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

Author: Trubetskoy, Vassily, Panagiotaropoulou, Georgia, Awasthi, Swapnil, Braun, Alice, Kraft, Julia, Skarabis, Nora, Walter, Henrik, Ripke, Stephan, Pardiñas, Antonio F., Dennison, Charlotte A., Hall, Lynsey S., Harwood, Janet C., Richards, Alexander L., Legge, Sophie E., Lynham, Amy, Williams, Nigel M., Bray, Nicholas J., Escott-Price, Valentina, Kirov, George, Holmans, Peter A., Pocklington, Andrew J., Owen, Michael J., Walters, James T. R., O’Donovan, Michael C., Qi, Ting, Sidorenko, Julia, Wu, Yang, Zeng, Jian, Gratten, Jacob, Visscher, Peter M., Yang, Jian, Wray, Naomi R., Bigdeli, Tim B., Fanous, Ayman H., Bryois, Julien, Bergen, Sarah E., Kähler, Anna K., Magnusson, Patrik K. E., Hultman, Christina M., Sullivan, Patrick F., Chen, Chia-Yen, Atkinson, Elizabeth G., Goldstein, Jacqueline I., Howrigan, Daniel P., Martin, Alicia R., Daly, Mark J., Huang, Hailiang, Neale, Benjamin M., Ge, Tian, Lam, Max, Belliveau, Richard A., Chambert, Kimberley D., Genovese, Giulio, Lee, Phil H., Pietiläinen, Olli, McCarroll, Steven A., Moran, Jennifer L., Smoller, Jordan W., Brown, Tyler C., Feng, Guoping, Hyman, Steven E., Sheng, Morgan, Chong, Siow Ann, Subramaniam, Mythily, Lencz, Todd, Malhotra, Anil K., Watanabe, Kyoko, Frei, Oleksandr, Agartz, Ingrid, Athanasiu, Lavinia, Melle, Ingrid, Andreassen, Ole A., Steen, Nils Eiel, DeLisi, Lynn E., Mesholam-Gately, Raquelle I., Seidman, Larry J., Koopmans, Frank, Magnusson, Sigurdur, Stefánsson, Hreinn, Stefansson, Kari, Grove, Jakob, Agerbo, Esben, Als, Thomas D., Bybjerg-Grauholm, Jonas, Demontis, Ditte, Hougaard, David M., Mors, Ole, Mortensen, Preben B., Nordentoft, Merete, Børglum, Anders D., Mattheisen, Manuel, Kim, Minsoo, Gandal, Michael J., Li, Zhiqiang, Shi, Yongyong, Zhou, Wei, Qin, Shengying, Voloudakis, Georgios, Zhang, Wen, Roussos, Panos, Adams, Mark, McIntosh, Andrew, Söderman, Erik, Jönsson, Erik G., McGrath, John J., Al Eissa, Mariam, Bass, Nicholas J., Fiorentino, Alessia, O’Brien, Niamh Louise, Pimm, Jonathan, Sharp, Sally Isabel, McQuillin, Andrew, Albus, Margot, Alexander, Madeline, Alizadeh, Behrooz Z., Bruggeman, Richard, Alptekin, Köksal, Amin, Farooq, Arolt, Volker, Lencer, Rebecca, Rothermundt, Matthias, Baune, Bernhard T., Arrojo, Manuel, Azevedo, Maria Helena, Bacanu, Silviu A., Webb, Bradley T., Wormley, Brandon K., Riley, Brien P., Kendler, Kenneth S., Begemann, Martin, Mitjans, Marina, Steixner-Kumar, Agnes A., Ehrenreich, Hannelore, Bene, Judit, Benyamin, Beben, Blasi, Giuseppe, Rampino, Antonio, Torretta, Silvia, Bertolino, Alessandro, Bobes, Julio, Bonassi, Stefano, Bressan, Rodrigo Affonseca, Gadelha, Ary, Noto, Cristiano, Ota, Vanessa Kiyomi, Santoro, Marcos Leite, Belangero, Sintia Iole, Bromet, Evelyn J., Buckley, Peter F., Buckner, Randy L., Cahn, Wiepke, Kahn, René S., Cairns, Murray J., Scott, Rodney J., Tooney, Paul A., Schall, Ulrich, Calkins, Monica E., Gur, Raquel E., Gur, Ruben C., Turetsky, Bruce I., Carr, Vaughan J., Castle, David, Harvey, Carol, Catts, Stanley V., Chan, Raymond C. K., Chaumette, Boris, Kebir, Oussama, Krebs, Marie-Odile, Cheng, Wei, Cheung, Eric F. C., Cohen, David, Consoli, Angèle, Giannitelli, Marianna, Laurent-Levinson, Claudine, Cordeiro, Quirino, Costas, Javier, Curtis, Charles, Quattrone, Diego, Breen, Gerome, Collier, David A., Di Forti, Marta, Vassos, Evangelos, Mondelli, Valeria, van Amelsvoort, Therese, Murray, Robin M., Davidson, Michael, Davis, Kenneth L., Haroutunian, Vahram, Malaspina, Dolores, Reichenberg, Abraham, Siever, Larry J., Silverman, Jeremy M., Buxbaum, Joseph D., de Haan, Lieuwe, Degenhardt, Franziska, Forstner, Andreas, Nöthen, Markus M., Dickerson, Faith, Dikeos, Dimitris, Papadimitriou, George N., Dinan, Timothy, Djurovic, Srdjan, Duan, Jubao, Gejman, Pablo V., Sanders, Alan R., Ducci, Giuseppe, Dudbridge, Frank, Eriksson, Johan G., Fañanás, Lourdes, Peñas, Javier González, González-Pinto, Ana, Molto, María Dolores, Moreno, Carmen, Parellada, Mara, Sanjuan, Julio, Crepo-Facorro, Benedicto, Mata, Ignacio, Arango, Celso, Faraone, Stephen V., Frank, Josef, Streit, Fabian, Witt, Stephanie H., Rietschel, Marcella, Freimer, Nelson B., Ophoff, Roel A., Fromer, Menachem, Stahl, Eli A., Frustaci, Alessandra, Gershon, Elliot S., Giegling, Ina, Hartmann, Annette M., Konte, Bettina, Rujescu, Dan, Giusti-Rodríguez, Paola, Szatkiewicz, Jin P., Godard, Stephanie, González Peñas, Javier, Gopal, Srihari, Savitz, Adam, Li, Qingqin S., Green, Michael F., Nuechterlein, Keith H., Sugar, Catherine A., Greenwood, Tiffany A., Light, Gregory A., Swerdlow, Neal R., Braff, David, Guillin, Olivier, Campion, Dominique, Gülöksüz, Sinan, Luykx, Jurjen J., Rutten, Bart P. F., van Winkel, Ruud, Gutiérrez, Blanca, Hahn, Eric, Hakonarson, Hakon, Pellegrino, Renata, Pantelis, Christos, Hayward, Caroline, Henskens, Frans A., Kelly, Brian J., Herms, Stefan, Hoffmann, Per, Ikeda, Masashi, Iwata, Nakao, Iyegbe, Conrad, van Os, Jim, Joa, Inge, Julià, Antonio, Marsal, Sara, Kam-Thong, Tony, Rautanen, Anna, Kamatani, Yoichiro, Karachanak-Yankova, Sena, Toncheva, Draga, Keller, Matthew C., Khrunin, Andrey, Limborska, Svetlana, Slominsky, Petr, Kim, Sung-Wan, Klovins, Janis, Nikitina-Zake, Liene, Kondratiev, Nikolay, Golimbet, Vera, Kubo, Michiaki, Kučinskas, Vaidutis, Kučinskiene, Zita Ausrele, Kusumawardhani, Agung, Kuzelova-Ptackova, Hana, Landi, Stefano, Lazzeroni, Laura C., Levinson, Douglas F., Petryshen, Tracey L., Lehrer, Douglas S., Lerer, Bernard, Li, Miaoxin, Lieberman, Jeffrey, Stroup, T. Scott, Liu, Chih-Min, Hwu, Hai-Gwo, Lönnqvist, Jouko, Loughland, Carmel M., Lubinski, Jan, Bakker, Steven, Kahn, René, Macek, Milan, Mackinnon, Andrew, Maher, Brion S., Maier, Wolfgang, Atbaşoğlu, Eşref Cem, Mallet, Jacques, Marder, Stephen R., Martorell, Lourdes, Muntané, Gerard, Vilella, Elisabet, Meier, Sandra, Schulze, Thomas G., McCarley, Robert W., McDonald, Colm, Donohoe, Gary, Morris, Derek W., Periyasamy, Sathish, Mowry, Bryan J., Medeiros, Helena, Sobell, Janet L., Melegh, Bela, Metspalu, Andres, Milani, Lili, Esko, Tõnu, Michie, Patricia T., Milanova, Vihra, Molden, Espen, Molina, Esther, Morley, Christopher P., Murphy, Kieran C., Myin-Germeys, Inez, Nenadić, Igor, Nestadt, Gerald, Pulver, Ann E., O’Neill, F. Anthony, Oh, Sang-Yun, Olincy, Ann, Freedman, Robert, Paunio, Tiina, Perkins, Diana O., Pfuhlmann, Bruno, Benner, Christian, Pirinen, Matti, Palotie, Aarno, Porteous, David, Powell, John, Quested, Digby, Radant, Allen D., Tsuang, Debby W., Rapaport, Mark H., Roe, Cheryl, Liu, Chunyu, Roffman, Joshua L., Roth, Julian, Gawlik, Micha, Saker-Delye, Safaa, Salomaa, Veikko, Suvisaari, Jaana, Shi, Jianxin, Sigurdsson, Engilbert, Sim, Kang, So, Hon-Cheong, Stain, Helen J., Stögmann, Elisabeth, Zimprich, Fritz, Stone, William S., Straub, Richard E., Hyde, Thomas, Jaffe, Andrew, Weinberger, Daniel R., Strengman, Eric, Svrakic, Dragan M., Cloninger, C. Robert, Ta, Thi Minh Tam, Takahashi, Atsushi, Terao, Chikashi, Thibaut, Florence, Tosato, Sarah, Tura, Gian Battista, Üçok, Alp, Vaaler, Arne, Veijola, Juha, Waddington, John, Waterreus, Anna, Morgan, Vera A., Jablensky, Assen V., Weiser, Mark, Wu, Jing Qin, Xu, Zhida, Yolken, Robert, Zai, Clement C., Kennedy, James L., Zhu, Feng, Saka, Meram C., Ayub, Muhammad, Black, Donald W., Buccola, Nancy G., Byerley, William F., Chen, Wei J., Crespo-Facorro, Benedicto, Galletly, Cherrie, Gennarelli, Massimo, Müller-Myhsok, Bertram, Neil, Amanda L., Pato, Michele T., Pato, Carlos N., Wang, Shi-Heng, Xu, Shuhua, Adolfsson, Rolf, Bramon, Elvira, Cervilla, Jorge A., Cichon, Sven, Corvin, Aiden, Gill, Michael, Curtis, David, Domenici, Enrico, Gareeva, Anna, Khusnutdinova, Elza, Glatt, Stephen J., Hong, Kyung Sue, Knowles, James A., Lee, Jimmy, Liu, Jianjun, Malhotra, Dheeraj, Menezes, Paulo R., Nimgaonkar, Vishwajit, Paciga, Sara A., Rivera, Margarita, Schwab, Sibylle G., Serretti, Alessandro, Sham, Pak C., Clair, David St, Tsuang, Ming T., Vawter, Marquis P., Werge, Thomas, Wildenauer, Dieter B., Yu, Xin, Yue, Weihua, Verhage, Matthijs, Sahasrabudhe, Dnyanada, Toonen, Ruud F., Posthuma, Danielle, Dai, Nan, Wenwen, Qin, Wildenauer, D. B., Agiananda, Feranindhya, Amir, Nurmiati, Antoni, Ronald, Arsianti, Tiana, Asmarahadi, Asmarahadi, Diatri, H., Djatmiko, Prianto, Irmansyah, Irmansyah, Khalimah, Siti, Kusumadewi, Irmia, Kusumaningrum, Profitasari, Lukman, Petrin R., Nasrun, Martina W., Safyuni, N. S., Prasetyawan, Prasetyawan, Semen, G., Siste, Kristiana, Tobing, Heriani, Widiasih, Natalia, Wiguna, Tjhin, Wulandari, D., Evalina, None, Hananto, A. J., Ismoyo, Joni H., Marini, T. M., Henuhili, Supiyani, Reza, Muhammad, Yusnadewi, Suzy, Abyzov, Alexej, Akbarian, Schahram, van Bakel, Harm, Breen, Michael, Charney, Alex, Dracheva, Stella, Girdhar, Kiran, Hoffman, Gabriel, Jiang, Yan, Pinto, Dalila, Purcell, Shaun, Roussos, Panagiotis, Wiseman, Jennifer, Ashley-Koch, Allison, Crawford, Gregory, Reddy, Tim, Brown, Miguel, Grennan, Kay, Carlyle, Becky, Emani, Prashant, Galeev, Timur, Gerstein, Mark, Gu, Mengting, Guerra, Brittney, Gursoy, Gamze, Kitchen, Robert, Lee, Donghoon, Li, Mingfeng, Liu, Shuang, Navarro, Fabio, Pan, Xinghua, Pochareddy, Sirisha, Rozowsky, Joel, Sestan, Nenad, Sethi, Anurag, Shi, Xu, Szekely, Anna, Wang, Daifeng, Warrell, Jonathan, Weissman, Sherman, Wu, Feinan, Xu, Xuming, Coetzee, Gerard, Farnham, Peggy, Lay, Fides, Rhie, Suhn, Witt, Heather, Wood, Shannon, Yao, Lijing, Gandal, Mike, Polioudakis, Damon, Swarup, Vivek, Won, Hyejung, Giase, Gina, Jiang, Shan, Kefi, Amira, Shieh, Annie, Goes, Fernando, Zandi, Peter, Kim, Yunjung, Mattei, Eugenio, Purcaro, Michael, Pratt, Henry, Peters, Mette A., Sanders, Stephan, Weng, Zhiping, White, Kevin, Arranz, Maria J., Lewis, Cathryn, Lin, Kuang, Walshe, Muriel, Bender, Stephan, Weisbrod, Matthias, Hall, Jeremy, Lawrie, Stephen, Linszen, Don H., Achsel, Tilmann, Bagni, Claudia, Andres-Alonso, Maria, Kreutz, Michael R., Bayés, Àlex, Biederer, Thomas, Brose, Nils, Chua, John Jia En, Coba, Marcelo P., Cornelisse, L. Niels, van Weering, Jan R. T., de Jong, Arthur P. H., MacGillavry, Harold D., de Juan-Sanz, Jaime, Dieterich, Daniela C., Pielot, Rainer, Smalla, Karl-Heinz, Gundelfinger, Eckart D., Goldschmidt, Hana L., Huganir, Richard L., Hoogenraad, Casper, Imig, Cordelia, Jahn, Reinhard, Jung, Hwajin, Kim, Eunjoon, Kaeser, Pascal S., Lipstein, Noa, Malenka, Robert, McPherson, Peter S., O’Connor, Vincent, Ryan, Timothy A., Sala, Carlo, Verpelli, Chiara, Smit, August B., Südhof, Thomas C., Thomas, Paul D., Medical Research Council (UK), National Natural Science Foundation of China, Royal Society (UK), Chinese Academy of Sciences, Shanghai Science and Technology Committee, Research Council of Norway, European Commission, Fundação de Amparo à Pesquisa do Estado de São Paulo, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Comunidad de Madrid, Fundación Alicia Koplowitz, Fundación Alonso Lozano, Mental Health Research UK, Wellcome Trust, Brain and Behavior Research Foundation, NIHR Biomedical Research Centre (UK), University College London, Generalitat Valenciana, Internal medicine, Human genetics, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Psychiatry, Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, RS: MHeNs - R3 - Neuroscience, MUMC+: MA Psychiatrie (3), MUMC+: MA Med Staf Spec Psychiatrie (9), MUMC+: Hersen en Zenuw Centrum (3), Trubetskoy, Vassily, Pardiñas, Antonio F., Qi, Ting, Panagiotaropoulou, Georgia, Benyamin, Beben, O'Donovan, Michael C, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Adult Psychiatry, APH - Mental Health, ANS - Complex Trait Genetics, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, Molecular and Cellular Neurobiology, Functional Genomics, and Complex Trait Genetics
Subjects: Genetics of the nervous system, Schizophrenia/genetics, VARIANTS, PROFILE, Polymorphism, Single Nucleotide, Genome-wide association studies, Article, DISEASE, SDG 3 - Good Health and Well-being, Humans, Genetic Predisposition to Disease, Alleles, Genomics, Genome-Wide Association Study, Schizophrenia, Polymorphism, RISK, ARCHITECTURE, Science & Technology, Multidisciplinary, MUTATIONS, Genetic Predisposition to Disease/genetics, Settore BIO/13, Single Nucleotide, ASSOCIATION, Polymorphism, Single Nucleotide/genetics, STATISTICS, Multidisciplinary Sciences, INDIVIDUALS, Science & Technology - Other Topics, Diseases of the nervous system, ddc:500, Single Nucleotide/genetics, INTEGRATION
Abstract: Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies., The work at Cardiff University was additionally supported by Medical Research Council Centre grant no. MR/L010305/1 and program grant no. G0800509. S. Xu also gratefully acknowledges the support of the National Natural Science Foundation of China (NSFC) grants (31525014, 91731303, 31771388, 31961130380 and 32041008), the UK Royal Society-Newton Advanced Fellowship (NAF\R1\191094), the Key Research Program of Frontier Sciences (QYZDJ-SSW-SYS009) and the Strategic Priority Research Program (XDB38000000) of the Chinese Academy of Sciences, and the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01). O. A. Andreassen was supported by the Research Council of Norway (283798, 262656, 248980, 273291, 248828, 248778, 223273); KG Jebsen Stiftelsen, South-East Norway Health Authority, EU H2020 no. 847776. B. Melegh was supported in part by the National Scientific Research Program (NKFIH) K 138669. S. V. Faraone is supported by the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 602805, the European Union’s Horizon 2020 research and innovation programme under grant agreements 667302 and 728018 and NIMH grants 5R01MH101519 and U01 MH109536-01. S. I. Belangero was supported by FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo), grant numbers: 2010/08968-6; 2014/07280-1 2011/50740-5 (including R. A. Bressan). The Singapore team (J. Lee, J. Liu, K. Sim, S. A. Chong and M. Subramanian) acknowledges the National Medical Research Council Translational and Clinical Research Flagship Programme (grant no.: NMRC/TCR/003/2008). M. Macek was supported by LM2018132, CZ.02.1.01/0.0/0.0/18_046/0015515 and IP6003 –VZFNM00064203. C. Arango has been funded by the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI19/024), co-financed by ERDF Funds from the European Commission, ‘A way of making Europe’, CIBERSAM, Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds, European Union Seventh Framework Program and European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking (grant agreement no 115916, project PRISM; and grant agreement no. 777394, project AIMS-2-TRIALS), Fundación Familia Alonso and Fundación Alicia Koplowitz. E. Bramon acknowledges support from the National Institute of Health Research UK (grant NIHR200756); Mental Health Research UK John Grace QC Scholarship 2018; an ESRC collaborative award 2020; BMA Margaret Temple Fellowship 2016; Medical Research Council New Investigator Award (G0901310); MRC Centenary Award (G1100583); MRC project grant G1100583; National Institute of Health Research UK post-doctoral fellowship (PDA/02/06/016); NARSAD Young Investigator awards 2005 and 2008; Wellcome Trust Research Training Fellowship; Wellcome Trust Case Control Consortium awards (085475/B/08/Z, 085475/Z/08/Z); European Commission Horizon 2020 (747429); NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and King’s College London; and NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London (UCLH BRC - Mental Health Theme). D. Molto is funded by the European Regional Development Fund (ERDF)–Valencian Community 2014–2020, Spain. E. G. Atkinson was supported by the NIMH K01MH121659.
Published: 2022

2. A polygenic resilience score moderates the genetic risk for schizophrenia

Author: Hess, Jonathan L, Tylee, Daniel S, Mors, Ole, Duan, Jubao, Dudbridge, Frank, Duncanson, Audrey, Durmishi, Naser, Edkins, Sarah, Ehrenreich, Hannelore, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Esko, Tõnu, Nordentoft, Merete, Essioux, Laurent, Fanous, Ayman H, Farh, Kai-How, Farrell, Martilias S, Frank, Josef, Franke, Lude, Freedman, Robert, Freeman, Colin, Freimer, Nelson B, Friedl, Marion, Hougaard, David M, Friedman, Joseph I, Fromer, Menachem, Gejman, Pablo V, Genovese, Giulio, Georgieva, Lyudmila, Giannoulatou, Eleni, Giegling, Ina, Gill, Michael, Gillman, Matthew, Giusti-Rodríguez, Paola, Byberg-Grauholm, Jonas, Godard, Stephanie, Goldstein, Jacqueline I, Golimbet, Vera, Gopal, Srihari, Gratten, Jacob, Gray, Emma, Gurling, Hugh, Gwilliam, Rhian, de Haan, Lieuwe, Hall, Jeremy, Bækvad-Hansen, Marie, Hammer, Christian, Hammond, Naomi, Hamshere, Marian L, Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M, Hellenthal, Garrett, Henskens, Frans A, Herms, Stefan, Greenwood, Tiffany A, Hirschhorn, Joel N, Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V, Huang, Hailiang, Hultman, Christina M, Hunt, Sarah E, Ikeda, Masashi, Iwata, Nakao, Iyegbe, Conrad, Tsuang, Ming T, Jablensky, Assen V, Jankowski, Janusz, Jayakumar, Alagurevathi, Joa, Inge, Jönsson, Erik G, Julià, Antonio, Kähler, Anna K, Kahn, René S, Kalaydjieva, Luba, Karachanak-Yankova, Sena, Curtis, David, Karjalainen, Juha, Kavanagh, David, Keller, Matthew C, Kendler, Kenneth S, Kennedy, James L, Khrunin, Andrey, Kim, Yunjung, Kirov, George, Klovins, Janis, Knight, Jo, Steinberg, Stacy, Knowles, James A, Konte, Bettina, Kucinskas, Vaidutis, Kucinskiene, Zita Ausrele, Kuzelova-Ptackova, Hana, Langford, Cordelia, Laurent, Claudine, Lawrie, Stephen, Lee, S Hong, Lee, Phil, Sigurdsson, Engilbert, Lee, Jimmy, Legge, Sophie E, Lencz, Todd, Lerer, Bernard, Levinson, Douglas F, Lewis, Cathryn M, Li, Tao, Li, Qingqin S, Li, Miaoxin, Liang, Kung-Yee, Mattheisen, Manuel, Stefánsson, Hreinn, Liddle, Jennifer, Lieberman, Jeffrey, Limborska, Svetlana, Lin, Kuang, Linszen, Don H, Liu, Jianjun, Lönnqvist, Jouko, Loughland, Carmel M, Lubinski, Jan, Macek, Milan, Stefánsson, Kári, Magnusson, Patrik K E, Maher, Brion S, Maier, Wolfgang, Malhotra, Anil K, Mallet, Jacques, Markus, Hugh S, Marsal, Sara, Mata, Ignacio, Mathew, Christopher G, Mattingsdal, Morten, Edenberg, Howard J, McCann, Owen T, McCarley, Robert W, McCarroll, Steven A, McCarthy, Mark I, McDonald, Colm, McIntosh, Andrew M, McQuillin, Andrew, Meier, Sandra, Meijer, Carin J, Melegh, Bela, Holmans, Peter, Melle, Ingrid, Mesholam-Gately, Raquelle I, Metspalu, Andres, Michie, Patricia T, Milani, Lili, Milanova, Vihra, Mokrab, Younes, Moran, Jennifer L, Morris, Derek W, Mowry, Bryan J, Faraone, Stephen V, Müller-Myhsok, Bertram, Murphy, Kieran C, Murray, Robin M, Myin-Germeys, Inez, Neale, Benjamin M, Nelis, Mari, Nenadic, Igor, Nertney, Deborah A, Nestadt, Gerald, Nicodemus, Kristin K, Glatt, Stephen J, Nikitina-Zake, Liene, Nisenbaum, Laura, Nordin, Annelie, Nöthen, Markus M, O'Callaghan, Eadbhard, O'Donovan, Michael C, O'Dushlaine, Colm, O'Neill, F Anthony, Oh, Sang-Yun, Olincy, Ann, Adolfsson, Rolf, Olsen, Line, Ophoff, Roel A, Van Os, Jim, Owen, Michael J, Palmer, Colin N A, Palotie, Aarno, Pantelis, Christos, Papadimitriou, George N, Papiol, Sergi, Parkhomenko, Elena, Agartz, Ingrid, Pato, Michele T, Pato, Carlos N, Paunio, Tiina, Pearson, Richard, Cairns, Murray J, DeLisi, Lynn E, Gershon, Elliot S, Kelly, Brian J, Lam, Max, Norgren, Nina, Agerbo, Esben, Paciga, Sara A, Tooney, Paul A, Wu, Jing Qin, Pejovic-Milovancevic, Milica, Perkins, Diana O, Pers, Tune H, Petryshen, Tracey L, Pietiläinen, Olli, Pimm, Jonathan, Pirinen, Matti, Albus, Margot, Plomin, Robert, Pocklington, Andrew J, Posthuma, Danielle, Potter, Simon C, Powell, John, Price, Alkes, Pulver, Ann E, Purcell, Shaun M, Quested, Digby, Rasmussen, Henrik B, Consortium, Schizophrenia Working Group of the Psychiatric Genomics, Alexander, Madeline, Rautanen, Anna, Ravindrarajah, Radhi, Reichenberg, Abraham, Reimers, Mark A, Richards, Alexander L, Ricketts, Michelle, Rietschel, Marcella, Riley, Brien P, Ripke, Stephan, Roffman, Joshua L, Amin, Farooq, Roussos, Panos, Ruderfer, Douglas M, Rujescu, Dan, Salomaa, Veikko, Sanders, Alan R, Sawcer, Stephen J, Schall, Ulrich, Schubert, Christian R, Schulze, Thomas G, Schwab, Sibylle G, Andreassen, Ole A, Scolnick, Edward M, Scott, Rodney J, Seidman, Larry J, Sham, Pak C, Shi, Jianxin, Silagadze, Teimuraz, Silverman, Jeremy M, Sim, Kang, Sklar, Pamela, Arranz, Maria J, Slominsky, Petr, Smoller, Jordan W, So, Hon-Cheong, Söderman, Erik, Spencer, Chris C A, Clair, David St, Stahl, Eli A, Stogmann, Elisabeth, Strange, Amy, Straub, Richard E, Bacanu, Silviu A, Strengman, Eric, Strohmaier, Jana, Stroup, T Scott, Su, Zhan, Subramaniam, Mythily, Sullivan, Patrick F, Suvisaari, Jaana, Svrakic, Dragan M, Szatkiewicz, Jin P, Tashakkori-Ghanbaria, Avazeh, Bakker, Steven, Thirumalai, Srinivas, Toncheva, Draga, Tosato, Sarah, Trembath, Richard C, Veijola, Juha, Visscher, Peter M, Viswanathan, Ananth C, Vukcevic, Damjan, Waddington, John, Waller, Matthew, Band, Gavin, Walsh, Dermot, Walshe, Muriel, Walters, James T R, Wang, Qiang, Wang, Dai, Webb, Bradley T, Weinberger, Daniel R, Weisbrod, Matthias, Weiser, Mark, Wendland, Jens R, Barroso, Ines, Weston, Paul, Whittaker, Pamela, Widaa, Sara, Wiersma, Durk, Wildenauer, Dieter B, Williams, Stephanie, Williams, Nigel M, Witt, Stephanie H, Wolen, Aaron R, Wong, Emily H M, Begemann, Martin, Wood, Nicholas W, Wormley, Brandon K, Wray, Naomi R, Xi, Hualin Simon, Zai, Clement C, Zheng, Xuebin, Zimprich, Fritz, Bellenguez, Céline, Research, Lundbeck Foundation Initiative for Integrative Psychiatric, Belliveau, Richard A, Bender, Stephan, Bene, Judit, Bergen, Sarah E, Bevilacqua, Elizabeth, Bigdeli, Tim B, Black, Donald W, Blackburn, Hannah, Blackwell, Jenefer M, Blackwood, Douglas H R, Børglum, Anders D, Bramon, Elvira, Brown, Matthew A, Bruggeman, Richard, Buccola, Nancy G, Buckner, Randy L, Bulik-Sullivan, Brendan, Bumpstead, Suzannah J, Buxbaum, Joseph D, Byerley, William, Cahn, Wiepke, Als, Thomas D, Cai, Guiqing, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Casas, Juan P, Catts, Stanley V, Chambert, Kimberley D, Chan, Ronald Y L, Chan, Raymond C K, Grove, Jakob, Chen, Eric Y H, Cheng, Wei, Cheung, Eric F C, Chong, Siow Ann, Cichon, Sven, Cloninger, C Robert, Cohen, David, Cohen, Nadine, Collier, David A, Cormican, Paul, Werge, Thomas, Corvin, Aiden, Craddock, Nick, Crespo-Facorro, Benedicto, Crowley, James J, Daly, Mark J, Darvasi, Ariel, Davidson, Michael, Davis, Kenneth L, Degenhardt, Franziska, Del Favero, Jurgen, Mortensen, Preben Bo, Deloukas, Panos, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Domenici, Enrico, Donnelly, Peter, Donohoe, Gary, Drapeau, Elodie, Dronov, Serge, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Adult Psychiatry, ANS - Complex Trait Genetics, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, Hess, Jonathan L, Tylee, Daniel S, Mattheisen, Manuel, Borglum, Anders D, Glatt, Stephen J, Lee, Sand Hong, Schizophrenia Working Group of thePsychiatric Genomics Consortium, Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Amsterdam Neuroscience - Complex Trait Genetics, Complex Trait Genetics, and Myin-Germeys, Inez
Subjects: Multifactorial Inheritance, Schizophrenia/genetics, Genome-wide association study, Disease, Medical and Health Sciences, 0302 clinical medicine, Risk Factors, schizophrenia, genetics, risk, 2.1 Biological and endogenous factors, genetics, polygenic score, Aetiology, genome wide association study, risk, Genetics, Psychiatry, 0303 health sciences, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Genetic Predisposition to Disease/genetics, Single Nucleotide, Genomics, Biological Sciences, Serious Mental Illness, Polymorphism, Single Nucleotide/genetics, Penetrance, 3. Good health, Psychiatry and Mental health, Mental Health, Mendelian disease, Erfðarannsóknir, Life Sciences & Biomedicine, Single Nucleotide/genetics, Biochemistry & Molecular Biology, Schizophrenia (object-oriented programming), high risk, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Geðklofi, Humans, Genetic Predisposition to Disease, ddc:610, Allele, Polymorphism, Resilience (network), Molecular Biology, resilience, Multifactorial Inheritance/genetics, Alleles, 030304 developmental biology, Science & Technology, Prevention, Human Genome, Psychology and Cognitive Sciences, Neurosciences, Brain Disorders, Lundbeck Foundation Initiative for Integrative Psychiatric Research, schizophrenia, Good Health and Well Being, Schizophrenia, Neurosciences & Neurology, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Publisher's version (útgefin grein), Based on the discovery by the Resilience Project (Chen R. et al. Nat Biotechnol 34:531–538, 2016) of rare variants that confer resistance to Mendelian disease, and protective alleles for some complex diseases, we posited the existence of genetic variants that promote resilience to highly heritable polygenic disorders1,0 such as schizophrenia. Resilience has been traditionally viewed as a psychological construct, although our use of the term resilience refers to a different construct that directly relates to the Resilience Project, namely: heritable variation that promotes resistance to disease by reducing the penetrance of risk loci, wherein resilience and risk loci operate orthogonal to one another. In this study, we established a procedure to identify unaffected individuals with relatively high polygenic risk for schizophrenia, and contrasted them with risk-matched schizophrenia cases to generate the first known “polygenic resilience score” that represents the additive contributions to SZ resistance by variants that are distinct from risk loci. The resilience score was derived from data compiled by the Psychiatric Genomics Consortium, and replicated in three independent samples. This work establishes a generalizable framework for finding resilience variants for any complex, heritable disorder., SJG is supported by grants from the U.S. National Institutes of Health (5R01MH101519, 5R01AG054002), the Sidney R. Baer, Jr. Foundation, and NARSAD: The Brain & Behavior Research Foundation. SVF is supported by the K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway, the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement number 602805, the European Union’s Horizon 2020 research and innovation programme under grant agreement number 667302 and NIMH grants 5R01MH101519 and U01 MH109536-01. HJE is supported by grants from the U.S. National Institutes of Health (U10 AA008401; U01 MH109532). Statistical analyses were conducted on the Genetic Cluster Computer, which is financially supported by the Netherlands Scientific Organization (NOW; 480-05-003) along with a supplement from the Dutch Brain Foundation and VU University. The Danish iPSYCH (The Lundbeck Foundation Initiative for Integrative Psychiatric Research) and GEMS2 teams acknowledge funding from The Lundbeck Foundation (grant no R102-A9118 and R155-2014-1724), the Stanley Medical Research Institute, an Advanced Grant from the European Research Council (project no: 294838), the Danish Strategic Research Council and grants from Aarhus University to the iSEQ and CIRRAU centers. The Danish National Biobank resource at Statens Serum Institut was supported by the Novo Nordisk Foundation. Computational resources for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility were provided by the iSEQ center, Aarhus University, Denmark (grant to ADB).
Published: 2021

3. Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia

Author: Vacic, Vladimir, McCarthy, Shane, Malhotra, Dheeraj, Murray, Fiona, Chou, Hsun-Hua, Peoples, Aine, Makarov, Vladimir, Yoon, Seungtai, Bhandari, Abhishek, Corominas, Roser, Iakoucheva, Lilia M., Krastoshevsky, Olga, Krause, Verena, Larach-Walters, Veronica, Welsh, David K., Craig, David, Kelsoe, John R., Gershon, Elliot S., Leal, Suzanne M., Aquila, Marie Dell, Morris, Derek W., Gill, Michael, Corvin, Aiden, Insel, Paul A., McClellan, Jon, King, Mary-Claire, Karayiorgou, Maria, Levy, Deborah L., DeLisi, Lynn E., and Sebat, Jonathan
Subjects: Schizophrenia -- Genetic aspects -- Drug therapy -- Research, Vasoactive intestinal peptides -- Physiological aspects -- Genetic aspects -- Research, Antipsychotic drugs -- Usage -- Health aspects, Neuropeptides -- Physiological aspects -- Genetic aspects -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: Rare copy number variants (CNVs) have a prominent role in the aetiology of schizophrenia and other neuropsychiatric disorders (1). Substantial risk for schizophrenia is conferred by large (>500-kilobase) CNVs at several loci, including microdeletions at 1q21.1 (ref. 2), 3q29 (ref. 3), 15q13.3 (ref. 2) and22q11.2 (ref. 4) and microduplication at 16p11.2 (ref. 5). However, these CNVs collectively account for a small fraction (2-4%) of cases, and the relevant genes and neurobiological mechanisms are not well understood. Here we performed a large two-stage genome-wide scan of rare CNVs and report the significant association of copy number gains at chromosome 7q36.3 with schizophrenia. Microduplications with variable breakpoints occurred within a 362-kilobase region and were detected in 29 of 8,290 (0.35%) patients versus 2 of 7,431 (0.03%) controls in the combined sample. All duplications overlapped or were located within 89 kilobases upstream of the vasoactive intestinal peptide receptor gene vipr2. vipr2 transcription and cyclic-AMP signalling were significantly increased in cultured lymphocytes from patients with microduplications of 7q36.3. These findings implicate altered vasoactive intestinal peptide signalling in the pathogenesis of schizophrenia and indicate the VPAC2 receptor as a potential target for the development of new antipsychotic drugs., A majority of the rare CNVs that have been implicated in schizophrenia involve large (>500 kb) genomic regions where local segmental duplication architecture promotes frequent and nearly identical re-arrangements by [...]
Published: 2011
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4. Biological insights from 108 schizophrenia-associated genetic loci

Author: Ripke, Stephan, Neale, Benjamin M., Corvin, Aiden, Walters, James T. R., Farh, Kai-How, Holmans, Peter A., Lee, Phil, Bulik-Sullivan, Brendan, Collier, David A., Huang, Hailiang, Pers, Tune H., Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A., Begemann, Martin, Belliveau Jr, Richard A., Bene, Judit, Bergen, Sarah E., Bevilacqua, Elizabeth, Bigdeli, Tim B., Black, Donald W., Bruggeman, Richard, Buccola, Nancy G., Buckner, Randy L., Byerley, William, Cahn, Wiepke, Cai, Guiqing, Campion, Dominique, Cantor, Rita M., Carr, Vaughan J., Carrera, Noa, Catts, Stanley V., Chambert, Kimberly D., Chan, Raymond C. K., Chen, Ronald Y. L., Chen, Eric Y. H., Cheng, Wei, Cheung, Eric F. C., Ann Chong, Siow, Robert Cloninger, C., Cohen, David, Cohen, Nadine, Cormican, Paul, Craddock, Nick, Crowley, James J., Curtis, David, Davidson, Michael, Davis, Kenneth L., Degenhardt, Franziska, Del Favero, Jurgen, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Durmishi, Naser, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H., Farrell, Martilias S., Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B., Friedl, Marion, Friedman, Joseph I., Fromer, Menachem, Genovese, Giulio, Georgieva, Lyudmila, Giegling, Ina, Giusti-Rodriguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I., Golimbet, Vera, Gopal, Srihari, Gratten, Jacob, de Haan, Lieuwe, Hammer, Christian, Hamshere, Marian L., Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M., Henskens, Frans A., Herms, Stefan, Hirschhorn, Joel N., Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V., Hougaard, David M., Ikeda, Masashi, Joa, Inge, Julia, Antonio, Kahn, Rene S., Kalaydjieva, Luba, Karachanak-Yankova, Sena, Karjalainen, Juha, Kavanagh, David, Keller, Matthew C., Kennedy, James L., Khrunin, Andrey, Kim, Yunjung, Klovins, Janis, Knowles, James A., Konte, Bettina, Kucinskas, Vaidutis, Ausrele Kucinskiene, Zita, Kuzelova-Ptackova, Hana, Kahler, Anna K., Laurent, Claudine, Lee Chee Keong, Jimmy, Hong Lee, S., Legge, Sophie E., Lerer, Bernard, Li, Miaoxin, Liang, Kung-Yee, Lieberman, Jeffrey, Limborska, Svetlana, Loughland, Carmel M., Lubinski, Jan, Lonnqvist, Jouko, Macek Jr, Milan, Magnusson, Patrik K. E., Maher, Brion S., Maier, Wolfgang, Mallet, Jacques, Marsal, Sara, Mattheisen, Manuel, Mattingsdal, Morten, McCarley, Robert W., McDonald, Colm, McIntosh, Andrew M., Meier, Sandra, Meijer, Carin J., Melegh, Bela, Melle, Ingrid, Mesholam-Gately, Raquelle I., Metspalu, Andres, Michie, Patricia T., Milani, Lili, Milanova, Vihra, Mokrab, Younes, Morris, Derek W., Mors, Ole, Murphy, Kieran C., Murray, Robin M., Myin-Germeys, Inez, Muller-Myhsok, Bertram, Nelis, Mari, Nenadic, Igor, Nertney, Deborah A., Nestadt, Gerald, Nicodemus, Kristin K., Nikitina-Zake, Liene, Nisenbaum, Laura, Nordin, Annelie, Oh, Sang-Yun, Olincy, Ann, Olsen, Line, Van Os, Jim, Endophenotypes International Consortium, Psychosis, Pantelis, Christos, Papadimitriou, George N., Papiol, Sergi, Parkhomenko, Elena, Pato, Michele T., Paunio, Tiina, Pejovic-Milovancevic, Milica, Perkins, Diana O., Pietilainen, Olli, Pimm, Jonathan, Pocklington, Andrew J., Powell, John, Price, Alkes, Pulver, Ann E., Purcell, Shaun M., Quested, Digby, Rasmussen, Henrik B., Reichenberg, Abraham, Reimers, Mark A., Richards, Alexander L., Roffman, Joshua L., Roussos, Panos, Ruderfer, Douglas M., Salomaa, Veikko, Sanders, Alan R., Schall, Ulrich, Schubert, Christian R., Schulze, Thomas G., Schwab, Sibylle G., Scolnick, Edward M., Scott, Rodney J., Seidman, Larry J., Shi, Jianxin, Sigurdsson, Engilbert, Silagadze, Teimuraz, Silverman, Jeremy M., Sim, Kang, Slominsky, Petr, Smoller, Jordan W., So, Hon-Cheong, Spencer, ChrisC. A., Stahl, Eli A., Stefansson, Hreinn, Steinberg, Stacy, Stogmann, Elisabeth, Straub, Richard E., Strengman, Eric, Strohmaier, Jana, Scott Stroup, T., Subramaniam, Mythily, Suvisaari, Jaana, Svrakic, Dragan M., Szatkiewicz, Jin P., Soderman, Erik, Thirumalai, Srinivas, Toncheva, Draga, Tosato, Sarah, Veijola, Juha, Waddington, John, Walsh, Dermot, Wang, Dai, Wang, Qiang, Webb, Bradley T., Weiser, Mark, Wildenauer, Dieter B., Williams, Nigel M., Williams, Stephanie, Witt, Stephanie H., Wolen, Aaron R., Wong, Emily H. M., Wormley, Brandon K., Simon Xi, Hualin, Zai, Clement C., Zheng, Xuebin, Zimprich, Fritz, Wray, Naomi R., Stefansson, Kari, Visscher, Peter M., Trust Case-Control Consortium, Wellcome, Adolfsson, Rolf, Andreassen, Ole A., Blackwood, Douglas H. R., Bramon, Elvira, Buxbaum, Joseph D., Borglum, Anders D., Cichon, Sven, Darvasi, Ariel, Domenici, Enrico, Ehrenreich, Hannelore, Esko, Tonu, Gejman, Pablo V., Gill, Michael, Gurling, Hugh, Hultman, Christina M., Iwata, Nakao, Jablensky, Assen V., Jonsson, Erik G., Kendler, Kenneth S., Kirov, George, Knight, Jo, Lencz, Todd, Levinson, Douglas F., Li, Qingqin S., Liu, Jianjun, Malhotra, Anil K., McCarroll, Steven A., McQuillin, Andrew, Moran, Jennifer L., Mortensen, Preben B., Mowry, Bryan J., Nothen, Markus M., Ophoff, Roel A., Owen, Michael J., Palotie, Aarno, Pato, Carlos N., Petryshen, Tracey L., Posthuma, Danielle, Rietschel, Marcella, Riley, Brien P., Rujescu, Dan, Sham, Pak C., Sklar, Pamela, St Clair, David, Weinberger, Daniel R., Wendland, Jens R., Werge, Thomas, Daly, Mark J., and Sullivan, Patrick F.
Subjects: Genetic research -- Analysis, Schizophrenia -- Research -- Health aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia., Author(s): Schizophrenia Working Group of the Psychiatric Genomics Consortium; Stephan Ripke [1, 2]; Benjamin M. Neale [1, 2, 3, 4]; Aiden Corvin [5]; James T. R. Walters [6]; Kai-How Farh [...]
Published: 2014
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5. MiR-137-derived polygenic risk: effects on cognitive performance in patients with schizophrenia and controls

Author: Cosgrove, D, Harold, D, Mothersill, O, Anney, Richard, Hill, Martin, Bray, Nicholas, Blokland, G, Petryshen, T, Donnelly, Peter, Bates, Lesley, Barroso, Ines, Blackwell, Jenefer M, Bramon, Elvira, Brown, Matthew A, Casas, Juan P, Corvin, Aiden, Deloukas, Panos, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S, Mathew, Christopher G, Palmer, Colin N A, Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J, Trembath, Richard C, Viswanathan, Ananth C, Wood, Nicholas W, Spencer, Chris C A, Band, Gavin, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Giannoulatou, Eleni, Hopkins, Lucinda, Pirinen, Matti, Pearson, Richard, Strange, Amy, Su, Zhan, Vukcevic, Damjan, Langford, Cordelia, Hunt, Sarah E, Edkins, Sarah, Gwilliam, Rhian, Blackburn, Hannah, Bumpstead, Suzannah J, Dronov, Serge, Gillman, Matthew, Gray, Emma, Hammond, Naomi, Jayakumar, Alagurevathi, McCann, Owen T, Liddle, Jennifer, Potter, Simon C, Ravindrarajah, Radhi, Ricketts, Michelle, Waller, Matthew, Weston, PaulWeston, Widaa, SaraWidaa, Whittaker, Pamela, Richards, Alexander, Mantripragada, Kiran, Owen, Michael, O'Donovan, Michael, Gill, M, Corvin, A, Morris, D W, Donohoe, G, Broad Institute of MIT and Harvard, and Petryshen, Tracey
Subjects: 0301 basic medicine, Adult, Male, Multifactorial Inheritance, Memory, Episodic, BF, Bioinformatics, Spatial memory, Polymorphism, Single Nucleotide, 03 medical and health sciences, Cellular and Molecular Neuroscience, Young Adult, 0302 clinical medicine, Cognition, Memory, Task Performance and Analysis, medicine, Humans, Effects of sleep deprivation on cognitive performance, Episodic memory, Biological Psychiatry, Intelligence quotient, Working memory, Memoria, Functional Neuroimaging, Brain, Middle Aged, medicine.disease, R1, Magnetic Resonance Imaging, Psychiatry and Mental health, MicroRNAs, 030104 developmental biology, Memory, Short-Term, Schizophrenia, Case-Control Studies, Original Article, Female, Schizophrenic Psychology, Psychology, Facial Recognition, 030217 neurology & neurosurgery, Clinical psychology
Abstract: Variants at microRNA-137 (MIR137), one of the most strongly associated schizophrenia risk loci identified to date, have been associated with poorer cognitive performance. As microRNA-137 is known to regulate the expression of ~1900 other genes, including several that are independently associated with schizophrenia, we tested whether this gene set was also associated with variation in cognitive performance. Our analysis was based on an empirically derived list of genes whose expression was altered by manipulation of MIR137 expression. This list was cross-referenced with genome-wide schizophrenia association data to construct individual polygenic scores. We then tested, in a sample of 808 patients and 192 controls, whether these risk scores were associated with altered performance on cognitive functions known to be affected in schizophrenia. A subgroup of healthy participants also underwent functional imaging during memory (n=108) and face processing tasks (n=83). Increased polygenic risk within the empirically derived miR-137 regulated gene score was associated with significantly lower performance on intelligence quotient, working memory and episodic memory. These effects were observed most clearly at a polygenic threshold of P=0.05, although significant results were observed at all three thresholds analyzed. This association was found independently for the gene set as a whole, excluding the schizophrenia-associated MIR137 SNP itself. Analysis of the spatial working memory fMRI task further suggested that increased risk score (thresholded at P=10−5) was significantly associated with increased activation of the right inferior occipital gyrus. In conclusion, these data are consistent with emerging evidence that MIR137 associated risk for schizophrenia may relate to its broader downstream genetic effects.
Published: 2016

6. Identification of common variants associated with human hippocampal and intracranial volumes

Author: Stein, Jason L, Medland, Sarah E, Bernard, Manon, Nauck, Matthias, Nöthen, Markus M., Olvera, Rene L, Pandolfo, Massimo, Pike, G Bruce, Puls, Ralf, Reinvang, Ivar, Rentería, Miguel E, Rietschel, Marcella, Roffman, Joshua L, Brown, Andrew A, Royle, Natalie A, Rujescu, Dan, Savitz, Jonathan, Schnack, Hugo G, Schnell, Knut, Seiferth, Nina, Smith, Colin, Steen, Vidar M, Valdés Hernández, Maria C, Van den Heuvel, Martijn, Cannon, Dara M, van der Wee, Nic J, Van Haren, Neeltje E M, Veltman, Joris A, Völzke, Henry, Walker, Robert, Westlye, Lars T, Whelan, Christopher D, Agartz, Ingrid, Boomsma, Dorret I, Cavalleri, Gianpiero L, Chakravarty, M Mallar, Dale, Anders M, Djurovic, Srdjan, Drevets, Wayne C, Hagoort, Peter, Hall, Jeremy, Heinz, Andreas, Jack, Clifford R, Foroud, Tatiana M, Le Hellard, Stephanie, Macciardi, Fabio, Christoforou, Andrea, Montgomery, Grant W, Poline, Jean Baptiste, Porteous, David J, Sisodiya, Sanjay M, Starr, John M, Sussmann, Jessika, Toga, Arthur W, Veltman, Dick J, Walter, Henrik, Weiner, Michael W, Domin, Martin, Initiative, Alzheimer's Disease Neuroimaging, Consortium, EPIGEN, Consortium, IMAGEN, Group, Saguenay Youth Study, Bis, Joshua C, Ikram, M Arfan, Smith, Albert V, Gudnason, Vilmundur, Tzourio, Christophe, Vernooij, Meike W, Grimm, Oliver, Launer, Lenore J, DeCarli, Charles, Seshadri, Sudha, Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology, Andreassen, Ole A, Apostolova, Liana G, Bastin, Mark E, Blangero, John, Brunner, Han G, Buckner, Randy L, Hollinshead, Marisa, Cichon, Sven, Coppola, Giovanni, de Zubicaray, Greig I, Deary, Ian J, Donohoe, Gary, de Geus, Eco J C, Espeseth, Thomas, Fernández, Guillén, Glahn, David C, Grabe, Hans J, Holmes, Avram J, Hardy, John, Hulshoff Pol, Hilleke E, Jenkinson, Mark, Kahn, René S, McDonald, Colm, McIntosh, Andrew M, McMahon, Francis J, McMahon, Katie L, Meyer-Lindenberg, Andreas, Morris, Derek W, Homuth, Georg, Müller-Myhsok, Bertram, Nichols, Thomas E, Ophoff, Roel A, Paus, Tomas, Pausova, Zdenka, Penninx, Brenda W, Potkin, Steven G, Sämann, Philipp G, Saykin, Andrew J, Schumann, Gunter, Vasquez, Alejandro Arias, Hottenga, Jouke-Jan, Smoller, Jordan W, Wardlaw, Joanna M, Weale, Michael E, Martin, Nicholas G, Franke, Barbara, Wright, Margaret J, Thompson, Paul M, Consortium, Enhancing Neuro Imaging Genetics through Meta-Analysis, Weiner, Michael, Aisen, Paul, Langan, Camilla, Petersen, Ronald, Jagust, William, Trojanowki, John Q, Beckett, Laurel, Green, Robert C, Morris, John, Liu, Enchi, Lopez, Lorna M, Montine, Tom, Gamst, Anthony, Thomas, Ronald G, Donohue, Michael, Walter, Sarah, Gessert, Devon, Sather, Tamie, Hansell, Narelle K, Harvey, Danielle, Kornak, John, Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Hwang, Kristy S, Thompson, Paul, Schuff, Norbert, Alexander, Gene, Bandy, Dan, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Kim, Sungeun, Cairns, Nigel J, Taylor-Reinwald, Lisa, Trojanowki, J. Q., Shaw, Les, Lee, Virginia M Y, Korecka, Magdalena, Crawford, Karen, Neu, Scott, Laje, Gonzalo, Potkin, Steven, Shen, Li, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J, Molchan, Susan, Kaye, Jeffrey, Quinn, Joseph, Lee, Phil H, Lind, Betty, Dolen, Sara, Schneider, Lon S, Pawluczyk, Sonia, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Heidebrink, Judith L, Lord, Joanne L, Liu, Xinmin, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Morris, John C, Ances, Beau, Carroll, Maria, Loth, Eva, Leon, Sue, Mintun, Mark A, Schneider, Stacy, Marson, Daniel, Griffith, Randall, Clark, David, Grossman, Hillel, Mitsis, Effie, Romirowsky, Aliza, deToledo-Morrell, Leyla, Hibar, Derrek P, Lourdusamy, Anbarasu, Shah, Raj C, Duara, Ranjan, Varon, Daniel, Roberts, Peggy, Albert, Marilyn, Onyike, Chiadi, Kielb, Stephanie, Rusinek, Henry, de Leon, Mony J, Glodzik, Lidia, Mattingsdal, Morten, De Santi, Susan, Doraiswamy, P Murali, Petrella, Jeffrey R, Coleman, R Edward, Arnold, Steven E, Karlawish, Jason H, Wolk, David, Smith, Charles D, Jicha, Greg, Hardy, Peter, Mohnke, Sebastian, Lopez, Oscar L, Oakley, MaryAnn, Simpson, Donna M, Porsteinsson, Anton P, Goldstein, Bonnie S, Martin, Kim, Makino, Kelly M, Ismail, M Saleem, Mulnard, Ruth A, Thai, Gaby, Maniega, Susana Muñoz, Mc-Adams-Ortiz, Catherine, Womack, Kyle, Mathews, Dana, Quiceno, Mary, Diaz-Arrastia, Ramon, King, Richard, Weiner, Myron, Martin-Cook, Kristen, DeVous, Michael, Levey, Allan I, Nho, Kwangsik, Lah, James J, Cellar, Janet S, Burns, Jeffrey M, Anderson, Heather S, Swerdlow, Russell H, Apostolova, Liana, Lu, Po H, Bartzokis, George, Silverman, Daniel H S, Graff-Radford, Neill R, Nugent, Allison C, Parfitt, Francine, Johnson, Heather, Farlow, Martin R, Hake, Ann Marie, Matthews, Brandy R, Herring, Scott, van Dyck, Christopher H, Carson, Richard E, MacAvoy, Martha G, Chertkow, Howard, O'Brien, Carol, Bergman, Howard, Hosei, Chris, Black, Sandra, Stefanovic, Bojana, Caldwell, Curtis, Hsiung, Ging-Yuek Robin, Feldman, Howard, Mudge, Benita, Assaly, Michele, Kertesz, Andrew, Papmeyer, Martina, Rogers, John, Trost, Dick, Bernick, Charles, Munic, Donna, Kerwin, Diana, Mesulam, Marek-Marsel, Lipowski, Kristina, Wu, Chuang-Kuo, Johnson, Nancy, Sadowsky, Carl, Pütz, Benno, Martinez, Walter, Villena, Teresa, Turner, Raymond Scott, Johnson, Kathleen, Reynolds, Brigid, Sperling, Reisa A, Johnson, Keith A, Marshall, Gad, Frey, Meghan, Yesavage, Jerome, Ramasamy, Adaikalavan, Taylor, Joy L, Lane, Barton, Rosen, Allyson, Tinklenberg, Jared, Sabbagh, Marwan, Belden, Christine, Jacobson, Sandra, Kowall, Neil, Killiany, Ronald, Budson, Andrew E, Senstad, Rudy E, Rasmussen, Jerod, Norbash, Alexander, Johnson, Patricia Lynn, Obisesan, Thomas O, Wolday, Saba, Bwayo, Salome K, Lerner, Alan, Hudson, Leon, Ogrocki, Paula, Fletcher, Evan, Carmichael, Owen, Rijpkema, Mark, Olichney, John, Kittur, Smita, Borrie, Michael, Lee, T-Y, Bartha, Rob, Johnson, Sterling, Asthana, Sanjay, Carlsson, Cynthia M, Risacher, Shannon L, Preda, Adrian, Nguyen, Dana, Tariot, Pierre, Fleisher, Adam, Reeder, Stephanie, Bates, Vernice, Capote, Horacio, Rainka, Michelle, Scharre, Douglas W, Kataki, Maria, Roddey, J Cooper, Zimmerman, Earl A, Celmins, Dzintra, Brown, Alice D, Pearlson, Godfrey D, Blank, Karen, Anderson, Karen, Santulli, Robert B, Schwartz, Eben S, Sink, Kaycee M, Rose, Emma J, Williamson, Jeff D, Garg, Pradeep, Watkins, Franklin, Ott, Brian R, Querfurth, Henry, Tremont, Geoffrey, Salloway, Stephen, Malloy, Paul, Correia, Stephen, Rosen, Howard J, Ryten, Mina, Miller, Bruce L, Mintzer, Jacobo, Longmire, Crystal Flynn, Spicer, Kenneth, Finger, Elizabeth, Rachinsky, Irina, Drost, Dick, Cavalleri, Gianpiero, Alhusaini, Saud, Delanty, Norman, Whelan, Christopher, Sisodiya, Sanjay, Kasperaviciute, Dalia, Matarin, Mar, Depondt, Chantal, Goldstein, David B, Heinzen, Erin L, Shianna, Kevin, Sprooten, Emma, Radtke, Rodney, Ottmann, Ruth, Sergievsky, G. H., Schumann, G., Conrod, P., Reed, L., Barker, G., Williams, S., Loth, E., Struve, M., Strengman, Eric, Lourdusamy, A., Cattrell, A., Nymberg, C., Topper, L., Smith, L., Havatzias, S., Stueber, K., Mallik, C., Stacey, D., Wong, C Peng, Teumer, Alexander, Werts, H., Andrew, C., Desrivieres, S., Heinz, A., Gallinat, J., Häke, I., Ivanov, N., Klär, A., Reuter, J., Winkler, Anderson M, Trabzuni, Daniah, Palafox, C., Hohmann, C., Schilling, C., Lüdemann, K., Romanowski, A., Ströhle, A., Wolff, E., Rapp, M., Ittermann, B., Brühl, R., Turner, Jessica, Ihlenfeld, A., Walaszek, B., Schubert, F., Garavan, H., Connolly, C., Jones, J., Lalor, E., McCabe, E., Ní Shiothcháin, A., Whelan, R., van Eijk, Kristel, Spanagel, R., Leonardi-Essmann, F., Sommer, W., Flor, H., Vollstaedt-Klein, S., Nees, F., Banaschewski, T., Poustka, L., Steiner, S., Mann, K., van Erp, Theo G M, Buehler, M., Rietschel, M., Stolzenburg, E., Schmal, C., Schirmbeck, F., Paus, T., Gowland, P., Heym, N., Lawrence, C., Newman, C., van Tol, Marie-Jose, Pausova, Z., Smolka, M., Huebner, T., Ripke, S., Mennigen, E., Muller, K., Ziesch, V., Büchel, C., Bromberg, U., Fadai, T., Wittfeld, Katharina, Lueken, L., Yacubian, J., Finsterbusch, J., Martinot, J. L., Artiges, E., Bordas, N., de Bournonville, S., Bricaud, Z., Gollier Briand, F., Lemaitre, H., Wolf, Christiane, Massicotte, J., Miranda, R., Paillère Martinot, M. L., Penttilä, J., Poline, J. B., Barbot, A., Schwartz, Y., Lalanne, C., Frouin, V., Thyreau, B., Woudstra, Saskia, Dalley, J., Mar, A., Robbins, T., Subramaniam, N., Theobald, D., Richmond, N., de Rover, M., Molander, A., Jordan, E., Robinson, E., Aleman, Andre, Hipolata, L., Moreno, M., Arroyo, M., Stephens, D., Ripley, T., Crombag, H., Pena, Y., Lathrop, M., Zelenika, D., Heath, S., Lanzerath, D., Heinrichs, B., Spranger, T., Fuchs, B., Speiser, C., Resch, F., Haffner, J., Parzer, P., Brunner, R., Klaassen, A., Toro, Roberto, Almasy, Laura, Klaassen, I., Constant, P., Mignon, X., Thomsen, T., Zysset, S., Vestboe, A., Ireland, J., Rogers, J., Binder, Elisabeth B, Chakravarty, Mallar, Smith, Albert Vernon, van der Lijn, Fedde, Crivello, Fabrice, Fornage, Myriam, Shulman, Joshua M, Brohawn, David G, Schmidt, Helena, Srikanth, Velandai, Schuur, Maaike, Yu, Lei, Choi, Seung-Hoan, Sigurdsson, Sigurdur, Verhaaren, Benjamin F J, DeStefano, Anita L, Lambert, Jean-Charles, Cantor, Rita M, Struchalin, Maksim, Stankovich, Jim, Ibrahim-Verbaas, Carla A, Fleischman, Debra, Zijdenbos, Alex, den Heijer, Tom, Mazoyer, Bernard, Coker, Laura H, Enzinger, Christian, Danoy, Patrick, Carless, Melanie A, Amin, Najaf, Arfanakis, Konstantinos, van Buchem, Mark A, de Bruijn, Renée F A G, Beiser, Alexa, Dufouil, Carole, Huang, Juebin, Cavalieri, Margherita, Thomson, Russell, Niessen, Wiro J, Corvin, Aiden, Chibnik, Lori B, Gislason, Gauti K, Hofman, Albert, Pikula, Aleksandra, Amouyel, Philippe, Freeman, Kevin B, Phan, Thanh G, Oostra, Ben A, Nalls, Michael A, Uitterlinden, Andre G, Czisch, Michael, Au, Rhoda, Elbaz, Alexis, Beare, Richard J, van Swieten, John C, Lopez, Oscar, Harris, Tamara B, Chouraki, Vincent, Breteler, Monique M B, De Jager, Philip L, Becker, James T, Curran, Joanne E, Knopman, David, Fazekas, Franz, Wolf, Philip A, van der Lugt, Aad, Longstreth, W. T., Brown, Mathew A, Bennett, David A, van Duijn, Cornelia M, Davies, Gail, Mosley, Thomas H, Schmidt, Reinhold, de Almeida, Marcio A A, Appel, Katja, Duggirala, Ravi, Dyer, Thomas D, Erk, Susanne, Fagerness, Jesen, Fox, Peter T, Freimer, Nelson B, Gill, Michael, Göring, Harald H H, Bartecek, Richard, Hagler, Donald J, Hoehn, David, Holsboer, Florian, Hoogman, Martine, Hosten, Norbert, Jahanshad, Neda, Johnson, Matthew P, Kent, Jack W, Kochunov, Peter, Bergmann, Ørjan, Lancaster, Jack L, Lawrie, Stephen M, Liewald, David C, Mandl, René, Mattheisen, Manuel, Meisenzahl, Eva, Melle, Ingrid, Moses, Eric K, Mühleisen, Thomas W, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, Queensland Institute of Medical Research, Radboud University Medical Center [Nijmegen], Yale University School of Medicine, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Universität Greifswald - University of Greifswald, Universität Heidelberg [Heidelberg], University Medical Center [Utrecht], University of Oslo (UiO), University of Toronto, National University of Ireland [Galway] (NUI Galway), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], University of Bergen (UiB), Harvard University [Cambridge], VU University Amsterdam, University of Edinburgh, Structure et Réactivité des Systèmes Moléculaires Complexes (SRSMC), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], National Institutes of Health [Bethesda] (NIH), Department of Forensic and Neurodevelopmental Sciences, King‘s College London, Institute of Psychiatry, Psychology & Neuroscience, King's College London, Georgia State University, University System of Georgia (USG), Department of Psychiatry and Human Behavior [Irvine], University of California [Irvine] (UCI), Leiden University Medical Center (LUMC), Dundee Technopole, CXR Biosciences Ltd, University of Groningen [Groningen], Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland (RCSI), Department of Genetics, Southwest Foundation for Biomedical Research, Bijvoet Center of Biomolecular Research [Utrecht], Utrecht University [Utrecht], Neurology Division, Beaumont Hospital, Dublin 9, Ireland, Beaumont Hospital, The University of Texas Health Science Center at Houston (UTHealth), Center for Neurobehavioral Genetics, Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Department of Computer Science, Durham University, Laboratoire des symbioses tropicales et méditerranéennes (UMR LSTM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Université Montpellier 1 (UM1)-Institut de Recherche pour le Développement (IRD)-Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], University of California, Institute of Neurology [London], University College of London [London] (UCL), University of California [San Francisco] (UCSF), Department of Medicine, University of Washington [Seattle], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre Émile Durkheim (CED), Sciences Po Bordeaux - Institut d'études politiques de Bordeaux (IEP Bordeaux)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Salermo, Università degli Studi di Salerno (UNISA), School of Psychology, University of Queensland, University of Queensland [Brisbane], Hartford Hospital, Lancaster University, Centre for Advanced Imaging, McConnell Brain Imaging Centre (MNI), McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], Stanley Center for Psychiatric Research, Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Faculteit Medische Wetenschappen/UMCG, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Perceptual and Cognitive Neuroscience (PCN), Biological Psychology, Neuroscience Campus Amsterdam - Brain Imaging, EMGO+ - Mental Health, EPIGEN Consortium, IMAGENConsortium, Saguenay Youth Study Group, the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium, Psychiatry, NCA - Brain Imaging, EMGO - Mental health, Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), Virology, Epidemiology, Clinical Chemistry, Erasmus MC other, Radiology & Nuclear Medicine, University of California (UC)-University of California (UC), Yale School of Medicine [New Haven, Connecticut] (YSM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Universität Heidelberg [Heidelberg] = Heidelberg University, Harvard University, Vrije Universiteit Amsterdam [Amsterdam] (VU), University of California [Irvine] (UC Irvine), Universiteit Leiden, University of California (UC), University of California [San Francisco] (UC San Francisco), Università degli Studi di Salerno = University of Salerno (UNISA), University of Iceland [Reykjavik], McGill University, University of Bergen (UIB), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Bijvoet Center of Biomolecular Research, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, UMR5116, Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), and McGill University-McGill University
Subjects: Netherlands Twin Register (NTR), Pathology, 110 012 Social cognition of verbal communication, [SDV]Life Sciences [q-bio], Hippocampus, Genome-wide association study, DCN PAC - Perception action and control, Hippocampal formation, physiopathology [Brain], Bioinformatics, 0302 clinical medicine, 130 000 Cognitive Neurology & Memory, TEMPORAL-LOBE EPILEPSY, 110 014 Public activities, Renal disorder [IGMD 9], 0303 health sciences, medicine.diagnostic_test, Translational research Immune Regulation [ONCOL 3], Brain, Human brain, Genomic disorders and inherited multi-system disorders [DCN PAC - Perception action and control IGMD 3], ALZHEIMERS-DISEASE, medicine.anatomical_structure, Brain size, genetics [Chromosomes, Human, Pair 12], genetics [Polymorphism, Single Nucleotide], Biomarker (medicine), NA+/H+ EXCHANGER, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Genetic Markers, medicine.medical_specialty, 110 000 Neurocognition of Language, DCN MP - Plasticity and memory, A neurocomputational model for the Processing of Linguistic Utterances based on the Unification-Space architecture [110 007 PLUS], BRAIN VOLUME, UNIFIED APPROACH, 110 013 Binding and the MUC-model, Neuroimaging, Biology, GENOTYPE IMPUTATION, Polymorphism, Single Nucleotide, Article, Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3], 03 medical and health sciences, AUTOMATED SEGMENTATION, Meta-Analysis as Topic, SDG 3 - Good Health and Well-being, ddc:570, FUNCTIONAL IMPLICATIONS, Genetics, medicine, Humans, GENOME-WIDE ASSOCIATION, 030304 developmental biology, Chromosomes, Human, Pair 12, Magnetic resonance imaging, Genetic Loci, physiopathology [Hippocampus], 110 009 The human brain and Chinese prosody, Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6], HUMAN HEIGHT, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Contains fulltext : 108202.pdf (Publisher’s version ) (Closed access) Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 x 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 x 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 x 10(-7)). 01 mei 2012
Published: 2012

7. The correlation between reading and mathematics ability at age twelve has a substantial genetic component

Author: Davis, Oliver S. P., Band, Gavin, Pirinen, Matti, Haworth, Claire M. A., Meaburn, Emma L., Kovas, Yulia, Harlaar, Nicole, Docherty, Sophia J., Hanscombe, Ken B., Trzaskowski, Maciej, Curtis, Charles J. C., Strange, Amy, Freeman, Colin, Bellenguez, Céline, Su, Zhan, Pearson, Richard, Vukcevic, Damjan, Langford, Cordelia, Deloukas, Panos, Hunt, Sarah, Gray, Emma, Dronov, Serge, Potter, Simon C., Tashakkori-Ghanbaria, Avazeh, Edkins, Sarah, Bumpstead, Suzannah J., Blackwell, Jenefer M., Bramon, Elvira, Brown, Matthew A., Casas, Juan P., Corvin, Aiden, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S., Mathew, Christopher G., Palmer, Colin N. A., Rautanen, Anna, Sawcer, Stephen J., Trembath, Richard C., Viswanathan, Ananth C., Wood, Nicholas W., Barroso, Ines, Peltonen, Leena, Dale, Philip S., Petrill, Stephen A., Schalkwyk, Leonard S., Craig, Ian W., Lewis, Cathryn M., Price, Thomas S., Donnelly, Peter, Plomin, Robert, and Spencer, Chris C. A.
Subjects: Male, LB1501, RJ, Twins, BF, A300, Polymorphism, Single Nucleotide, Article, United Kingdom, Dyslexia, psyc, Genetics, Population, Quantitative Trait, Heritable, Reading, HQ, Humans, Learning, Female, LB, Child, Mathematics, Genome-Wide Association Study
Abstract: Dissecting how genetic and environmental influences impact on learning is helpful for maximizing numeracy and literacy. Here we show, using twin and genome-wide analysis, that there is a substantial genetic component to children’s ability in reading and mathematics, and estimate that around one half of the observed correlation in these traits is due to shared genetic effects (so-called Generalist Genes). Thus, our results highlight the potential role of the learning environment in contributing to differences in a child’s cognitive abilities at age twelve., Understanding the genetic basis of cognitive traits could aid the development of numeracy and literacy skills in children. Here the authors show that reading and mathematics have a large overlapping genetic component and suggest that a child's learning environment has a key role in creating differences between them.
Published: 2014

8. Don't give up on GWAS

Author: Sullivan, P., Andreassen, Ole A, Anney, Richard J L, Asherson, Philip, Ashley-Koch, Allison, Blackwood, Douglas, Boomsma, Dorret I, Breen, Gerome, Buitelaar, Jan, Bulik, Cynthia M, Cichon, Sven, Collier, David, Corvin, Aiden, Craddock, Nicholas, DeLisi, Lynn E, Ebstein, Richard, Edenberg, Howard J, Estivill, Xavier, Faraone, Stephen V, Farmer, Anne E, Fernandez-Aranda, Fernando, Flint, Jonathan, Foroud, Tatiana, Franke, Barbara, Gelernter, Joel, Gill, Michael, Grabe, Hans J, Hamilton, Steven P, Hickie, Ian B, Hoogendijk, Witte, Jablensky, Assen, Kalaydjieva, Luba, Kaprio, Jaakko, Kas, Martien, Keller, Matthew, Kelsoe, John, Kendler, Kenneth S, Kennedy, Martin, Kent, Lindsey, Klump, Kelly, Knowles, James A, Levinson, Douglas F, Lewis, Cathryn M, Lichtenstein, Paul, Lucae, Susanne, Martin, Nicholas G, McCarroll, Steve, McGough, James, McGrath, John J, McGuffin, Peter, Mitchell, Philip, Mowry, Bryan, Muglia, Pierandrea, Müller-Myhsok, Bertram, Neale, Benjamin, Nöthen, Markus, Nurnberger, John I, Oades, Robert D., O'Donovan, Michael, Ophoff, Roel, Owen, Michael, Pato, Carlos N, Pato, Michele T, Penninx, Brenda W, Perlis, Roy H, Porjesz, Bernice, Posthuma, Danielle, Potash, James B, Preisig, Martin, Reichborn-Kjennerud, Ted, Rice, John P, Rietschel, Marcella, Riley, Brien, Ripke, Stephan, Rothenberger, Aribert, Rujescu, Dan, Santangelo, Susan L, Schachar, Russell, Schellenberg, Gerard D, Scherer, Stephen W, Schofield, Peter, Schulze, Thomas G, Sklar, Pamela, Smoller, Jordan W, Stefansson, Hreinn, Stefansson, Kari, Todorov, Alexandre, Tozzi, Federica, Tzeng, Jung-Ying, van den Oord, Edwin J. C. G., Vorstman, Jacob A S, Wang, Kai, Weissman, Myrna M, Werge, Thomas, Wray, Naomi R, Zeggini, Eleftheria, Psychiatry, Human genetics, EMGO - Mental health, NCA - Attention & Cognition, Functional Genomics, Biological Psychology, Neuroscience Campus Amsterdam - Attention & Cognition, and EMGO+ - Mental Health
Subjects: Netherlands Twin Register (NTR), Mental Disorders, Medizin, Genomic disorders and inherited multi-system disorders [DCN PAC - Perception action and control IGMD 3], Article, Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3], Cellular and Molecular Neuroscience, Psychiatry and Mental health, Financial Support, Humans, DCN PAC - Perception action and control NCEBP 9 - Mental health, Psychology, Molecular Biology, Humanities, Genome-Wide Association Study
Abstract: Item does not contain fulltext Buitelaar J, Bulik CM, Cichon S, Collier D, Corvin A, Craddock N, DeLisi LE, Ebstein R, Edenberg HJ, Estivill X, Faraone SV, Farmer AE, Fernandez-Aranda F, Flint J, Foroud T, Franke B, Gelernter J, Gill M, Grabe HJ, Hamilton SP, Hickie IB, Hoogendijk W, Jablensky A, Kalaydjieva L, Kaprio J, Kas M, Keller M, Kelsoe J, Kendler KS, Kennedy M, Kent L, Klump K, Knowles JA, Levinson DF, Lewis CM, Lichtenstein P, Lucae S, Martin NG, McCarroll S, McGough J, McGrath JJ, McGuffin P, Mitchell P, Mowry B, Muglia P, Müller-Myhsok B, Neale B, Nöthen M, Nurnberger JI, Oades RD, O'Donovan M, Ophoff R, Owen M, Pato CN, Pato MT, Penninx BW, Perlis RH, Porjesz B, Posthuma D, Potash JB, Preisig M, Reichborn-Kjennerud T, Rice JP, Rietschel M, Riley B, Ripke S, Rothenberger A, Rujescu D, Santangelo SL, Schachar R, Schellenberg GD, Scherer SW, Schofield P, Schulze TG, Sklar P, Smoller JW, Stefansson H, Stefansson K, Sullivan P, Todorov A, Tozzi F, Tzeng JY, van den Oord EJ, Vorstman JA, Wang K, Weissman MM, Werge T, Wray NR, Zeggini E 01 januari 2012
Published: 2012

9. The Wellcome trust UK-Irish bipolar affective disorder sibling-pair genome screen: first stage report

Author: CORVIN, AIDEN PETER, GILL, MICHAEL, and SEGURADO, RICARDO
Subjects: Linkage, Genetics, lod score, manic-depressive, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), microsatellite repeats
Abstract: PUBLISHED, We have completed the first stage of a two-stage genome wide screen designed to identify chromosomal regions that may harbour susceptibility genes for bipolar affective disorder. The first stage screening sample included 509 subjects from 151 nuclear families recruited within the United Kingdom and Republic of Ireland. This sample contained 154 narrowly defined affected sibling pairs (DSM-IV BPI) and 258 broadly defined affected sibling pairs (DSM-IV BPI, SABP, BPII, BPNOS or MDD(R)), approximately two thirds of all families contained at least one other additional typed individual. All individuals were genotyped using 398 highly polymorphic microsatellite markers from Applied Biosystems's Linkage Mapping Set Version 2. The average inter-marker distance was 9.6 cM and the mean heterozygosity was 0.78. Analysis of these data using non-parametric linkage methods (MAPMAKER/SIBS) found no evidence for loci of major effect and no regions reached genome-wide significance for either suggestive or significant linkage. We identified 19 points across the genome where the MLS exceeded a value set for follow up in our second stage screen (MLS0.74 (equivalent to a nominal pointwise significance of 5%) under the narrowest diagnostic model). These points were on chromosomes 2, 3, 4, 6, 7, 9, 10, 12, 17, 18 & X. Some of these points overlapped with previous linkage reports both within bipolar affective disorder and other psychiatric illnesses. Under the narrowest diagnostic model, the single most significant multipoint linkage was on chromosome 18 at marker D18S452 (MLS=1.54). Overall the highest MLS was 1.70 on chromosome 2 at marker D2S125, under the broadest diagnostic model., Wellcome Trust
Published: 2002
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10. Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

Author: McLaughlin, Russell L., Schijven, Dick, van Rheenen, Wouter, van Eijk, Kristel R., O'Brien, Margaret, Kahn, René S., Ophoff, Roel A., Goris, An, Bradley, Daniel G., Al-Chalabi, Ammar, van den Berg, Leonard H., Luykx, Jurjen J., Hardiman, Orla, Veldink, Jan H., Shatunov, Aleksey, Dekker, Annelot M., Diekstra, Frank P., Pulit, Sara L., van der Spek, Rick A. A., van Doormaal, Perry T. C., Sproviero, William, Jones, Ashley R., Nicholson, Garth A., Rowe, Dominic B., Pamphlett, Roger, Kiernan, Matthew C., Bauer, Denis, Kahlke, Tim, Williams, Kelly, Eftimov, Filip, Fogh, Isabella, Ticozzi, Nicola, Lin, Kuang, Millecamps, Stéphanie, Salachas, François, Meininger, Vincent, de Carvalho, Mamede, Pinto, Susana, Mora, Jesus S., Rojas-García, Ricardo, Polak, Meraida, Chandran, Siddharthan, Colville, Shuna, Swingler, Robert, Morrison, Karen E., Shaw, Pamela J., Hardy, John, Orrell, Richard W., Pittman, Alan, Sidle, Katie, Fratta, Pietro, Malaspina, Andrea, Petri, Susanne, Abdulla, Susanna, Drepper, Carsten, Sendtner, Michael, Meyer, Thomas, Wiedau-Pazos, Martina, Lomen-Hoerth, Catherine, Van Deerlin, Vivianna M., Trojanowski, John Q., Elman, Lauren, McCluskey, Leo, Basak, Nazli, Meitinger, Thomas, Lichtner, Peter, Blagojevic-Radivojkov, Milena, Andres, Christian R., Maurel, Cindy, Bensimon, Gilbert, Landwehrmeyer, Bernhard, Brice, Alexis, Payan, Christine A. M., Saker-Delye, Safa, Dürr, Alexandra, Wood, Nicholas, Tittmann, Lukas, Lieb, Wolfgang, Franke, Andre, Rietschel, Marcella, Cichon, Sven, Nöuthen, Markus M., Amouyel, Philippe, Tzourio, Christophe, Dartigues, Jean- François, Uitterlinden, Andre G., Rivadeneira, Fernando, Estrada, Karol, Hofman, Albert, Curtis, Charles, van der Kooi, Anneke J., de Visser, Marianne, Weber, Markus, Shaw, Christopher E., Smith, Bradley N., Pansarasa, Orietta, Cereda, Cristina, Del Bo, Roberto, Comi, Giacomo P., D'Alfonso, Sandra, Bertolin, Cinzia, Sorarù, Gianni, Mazzini, Letizia, Pensato, Viviana, Gellera, Cinzia, Tiloca, Cinzia, Ratti, Antonia, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Arcuti, Simon, Capozzo, Rosa, Zecca, Chiara, Lunetta, Christian, Penco, Silvana, Riva, Nilo, Padovani, Alessandro, Filosto, Massimiliano, Blair, Ian, Leigh, P Nigel, Casale, Federico, Chio, Adriano, Beghi, Ettore, Pupillo, Elisabetta, Tortelli, Rosanna, Logroscino, Giancarlo, Powell, John, Ludolph, Albert C., Weishaupt, Jochen H., Robberecht, Wim, Van Damme, Philip, Brown, Robert H., Glass, Jonathan, Landers, John E., Andersen, Peter M., Corcia, Philippe, Vourc'h, Patrick, Silani, Vincenzo, van Es, Michael A., Pasterkamp, R Jeroen, Lewis, Cathryn M., Breen, Gerome, Ripke, Stephan, Neale, Benjamin M., Corvin, Aiden, Walters, James T. R., Farh, Kai-How, Holmans, Peter A, Lee, Phil, Bulik-Sullivan, Brendan, Collier, David A., Huang, Hailiang, Pers, Tune H., Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A., Begemann, Martin, Belliveau, Richard A., Bene, Judit, Bergen, Sarah E., Bevilacqua, Elizabeth, Bigdeli, Tim B., Black, Donald W., Bruggeman, Richard, Buccola, Nancy G., Buckner, Randy L., Byerley, William, Cahn, Wiepke, Cai, Guiqing, Campion, Dominique, Cantor, Rita M., Carr, Vaughan J., Carrera, Noa, Catts, Stanley V., Chambert, Kimberley D., Chan, Raymond C. K., Chan, Ronald Y. L., Chen, Eric Y. H., Cheng, Wei, Cheung, Eric F. C., Chong, Siow Ann, Cloninger, C Robert, Cohen, David, Cohen, Nadine, Cormican, Paul, Craddock, Nick, Crowley, James J., Curtis, David, Davidson, Michael, Davis, Kenneth L., Degenhardt, Franziska, Del Favero, Jurgen, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Durmishi, Naser, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H., Farrell, Martilias S., Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B., Friedl, Marion, Friedman, Joseph I., Fromer, Menachem, Genovese, Giulio, Georgieva, Lyudmila, Giegling, Ina, Giusti-Rodríguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I., Golimbet, Vera, Gopal, Srihari, Gratten, Jacob, de Haan, Lieuwe, Hammer, Christian, Hamshere, Marian L., Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M., Henskens, Frans A., Herms, Stefan, Hirschhorn, Joel N., Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V., Hougaard, David M., Ikeda, Masashi, Joa, Inge, Julià, Antonio, Kalaydjieva, Luba, Karachanak-Yankova, Sena, Karjalainen, Juha, Kavanagh, David, Keller, Matthew C., Kennedy, James L., Khrunin, Andrey, Kim, Yunjung, Klovins, Janis, Knowles, James A., Konte, Bettina, Kucinskas, Vaidutis, Kucinskiene, Zita Ausrele, Kuzelova-Ptackova, Hana, Kähler, Anna K., Laurent, Claudine, Lee, Jimmy, Lee, S Hong, Legge, Sophie E., Lerer, Bernard, Li, Miaoxin, Li, Tao, Liang, Kung-Yee, Lieberman, Jeffrey, Limborska, Svetlana, Loughland, Carmel M., Lubinski, Jan, Lönnqvist, Jouko, Macek, Milan, Magnusson, Patrik K. E., Maher, Brion S., Maier, Wolfgang, Mallet, Jacques, Marsal, Sara, Mattheisen, Manuel, Mattingsdal, Morten, McCarley, Robert W., McDonald, Colm, McIntosh, Andrew M., Meier, Sandra, Meijer, Carin J., Melegh, Bela, Melle, Ingrid, Mesholam-Gately, Raquelle I., Metspalu, Andres, Michie, Patricia T., Milani, Lili, Milanova, Vihra, Mokrab, Younes, Morris, Derek W., Mors, Ole, Murphy, Kieran C., Murray, Robin M., Myin-Germeys, Inez, Müller-Myhsok, Bertram, Nelis, Mari, Nenadic, Igor, Nertney, Deborah A., Nestadt, Gerald, Nicodemus, Kristin K., Nikitina-Zake, Liene, Nisenbaum, Laura, Nordin, Annelie, O'Callaghan, Eadbhard, O'Dushlaine, Colm, O'Neill, F Anthony, Oh, Sang-Yun, Olincy, Ann, Olsen, Line, Van Os, Jim, Pantelis, Christos, Papadimitriou, George N., Papiol, Sergi, Parkhomenko, Elena, Pato, Michele T., Paunio, Tiina, Pejovic-Milovancevic, Milica, Perkins, Diana O., Pietiläinen, Olli, Pimm, Jonathan, Pocklington, Andrew J., Price, Alkes, Pulver, Ann E., Purcell, Shaun M., Quested, Digby, Rasmussen, Henrik B., Reichenberg, Abraham, Reimers, Mark A., Richards, Alexander L., Roffman, Joshua L., Roussos, Panos, Ruderfer, Douglas M., Salomaa, Veikko, Sanders, Alan R., Schall, Ulrich, Schubert, Christian R., Schulze, Thomas G., Schwab, Sibylle G., Scolnick, Edward M., Scott, Rodney J., Seidman, Larry J., Shi, Jianxin, Sigurdsson, Engilbert, Silagadze, Teimuraz, Silverman, Jeremy M., Sim, Kang, Slominsky, Petr, Smoller, Jordan W., So, Hon-Cheong, Spencer, Chris C. A., Stahl, Eli A., Stefansson, Hreinn, Steinberg, Stacy, Stogmann, Elisabeth, Straub, Richard E., Strengman, Eric, Strohmaier, Jana, Stroup, T Scott, Subramaniam, Mythily, Suvisaari, Jaana, Svrakic, Dragan M., Szatkiewicz, Jin P., Söderman, Erik, Thirumalai, Srinivas, Toncheva, Draga, Tosato, Sarah, Veijola, Juha, Waddington, John, Walsh, Dermot, Wang, Dai, Wang, Qiang, Webb, Bradley T., Weiser, Mark, Wildenauer, Dieter B., Williams, Nigel M., Williams, Stephanie, Witt, Stephanie H., Wolen, Aaron R., Wong, Emily H. M., Wormley, Brandon K., Xi, Hualin Simon, Zai, Clement C., Zheng, Xuebin, Zimprich, Fritz, Wray, Naomi R., Stefansson, Kari, Visscher, Peter M., Adolfsson, Rolf, Andreassen, Ole A., Blackwood, Douglas H. R., Bramon, Elvira, Buxbaum, Joseph D., Børglum, Anders D., Darvasi, Ariel, Domenici, Enrico, Ehrenreich, Hannelore, Esko, Tõnu, Gejman, Pablo V., Gill, Michael, Gurling, Hugh, Hultman, Christina M., Iwata, Nakao, Jablensky, Assen V., Jönsson, Erik G., Kendler, Kenneth S., Kirov, George, Knight, Jo, Lencz, Todd, Levinson, Douglas F., Li, Qingqin S., Liu, Jianjun, Malhotra, Anil K., McCarroll, Steven A., McQuillin, Andrew, Moran, Jennifer L., Mortensen, Preben B., Mowry, Bryan J., Owen, Michael J., Palotie, Aarno, Pato, Carlos N., Petryshen, Tracey L., Posthuma, Danielle, Riley, Brien P., Rujescu, Dan, Sham, Pak C., Sklar, Pamela, St Clair, David, Weinberger, Daniel R., Wendland, Jens R., Werge, Thomas, Daly, Mark J., Sullivan, Patrick F., and O'Donovan, Michael C.
Abstract: We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05–21.6; P=1 × 10−4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10−7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08–1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.
Published: 2017
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11. Novel genetic loci associated with hippocampal volume

Author: Hibar, Derrek P., Adams, Hieab H. H., Jahanshad, Neda, Chauhan, Ganesh, Stein, Jason L., Hofer, Edith, Renteria, Miguel E., Bis, Joshua C., Arias-Vasquez, Alejandro, Ikram, M. Kamran, Desrivières, Sylvane, Vernooij, Meike W., Abramovic, Lucija, Alhusaini, Saud, Amin, Najaf, Andersson, Micael, Arfanakis, Konstantinos, Aribisala, Benjamin S., Armstrong, Nicola J., Athanasiu, Lavinia, Axelsson, Tomas, Beecham, Ashley H., Beiser, Alexa, Bernard, Manon, Blanton, Susan H., Bohlken, Marc M., Boks, Marco P., Bralten, Janita, Brickman, Adam M., Carmichael, Owen, Chakravarty, M. Mallar, Chen, Qiang, Ching, Christopher R. K., Chouraki, Vincent, Cuellar-Partida, Gabriel, Crivello, Fabrice, Den Braber, Anouk, Doan, Nhat Trung, Ehrlich, Stefan, Giddaluru, Sudheer, Goldman, Aaron L., Gottesman, Rebecca F., Grimm, Oliver, Griswold, Michael E., Guadalupe, Tulio, Gutman, Boris A., Hass, Johanna, Haukvik, Unn K., Hoehn, David, Holmes, Avram J., Hoogman, Martine, Janowitz, Deborah, Jia, Tianye, Jørgensen, Kjetil N., Karbalai, Nazanin, Kasperaviciute, Dalia, Kim, Sungeun, Klein, Marieke, Kraemer, Bernd, Lee, Phil H., Liewald, David C. M., Lopez, Lorna M., Luciano, Michelle, Macare, Christine, Marquand, Andre F., Matarin, Mar, Mather, Karen A., Mattheisen, Manuel, McKay, David R., Milaneschi, Yuri, Muñoz Maniega, Susana, Nho, Kwangsik, Nugent, Allison C., Nyquist, Paul, Loohuis, Loes M. Olde, Oosterlaan, Jaap, Papmeyer, Martina, Pirpamer, Lukas, Pütz, Benno, Ramasamy, Adaikalavan, Richards, Jennifer S., Risacher, Shannon L., Roiz-Santiañez, Roberto, Rommelse, Nanda, Ropele, Stefan, Rose, Emma J., Royle, Natalie A., Rundek, Tatjana, Sämann, Philipp G., Saremi, Arvin, Satizabal, Claudia L., Schmaal, Lianne, Schork, Andrew J., Shen, Li, Shin, Jean, Shumskaya, Elena, Smith, Albert V., Sprooten, Emma, Strike, Lachlan T., Teumer, Alexander, Tordesillas-Gutierrez, Diana, Toro, Roberto, Trabzuni, Daniah, Trompet, Stella, Vaidya, Dhananjay, Van der Grond, Jeroen, Van der Lee, Sven J., Van der Meer, Dennis, Van Donkelaar, Marjolein M. J., Van Eijk, Kristel R., Van Erp, Theo G. M., Van Rooij, Daan, Walton, Esther, Westlye, Lars T., Whelan, Christopher D., Windham, Beverly G., Winkler, Anderson M., Wittfeld, Katharina, Woldehawariat, Girma, Wolf, Christiane, Wolfers, Thomas, Yanek, Lisa R., Yang, Jingyun, Zijdenbos, Alex, Zwiers, Marcel P., Agartz, Ingrid, Almasy, Laura, Ames, David, Amouyel, Philippe, Andreassen, Ole A., Arepalli, Sampath, Assareh, Amelia A., Barral, Sandra, Bastin, Mark E., Becker, Diane M., Becker, James T., Bennett, David A., Blangero, John, van Bokhoven, Hans, Boomsma, Dorret I., Brodaty, Henry, Brouwer, Rachel M., Brunner, Han G., Buckner, Randy L., Buitelaar, Jan K., Bulayeva, Kazima B., Cahn, Wiepke, Calhoun, Vince D., Cannon, Dara M., Cavalleri, Gianpiero L., Cheng, Ching-Yu, Cichon, Sven, Cookson, Mark R., Corvin, Aiden, Crespo-Facorro, Benedicto, Curran, Joanne E., Czisch, Michael, Dale, Anders M., Davies, Gareth E., De Craen, Anton J. M., De Geus, Eco J. C., De Jager, Philip L., De Zubicaray, Greig I., Deary, Ian J., Debette, Stéphanie, DeCarli, Charles, Delanty, Norman, Depondt, Chantal, DeStefano, Anita, Dillman, Allissa, Djurovic, Srdjan, Donohoe, Gary, Drevets, Wayne C., Duggirala, Ravi, Dyer, Thomas D., Enzinger, Christian, Erk, Susanne, Espeseth, Thomas, Fedko, Iryna O., Fernández, Guillén, Ferrucci, Luigi, Fisher, Simon E., Fleischman, Debra A., Ford, Ian, Fornage, Myriam, Foroud, Tatiana M., Fox, Peter T., Francks, Clyde, Fukunaga, Masaki, Gibbs, J. Raphael, Glahn, David C., Gollub, Randy L., Göring, Harald H. H., Green, Robert C., Gruber, Oliver, Gudnason, Vilmundur, Guelfi, Sebastian, Håberg, Asta K., Hansell, Narelle K., Hardy, John, Hartman, Catharina A., Hashimoto, Ryota, Hegenscheid, Katrin, Heinz, Andreas, Le Hellard, Stephanie, Hernandez, Dena G., Heslenfeld, Dirk J., Ho, Beng-Choon, Hoekstra, Pieter J., Hoffmann, Wolfgang, Hofman, Albert, Holsboer, Florian, Homuth, Georg, Hosten, Norbert, Hottenga, Jouke-Jan, Huentelman, Matthew, Pol, Hilleke E. Hulshoff, Ikeda, Masashi, Jack Jr, Clifford R., Jenkinson, Mark, Johnson, Robert, Jönsson, Erik G., Jukema, J. Wouter, Kahn, René S., Kanai, Ryota, Kloszewska, Iwona, Knopman, David S., Kochunov, Peter, Kwok, John B., Lawrie, Stephen M., Lemaître, Hervé, Liu, Xinmin, Longo, Dan L., Lopez, Oscar L., Lovestone, Simon, Martinez, Oliver, Martinot, Jean-Luc, Mattay, Venkata S., McDonald, Colm, McIntosh, Andrew M., McMahon, Francis J., McMahon, Katie L., Mecocci, Patrizia, Melle, Ingrid, Meyer-Lindenberg, Andreas, Mohnke, Sebastian, Montgomery, Grant W., Morris, Derek W., Mosley, Thomas H., Mühleisen, Thomas W., Müller-Myhsok, Bertram, Nalls, Michael A., Nauck, Matthias, Nichols, Thomas E., Niessen, Wiro J., Nöthen, Markus M., Nyberg, Lars, Ohi, Kazutaka, Olvera, Rene L., Ophoff, Roel A., Pandolfo, Massimo, Paus, Tomas, Pausova, Zdenka, Penninx, Brenda W. J. H., Pike, G. Bruce, Potkin, Steven G., Psaty, Bruce M., Reppermund, Simone, Rietschel, Marcella, Roffman, Joshua L., Romanczuk-Seiferth, Nina, Rotter, Jerome I., Ryten, Mina, Sacco, Ralph L., Sachdev, Perminder S., Saykin, Andrew J., Schmidt, Reinhold, Schmidt, Helena, Schofield, Peter R., Sigursson, Sigurdur, Simmons, Andrew, Singleton, Andrew, Sisodiya, Sanjay M., Smith, Colin, Smoller, Jordan W., Soininen, Hilkka, Steen, Vidar M., Stott, David J., Sussmann, Jessika E., Thalamuthu, Anbupalam, Toga, Arthur W., Traynor, Bryan J., Troncoso, Juan, Tsolaki, Magda, Tzourio, Christophe, Uitterlinden, Andre G., Hernández, Maria C. Valdés, Van der Brug, Marcel, van der Lugt, Aad, van der Wee, Nic J. A., Van Haren, Neeltje E. M., van 't Ent, Dennis, Van Tol, Marie-Jose, Vardarajan, Badri N., Vellas, Bruno, Veltman, Dick J., Völzke, Henry, Walter, Henrik, Wardlaw, Joanna M., Wassink, Thomas H., Weale, Michael E., Weinberger, Daniel R., Weiner, Michael W., Wen, Wei, Westman, Eric, White, Tonya, Wong, Tien Y., Wright, Clinton B., Zielke, Ronald H., Zonderman, Alan B., Martin, Nicholas G., Van Duijn, Cornelia M., Wright, Margaret J., Longstreth, W. T., Schumann, Gunter, Grabe, Hans J., Franke, Barbara, Launer, Lenore J., Medland, Sarah E., Seshadri, Sudha, Thompson, Paul M., and Ikram, M. Arfan
Abstract: The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg=−0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
Published: 2017
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12. Investigating copy number variants in schizophrenia pedigrees using a new consensus pipeline called PECAN.

Author: Ormond C, Ryan NM, Byerley W, Heron EA, and Corvin A
Subjects: Humans, Male, Female, Whole Genome Sequencing methods, DNA Copy Number Variations, Schizophrenia genetics, Pedigree
Abstract: Copy number variants (CNVs) have been implicated in many human diseases, including psychiatric disorders. Whole genome sequencing offers advantages in CNV calling compared to previous array-based methods. Here we present a robust and transparent CNV calling pipeline, PECAN (PEdigree Copy number vAriaNt calling), for short-read, whole genome sequencing data, comprised of a novel combination of four calling methods and structural variant genotyping. This method is scalable and can incorporate pedigree information to retain lower-confidence CNVs that would otherwise be discarded. We have robustly benchmarked PECAN using gold-standard CNV calls for two well-established evaluation samples, NA12878 and HG002, showing that PECAN performs with high precision and recall on both datasets, outperforming another pedigree-based CNV calling pipeline. As part of this work, we provide a list of high-confidence gold standard CNVs for the NA12878 reference sample, curated from multiple studies. We applied PECAN to a collection of pedigrees multiply affected with schizophrenia and identified a rare deletion that perfectly co-segregates with schizophrenia in one of the pedigrees. The CNV overlaps the gene PITRM1, which has been implicated in a complex phenotype including ataxia, developmental delay, and schizophrenia-like episodes in affected adults., (© 2024. The Author(s).)
Published: 2024
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13. Rare coding variants in ten genes confer substantial risk for schizophrenia.

Author: Singh T, Poterba T, Curtis D, Akil H, Al Eissa M, Barchas JD, Bass N, Bigdeli TB, Breen G, Bromet EJ, Buckley PF, Bunney WE, Bybjerg-Grauholm J, Byerley WF, Chapman SB, Chen WJ, Churchhouse C, Craddock N, Cusick CM, DeLisi L, Dodge S, Escamilla MA, Eskelinen S, Fanous AH, Faraone SV, Fiorentino A, Francioli L, Gabriel SB, Gage D, Gagliano Taliun SA, Ganna A, Genovese G, Glahn DC, Grove J, Hall MH, Hämäläinen E, Heyne HO, Holi M, Hougaard DM, Howrigan DP, Huang H, Hwu HG, Kahn RS, Kang HM, Karczewski KJ, Kirov G, Knowles JA, Lee FS, Lehrer DS, Lescai F, Malaspina D, Marder SR, McCarroll SA, McIntosh AM, Medeiros H, Milani L, Morley CP, Morris DW, Mortensen PB, Myers RM, Nordentoft M, O'Brien NL, Olivares AM, Ongur D, Ouwehand WH, Palmer DS, Paunio T, Quested D, Rapaport MH, Rees E, Rollins B, Satterstrom FK, Schatzberg A, Scolnick E, Scott LJ, Sharp SI, Sklar P, Smoller JW, Sobell JL, Solomonson M, Stahl EA, Stevens CR, Suvisaari J, Tiao G, Watson SJ, Watts NA, Blackwood DH, Børglum AD, Cohen BM, Corvin AP, Esko T, Freimer NB, Glatt SJ, Hultman CM, McQuillin A, Palotie A, Pato CN, Pato MT, Pulver AE, St Clair D, Tsuang MT, Vawter MP, Walters JT, Werge TM, Ophoff RA, Sullivan PF, Owen MJ, Boehnke M, O'Donovan MC, Neale BM, and Daly MJ
Subjects: Case-Control Studies, Exome, Genetic Predisposition to Disease genetics, Humans, Receptors, N-Methyl-D-Aspartate genetics, Mutation, Neurodevelopmental Disorders genetics, Schizophrenia genetics
Abstract: Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3-50, P < 2.14 × 10 -6 ) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-D-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders 1 , epilepsy and severe neurodevelopmental disorders 2 , although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk 3 , suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Published: 2022
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14. Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics.

Author: Lam M, Chen CY, Ge T, Xia Y, Hill DW, Trampush JW, Yu J, Knowles E, Davies G, Stahl EA, Huckins L, Liewald DC, Djurovic S, Melle I, Christoforou A, Reinvang I, DeRosse P, Lundervold AJ, Steen VM, Espeseth T, Räikkönen K, Widen E, Palotie A, Eriksson JG, Giegling I, Konte B, Hartmann AM, Roussos P, Giakoumaki S, Burdick KE, Payton A, Ollier W, Chiba-Falek O, Koltai DC, Need AC, Cirulli ET, Voineskos AN, Stefanis NC, Avramopoulos D, Hatzimanolis A, Smyrnis N, Bilder RM, Freimer NB, Cannon TD, London E, Poldrack RA, Sabb FW, Congdon E, Conley ED, Scult MA, Dickinson D, Straub RE, Donohoe G, Morris D, Corvin A, Gill M, Hariri AR, Weinberger DR, Pendleton N, Bitsios P, Rujescu D, Lahti J, Le Hellard S, Keller MC, Andreassen OA, Deary IJ, Glahn DC, Huang H, Liu C, Malhotra AK, and Lencz T
Subjects: Cognition, Genome-Wide Association Study, Humans, Transcriptome, Nootropic Agents, Schizophrenia drug therapy, Schizophrenia genetics
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., (© 2021. The Author(s).)
Published: 2021
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15. Methyl-CpG-binding protein 2 mediates overlapping mechanisms across brain disorders.

Author: Bach S, Ryan NM, Guasoni P, Corvin AP, El-Nemr RA, Khan D, Sanfeliu A, and Tropea D
Subjects: Animals, Brain metabolism, Brain pathology, Brain Diseases pathology, DNA Methylation genetics, Disease Models, Animal, Gene Expression Profiling, Humans, Mice, Mutation genetics, Neurons metabolism, Neurons pathology, Rett Syndrome pathology, Brain Diseases genetics, Methyl-CpG-Binding Protein 2 genetics, Rett Syndrome genetics
Abstract: MECP2 and its product, Methyl-CpG binding protein 2 (MeCP2), are mostly known for their association to Rett Syndrome (RTT), a rare neurodevelopmental disorder. Additional evidence suggests that MECP2 may underlie other neuropsychiatric and neurological conditions, and perhaps modulate common presentations and pathophysiology across disorders. To clarify the mechanisms of these interactions, we develop a method that uses the binding properties of MeCP2 to identify its targets, and in particular, the genes recognized by MeCP2 and associated to several neurological and neuropsychiatric disorders. Analysing mechanisms and pathways modulated by these genes, we find that they are involved in three main processes: neuronal transmission, immuno-reactivity, and development. Also, while the nervous system is the most relevant in the pathophysiology of the disorders, additional systems may contribute to MeCP2 action through its target genes. We tested our results with transcriptome analysis on Mecp2-null models and cells derived from a patient with RTT, confirming that the genes identified by our procedure are directly modulated by MeCP2. Thus, MeCP2 may modulate similar mechanisms in different pathologies, suggesting that treatments for one condition may be effective for related disorders.
Published: 2020
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16. Cognitive Characterization of Schizophrenia Risk Variants Involved in Synaptic Transmission: Evidence of CACNA1C's Role in Working Memory.

Author: Cosgrove D, Mothersill O, Kendall K, Konte B, Harold D, Giegling I, Hartmann A, Richards A, Mantripragada K, Owen MJ, O'Donovan MC, Gill M, Rujescu D, Walters J, Corvin A, Morris DW, and Donohoe G
Subjects: Adult, Brain diagnostic imaging, Brain physiology, Brain Mapping, Female, Genetic Loci, Genome-Wide Association Study, Humans, Magnetic Resonance Imaging, Male, Neural Pathways diagnostic imaging, Neural Pathways physiology, Neuropsychological Tests, Polymorphism, Single Nucleotide, Psychotic Disorders genetics, Calcium Channels, L-Type genetics, Cognition, Genetic Predisposition to Disease, Memory, Short-Term physiology, Schizophrenia genetics, Synaptic Transmission genetics
Abstract: With >100 common variants associated with schizophrenia risk, establishing their biological significance is a priority. We sought to establish cognitive effects of risk variants at loci implicated in synaptic transmission by (1) identifying GWAS schizophrenia variants whose associated gene function is related to synaptic transmission, and (2) testing for association between these and measures of neurocognitive function. We selected variants, reported in the largest GWAS to date, associated with genes involved in synaptic transmission. Associations between genotype and cognitive test score were analyzed in a discovery sample (988 Irish participants, including 798 with psychosis), and replication samples (528 UK patients with schizophrenia/schizoaffective disorder; 921 German participants including 362 patients with schizophrenia). Three loci showed significant associations with neuropsychological performance in the discovery samples. This included an association between the rs2007044 (risk allele G) within CACNA1C and poorer working memory performance (increased errors B (95% CI)=0.635-4.535, p=0.012), an effect driven mainly by the psychosis groups. In an fMRI analysis of working memory performance (n=84 healthy participants, a subset of the discovery sample), we further found evidence that the same CACNA1C allele was associated with decreased functional connectivity between the right dorsolateral prefrontal cortex and right superior occipital gyrus/cuneus and anterior cingulate cortex. In conclusion, these data provide evidence to suggest that the CACNA1C risk variant rs2007044 is associated with poorer memory function that may result from risk carriers' difficulty with top-down initiated responses caused by dysconnectivity between the right DLPFC and several cortical regions.
Published: 2017
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17. Novel genetic loci underlying human intracranial volume identified through genome-wide association.

Author: Adams HH, Hibar DP, Chouraki V, Stein JL, Nyquist PA, Rentería ME, Trompet S, Arias-Vasquez A, Seshadri S, Desrivières S, Beecham AH, Jahanshad N, Wittfeld K, Van der Lee SJ, Abramovic L, Alhusaini S, Amin N, Andersson M, Arfanakis K, Aribisala BS, Armstrong NJ, Athanasiu L, Axelsson T, Beiser A, Bernard M, Bis JC, Blanken LM, Blanton SH, Bohlken MM, Boks MP, Bralten J, Brickman AM, Carmichael O, Chakravarty MM, Chauhan G, Chen Q, Ching CR, Cuellar-Partida G, Braber AD, Doan NT, Ehrlich S, Filippi I, Ge T, Giddaluru S, Goldman AL, Gottesman RF, Greven CU, Grimm O, Griswold ME, Guadalupe T, Hass J, Haukvik UK, Hilal S, Hofer E, Hoehn D, Holmes AJ, Hoogman M, Janowitz D, Jia T, Kasperaviciute D, Kim S, Klein M, Kraemer B, Lee PH, Liao J, Liewald DC, Lopez LM, Luciano M, Macare C, Marquand A, Matarin M, Mather KA, Mattheisen M, Mazoyer B, McKay DR, McWhirter R, Milaneschi Y, Mirza-Schreiber N, Muetzel RL, Maniega SM, Nho K, Nugent AC, Loohuis LM, Oosterlaan J, Papmeyer M, Pappa I, Pirpamer L, Pudas S, Pütz B, Rajan KB, Ramasamy A, Richards JS, Risacher SL, Roiz-Santiañez R, Rommelse N, Rose EJ, Royle NA, Rundek T, Sämann PG, Satizabal CL, Schmaal L, Schork AJ, Shen L, Shin J, Shumskaya E, Smith AV, Sprooten E, Strike LT, Teumer A, Thomson R, Tordesillas-Gutierrez D, Toro R, Trabzuni D, Vaidya D, Van der Grond J, Van der Meer D, Van Donkelaar MM, Van Eijk KR, Van Erp TG, Van Rooij D, Walton E, Westlye LT, Whelan CD, Windham BG, Winkler AM, Woldehawariat G, Wolf C, Wolfers T, Xu B, Yanek LR, Yang J, Zijdenbos A, Zwiers MP, Agartz I, Aggarwal NT, Almasy L, Ames D, Amouyel P, Andreassen OA, Arepalli S, Assareh AA, Barral S, Bastin ME, Becker DM, Becker JT, Bennett DA, Blangero J, van Bokhoven H, Boomsma DI, Brodaty H, Brouwer RM, Brunner HG, Buckner RL, Buitelaar JK, Bulayeva KB, Cahn W, Calhoun VD, Cannon DM, Cavalleri GL, Chen C, Cheng CY, Cichon S, Cookson MR, Corvin A, Crespo-Facorro B, Curran JE, Czisch M, Dale AM, Davies GE, De Geus EJ, De Jager PL, de Zubicaray GI, Delanty N, Depondt C, DeStefano AL, Dillman A, Djurovic S, Donohoe G, Drevets WC, Duggirala R, Dyer TD, Erk S, Espeseth T, Evans DA, Fedko IO, Fernández G, Ferrucci L, Fisher SE, Fleischman DA, Ford I, Foroud TM, Fox PT, Francks C, Fukunaga M, Gibbs JR, Glahn DC, Gollub RL, Göring HH, Grabe HJ, Green RC, Gruber O, Gudnason V, Guelfi S, Hansell NK, Hardy J, Hartman CA, Hashimoto R, Hegenscheid K, Heinz A, Le Hellard S, Hernandez DG, Heslenfeld DJ, Ho BC, Hoekstra PJ, Hoffmann W, Hofman A, Holsboer F, Homuth G, Hosten N, Hottenga JJ, Hulshoff Pol HE, Ikeda M, Ikram MK, Jack CR Jr, Jenkinson M, Johnson R, Jönsson EG, Jukema JW, Kahn RS, Kanai R, Kloszewska I, Knopman DS, Kochunov P, Kwok JB, Lawrie SM, Lemaître H, Liu X, Longo DL, Longstreth WT Jr, Lopez OL, Lovestone S, Martinez O, Martinot JL, Mattay VS, McDonald C, McIntosh AM, McMahon KL, McMahon FJ, Mecocci P, Melle I, Meyer-Lindenberg A, Mohnke S, Montgomery GW, Morris DW, Mosley TH, Mühleisen TW, Müller-Myhsok B, Nalls MA, Nauck M, Nichols TE, Niessen WJ, Nöthen MM, Nyberg L, Ohi K, Olvera RL, Ophoff RA, Pandolfo M, Paus T, Pausova Z, Penninx BW, Pike GB, Potkin SG, Psaty BM, Reppermund S, Rietschel M, Roffman JL, Romanczuk-Seiferth N, Rotter JI, Ryten M, Sacco RL, Sachdev PS, Saykin AJ, Schmidt R, Schofield PR, Sigurdsson S, Simmons A, Singleton A, Sisodiya SM, Smith C, Smoller JW, Soininen H, Srikanth V, Steen VM, Stott DJ, Sussmann JE, Thalamuthu A, Tiemeier H, Toga AW, Traynor BJ, Troncoso J, Turner JA, Tzourio C, Uitterlinden AG, Hernández MC, Van der Brug M, Van der Lugt A, Van der Wee NJ, Van Duijn CM, Van Haren NE, Van T Ent D, Van Tol MJ, Vardarajan BN, Veltman DJ, Vernooij MW, Völzke H, Walter H, Wardlaw JM, Wassink TH, Weale ME, Weinberger DR, Weiner MW, Wen W, Westman E, White T, Wong TY, Wright CB, Zielke HR, Zonderman AB, Deary IJ, DeCarli C, Schmidt H, Martin NG, De Craen AJ, Wright MJ, Launer LJ, Schumann G, Fornage M, Franke B, Debette S, Medland SE, Ikram MA, and Thompson PM
Subjects: Brain growth & development, Brain pathology, Genetic Loci genetics, Humans, Oncogene Protein v-akt genetics, Parkinson Disease genetics, Phenotype, Phosphatidylinositol 3-Kinases genetics, White People, Cognition physiology, Genetic Predisposition to Disease, Genome-Wide Association Study methods, Polymorphism, Single Nucleotide genetics
Abstract: Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρ genetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (N combined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.
Published: 2016
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18. Common polygenic variation in coeliac disease and confirmation of ZNF335 and NIFA as disease susceptibility loci.

Author: Coleman C, Quinn EM, Ryan AW, Conroy J, Trimble V, Mahmud N, Kennedy N, Corvin AP, Morris DW, Donohoe G, O'Morain C, MacMathuna P, Byrnes V, Kiat C, Trynka G, Wijmenga C, Kelleher D, Ennis S, Anney RJ, and McManus R
Subjects: Alleles, DNA-Binding Proteins, Genetic Predisposition to Disease, Genotype, Gliadin genetics, Gliadin immunology, HLA-DQ Antigens genetics, HLA-DQ Antigens immunology, Humans, Intestinal Mucosa pathology, Transcription Factors, Genome-Wide Association Study, Immune System, Intracellular Signaling Peptides and Proteins genetics, Nuclear Proteins genetics
Abstract: Coeliac disease (CD) is a chronic immune-mediated disease triggered by the ingestion of gluten. It has an estimated prevalence of approximately 1% in European populations. Specific HLA-DQA1 and HLA-DQB1 alleles are established coeliac susceptibility genes and are required for the presentation of gliadin to the immune system resulting in damage to the intestinal mucosa. In the largest association analysis of CD to date, 39 non-HLA risk loci were identified, 13 of which were new, in a sample of 12,014 individuals with CD and 12 228 controls using the Immunochip genotyping platform. Including the HLA, this brings the total number of known CD loci to 40. We have replicated this study in an independent Irish CD case-control population of 425 CD and 453 controls using the Immunochip platform. Using a binomial sign test, we show that the direction of the effects of previously described risk alleles were highly correlated with those reported in the Irish population, (P=2.2 × 10(-16)). Using the Polygene Risk Score (PRS) approach, we estimated that up to 35% of the genetic variance could be explained by loci present on the Immunochip (P=9 × 10(-75)). When this is limited to non-HLA loci, we explain a maximum of 4.5% of the genetic variance (P=3.6 × 10(-18)). Finally, we performed a meta-analysis of our data with the previous reports, identifying two further loci harbouring the ZNF335 and NIFA genes which now exceed genome-wide significance, taking the total number of CD susceptibility loci to 42.
Published: 2016
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19. Common genetic variants influence human subcortical brain structures.

Author: Hibar DP, Stein JL, Renteria ME, Arias-Vasquez A, Desrivières S, Jahanshad N, Toro R, Wittfeld K, Abramovic L, Andersson M, Aribisala BS, Armstrong NJ, Bernard M, Bohlken MM, Boks MP, Bralten J, Brown AA, Chakravarty MM, Chen Q, Ching CR, Cuellar-Partida G, den Braber A, Giddaluru S, Goldman AL, Grimm O, Guadalupe T, Hass J, Woldehawariat G, Holmes AJ, Hoogman M, Janowitz D, Jia T, Kim S, Klein M, Kraemer B, Lee PH, Olde Loohuis LM, Luciano M, Macare C, Mather KA, Mattheisen M, Milaneschi Y, Nho K, Papmeyer M, Ramasamy A, Risacher SL, Roiz-Santiañez R, Rose EJ, Salami A, Sämann PG, Schmaal L, Schork AJ, Shin J, Strike LT, Teumer A, van Donkelaar MM, van Eijk KR, Walters RK, Westlye LT, Whelan CD, Winkler AM, Zwiers MP, Alhusaini S, Athanasiu L, Ehrlich S, Hakobjan MM, Hartberg CB, Haukvik UK, Heister AJ, Hoehn D, Kasperaviciute D, Liewald DC, Lopez LM, Makkinje RR, Matarin M, Naber MA, McKay DR, Needham M, Nugent AC, Pütz B, Royle NA, Shen L, Sprooten E, Trabzuni D, van der Marel SS, van Hulzen KJ, Walton E, Wolf C, Almasy L, Ames D, Arepalli S, Assareh AA, Bastin ME, Brodaty H, Bulayeva KB, Carless MA, Cichon S, Corvin A, Curran JE, Czisch M, de Zubicaray GI, Dillman A, Duggirala R, Dyer TD, Erk S, Fedko IO, Ferrucci L, Foroud TM, Fox PT, Fukunaga M, Gibbs JR, Göring HH, Green RC, Guelfi S, Hansell NK, Hartman CA, Hegenscheid K, Heinz A, Hernandez DG, Heslenfeld DJ, Hoekstra PJ, Holsboer F, Homuth G, Hottenga JJ, Ikeda M, Jack CR Jr, Jenkinson M, Johnson R, Kanai R, Keil M, Kent JW Jr, Kochunov P, Kwok JB, Lawrie SM, Liu X, Longo DL, McMahon KL, Meisenzahl E, Melle I, Mohnke S, Montgomery GW, Mostert JC, Mühleisen TW, Nalls MA, Nichols TE, Nilsson LG, Nöthen MM, Ohi K, Olvera RL, Perez-Iglesias R, Pike GB, Potkin SG, Reinvang I, Reppermund S, Rietschel M, Romanczuk-Seiferth N, Rosen GD, Rujescu D, Schnell K, Schofield PR, Smith C, Steen VM, Sussmann JE, Thalamuthu A, Toga AW, Traynor BJ, Troncoso J, Turner JA, Valdés Hernández MC, van 't Ent D, van der Brug M, van der Wee NJ, van Tol MJ, Veltman DJ, Wassink TH, Westman E, Zielke RH, Zonderman AB, Ashbrook DG, Hager R, Lu L, McMahon FJ, Morris DW, Williams RW, Brunner HG, Buckner RL, Buitelaar JK, Cahn W, Calhoun VD, Cavalleri GL, Crespo-Facorro B, Dale AM, Davies GE, Delanty N, Depondt C, Djurovic S, Drevets WC, Espeseth T, Gollub RL, Ho BC, Hoffmann W, Hosten N, Kahn RS, Le Hellard S, Meyer-Lindenberg A, Müller-Myhsok B, Nauck M, Nyberg L, Pandolfo M, Penninx BW, Roffman JL, Sisodiya SM, Smoller JW, van Bokhoven H, van Haren NE, Völzke H, Walter H, Weiner MW, Wen W, White T, Agartz I, Andreassen OA, Blangero J, Boomsma DI, Brouwer RM, Cannon DM, Cookson MR, de Geus EJ, Deary IJ, Donohoe G, Fernández G, Fisher SE, Francks C, Glahn DC, Grabe HJ, Gruber O, Hardy J, Hashimoto R, Hulshoff Pol HE, Jönsson EG, Kloszewska I, Lovestone S, Mattay VS, Mecocci P, McDonald C, McIntosh AM, Ophoff RA, Paus T, Pausova Z, Ryten M, Sachdev PS, Saykin AJ, Simmons A, Singleton A, Soininen H, Wardlaw JM, Weale ME, Weinberger DR, Adams HH, Launer LJ, Seiler S, Schmidt R, Chauhan G, Satizabal CL, Becker JT, Yanek L, van der Lee SJ, Ebling M, Fischl B, Longstreth WT Jr, Greve D, Schmidt H, Nyquist P, Vinke LN, van Duijn CM, Xue L, Mazoyer B, Bis JC, Gudnason V, Seshadri S, Ikram MA, Martin NG, Wright MJ, Schumann G, Franke B, Thompson PM, and Medland SE
Subjects: Adolescent, Adult, Aged, Aged, 80 and over, Aging genetics, Apoptosis genetics, Caudate Nucleus anatomy & histology, Child, Female, Gene Expression Regulation, Developmental genetics, Genetic Loci genetics, Hippocampus anatomy & histology, Humans, Magnetic Resonance Imaging, Male, Membrane Proteins genetics, Middle Aged, Organ Size genetics, Putamen anatomy & histology, Sex Characteristics, Skull anatomy & histology, Young Adult, Brain anatomy & histology, Genetic Variation genetics, Genome-Wide Association Study
Abstract: The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.
Published: 2015
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20. Mosaic copy number variation in schizophrenia.

Author: Ruderfer DM, Chambert K, Moran J, Talkowski M, Chen ES, Gigek C, Gusella JF, Blackwood DH, Corvin A, Gurling HM, Hultman CM, Kirov G, Magnusson P, O'Donovan MC, Owen MJ, Pato C, St Clair D, Sullivan PF, Purcell SM, Sklar P, and Ernst C
Subjects: Case-Control Studies, Chromosomes, Human, Pair 7 genetics, Chromosomes, Human, Pair 8 genetics, DNA Mutational Analysis, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Lod Score, Mosaicism, Polymorphism, Single Nucleotide, Sequence Deletion, Trisomy, DNA Copy Number Variations, Schizophrenia genetics
Abstract: Recent reports suggest that somatic structural changes occur in the human genome, but how these genomic alterations might contribute to disease is unknown. Using samples collected as part of the International Schizophrenia Consortium (schizophrenia, n=3518; control, n=4238) recruited across multiple university research centers, we assessed single-nucleotide polymorphism genotyping arrays for evidence of chromosomal anomalies. Data from genotyping arrays on each individual were processed using Birdsuite and analyzed with PLINK. We validated potential chromosomal anomalies using custom nanostring probes and quantitative PCR. We estimate chromosomal alterations in the schizophrenia population to be 0.42%, which is not significantly different from controls (0.26%). We identified and validated a set of four extremely large (>10 Mb) chromosomal anomalies in subjects with schizophrenia, including a chromosome 8 trisomy and deletion of the q arm of chromosome 7. These data demonstrate that chromosomal anomalies are present at low frequency in blood cells of both control and schizophrenia subjects.
Published: 2013
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21. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Author: Sawcer S, Hellenthal G, Pirinen M, Spencer CC, Patsopoulos NA, Moutsianas L, Dilthey A, Su Z, Freeman C, Hunt SE, Edkins S, Gray E, Booth DR, Potter SC, Goris A, Band G, Oturai AB, Strange A, Saarela J, Bellenguez C, Fontaine B, Gillman M, Hemmer B, Gwilliam R, Zipp F, Jayakumar A, Martin R, Leslie S, Hawkins S, Giannoulatou E, D'alfonso S, Blackburn H, Martinelli Boneschi F, Liddle J, Harbo HF, Perez ML, Spurkland A, Waller MJ, Mycko MP, Ricketts M, Comabella M, Hammond N, Kockum I, McCann OT, Ban M, Whittaker P, Kemppinen A, Weston P, Hawkins C, Widaa S, Zajicek J, Dronov S, Robertson N, Bumpstead SJ, Barcellos LF, Ravindrarajah R, Abraham R, Alfredsson L, Ardlie K, Aubin C, Baker A, Baker K, Baranzini SE, Bergamaschi L, Bergamaschi R, Bernstein A, Berthele A, Boggild M, Bradfield JP, Brassat D, Broadley SA, Buck D, Butzkueven H, Capra R, Carroll WM, Cavalla P, Celius EG, Cepok S, Chiavacci R, Clerget-Darpoux F, Clysters K, Comi G, Cossburn M, Cournu-Rebeix I, Cox MB, Cozen W, Cree BA, Cross AH, Cusi D, Daly MJ, Davis E, de Bakker PI, Debouverie M, D'hooghe MB, Dixon K, Dobosi R, Dubois B, Ellinghaus D, Elovaara I, Esposito F, Fontenille C, Foote S, Franke A, Galimberti D, Ghezzi A, Glessner J, Gomez R, Gout O, Graham C, Grant SF, Guerini FR, Hakonarson H, Hall P, Hamsten A, Hartung HP, Heard RN, Heath S, Hobart J, Hoshi M, Infante-Duarte C, Ingram G, Ingram W, Islam T, Jagodic M, Kabesch M, Kermode AG, Kilpatrick TJ, Kim C, Klopp N, Koivisto K, Larsson M, Lathrop M, Lechner-Scott JS, Leone MA, Leppä V, Liljedahl U, Bomfim IL, Lincoln RR, Link J, Liu J, Lorentzen AR, Lupoli S, Macciardi F, Mack T, Marriott M, Martinelli V, Mason D, McCauley JL, Mentch F, Mero IL, Mihalova T, Montalban X, Mottershead J, Myhr KM, Naldi P, Ollier W, Page A, Palotie A, Pelletier J, Piccio L, Pickersgill T, Piehl F, Pobywajlo S, Quach HL, Ramsay PP, Reunanen M, Reynolds R, Rioux JD, Rodegher M, Roesner S, Rubio JP, Rückert IM, Salvetti M, Salvi E, Santaniello A, Schaefer CA, Schreiber S, Schulze C, Scott RJ, Sellebjerg F, Selmaj KW, Sexton D, Shen L, Simms-Acuna B, Skidmore S, Sleiman PM, Smestad C, Sørensen PS, Søndergaard HB, Stankovich J, Strange RC, Sulonen AM, Sundqvist E, Syvänen AC, Taddeo F, Taylor B, Blackwell JM, Tienari P, Bramon E, Tourbah A, Brown MA, Tronczynska E, Casas JP, Tubridy N, Corvin A, Vickery J, Jankowski J, Villoslada P, Markus HS, Wang K, Mathew CG, Wason J, Palmer CN, Wichmann HE, Plomin R, Willoughby E, Rautanen A, Winkelmann J, Wittig M, Trembath RC, Yaouanq J, Viswanathan AC, Zhang H, Wood NW, Zuvich R, Deloukas P, Langford C, Duncanson A, Oksenberg JR, Pericak-Vance MA, Haines JL, Olsson T, Hillert J, Ivinson AJ, De Jager PL, Peltonen L, Stewart GJ, Hafler DA, Hauser SL, McVean G, Donnelly P, and Compston A
Subjects: Alleles, Cell Differentiation immunology, Europe ethnology, Genome, Human genetics, Genome-Wide Association Study, HLA-A Antigens genetics, HLA-DR Antigens genetics, HLA-DRB1 Chains, Humans, Immunity, Cellular genetics, Major Histocompatibility Complex genetics, Polymorphism, Single Nucleotide genetics, Sample Size, T-Lymphocytes, Helper-Inducer cytology, T-Lymphocytes, Helper-Inducer immunology, Genetic Predisposition to Disease genetics, Immunity, Cellular immunology, Multiple Sclerosis genetics, Multiple Sclerosis immunology
Abstract: Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
Published: 2011
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22. Population structure and genome-wide patterns of variation in Ireland and Britain.

Author: O'Dushlaine CT, Morris D, Moskvina V, Kirov G, Gill M, Corvin A, Wilson JF, and Cavalleri GL
Subjects: Bayes Theorem, Bulgaria, Europe, Genotype, Geography, Haplotypes, Humans, Ireland, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Portugal, Principal Component Analysis, Scotland, Sweden, United Kingdom, Genetic Variation genetics, Genetics, Population, Genome, Human genetics
Abstract: Located off the northwestern coast of the European mainland, Britain and Ireland were among the last regions of Europe to be colonized by modern humans after the last glacial maximum. Further, the geographical location of Britain, and in particular of Ireland, is such that the impact of historical migration has been minimal. Genetic diversity studies applying the Y chromosome and mitochondrial systems have indicated reduced diversity and an increased population structure across Britain and Ireland relative to the European mainland. Such characteristics would have implications for genetic mapping studies of complex disease. We set out to further our understanding of the genetic architecture of the region from the perspective of (i) population structure, (ii) linkage disequilibrium (LD), (iii) homozygosity and (iv) haplotype diversity (HD). Analysis was conducted on 3654 individuals from Ireland, Britain (with regional sampling in Scotland), Bulgaria, Portugal, Sweden and the Utah HapMap collection. Our results indicate a subtle but clear genetic structure across Britain and Ireland, although levels of structure were reduced in comparison with average cross-European structure. We observed slightly elevated levels of LD and homozygosity in the Irish population compared with neighbouring European populations. We also report on a cline of HD across Europe with greatest levels in southern populations and lowest levels in Ireland and Scotland. These results are consistent with our understanding of the population history of Europe and promote Ireland and Scotland as relatively homogenous resources for genetic mapping of rare variants.
Published: 2010
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23. Genes predict village of origin in rural Europe.

Author: O'Dushlaine C, McQuillan R, Weale ME, Crouch DJ, Johansson A, Aulchenko Y, Franklin CS, Polašek O, Fuchsberger C, Corvin A, Hicks AA, Vitart V, Hayward C, Wild SH, Meitinger T, van Duijn CM, Gyllensten U, Wright AF, Campbell H, Pramstaller PP, Rudan I, and Wilson JF
Subjects: Europe, Family Health, Humans, Models, Genetic, Polymorphism, Single Nucleotide, Principal Component Analysis, Genetics, Population methods, Genome, Human genetics, Rural Population
Abstract: The genetic structure of human populations is important in population genetics, forensics and medicine. Using genome-wide scans and individuals with all four grandparents born in the same settlement, we here demonstrate remarkable geographical structure across 8-30 km in three different parts of rural Europe. After excluding close kin and inbreeding, village of origin could still be predicted correctly on the basis of genetic data for 89-100% of individuals.
Published: 2010
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24. Reduced occipital and prefrontal brain volumes in dysbindin-associated schizophrenia.

Author: Donohoe G, Frodl T, Morris D, Spoletini I, Cannon DM, Cherubini A, Caltagirone C, Bossù P, McDonald C, Gill M, Corvin AP, and Spalletta G
Subjects: Adult, Analysis of Variance, Brain Mapping, Dysbindin, Dystrophin-Associated Proteins, Electroencephalography methods, Female, Haplotypes, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging methods, Male, Memory Disorders etiology, Memory, Short-Term physiology, Middle Aged, Neuropsychological Tests, Psychiatric Status Rating Scales, Schizophrenia physiopathology, Carrier Proteins genetics, Genetic Predisposition to Disease, Occipital Lobe pathology, Prefrontal Cortex pathology, Schizophrenia genetics, Schizophrenia pathology
Abstract: A three-marker C-A-T dysbindin haplotype identified by Williams et al (PMID: 15066891) is associated with increased risk for schizophrenia, decreased mRNA expression, poorer cognitive performance, and early sensory processing deficits. We investigated whether this same dysbindin risk haplotype was also associated with structural variation in the gray matter volume (GMV). Using voxel-based morphometry, whole-volume analysis revealed significantly reduced GMVs in both the right dorsolateral prefrontal and left occipital cortex, corresponding to the behavioral findings of impaired spatial working memory and EEG findings of impaired visual processing already reported. These data provide important evidence of the influence of dysbindin risk variants on brain structure, and suggest a possible mechanism by which disease risk is being increased.
Published: 2010
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25. An assessment of the Irish population for large-scale genetic mapping studies involving epilepsy and other complex diseases.

Author: O'Dushlaine CT, Dolan C, Weale ME, Stanton A, Croke DT, Kalviainen R, Eriksson K, Kantanen AM, Gibson RA, Hosford D, Sisodiya SM, Gill M, Corvin AP, Morris DW, Delanty N, and Cavalleri GL
Subjects: Gene Frequency, Genetics, Population, Haplotypes, Humans, Ireland, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Chromosome Mapping, Epilepsy genetics, Multifactorial Inheritance genetics
Abstract: The recent completion of the International HapMap Project has rapidly advanced our understanding of linkage disequilibrium (LD) in the human genome. Today, tagging SNPs (tSNPs) can be quickly and easily selected and consequently HapMap data are regularly applied to both small- and large-scale genetic mapping studies. However, to correctly interpret the application of HapMap-derived tSNPs in a genetic mapping study, an understanding of how well HapMap data represents LD in the study population is critical. The Irish population had not previously been characterised in this way. Here, we do so using a set of 4424 SNPs selected from 279 candidate genes for epilepsy genotyped across 1118 healthy individuals from the Irish, British, Finnish and Australian populations. By considering the Irish population alongside surrounding European populations, our results confirm that the HapMap European-derived population accurately estimates patterning of LD in European descent populations. The Irish population appears notably well matched to the European HapMap population, and is markedly similar to the neighbouring British population. Although we were unable to detect significant substructure within the Irish population (a favourable result for genetic mapping), methods for controlling stratification should always be incorporated. This analysis therefore confirms that the genetic architecture of the Irish population is well suited to the study of complex traits and that tSNPs selected using the HapMap data can be confidently applied to the Irish population.
Published: 2008
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25 results on '"Corvin, Aiden"'

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

2. A polygenic resilience score moderates the genetic risk for schizophrenia

3. Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia

4. Biological insights from 108 schizophrenia-associated genetic loci

5. MiR-137-derived polygenic risk: effects on cognitive performance in patients with schizophrenia and controls

6. Identification of common variants associated with human hippocampal and intracranial volumes

7. The correlation between reading and mathematics ability at age twelve has a substantial genetic component

8. Don't give up on GWAS

9. The Wellcome trust UK-Irish bipolar affective disorder sibling-pair genome screen: first stage report

10. Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

11. Novel genetic loci associated with hippocampal volume

12. Investigating copy number variants in schizophrenia pedigrees using a new consensus pipeline called PECAN.

13. Rare coding variants in ten genes confer substantial risk for schizophrenia.

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

15. Methyl-CpG-binding protein 2 mediates overlapping mechanisms across brain disorders.

16. Cognitive Characterization of Schizophrenia Risk Variants Involved in Synaptic Transmission: Evidence of CACNA1C's Role in Working Memory.

17. Novel genetic loci underlying human intracranial volume identified through genome-wide association.

18. Common polygenic variation in coeliac disease and confirmation of ZNF335 and NIFA as disease susceptibility loci.

19. Common genetic variants influence human subcortical brain structures.

20. Mosaic copy number variation in schizophrenia.

21. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

22. Population structure and genome-wide patterns of variation in Ireland and Britain.

23. Genes predict village of origin in rural Europe.

24. Reduced occipital and prefrontal brain volumes in dysbindin-associated schizophrenia.

25. An assessment of the Irish population for large-scale genetic mapping studies involving epilepsy and other complex diseases.

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