Identification of common genetic risk variants for autism spectrum disorder

Grove, Jakob; Ripke, Stephan; Als, Thomas D.; Mattheisen, Manuel; Walters, Raymond K.; Won, Hyejung; Pallesen, Jonatan; Agerbo, Esben; Andreassen, Ole A.; Anney, Richard; Awashti, Swapnil; Belliveau, Rich; Bettella, Francesco; Buxbaum, Joseph D.; Bybjerg-Grauholm, Jonas; Bækvad-Hansen, Marie; Cerrato, Felecia; Chambert, Kimberly; Christensen, Jane H.; Churchhouse, Claire; Dellenvall, Karin; Demontis, Ditte; De Rubeis, Silvia; Devlin, Bernie; Djurovic, Srdjan; Dumont, Ashley L.; Goldstein, Jacqueline I.; Hansen, Christine S.; Hauberg, Mads Engel; Hollegaard, Mads V.; Hope, Sigrun; Howrigan, Daniel P.; Huang, Hailiang; Hultman, Christina M.; Klei, Lambertus; Maller, Julian; Martin, Joanna; Martin, Alicia R.; Moran, Jennifer L.; Nyegaard, Mette; Nærland, Terje; Palmer, Duncan S.; Palotie, Aarno; Pedersen, Carsten Bøcker; Pedersen, Marianne Giørtz; Dpoterba, Timothy; Poulsen, Jesper Buchhave; Pourcain, Beate St; Qvist, Per; Rehnström, Karola; Reichenberg, Abraham; Reichert, Jennifer; Robinson, Elise B.; Roeder, Kathryn; Roussos, Panos; Saemundsen, Evald; Sandin, Sven; Satterstrom, F. Kyle; Davey Smith, George; Stefansson, Hreinn; Steinberg, Stacy; Stevens, Christine R.; Sullivan, Patrick F.; Turley, Patrick; Walters, G. Bragi; Xinyi, Xu; Wray, Naomi R.; Trzaskowski, Maciej; Byrne, Enda M.; Abdellaoui, Abdel; Adams, Mark J.; Air, Tracy M.; Andlauer, Till F. M.; Bacanu, Silviu-Alin; Beekman, Aartjan T. F.; Bigdeli, Tim B.; Binder, Elisabeth B.; Blackwood, Douglas H. R.; Bryois, Julien; Buttenschøn, Henriette N.; Cai, Na; Castelao, Enrique; Clarke, Toni-Kim; Coleman, Jonathan R. I.; Colodro-Conde, Lucía; Couvy-Duchesne, Baptiste; Craddock, Nick; Crawford, Gregory E.; Davies, Gail; Deary, Ian J.; Degenhardt, Franziska; Derks, Eske M.; Direk, Nese; Dolan, Conor V.; Dunn, Erin C.; Eley, Thalia C.; Escott-Price, Valentina; Kiadeh, Farnush Farhadi Hassan; Finucane, Hilary K.; Forstner, Andreas J.; Frank, Josef; Gaspar, Héléna A.; Gill, Michael; Goes, Fernando S.; Gordon, Scott D.; Hall, Lynsey S.; Hansen, Thomas F.; Herms, Stefan; Hickie, Ian B.; Hoffmann, Per; Homuth, Georg; Horn, Carsten; Hottenga, Jouke-Jan; Ising, Marcus; Jansen, Rick; Jorgenson, Eric; Knowles, James A.; Kohane, Isaac S.; Kraft, Julia; Kretzschmar, Warren W.; Krogh, Jesper; Kutalik, Zoltán; Yihan, Li; Lind, Penelope A.; Macintyre, Donald J.; Mackinnon, Dean F.; Maier, Robert M.; Maier, Wolfgang; Marchini, Jonathan; Mbarek, Hamdi; Mcgrath, Patrick; Mcguffin, Peter; Medland, Sarah E.; Mehta, Divya; Middeldorp, Christel M.; Mihailov, Evelin; Milaneschi, Yuri; Milani, Lili; Mondimore, Francis M.; Montgomery, Grant W.; Mostafavi, Sara; Mullins, Niamh; Nauck, Matthias; Bernard, Ng; Nivard, Michel G.; Nyholt, Dale R.; O’Reilly, Paul F.; Oskarsson, Hogni; Owen, Michael J.; Painter, Jodie N.; Peterson, Roseann E.; Pettersson, Erik; Peyrot, Wouter J.; Pistis, Giorgio; Posthuma, Danielle; Quiroz, Jorge A.; Rice, John P.; Riley, Brien P.; Rivera, Margarita; Mirza, Saira Saeed; Schoevers, Robert; Schulte, Eva C.; Shen, Ling; Shi, Jianxin; Shyn, Stanley I.; Sigurdsson, Engilbert; Sinnamon, Grant C. B.; Smit, Johannes H.; Smith, Daniel J.; Streit, Fabian; Strohmaier, Jana; Tansey, Katherine E.; Teismann, Henning; Teumer, Alexander; Thompson, Wesley; Thomson, Pippa A.; Thorgeirsson, Thorgeir E.; Traylor, Matthew; Treutlein, Jens; Trubetskoy, Vassily; Uitterlinden, André G.; Umbricht, Daniel; Van der Auwera, Sandra; van Hemert, Albert M.; Viktorin, Alexander; Visscher, Peter M.; Wang, Yunpeng; Webb, Bradley T.; Weinsheimer, Shantel Marie; Wellmann, Jürgen; Willemsen, Gonneke; Witt, Stephanie H.; Yang, Wu; Hualin S., Xi; Yang, Jian; Zhang, Futao; Arolt, Volker; Baune, Bernhard T.; Berger, Klaus; Boomsma, Dorret I.; Cichon, Sven; Dannlowski, Udo; de Geus, E. J. C.; Depaulo, J. Raymond; Domenici, Enrico; Domschke, Katharina; Esko, Tõnu; Grabe, Hans J.; Hamilton, Steven P.; Hayward, Caroline; Heath, Andrew C.; Kendler, Kenneth S.; Kloiber, Stefan; Lewis, Glyn; Qingqin S., Li; Lucae, Susanne; Madden, Pamela A. F.; Magnusson, Patrik K.; Martin, Nicholas G.; Mcintosh, Andrew M.; Metspalu, Andres; Müller-Myhsok, Bertram; Nöthen, Markus M.; O’Donovan, Michael C.; Paciga, Sara A.; Pedersen, Nancy L.; Penninx, Brenda W. J. H.; Perlis, Roy H.; Porteous, David J.; Potash, James B.; Preisig, Martin; Rietschel, Marcella; Schaefer, Catherine; Schulze, Thomas G.; Smoller, Jordan W.; Tiemeier, Henning; Uher, Rudolf; Völzke, Henry; Weissman, Myrna M.; Lewis, Cathryn M.; Levinson, Douglas F.; Breen, Gerome; Agee, Michelle; Alipanahi, Babak; Auton, Adam; Bell, Robert K.; Bryc, Katarzyna; Elson, Sarah L.; Fontanillas, Pierre; Furlotte, Nicholas A.; Hromatka, Bethann S.; Huber, Karen E.; Kleinman, Aaron; Litterman, Nadia K.; Mcintyre, Matthew H.; Mountain, Joanna L.; Noblin, Elizabeth S.; Northover, Carrie A. M.; Pitts, Steven J.; Sathirapongsasuti, J. Fah; Sazonova, Olga V.; Shelton, Janie F.; Shringarpure, Suyash; Tung, Joyce Y.; Vacic, Vladimir; Wilson, Catherine H.; Stefansson, Kari; Geschwind, Daniel H.; Nordentoft, Merete; Hougaard, David M.; Werge, Thomas; Mors, Ole; Mortensen, Preben Bo; Neale, Benjamin M.; Daly, Mark J.; Børglum, Anders D.

doi:10.1038/s41588-019-0344-8

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.

Identification of common genetic risk variants for autism spectrum disorder / Grove, Jakob; Ripke, Stephan; Als, Thomas D.; Mattheisen, Manuel; Walters, Raymond K.; Won, Hyejung; Pallesen, Jonatan; Agerbo, Esben; Andreassen, Ole A.; Anney, Richard; Awashti, Swapnil; Belliveau, Rich; Bettella, Francesco; Buxbaum, Joseph D.; Bybjerg-Grauholm, Jonas; Bækvad-Hansen, Marie; Cerrato, Felecia; Chambert, Kimberly; Christensen, Jane H.; Churchhouse, Claire; Dellenvall, Karin; Demontis, Ditte; De Rubeis, Silvia; Devlin, Bernie; Djurovic, Srdjan; Dumont, Ashley L.; Goldstein, Jacqueline I.; Hansen, Christine S.; Hauberg, Mads Engel; Hollegaard, Mads V.; Hope, Sigrun; Howrigan, Daniel P.; Huang, Hailiang; Hultman, Christina M.; Klei, Lambertus; Maller, Julian; Martin, Joanna; Martin, Alicia R.; Moran, Jennifer L.; Nyegaard, Mette; Nærland, Terje; Palmer, Duncan S.; Palotie, Aarno; Pedersen, Carsten Bøcker; Pedersen, Marianne Giørtz; Dpoterba, Timothy; Poulsen, Jesper Buchhave; Pourcain, Beate St; Qvist, Per; Rehnström, Karola; Reichenberg, Abraham; Reichert, Jennifer; Robinson, Elise B.; Roeder, Kathryn; Roussos, Panos; Saemundsen, Evald; Sandin, Sven; Satterstrom, F. Kyle; Davey Smith, George; Stefansson, Hreinn; Steinberg, Stacy; Stevens, Christine R.; Sullivan, Patrick F.; Turley, Patrick; Walters, G. Bragi; Xu, Xinyi; Wray, Naomi R.; Trzaskowski, Maciej; Byrne, Enda M.; Abdellaoui, Abdel; Adams, Mark J.; Air, Tracy M.; Andlauer, Till F. M.; Bacanu, Silviu-Alin; Beekman, Aartjan T. F.; Bigdeli, Tim B.; Binder, Elisabeth B.; Blackwood, Douglas H. R.; Bryois, Julien; Buttenschøn, Henriette N.; Cai, Na; Castelao, Enrique; Clarke, Toni-Kim; Coleman, Jonathan R. I.; Colodro-Conde, Lucía; Couvy-Duchesne, Baptiste; Craddock, Nick; Crawford, Gregory E.; Davies, Gail; Deary, Ian J.; Degenhardt, Franziska; Derks, Eske M.; Direk, Nese; Dolan, Conor V.; Dunn, Erin C.; Eley, Thalia C.; Escott-Price, Valentina; Kiadeh, Farnush Farhadi Hassan; Finucane, Hilary K.; Forstner, Andreas J.; Frank, Josef; Gaspar, Héléna A.; Gill, Michael; Goes, Fernando S.; Gordon, Scott D.; Hall, Lynsey S.; Hansen, Thomas F.; Herms, Stefan; Hickie, Ian B.; Hoffmann, Per; Homuth, Georg; Horn, Carsten; Hottenga, Jouke-Jan; Ising, Marcus; Jansen, Rick; Jorgenson, Eric; Knowles, James A.; Kohane, Isaac S.; Kraft, Julia; Kretzschmar, Warren W.; Krogh, Jesper; Kutalik, Zoltán; Li, Yihan; Lind, Penelope A.; Macintyre, Donald J.; Mackinnon, Dean F.; Maier, Robert M.; Maier, Wolfgang; Marchini, Jonathan; Mbarek, Hamdi; Mcgrath, Patrick; Mcguffin, Peter; Medland, Sarah E.; Mehta, Divya; Middeldorp, Christel M.; Mihailov, Evelin; Milaneschi, Yuri; Milani, Lili; Mondimore, Francis M.; Montgomery, Grant W.; Mostafavi, Sara; Mullins, Niamh; Nauck, Matthias; Ng, Bernard; Nivard, Michel G.; Nyholt, Dale R.; O’Reilly, Paul F.; Oskarsson, Hogni; Owen, Michael J.; Painter, Jodie N.; Peterson, Roseann E.; Pettersson, Erik; Peyrot, Wouter J.; Pistis, Giorgio; Posthuma, Danielle; Quiroz, Jorge A.; Rice, John P.; Riley, Brien P.; Rivera, Margarita; Mirza, Saira Saeed; Schoevers, Robert; Schulte, Eva C.; Shen, Ling; Shi, Jianxin; Shyn, Stanley I.; Sigurdsson, Engilbert; Sinnamon, Grant C. B.; Smit, Johannes H.; Smith, Daniel J.; Streit, Fabian; Strohmaier, Jana; Tansey, Katherine E.; Teismann, Henning; Teumer, Alexander; Thompson, Wesley; Thomson, Pippa A.; Thorgeirsson, Thorgeir E.; Traylor, Matthew; Treutlein, Jens; Trubetskoy, Vassily; Uitterlinden, André G.; Umbricht, Daniel; Van der Auwera, Sandra; van Hemert, Albert M.; Viktorin, Alexander; Visscher, Peter M.; Wang, Yunpeng; Webb, Bradley T.; Weinsheimer, Shantel Marie; Wellmann, Jürgen; Willemsen, Gonneke; Witt, Stephanie H.; Wu, Yang; Xi, Hualin S.; Yang, Jian; Zhang, Futao; Arolt, Volker; Baune, Bernhard T.; Berger, Klaus; Boomsma, Dorret I.; Cichon, Sven; Dannlowski, Udo; de Geus, E. J. C.; Depaulo, J. Raymond; Domenici, Enrico; Domschke, Katharina; Esko, Tõnu; Grabe, Hans J.; Hamilton, Steven P.; Hayward, Caroline; Heath, Andrew C.; Kendler, Kenneth S.; Kloiber, Stefan; Lewis, Glyn; Li, Qingqin S.; Lucae, Susanne; Madden, Pamela A. F.; Magnusson, Patrik K.; Martin, Nicholas G.; Mcintosh, Andrew M.; Metspalu, Andres; Müller-Myhsok, Bertram; Nöthen, Markus M.; O’Donovan, Michael C.; Paciga, Sara A.; Pedersen, Nancy L.; Penninx, Brenda W. J. H.; Perlis, Roy H.; Porteous, David J.; Potash, James B.; Preisig, Martin; Rietschel, Marcella; Schaefer, Catherine; Schulze, Thomas G.; Smoller, Jordan W.; Tiemeier, Henning; Uher, Rudolf; Völzke, Henry; Weissman, Myrna M.; Lewis, Cathryn M.; Levinson, Douglas F.; Breen, Gerome; Agee, Michelle; Alipanahi, Babak; Auton, Adam; Bell, Robert K.; Bryc, Katarzyna; Elson, Sarah L.; Fontanillas, Pierre; Furlotte, Nicholas A.; Hromatka, Bethann S.; Huber, Karen E.; Kleinman, Aaron; Litterman, Nadia K.; Mcintyre, Matthew H.; Mountain, Joanna L.; Noblin, Elizabeth S.; Northover, Carrie A. M.; Pitts, Steven J.; Sathirapongsasuti, J. Fah; Sazonova, Olga V.; Shelton, Janie F.; Shringarpure, Suyash; Tung, Joyce Y.; Vacic, Vladimir; Wilson, Catherine H.; Stefansson, Kari; Geschwind, Daniel H.; Nordentoft, Merete; Hougaard, David M.; Werge, Thomas; Mors, Ole; Mortensen, Preben Bo; Neale, Benjamin M.; Daly, Mark J.; Børglum, Anders D.. - In: NATURE GENETICS. - ISSN 1061-4036. - 2019, 51:3(2019), pp. 431-444. [10.1038/s41588-019-0344-8]