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Item Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression(Nature Publishing Group, 2018-01) Culverhouse, Robert C.; Saccone, Nancy L.; Horton, Amy C.; Ma, Yinjiao; Anstey, Kaarin J.; Banaschewski, Tobias; Burmeister, Margit; Cohen-Woods, Sarah; Etain, Bruno; Fisher, Helen L.; Goldman, Noreen; Guillaume, Sébastien; Horwood, John; Juhasz, Gabriella; Lester, Kathryn J.; Mandelli, Laura; Middeldorp, Christel M.; Olié, Emilie; Villafuerte, Sandra; Air, Tracy M.; Araya, Ricardo; Bowes, Lucy; Burns, Richard; Byrne, Enda M.; Coffey, Carolyn; Coventry, William L.; Gawronski, Katerina; Glei, Dana; Hatzimanolis, Alex; Hottenga, Jouke-Jan; Jaussent, Isabelle; Jawahar, Catharine; Jennen-Steinmetz, Christine; Kramer, John R.; Lajnef, Mohamed; Little, Keriann; zu Schwabedissen, Henriette Meyer; Nauck, Matthias; Nederhof, Esther; Petschner, Peter; Peyrot, Wouter J.; Schwahn, Christian; Sinnamon, Grant; Stacey, David; Tian, Yan; Toben, Catherine; Auwera, Sandra Van der; Wainwright, Nick; Wang, Jen-Chyong; Willemsen, Gonneke; Anderson, Ian M.; Arolt, Volker; Åslund, Cecilia; Bagdy, Gyorgy; Baune, Bernhard T.; Bellivier, Frank; Boomsma, Dorret I.; Courtet, Philippe; Dannlowski, Udo; de Geus, Eco J.C.; Deakin, John F. W.; Easteal, Simon; Eley, Thalia; Fergusson, David M.; Goate, Alison M.; Gonda, Xenia; Grabe, Hans J.; Holzman, Claudia; Johnson, Eric O.; Kennedy, Martin; Laucht, Manfred; Martin, Nicholas G.; Munafò, Marcus; Nilsson, Kent W.; Oldehinkel, Albertine J.; Olsson, Craig; Ormel, Johan; Otte, Christian; Patton, George C.; Penninx, Brenda W.J.H.; Ritchie, Karen; Sarchiapone, Marco; Scheid, JM; Serretti, Alessandro; Smit, Johannes H.; Stefanis, Nicholas C.; Surtees, Paul G.; Völzke, Henry; Weinstein, Maxine; Whooley, Mary; Nurnberger, John I., Jr.; Breslau, Naomi; Bierut, Laura J.; Psychiatry, School of MedicineThe hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research, and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 datasets containing 38 802 European-ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analyzed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis1) with qualifying unpublished data were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction, and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalizable, but must be of modest effect size and only observable in limited situations.Item Common genetic variants influence human subcortical brain structures(Nature Publishing Group, 2015-04-09) Hibar, Derrek P.; Stein, Jason L.; Renteria, Miguel E.; Arias-Vasquez, Alejandro; Desrivières, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S.; Armstrong, Nicola J.; Bernard, Manon; Bohlken, Marc M.; Boks, Marco P.; Bralten, Janita; Brown, Andrew A.; Chakravarty, M. Mallar; Chen, Qiang; Ching, Christopher R. K.; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L.; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J.; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H.; Olde Loohuis, Loes M.; Luciano, Michelle; Macare, Christine; Mather, Karen A.; Mattheisen, Manuel; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L.; Roiz-Santiañez, Roberto; Rose, Emma J.; Salami, Alireza; Sämann, Philipp G.; Schmaal, Lianne; Schork, Andrew J.; Shin, Jean; Strike, Lachlan T.; Teumer, Alexander; van Donkelaar, Marjolein M. J.; van Eijk, Kristel R.; Walters, Raymond K.; Westlye, Lars T.; Whelan, Christopher D.; Winkler, Anderson M.; Zwiers, Marcel P.; Alhusaini, Saud; Athanasiu, Lavinia; Ehrlich, Stefan; Hakobjan, Marina M. H.; Hartberg, Cecilie B.; Haukvik, Unn K.; Heister, Angelien J. G. A. M.; Hoehn, David; Kasperaviciute, Dalia; Liewald, David C. M.; Lopez, Lorna M.; Makkinje, Remco R. R.; Matarin, Mar; Naber, Marlies A. M.; McKay, D. Reese; Needham, Margaret; Nugent, Allison C.; Pütz, Benno; Royle, Natalie A.; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S. L.; van Hulzen, Kimm J. E.; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A.; Bastin, Mark E.; Brodaty, Henry; Bulayeva, Kazima B.; Carless, Melanie A.; Cichon, Sven; Corvin, Aiden; Curran, Joanne E.; Czisch, Michael; de Zubicaray, Greig I.; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D.; Erk, Susanne; Fedko, Iryna O.; Ferrucci, Luigi; Foroud, Tatiana M.; Fox, Peter T.; Fukunaga, Masaki; Gibbs, J. Raphael; Göring, Harald H. H.; Green, Robert C.; Guelfi, Sebastian; Hansell, Narelle K.; Hartman, Catharina A.; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G.; Heslenfeld, Dirk J.; Hoekstra, Pieter J.; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Ikeda, Masashi; Jack, Clifford R.; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W.; Kochunov, Peter; Kwok, John B.; Lawrie, Stephen M.; Liu, Xinmin; Longo, Dan L.; McMahon, Katie L.; Meisenzahl, Eva; Melle, Ingrid; Mohnke, Sebastian; Montgomery, Grant W.; Mostert, Jeanette C.; Mühleisen, Thomas W.; Nalls, Michael A.; Nichols, Thomas E.; Nilsson, Lars G.; Nöthen, Markus M.; Ohi, Kazutaka; Olvera, Rene L.; Perez-Iglesias, Rocio; Pike, G. Bruce; Potkin, Steven G.; Reinvang, Ivar; Reppermund, Simone; Rietschel, Marcella; Romanczuk-Seiferth, Nina; Rosen, Glenn D.; Rujescu, Dan; Schnell, Knut; Schofield, Peter R.; Smith, Colin; Steen, Vidar M.; Sussmann, Jessika E.; Thalamuthu, Anbupalam; Toga, Arthur W.; Traynor, Bryan J.; Troncoso, Juan; Turner, Jessica A.; Valdés Hernández, Maria C.; van ’t Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J. A.; van Tol, Marie-Jose; Veltman, Dick J.; Wassink, Thomas H.; Westman, Eric; Zielke, Ronald H.; Zonderman, Alan B.; Ashbrook, David G.; Hager, Reinmar; Lu, Lu; McMahon, Francis J.; Morris, Derek W.; Williams, Robert W.; Brunner, Han G.; Buckner, Randy L.; Buitelaar, Jan K.; Cahn, Wiepke; Calhoun, Vince D.; Cavalleri, Gianpiero L.; Crespo-Facorro, Benedicto; Dale, Anders M.; Davies, Gareth E.; Delanty, Norman; Depondt, Chantal; Djurovic, Srdjan; Drevets, Wayne C.; Espeseth, Thomas; Gollub, Randy L.; Ho, Beng-Choon; Hoffmann, Wolfgang; Hosten, Norbert; Kahn, René S.; Le Hellard, Stephanie; Meyer-Lindenberg, Andreas; Müller-Myhsok, Bertram; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W. J. H.; Roffman, Joshua L.; Sisodiya, Sanjay M.; Smoller, Jordan W.; van Bokhoven, Hans; van Haren, Neeltje E. M.; Völzke, Henry; Walter, Henrik; Weiner, Michael W.; Wen, Wei; White, Tonya; Agartz, Ingrid; Andreassen, Ole A.; Blangero, John; Boomsma, Dorret I.; Brouwer, Rachel M.; Cannon, Dara M.; Cookson, Mark R.; de Geus, Eco J. C.; Deary, Ian J.; Donohoe, Gary; Fernández, Guillén; Fisher, Simon E.; Francks, Clyde; Glahn, David C.; Grabe, Hans J.; Gruber, Oliver; Hardy, John; Hashimoto, Ryota; Hulshoff Pol, Hilleke E.; Jönsson, Erik G.; Kloszewska, Iwona; Lovestone, Simon; Mattay, Venkata S.; Mecocci, Patrizia; McDonald, Colm; McIntosh, Andrew M.; Ophoff, Roel A.; Paus, Tomas; Pausova, Zdenka; Ryten, Mina; Sachdev, Perminder S.; Saykin, Andrew J.; Simmons, Andy; Singleton, Andrew; Soininen, Hilkka; Wardlaw, Joanna M.; Weale, Michael E.; Weinberger, Daniel R.; Adams, Hieab H. H.; Launer, Lenore J.; Seiler, Stephan; Schmidt, Reinhold; Chauhan, Ganesh; Satizabal, Claudia L.; Becker, James T.; Yanek, Lisa; van der Lee, Sven J.; Ebling, Maritza; Fischl, Bruce; Longstreth, W. T.; Greve, Douglas; Schmidt, Helena; Nyquist, Paul; Vinke, Louis N.; van Duijn, Cornelia M.; Xue, Luting; Mazoyer, Bernard; Bis, Joshua C.; Gudnason, Vilmundur; Seshadri, Sudha; Ikram, M. Arfan; Martin, Nicholas G.; Wright, Margaret J.; Schumann, Gunter; Franke, Barbara; Thompson, Paul M.; Medland, Sarah E.; Department of Radiology and Imaging Sciences, IU School of MedicineThe 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 (rs945270Item Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors(Elsevier, 2022-02-01) Mullins, Niamh; Kang, JooEun; Campos, Adrian I.; Coleman, Jonathan R. I.; Edwards, Alexis C.; Galfalvy, Hanga; Levey, Daniel F.; Lori, Adriana; Shabalin, Andrey; Starnawska, Anna; Su, Mei-Hsin; Watson, Hunna J.; Adams, Mark; Awasthi, Swapnil; Gandal, Michael; Hafferty, Jonathan D.; Hishimoto, Akitoyo; Kim, Minsoo; Okazaki, Satoshi; Otsuka, Ikuo; Ripke, Stephan; Ware, Erin B.; Bergen, Andrew W.; Berrettini, Wade H.; Bohus, Martin; Brandt, Harry; Chang, Xiao; Chen, Wei J.; Chen, Hsi-Chung; Crawford, Steven; Crow, Scott; DiBlasi, Emily; Duriez, Philibert; Fernández-Aranda, Fernando; Fichter, Manfred M.; Gallinger, Steven; Glatt, Stephen J.; Gorwood, Philip; Guo, Yiran; Hakonarson, Hakon; Halmi, Katherine A.; Hwu, Hai-Gwo; Jain, Sonia; Jamain, Stéphane; Jiménez-Murcia, Susana; Johnson, Craig; Kaplan, Allan S.; Kaye, Walter H.; Keel, Pamela K.; Kennedy, James L.; Klump, Kelly L.; Li, Dong; Liao, Shih-Cheng; Lieb, Klaus; Lilenfeld, Lisa; Liu, Chih-Min; Magistretti, Pierre J.; Marshall, Christian R.; Mitchell, James E.; Monson, Eric T.; Myers, Richard M.; Pinto, Dalila; Powers, Abigail; Ramoz, Nicolas; Roepke, Stefan; Rozanov, Vsevolod; Scherer, Stephen W.; Schmahl, Christian; Sokolowski, Marcus; Strober, Michael; Thornton, Laura M.; Treasure, Janet; Tsuang, Ming T.; Witt, Stephanie H.; Woodside, D. Blake; Yilmaz, Zeynep; Zillich, Lea; Adolfsson, Rolf; Agartz, Ingrid; Air, Tracy M.; Alda, Martin; Alfredsson, Lars; Andreassen, Ole A.; Anjorin, Adebayo; Appadurai, Vivek; Artigas, María Soler; Van der Auwera, Sandra; Azevedo, M. Helena; Bass, Nicholas; Bau, Claiton H. D.; Baune, Bernhard T.; Bellivier, Frank; Berger, Klaus; Biernacka, Joanna M.; Bigdeli, Tim B.; Binder, Elisabeth B.; Boehnke, Michael; Boks, Marco P.; Bosch, Rosa; Braff, David L.; Bryant, Richard; Budde, Monika; Byrne, Enda M.; Cahn, Wiepke; Casas, Miguel; Castelao, Enrique; Cervilla, Jorge A.; Chaumette, Boris; Cichon, Sven; Corvin, Aiden; Craddock, Nicholas; Craig, David; Degenhardt, Franziska; Djurovic, Srdjan; Edenberg, Howard J.; Fanous, Ayman H.; Foo, Jerome C.; Forstner, Andreas J.; Frye, Mark; Fullerton, Janice M.; Gatt, Justine M.; Gejman, Pablo V.; Giegling, Ina; Grabe, Hans J.; Green, Melissa J.; Grevet, Eugenio H.; Grigoroiu-Serbanescu, Maria; Gutierrez, Blanca; Guzman-Parra, Jose; Hamilton, Steven P.; Hamshere, Marian L.; Hartmann, Annette; Hauser, Joanna; Heilmann-Heimbach, Stefanie; Hoffmann, Per; Ising, Marcus; Jones, Ian; Jones, Lisa A.; Jonsson, Lina; Kahn, René S.; Kelsoe, John R.; Kendler, Kenneth S.; Kloiber, Stefan; Koenen, Karestan C.; Kogevinas, Manolis; Konte, Bettina; Krebs, Marie-Odile; Landén, Mikael; Lawrence, Jacob; Leboyer, Marion; Lee, Phil H.; Levinson, Douglas F.; Liao, Calwing; Lissowska, Jolanta; Lucae, Susanne; Mayoral, Fermin; McElroy, Susan L.; McGrath, Patrick; McGuffin, Peter; McQuillin, Andrew; Medland, Sarah E.; Mehta, Divya; Melle, Ingrid; Milaneschi, Yuri; Mitchell, Philip B.; Molina, Esther; Morken, Gunnar; Mortensen, Preben Bo; Müller-Myhsok, Bertram; Nievergelt, Caroline; Nimgaonkar, Vishwajit; Nöthen, Markus M.; O’Donovan, Michael C.; Ophoff, Roel A.; Owen, Michael J.; Pato, Carlos; Pato, Michele T.; Penninx, Brenda W. J. H.; Pimm, Jonathan; Pistis, Giorgio; Potash, James B.; Power, Robert A.; Preisig, Martin; Quested, Digby; Ramos-Quiroga, Josep Antoni; Reif, Andreas; Ribasés , Marta; Richarte, Vanesa; Rietschel, Marcella; Rivera, Margarita; Roberts, Andrea; Roberts, Gloria; Rouleau, Guy A.; Rovaris, Diego L.; Rujescu, Dan; Sánchez-Mora, Cristina; Sanders, Alan R.; Schofield, Peter R.; Schulze, Thomas G.; Scott, Laura J.; Serretti, Alessandro; Shi, Jianxin; Shyn, Stanley I.; Sirignano, Lea; Sklar, Pamela; Smeland, Olav B.; Smoller, Jordan W.; Sonuga-Barke, Edmund J. S.; Spalletta, Gianfranco; Strauss, John S.; Świątkowska, Beata; Trzaskowski, Maciej; Turecki, Gustavo; Vilar-Ribó, Laura; Vincent, John B.; Völzke, Henry; Walters, James T. R.; Weickert, Cynthia Shannon; Weickert, Thomas W.; Weissman, Myrna M.; Williams, Leanne M.; Wray, Naomi R.; Zai, Clement C.; Ashley-Koch, Allison E.; Beckham, Jean C.; Hauser, Elizabeth R.; Hauser, Michael A.; Kimbrel, Nathan A.; Lindquist, Jennifer H.; McMahon, Benjamin; Oslin, David W.; Qin, Xuejun; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Bipolar Disorder Working Group of the Psychiatric Genomics Consortium; Eating Disorders Working Group of the Psychiatric Genomics Consortium; German Borderline Genomics Consortium; MVP Suicide Exemplar Workgroup; VA Million Veteran Program; Medical & Molecular Genetics, School of MedicineBACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Item ENIGMA and the individual: Predicting factors that affect the brain in 35 countries worldwide(Elsevier, 2017-01-15) Thompson, Paul M.; Andreassen, Ole A.; Arias-Vasquez, Alejandro; Bearden, Carrie E.; Boedhoe, Premika S.; Brouwer, Rachel M.; Buckner, Randy L.; Buitelaar, Jan K.; Bulayeva, Kazima B.; Cannon, Dara M.; Cohen, Ronald A.; Conrod, Patricia J.; Dale, Anders M.; Deary, Ian J.; Dennis, Emily L.; de Reus, Marcel A.; Desrivieres, Sylvane; Dima, Danai; Donohoe, Gary; Fisher, Simon E.; Fouche, Jean-Paul; Francks, Clyde; Frangou, Sophia; Franke, Barbara; Ganjgahi, Habib; Garavan, Hugh; Glahn, David C.; Grabe, Hans J.; Guadalupe, Tulio; Gutman, Boris A.; Hashimoto, Ryota; Hibar, Derrek P.; Holland, Dominic; Hoogman, Martine; Pol, Hilleke E. Hulshoff; Hosten, Norbert; Jahanshad, Neda; Kelly, Sinead; Kochunov, Peter; Kremen, William S.; Lee, Phil H.; Mackey, Scott; Martin, Nicholas G.; Mazoyer, Bernard; McDonald, Colm; Medland, Sarah E.; Morey, Rajendra A.; Nichols, Thomas E.; Paus, Tomas; Pausova, Zdenka; Schmaal, Lianne; Schumann, Gunter; Shen, Li; Sisodiya, Sanjay M.; Smit, Dirk J.A.; Smoller, Jordan W.; Stein, Dan J.; Stein, Jason L.; Toro, Roberto; Turner, Jessica A.; Heuvel, Martijn P. van den; Heuvel, Odile L. van den; Erp, Theo G.M. van; Rooij, Daan van; Veltman, Dick J.; Walter, Henrik; Wang, Yalin; Wardlaw, Joanna M.; Whelan, Christopher D.; Wright, Margaret J.; Ye, Jieping; ENIGMA Consortium; Radiology and Imaging Sciences, School of MedicineIn this review, we discuss recent work by the ENIGMA Consortium (http://enigma.ini.usc.edu) – a global alliance of over 500 scientists spread across 200 institutions in 35 countries collectively analyzing brain imaging, clinical, and genetic data. Initially formed to detect genetic influences on brain measures, ENIGMA has grown to over 30 working groups studying 12 major brain diseases by pooling and comparing brain data. In some of the largest neuroimaging studies to date – of schizophrenia and major depression – ENIGMA has found replicable disease effects on the brain that are consistent worldwide, as well as factors that modulate disease effects. In partnership with other consortia including ADNI, CHARGE, IMAGEN and others1, ENIGMA's genomic screens – now numbering over 30,000 MRI scans – have revealed at least 8 genetic loci that affect brain volumes. Downstream of gene findings, ENIGMA has revealed how these individual variants – and genetic variants in general – may affect both the brain and risk for a range of diseases. The ENIGMA consortium is discovering factors that consistently affect brain structure and function that will serve as future predictors linking individual brain scans and genomic data. It is generating vast pools of normative data on brain measures – from tens of thousands of people – that may help detect deviations from normal development or aging in specific groups of subjects. We discuss challenges and opportunities in applying these predictors to individual subjects and new cohorts, as well as lessons we have learned in ENIGMA's efforts so far.Item Genetic architecture of subcortical brain structures in 38,851 individuals(Nature, 2019-11) Satizabal, Claudia L.; Adams, Hieab H. H.; Hibar, Derrek P.; White, Charles C.; Knol, Maria J.; Stein, Jason L.; Scholz, Markus; Sargurupremraj, Muralidharan; Jahanshad, Neda; Roshchupkin, Gennady V.; Smith, Albert V.; Bis, Joshua C.; Jian, Xueqiu; Luciano, Michelle; Hofer, Edith; Teumer, Alexander; van der Lee, Sven J.; Yang, Jingyun; Yanek, Lisa R.; Lee, Tom V.; Li, Shuo; Hu, Yanhui; Koh, Jia Yu; Eicher, John D.; Desrivières, Sylvane; Arias-Vasquez, Alejandro; Chauhan, Ganesh; Athanasiu, Lavinia; Rentería, Miguel E.; Kim, Sungeun; Hoehn, David; Armstrong, Nicola J.; Chen, Qiang; Holmes, Avram J.; den Braber, Anouk; Kloszewska, Iwona; Andersson, Micael; Espeseth, Thomas; Grimm, Oliver; Abramovic, Lucija; Alhusaini, Saud; Milaneschi, Yuri; Papmeyer, Martina; Axelsson, Tomas; Ehrlich, Stefan; Roiz-Santiañez, Roberto; Kraemer, Bernd; Håberg, Asta K.; Jones, Hannah J.; Pike, G. Bruce; Stein, Dan J.; Stevens, Allison; Bralten, Janita; Vernooij, Meike W.; Harris, Tamara B.; Filippi, Irina; Witte, A. Veronica; Guadalupe, Tulio; Wittfeld, Katharina; Mosley, Thomas H.; Becker, James T.; Doan, Nhat Trung; Hagenaars, Saskia P.; Saba, Yasaman; Cuellar-Partida, Gabriel; Amin, Najaf; Hilal, Saima; Nho, Kwangsik; Mirza-Schreiber, Nazanin; Arfanakis, Konstantinos; Becker, Diane M.; Ames, David; Goldman, Aaron L.; Lee, Phil H.; Boomsma, Dorret I.; Lovestone, Simon; Giddaluru, Sudheer; Le Hellard, Stephanie; Mattheisen, Manuel; Bohlken, Marc M.; Kasperaviciute, Dalia; Schmaal, Lianne; Lawrie, Stephen M.; Agartz, Ingrid; Walton, Esther; Tordesillas-Gutierrez, Diana; Davies, Gareth E.; Shin, Jean; Ipser, Jonathan C.; Vinke, Louis N.; Hoogman, Martine; Jia, Tianye; Burkhardt, Ralph; Klein, Marieke; Crivello, Fabrice; Janowitz, Deborah; Carmichael, Owen; Haukvik, Unn K.; Aribisala, Benjamin S.; Schmidt, Helena; Strike, Lachlan T.; Cheng, Ching-Yu; Risacher, Shannon L.; Pütz, Benno; Fleischman, Debra A.; Assareh, Amelia A.; Mattay, Venkata S.; Buckner, Randy L.; Mecocci, Patrizia; Dale, Anders M.; Cichon, Sven; Boks, Marco P.; Matarin, Mar; Penninx, Brenda W. J. H.; Calhoun, Vince D.; Chakravarty, M. Mallar; Marquand, Andre F.; Macare, Christine; Kharabian Masouleh, Shahrzad; Oosterlaan, Jaap; Amouyel, Philippe; Hegenscheid, Katrin; Rotter, Jerome I.; Schork, Andrew J.; Liewald, David C. M.; de Zubicaray, Greig I.; Wong, Tien Yin; Shen, Li; Sämann, Philipp G.; Brodaty, Henry; Roffman, Joshua L.; de Geus, Eco J. C.; Tsolaki, Magda; Erk, Susanne; van Eijk, Kristel R.; Cavalleri, Gianpiero L.; van der Wee, Nic J. A.; McIntosh, Andrew M.; Gollub, Randy L.; Bulayeva, Kazima B.; Bernard, Manon; Richards, Jennifer S.; Himali, Jayandra J.; Loeffler, Markus; Rommelse, Nanda; Hoffmann, Wolfgang; Westlye, Lars T.; Valdés Hernández, Maria C.; Hansell, Narelle K.; van Erp, Theo G. M.; Wolf, Christiane; Kwok, John B. J.; Vellas, Bruno; Heinz, Andreas; Olde Loohuis, Loes M.; Delanty, Norman; Ho, Beng-Choon; Ching, Christopher R. K.; Shumskaya, Elena; Singh, Baljeet; Hofman, Albert; van der Meer, Dennis; Homuth, Georg; Psaty, Bruce M.; Bastin, Mark E.; Montgomery, Grant W.; Foroud, Tatiana M.; Reppermund, Simone; Hottenga, Jouke-Jan; Simmons, Andrew; Meyer-Lindenberg, Andreas; Cahn, Wiepke; Whelan, Christopher D.; van Donkelaar, Marjolein M. J.; Yang, Qiong; Hosten, Norbert; Green, Robert C; Thalamuthu, Anbupalam; Mohnke, Sebastian; Hulshoff Pol, Hilleke E.; Lin, Honghuang; Jack, Clifford R.; Schofield, Peter R.; Mühleisen, Thomas W.; Maillard, Pauline; Potkin, Steven G.; Wen, Wei; Fletcher, Evan; Toga, Arthur W.; Gruber, Oliver; Huentelman, Matthew; Davey Smith, George; Launer, Lenore J.; Nyberg, Lars; Jönsson, Erik G.; Crespo-Facorro, Benedicto; Koen, Nastassja; Greve, Douglas N.; Uitterlinden, André G.; Weinberger, Daniel R.; Steen, Vidar M.; Fedko, Iryna O.; Groenewold, Nynke A.; Niessen, Wiro J.; Toro, Roberto; Tzourio, Christophe; Longstreth, William T.; Ikram, M. Kamran; Smoller, Jordan W.; van Tol, Marie-Jose; Sussmann, Jessika E.; Paus, Tomas; Lemaître, Hervé; Schroeter, Matthias L.; Mazoyer, Bernard; Andreassen, Ole A.; Holsboer, Florian; Depondt, Chantal; Veltman, Dick J.; Turner, Jessica A.; Pausova, Zdenka; Schumann, Gunter; van Rooij, Daan; Djurovic, Srdjan; Deary, Ian J.; McMahon, Katie L.; Müller-Myhsok, Bertram; Brouwer, Rachel M.; Soininen, Hilkka; Pandolfo, Massimo; Wassink, Thomas H.; Cheung, Joshua W.; Wolfers, Thomas; Martinot, Jean-Luc; Zwiers, Marcel P.; Nauck, Matthias; Melle, Ingrid; Martin, Nicholas G.; Kanai, Ryota; Westman, Eric; Kahn, René S.; Sisodiya, Sanjay M.; White, Tonya; Saremi, Arvin; van Bokhoven, Hans; Brunner, Han G.; Völzke, Henry; Wright, Margaret J.; van ‘t Ent, Dennis; Nöthen, Markus M.; Ophoff, Roel A.; Buitelaar, Jan K.; Fernández, Guillén; Sachdev, Perminder S.; Rietschel, Marcella; van Haren, Neeltje E. M.; Fisher, Simon E.; Beiser, Alexa S.; Francks, Clyde; Saykin, Andrew J.; Mather, Karen A.; Romanczuk-Seiferth, Nina; Hartman, Catharina A.; DeStefano, Anita L.; Heslenfeld, Dirk J.; Weiner, Michael W.; Walter, Henrik; Hoekstra, Pieter J.; Nyquist, Paul A.; Franke, Barbara; Bennett, David A.; Grabe, Hans J.; Johnson, Andrew D.; Chen, Christopher; van Duijn, Cornelia M.; Lopez, Oscar L.; Fornage, Myriam; Wardlaw, Joanna M.; Schmidt, Reinhold; DeCarli, Charles; De Jager, Philip L.; Villringer, Arno; Debette, Stéphanie; Gudnason, Vilmundur; Medland, Sarah E.; Shulman, Joshua M.; Thompson, Paul M.; Seshadri, Sudha; Ikram, M. Arfan; Medical and Molecular Genetics, School of MedicineSubcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.Item The Genetic Architecture of the Human Cerebral Cortex(American Association for the Advancement of Science, 2020-03-20) Grasby, Katrina L.; Jahanshad, Neda; Painter, Jodie N.; Colodro-Conde, Lucía; Bralten, Janita; Hibar, Derrek P.; Lind, Penelope A.; Pizzagalli, Fabrizio; Ching, Christopher R.K.; McMahon, Mary Agnes B.; Shatokhina, Natalia; Zsembik, Leo C.P.; Thomopoulos, Sophia I.; Zhu, Alyssa H.; Strike, Lachlan T.; Agartz, Ingrid; Alhusaini, Saud; Almeida, Marcio A.A.; Alnæs, Dag; Amlien, Inge K.; Andersson, Micael; Ard, Tyler; Armstrong, Nicola J.; Ashley-Koch, Allison; Atkins, Joshua R.; Bernard, Manon; Brouwer, Rachel M.; Buimer, Elizabeth E.L.; Bülow, Robin; Bürger, Christian; Cannon, Dara M.; Chakravarty, Mallar; Chen, Qiang; Cheung, Joshua W.; Couvy-Duchesne, Baptiste; Dale, Anders M.; Dalvie, Shareefa; de Araujo, Tânia K.; de Zubicaray, Greig I.; de Zwarte, Sonja M.C.; den Braber, Anouk; Doan, Nhat Trung; Dohm, Katharina; Ehrlich, Stefan; Engelbrecht, Hannah-Ruth; Erk, Susanne; Fan, Chun Chieh; Fedko, Iryna O.; Foley, Sonya F.; Ford, Judith M.; Fukunaga, Masaki; Garrett, Melanie E.; Ge, Tian; Giddaluru, Sudheer; Goldman, Aaron L.; Green, Melissa J.; Groenewold, Nynke A.; Grotegerd, Dominik; Gurholt, Tiril P.; Gutman, Boris A.; Hansell, Narelle K.; Harris, Mathew A.; Harrison, Marc B.; Haswell, Courtney C.; Hauser, Michael; Herms, Stefan; Heslenfeld, Dirk J.; Ho, New Fei; Hoehn, David; Hoffmann, Per; Holleran, Laurena; Hoogman, Martine; Hottenga, Jouke-Jan; Ikeda, Masashi; Janowitz, Deborah; Jansen, Iris E.; Jia, Tianye; Jockwitz, Christiane; Kanai, Ryota; Karama, Sherif; Kasperaviciute, Dalia; Kaufmann, Tobias; Kelly, Sinead; Kikuchi, Masataka; Klein, Marieke; Knapp, Michael; Knodt, Annchen R.; Krämer, Bernd; Lam, Max; Lancaster, Thomas M.; Lee, Phil H.; Lett, Tristram A.; Lewis, Lindsay B.; Lopes-Cendes, Iscia; Luciano, Michelle; Macciardi, Fabio; Marquand, Andre F.; Mathias, Samuel R.; Melzer, Tracy R.; Milaneschi, Yuri; Mirza-Schreiber, Nazanin; Moreira, Jose C.V.; Mühleisen, Thomas W.; Müller-Myhsok, Bertram; Najt, Pablo; Nakahara, Soichiro; Nho, Kwangsik; lde Loohuis, Loes M.O.; Orfanos, Dimitri Papadopoulos; Pearson, John F.; Pitcher, Toni L.; Pütz, Benno; Quidé, Yann; Ragothaman, Anjanibhargavi; Rashid, Faisal M.; Reay, William R.; Redlich, Ronny; Reinbold, Céline S.; Repple, Jonathan; Richard, Geneviève; Riedel, Brandalyn C.; Risacher, Shannon L.; Rocha, Cristiane S.; Roth Mota, Nina; Salminen, Lauren; Saremi, Arvin; Saykin, Andrew J.; Schlag, Fenja; Schmaal, Lianne; Schofield, Peter R.; Secolin, Rodrigo; Shapland, Chin Yang; Shen, Li; Shin, Jean; Shumskaya, Elena; Sønderby, Ida E.; Sprooten, Emma; Tansey, Katherine E.; Teumer, Alexander; Thalamuthu, Anbupalam; Tordesillas-Gutiérrez, Diana; Turner, Jessica A.; Uhlmann, Anne; Vallerga, Costanza Ludovica; van der Meer, Dennis; van Donkelaar, Marjolein M.J.; van Eijk, Liza; van Erp, Theo G.M.; van Haren, Neeltje E.M.; van Rooij, Daan; van Tol, Marie-José; Veldink, Jan H.; Verhoef, Ellen; Walton, Esther; Wang, Mingyuan; Wang, Yunpeng; Wardlaw, Joanna M.; Wen, Wei; Westlye, Lars T.; Whelan, Christopher D.; Witt, Stephanie H.; Wittfeld, Katharina; Wolf, Christiane; Wolfers, Thomas; Wu, Jing Qin; Yasuda, Clarissa L.; Zaremba, Dario; Zhang, Zuo; Zwiers, Marcel P.; Artiges, Eric; Assareh, Amelia A.; Ayesa-Arriol, Rosa; Belger, Aysenil; Brandt, Christine L.; Brown, Gregory G.; Cichon, Sven; Curran, Joanne E.; Davies, Gareth E.; Degenhard, Franziska; Dennis, Michelle F.; Dietsche, Bruno; Djurovic, Srdjan; Doherty, Colin P.; Espiritu, Ryan; Garijo, Daniel; Gil, Yolanda; Gowland, Penny A.; Green, Robert C.; Häusler, Alexander N.; Heindel, Walter; Ho, Beng-Choon; Hoffmann, Wolfgang U.; Holsboer, Florian; Homuth, Georg; Hosten, Norbert; Jack, Clifford R.,Jr.; Jang, MiHyun; Jansen, Andreas; Kimbrel, Nathan A.; Kolskår, Knut; Koops, Sanne; Krug, Axel; Lim, Kelvin O.; Luykx, Jurjen J.; Mathalon, Daniel H.; Mather, Karen A.; Mattay, Venkata S.; Matthews, Sarah; Mayoral Van Son, Jaqueline; McEwen, Sarah C.; Melle, Ingrid; Morris, Derek W.; Mueller, Bryon A.; Nauck, Matthias; Nordvik, Jan E.; Nöthen, Markus M.; O'Leary, Daniel S.; Opel, Nils; Paillère Martinot, Marie-Laure; Pike, G. Bruce; Preda, Adrian; Quinlan, Erin B.; Rasser, Paul E.; Ratnakar, Varun; Reppermund, Simone; Steen, Vidar M.; Tooney, Paul A.; Torres, Fábio R.; Veltman, Dick J.; Voyvodic, James T.; Whelan, Robert; White, Tonya; Yamamori, Hidenaga; Adams, Hieab H.H.; Bis, Joshua C.; Debette, Stephanie; Decarli, Charles; Fornage, Myriam; Gudnason, Vilmundur; Hofer, Edith; Ikram, M. Arfan; Launer, Lenore; Longstreth, W.T.; Lopez, Oscar L.; Mazoyer, Bernard; Mosley, Thomas H.; Roshchupkin, Gennady V.; Satizabal, Claudia L.; Schmidt, Reinhold; Seshadri, Sudha; Yang, Qiong; Alvim, Marina K.M.; Ames, David; Anderson, Tim J.; Andreassen, Ole A.; Arias-Vasquez, Alejandro; Bastin, Mark E.; Baune, Bernhard T.; Beckham, Jean C.; Blangero, John; Boomsma, Dorret I.; Brodaty, Henry; Brunner, Han G.; Buckner, Randy L.; Buitelaar, Jan K.; Bustillo, Juan R.; Cahn, Wiepke; Cairns, Murray J.; Calhoun, Vince; Carr, Vaughan J.; Caseras, Xavier; Caspers, Svenja; Cavalleri, Gianpiero L.; Cendes, Fernando; Corvin, Aiden; Crespo-Facorro, Benedicto; Dalrymple-Alford, John C.; Dannlowski, Udo; de Geus, Eco J.C.; Deary, Ian J.; Delanty, Norman; Depondt, Chantal; Desrivières, Sylvane; Donohoe, Gary; Espeseth, Thomas; Fernández, Guillén; Fisher, Simon E.; Flor, Herta; Forstner, Andreas J.; Francks, Clyde; Franke, Barbara; Glahn, David C.; Gollub, Randy L.; Grabe, Hans J.; Gruber, Oliver; Håberg, Asta K.; Hariri, Ahmad R.; Hartman, Catharina A.; Hashimoto, Ryota; Heinz, Andreas; Henskens, Frans A.; Hillegers, Manon H.J.; Hoekstra, Pieter J.; Holmes, Avram J.; Hong, L. Elliot; Hopkins, William D.; Hulshoff Pol, Hilleke E.; Jernigan, Terry L.; Jönsson, Erik G.; Kahn, René S.; Kennedy, Martin A.; Kircher, Tilo T.J.; Kochunov, Peter; Kwok, John B.J.; Le Hellard, Stephanie; Loughland, Carmel M.; Martin, Nicholas G.; Martinot, Jean-Luc; McDonald, Colm; McMahon, Katie L.; Meyer-Lindenberg, Andreas; Michie, Patricia T.; Morey, Rajendra A.; Mowry, Bryan; Nyberg, Lars; Oosterlaan, Jaap; Ophoff, Roel A.; Pantelis, Christos; Paus, Tomas; Pausova, Zdenka; Penninx, Brenda W.J.H.; Polderman, Tinca J.C.; Posthuma, Danielle; Rietschel, Marcella; Roffman, Joshua L.; Rowland, Laura M.; Sachdev, Perminder S.; Sämann, Philipp G.; Schall, Ulrich; Schumann, Gunter; Scott, Rodney J.; Sim, Kang; Sisodiya, Sanjay M.; Smoller, Jordan W.; Sommer, Iris E.; St. Pourcain, Beate; Stein, Dan J.; Toga, Arthur W.; Trollor, Julian N.; Van der Wee, Nic J.A.; van't Ent, Dennis; Völzke, Henry; Walter, Henrik; Weber, Bernd; Weinberger, Daniel R.; Wright, Margaret J.; Zhou, Juan; Stein, Jason L.; Thompson, Paul M.; Medland, Sarah E.; Radiology and Imaging Sciences, School of MedicineThe cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.Item Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning(Springer Nature, 2022) Lahti, Jari; Tuominen, Samuli; Yang, Qiong; Pergola, Giulio; Ahmad, Shahzad; Amin, Najaf; Armstrong, Nicola J.; Beiser, Alexa; Bey, Katharina; Bis, Joshua C.; Boerwinkle, Eric; Bressler, Jan; Campbell, Archie; Campbell, Harry; Chen, Qiang; Corley, Janie; Cox, Simon R.; Davies, Gail; De Jager, Philip L.; Derks, Eske M.; Faul, Jessica D.; Fitzpatrick, Annette L.; Fohner, Alison E.; Ford, Ian; Fornage, Myriam; Gerring, Zachary; Grabe, Hans J.; Grodstein, Francine; Gudnason, Vilmundur; Simonsick, Eleanor; Holliday, Elizabeth G.; Joshi, Peter K.; Kajantie, Eero; Kaprio, Jaakko; Karell, Pauliina; Kleineidam, Luca; Knol, Maria J.; Kochan, Nicole A.; Kwok, John B.; Leber, Markus; Lam, Max; Lee, Teresa; Li, Shuo; Loukola, Anu; Luck, Tobias; Marioni, Riccardo E.; Mather, Karen A.; Medland, Sarah; Mirza, Saira S.; Nalls, Mike A.; Nho, Kwangsik; O'Donnell, Adrienne; Oldmeadow, Christopher; Painter, Jodie; Pattie, Alison; Reppermund, Simone; Risacher, Shannon L.; Rose, Richard J.; Sadashivaiah, Vijay; Scholz, Markus; Satizabal, Claudia L.; Schofield, Peter W.; Schraut, Katharina E.; Scott, Rodney J.; Simino, Jeannette; Smith, Albert V.; Smith, Jennifer A.; Stott, David J.; Surakka, Ida; Teumer, Alexander; Thalamuthu, Anbupalam; Trompet, Stella; Turner, Stephen T.; van der Lee, Sven J.; Villringer, Arno; Völker, Uwe; Wilson, Robert S.; Wittfeld, Katharina; Vuoksimaa, Eero; Xia, Rui; Yaffe, Kristine; Yu, Lei; Zare, Habil; Zhao, Wei; Ames, David; Attia, John; Bennett, David A.; Brodaty, Henry; Chasman, Daniel I.; Goldman, Aaron L.; Hayward, Caroline; Ikram, M. Arfan; Jukema, J. Wouter; Kardia, Sharon L.R.; Lencz, Todd; Loeffler, Markus; Mattay, Venkata S.; Palotie, Aarno; Psaty, Bruce M.; Ramirez, Alfredo; Ridker, Paul M.; Riedel-Heller, Steffi G.; Sachdev, Perminder S.; Saykin, Andrew J.; Scherer, Martin; Schofield, Peter R.; Sidney, Stephen; Starr, John M.; Trollor, Julian; Ulrich, William; Wagner, Michael; Weir, David R.; Wilson, James F.; Wright, Margaret J.; Weinberger, Daniel R.; Debette, Stephanie; Eriksson, Johan G.; Mosley, Thomas H., Jr.; Launer, Lenore J.; van Duijn, Cornelia M.; Deary, Ian J.; Seshadri, Sudha; Räikkönen, Katri; Radiology and Imaging Sciences, School of MedicineUnderstanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.Item Greater male than female variability in regional brain structure across the lifespan(Wiley, 2021) Wierenga, Lara M.; Doucet, Gaelle E.; Dima, Danai; Agartz, Ingrid; Aghajani, Moji; Akudjedu, Theophilus N.; Albajes‐Eizagirre, Anton; Alnæs, Dag; Alpert, Kathryn I.; Andreassen, Ole A.; Anticevic, Alan; Asherson, Philip; Banaschewski, Tobias; Bargallo, Nuria; Baumeister, Sarah; Baur‐Streubel, Ramona; Bertolino, Alessandro; Bonvino, Aurora; Boomsma, Dorret I.; Borgwardt, Stefan; Bourque, Josiane; Braber, Anouk; Brandeis, Daniel; Breier, Alan; Brodaty, Henry; Brouwer, Rachel M.; Buitelaar, Jan K.; Busatto, Geraldo F.; Calhoun, Vince D.; Canales‐Rodríguez, Erick J.; Cannon, Dara M.; Caseras, Xavier; Castellanos, Francisco X.; Chaim‐Avancini, Tiffany M.; Ching, Christopher R. K.; Clark, Vincent P.; Conrod, Patricia J.; Conzelmann, Annette; Crivello, Fabrice; Davey, Christopher G.; Dickie, Erin W.; Ehrlich, Stefan; Ent, Dennis; Fisher, Simon E.; Fouche, Jean‐Paul; Franke, Barbara; Fuentes‐Claramonte, Paola; Geus, Eco J. C.; Di Giorgio, Annabella; Glahn, David C.; Gotlib, Ian H.; Grabe, Hans J.; Gruber, Oliver; Gruner, Patricia; Gur, Raquel E.; Gur, Ruben C.; Gurholt, Tiril P.; Haan, Lieuwe; Haatveit, Beathe; Harrison, Ben J.; Hartman, Catharina A.; Hatton, Sean N.; Heslenfeld, Dirk J.; Heuvel, Odile A.; Hickie, Ian B.; Hoekstra, Pieter J.; Hohmann, Sarah; Holmes, Avram J.; Hoogman, Martine; Hosten, Norbert; Howells, Fleur M.; Hulshoff Pol, Hilleke E.; Huyser, Chaim; Jahanshad, Neda; James, Anthony C.; Jiang, Jiyang; Jönsson, Erik G.; Joska, John A.; Kalnin, Andrew J.; Karolinska Schizophrenia Project (KaSP) Consortium; Klein, Marieke; Koenders, Laura; Kolskår, Knut K.; Krämer, Bernd; Kuntsi, Jonna; Lagopoulos, Jim; Lazaro, Luisa; Lebedeva, Irina S.; Lee, Phil H.; Lochner, Christine; Machielsen, Marise W. J.; Maingault, Sophie; Martin, Nicholas G.; Martínez‐Zalacaín, Ignacio; Mataix‐Cols, David; Mazoyer, Bernard; McDonald, Brenna C.; McDonald, Colm; McIntosh, Andrew M.; McMahon, Katie L.; McPhilemy, Genevieve; Meer, Dennis; Menchón, José M.; Naaijen, Jilly; Nyberg, Lars; Oosterlaan, Jaap; Paloyelis, Yannis; Pauli, Paul; Pergola, Giulio; Pomarol‐Clotet, Edith; Portella, Maria J.; Radua, Joaquim; Reif, Andreas; Richard, Geneviève; Roffman, Joshua L.; Rosa, Pedro G. P.; Sacchet, Matthew D.; Sachdev, Perminder S.; Salvador, Raymond; Sarró, Salvador; Satterthwaite, Theodore D.; Saykin, Andrew J.; Serpa, Mauricio H.; Sim, Kang; Simmons, Andrew; Smoller, Jordan W.; Sommer, Iris E.; Soriano‐Mas, Carles; Stein, Dan J.; Strike, Lachlan T.; Szeszko, Philip R.; Temmingh, Henk S.; Thomopoulos, Sophia I.; Tomyshev, Alexander S.; Trollor, Julian N.; Uhlmann, Anne; Veer, Ilya M.; Veltman, Dick J.; Voineskos, Aristotle; Völzke, Henry; Walter, Henrik; Wang, Lei; Wang, Yang; Weber, Bernd; Wen, Wei; West, John D.; Westlye, Lars T.; Whalley, Heather C.; Williams, Steven C. R.; Wittfeld, Katharina; Wolf, Daniel H.; Wright, Margaret J.; Yoncheva, Yuliya N.; Zanetti, Marcus V.; Ziegler, Georg C.; Zubicaray, Greig I.; Thompson, Paul M.; Crone, Eveline A.; Frangou, Sophia; Tamnes, Christian K.; Psychiatry, School of MedicineFor many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1-90 years old (47% females). We observed significant patterns of greater male than female between-subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene-environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex-specific vulnerability to disorders.Item GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors(American Psychiatric Association, 2023) Docherty, Anna R.; Mullins, Niamh; Ashley-Koch, Allison E.; Qin, Xuejun; Coleman, Jonathan R. I.; Shabalin, Andrey; Kang, JooEun; Murnyak, Balasz; Wendt, Frank; Adams, Mark; Campos, Adrian I.; DiBlasi, Emily; Fullerton, Janice M.; Kranzler, Henry R.; Bakian, Amanda V.; Monson, Eric T.; Rentería, Miguel E.; Walss-Bass, Consuelo; Andreassen, Ole A.; Behera, Chittaranjan; Bulik, Cynthia M.; Edenberg, Howard J.; Kessler, Ronald C.; Mann, J. John; Nurnberger, John I., Jr.; Pistis, Giorgio; Streit, Fabian; Ursano, Robert J.; Polimanti, Renato; Dennis, Michelle; Garrett, Melanie; Hair, Lauren; Harvey, Philip; Hauser, Elizabeth R.; Hauser, Michael A.; Huffman, Jennifer; Jacobson, Daniel; Madduri, Ravi; McMahon, Benjamin; Oslin, David W.; Trafton, Jodie; Awasthi, Swapnil; Berrettini, Wade H.; Bohus, Martin; Chang, Xiao; Chen, Hsi-Chung; Chen, Wei J.; Christensen, Erik D.; Crow, Scott; Duriez, Philibert; Edwards, Alexis C.; Fernández-Aranda, Fernando; Galfalvy, Hanga; Gandal, Michael; Gorwood, Philip; Guo, Yiran; Hafferty, Jonathan D.; Hakonarson, Hakon; Halmi, Katherine A.; Hishimoto, Akitoyo; Jain, Sonia; Jamain, Stéphane; Jiménez-Murcia, Susana; Johnson, Craig; Kaplan, Allan S.; Kaye, Walter H.; Keel, Pamela K.; Kennedy, James L.; Kim, Minsoo; Klump, Kelly L.; Levey, Daniel F.; Li, Dong; Liao, Shih-Cheng; Lieb, Klaus; Lilenfeld, Lisa; Marshall, Christian R.; Mitchell, James E.; Okazaki, Satoshi; Otsuka, Ikuo; Pinto, Dalila; Powers, Abigail; Ramoz, Nicolas; Ripke, Stephan; Roepke, Stefan; Rozanov, Vsevolod; Scherer, Stephen W.; Schmahl, Christian; Sokolowski, Marcus; Starnawska, Anna; Strober, Michael; Su, Mei-Hsin; Thornton, Laura M.; Treasure, Janet; Ware, Erin B.; Watson, Hunna J.; Witt, Stephanie H.; Woodside, D. Blake; Yilmaz, Zeynep; Zillich, Lea; Adolfsson, Rolf; Agartz, Ingrid; Alda, Martin; Alfredsson, Lars; Appadurai, Vivek; Artigas, María Soler; Van der Auwera, Sandra; Azevedo, M. Helena; Bass, Nicholas; Bau, Claiton H. D.; Baune, Bernhard T.; Bellivier, Frank; Berger, Klaus; Biernacka, Joanna M.; Bigdeli, Tim B.; Binder, Elisabeth B.; Boehnke, Michael; Boks, Marco P.; Braff, David L.; Bryant, Richard; Budde, Monika; Byrne, Enda M.; Cahn, Wiepke; Castelao, Enrique; Cervilla, Jorge A.; Chaumette, Boris; Corvin, Aiden; Craddock, Nicholas; Djurovic, Srdjan; Foo, Jerome C.; Forstner, Andreas J.; Frye, Mark; Gatt, Justine M.; Giegling, Ina; Grabe, Hans J.; Green, Melissa J.; Grevet, Eugenio H.; Grigoroiu-Serbanescu, Maria; Gutierrez, Blanca; Guzman-Parra, Jose; Hamshere, Marian L.; Hartmann, Annette M.; Hauser, Joanna; Heilmann-Heimbach, Stefanie; Hoffmann, Per; Ising, Marcus; Jones, Ian; Jones, Lisa A.; Jonsson, Lina; Kahn, René S.; Kelsoe, John R.; Kendler, Kenneth S.; Kloiber, Stefan; Koenen, Karestan C.; Kogevinas, Manolis; Krebs, Marie-Odile; Landén, Mikael; Leboyer, Marion; Lee, Phil H.; Levinson, Douglas F.; Liao, Calwing; Lissowska, Jolanta; Mayoral, Fermin; McElroy, Susan L.; McGrath, Patrick; McGuffin, Peter; McQuillin, Andrew; Mehta, Divya; Melle, Ingrid; Mitchell, Philip B.; Molina, Esther; Morken, Gunnar; Nievergelt, Caroline; Nöthen, Markus M.; O'Donovan, Michael C.; Ophoff, Roel A.; Owen, Michael J.; Pato, Carlos; Pato, Michele T.; Penninx, Brenda W. J. H.; Potash, James B.; Power, Robert A.; Preisig, Martin; Quested, Digby; Ramos-Quiroga, Josep Antoni; Reif, Andreas; Ribasés, Marta; Richarte, Vanesa; Rietschel, Marcella; Rivera, Margarita; Roberts, Andrea; Roberts, Gloria; Rouleau, Guy A.; Rovaris, Diego L.; Sanders, Alan R.; Schofield, Peter R.; Schulze, Thomas G.; Scott, Laura J.; Serretti, Alessandro; Shi, Jianxin; Sirignano, Lea; Sklar, Pamela; Smeland, Olav B.; Smoller, Jordan W.; Sonuga-Barke, Edmund J. S.; Trzaskowski, Maciej; Tsuang, Ming T.; Turecki, Gustavo; Vilar-Ribó, Laura; Vincent, John B.; Völzke, Henry; Walters, James T. R.; Weickert, Cynthia Shannon; Weickert, Thomas W.; Weissman, Myrna M.; Williams, Leanne M.; Wray, Naomi R.; Zai, Clement C.; Agerbo, Esben; Børglum, Anders D.; Breen, Gerome; Demontis, Ditte; Erlangsen, Annette; Gelernter, Joel; Glatt, Stephen J.; Hougaard, David M.; Hwu, Hai-Gwo; Kuo, Po-Hsiu; Lewis, Cathryn M.; Li, Qingqin S.; Liu, Chih-Min; Martin, Nicholas G.; McIntosh, Andrew M.; Medland, Sarah E.; Mors, Ole; Nordentoft, Merete; Olsen, Catherine M.; Porteous, David; Smith, Daniel J.; Stahl, Eli A.; Stein, Murray B.; Wasserman, Danuta; Werge, Thomas; Whiteman, David C.; Willour, Virginia; VA Million Veteran Program (MVP); MVP Suicide Exemplar Workgroup; Suicide Working Group of the Psychiatric Genomics Consortium; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Bipolar Disorder Working Group of the Psychiatric Genomics Consortium; Schizophrenia Working Group of the Psychiatric Genomics Consortium; Eating Disorder Working Group of the Psychiatric Genomics Consortium; German Borderline Genomics Consortium; Coon, Hilary; Beckham, Jean C.; Kimbrel, Nathan A.; Ruderfer, Douglas M.; Psychiatry, School of MedicineObjective: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. Methods: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses. Results: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors. Conclusions: This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.Item Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci(Springer Nature, 2019-01-07) Erzurumluoglu, A. Mesut; Liu, Mengzhen; Jackson, Victoria E.; Barnes, Daniel R.; Datta, Gargi; Melbourne, Carl A.; Young, Robin; Batini, Chiara; Surendran, Praveen; Jiang, Tao; Adnan, Sheikh Daud; Afaq, Saima; Agrawal, Arpana; Altmaier, Elisabeth; Antoniou, Antonis C.; Asselbergs, Folkert W.; Baumbach, Clemens; Bierut, Laura; Bertelsen, Sarah; Boehnke, Michael; Bots, Michiel L.; Brazel, David M.; Chambers, John C.; Chang-Claude, Jenny; Chen, Chu; Corley, Janie; Chou, Yi-Ling; David, Sean P.; Boer, Rudolf A. de; Leeuw, Christiaan A. de; Dennis, Joe G.; Dominiczak, Anna F.; Dunning, Alison M.; Easton, Douglas F.; Eaton, Charles; Elliott, Paul; Evangelou, Evangelos; Faul, Jessica D.; Foroud, Tatiana; Goate, Alison; Gong, Jian; Grabe, Hans J.; Haessler, Jeff; Haiman, Christopher; Hallmans, Göran; Hammerschlag, Anke R.; Harris, Sarah E.; Hattersley, Andrew; Heath, Andrew; Hsu, Chris; Iacono, William G.; Kanoni, Stavroula; Kapoor, Manav; Kaprio, Jaakko; Kardia, Sharon L.; Karpe, Fredrik; Kontto, Jukka; Kooner, Jaspal S.; Kooperberg, Charles; Kuulasmaa, Kari; Laakso, Markku; Lai, Dongbing; Langenberg, Claudia; Le, Nhung; Lettre, Guillaume; Loukola, Anu; Luan, Jian’an; Madden, Pamela A. F.; Mangino, Massimo; Marioni, Riccardo E.; Marouli, Eirini; Marten, Jonathan; Martin, Nicholas G.; McGue, Matt; Michailidou, Kyriaki; Mihailov, Evelin; Moayyeri, Alireza; Moitry, Marie; Müller-Nurasyid, Martina; Naheed, Aliya; Nauck, Matthias; Neville, Matthew J.; Nielsen, Sune Fallgaard; North, Kari; Perola, Markus; Pharoah, Paul D. P.; Pistis, Giorgio; Polderman, Tinca J.; Posthuma, Danielle; Poulter, Neil; Qaiser, Beenish; Rasheed, Asif; Reiner, Alex; Renström, Frida; Rice, John; Rohde, Rebecca; Rolandsson, Olov; Samani, Nilesh J.; Samuel, Maria; Schlessinger, David; Scholte, Steven H.; Scott, Robert A.; Sever, Peter; Shao, Yaming; Shrine, Nick; Smith, Jennifer A.; Starr, John M.; Stirrups, Kathleen; Stram, Danielle; Stringham, Heather M.; Tachmazidou, Ioanna; Tardif, Jean-Claude; Thompson, Deborah J.; Tindle, Hilary A.; Tragante, Vinicius; Trompet, Stella; Turcot, Valerie; Tyrrell, Jessica; Vaartjes, Ilonca; Leij, Andries R. van der; Meer, Peter van der; Varga, Tibor V.; Verweij, Niek; Völzke, Henry; Wareham, Nicholas J.; Warren, Helen R.; Weir, David R.; Weiss, Stefan; Wetherill, Leah; Yaghootkar, Hanieh; Yavas, Ersin; Jiang, Yu; Chen, Fang; Zhan, Xiaowei; Zhang, Weihua; Zhao, Wei; Zhao, Wei; Zhou, Kaixin; Amouyel, Philippe; Blankenberg, Stefan; Caulfield, Mark J.; Chowdhury, Rajiv; Cucca, Francesco; Deary, Ian J.; Deloukas, Panos; Angelantonio, Emanuele Di; Ferrario, Marco; Ferrières, Jean; Franks, Paul W.; Frayling, Tim M.; Frossard, Philippe; Hall, Ian P.; Hayward, Caroline; Jansson, Jan-Håkan; Jukema, J. Wouter; Kee, Frank; Männistö, Satu; Metspalu, Andres; Munroe, Patricia B.; Nordestgaard, Børge Grønne; Palmer, Colin N. A.; Salomaa, Veikko; Sattar, Naveed; Spector, Timothy; Strachan, David Peter; Harst, Pim van der; Zeggini, Eleftheria; Saleheen, Danish; Butterworth, Adam S.; Wain, Louise V.; Abecasis, Goncalo R.; Danesh, John; Tobin, Martin D.; Vrieze, Scott; Liu, Dajiang J.; Howson, Joanna M. M.; Medical and Molecular Genetics, School of MedicineSmoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10−8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10−8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10−3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.