Browsing by Author "Martin, Nicholas G."
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Item Association of the OPRM1 Variant rs1799971 (A118G) with Non-Specific Liability to Substance Dependence in a Collaborative de novo Meta-Analysis of European-Ancestry Cohorts(Springer, 2016-03) Schwantes-An, Tae-Hwi; Zhang, Juan; Chen, Li-Shiun; Hartz, Sarah M.; Culverhouse, Robert C.; Chen, Xiangning; Coon, Hilary; Frank, Josef; Kamens, Helen M.; Konte, Bettina; Kovanen, Leena; Latvala, Antti; Legrand, Lisa N.; Maher, Brion S.; Melroy, Whitney E.; Nelson, Elliot C.; Reid, Mark W.; Robinson, Jason D.; Shen, Pei-Hong; Yang, Bao-Zhu; Andrews, Judy A.; Aveyard, Paul; Beltcheva, Olga; Brown, Sandra A.; Cannon, Dale S.; Cichon, Sven; Corley, Robin P.; Dahmen, Norbert; Degenhardt, Louisa; Foroud, Tatiana; Gaebel, Wolfgang; Giegling, Ina; Glatt, Stephen J.; Grucza, Richard A.; Hardin, Jill; Hartmann, Annette M.; Heath, Andrew C.; Herms, Stefan; Hodgkinson, Colin A.; Hoffmann, Per; Hops, Hyman; Huizinga, David; Ising, Marcus; Johnson, Eric O.; Johnstone, Elaine; Kaneva, Radka P.; Kendler, Kenneth S.; Kiefer, Falk; Kranzler, Henry R.; Krauter, Ken S.; Levran, Orna; Lucae, Susanne; Lynskey, Michael T.; Maier, Wolfgang; Mann, Karl; Martin, Nicholas G.; Mattheisen, Manuel; Montgomery, Grant W.; Müller-Myhsok, Bertram; Murphy, Michael F.; Neale, Michael C.; Nikolov, Momchil A.; Nishita, Denise; Nöthen, Markus M.; Nurnberger, John; Partonen, Timo; Pergadia, Michele L.; Reynolds, Maureen; Ridinger, Monika; Rose, Richard J.; Rouvinen-Lagerström, Noora; Scherbaum, Norbert; Schmäl, Christine; Soyka, Michael; Stallings, Michael C.; Steffens, Michael; Treutlein, Jens; Tsuang, Ming; Wallace, Tamara L.; Wodarz, Norbert; Yuferov, Vadim; Zill, Peter; Bergen, Andrew W.; Chen, Jingchun; Cinciripini, Paul M.; Edenberg, Howard J.; Ehringer, Marissa A.; Ferrell, Robert E.; Gelernter, Joel; Goldman, David; Hewitt, John K.; Hopfer, Christian J.; Iacono, William G.; Kaprio, Jaakko; Kreek, Mary Jeanne; Kremensky, Ivo M.; Madden, Pamela A.F.; McGue, Matt; Munafò, Marcus R.; Philibert, Robert A.; Rietschel, Marcella; Roy, Alec; Rujescu, Dan; Saarikoski, Sirkku T.; Swan, Gary E.; Todorov, Alexandre A.; Vanyukov, Michael M.; Weiss, Robert B.; Bierut, Laura J.; Saccone, Nancy L.; Department of Medical & Molecular Genetics, IU School of MedicineThe mu1 opioid receptor gene, OPRM1, has long been a high-priority candidate for human genetic studies of addiction. Because of its potential functional significance, the non-synonymous variant rs1799971 (A118G, Asn40Asp) in OPRM1 has been extensively studied, yet its role in addiction has remained unclear, with conflicting association findings. To resolve the question of what effect, if any, rs1799971 has on substance dependence risk, we conducted collaborative meta-analyses of 25 datasets with over 28,000 European-ancestry subjects. We investigated non-specific risk for "general" substance dependence, comparing cases dependent on any substance to controls who were non-dependent on all assessed substances. We also examined five specific substance dependence diagnoses: DSM-IV alcohol, opioid, cannabis, and cocaine dependence, and nicotine dependence defined by the proxy of heavy/light smoking (cigarettes-per-day >20 vs. ≤ 10). The G allele showed a modest protective effect on general substance dependence (OR = 0.90, 95% C.I. [0.83-0.97], p value = 0.0095, N = 16,908). We observed similar effects for each individual substance, although these were not statistically significant, likely because of reduced sample sizes. We conclude that rs1799971 contributes to mechanisms of addiction liability that are shared across different addictive substances. This project highlights the benefits of examining addictive behaviors collectively and the power of collaborative data sharing and meta-analyses.Item Associations Between Cannabis Use, Polygenic Liability for Schizophrenia, and Cannabis-related Experiences in a Sample of Cannabis Users(Oxford University Press, 2023) Johnson, Emma C.; Colbert, Sarah M. C.; Jeffries, Paul W.; Tillman, Rebecca; Bigdeli, Tim B.; Karcher, Nicole R.; Chan, Grace; Kuperman, Samuel; Meyers, Jacquelyn L.; Nurnberger, John I.; Plawecki, Martin H.; Degenhardt, Louisa; Martin, Nicholas G.; Kamarajan, Chella; Schuckit, Marc A.; Murray, Robin M.; Dick, Danielle M.; Edenberg, Howard J.; D'Souza, Deepak Cyril; Di Forti, Marta; Porjesz, Bernice; Nelson, Elliot C.; Agrawal, Arpana; Medical and Molecular Genetics, School of MedicineBackground and hypothesis: Risk for cannabis use and schizophrenia is influenced in part by genetic factors, and there is evidence that genetic risk for schizophrenia is associated with subclinical psychotic-like experiences (PLEs). Few studies to date have examined whether genetic risk for schizophrenia is associated with cannabis-related PLEs. Study design: We tested whether measures of cannabis involvement and polygenic risk scores (PRS) for schizophrenia were associated with self-reported cannabis-related experiences in a sample ascertained for alcohol use disorders (AUDs), the Collaborative Study on the Genetics of Alcoholism (COGA). We analyzed 4832 subjects (3128 of European ancestry and 1704 of African ancestry; 42% female; 74% meeting lifetime criteria for an AUD). Study results: Cannabis use disorder (CUD) was prevalent in this analytic sample (70%), with 40% classified as mild, 25% as moderate, and 35% as severe. Polygenic risk for schizophrenia was positively associated with cannabis-related paranoia, feeling depressed or anhedonia, social withdrawal, and cognitive difficulties, even when controlling for duration of daily cannabis use, CUD, and age at first cannabis use. The schizophrenia PRS was most robustly associated with cannabis-related cognitive difficulties (β = 0.22, SE = 0.04, P = 5.2e-7). In an independent replication sample (N = 1446), associations between the schizophrenia PRS and cannabis-related experiences were in the expected direction and not statistically different in magnitude from those in the COGA sample. Conclusions: Among individuals who regularly use cannabis, genetic liability for schizophrenia-even in those without clinical features-may increase the likelihood of reporting unusual experiences related to cannabis use.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 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 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 Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group(Springer Nature, 2021) Jia, Tianye; Chu, Congying; Liu, Yun; Van Dongen, Jenny; Papastergios, Evangelos; Armstrong, Nicola J.; Bastin, Mark E.; Carrillo-Roa, Tania; den Braber, Anouk; Harris, Mathew; Jansen, Rick; Liu, Jingyu; Luciano, Michelle; Ori, Anil P.S.; Santiañez, Roberto Roiz; Ruggeri, Barbara; Sarkisyan, Daniil; Shin, Jean; Sungeun, Kim; Tordesillas Gutiérrez, Diana; van't Ent, Dennis; Ames, David; Artiges, Eric; Bakalkin, Georgy; Banaschewski, Tobias; Bokde, Arun L.W.; Brodaty, Henry; Bromberg, Uli; Brouwer, Rachel; Büchel, Christian; Burke Quinlan, Erin; Cahn, Wiepke; de Zubicaray, Greig I.; Ehrlich, Stefan; Ekström, Tomas J.; Flor, Herta; Fröhner, Juliane H.; Frouin, Vincent; Garavan, Hugh; Gowland, Penny; Heinz, Andreas; Hoare, Jacqueline; Ittermann, Bernd; Jahanshad, Neda; Jiang, Jiyang; Kwok, John B.; Martin, Nicholas G.; Martinot, Jean-Luc; Mather, Karen A.; McMahon, Katie L.; McRae, Allan F.; Nees, Frauke; Orfanos, Dimitri Papadopoulos; Paus, Tomáš; Poustka, Luise; Sämann, Philipp G.; Schofield, Peter R.; Smolka, Michael N.; Stein, Dan J.; Strike, Lachlan T.; Teeuw, Jalmar; Thalamuthu, Anbupalam; Trollor, Julian; Walter, Henrik; Wardlaw, Joanna M.; Wen, Wei; Whelan, Robert; Apostolova, Liana G.; Binder, Elisabeth B.; Boomsma, Dorret I.; Calhoun, Vince; Crespo-Facorro, Benedicto; Deary, Ian J.; Hulshoff Pol, Hilleke; Ophoff, Roel A.; Pausova, Zdenka; Sachdev, Perminder S.; Saykin, Andrew; Wright, Margaret J.; Thompson, Paul M.; Schumann, Gunter; Desrivières, Sylvane; Radiology and Imaging Sciences, School of MedicineDNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)—three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.Item Evidence of causal effect of major depression on alcohol dependence: findings from the psychiatric genomics consortium(Cambridge University Press, 2019-05) Polimanti, Renato; Peterson, Roseann E.; Ong, Jue-Sheng; MacGregor, Stuart; Edwards, Alexis C.; Clarke, Toni-Kim; Frank, Josef; Gerring, Zachary; Gillespie, Nathan A.; Lind, Penelope A.; Maes, Hermine H.; Martin, Nicholas G.; Mbarek, Hamdi; Medland, Sarah E.; Streit, Fabian; Agrawal, Arpana; Edenberg, Howard J.; Kendler, Kenneth S.; Lewis, Cathryn M.; Sullivan, Patrick F.; Wray, Naomi R.; Gelernter, Joel; Derks, Eske M.; Biochemistry and Molecular Biology, School of MedicineBACKGROUND: Despite established clinical associations among major depression (MD), alcohol dependence (AD), and alcohol consumption (AC), the nature of the causal relationship between them is not completely understood. We leveraged genome-wide data from the Psychiatric Genomics Consortium (PGC) and UK Biobank to test for the presence of shared genetic mechanisms and causal relationships among MD, AD, and AC. METHODS: Linkage disequilibrium score regression and Mendelian randomization (MR) were performed using genome-wide data from the PGC (MD: 135 458 cases and 344 901 controls; AD: 10 206 cases and 28 480 controls) and UK Biobank (AC-frequency: 438 308 individuals; AC-quantity: 307 098 individuals). RESULTS: Positive genetic correlation was observed between MD and AD (rgMD-AD = + 0.47, P = 6.6 × 10-10). AC-quantity showed positive genetic correlation with both AD (rgAD-AC quantity = + 0.75, P = 1.8 × 10-14) and MD (rgMD-AC quantity = + 0.14, P = 2.9 × 10-7), while there was negative correlation of AC-frequency with MD (rgMD-AC frequency = -0.17, P = 1.5 × 10-10) and a non-significant result with AD. MR analyses confirmed the presence of pleiotropy among these four traits. However, the MD-AD results reflect a mediated-pleiotropy mechanism (i.e. causal relationship) with an effect of MD on AD (beta = 0.28, P = 1.29 × 10-6). There was no evidence for reverse causation. CONCLUSION: This study supports a causal role for genetic liability of MD on AD based on genetic datasets including thousands of individuals. Understanding mechanisms underlying MD-AD comorbidity addresses important public health concerns and has the potential to facilitate prevention and intervention efforts.Item Exome chip meta-analysis fine maps causal variants and elucidates the genetic architecture of rare coding variants in smoking and alcohol use(Elsevier, 2018) Brazel, David M.; Jiang, Yu; Hughey, Jordan M.; Turcot, Valérie; Zhan, Xiaowei; Gong, Jian; Batini, Chiara; Weissenkampen, J. Dylan; Liu, MengZhen; Barnes, Daniel R.; Bertelsen, Sarah; Chou, Yi-Ling; Erzurumluoglu, A. Mesut; Faul, Jessica D.; Haessler, Jeff; Hammerschlag, Anke R.; Hsu, Chris; Kapoor, Manav; Lai, Dongbing; Le, Nhung; de Leeuw, Christiaan A.; Loukola, Anu; Mangino, Massimo; Melbourne, Carl A.; Pistis, Giorgio; Qaiser, Beenish; Rohde, Rebecca; Shao, Yaming; Stringham, Heather; Wetherill, Leah; Zhao, Wei; Agrawal, Arpana; Bierut, Laura; Chen, Chu; Eaton, Charles B.; Goate, Alison; Haiman, Christopher; Heath, Andrew; Iacono, William G.; Martin, Nicholas G.; Polderman, Tinca J.; Reiner, Alex; Rice, John; Schlessinger, David; Scholte, H. Steven; Smith, Jennifer A.; Tardif, Jean-Claude; Tindle, Hilary A.; van der Leij, Andries R.; Boehnke, Michael; Chang-Claude, Jenny; Cucca, Francesco; David, Sean P.; Foroud, Tatiana; Howson, Joanna M. M.; Kardia, Sharon L. R.; Kooperberg, Charles; Laakso, Markku; Lettre, Guillaume; Madden, Pamela; McGue, Matt; North, Kari; Posthuma, Danielle; Spector, Timothy; Stram, Daniel; Tobin, Martin D.; Weir, David R.; Kaprio, Jaakko; Abecasis, Gonçalo R.; Liu, Dajiang J.; Vrieze, Scott; Medical and Molecular Genetics, School of MedicineBackground Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences, and contribute to disease risk. Methods We analyzed ∼250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss of function coding variants. We performed a novel fine mapping analysis to winnow the number of putative causal variants within associated loci. Results Meta-analytic sample sizes ranged from 152,348-433,216, depending on the phenotype. Rare coding variation explained 1.1-2.2% of phenotypic variance, reflecting 11%-18% of the total SNP heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between 3 and 10 variants for 65 loci. 20 loci contained rare coding variants in the 95% credible intervals. Conclusions Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine mapping GWAS loci identifies specific variants contributing to the biological etiology of substance use behavior.Item Fine-mapping genomic loci refines bipolar disorder risk genes(medRxiv, 2024-02-13) Koromina, Maria; Ravi, Ashvin; Panagiotaropoulou, Georgia; Schilder, Brian M.; Humphrey, Jack; Braun, Alice; Bidgeli, Tim; Chatzinakos, Chris; Coombes, Brandon; Kim, Jaeyoung; Liu, Xiaoxi; Terao, Chikashi; O'Connell, Kevin S.; Adams, Mark; Adolfsson, Rolf; Alda, Martin; Alfredsson, Lars; Andlauer, Till F. M.; Andreassen, Ole A.; Antoniou, Anastasia; Baune, Bernhard T.; Bengesser, Susanne; Biernacka, Joanna; Boehnke, Michael; Bosch, Rosa; Cairns, Murray; Carr, Vaughan J.; Casas, Miquel; Catts, Stanley; Cichon, Sven; Corvin, Aiden; Craddock, Nicholas; Dafnas, Konstantinos; Dalkner, Nina; Dannlowski, Udo; Degenhardt, Franziska; Di Florio, Arianna; Dikeos, Dimitris; Fellendorf, Frederike Tabea; Ferentinos, Panagiotis; Forstner, Andreas J.; Forty, Liz; Frye, Mark; Fullerton, Janice M.; Gawlik, Micha; Gizer, Ian R.; Gordon-Smith, Katherine; Green, Melissa J.; Grigoroiu-Serbanescu, Maria; Guzman-Parra, José; Hahn, Tim; Henskens, Frans; Hillert, Jan; Jablensky, Assen V.; Jones, Lisa; Jones, Ian; Jonsson, Lina; Kelsoe, John R.; Kircher, Tilo; Kirov, George; Kittel-Schneider, Sarah; Kogevinas, Manolis; Landén, Mikael; Leboyer, Marion; Lenger, Melanie; Lissowska, Jolanta; Lochner, Christine; Loughland, Carmel; MacIntyre, Donald; Martin, Nicholas G.; Maratou, Eirini; Mathews, Carol A.; Mayoral, Fermin; McElroy, Susan L.; McGregor, Nathaniel W.; McIntosh, Andrew; McQuillin, Andrew; Michie, Patricia; Milanova, Vihra; Mitchell, Philip B.; Moutsatsou, Paraskevi; Mowry, Bryan; Müller-Myhsok, Bertram; Myers, Richard; Nenadić, Igor; Nöthen, Markus M.; O'Donovan, Claire; O'Donovan, Michael; Ophoff, Roel A.; Owen, Michael J.; Pantelis, Chris; Pato, Carlos; Pato, Michele T.; Patrinos, George P.; Pawlak, Joanna M.; Perlis, Roy H.; Porichi, Evgenia; Posthuma, Danielle; Ramos-Quiroga, Josep Antoni; Reif, Andreas; Reininghaus, Eva Z.; Ribasés, Marta; Rietschel, Marcella; Schall, Ulrich; Schulze, Thomas G.; Scott, Laura; Scott, Rodney J.; Serretti, Alessandro; Shannon Weickert, Cynthia; Smoller, Jordan W.; Soler Artigas, Maria; Stein, Dan J.; Streit, Fabian; Toma, Claudio; Tooney, Paul; Vieta, Eduard; Vincent, John B.; Waldman, Irwin D.; Weickert, Thomas; Witt, Stephanie H.; Hong, Kyung Sue; Ikeda, Masashi; Iwata, Nakao; Świątkowska, Beata; Won, Hong-Hee; Edenberg, Howard J.; Ripke, Stephan; Raj, Towfique; Coleman, Jonathan R. I.; Mullins, Niamh; Biochemistry and Molecular Biology, School of MedicineBipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).