan, Donohoe, Gary, Conley, Emily Drabant, Eriksson, Johan G, Espeseth, Thomas, Freimer, Nelson A, Giakoumaki, Stella, Giegling, Ina, Gill, Michael, Glahn, David C, Hariri, Ahmad R, Hatzimanolis, Alex, Keller, Matthew C, Knowles, Emma, Koltai, Deborah, Konte, Bettina, Lahti, Jari, Le Hellard, Stephanie, Lencz, Todd, Liewald, David C, London, Edythe, Lundervold, Astri J, Malhotra, Anil K, Melle, Ingrid, Morris, Derek, Need, Anna C, Ollier, William, Palotie, Aarno, Payton, Antony, Pendleton, Neil, Poldrack, Russell A, Räikkönen, Katri, Reinvang, Ivar, Roussos, Panos, Rujescu, Dan, Sabb, Fred W, Scult, Matthew A, Smeland, Olav B, Smyrnis, Nikolaos, Starr, John M, Steen, Vidar M, Stefanis, Nikos C, Straub, Richard E, Sundet, Kjetil, Tiemeier, Henning, Voineskos, Aristotle N, Weinberger, Daniel R, Widen, Elisabeth, Yu, Jin, Abecasis, Goncalo, Andreassen, Ole A, Breen, Gerome, and Christiansen, Lene
Abstract: Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.
Published: 2018

35. Multi-Trait Analysis of GWAS and Biological Insights Into Cognition: A Response to Hill (2018).

Author: Lam, Max, Lam, Max, Trampush, Joey W, Yu, Jin, Knowles, Emma, Djurovic, Srdjan, Melle, Ingrid, Sundet, Kjetil, Christoforou, Andrea, Reinvang, Ivar, DeRosse, Pamela, Lundervold, Astri J, Steen, Vidar M, Espeseth, Thomas, Räikkönen, Katri, Widen, Elisabeth, Palotie, Aarno, Eriksson, Johan G, Giegling, Ina, Konte, Bettina, Roussos, Panos, Giakoumaki, Stella, Burdick, Katherine E, Payton, Antony, Ollier, William, Chiba-Falek, Ornit, Attix, Deborah K, Need, Anna C, Cirulli, Elizabeth T, Voineskos, Aristotle N, Stefanis, Nikos C, Avramopoulos, Dimitrios, Hatzimanolis, Alex, Arking, Dan E, Smyrnis, Nikolaos, Bilder, Robert M, Freimer, Nelson A, Cannon, Tyrone D, London, Edythe, Poldrack, Russell A, Sabb, Fred W, Congdon, Eliza, Conley, Emily Drabant, Scult, Matthew A, Dickinson, Dwight, Straub, Richard E, Donohoe, Gary, Morris, Derek, Corvin, Aiden, Gill, Michael, Hariri, Ahmad R, Weinberger, Daniel R, Pendleton, Neil, Bitsios, Panos, Rujescu, Dan, Lahti, Jari, Hellard, Stephanie Le, Keller, Matthew C, Andreassen, Ole A, Glahn, David C, Malhotra, Anil K, Lencz, Todd, Lam, Max, Lam, Max, Trampush, Joey W, Yu, Jin, Knowles, Emma, Djurovic, Srdjan, Melle, Ingrid, Sundet, Kjetil, Christoforou, Andrea, Reinvang, Ivar, DeRosse, Pamela, Lundervold, Astri J, Steen, Vidar M, Espeseth, Thomas, Räikkönen, Katri, Widen, Elisabeth, Palotie, Aarno, Eriksson, Johan G, Giegling, Ina, Konte, Bettina, Roussos, Panos, Giakoumaki, Stella, Burdick, Katherine E, Payton, Antony, Ollier, William, Chiba-Falek, Ornit, Attix, Deborah K, Need, Anna C, Cirulli, Elizabeth T, Voineskos, Aristotle N, Stefanis, Nikos C, Avramopoulos, Dimitrios, Hatzimanolis, Alex, Arking, Dan E, Smyrnis, Nikolaos, Bilder, Robert M, Freimer, Nelson A, Cannon, Tyrone D, London, Edythe, Poldrack, Russell A, Sabb, Fred W, Congdon, Eliza, Conley, Emily Drabant, Scult, Matthew A, Dickinson, Dwight, Straub, Richard E, Donohoe, Gary, Morris, Derek, Corvin, Aiden, Gill, Michael, Hariri, Ahmad R, Weinberger, Daniel R, Pendleton, Neil, Bitsios, Panos, Rujescu, Dan, Lahti, Jari, Hellard, Stephanie Le, Keller, Matthew C, Andreassen, Ole A, Glahn, David C, Malhotra, Anil K, and Lencz, Todd
Abstract: Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88) presented a critique of our recently published paper in Cell Reports entitled 'Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets' (Lam et al., Cell Reports, Vol. 21, 2017, 2597-2613). Specifically, Hill offered several interrelated comments suggesting potential problems with our use of a new analytic method called Multi-Trait Analysis of GWAS (MTAG) (Turley et al., Nature Genetics, Vol. 50, 2018, 229-237). In this brief article, we respond to each of these concerns. Using empirical data, we conclude that our MTAG results do not suffer from 'inflation in the FDR [false discovery rate]', as suggested by Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88), and are not 'more relevant to the genetic contributions to education than they are to the genetic contributions to intelligence'.
Published: 2018

36. Digital Trajectories to Care in First-Episode Psychosis.

Author: Birnbaum, Michael L, Birnbaum, Michael L, Rizvi, Asra F, Faber, Keren, Addington, Jean, Correll, Christoph U, Gerber, Carla, Lahti, Adrienne C, Loewy, Rachel L, Mathalon, Daniel H, Nelson, Leigh Anne, Voineskos, Aristotle N, Walker, Elaine F, Ward, Elise, Kane, John M, Birnbaum, Michael L, Birnbaum, Michael L, Rizvi, Asra F, Faber, Keren, Addington, Jean, Correll, Christoph U, Gerber, Carla, Lahti, Adrienne C, Loewy, Rachel L, Mathalon, Daniel H, Nelson, Leigh Anne, Voineskos, Aristotle N, Walker, Elaine F, Ward, Elise, and Kane, John M
Abstract: ObjectiveThe emphasis on reducing the duration of untreated psychosis (DUP) has highlighted complex barriers to accessing appropriate services. Internet and social media use by individuals with first-episode psychosis (FEP) was examined to explore how these platforms might be used to facilitate treatment initiation.MethodsParticipants ages 15-35 were interviewed with the Pathways to Care for Psychosis Questionnaire, an 81-item instrument designed to explore online activity during symptom emergence.ResultsOf 112 participants, 90% used the Internet and social media daily. The Internet was listed as the most used resource (62%) for information while symptoms were emerging. A minority (19%) shared concerns via social media, and 76% responded favorably to the possibility of receiving online mental health support.ConclusionsThe Internet and social media were part of daily life for participants with FEP. Activity continued throughout the DUP, offering the prospect of earlier intervention. Participants expressed positive attitudes toward Internet-based outreach and engagement efforts.
Published: 2018

37. Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence

Author: Savage, Jeanne E, Jansen, Philip R, Stringer, Sven, Watanabe, Kyoko, Bryois, Julien, de Leeuw, Christiaan A, Nagel, Mats, Awasthi, Swapnil, Barr, Peter B, Coleman, Jonathan RI, Grasby, Katrina L, Hammerschlag, Anke R, Kaminski, Jakob A, Karlsson, Robert, Krapohl, Eva, Lam, Max, Nygaard, Marianne, Reynolds, Chandra A, Trampush, Joey W, Young, Hannah, Zabaneh, Delilah, Hägg, Sara, Hansell, Narelle K, Karlsson, Ida K, Linnarsson, Sten, Montgomery, Grant W, Muñoz-Manchado, Ana B, Quinlan, Erin B, Schumann, Gunter, Skene, Nathan G, Webb, Bradley T, White, Tonya, Arking, Dan E, Avramopoulos, Dimitrios, Bilder, Robert M, Bitsios, Panos, Burdick, Katherine E, Cannon, Tyrone D, Chiba-Falek, Ornit, Christoforou, Andrea, Cirulli, Elizabeth T, Congdon, Eliza, Corvin, Aiden, Davies, Gail, Deary, Ian J, DeRosse, Pamela, Dickinson, Dwight, Djurovic, Srdjan, Donohoe, Gary, Conley, Emily Drabant, Eriksson, Johan G, Espeseth, Thomas, Freimer, Nelson A, Giakoumaki, Stella, Giegling, Ina, Gill, Michael, Glahn, David C, Hariri, Ahmad R, Hatzimanolis, Alex, Keller, Matthew C, Knowles, Emma, Koltai, Deborah, Konte, Bettina, Lahti, Jari, Le Hellard, Stephanie, Lencz, Todd, Liewald, David C, London, Edythe, Lundervold, Astri J, Malhotra, Anil K, Melle, Ingrid, Morris, Derek, Need, Anna C, Ollier, William, Palotie, Aarno, Payton, Antony, Pendleton, Neil, Poldrack, Russell A, Räikkönen, Katri, Reinvang, Ivar, Roussos, Panos, Rujescu, Dan, Sabb, Fred W, Scult, Matthew A, Smeland, Olav B, Smyrnis, Nikolaos, Starr, John M, Steen, Vidar M, Stefanis, Nikos C, Straub, Richard E, Sundet, Kjetil, Tiemeier, Henning, Voineskos, Aristotle N, Weinberger, Daniel R, Widen, Elisabeth, Yu, Jin, Abecasis, Goncalo, Andreassen, Ole A, Breen, Gerome, Christiansen, Lene, Debrabant, Birgit, Dick, Danielle M, Heinz, Andreas, Hjerling-Leffler, Jens, Ikram, M Arfan, Kendler, Kenneth S, Martin, Nicholas G, Medland, Sarah E, Pedersen, Nancy L, Plomin, Robert, Polderman, Tinca JC, Ripke, Stephan, van der Sluis, Sophie, Sullivan, Patrick F, Vrieze, Scott I, Wright, Margaret J, Posthuma, Danielle, Savage, Jeanne E, Jansen, Philip R, Stringer, Sven, Watanabe, Kyoko, Bryois, Julien, de Leeuw, Christiaan A, Nagel, Mats, Awasthi, Swapnil, Barr, Peter B, Coleman, Jonathan RI, Grasby, Katrina L, Hammerschlag, Anke R, Kaminski, Jakob A, Karlsson, Robert, Krapohl, Eva, Lam, Max, Nygaard, Marianne, Reynolds, Chandra A, Trampush, Joey W, Young, Hannah, Zabaneh, Delilah, Hägg, Sara, Hansell, Narelle K, Karlsson, Ida K, Linnarsson, Sten, Montgomery, Grant W, Muñoz-Manchado, Ana B, Quinlan, Erin B, Schumann, Gunter, Skene, Nathan G, Webb, Bradley T, White, Tonya, Arking, Dan E, Avramopoulos, Dimitrios, Bilder, Robert M, Bitsios, Panos, Burdick, Katherine E, Cannon, Tyrone D, Chiba-Falek, Ornit, Christoforou, Andrea, Cirulli, Elizabeth T, Congdon, Eliza, Corvin, Aiden, Davies, Gail, Deary, Ian J, DeRosse, Pamela, Dickinson, Dwight, Djurovic, Srdjan, Donohoe, Gary, Conley, Emily Drabant, Eriksson, Johan G, Espeseth, Thomas, Freimer, Nelson A, Giakoumaki, Stella, Giegling, Ina, Gill, Michael, Glahn, David C, Hariri, Ahmad R, Hatzimanolis, Alex, Keller, Matthew C, Knowles, Emma, Koltai, Deborah, Konte, Bettina, Lahti, Jari, Le Hellard, Stephanie, Lencz, Todd, Liewald, David C, London, Edythe, Lundervold, Astri J, Malhotra, Anil K, Melle, Ingrid, Morris, Derek, Need, Anna C, Ollier, William, Palotie, Aarno, Payton, Antony, Pendleton, Neil, Poldrack, Russell A, Räikkönen, Katri, Reinvang, Ivar, Roussos, Panos, Rujescu, Dan, Sabb, Fred W, Scult, Matthew A, Smeland, Olav B, Smyrnis, Nikolaos, Starr, John M, Steen, Vidar M, Stefanis, Nikos C, Straub, Richard E, Sundet, Kjetil, Tiemeier, Henning, Voineskos, Aristotle N, Weinberger, Daniel R, Widen, Elisabeth, Yu, Jin, Abecasis, Goncalo, Andreassen, Ole A, Breen, Gerome, Christiansen, Lene, Debrabant, Birgit, Dick, Danielle M, Heinz, Andreas, Hjerling-Leffler, Jens, Ikram, M Arfan, Kendler, Kenneth S, Martin, Nicholas G, Medland, Sarah E, Pedersen, Nancy L, Plomin, Robert, Polderman, Tinca JC, Ripke, Stephan, van der Sluis, Sophie, Sullivan, Patrick F, Vrieze, Scott I, Wright, Margaret J, and Posthuma, Danielle
Abstract: Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3,4,5,6,7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer’s disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.
Published: 2018

38. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Author: Davies, Gail, Lam, Max, Harris, Sarah E, Trampush, Joey W, Luciano, Michelle, Hill, W David, Hagenaars, Saskia P, Ritchie, Stuart J, Marioni, Riccardo E, Fawns-Ritchie, Chloe, Liewald, David CM, Okely, Judith A, Ahola-Olli, Ari V, Barnes, Catriona LK, Bertram, Lars, Bis, Joshua C, Burdick, Katherine E, Christoforou, Andrea, DeRosse, Pamela, Djurovic, Srdjan, Espeseth, Thomas, Giakoumaki, Stella, Giddaluru, Sudheer, Gustavson, Daniel E, Hayward, Caroline, Hofer, Edith, Ikram, M Arfan, Karlsson, Robert, Knowles, Emma, Lahti, Jari, Leber, Markus, Li, Shuo, Mather, Karen A, Melle, Ingrid, Morris, Derek, Oldmeadow, Christopher, Palviainen, Teemu, Payton, Antony, Pazoki, Raha, Petrovic, Katja, Reynolds, Chandra A, Sargurupremraj, Muralidharan, Scholz, Markus, Smith, Jennifer A, Smith, Albert V, Terzikhan, Natalie, Thalamuthu, Anbupalam, Trompet, Stella, van der Lee, Sven J, Ware, Erin B, Windham, B Gwen, Wright, Margaret J, Yang, Jingyun, Yu, Jin, Ames, David, Amin, Najaf, Amouyel, Philippe, Andreassen, Ole A, Armstrong, Nicola J, Assareh, Amelia A, Attia, John R, Attix, Deborah, Avramopoulos, Dimitrios, Bennett, David A, Böhmer, Anne C, Boyle, Patricia A, Brodaty, Henry, Campbell, Harry, Cannon, Tyrone D, Cirulli, Elizabeth T, Congdon, Eliza, Conley, Emily Drabant, Corley, Janie, Cox, Simon R, Dale, Anders M, Dehghan, Abbas, Dick, Danielle, Dickinson, Dwight, Eriksson, Johan G, Evangelou, Evangelos, Faul, Jessica D, Ford, Ian, Freimer, Nelson A, Gao, He, Giegling, Ina, Gillespie, Nathan A, Gordon, Scott D, Gottesman, Rebecca F, Griswold, Michael E, Gudnason, Vilmundur, Harris, Tamara B, Hartmann, Annette M, Hatzimanolis, Alex, Heiss, Gerardo, Holliday, Elizabeth G, Joshi, Peter K, Kähönen, Mika, Kardia, Sharon LR, Karlsson, Ida, Kleineidam, Luca, Knopman, David S, Kochan, Nicole A, Konte, Bettina, Kwok, John B, Le Hellard, Stephanie, Lee, Teresa, Lehtimäki, Terho, Li, Shu-Chen, Lill, Christina M, Liu, Tian, Koini, Marisa, London, Edythe, Longstreth, Will T, Lopez, Oscar L, Loukola, Anu, Luck, Tobias, Lundervold, Astri J, Lundquist, Anders, Lyytikäinen, Leo-Pekka, Martin, Nicholas G, Montgomery, Grant W, Murray, Alison D, Need, Anna C, Noordam, Raymond, Nyberg, Lars, Ollier, William, Papenberg, Goran, Pattie, Alison, Polasek, Ozren, Poldrack, Russell A, Psaty, Bruce M, Reppermund, Simone, Riedel-Heller, Steffi G, Rose, Richard J, Rotter, Jerome I, Roussos, Panos, Rovio, Suvi P, Saba, Yasaman, Sabb, Fred W, Sachdev, Perminder S, Satizabal, Claudia L, Schmid, Matthias, Scott, Rodney J, Scult, Matthew A, Simino, Jeannette, Slagboom, P Eline, Smyrnis, Nikolaos, Soumaré, Aïcha, Stefanis, Nikos C, Stott, David J, Straub, Richard E, Sundet, Kjetil, Taylor, Adele M, Taylor, Kent D, Tzoulaki, Ioanna, Tzourio, Christophe, Uitterlinden, André, Vitart, Veronique, Voineskos, Aristotle N, Kaprio, Jaakko, Wagner, Michael, Wagner, Holger, Weinhold, Leonie, Wen, K Hoyan, Widen, Elisabeth, Yang, Qiong, Zhao, Wei, Adams, Hieab HH, Arking, Dan E, Bilder, Robert M, Bitsios, Panos, Boerwinkle, Eric, Chiba-Falek, Ornit, Corvin, Aiden, De Jager, Philip L, Debette, Stéphanie, Donohoe, Gary, Elliott, Paul, Fitzpatrick, Annette L, Gill, Michael, Glahn, David C, Hägg, Sara, Hansell, Narelle K, Hariri, Ahmad R, Ikram, M Kamran, Jukema, J Wouter, Vuoksimaa, Eero, Keller, Matthew C, Kremen, William S, Launer, Lenore, Lindenberger, Ulman, Palotie, Aarno, Pedersen, Nancy L, Pendleton, Neil, Porteous, David J, Räikkönen, Katri, Raitakari, Olli T, Ramirez, Alfredo, Reinvang, Ivar, Rudan, Igor, Dan Rujescu, Schmidt, Reinhold, Schmidt, Helena, Schofield, Peter W, Schofield, Peter R, Starr, John M, Steen, Vidar M, Trollor, Julian N, Turner, Steven T, Van Duijn, Cornelia M, Villringer, Arno, Weinberger, Daniel R, Weir, David R, Wilson, James F, Malhotra, Anil, McIntosh, Andrew M, Gale, Catharine R, Seshadri, Sudha, Mosley, Thomas H, Bressler, Jan, Lencz, Todd, Deary, Ian J, Davies, Gail, Lam, Max, Harris, Sarah E, Trampush, Joey W, Luciano, Michelle, Hill, W David, Hagenaars, Saskia P, Ritchie, Stuart J, Marioni, Riccardo E, Fawns-Ritchie, Chloe, Liewald, David CM, Okely, Judith A, Ahola-Olli, Ari V, Barnes, Catriona LK, Bertram, Lars, Bis, Joshua C, Burdick, Katherine E, Christoforou, Andrea, DeRosse, Pamela, Djurovic, Srdjan, Espeseth, Thomas, Giakoumaki, Stella, Giddaluru, Sudheer, Gustavson, Daniel E, Hayward, Caroline, Hofer, Edith, Ikram, M Arfan, Karlsson, Robert, Knowles, Emma, Lahti, Jari, Leber, Markus, Li, Shuo, Mather, Karen A, Melle, Ingrid, Morris, Derek, Oldmeadow, Christopher, Palviainen, Teemu, Payton, Antony, Pazoki, Raha, Petrovic, Katja, Reynolds, Chandra A, Sargurupremraj, Muralidharan, Scholz, Markus, Smith, Jennifer A, Smith, Albert V, Terzikhan, Natalie, Thalamuthu, Anbupalam, Trompet, Stella, van der Lee, Sven J, Ware, Erin B, Windham, B Gwen, Wright, Margaret J, Yang, Jingyun, Yu, Jin, Ames, David, Amin, Najaf, Amouyel, Philippe, Andreassen, Ole A, Armstrong, Nicola J, Assareh, Amelia A, Attia, John R, Attix, Deborah, Avramopoulos, Dimitrios, Bennett, David A, Böhmer, Anne C, Boyle, Patricia A, Brodaty, Henry, Campbell, Harry, Cannon, Tyrone D, Cirulli, Elizabeth T, Congdon, Eliza, Conley, Emily Drabant, Corley, Janie, Cox, Simon R, Dale, Anders M, Dehghan, Abbas, Dick, Danielle, Dickinson, Dwight, Eriksson, Johan G, Evangelou, Evangelos, Faul, Jessica D, Ford, Ian, Freimer, Nelson A, Gao, He, Giegling, Ina, Gillespie, Nathan A, Gordon, Scott D, Gottesman, Rebecca F, Griswold, Michael E, Gudnason, Vilmundur, Harris, Tamara B, Hartmann, Annette M, Hatzimanolis, Alex, Heiss, Gerardo, Holliday, Elizabeth G, Joshi, Peter K, Kähönen, Mika, Kardia, Sharon LR, Karlsson, Ida, Kleineidam, Luca, Knopman, David S, Kochan, Nicole A, Konte, Bettina, Kwok, John B, Le Hellard, Stephanie, Lee, Teresa, Lehtimäki, Terho, Li, Shu-Chen, Lill, Christina M, Liu, Tian, Koini, Marisa, London, Edythe, Longstreth, Will T, Lopez, Oscar L, Loukola, Anu, Luck, Tobias, Lundervold, Astri J, Lundquist, Anders, Lyytikäinen, Leo-Pekka, Martin, Nicholas G, Montgomery, Grant W, Murray, Alison D, Need, Anna C, Noordam, Raymond, Nyberg, Lars, Ollier, William, Papenberg, Goran, Pattie, Alison, Polasek, Ozren, Poldrack, Russell A, Psaty, Bruce M, Reppermund, Simone, Riedel-Heller, Steffi G, Rose, Richard J, Rotter, Jerome I, Roussos, Panos, Rovio, Suvi P, Saba, Yasaman, Sabb, Fred W, Sachdev, Perminder S, Satizabal, Claudia L, Schmid, Matthias, Scott, Rodney J, Scult, Matthew A, Simino, Jeannette, Slagboom, P Eline, Smyrnis, Nikolaos, Soumaré, Aïcha, Stefanis, Nikos C, Stott, David J, Straub, Richard E, Sundet, Kjetil, Taylor, Adele M, Taylor, Kent D, Tzoulaki, Ioanna, Tzourio, Christophe, Uitterlinden, André, Vitart, Veronique, Voineskos, Aristotle N, Kaprio, Jaakko, Wagner, Michael, Wagner, Holger, Weinhold, Leonie, Wen, K Hoyan, Widen, Elisabeth, Yang, Qiong, Zhao, Wei, Adams, Hieab HH, Arking, Dan E, Bilder, Robert M, Bitsios, Panos, Boerwinkle, Eric, Chiba-Falek, Ornit, Corvin, Aiden, De Jager, Philip L, Debette, Stéphanie, Donohoe, Gary, Elliott, Paul, Fitzpatrick, Annette L, Gill, Michael, Glahn, David C, Hägg, Sara, Hansell, Narelle K, Hariri, Ahmad R, Ikram, M Kamran, Jukema, J Wouter, Vuoksimaa, Eero, Keller, Matthew C, Kremen, William S, Launer, Lenore, Lindenberger, Ulman, Palotie, Aarno, Pedersen, Nancy L, Pendleton, Neil, Porteous, David J, Räikkönen, Katri, Raitakari, Olli T, Ramirez, Alfredo, Reinvang, Ivar, Rudan, Igor, Dan Rujescu, Schmidt, Reinhold, Schmidt, Helena, Schofield, Peter W, Schofield, Peter R, Starr, John M, Steen, Vidar M, Trollor, Julian N, Turner, Steven T, Van Duijn, Cornelia M, Villringer, Arno, Weinberger, Daniel R, Weir, David R, Wilson, James F, Malhotra, Anil, McIntosh, Andrew M, Gale, Catharine R, Seshadri, Sudha, Mosley, Thomas H, Bressler, Jan, Lencz, Todd, and Deary, Ian J
Abstract: General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.
Published: 2018

39. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Author: Davies, Gail, Lam, Max, Harris, Sarah E., Trampush, Joey W., Luciano, Michelle, Hill, W. David, Hagenaars, Saskia P., Ritchie, Stuart J., Marioni, Riccardo E., Fawns-Ritchie, Chloe, Liewald, David C. M., Okely, Judith A., Ahola-Olli, Ari V., Barnes, Catriona L. K., Bertram, Lars, Bis, Joshua C., Burdick, Katherine E., Christoforou, Andrea, DeRosse, Pamela, Djurovic, Srdjan, Espeseth, Thomas, Giakoumaki, Stella, Giddaluru, Sudheer, Gustavson, Daniel E., Hayward, Caroline, Hofer, Edith, Ikram, M. Arfan, Karlsson, Robert, Knowles, Emma, Lahti, Jari, Leber, Markus, Li, Shuo, Mather, Karen A., Melle, Ingrid, Morris, Derek, Oldmeadow, Christopher, Palviainen, Teemu, Payton, Antony, Pazoki, Raha, Petrovic, Katja, Reynolds, Chandra A., Sargurupremraj, Muralidharan, Scholz, Markus, Smith, Jennifer A., Smith, Albert V., Terzikhan, Natalie, Thalamuthu, Anbupalam, Trompet, Stella, van der Lee, Sven J., Ware, Erin B., Windham, B. Gwen, Wright, Margaret J., Yang, Jingyun, Yu, Jin, Ames, David, Amin, Najaf, Amouyel, Philippe, Andreassen, Ole A., Armstrong, Nicola J., Assareh, Amelia A., Attia, John R., Attix, Deborah, Avramopoulos, Dimitrios, Bennett, David A., Boehmer, Anne C., Boyle, Patricia A., Brodaty, Henry, Campbell, Harry, Cannon, Tyrone D., Cirulli, Elizabeth T., Congdon, Eliza, Conley, Emily Drabant, Corley, Janie, Cox, Simon R., Dale, Anders M., Dehghan, Abbas, Dick, Danielle, Dickinson, Dwight, Eriksson, Johan G., Evangelou, Evangelos, Faul, Jessica D., Ford, Ian, Freimer, Nelson A., Gao, He, Giegling, Ina, Gillespie, Nathan A., Gordon, Scott D., Gottesman, Rebecca F., Griswold, Michael E., Gudnason, Vilmundur, Harris, Tamara B., Hartmann, Annette M., Hatzimanolis, Alex, Heiss, Gerardo, Holliday, Elizabeth G., Joshi, Peter K., Kahonen, Mika, Kardia, Sharon L. R., Karlsson, Ida, Kleineidam, Luca, Knopman, David S., Kochan, Nicole A., Konte, Bettina, Kwok, John B., Le Hellard, Stephanie, Lee, Teresa, Lehtimaki, Terho, Li, Shu-Chen, Liu, Tian, Koini, Marisa, London, Edythe, Longstreth, Will T., Jr., Lopez, Oscar L., Loukola, Anu, Luck, Tobias, Lundervold, Astri J., Lundquist, Anders, Lyytikainen, Leo-Pekka, Martin, Nicholas G., Montgomery, Grant W., Murray, Alison D., Need, Anna C., Noordam, Raymond, Nyberg, Lars, Ollier, William, Papenberg, Goran, Pattie, Alison, Polasek, Ozren, Poldrack, Russell A., Psaty, Bruce M., Reppermund, Simone, Riedel-Heller, Steffi G., Rose, Richard J., Rotter, Jerome I., Roussos, Panos, Rovio, Suvi P., Saba, Yasaman, Sabb, Fred W., Sachdev, Perminder S., Satizabal, Claudia L., Schmid, Matthias, Scott, Rodney J., Scult, Matthew A., Simino, Jeannette, Slagboom, P. Eline, Smyrnis, Nikolaos, Soumare, Aicha, Stefanis, Nikos C., Stott, David J., Straub, Richard E., Sundet, Kjetil, Taylor, Adele M., Taylor, Kent D., Tzoulaki, Ioanna, Tzourio, Christophe, Uitterlinden, Andre, Vitart, Veronique, Voineskos, Aristotle N., Kaprio, Jaakko, Wagner, Michael, Wagner, Holger, Weinhold, Leonie, Wen, K. Hoyan, Widen, Elisabeth, Yang, Qiong, Zhao, Wei, Adams, Hieab H. H., Arking, Dan E., Bilder, Robert M., Bitsios, Panos, Boerwinkle, Eric, Chiba-Falek, Ornit, Corvin, Aiden, De Jager, Philip L., Debette, Stephanie, Donohoe, Gary, Elliott, Paul, Fitzpatrick, Annette L., Gill, Michael, Glahn, David C., Hagg, Sara, Hansell, Narelle K., Hariri, Ahmad R., Ikram, M. Kamran, Jukema, J. Wouter, Vuoksimaa, Eero, Keller, Matthew C., Kremen, William S., Launer, Lenore, Lindenberger, Ulman, Palotie, Aarno, Pedersen, Nancy L., Pendleton, Neil, Porteous, David J., Raikkonen, Katri, Raitakari, Olli T., Ramirez, Alfredo, Reinvang, Ivar, Rudan, Igor, Rujescu, Dan, Schmidt, Reinhold, Schmidt, Helena, Schofield, Peter W., Schofield, Peter R., Starr, John M., Steen, Vidar M., Trollor, Julian N., Turner, Steven T., Van Duijn, Cornelia M., Villringer, Arno, Weinberger, Daniel R., Weir, David R., Wilson, James F., Malhotra, Anil, McIntosh, Andrew M., Gale, Catharine R., Seshadri, Sudha, Mosley, Thomas H., Jr., Bressler, Jan, Lencz, Todd, Deary, Ian J., Davies, Gail, Lam, Max, Harris, Sarah E., Trampush, Joey W., Luciano, Michelle, Hill, W. David, Hagenaars, Saskia P., Ritchie, Stuart J., Marioni, Riccardo E., Fawns-Ritchie, Chloe, Liewald, David C. M., Okely, Judith A., Ahola-Olli, Ari V., Barnes, Catriona L. K., Bertram, Lars, Bis, Joshua C., Burdick, Katherine E., Christoforou, Andrea, DeRosse, Pamela, Djurovic, Srdjan, Espeseth, Thomas, Giakoumaki, Stella, Giddaluru, Sudheer, Gustavson, Daniel E., Hayward, Caroline, Hofer, Edith, Ikram, M. Arfan, Karlsson, Robert, Knowles, Emma, Lahti, Jari, Leber, Markus, Li, Shuo, Mather, Karen A., Melle, Ingrid, Morris, Derek, Oldmeadow, Christopher, Palviainen, Teemu, Payton, Antony, Pazoki, Raha, Petrovic, Katja, Reynolds, Chandra A., Sargurupremraj, Muralidharan, Scholz, Markus, Smith, Jennifer A., Smith, Albert V., Terzikhan, Natalie, Thalamuthu, Anbupalam, Trompet, Stella, van der Lee, Sven J., Ware, Erin B., Windham, B. Gwen, Wright, Margaret J., Yang, Jingyun, Yu, Jin, Ames, David, Amin, Najaf, Amouyel, Philippe, Andreassen, Ole A., Armstrong, Nicola J., Assareh, Amelia A., Attia, John R., Attix, Deborah, Avramopoulos, Dimitrios, Bennett, David A., Boehmer, Anne C., Boyle, Patricia A., Brodaty, Henry, Campbell, Harry, Cannon, Tyrone D., Cirulli, Elizabeth T., Congdon, Eliza, Conley, Emily Drabant, Corley, Janie, Cox, Simon R., Dale, Anders M., Dehghan, Abbas, Dick, Danielle, Dickinson, Dwight, Eriksson, Johan G., Evangelou, Evangelos, Faul, Jessica D., Ford, Ian, Freimer, Nelson A., Gao, He, Giegling, Ina, Gillespie, Nathan A., Gordon, Scott D., Gottesman, Rebecca F., Griswold, Michael E., Gudnason, Vilmundur, Harris, Tamara B., Hartmann, Annette M., Hatzimanolis, Alex, Heiss, Gerardo, Holliday, Elizabeth G., Joshi, Peter K., Kahonen, Mika, Kardia, Sharon L. R., Karlsson, Ida, Kleineidam, Luca, Knopman, David S., Kochan, Nicole A., Konte, Bettina, Kwok, John B., Le Hellard, Stephanie, Lee, Teresa, Lehtimaki, Terho, Li, Shu-Chen, Liu, Tian, Koini, Marisa, London, Edythe, Longstreth, Will T., Jr., Lopez, Oscar L., Loukola, Anu, Luck, Tobias, Lundervold, Astri J., Lundquist, Anders, Lyytikainen, Leo-Pekka, Martin, Nicholas G., Montgomery, Grant W., Murray, Alison D., Need, Anna C., Noordam, Raymond, Nyberg, Lars, Ollier, William, Papenberg, Goran, Pattie, Alison, Polasek, Ozren, Poldrack, Russell A., Psaty, Bruce M., Reppermund, Simone, Riedel-Heller, Steffi G., Rose, Richard J., Rotter, Jerome I., Roussos, Panos, Rovio, Suvi P., Saba, Yasaman, Sabb, Fred W., Sachdev, Perminder S., Satizabal, Claudia L., Schmid, Matthias, Scott, Rodney J., Scult, Matthew A., Simino, Jeannette, Slagboom, P. Eline, Smyrnis, Nikolaos, Soumare, Aicha, Stefanis, Nikos C., Stott, David J., Straub, Richard E., Sundet, Kjetil, Taylor, Adele M., Taylor, Kent D., Tzoulaki, Ioanna, Tzourio, Christophe, Uitterlinden, Andre, Vitart, Veronique, Voineskos, Aristotle N., Kaprio, Jaakko, Wagner, Michael, Wagner, Holger, Weinhold, Leonie, Wen, K. Hoyan, Widen, Elisabeth, Yang, Qiong, Zhao, Wei, Adams, Hieab H. H., Arking, Dan E., Bilder, Robert M., Bitsios, Panos, Boerwinkle, Eric, Chiba-Falek, Ornit, Corvin, Aiden, De Jager, Philip L., Debette, Stephanie, Donohoe, Gary, Elliott, Paul, Fitzpatrick, Annette L., Gill, Michael, Glahn, David C., Hagg, Sara, Hansell, Narelle K., Hariri, Ahmad R., Ikram, M. Kamran, Jukema, J. Wouter, Vuoksimaa, Eero, Keller, Matthew C., Kremen, William S., Launer, Lenore, Lindenberger, Ulman, Palotie, Aarno, Pedersen, Nancy L., Pendleton, Neil, Porteous, David J., Raikkonen, Katri, Raitakari, Olli T., Ramirez, Alfredo, Reinvang, Ivar, Rudan, Igor, Rujescu, Dan, Schmidt, Reinhold, Schmidt, Helena, Schofield, Peter W., Schofield, Peter R., Starr, John M., Steen, Vidar M., Trollor, Julian N., Turner, Steven T., Van Duijn, Cornelia M., Villringer, Arno, Weinberger, Daniel R., Weir, David R., Wilson, James F., Malhotra, Anil, McIntosh, Andrew M., Gale, Catharine R., Seshadri, Sudha, Mosley, Thomas H., Jr., Bressler, Jan, Lencz, Todd, and Deary, Ian J.
Abstract: General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 x 10(-8)) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.
Published: 2018

40. Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence

Author: Savage, Jeanne E, Jansen, Philip R, Stringer, Sven, Watanabe, Kyoko, Bryois, Julien, de Leeuw, Christiaan A, Nagel, Mats, Awasthi, Swapnil, Barr, Peter B, Coleman, Jonathan R I, Grasby, Katrina L, Hammerschlag, Anke R, Kaminski, Jakob A, Karlsson, Robert, Krapohl, Eva, Lam, Max, Nygaard, Marianne, Reynolds, Chandra A, Trampush, Joey W, Young, Hannah, Zabaneh, Delilah, Hägg, Sara, Hansell, Narelle K, Karlsson, Ida K, Linnarsson, Sten, Montgomery, Grant W, Muñoz-Manchado, Ana B, Quinlan, Erin B, Schumann, Gunter, Skene, Nathan G, Webb, Bradley T, White, Tonya, Arking, Dan E, Avramopoulos, Dimitrios, Bilder, Robert M, Bitsios, Panos, Burdick, Katherine E, Cannon, Tyrone D, Chiba-Falek, Ornit, Christoforou, Andrea, Cirulli, Elizabeth T, Congdon, Eliza, Corvin, Aiden, Davies, Gail, Deary, Ian J, DeRosse, Pamela, Dickinson, Dwight, Djurovic, Srdjan, Donohoe, Gary, Conley, Emily Drabant, Eriksson, Johan G, Espeseth, Thomas, Freimer, Nelson A, Giakoumaki, Stella, Giegling, Ina, Gill, Michael, Glahn, David C, Hariri, Ahmad R, Hatzimanolis, Alex, Keller, Matthew C, Knowles, Emma, Koltai, Deborah, Konte, Bettina, Lahti, Jari, Le Hellard, Stephanie, Lencz, Todd, Liewald, David C, London, Edythe, Lundervold, Astri J, Malhotra, Anil K, Melle, Ingrid, Morris, Derek, Need, Anna C, Ollier, William, Palotie, Aarno, Payton, Antony, Pendleton, Neil, Poldrack, Russell A, Räikkönen, Katri, Reinvang, Ivar, Roussos, Panos, Rujescu, Dan, Sabb, Fred W, Scult, Matthew A, Smeland, Olav B, Smyrnis, Nikolaos, Starr, John M, Steen, Vidar M, Stefanis, Nikos C, Straub, Richard E, Sundet, Kjetil, Tiemeier, Henning, Voineskos, Aristotle N, Weinberger, Daniel R, Widen, Elisabeth, Yu, Jin, Abecasis, Goncalo, Andreassen, Ole A, Breen, Gerome, Christiansen, Lene, Debrabant, Birgit, Dick, Danielle M, Heinz, Andreas, Hjerling-Leffler, Jens, Ikram, M Arfan, Kendler, Kenneth S, Martin, Nicholas G, Medland, Sarah E, Pedersen, Nancy L, Plomin, Robert, Polderman, Tinca J C, Ripke, Stephan, van der Sluis, Sophie, Sullivan, Patrick F, Vrieze, Scott I, Wright, Margaret J, Posthuma, Danielle, Savage, Jeanne E, Jansen, Philip R, Stringer, Sven, Watanabe, Kyoko, Bryois, Julien, de Leeuw, Christiaan A, Nagel, Mats, Awasthi, Swapnil, Barr, Peter B, Coleman, Jonathan R I, Grasby, Katrina L, Hammerschlag, Anke R, Kaminski, Jakob A, Karlsson, Robert, Krapohl, Eva, Lam, Max, Nygaard, Marianne, Reynolds, Chandra A, Trampush, Joey W, Young, Hannah, Zabaneh, Delilah, Hägg, Sara, Hansell, Narelle K, Karlsson, Ida K, Linnarsson, Sten, Montgomery, Grant W, Muñoz-Manchado, Ana B, Quinlan, Erin B, Schumann, Gunter, Skene, Nathan G, Webb, Bradley T, White, Tonya, Arking, Dan E, Avramopoulos, Dimitrios, Bilder, Robert M, Bitsios, Panos, Burdick, Katherine E, Cannon, Tyrone D, Chiba-Falek, Ornit, Christoforou, Andrea, Cirulli, Elizabeth T, Congdon, Eliza, Corvin, Aiden, Davies, Gail, Deary, Ian J, DeRosse, Pamela, Dickinson, Dwight, Djurovic, Srdjan, Donohoe, Gary, Conley, Emily Drabant, Eriksson, Johan G, Espeseth, Thomas, Freimer, Nelson A, Giakoumaki, Stella, Giegling, Ina, Gill, Michael, Glahn, David C, Hariri, Ahmad R, Hatzimanolis, Alex, Keller, Matthew C, Knowles, Emma, Koltai, Deborah, Konte, Bettina, Lahti, Jari, Le Hellard, Stephanie, Lencz, Todd, Liewald, David C, London, Edythe, Lundervold, Astri J, Malhotra, Anil K, Melle, Ingrid, Morris, Derek, Need, Anna C, Ollier, William, Palotie, Aarno, Payton, Antony, Pendleton, Neil, Poldrack, Russell A, Räikkönen, Katri, Reinvang, Ivar, Roussos, Panos, Rujescu, Dan, Sabb, Fred W, Scult, Matthew A, Smeland, Olav B, Smyrnis, Nikolaos, Starr, John M, Steen, Vidar M, Stefanis, Nikos C, Straub, Richard E, Sundet, Kjetil, Tiemeier, Henning, Voineskos, Aristotle N, Weinberger, Daniel R, Widen, Elisabeth, Yu, Jin, Abecasis, Goncalo, Andreassen, Ole A, Breen, Gerome, Christiansen, Lene, Debrabant, Birgit, Dick, Danielle M, Heinz, Andreas, Hjerling-Leffler, Jens, Ikram, M Arfan, Kendler, Kenneth S, Martin, Nicholas G, Medland, Sarah E, Pedersen, Nancy L, Plomin, Robert, Polderman, Tinca J C, Ripke, Stephan, van der Sluis, Sophie, Sullivan, Patrick F, Vrieze, Scott I, Wright, Margaret J, and Posthuma, Danielle
Abstract: Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.
Published: 2018
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41. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Author: Davies, Gail, Lam, Max, Harris, Sarah E., Trampush, Joey W., Luciano, Michelle, Hill, W. David, Hagenaars, Saskia P., Ritchie, Stuart J., Marioni, Riccardo E., Fawns-Ritchie, Chloe, Liewald, David C. M., Okely, Judith A., Ahola-Olli, Ari V., Barnes, Catriona L. K., Bertram, Lars, Bis, Joshua C., Burdick, Katherine E., Christoforou, Andrea, DeRosse, Pamela, Djurovic, Srdjan, Espeseth, Thomas, Giakoumaki, Stella, Giddaluru, Sudheer, Gustavson, Daniel E., Hayward, Caroline, Hofer, Edith, Ikram, M. Arfan, Karlsson, Robert, Knowles, Emma, Lahti, Jari, Leber, Markus, Li, Shuo, Mather, Karen A., Melle, Ingrid, Morris, Derek, Oldmeadow, Christopher, Palviainen, Teemu, Payton, Antony, Pazoki, Raha, Petrovic, Katja, Reynolds, Chandra A., Sargurupremraj, Muralidharan, Scholz, Markus, Smith, Jennifer A., Smith, Albert V., Terzikhan, Natalie, Thalamuthu, Anbupalam, Trompet, Stella, van der Lee, Sven J., Ware, Erin B., Windham, B. Gwen, Wright, Margaret J., Yang, Jingyun, Yu, Jin, Ames, David, Amin, Najaf, Amouyel, Philippe, Andreassen, Ole A., Armstrong, Nicola J., Assareh, Amelia A., Attia, John R., Attix, Deborah, Avramopoulos, Dimitrios, Bennett, David A., Boehmer, Anne C., Boyle, Patricia A., Brodaty, Henry, Campbell, Harry, Cannon, Tyrone D., Cirulli, Elizabeth T., Congdon, Eliza, Conley, Emily Drabant, Corley, Janie, Cox, Simon R., Dale, Anders M., Dehghan, Abbas, Dick, Danielle, Dickinson, Dwight, Eriksson, Johan G., Evangelou, Evangelos, Faul, Jessica D., Ford, Ian, Freimer, Nelson A., Gao, He, Giegling, Ina, Gillespie, Nathan A., Gordon, Scott D., Gottesman, Rebecca F., Griswold, Michael E., Gudnason, Vilmundur, Harris, Tamara B., Hartmann, Annette M., Hatzimanolis, Alex, Heiss, Gerardo, Holliday, Elizabeth G., Joshi, Peter K., Kahonen, Mika, Kardia, Sharon L. R., Karlsson, Ida, Kleineidam, Luca, Knopman, David S., Kochan, Nicole A., Konte, Bettina, Kwok, John B., Le Hellard, Stephanie, Lee, Teresa, Lehtimaki, Terho, Li, Shu-Chen, Liu, Tian, Koini, Marisa, London, Edythe, Longstreth, Will T., Jr., Lopez, Oscar L., Loukola, Anu, Luck, Tobias, Lundervold, Astri J., Lundquist, Anders, Lyytikainen, Leo-Pekka, Martin, Nicholas G., Montgomery, Grant W., Murray, Alison D., Need, Anna C., Noordam, Raymond, Nyberg, Lars, Ollier, William, Papenberg, Goran, Pattie, Alison, Polasek, Ozren, Poldrack, Russell A., Psaty, Bruce M., Reppermund, Simone, Riedel-Heller, Steffi G., Rose, Richard J., Rotter, Jerome I., Roussos, Panos, Rovio, Suvi P., Saba, Yasaman, Sabb, Fred W., Sachdev, Perminder S., Satizabal, Claudia L., Schmid, Matthias, Scott, Rodney J., Scult, Matthew A., Simino, Jeannette, Slagboom, P. Eline, Smyrnis, Nikolaos, Soumare, Aicha, Stefanis, Nikos C., Stott, David J., Straub, Richard E., Sundet, Kjetil, Taylor, Adele M., Taylor, Kent D., Tzoulaki, Ioanna, Tzourio, Christophe, Uitterlinden, Andre, Vitart, Veronique, Voineskos, Aristotle N., Kaprio, Jaakko, Wagner, Michael, Wagner, Holger, Weinhold, Leonie, Wen, K. Hoyan, Widen, Elisabeth, Yang, Qiong, Zhao, Wei, Adams, Hieab H. H., Arking, Dan E., Bilder, Robert M., Bitsios, Panos, Boerwinkle, Eric, Chiba-Falek, Ornit, Corvin, Aiden, De Jager, Philip L., Debette, Stephanie, Donohoe, Gary, Elliott, Paul, Fitzpatrick, Annette L., Gill, Michael, Glahn, David C., Hagg, Sara, Hansell, Narelle K., Hariri, Ahmad R., Ikram, M. Kamran, Jukema, J. Wouter, Vuoksimaa, Eero, Keller, Matthew C., Kremen, William S., Launer, Lenore, Lindenberger, Ulman, Palotie, Aarno, Pedersen, Nancy L., Pendleton, Neil, Porteous, David J., Raikkonen, Katri, Raitakari, Olli T., Ramirez, Alfredo, Reinvang, Ivar, Rudan, Igor, Rujescu, Dan, Schmidt, Reinhold, Schmidt, Helena, Schofield, Peter W., Schofield, Peter R., Starr, John M., Steen, Vidar M., Trollor, Julian N., Turner, Steven T., Van Duijn, Cornelia M., Villringer, Arno, Weinberger, Daniel R., Weir, David R., Wilson, James F., Malhotra, Anil, McIntosh, Andrew M., Gale, Catharine R., Seshadri, Sudha, Mosley, Thomas H., Jr., Bressler, Jan, Lencz, Todd, Deary, Ian J., Davies, Gail, Lam, Max, Harris, Sarah E., Trampush, Joey W., Luciano, Michelle, Hill, W. David, Hagenaars, Saskia P., Ritchie, Stuart J., Marioni, Riccardo E., Fawns-Ritchie, Chloe, Liewald, David C. M., Okely, Judith A., Ahola-Olli, Ari V., Barnes, Catriona L. K., Bertram, Lars, Bis, Joshua C., Burdick, Katherine E., Christoforou, Andrea, DeRosse, Pamela, Djurovic, Srdjan, Espeseth, Thomas, Giakoumaki, Stella, Giddaluru, Sudheer, Gustavson, Daniel E., Hayward, Caroline, Hofer, Edith, Ikram, M. Arfan, Karlsson, Robert, Knowles, Emma, Lahti, Jari, Leber, Markus, Li, Shuo, Mather, Karen A., Melle, Ingrid, Morris, Derek, Oldmeadow, Christopher, Palviainen, Teemu, Payton, Antony, Pazoki, Raha, Petrovic, Katja, Reynolds, Chandra A., Sargurupremraj, Muralidharan, Scholz, Markus, Smith, Jennifer A., Smith, Albert V., Terzikhan, Natalie, Thalamuthu, Anbupalam, Trompet, Stella, van der Lee, Sven J., Ware, Erin B., Windham, B. Gwen, Wright, Margaret J., Yang, Jingyun, Yu, Jin, Ames, David, Amin, Najaf, Amouyel, Philippe, Andreassen, Ole A., Armstrong, Nicola J., Assareh, Amelia A., Attia, John R., Attix, Deborah, Avramopoulos, Dimitrios, Bennett, David A., Boehmer, Anne C., Boyle, Patricia A., Brodaty, Henry, Campbell, Harry, Cannon, Tyrone D., Cirulli, Elizabeth T., Congdon, Eliza, Conley, Emily Drabant, Corley, Janie, Cox, Simon R., Dale, Anders M., Dehghan, Abbas, Dick, Danielle, Dickinson, Dwight, Eriksson, Johan G., Evangelou, Evangelos, Faul, Jessica D., Ford, Ian, Freimer, Nelson A., Gao, He, Giegling, Ina, Gillespie, Nathan A., Gordon, Scott D., Gottesman, Rebecca F., Griswold, Michael E., Gudnason, Vilmundur, Harris, Tamara B., Hartmann, Annette M., Hatzimanolis, Alex, Heiss, Gerardo, Holliday, Elizabeth G., Joshi, Peter K., Kahonen, Mika, Kardia, Sharon L. R., Karlsson, Ida, Kleineidam, Luca, Knopman, David S., Kochan, Nicole A., Konte, Bettina, Kwok, John B., Le Hellard, Stephanie, Lee, Teresa, Lehtimaki, Terho, Li, Shu-Chen, Liu, Tian, Koini, Marisa, London, Edythe, Longstreth, Will T., Jr., Lopez, Oscar L., Loukola, Anu, Luck, Tobias, Lundervold, Astri J., Lundquist, Anders, Lyytikainen, Leo-Pekka, Martin, Nicholas G., Montgomery, Grant W., Murray, Alison D., Need, Anna C., Noordam, Raymond, Nyberg, Lars, Ollier, William, Papenberg, Goran, Pattie, Alison, Polasek, Ozren, Poldrack, Russell A., Psaty, Bruce M., Reppermund, Simone, Riedel-Heller, Steffi G., Rose, Richard J., Rotter, Jerome I., Roussos, Panos, Rovio, Suvi P., Saba, Yasaman, Sabb, Fred W., Sachdev, Perminder S., Satizabal, Claudia L., Schmid, Matthias, Scott, Rodney J., Scult, Matthew A., Simino, Jeannette, Slagboom, P. Eline, Smyrnis, Nikolaos, Soumare, Aicha, Stefanis, Nikos C., Stott, David J., Straub, Richard E., Sundet, Kjetil, Taylor, Adele M., Taylor, Kent D., Tzoulaki, Ioanna, Tzourio, Christophe, Uitterlinden, Andre, Vitart, Veronique, Voineskos, Aristotle N., Kaprio, Jaakko, Wagner, Michael, Wagner, Holger, Weinhold, Leonie, Wen, K. Hoyan, Widen, Elisabeth, Yang, Qiong, Zhao, Wei, Adams, Hieab H. H., Arking, Dan E., Bilder, Robert M., Bitsios, Panos, Boerwinkle, Eric, Chiba-Falek, Ornit, Corvin, Aiden, De Jager, Philip L., Debette, Stephanie, Donohoe, Gary, Elliott, Paul, Fitzpatrick, Annette L., Gill, Michael, Glahn, David C., Hagg, Sara, Hansell, Narelle K., Hariri, Ahmad R., Ikram, M. Kamran, Jukema, J. Wouter, Vuoksimaa, Eero, Keller, Matthew C., Kremen, William S., Launer, Lenore, Lindenberger, Ulman, Palotie, Aarno, Pedersen, Nancy L., Pendleton, Neil, Porteous, David J., Raikkonen, Katri, Raitakari, Olli T., Ramirez, Alfredo, Reinvang, Ivar, Rudan, Igor, Rujescu, Dan, Schmidt, Reinhold, Schmidt, Helena, Schofield, Peter W., Schofield, Peter R., Starr, John M., Steen, Vidar M., Trollor, Julian N., Turner, Steven T., Van Duijn, Cornelia M., Villringer, Arno, Weinberger, Daniel R., Weir, David R., Wilson, James F., Malhotra, Anil, McIntosh, Andrew M., Gale, Catharine R., Seshadri, Sudha, Mosley, Thomas H., Jr., Bressler, Jan, Lencz, Todd, and Deary, Ian J.
Abstract: General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 x 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function., Errata: Davies, G., Lam, M., Harris, S. E., Trampush, J. W., Luciano, M., Hill, W. D., … Deary, I. J. (2019). Author correction to Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. [Nature Communications (2018), 9, Article number 2098]. Nature Communications, 10, Article number: 2068. DOI: 10.1038/s41467-019-10160-w
Published: 2018
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42. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Author: Davies, Gail, Lam, Max, Harris, Sarah E., Trampush, Joey W., Luciano, Michelle, Hill, W. David, Hagenaars, Saskia P., Ritchie, Stuart J., Marioni, Riccardo E., Fawns-Ritchie, Chloe, Liewald, David C. M., Okely, Judith A., Ahola-Olli, Ari V., Barnes, Catriona L. K., Bertram, Lars, Bis, Joshua C., Burdick, Katherine E., Christoforou, Andrea, DeRosse, Pamela, Djurovic, Srdjan, Espeseth, Thomas, Giakoumaki, Stella, Giddaluru, Sudheer, Gustavson, Daniel E., Hayward, Caroline, Hofer, Edith, Ikram, M. Arfan, Karlsson, Robert, Knowles, Emma, Lahti, Jari, Leber, Markus, Li, Shuo, Mather, Karen A., Melle, Ingrid, Morris, Derek, Oldmeadow, Christopher, Palviainen, Teemu, Payton, Antony, Pazoki, Raha, Petrovic, Katja, Reynolds, Chandra A., Sargurupremraj, Muralidharan, Scholz, Markus, Smith, Jennifer A., Smith, Albert V., Terzikhan, Natalie, Thalamuthu, Anbupalam, Trompet, Stella, van der Lee, Sven J., Ware, Erin B., Windham, B. Gwen, Wright, Margaret J., Yang, Jingyun, Yu, Jin, Ames, David, Amin, Najaf, Amouyel, Philippe, Andreassen, Ole A., Armstrong, Nicola J., Assareh, Amelia A., Attia, John R., Attix, Deborah, Avramopoulos, Dimitrios, Bennett, David A., Boehmer, Anne C., Boyle, Patricia A., Brodaty, Henry, Campbell, Harry, Cannon, Tyrone D., Cirulli, Elizabeth T., Congdon, Eliza, Conley, Emily Drabant, Corley, Janie, Cox, Simon R., Dale, Anders M., Dehghan, Abbas, Dick, Danielle, Dickinson, Dwight, Eriksson, Johan G., Evangelou, Evangelos, Faul, Jessica D., Ford, Ian, Freimer, Nelson A., Gao, He, Giegling, Ina, Gillespie, Nathan A., Gordon, Scott D., Gottesman, Rebecca F., Griswold, Michael E., Gudnason, Vilmundur, Harris, Tamara B., Hartmann, Annette M., Hatzimanolis, Alex, Heiss, Gerardo, Holliday, Elizabeth G., Joshi, Peter K., Kahonen, Mika, Kardia, Sharon L. R., Karlsson, Ida, Kleineidam, Luca, Knopman, David S., Kochan, Nicole A., Konte, Bettina, Kwok, John B., Le Hellard, Stephanie, Lee, Teresa, Lehtimaki, Terho, Li, Shu-Chen, Liu, Tian, Koini, Marisa, London, Edythe, Longstreth, Will T., Jr., Lopez, Oscar L., Loukola, Anu, Luck, Tobias, Lundervold, Astri J., Lundquist, Anders, Lyytikainen, Leo-Pekka, Martin, Nicholas G., Montgomery, Grant W., Murray, Alison D., Need, Anna C., Noordam, Raymond, Nyberg, Lars, Ollier, William, Papenberg, Goran, Pattie, Alison, Polasek, Ozren, Poldrack, Russell A., Psaty, Bruce M., Reppermund, Simone, Riedel-Heller, Steffi G., Rose, Richard J., Rotter, Jerome I., Roussos, Panos, Rovio, Suvi P., Saba, Yasaman, Sabb, Fred W., Sachdev, Perminder S., Satizabal, Claudia L., Schmid, Matthias, Scott, Rodney J., Scult, Matthew A., Simino, Jeannette, Slagboom, P. Eline, Smyrnis, Nikolaos, Soumare, Aicha, Stefanis, Nikos C., Stott, David J., Straub, Richard E., Sundet, Kjetil, Taylor, Adele M., Taylor, Kent D., Tzoulaki, Ioanna, Tzourio, Christophe, Uitterlinden, Andre, Vitart, Veronique, Voineskos, Aristotle N., Kaprio, Jaakko, Wagner, Michael, Wagner, Holger, Weinhold, Leonie, Wen, K. Hoyan, Widen, Elisabeth, Yang, Qiong, Zhao, Wei, Adams, Hieab H. H., Arking, Dan E., Bilder, Robert M., Bitsios, Panos, Boerwinkle, Eric, Chiba-Falek, Ornit, Corvin, Aiden, De Jager, Philip L., Debette, Stephanie, Donohoe, Gary, Elliott, Paul, Fitzpatrick, Annette L., Gill, Michael, Glahn, David C., Hagg, Sara, Hansell, Narelle K., Hariri, Ahmad R., Ikram, M. Kamran, Jukema, J. Wouter, Vuoksimaa, Eero, Keller, Matthew C., Kremen, William S., Launer, Lenore, Lindenberger, Ulman, Palotie, Aarno, Pedersen, Nancy L., Pendleton, Neil, Porteous, David J., Raikkonen, Katri, Raitakari, Olli T., Ramirez, Alfredo, Reinvang, Ivar, Rudan, Igor, Rujescu, Dan, Schmidt, Reinhold, Schmidt, Helena, Schofield, Peter W., Schofield, Peter R., Starr, John M., Steen, Vidar M., Trollor, Julian N., Turner, Steven T., Van Duijn, Cornelia M., Villringer, Arno, Weinberger, Daniel R., Weir, David R., Wilson, James F., Malhotra, Anil, McIntosh, Andrew M., Gale, Catharine R., Seshadri, Sudha, Mosley, Thomas H., Jr., Bressler, Jan, Lencz, Todd, Deary, Ian J., Davies, Gail, Lam, Max, Harris, Sarah E., Trampush, Joey W., Luciano, Michelle, Hill, W. David, Hagenaars, Saskia P., Ritchie, Stuart J., Marioni, Riccardo E., Fawns-Ritchie, Chloe, Liewald, David C. M., Okely, Judith A., Ahola-Olli, Ari V., Barnes, Catriona L. K., Bertram, Lars, Bis, Joshua C., Burdick, Katherine E., Christoforou, Andrea, DeRosse, Pamela, Djurovic, Srdjan, Espeseth, Thomas, Giakoumaki, Stella, Giddaluru, Sudheer, Gustavson, Daniel E., Hayward, Caroline, Hofer, Edith, Ikram, M. Arfan, Karlsson, Robert, Knowles, Emma, Lahti, Jari, Leber, Markus, Li, Shuo, Mather, Karen A., Melle, Ingrid, Morris, Derek, Oldmeadow, Christopher, Palviainen, Teemu, Payton, Antony, Pazoki, Raha, Petrovic, Katja, Reynolds, Chandra A., Sargurupremraj, Muralidharan, Scholz, Markus, Smith, Jennifer A., Smith, Albert V., Terzikhan, Natalie, Thalamuthu, Anbupalam, Trompet, Stella, van der Lee, Sven J., Ware, Erin B., Windham, B. Gwen, Wright, Margaret J., Yang, Jingyun, Yu, Jin, Ames, David, Amin, Najaf, Amouyel, Philippe, Andreassen, Ole A., Armstrong, Nicola J., Assareh, Amelia A., Attia, John R., Attix, Deborah, Avramopoulos, Dimitrios, Bennett, David A., Boehmer, Anne C., Boyle, Patricia A., Brodaty, Henry, Campbell, Harry, Cannon, Tyrone D., Cirulli, Elizabeth T., Congdon, Eliza, Conley, Emily Drabant, Corley, Janie, Cox, Simon R., Dale, Anders M., Dehghan, Abbas, Dick, Danielle, Dickinson, Dwight, Eriksson, Johan G., Evangelou, Evangelos, Faul, Jessica D., Ford, Ian, Freimer, Nelson A., Gao, He, Giegling, Ina, Gillespie, Nathan A., Gordon, Scott D., Gottesman, Rebecca F., Griswold, Michael E., Gudnason, Vilmundur, Harris, Tamara B., Hartmann, Annette M., Hatzimanolis, Alex, Heiss, Gerardo, Holliday, Elizabeth G., Joshi, Peter K., Kahonen, Mika, Kardia, Sharon L. R., Karlsson, Ida, Kleineidam, Luca, Knopman, David S., Kochan, Nicole A., Konte, Bettina, Kwok, John B., Le Hellard, Stephanie, Lee, Teresa, Lehtimaki, Terho, Li, Shu-Chen, Liu, Tian, Koini, Marisa, London, Edythe, Longstreth, Will T., Jr., Lopez, Oscar L., Loukola, Anu, Luck, Tobias, Lundervold, Astri J., Lundquist, Anders, Lyytikainen, Leo-Pekka, Martin, Nicholas G., Montgomery, Grant W., Murray, Alison D., Need, Anna C., Noordam, Raymond, Nyberg, Lars, Ollier, William, Papenberg, Goran, Pattie, Alison, Polasek, Ozren, Poldrack, Russell A., Psaty, Bruce M., Reppermund, Simone, Riedel-Heller, Steffi G., Rose, Richard J., Rotter, Jerome I., Roussos, Panos, Rovio, Suvi P., Saba, Yasaman, Sabb, Fred W., Sachdev, Perminder S., Satizabal, Claudia L., Schmid, Matthias, Scott, Rodney J., Scult, Matthew A., Simino, Jeannette, Slagboom, P. Eline, Smyrnis, Nikolaos, Soumare, Aicha, Stefanis, Nikos C., Stott, David J., Straub, Richard E., Sundet, Kjetil, Taylor, Adele M., Taylor, Kent D., Tzoulaki, Ioanna, Tzourio, Christophe, Uitterlinden, Andre, Vitart, Veronique, Voineskos, Aristotle N., Kaprio, Jaakko, Wagner, Michael, Wagner, Holger, Weinhold, Leonie, Wen, K. Hoyan, Widen, Elisabeth, Yang, Qiong, Zhao, Wei, Adams, Hieab H. H., Arking, Dan E., Bilder, Robert M., Bitsios, Panos, Boerwinkle, Eric, Chiba-Falek, Ornit, Corvin, Aiden, De Jager, Philip L., Debette, Stephanie, Donohoe, Gary, Elliott, Paul, Fitzpatrick, Annette L., Gill, Michael, Glahn, David C., Hagg, Sara, Hansell, Narelle K., Hariri, Ahmad R., Ikram, M. Kamran, Jukema, J. Wouter, Vuoksimaa, Eero, Keller, Matthew C., Kremen, William S., Launer, Lenore, Lindenberger, Ulman, Palotie, Aarno, Pedersen, Nancy L., Pendleton, Neil, Porteous, David J., Raikkonen, Katri, Raitakari, Olli T., Ramirez, Alfredo, Reinvang, Ivar, Rudan, Igor, Rujescu, Dan, Schmidt, Reinhold, Schmidt, Helena, Schofield, Peter W., Schofield, Peter R., Starr, John M., Steen, Vidar M., Trollor, Julian N., Turner, Steven T., Van Duijn, Cornelia M., Villringer, Arno, Weinberger, Daniel R., Weir, David R., Wilson, James F., Malhotra, Anil, McIntosh, Andrew M., Gale, Catharine R., Seshadri, Sudha, Mosley, Thomas H., Jr., Bressler, Jan, Lencz, Todd, and Deary, Ian J.
Abstract: General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 x 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function., Errata: Davies, G., Lam, M., Harris, S. E., Trampush, J. W., Luciano, M., Hill, W. D., … Deary, I. J. (2019). Author correction to Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. [Nature Communications (2018), 9, Article number 2098]. Nature Communications, 10, Article number: 2068. DOI: 10.1038/s41467-019-10160-w
Published: 2018
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43. Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets.

Author: Lam, Max, Lam, Max, Trampush, Joey W, Yu, Jin, Knowles, Emma, Davies, Gail, Liewald, David C, Starr, John M, Djurovic, Srdjan, Melle, Ingrid, Sundet, Kjetil, Christoforou, Andrea, Reinvang, Ivar, DeRosse, Pamela, Lundervold, Astri J, Steen, Vidar M, Espeseth, Thomas, Räikkönen, Katri, Widen, Elisabeth, Palotie, Aarno, Eriksson, Johan G, Giegling, Ina, Konte, Bettina, Roussos, Panos, Giakoumaki, Stella, Burdick, Katherine E, Payton, Antony, Ollier, William, Chiba-Falek, Ornit, Attix, Deborah K, Need, Anna C, Cirulli, Elizabeth T, Voineskos, Aristotle N, Stefanis, Nikos C, Avramopoulos, Dimitrios, Hatzimanolis, Alex, Arking, Dan E, Smyrnis, Nikolaos, Bilder, Robert M, Freimer, Nelson A, Cannon, Tyrone D, London, Edythe, Poldrack, Russell A, Sabb, Fred W, Congdon, Eliza, Conley, Emily Drabant, Scult, Matthew A, Dickinson, Dwight, Straub, Richard E, Donohoe, Gary, Morris, Derek, Corvin, Aiden, Gill, Michael, Hariri, Ahmad R, Weinberger, Daniel R, Pendleton, Neil, Bitsios, Panos, Rujescu, Dan, Lahti, Jari, Le Hellard, Stephanie, Keller, Matthew C, Andreassen, Ole A, Deary, Ian J, Glahn, David C, Malhotra, Anil K, Lencz, Todd, Lam, Max, Lam, Max, Trampush, Joey W, Yu, Jin, Knowles, Emma, Davies, Gail, Liewald, David C, Starr, John M, Djurovic, Srdjan, Melle, Ingrid, Sundet, Kjetil, Christoforou, Andrea, Reinvang, Ivar, DeRosse, Pamela, Lundervold, Astri J, Steen, Vidar M, Espeseth, Thomas, Räikkönen, Katri, Widen, Elisabeth, Palotie, Aarno, Eriksson, Johan G, Giegling, Ina, Konte, Bettina, Roussos, Panos, Giakoumaki, Stella, Burdick, Katherine E, Payton, Antony, Ollier, William, Chiba-Falek, Ornit, Attix, Deborah K, Need, Anna C, Cirulli, Elizabeth T, Voineskos, Aristotle N, Stefanis, Nikos C, Avramopoulos, Dimitrios, Hatzimanolis, Alex, Arking, Dan E, Smyrnis, Nikolaos, Bilder, Robert M, Freimer, Nelson A, Cannon, Tyrone D, London, Edythe, Poldrack, Russell A, Sabb, Fred W, Congdon, Eliza, Conley, Emily Drabant, Scult, Matthew A, Dickinson, Dwight, Straub, Richard E, Donohoe, Gary, Morris, Derek, Corvin, Aiden, Gill, Michael, Hariri, Ahmad R, Weinberger, Daniel R, Pendleton, Neil, Bitsios, Panos, Rujescu, Dan, Lahti, Jari, Le Hellard, Stephanie, Keller, Matthew C, Andreassen, Ole A, Deary, Ian J, Glahn, David C, Malhotra, Anil K, and Lencz, Todd
Abstract: Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth.
Published: 2017

44. Neural Activity while Imitating Emotional Faces is Related to Both Lower and Higher-Level Social Cognitive Performance.

Author: Hawco, Colin, Hawco, Colin, Kovacevic, Natasa, Malhotra, Anil K, Buchanan, Robert W, Viviano, Joseph D, Iacoboni, Marco, McIntosh, Anthony R, Voineskos, Aristotle N, Hawco, Colin, Hawco, Colin, Kovacevic, Natasa, Malhotra, Anil K, Buchanan, Robert W, Viviano, Joseph D, Iacoboni, Marco, McIntosh, Anthony R, and Voineskos, Aristotle N
Abstract: Imitation and observation of actions and facial emotional expressions activates the human fronto-parietal mirror network. There is skepticism regarding the role of this low-level network in more complex high-level social behaviour. We sought to test whether neural activation during an observation/imitation task was related to both lower and higher level social cognition. We employed an established observe/imitate task of emotional faces during functional MRI in 28 healthy adults, with final analyses based on 20 individuals following extensive quality control. Partial least squares (PLS) identified patterns of relationships between spatial activation and a battery of objective out-of-scanner assessments that index lower and higher-level social cognitive performance, including the Penn emotion recognition task, reading the mind in the eyes, the awareness of social inference test (TASIT) parts 1, 2, and 3, and the relationships across domains (RAD) test. Strikingly, activity in limbic, right inferior frontal, and inferior parietal areas during imitation of emotional faces correlated with performance on emotion evaluation (TASIT1), social inference - minimal (TASIT2), social inference - enriched (TASIT3), and the RAD tests. These results show a role for this network in both lower-level and higher-level social cognitive processes which are collectively critical for social functioning in everyday life.
Published: 2017

45. Neural Activity while Imitating Emotional Faces is Related to Both Lower and Higher-Level Social Cognitive Performance.

Author: Hawco, Colin, Hawco, Colin, Kovacevic, Natasa, Malhotra, Anil K, Buchanan, Robert W, Viviano, Joseph D, Iacoboni, Marco, McIntosh, Anthony R, Voineskos, Aristotle N, Hawco, Colin, Hawco, Colin, Kovacevic, Natasa, Malhotra, Anil K, Buchanan, Robert W, Viviano, Joseph D, Iacoboni, Marco, McIntosh, Anthony R, and Voineskos, Aristotle N
Abstract: Imitation and observation of actions and facial emotional expressions activates the human fronto-parietal mirror network. There is skepticism regarding the role of this low-level network in more complex high-level social behaviour. We sought to test whether neural activation during an observation/imitation task was related to both lower and higher level social cognition. We employed an established observe/imitate task of emotional faces during functional MRI in 28 healthy adults, with final analyses based on 20 individuals following extensive quality control. Partial least squares (PLS) identified patterns of relationships between spatial activation and a battery of objective out-of-scanner assessments that index lower and higher-level social cognitive performance, including the Penn emotion recognition task, reading the mind in the eyes, the awareness of social inference test (TASIT) parts 1, 2, and 3, and the relationships across domains (RAD) test. Strikingly, activity in limbic, right inferior frontal, and inferior parietal areas during imitation of emotional faces correlated with performance on emotion evaluation (TASIT1), social inference - minimal (TASIT2), social inference - enriched (TASIT3), and the RAD tests. These results show a role for this network in both lower-level and higher-level social cognitive processes which are collectively critical for social functioning in everyday life.
Published: 2017

46. Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets.

Author: Lam, Max, Lam, Max, Trampush, Joey W, Yu, Jin, Knowles, Emma, Davies, Gail, Liewald, David C, Starr, John M, Djurovic, Srdjan, Melle, Ingrid, Sundet, Kjetil, Christoforou, Andrea, Reinvang, Ivar, DeRosse, Pamela, Lundervold, Astri J, Steen, Vidar M, Espeseth, Thomas, Räikkönen, Katri, Widen, Elisabeth, Palotie, Aarno, Eriksson, Johan G, Giegling, Ina, Konte, Bettina, Roussos, Panos, Giakoumaki, Stella, Burdick, Katherine E, Payton, Antony, Ollier, William, Chiba-Falek, Ornit, Attix, Deborah K, Need, Anna C, Cirulli, Elizabeth T, Voineskos, Aristotle N, Stefanis, Nikos C, Avramopoulos, Dimitrios, Hatzimanolis, Alex, Arking, Dan E, Smyrnis, Nikolaos, Bilder, Robert M, Freimer, Nelson A, Cannon, Tyrone D, London, Edythe, Poldrack, Russell A, Sabb, Fred W, Congdon, Eliza, Conley, Emily Drabant, Scult, Matthew A, Dickinson, Dwight, Straub, Richard E, Donohoe, Gary, Morris, Derek, Corvin, Aiden, Gill, Michael, Hariri, Ahmad R, Weinberger, Daniel R, Pendleton, Neil, Bitsios, Panos, Rujescu, Dan, Lahti, Jari, Le Hellard, Stephanie, Keller, Matthew C, Andreassen, Ole A, Deary, Ian J, Glahn, David C, Malhotra, Anil K, Lencz, Todd, Lam, Max, Lam, Max, Trampush, Joey W, Yu, Jin, Knowles, Emma, Davies, Gail, Liewald, David C, Starr, John M, Djurovic, Srdjan, Melle, Ingrid, Sundet, Kjetil, Christoforou, Andrea, Reinvang, Ivar, DeRosse, Pamela, Lundervold, Astri J, Steen, Vidar M, Espeseth, Thomas, Räikkönen, Katri, Widen, Elisabeth, Palotie, Aarno, Eriksson, Johan G, Giegling, Ina, Konte, Bettina, Roussos, Panos, Giakoumaki, Stella, Burdick, Katherine E, Payton, Antony, Ollier, William, Chiba-Falek, Ornit, Attix, Deborah K, Need, Anna C, Cirulli, Elizabeth T, Voineskos, Aristotle N, Stefanis, Nikos C, Avramopoulos, Dimitrios, Hatzimanolis, Alex, Arking, Dan E, Smyrnis, Nikolaos, Bilder, Robert M, Freimer, Nelson A, Cannon, Tyrone D, London, Edythe, Poldrack, Russell A, Sabb, Fred W, Congdon, Eliza, Conley, Emily Drabant, Scult, Matthew A, Dickinson, Dwight, Straub, Richard E, Donohoe, Gary, Morris, Derek, Corvin, Aiden, Gill, Michael, Hariri, Ahmad R, Weinberger, Daniel R, Pendleton, Neil, Bitsios, Panos, Rujescu, Dan, Lahti, Jari, Le Hellard, Stephanie, Keller, Matthew C, Andreassen, Ole A, Deary, Ian J, Glahn, David C, Malhotra, Anil K, and Lencz, Todd
Abstract: Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth.
Published: 2017

47. Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets

Author: Lam, Max, Lam, Max, Trampush, Joey W, Yu, Jin, Knowles, Emma, Davies, Gail, Liewald, David C, Starr, John M, Djurovic, Srdjan, Melle, Ingrid, Sundet, Kjetil, Christoforou, Andrea, Reinvang, Ivar, DeRosse, Pamela, Lundervold, Astri J, Steen, Vidar M, Espeseth, Thomas, Räikkönen, Katri, Widen, Elisabeth, Palotie, Aarno, Eriksson, Johan G, Giegling, Ina, Konte, Bettina, Roussos, Panos, Giakoumaki, Stella, Burdick, Katherine E, Payton, Antony, Ollier, William, Chiba-Falek, Ornit, Attix, Deborah K, Need, Anna C, Cirulli, Elizabeth T, Voineskos, Aristotle N, Stefanis, Nikos C, Avramopoulos, Dimitrios, Hatzimanolis, Alex, Arking, Dan E, Smyrnis, Nikolaos, Bilder, Robert M, Freimer, Nelson A, Cannon, Tyrone D, London, Edythe, Poldrack, Russell A, Sabb, Fred W, Congdon, Eliza, Conley, Emily Drabant, Scult, Matthew A, Dickinson, Dwight, Straub, Richard E, Donohoe, Gary, Morris, Derek, Corvin, Aiden, Gill, Michael, Hariri, Ahmad R, Weinberger, Daniel R, Pendleton, Neil, Bitsios, Panos, Rujescu, Dan, Lahti, Jari, Le Hellard, Stephanie, Keller, Matthew C, Andreassen, Ole A, Deary, Ian J, Glahn, David C, Malhotra, Anil K, Lencz, Todd, Lam, Max, Lam, Max, Trampush, Joey W, Yu, Jin, Knowles, Emma, Davies, Gail, Liewald, David C, Starr, John M, Djurovic, Srdjan, Melle, Ingrid, Sundet, Kjetil, Christoforou, Andrea, Reinvang, Ivar, DeRosse, Pamela, Lundervold, Astri J, Steen, Vidar M, Espeseth, Thomas, Räikkönen, Katri, Widen, Elisabeth, Palotie, Aarno, Eriksson, Johan G, Giegling, Ina, Konte, Bettina, Roussos, Panos, Giakoumaki, Stella, Burdick, Katherine E, Payton, Antony, Ollier, William, Chiba-Falek, Ornit, Attix, Deborah K, Need, Anna C, Cirulli, Elizabeth T, Voineskos, Aristotle N, Stefanis, Nikos C, Avramopoulos, Dimitrios, Hatzimanolis, Alex, Arking, Dan E, Smyrnis, Nikolaos, Bilder, Robert M, Freimer, Nelson A, Cannon, Tyrone D, London, Edythe, Poldrack, Russell A, Sabb, Fred W, Congdon, Eliza, Conley, Emily Drabant, Scult, Matthew A, Dickinson, Dwight, Straub, Richard E, Donohoe, Gary, Morris, Derek, Corvin, Aiden, Gill, Michael, Hariri, Ahmad R, Weinberger, Daniel R, Pendleton, Neil, Bitsios, Panos, Rujescu, Dan, Lahti, Jari, Le Hellard, Stephanie, Keller, Matthew C, Andreassen, Ole A, Deary, Ian J, Glahn, David C, Malhotra, Anil K, and Lencz, Todd
Abstract: Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth.
Published: 2017

48. CERES: A new cerebellum lobule segmentation method

Author: Universitat Politècnica de València. Departamento de Física Aplicada - Departament de Física Aplicada, Ministerio de Economía, Industria y Competitividad, Romero Gómez, José Enrique, Coupe, Pierrick, Giraud, Remi, Ta, Vinh-Thong, Fonov, Vladimir, Park, Min Tae M, Chalcravarty, M. Mallar, Voineskos, Aristotle N., Manjón Herrera, José Vicente, Universitat Politècnica de València. Departamento de Física Aplicada - Departament de Física Aplicada, Ministerio de Economía, Industria y Competitividad, Romero Gómez, José Enrique, Coupe, Pierrick, Giraud, Remi, Ta, Vinh-Thong, Fonov, Vladimir, Park, Min Tae M, Chalcravarty, M. Mallar, Voineskos, Aristotle N., and Manjón Herrera, José Vicente
Abstract: [EN] The human cerebellum is involved in language, motor tasks and cognitive processes such as attention or emotional processing. Therefore, an automatic and accurate segmentation method is highly desirable to measure and understand the cerebellum role in normal and pathological brain development. In this work, we propose a patch-based multi-atlas segmentation tool called CERES (CEREbellum Segmentation) that is able to automatically parcellate the cerebellum lobules. The proposed method works with standard resolution magnetic resonance T1-weighted images and uses the Optimized PatchMatch algorithm to speed up the patch matching process. The proposed method was compared with related recent state-of-the-art methods showing competitive results in both accuracy (average DICE of 0.7729) and execution time (around 5 minutes).
Published: 2017

49. CERES: A new cerebellum lobule segmentation method

Author: Universitat Politècnica de València. Departamento de Física Aplicada - Departament de Física Aplicada, Ministerio de Economía, Industria y Competitividad, Romero Gómez, José Enrique, Coupe, Pierrick, Giraud, Remi, Ta, Vinh-Thong, Fonov, Vladimir, Park, Min Tae M, Chalcravarty, M. Mallar, Voineskos, Aristotle N., Manjón Herrera, José Vicente, Universitat Politècnica de València. Departamento de Física Aplicada - Departament de Física Aplicada, Ministerio de Economía, Industria y Competitividad, Romero Gómez, José Enrique, Coupe, Pierrick, Giraud, Remi, Ta, Vinh-Thong, Fonov, Vladimir, Park, Min Tae M, Chalcravarty, M. Mallar, Voineskos, Aristotle N., and Manjón Herrera, José Vicente
Abstract: [EN] The human cerebellum is involved in language, motor tasks and cognitive processes such as attention or emotional processing. Therefore, an automatic and accurate segmentation method is highly desirable to measure and understand the cerebellum role in normal and pathological brain development. In this work, we propose a patch-based multi-atlas segmentation tool called CERES (CEREbellum Segmentation) that is able to automatically parcellate the cerebellum lobules. The proposed method works with standard resolution magnetic resonance T1-weighted images and uses the Optimized PatchMatch algorithm to speed up the patch matching process. The proposed method was compared with related recent state-of-the-art methods showing competitive results in both accuracy (average DICE of 0.7729) and execution time (around 5 minutes).
Published: 2017

50. Manual segmentation of the fornix, fimbria, and alveus on high-resolution 3T MRI: Application via fully-automated mapping of the human memory circuit white and grey matter in healthy and pathological aging

Author: Amaral, Robert, Park, Min, Devenyi, Gabriel, Lynn, Vivian, Pipitone, Jon, Winterburn, Julie, Chavez, Sofia, Schira, Mark M, Lobaugh, Nancy J, Voineskos, Aristotle N, Pruessner, Jens C, Chakravarty, M Mallar, Amaral, Robert, Park, Min, Devenyi, Gabriel, Lynn, Vivian, Pipitone, Jon, Winterburn, Julie, Chavez, Sofia, Schira, Mark M, Lobaugh, Nancy J, Voineskos, Aristotle N, Pruessner, Jens C, and Chakravarty, M Mallar
Abstract: 2016 Elsevier Inc.Recently, much attention has been focused on the definition and structure of the hippocampus and its subfields, while the projections from the hippocampus have been relatively understudied. Here, we derive a reliable protocol for manual segmentation of hippocampal white matter regions (alveus, fimbria, and fornix) using high-resolution magnetic resonance images that are complementary to our previous definitions of the hippocampal subfields, both of which are freely available at . https://github.com/cobralab/atlases. Our segmentation methods demonstrated high inter- and intra-rater reliability, were validated as inputs in automated segmentation, and were used to analyze the trajectory of these regions in both healthy aging (OASIS), and Alzheimer's disease (AD) and mild cognitive impairment (MCI; using ADNI). We observed significant bilateral decreases in the fornix in healthy aging while the alveus and cornu ammonis (CA) 1 were well preserved (all p's<0.006). MCI and AD demonstrated significant decreases in fimbriae and fornices. Many hippocampal subfields exhibited decreased volume in both MCI and AD, yet no significant differences were found between MCI and AD cohorts themselves. Our results suggest a neuroprotective or compensatory role for the alveus and CA1 in healthy aging and suggest that an improved understanding of the volumetric trajectories of these structures is required.
Published: 2016

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