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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 Cortical thickness across the lifespan: Data from 17,075 healthy individuals aged 3-90 years(Wiley, 2022-01) Frangou, Sophia; Modabbernia, Amirhossein; Williams, Steven C.R.; Papachristou, Efstathios; Doucet, Gaelle E.; Agartz, Ingrid; Aghajani, Moji; Akudjedu, Theophilus N.; Albajes-Eizagirre, Anton; Alnæs, Dag; Alpert, Kathryn I.; Andersson, Micael; Andreasen, Nancy C.; Andreassen, Ole A.; Asherson, Philip; Banaschewski, Tobias; Bargallo, Nuria; Baumeister, Sarah; Baur-Streubel, Ramona; Bertolino, Alessandro; Bonvino, Aurora; Boomsma, Dorret I.; Borgwardt, Stefan; Bourque, Josiane; Brandeis, Daniel; Breier, Alan; Brodaty, Henry; Brouwer, Rachel M.; Buitelaar, Jan K.; Busatto, Geraldo F.; Buckner, Randy L.; Calhoun, Vincent; Canales-Rodríguez, Erick J.; Cannon, Dara M.; Caseras, Xavier; Castellanos, Francisco X.; Cervenka, Simon; Chaim-Avancini, Tiffany M.; Ching, Christopher R.K.; Chubar, Victoria; Clark, Vincent P.; Conrod, Patricia; Conzelmann, Annette; Crespo-Facorro, Benedicto; Crivello, Fabrice; Crone, Eveline A.; Dale, Anders M.; Dannlowski, Udo; Davey, Christopher; de Geus, Eco J.C.; de Haan, Lieuwe; de Zubicaray, Greig I.; den Braber, Anouk; Dickie, Erin W.; Di Giorgio, Annabella; Doan, Nhat Trung; Dørum, Erlend S.; Ehrlich, Stefan; Erk, Susanne; Espeseth, Thomas; Fatouros-Bergman, Helena; Fisher, Simon E.; Fouche, Jean-Paul; Franke, Barbara; Frodl, Thomas; Fuentes-Claramonte, Paola; Glahn, David C.; Gotlib, Ian H.; Grabe, Hans-Jörgen; Grimm, Oliver; Groenewold, Nynke A.; Grotegerd, Dominik; Gruber, Oliver; Gruner, Patricia; Gur, Rachel E.; Gur, Ruben C.; Hahn, Tim; Harrison, Ben J.; Hartman, Catharine A.; Hatton, Sean N.; Heinz, Andreas; Heslenfeld, Dirk J.; Hibar, Derrek P.; Hickie, Ian B.; Ho, Beng-Choon; 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; Jernigan, Terry L.; Jiang, Jiyang; Jönsson, Erik G.; Joska, John A.; Kahn, Rene; Kalnin, Andrew; Kanai, Ryota; Klein, Marieke; Klyushnik, Tatyana P.; Koenders, Laura; Koops, Sanne; Krämer, Bernd; Kuntsi, Jonna; Lagopoulos, Jim; Lázaro, Luisa; Lebedeva, Irina; Lee, Won Hee; Lesch, Klaus-Peter; Lochner, Christine; Machielsen, Marise W.J.; Maingault, Sophie; Martin, Nicholas G.; Martínez-Zalacaín, Ignacio; Mataix-Cols, David; Mazoyer, Bernard; McDonald, Colm; McDonald, Brenna C.; McIntosh, Andrew M.; McMahon, Katie L.; McPhilemy, Genevieve; Meinert, Susanne; Menchón, José M.; Medland, Sarah E.; Meyer-Lindenberg, Andreas; Naaijen, Jilly; Najt, Pablo; Nakao, Tomohiro; Nordvik, Jan E.; Nyberg, Lars; Oosterlaan, Jaap; Ortiz-García de la Foz, Víctor; Paloyelis, Yannis; Pauli, Paul; Pergola, Giulio; Pomarol-Clotet, Edith; Portella, Maria J.; Potkin, Steven G.; Radua, Joaquim; Reif, Andreas; Rinker, Daniel A.; Roffman, Joshua L.; Rosa, Pedro G.P.; Sacchet, Matthew D.; Sachdev, Perminder S.; Salvador, Raymond; Sánchez-Juan, Pascual; Sarró, Salvador; Satterthwaite, Theodore D.; Saykin, Andrew J.; Serpa, Mauricio H.; Schmaal, Lianne; Schnell, Knut; Schumann, Gunter; Sim, Kang; Smoller, Jordan W.; Sommer, Iris; Soriano-Mas, Carles; Stein, Dan J.; Strike, Lachlan T.; Swagerman, Suzanne C.; Tamnes, Christian K.; Temmingh, Henk S.; Thomopoulos, Sophia I.; Tomyshev, Alexander S.; Tordesillas-Gutiérrez, Diana; Trollor, Julian N.; Turner, Jessica A.; Uhlmann, Anne; van den Heuvel, Odile A.; van den Meer, Dennis; van der Wee, Nic J.A.; van Haren, Neeltje E.M.; van't Ent, Dennis; van Erp, Theo G.M.; Veer, Ilya M.; Veltman, Dick J.; Voineskos, Aristotle; Völzke, Henry; Walter, Henrik; Walton, Esther; Wang, Lei; Wang, Yang; Wassink, Thomas H.; Weber, Bernd; Wen, Wei; West, John D.; Westlye, Lars T.; Whalley, Heather; Wierenga, Lara M.; Wittfeld, Katharina; Wolf, Daniel H.; Worker, Amanda; Wright, Margaret J.; Yang, Kun; Yoncheva, Yulyia; Zanetti, Marcus V.; Ziegler, Georg C.; Karolinska Schizophrenia Project (KaSP); Thompson, Paul M.; Dima, Danai; Radiology and Imaging Sciences, School of MedicineDelineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.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 Genetic studies of quantitative MCI and AD phenotypes in ADNI: Progress, opportunities, and plans(Elsevier, 2015-07) Saykin, Andrew J.; Shen, Li; Yao, Xiaohui; Kim, Sungeun; Nho, Kwangsik; Risacher, Shannon L.; Ramanan, Vijay K.; Foroud, Tatiana M.; Faber, Kelly M.; Sarwar, Nadeem; Munsie, Leanne M.; Hu, Xiaolan; Soares, Holly D.; Potkin, Steven G.; Thompson, Paul M.; Kauwe, John S. K.; Kaddurah-Daouk, Rima; Green, Robert C.; Toga, Arthur W.; Weiner, Michael W.; Alzheimer's Disease Neuroimaging Initiative; Department of Radiology and Imaging Sciences, IU School of MedicineINTRODUCTION: Genetic data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) have been crucial in advancing the understanding of Alzheimer's disease (AD) pathophysiology. Here, we provide an update on sample collection, scientific progress and opportunities, conceptual issues, and future plans. METHODS: Lymphoblastoid cell lines and DNA and RNA samples from blood have been collected and banked, and data and biosamples have been widely disseminated. To date, APOE genotyping, genome-wide association study (GWAS), and whole exome and whole genome sequencing data have been obtained and disseminated. RESULTS: ADNI genetic data have been downloaded thousands of times, and >300 publications have resulted, including reports of large-scale GWAS by consortia to which ADNI contributed. Many of the first applications of quantitative endophenotype association studies used ADNI data, including some of the earliest GWAS and pathway-based studies of biospecimen and imaging biomarkers, as well as memory and other clinical/cognitive variables. Other contributions include some of the first whole exome and whole genome sequencing data sets and reports in healthy controls, mild cognitive impairment, and AD. DISCUSSION: Numerous genetic susceptibility and protective markers for AD and disease biomarkers have been identified and replicated using ADNI data and have heavily implicated immune, mitochondrial, cell cycle/fate, and other biological processes. Early sequencing studies suggest that rare and structural variants are likely to account for significant additional phenotypic variation. Longitudinal analyses of transcriptomic, proteomic, metabolomic, and epigenomic changes will also further elucidate dynamic processes underlying preclinical and prodromal stages of disease. Integration of this unique collection of multiomics data within a systems biology framework will help to separate truly informative markers of early disease mechanisms and potential novel therapeutic targets from the vast background of less relevant biological processes. Fortunately, a broad swath of the scientific community has accepted this grand challenge.Item Machine Learning for Large-Scale Quality Control of 3D Shape Models in Neuroimaging(Springer Nature, 2017-09) Petrov, Dmitry; Gutman, Boris A.; Yu, Shih-Hua (Julie); van Erp, Theo G.M.; Turner, Jessica A.; Schmaal, Lianne; Veltman, Dick; Wang, Lei; Alpert, Kathryn; Isaev, Dmitry; Zavaliangos-Petropulu, Artemis; Ching, Christopher R.K.; Calhoun, Vince; Glahn, David; Satterthwaite, Theodore D.; Andreasen, Ole Andreas; Borgwardt, Stefan; Howells, Fleur; Groenewold, Nynke; Voineskos, Aristotle; Radua, Joaquim; Potkin, Steven G.; Crespo-Facorro, Benedicto; Tordesillas-Gutirrez, Diana; Shen, Li; Lebedeva, Irina; Spalletta, Gianfranco; Donohoe, Gary; Kochunov, Peter; Rosa, Pedro G.P.; James, Anthony; Dannlowski, Udo; Baune, Berhard T.; Aleman, Andre; Gotlib, Ian H.; Walter, Henrik; Walter, Martin; Soares, Jair C.; Ehrlich, Stefan; Gur, Ruben C.; Doan, N. Trung; Agartz, Ingrid; Westlye, Lars T.; Harrisberger, Fabienne; Richer-Rossler, Anita; Uhlmann, Anne; Stein, Dan J.; Dickie, Erin W.; Pomarol-Clotet, Edith; Fuentes-Claramonte, Paola; Canales-Rodriguez, Erick Jorge; Salvador, Raymond; Huang, Alexander J.; Roiz-Santianez, Roberto; Cong, Shan; Tomyshev, Alexander; Piras, Fabrizio; Vecchio, Daniela; Banaj, Nerisa; Ciullo, Valentina; Hong, Elliot; Busatto, Geraldo; Zanetti, Marcus V.; Serpa, Mauricio H.; Cervenka, Simon; Kelly, Sinead; Grotegerd, Dominik; Sacchet, Matthew D.; Veer, Illya M.; Li, Meng; Wu, Mon-Ju; Irungu, Benson; Walton, Esther; Thompson, Paul M.; Medicine, School of MedicineAs very large studies of complex neuroimaging phenotypes become more common, human quality assessment of MRI-derived data remains one of the last major bottlenecks. Few attempts have so far been made to address this issue with machine learning. In this work, we optimize predictive models of quality for meshes representing deep brain structure shapes. We use standard vertex-wise and global shape features computed homologously across 19 cohorts and over 7500 human-rated subjects, training kernelized Support Vector Machine and Gradient Boosted Decision Trees classifiers to detect meshes of failing quality. Our models generalize across datasets and diseases, reducing human workload by 30-70%, or equivalently hundreds of human rater hours for datasets of comparable size, with recall rates approaching inter-rater reliability.Item Novel genetic loci associated with hippocampal volume(SpringerNature, 2017-01-18) 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, 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; Maniega, Susana Muñoz; Nho, Kwangsik; Nugent, Allison C.; Nyquist, Paul; Loohuis, Loes M.; 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-Coon; Hoekstra, Pieter J.; Hoffman, 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; 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.; 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; Purohit, 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.; Valdés Hernández, Maria C.; 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; 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.; Arfan, M.; Department of Radiology and Imaging Sciences, IU School of MedicineThe 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.Item Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3–90 years(Wiley, 2022) Dima, Danai; Modabbernia, Amirhossein; Papachristou, Efstathios; Doucet, Gaelle E.; Agartz, Ingrid; Aghajani, Moji; Akudjedu, Theophilus N.; Albajes-Eizagirre, Anton; Alnæs, Dag; Alpert, Kathryn I.; Andersson, Micael; Andreasen, Nancy C.; Andreassen, Ole A.; Asherson, Philip; Banaschewski, Tobias; Bargallo, Nuria; Baumeister, Sarah; Baur-Streubel, Ramona; Bertolino, Alessandro; Bonvino, Aurora; Boomsma, Dorret I.; Borgwardt, Stefan; Bourque, Josiane; Brandeis, Daniel; Breier, Alan; Brodaty, Henry; Brouwer, Rachel M.; Buitelaar, Jan K.; Busatto, Geraldo F.; Buckner, Randy L.; Calhoun, Vincent; Canales-Rodríguez, Erick J.; Cannon, Dara M.; Caseras, Xavier; Castellanos, Francisco X.; Cervenka, Simon; Chaim-Avancini, Tiffany M.; Ching, Christopher R.K.; Chubar, Victoria; Clark, Vincent P.; Conrod, Patricia; Conzelmann, Annette; Crespo-Facorro, Benedicto; Crivello, Fabrice; Crone, Eveline A.; Dannlowski, Udo; Dale, Anders M.; Davey, Christopher; de Geus, Eco J.C.; de Haan, Lieuwe; de Zubicaray, Greig I.; den Braber, Anouk; Dickie, Erin W.; Di Giorgio, Annabella; Doan, Nhat Trung; Dørum, Erlend S.; Ehrlich, Stefan; Erk, Susanne; Espeseth, Thomas; Fatouros-Bergman, Helena; Fisher, Simon E.; Fouche, Jean-Paul; Franke, Barbara; Frodl, Thomas; Fuentes-Claramonte, Paola; Glahn, David C.; Gotlib, Ian H.; Grabe, Hans-Jörgen; Grimm, Oliver; Groenewold, Nynke A.; Grotegerd, Dominik; Gruber, Oliver; Gruner, Patricia; Gur, Rachel E.; Gur, Ruben C.; Hahn, Tim; Harrison, Ben J.; Hartman, Catharine A.; Hatton, Sean N.; Heinz, Andreas; Heslenfeld, Dirk J.; Hibar, Derrek P.; Hickie, Ian B.; Ho, Beng-Choon; 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; Jernigan, Terry L.; Jiang, Jiyang; Jönsson, Erik G.; Joska, John A.; Kahn, Rene; Kalnin, Andrew; Kanai, Ryota; Klein, Marieke; Klyushnik, Tatyana P.; Koenders, Laura; Koops, Sanne; Krämer, Bernd; Kuntsi, Jonna; Lagopoulos, Jim; Lázaro, Luisa; Lebedeva, Irina; Lee, Won Hee; Lesch, Klaus-Peter; Lochner, Christine; Machielsen, Marise W.J.; Maingault, Sophie; Martin, Nicholas G.; Martínez-Zalacaín, Ignacio; Mataix-Cols, David; Mazoyer, Bernard; McDonald, Colm; McDonald, Brenna C.; McIntosh, Andrew M.; McMahon, Katie L.; McPhilemy, Genevieve; Menchón, José M.; Medland, Sarah E.; Meyer-Lindenberg, Andreas; Naaijen, Jilly; Najt, Pablo; Nakao, Tomohiro; Meinert, Susanne; Nordvik, Jan E.; Nyberg, Lars; Oosterlaan, Jaap; Ortiz-García de la Foz, Víctor; Paloyelis, Yannis; Pauli, Paul; Pergola, Giulio; Pomarol-Clotet, Edith; Portella, Maria J.; Potkin, Steven G.; Radua, Joaquim; Reif, Andreas; Rinker, Daniel A.; Roffman, Joshua L.; Rosa, Pedro G.P.; Sacchet, Matthew D.; Sachdev, Perminder S.; Salvador, Raymond; Sánchez-Juan, Pascual; Sarró, Salvador; Satterthwaite, Theodore D.; Saykin, Andrew J.; Serpa, Mauricio H.; Schmaal, Lianne; Schnell, Knut; Schumann, Gunter; Sim, Kang; Smoller, Jordan W.; Sommer, Iris; Soriano-Mas, Carles; Stein, Dan J.; Strike, Lachlan T.; Swagerman, Suzanne C.; Tamnes, Christian K.; Temmingh, Henk S.; Thomopoulos, Sophia I.; Tomyshev, Alexander S.; Tordesillas-Gutiérrez, Diana; Trollor, Julian N.; Turner, Jessica A.; Uhlmann, Anne; van den Heuvel, Odile A.; van den Meer, Dennis; van der Wee, Nic J.A.; van Haren, Neeltje E.M.; van't Ent, Dennis; van Erp, Theo G.M.; Veer, Ilya M.; Veltman, Dick J.; Voineskos, Aristotle; Völzke, Henry; Walter, Henrik; Walton, Esther; Wang, Lei; Wang, Yang; Wassink, Thomas H.; Weber, Bernd; Wen, Wei; West, John D.; Westlye, Lars T.; Whalley, Heather; Wierenga, Lara M.; Williams, Steven C.R.; Wittfeld, Katharina; Wolf, Daniel H.; Worker, Amanda; Wright, Margaret J.; Yang, Kun; Yoncheva, Yulyia; Zanetti, Marcus V.; Ziegler, Georg C.; Thompson, Paul M.; Frangou, Sophia; Karolinska Schizophrenia Project (KaSP); Radiology and Imaging Sciences, School of MedicineAge has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.