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1. Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers.

Author

Boen, Rune, Kaufmann, Tobias, van der Meer, Dennis, Frei, Oleksandr, Agartz, Ingrid, Ames, David, Andersson, Micael, Armstrong, Nicola, Artiges, Eric, Atkins, Joshua, Bauer, Jochen, Benedetti, Francesco, Boomsma, Dorret, Brodaty, Henry, Brosch, Katharina, Buckner, Randy, Cairns, Murray, Calhoun, Vince, Caspers, Svenja, Cichon, Sven, Corvin, Aiden, Crespo-Facorro, Benedicto, Dannlowski, Udo, David, Friederike, de Geus, Eco, de Zubicaray, Greig, Desrivières, Sylvane, Doherty, Joanne, Donohoe, Gary, Ehrlich, Stefan, Eising, Else, Espeseth, Thomas, Fisher, Simon, Forstner, Andreas, Fortaner-Uyà, Lidia, Frouin, Vincent, Fukunaga, Masaki, Ge, Tian, Glahn, David, Goltermann, Janik, Grabe, Hans, Green, Melissa, Groenewold, Nynke, Grotegerd, Dominik, Grøntvedt, Gøril, Hahn, Tim, Hashimoto, Ryota, Hehir-Kwa, Jayne, Henskens, Frans, Holmes, Avram, Håberg, Asta, Haavik, Jan, Jacquemont, Sebastien, Jansen, Andreas, Jockwitz, Christiane, Jönsson, Erik, Kikuchi, Masataka, Kircher, Tilo, Kumar, Kuldeep, Le Hellard, Stephanie, Leu, Costin, Linden, David, Liu, Jingyu, Loughnan, Robert, Mather, Karen, McMahon, Katie, McRae, Allan, Medland, Sarah, Meinert, Susanne, Moreau, Clara, Morris, Derek, Mowry, Bryan, Mühleisen, Thomas, Nenadić, Igor, Nöthen, Markus, Nyberg, Lars, Ophoff, Roel, Owen, Michael, Pantelis, Christos, Paolini, Marco, Paus, Tomas, Pausova, Zdenka, Persson, Karin, Quidé, Yann, Marques, Tiago, Sachdev, Perminder, Sando, Sigrid, Schall, Ulrich, Scott, Rodney, Selbæk, Geir, Shumskaya, Elena, Silva, Ana, Sisodiya, Sanjay, Stein, Frederike, Stein, Dan, Straube, Benjamin, Streit, Fabian, Strike, Lachlan, Teumer, Alexander, and Teutenberg, Lea

Subjects
15q11.2 BP1-BP2, 1q21.1 distal, Brain structure, Copy number variants, Intraindividual variability, Magnetic resonance imaging, Humans, Chromosome Deletion, Brain, Magnetic Resonance Imaging, Abnormalities, Multiple, Chromosomes, Human, Pair 15, DNA Copy Number Variations
Abstract

BACKGROUND: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure. METHODS: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individuals regional difference and global difference, were used to test for regional differences that diverge from the global difference. RESULTS: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness. CONCLUSIONS: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment.

Published
2024

2. Virtual Ontogeny of Cortical Growth Preceding Mental Illness

Author

Patel, Yash, Shin, Jean, Abé, Christoph, Agartz, Ingrid, Alloza, Clara, Alnæs, Dag, Ambrogi, Sonia, Antonucci, Linda A, Arango, Celso, Arolt, Volker, Auzias, Guillaume, Ayesa-Arriola, Rosa, Banaj, Nerisa, Banaschewski, Tobias, Bandeira, Cibele, Başgöze, Zeynep, Cupertino, Renata Basso, Bau, Claiton HD, Bauer, Jochen, Baumeister, Sarah, Bernardoni, Fabio, Bertolino, Alessandro, Bonnin, Caterina Del Mar, Brandeis, Daniel, Brem, Silvia, Bruggemann, Jason, Bülow, Robin, Bustillo, Juan R, Calderoni, Sara, Calvo, Rosa, Canales-Rodríguez, Erick J, Cannon, Dara M, Carmona, Susanna, Carr, Vaughan J, Catts, Stanley V, Chenji, Sneha, Chew, Qian Hui, Coghill, David, Connolly, Colm G, Conzelmann, Annette, Craven, Alexander R, Crespo-Facorro, Benedicto, Cullen, Kathryn, Dahl, Andreas, Dannlowski, Udo, Davey, Christopher G, Deruelle, Christine, Díaz-Caneja, Covadonga M, Dohm, Katharina, Ehrlich, Stefan, Epstein, Jeffery, Erwin-Grabner, Tracy, Eyler, Lisa T, Fedor, Jennifer, Fitzgerald, Jacqueline, Foran, William, Ford, Judith M, Fortea, Lydia, Fuentes-Claramonte, Paola, Fullerton, Janice, Furlong, Lisa, Gallagher, Louise, Gao, Bingchen, Gao, Si, Goikolea, Jose M, Gotlib, Ian, Goya-Maldonado, Roberto, Grabe, Hans J, Green, Melissa, Grevet, Eugenio H, Groenewold, Nynke A, Grotegerd, Dominik, Gruber, Oliver, Haavik, Jan, Hahn, Tim, Harrison, Ben J, Heindel, Walter, Henskens, Frans, Heslenfeld, Dirk J, Hilland, Eva, Hoekstra, Pieter J, Hohmann, Sarah, Holz, Nathalie, Howells, Fleur M, Ipser, Jonathan C, Jahanshad, Neda, Jakobi, Babette, Jansen, Andreas, Janssen, Joost, Jonassen, Rune, Kaiser, Anna, Kaleda, Vasiliy, Karantonis, James, King, Joseph A, Kircher, Tilo, Kochunov, Peter, Koopowitz, Sheri-Michelle, Landén, Mikael, Landrø, Nils Inge, and Lawrie, Stephen

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Psychology, Neurosciences, Genetics, Mental Health, Serious Mental Illness, Mental Illness, Women's Health, Brain Disorders, Preterm, Low Birth Weight and Health of the Newborn, Pregnancy, Pediatric, Perinatal Period - Conditions Originating in Perinatal Period, Behavioral and Social Science, Prevention, Schizophrenia, 2.1 Biological and endogenous factors, 2.3 Psychological, social and economic factors, Neurological, Reproductive health and childbirth, Mental health, Good Health and Well Being, Attention Deficit Disorder with Hyperactivity, Autism Spectrum Disorder, Bipolar Disorder, Cerebral Cortex, Child, Depressive Disorder, Major, Female, Humans, Infant, Newborn, Magnetic Resonance Imaging, Premature Birth, Cortical growth, Cortical surface area, Mental illness, Neurodevelopment, Neurogenesis, Psychiatric disorders, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Biological sciences, Biomedical and clinical sciences
Abstract

BackgroundMorphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life.MethodsInterregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed.ResultsAcross the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth.ConclusionsOur findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy.

Published
2022

3. Effects of copy number variations on brain structure and risk for psychiatric illness: Large‐scale studies from the ENIGMA working groups on CNVs

Author

Sønderby, Ida E, Ching, Christopher RK, Thomopoulos, Sophia I, van der Meer, Dennis, Sun, Daqiang, Villalon‐Reina, Julio E, Agartz, Ingrid, Amunts, Katrin, Arango, Celso, Armstrong, Nicola J, Ayesa‐Arriola, Rosa, Bakker, Geor, Bassett, Anne S, Boomsma, Dorret I, Bülow, Robin, Butcher, Nancy J, Calhoun, Vince D, Caspers, Svenja, Chow, Eva WC, Cichon, Sven, Ciufolini, Simone, Craig, Michael C, Crespo‐Facorro, Benedicto, Cunningham, Adam C, Dale, Anders M, Dazzan, Paola, de Zubicaray, Greig I, Djurovic, Srdjan, Doherty, Joanne L, Donohoe, Gary, Draganski, Bogdan, Durdle, Courtney A, Ehrlich, Stefan, Emanuel, Beverly S, Espeseth, Thomas, Fisher, Simon E, Ge, Tian, Glahn, David C, Grabe, Hans J, Gur, Raquel E, Gutman, Boris A, Haavik, Jan, Håberg, Asta K, Hansen, Laura A, Hashimoto, Ryota, Hibar, Derrek P, Holmes, Avram J, Hottenga, Jouke‐Jan, Pol, Hilleke E Hulshoff, Jalbrzikowski, Maria, Knowles, Emma EM, Kushan, Leila, Linden, David EJ, Liu, Jingyu, Lundervold, Astri J, Martin‐Brevet, Sandra, Martínez, Kenia, Mather, Karen A, Mathias, Samuel R, McDonald‐McGinn, Donna M, McRae, Allan F, Medland, Sarah E, Moberget, Torgeir, Modenato, Claudia, Sánchez, Jennifer Monereo, Moreau, Clara A, Mühleisen, Thomas W, Paus, Tomas, Pausova, Zdenka, Prieto, Carlos, Ragothaman, Anjanibhargavi, Reinbold, Céline S, Marques, Tiago Reis, Repetto, Gabriela M, Reymond, Alexandre, Roalf, David R, Rodriguez‐Herreros, Borja, Rucker, James J, Sachdev, Perminder S, Schmitt, James E, Schofield, Peter R, Silva, Ana I, Stefansson, Hreinn, Stein, Dan J, Tamnes, Christian K, Tordesillas‐Gutiérrez, Diana, Ulfarsson, Magnus O, Vajdi, Ariana, van 't Ent, Dennis, van den Bree, Marianne BM, Vassos, Evangelos, Vázquez‐Bourgon, Javier, Vila‐Rodriguez, Fidel, Walters, G Bragi, Wen, Wei, Westlye, Lars T, Wittfeld, Katharina, Zackai, Elaine H, Stefánsson, Kári, and Jacquemont, Sebastien

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Psychology, Mental Health, Clinical Research, Pediatric, Genetics, Basic Behavioral and Social Science, Human Genome, Prevention, Brain Disorders, Behavioral and Social Science, Neurosciences, Aetiology, 2.1 Biological and endogenous factors, Mental health, Neurological, Brain, DNA Copy Number Variations, Humans, Magnetic Resonance Imaging, Mental Disorders, Multicenter Studies as Topic, Neurodevelopmental Disorders, Neuroimaging, brain structural imaging, copy number variant, diffusion tensor imaging, evolution, genetics-first approach, neurodevelopmental disorders, psychiatric disorders, ENIGMA-CNV Working Group, ENIGMA 22q11.2 Deletion Syndrome Working Group, Cognitive Sciences, Experimental Psychology, Biological psychology, Cognitive and computational psychology
Abstract

The Enhancing NeuroImaging Genetics through Meta-Analysis copy number variant (ENIGMA-CNV) and 22q11.2 Deletion Syndrome Working Groups (22q-ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA-CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q-ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest-ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi-site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene-dosage effects on distinct brain regions also emerged, providing further insight into genotype-phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This "genotype-first" approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior.

Published
2022

4. Reproducibility in the absence of selective reporting: An illustration from large‐scale brain asymmetry research

Author

Kong, Xiang‐Zhen, Mathias, Samuel R, Guadalupe, Tulio, Abé, Christoph, Agartz, Ingrid, Akudjedu, Theophilus N, Aleman, Andre, Alhusaini, Saud, Allen, Nicholas B, Ames, David, Andreassen, Ole A, Vasquez, Alejandro Arias, Armstrong, Nicola J, Asherson, Phil, Bergo, Felipe, Bastin, Mark E, Batalla, Albert, Bauer, Jochen, Baune, Bernhard T, Baur‐Streubel, Ramona, Biederman, Joseph, Blaine, Sara K, Boedhoe, Premika, Bøen, Erlend, Bose, Anushree, Bralten, Janita, Brandeis, Daniel, Brem, Silvia, Brodaty, Henry, Yüksel, Dilara, Brooks, Samantha J, Buitelaar, Jan, Bürger, Christian, Bülow, Robin, Calhoun, Vince, Calvo, Anna, Canales‐Rodríguez, Erick Jorge, Cannon, Dara M, Caparelli, Elisabeth C, Castellanos, Francisco X, Cendes, Fernando, Chaim‐Avancini, Tiffany Moukbel, Chantiluke, Kaylita, Chen, Qun‐lin, Chen, Xiayu, Cheng, Yuqi, Christakou, Anastasia, Clark, Vincent P, Coghill, David, Connolly, Colm G, Conzelmann, Annette, Córdova‐Palomera, Aldo, Cousijn, Janna, Crow, Tim, Cubillo, Ana, Dannlowski, Udo, de Bruttopilo, Sara Ambrosino, de Zeeuw, Patrick, Deary, Ian J, Demeter, Damion V, Di Martino, Adriana, Dickie, Erin W, Dietsche, Bruno, Doan, Nhat Trung, Doherty, Colin P, Doyle, Alysa, Durston, Sarah, Earl, Eric, Ehrlich, Stefan, Ekman, Carl Johan, Elvsåshagen, Torbjørn, Epstein, Jeffery N, Fair, Damien A, Faraone, Stephen V, Fernández, Guillén, Flint, Claas, Filho, Geraldo Busatto, Förster, Katharina, Fouche, Jean‐Paul, Foxe, John J, Frodl, Thomas, Fuentes‐Claramonte, Paola, Fullerton, Janice M, Garavan, Hugh, do Santos Garcia, Danielle, Gotlib, Ian H, Goudriaan, Anna E, Grabe, Hans Jörgen, Groenewold, Nynke A, Grotegerd, Dominik, Gruber, Oliver, Gurholt, Tiril, Haavik, Jan, Hahn, Tim, Hansell, Narelle K, Harris, Mathew A, Hartman, Catharina A, del Carmen Valdés Hernández, Maria, and Heslenfeld, Dirk

Subjects
Biological Psychology, Psychology, Neurosciences, Neurological, Adolescent, Adult, Aged, Brain Cortical Thickness, Cerebral Cortex, Datasets as Topic, Humans, Magnetic Resonance Imaging, Middle Aged, Multicenter Studies as Topic, Neuroimaging, Publication Bias, Reproducibility of Results, Young Adult, ENIGMA Laterality Working Group, P-hacking, multisite collaboration, publication bias, reproducibility, team science, Cognitive Sciences, Experimental Psychology, Biological psychology, Cognitive and computational psychology
Abstract

The problem of poor reproducibility of scientific findings has received much attention over recent years, in a variety of fields including psychology and neuroscience. The problem has been partly attributed to publication bias and unwanted practices such as p-hacking. Low statistical power in individual studies is also understood to be an important factor. In a recent multisite collaborative study, we mapped brain anatomical left-right asymmetries for regional measures of surface area and cortical thickness, in 99 MRI datasets from around the world, for a total of over 17,000 participants. In the present study, we revisited these hemispheric effects from the perspective of reproducibility. Within each dataset, we considered that an effect had been reproduced when it matched the meta-analytic effect from the 98 other datasets, in terms of effect direction and significance threshold. In this sense, the results within each dataset were viewed as coming from separate studies in an "ideal publishing environment," that is, free from selective reporting and p hacking. We found an average reproducibility rate of 63.2% (SD = 22.9%, min = 22.2%, max = 97.0%). As expected, reproducibility was higher for larger effects and in larger datasets. Reproducibility was not obviously related to the age of participants, scanner field strength, FreeSurfer software version, cortical regional measurement reliability, or regional size. These findings constitute an empirical illustration of reproducibility in the absence of publication bias or p hacking, when assessing realistic biological effects in heterogeneous neuroscience data, and given typically-used sample sizes.

Published
2022

5. Analysis of structural brain asymmetries in attention‐deficit/hyperactivity disorder in 39 datasets

Author

Postema, Merel C, Hoogman, Martine, Ambrosino, Sara, Asherson, Philip, Banaschewski, Tobias, Bandeira, Cibele E, Baranov, Alexandr, Bau, Claiton HD, Baumeister, Sarah, Baur‐Streubel, Ramona, Bellgrove, Mark A, Biederman, Joseph, Bralten, Janita, Brandeis, Daniel, Brem, Silvia, Buitelaar, Jan K, Busatto, Geraldo F, Castellanos, Francisco X, Cercignani, Mara, Chaim‐Avancini, Tiffany M, Chantiluke, Kaylita C, Christakou, Anastasia, Coghill, David, Conzelmann, Annette, Cubillo, Ana I, Cupertino, Renata B, de Zeeuw, Patrick, Doyle, Alysa E, Durston, Sarah, Earl, Eric A, Epstein, Jeffery N, Ethofer, Thomas, Fair, Damien A, Fallgatter, Andreas J, Faraone, Stephen V, Frodl, Thomas, Gabel, Matt C, Gogberashvili, Tinatin, Grevet, Eugenio H, Haavik, Jan, Harrison, Neil A, Hartman, Catharina A, Heslenfeld, Dirk J, Hoekstra, Pieter J, Hohmann, Sarah, Høvik, Marie F, Jernigan, Terry L, Kardatzki, Bernd, Karkashadze, Georgii, Kelly, Clare, Kohls, Gregor, Konrad, Kerstin, Kuntsi, Jonna, Lazaro, Luisa, Lera‐Miguel, Sara, Lesch, Klaus‐Peter, Louza, Mario R, Lundervold, Astri J, Malpas, Charles B, Mattos, Paulo, McCarthy, Hazel, Namazova‐Baranova, Leyla, Nicolau, Rosa, Nigg, Joel T, Novotny, Stephanie E, Weiss, Eileen Oberwelland, Tuura, Ruth L O'Gorman, Oosterlaan, Jaap, Oranje, Bob, Paloyelis, Yannis, Pauli, Paul, Picon, Felipe A, Plessen, Kerstin J, Ramos‐Quiroga, J Antoni, Reif, Andreas, Reneman, Liesbeth, Rosa, Pedro GP, Rubia, Katya, Schrantee, Anouk, Schweren, Lizanne JS, Seitz, Jochen, Shaw, Philip, Silk, Tim J, Skokauskas, Norbert, Vila, Juan C Soliva, Stevens, Michael C, Sudre, Gustavo, Tamm, Leanne, Tovar‐Moll, Fernanda, van Erp, Theo GM, Vance, Alasdair, Vilarroya, Oscar, Vives‐Gilabert, Yolanda, von Polier, Georg G, Walitza, Susanne, Yoncheva, Yuliya N, Zanetti, Marcus V, Ziegler, Georg C, Glahn, David C, and Jahanshad, Neda

Subjects
Biological Psychology, Psychology, Pediatric, Brain Disorders, Mental Health, Neurosciences, Attention Deficit Hyperactivity Disorder (ADHD), Pediatric Research Initiative, Aetiology, 2.1 Biological and endogenous factors, Mental health, Adolescent, Adult, Attention Deficit Disorder with Hyperactivity, Autism Spectrum Disorder, Brain, Caudate Nucleus, Child, Humans, Magnetic Resonance Imaging, Attention&#8208, deficit, hyperactivity disorder, brain asymmetry, brain laterality, structural MRI, large&#8208, scale data, ENIGMA ADHD Working Group, Attention-deficit, large-scale data, Clinical Sciences, Cognitive Sciences, Developmental & Child Psychology, Clinical sciences, Applied and developmental psychology, Clinical and health psychology
Abstract

ObjectiveSome studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium.MethodsWe analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries.ResultsThere was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen's d from -0.18 to 0.18) and would not survive study-wide correction for multiple testing.ConclusionPrior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.

Published
2021

6. The World Federation of ADHD International Consensus Statement: 208 Evidence-based conclusions about the disorder

Author

Faraone, Stephen V, Banaschewski, Tobias, Coghill, David, Zheng, Yi, Biederman, Joseph, Bellgrove, Mark A, Newcorn, Jeffrey H, Gignac, Martin, Al Saud, Nouf M, Manor, Iris, Rohde, Luis Augusto, Yang, Li, Cortese, Samuele, Almagor, Doron, Stein, Mark A, Albatti, Turki H, Aljoudi, Haya F, Alqahtani, Mohammed MJ, Asherson, Philip, Atwoli, Lukoye, Bölte, Sven, Buitelaar, Jan K, Crunelle, Cleo L, Daley, David, Dalsgaard, Søren, Döpfner, Manfred, Espinet, Stacey, Fitzgerald, Michael, Franke, Barbara, Gerlach, Manfred, Haavik, Jan, Hartman, Catharina A, Hartung, Cynthia M, Hinshaw, Stephen P, Hoekstra, Pieter J, Hollis, Chris, Kollins, Scott H, Kooij, JJ Sandra, Kuntsi, Jonna, Larsson, Henrik, Li, Tingyu, Liu, Jing, Merzon, Eugene, Mattingly, Gregory, Mattos, Paulo, McCarthy, Suzanne, Mikami, Amori Yee, Molina, Brooke SG, Nigg, Joel T, Purper-Ouakil, Diane, Omigbodun, Olayinka O, Polanczyk, Guilherme V, Pollak, Yehuda, Poulton, Alison S, Rajkumar, Ravi Philip, Reding, Andrew, Reif, Andreas, Rubia, Katya, Rucklidge, Julia, Romanos, Marcel, Ramos-Quiroga, J Antoni, Schellekens, Arnt, Scheres, Anouk, Schoeman, Renata, Schweitzer, Julie B, Shah, Henal, Solanto, Mary V, Sonuga-Barke, Edmund, Soutullo, César, Steinhausen, Hans-Christoph, Swanson, James M, Thapar, Anita, Tripp, Gail, van de Glind, Geurt, van den Brink, Wim, Van der Oord, Saskia, Venter, Andre, Vitiello, Benedetto, Walitza, Susanne, and Wang, Yufeng

Subjects
Epidemiology, Health Sciences, Clinical Research, Pediatric, Mental Health, Comparative Effectiveness Research, Behavioral and Social Science, Attention Deficit Hyperactivity Disorder (ADHD), Brain Disorders, Mental Illness, Mental health, Attention Deficit Disorder with Hyperactivity, Humans, Network Meta-Analysis, Publication Bias, ADHD, Diagnosis, Treatment, Course, Outcome, Genetics, Brain, Medical and Health Sciences, Psychology and Cognitive Sciences, Behavioral Science & Comparative Psychology, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundMisconceptions about ADHD stigmatize affected people, reduce credibility of providers, and prevent/delay treatment. To challenge misconceptions, we curated findings with strong evidence base.MethodsWe reviewed studies with more than 2000 participants or meta-analyses from five or more studies or 2000 or more participants. We excluded meta-analyses that did not assess publication bias, except for meta-analyses of prevalence. For network meta-analyses we required comparison adjusted funnel plots. We excluded treatment studies with waiting-list or treatment as usual controls. From this literature, we extracted evidence-based assertions about the disorder.ResultsWe generated 208 empirically supported statements about ADHD. The status of the included statements as empirically supported is approved by 80 authors from 27 countries and 6 continents. The contents of the manuscript are endorsed by 366 people who have read this document and agree with its contents.ConclusionsMany findings in ADHD are supported by meta-analysis. These allow for firm statements about the nature, course, outcome causes, and treatments for disorders that are useful for reducing misconceptions and stigma.

Published
2021

7. Characterizing neuroanatomic heterogeneity in people with and without ADHD based on subcortical brain volumes

Author

Li, Ting, van Rooij, Daan, Mota, Nina Roth, Buitelaar, Jan K, Ambrosino, Sara, Banaschewski, Tobias, Bandeira, Cibele E, Bau, Claiton HD, Baumeister, Sarah, Baur‐Streubel, Ramona, Bellgrove, Mark A, Biederman, Joseph, Bralten, Janita, Bramati, Ivanei E, Brandeis, Daniel, Berm, Silvia, Busatto, Geraldo F, Calvo, Anna, Castellanos, Francisco X, Cercignani, Mara, Chantiluke, Kaylita C, Christakou, Anastasia, Coghill, David, Conzelmann, Annette, Cubillo, Ana I, Cupertino, Renata B, de Zeeuw, Parick, Durston, Sarah, Earl, Eric A, Epstein, Jeffery N, Ethofer, Thomas, Fallgatter, Andreas J, Fair, Damien A, Faraone, Stephen V, Frodl, Thomas, Gabel, Matt C, Gogberashvili, Tinatin, Grevet, Eugenio H, Haavik, Jan, Harrison, Neil A, Hartman, Catharina A, Heslenfeld, Dirk J, Hoekstra, Pieter J, Høvik, Marie F, Jahanshad, Neda, Kardatzki, Bernd, Karkashadze, Georgii, Kelly, Clare, Kohls, Gregor, Konrad, Kerstin, Kuntsi, Jonna, Lazaro, Luisa, Lera‐Miguel, Sara, Lesch, Klaus‐Peter, Louza, Mario R, Lundervold, Astri J, Malpas, Charles B, Mattos, Paulo, McCarthy, Hazel, Nicolau, Rosa, Nigg, Joel T, Tuura, Ruth L O'Gorman, Oosterlaan, Jaap, Oranje, Bob, Paloyelis, Yannis, Pauli, Paul, Picon, Felipe A, Plessen, Kerstin J, Ramos‐Quiroga, J Antoni, Reif, Andreas, Reneman, Liesbeth, Rosa, Pedro GP, Rubia, Katya, Schrantee, Anouk, Schweren, Lizanne JS, Seitz, Jochen, Shaw, Philip, Silk, Tim J, Skokauskas, Norbert, Vila, Juan Carlos Soliva, Soloveva, Anastasiia, Stevens, Michael C, Sudre, Gustavo, Tamm, Leanne, Thompson, Paul M, Tovar‐Moll, Fernanda, van Erp, Theo GM, Vance, Alasdair, Vilarroya, Oscar, Vives‐Gilabert, Yolanda, von Polier, Georg G, Walitza, Susanne, Yoncheva, Yuliya N, Zanetti, Marcus V, Ziegler, Georg C, Anikin, Anatoly, Asherson, Philip, Baranov, Alexandr, Chaim‐Avanicini, Tiffany, and Dale, Anders M

Subjects
Biological Psychology, Psychology, Mental Health, Pediatric, Brain Disorders, Attention Deficit Hyperactivity Disorder (ADHD), Clinical Research, Neurosciences, Adult, Attention Deficit Disorder with Hyperactivity, Brain, Case-Control Studies, Female, Humans, Magnetic Resonance Imaging, Male, Thalamus, ADHD, subcortical volume, neuroanatomic heterogeneity, community detection, effect sizes, ENIGMA ADHD Working Group, Clinical Sciences, Cognitive Sciences, Developmental & Child Psychology, Clinical sciences, Applied and developmental psychology, Clinical and health psychology
Abstract

BackgroundAttention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder. Neuroanatomic heterogeneity limits our understanding of ADHD's etiology. This study aimed to parse heterogeneity of ADHD and to determine whether patient subgroups could be discerned based on subcortical brain volumes.MethodsUsing the large ENIGMA-ADHD Working Group dataset, four subsamples of 993 boys with and without ADHD and to subsamples of 653 adult men, 400 girls, and 447 women were included in analyses. We applied exploratory factor analysis (EFA) to seven subcortical volumes in order to constrain the complexity of the input variables and ensure more stable clustering results. Factor scores derived from the EFA were used to build networks. A community detection (CD) algorithm clustered participants into subgroups based on the networks.ResultsExploratory factor analysis revealed three factors (basal ganglia, limbic system, and thalamus) in boys and men with and without ADHD. Factor structures for girls and women differed from those in males. Given sample size considerations, we concentrated subsequent analyses on males. Male participants could be separated into four communities, of which one was absent in healthy men. Significant case-control differences of subcortical volumes were observed within communities in boys, often with stronger effect sizes compared to the entire sample. As in the entire sample, none were observed in men. Affected men in two of the communities presented comorbidities more frequently than those in other communities. There were no significant differences in ADHD symptom severity, IQ, and medication use between communities in either boys or men.ConclusionsOur results indicate that neuroanatomic heterogeneity in subcortical volumes exists, irrespective of ADHD diagnosis. Effect sizes of case-control differences appear more pronounced at least in some of the subgroups.

Published
2021

8. Genetic association study of childhood aggression across raters, instruments, and age.

Author

Ip, Hill, van der Laan, Camiel, Krapohl, Eva, Brikell, Isabell, Sánchez-Mora, Cristina, Nolte, Ilja, St Pourcain, Beate, Bolhuis, Koen, Palviainen, Teemu, Zafarmand, Hadi, Colodro-Conde, Lucía, Gordon, Scott, Zayats, Tetyana, Aliev, Fazil, Jiang, Chang, Wang, Carol, Saunders, Gretchen, Karhunen, Ville, Hammerschlag, Anke, Adkins, Daniel, Border, Richard, Peterson, Roseann, Prinz, Joseph, Thiering, Elisabeth, Seppälä, Ilkka, Vilor-Tejedor, Natàlia, Ahluwalia, Tarunveer, Day, Felix, Hottenga, Jouke-Jan, Allegrini, Andrea, Rimfeld, Kaili, Chen, Qi, Lu, Yi, Martin, Joanna, Soler Artigas, María, Rovira, Paula, Bosch, Rosa, Español, Gemma, Ramos Quiroga, Josep, Neumann, Alexander, Ensink, Judith, Grasby, Katrina, Morosoli, José, Tong, Xiaoran, Marrington, Shelby, Middeldorp, Christel, Scott, James, Vinkhuyzen, Anna, Shabalin, Andrey, Corley, Robin, Evans, Luke, Sugden, Karen, Alemany, Silvia, Sass, Lærke, Vinding, Rebecca, Ruth, Kate, Tyrrell, Jess, Davies, Gareth, Ehli, Erik, Hagenbeek, Fiona, De Zeeuw, Eveline, Van Beijsterveldt, Toos, Larsson, Henrik, Snieder, Harold, Verhulst, Frank, Amin, Najaf, Whipp, Alyce, Korhonen, Tellervo, Vuoksimaa, Eero, Rose, Richard, Uitterlinden, André, Heath, Andrew, Madden, Pamela, Haavik, Jan, Harris, Jennifer, Helgeland, Øyvind, Johansson, Stefan, Knudsen, Gun, Njolstad, Pal, Lu, Qing, Rodriguez, Alina, Henders, Anjali, Mamun, Abdullah, Najman, Jackob, Brown, Sandy, Hopfer, Christian, Krauter, Kenneth, Reynolds, Chandra, Smolen, Andrew, Stallings, Michael, Wadsworth, Sally, Wall, Tamara, Silberg, Judy, Miller, Allison, Keltikangas-Järvinen, Liisa, Hakulinen, Christian, Pulkki-Råback, Laura, Havdahl, Alexandra, Magnus, Per, and Raitakari, Olli

Subjects
Adolescent, Aggression, Child, Child, Preschool, Female, Genetic Association Studies, Genome-Wide Association Study, Humans, Infant, Mental Disorders, Retrospective Studies
Abstract

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E-06), PCDH7 (P = 2.0E-06), and IPO13 (P = 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg = 0.46 between self- and teacher-assessment to rg = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range [Formula: see text]: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg = ~-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range [Formula: see text]: 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.

Published
2021

9. 1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans

Author

Sønderby, Ida E, van der Meer, Dennis, Moreau, Clara, Kaufmann, Tobias, Walters, G Bragi, Ellegaard, Maria, Abdellaoui, Abdel, Ames, David, Amunts, Katrin, Andersson, Micael, Armstrong, Nicola J, Bernard, Manon, Blackburn, Nicholas B, Blangero, John, Boomsma, Dorret I, Brodaty, Henry, Brouwer, Rachel M, Bülow, Robin, Bøen, Rune, Cahn, Wiepke, Calhoun, Vince D, Caspers, Svenja, Ching, Christopher RK, Cichon, Sven, Ciufolini, Simone, Crespo-Facorro, Benedicto, Curran, Joanne E, Dale, Anders M, Dalvie, Shareefa, Dazzan, Paola, de Geus, Eco JC, de Zubicaray, Greig I, de Zwarte, Sonja MC, Desrivieres, Sylvane, Doherty, Joanne L, Donohoe, Gary, Draganski, Bogdan, Ehrlich, Stefan, Eising, Else, Espeseth, Thomas, Fejgin, Kim, Fisher, Simon E, Fladby, Tormod, Frei, Oleksandr, Frouin, Vincent, Fukunaga, Masaki, Gareau, Thomas, Ge, Tian, Glahn, David C, Grabe, Hans J, Groenewold, Nynke A, Gústafsson, Ómar, Haavik, Jan, Haberg, Asta K, Hall, Jeremy, Hashimoto, Ryota, Hehir-Kwa, Jayne Y, Hibar, Derrek P, Hillegers, Manon HJ, Hoffmann, Per, Holleran, Laurena, Holmes, Avram J, Homuth, Georg, Hottenga, Jouke-Jan, Hulshoff Pol, Hilleke E, Ikeda, Masashi, Jahanshad, Neda, Jockwitz, Christiane, Johansson, Stefan, Jönsson, Erik G, Jørgensen, Niklas R, Kikuchi, Masataka, Knowles, Emma EM, Kumar, Kuldeep, Le Hellard, Stephanie, Leu, Costin, Linden, David EJ, Liu, Jingyu, Lundervold, Arvid, Lundervold, Astri Johansen, Maillard, Anne M, Martin, Nicholas G, Martin-Brevet, Sandra, Mather, Karen A, Mathias, Samuel R, McMahon, Katie L, McRae, Allan F, Medland, Sarah E, Meyer-Lindenberg, Andreas, Moberget, Torgeir, Modenato, Claudia, Sánchez, Jennifer Monereo, Morris, Derek W, Mühleisen, Thomas W, Murray, Robin M, Nielsen, Jacob, Nordvik, Jan E, Nyberg, Lars, Loohuis, Loes M Olde, and Ophoff, Roel A

Subjects
Intellectual and Developmental Disabilities (IDD), Brain Disorders, Genetics, Neurosciences, Behavioral and Social Science, Mental Health, Autism, Schizophrenia, Neurological, Mental health, Brain, Chromosome Deletion, Cognition, DNA Copy Number Variations, Female, Humans, Male, ENIGMA-CNV working group, Clinical Sciences, Public Health and Health Services, Psychology
Abstract

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

Published
2021

10. Subcortical Brain Volume, Regional Cortical Thickness, and Cortical Surface Area Across Disorders: Findings From the ENIGMA ADHD, ASD, and OCD Working Groups

Author

Boedhoe, Premika SW, van Rooij, Daan, Hoogman, Martine, Twisk, Jos WR, Schmaal, Lianne, Abe, Yoshinari, Alonso, Pino, Ameis, Stephanie H, Anikin, Anatoly, Anticevic, Alan, Arango, Celso, Arnold, Paul D, Asherson, Philip, Assogna, Francesca, Auzias, Guillaume, Banaschewski, Tobias, Baranov, Alexander, Batistuzzo, Marcelo C, Baumeister, Sarah, Baur-Streubel, Ramona, Behrmann, Marlene, Bellgrove, Mark A, Benedetti, Francesco, Beucke, Jan C, Biederman, Joseph, Bollettini, Irene, Bose, Anushree, Bralten, Janita, Bramati, Ivanei E, Brandeis, Daniel, Brem, Silvia, Brennan, Brian P, Busatto, Geraldo F, Calderoni, Sara, Calvo, Anna, Calvo, Rosa, Castellanos, Francisco X, Cercignani, Mara, Chaim-Avancini, Tiffany M, Chantiluke, Kaylita C, Cheng, Yuqi, Cho, Kang Ik K, Christakou, Anastasia, Coghill, David, Conzelmann, Annette, Cubillo, Ana I, Dale, Anders M, Dallaspezia, Sara, Daly, Eileen, Denys, Damiaan, Deruelle, Christine, Di Martino, Adriana, Dinstein, Ilan, Doyle, Alysa E, Durston, Sarah, Earl, Eric A, Ecker, Christine, Ehrlich, Stefan, Ely, Benjamin A, Epstein, Jeffrey N, Ethofer, Thomas, Fair, Damien A, Fallgatter, Andreas J, Faraone, Stephen V, Fedor, Jennifer, Feng, Xin, Feusner, Jamie D, Fitzgerald, Jackie, Fitzgerald, Kate D, Fouche, Jean-Paul, Freitag, Christine M, Fridgeirsson, Egill A, Frodl, Thomas, Gabel, Matt C, Gallagher, Louise, Gogberashvili, Tinatin, Gori, Ilaria, Gruner, Patricia, Gürsel, Deniz A, Haar, Shlomi, Haavik, Jan, Hall, Geoffrey B, Harrison, Neil A, Hartman, Catharina A, Heslenfeld, Dirk J, Hirano, Yoshiyuki, Hoekstra, Pieter J, Hoexter, Marcelo Q, Hohmann, Sarah, Høvik, Marie F, Hu, Hao, Huyser, Chaim, Jahanshad, Neda, Jalbrzikowski, Maria, James, Anthony, Janssen, Joost, Jaspers-Fayer, Fern, Jernigan, Terry L, Kapilushniy, Dmitry, and Kardatzki, Bernd

Subjects
Attention Deficit Hyperactivity Disorder (ADHD), Behavioral and Social Science, Clinical Research, Mental Health, Neurosciences, Pediatric, Autism, Intellectual and Developmental Disabilities (IDD), Brain Disorders, 2.1 Biological and endogenous factors, 2.3 Psychological, social and economic factors, Aetiology, Mental health, Neurological, Adolescent, Adult, Attention Deficit Disorder with Hyperactivity, Autism Spectrum Disorder, Cerebrum, Child, Female, Human Development, Humans, Male, Neuroimaging, Obsessive-Compulsive Disorder, Organ Size, Psychopathology, Research Report, Systems Analysis, ENIGMA ADHD working group, ENIGMA ASD working group, ENIGMA OCD working group, Attention Deficit Hyperactivity Disorder, ENIGMA, Structural MRI, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

ObjectiveAttention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. The authors sought to directly compare these disorders using structural brain imaging data from ENIGMA consortium data.MethodsStructural T1-weighted whole-brain MRI data from healthy control subjects (N=5,827) and from patients with ADHD (N=2,271), ASD (N=1,777), and OCD (N=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. The authors examined subcortical volume, cortical thickness, and cortical surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults, using linear mixed-effects models adjusting for age, sex, and site (and intracranial volume for subcortical and surface area measures).ResultsNo shared differences were found among all three disorders, and shared differences between any two disorders did not survive correction for multiple comparisons. Children with ADHD compared with those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller intracranial volume than control subjects and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared with adult control subjects and other clinical groups. No OCD-specific differences were observed across different age groups and surface area differences among all disorders in childhood and adulthood.ConclusionsThe study findings suggest robust but subtle differences across different age groups among ADHD, ASD, and OCD. ADHD-specific intracranial volume and hippocampal differences in children and adolescents, and ASD-specific cortical thickness differences in the frontal cortex in adults, support previous work emphasizing structural brain differences in these disorders.

Published
2020

11. Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia

Author

Sønderby, Ida E, Gústafsson, Ómar, Doan, Nhat Trung, Hibar, Derrek P, Martin-Brevet, Sandra, Abdellaoui, Abdel, Ames, David, Amunts, Katrin, Andersson, Michael, Armstrong, Nicola J, Bernard, Manon, Blackburn, Nicholas, Blangero, John, Boomsma, Dorret I, Bralten, Janita, Brattbak, Hans-Richard, Brodaty, Henry, Brouwer, Rachel M, Bülow, Robin, Calhoun, Vince, Caspers, Svenja, Cavalleri, Gianpiero, Chen, Chi-Hua, Cichon, Sven, Ciufolini, Simone, Corvin, Aiden, Crespo-Facorro, Benedicto, Curran, Joanne E, Dale, Anders M, Dalvie, Shareefa, Dazzan, Paola, de Geus, Eco JC, de Zubicaray, Greig I, de Zwarte, Sonja MC, Delanty, Norman, den Braber, Anouk, Desrivières, Sylvane, Donohoe, Gary, Draganski, Bogdan, Ehrlich, Stefan, Espeseth, Thomas, Fisher, Simon E, Franke, Barbara, Frouin, Vincent, Fukunaga, Masaki, Gareau, Thomas, Glahn, David C, Grabe, Hans, Groenewold, Nynke A, Haavik, Jan, Håberg, Asta, Hashimoto, Ryota, Hehir-Kwa, Jayne Y, Heinz, Andreas, Hillegers, Manon HJ, Hoffmann, Per, Holleran, Laurena, Hottenga, Jouke-Jan, Hulshoff, Hilleke E, Ikeda, Masashi, Jahanshad, Neda, Jernigan, Terry, Jockwitz, Christiane, Johansson, Stefan, Jonsdottir, Gudrun A, Jönsson, Erik G, Kahn, Rene, Kaufmann, Tobias, Kelly, Sinead, Kikuchi, Masataka, Knowles, Emma EM, Kolskår, Knut K, Kwok, John B, Hellard, Stephanie Le, Leu, Costin, Liu, Jingyu, Lundervold, Astri J, Lundervold, Arvid, Martin, Nicholas G, Mather, Karen, Mathias, Samuel R, McCormack, Mark, McMahon, Katie L, McRae, Allan, Milaneschi, Yuri, Moreau, Clara, Morris, Derek, Mothersill, David, Mühleisen, Thomas W, Murray, Robin, Nordvik, Jan E, Nyberg, Lars, Olde Loohuis, Loes M, Ophoff, Roel, Paus, Tomas, Pausova, Zdenka, Penninx, Brenda, Peralta, Juan M, Pike, Bruce, and Prieto, Carlos

Subjects
Intellectual and Developmental Disabilities (IDD), Neurosciences, Brain Disorders, Autism, Biomedical Imaging, Mental Health, Mental health, Adult, Autism Spectrum Disorder, Autistic Disorder, Basal Ganglia, Brain, Chromosome Deletion, Chromosome Disorders, Chromosome Duplication, Chromosomes, Human, Pair 16, DNA Copy Number Variations, Databases, Factual, Female, Globus Pallidus, Humans, Image Processing, Computer-Assisted, Intellectual Disability, Magnetic Resonance Imaging, Male, Middle Aged, Neurodevelopmental Disorders, Organ Size, Putamen, Schizophrenia, 16p11.2 European Consortium, for the ENIGMA-CNV working group, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = -0.71 to -1.37; P

Published
2020

12. Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Author

Consortium, Cross-Disorder Group of the Psychiatric Genomics, Lee, Phil H, Anttila, Verneri, Won, Hyejung, Feng, Yen-Chen A, Rosenthal, Jacob, Zhu, Zhaozhong, Tucker-Drob, Elliot M, Nivard, Michel G, Grotzinger, Andrew D, Posthuma, Danielle, Wang, Meg M-J, Yu, Dongmei, Stahl, Eli A, Walters, Raymond K, Anney, Richard JL, Duncan, Laramie E, Ge, Tian, Adolfsson, Rolf, Banaschewski, Tobias, Belangero, Sintia, Cook, Edwin H, Coppola, Giovanni, Derks, Eske M, Hoekstra, Pieter J, Kaprio, Jaakko, Keski-Rahkonen, Anna, Kirov, George, Kranzler, Henry R, Luykx, Jurjen J, Rohde, Luis A, Zai, Clement C, Agerbo, Esben, Arranz, MJ, Asherson, Philip, Bækvad-Hansen, Marie, Baldursson, Gísli, Bellgrove, Mark, Belliveau, Richard A, Buitelaar, Jan, Burton, Christie L, Bybjerg-Grauholm, Jonas, Casas, Miquel, Cerrato, Felecia, Chambert, Kimberly, Churchhouse, Claire, Cormand, Bru, Crosbie, Jennifer, Dalsgaard, Søren, Demontis, Ditte, Doyle, Alysa E, Dumont, Ashley, Elia, Josephine, Grove, Jakob, Gudmundsson, Olafur O, Haavik, Jan, Hakonarson, Hakon, Hansen, Christine S, Hartman, Catharina A, Hawi, Ziarih, Hervás, Amaia, Hougaard, David M, Howrigan, Daniel P, Huang, Hailiang, Kuntsi, Jonna, Langley, Kate, Lesch, Klaus-Peter, Leung, Patrick WL, Loo, Sandra K, Martin, Joanna, Martin, Alicia R, McGough, James J, Medland, Sarah E, Moran, Jennifer L, Mors, Ole, Mortensen, Preben B, Oades, Robert D, Palmer, Duncan S, Pedersen, Carsten B, Pedersen, Marianne G, Peters, Triinu, Poterba, Timothy, Poulsen, Jesper B, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Ribasés, Marta, Rothenberger, Aribert, Rovira, Paula, Sánchez-Mora, Cristina, Satterstrom, F Kyle, Schachar, Russell, Artigas, Maria Soler, Steinberg, Stacy, Stefansson, Hreinn, Turley, Patrick, Walters, G Bragi, Team, 23andMe Research, Werge, Thomas, Zayats, Tetyana, and Arking, Dan E

Subjects
Neurosciences, Serious Mental Illness, Human Genome, Schizophrenia, Intellectual and Developmental Disabilities (IDD), Brain Disorders, Genetics, Pediatric, Mental Health, Aetiology, 2.1 Biological and endogenous factors, Mental health, Genetic Pleiotropy, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mental Disorders, Neurogenesis, Quantitative Trait Loci, Cross-Disorder Group of the Psychiatric Genomics Consortium. Electronic address: plee0@mgh.harvard.edu, Cross-Disorder Group of the Psychiatric Genomics Consortium, GWAS, Psychiatric genetics, cross-disorder genetics, functional genomics, gene expression, genetic architecture, genetic correlation, neurodevelopment, pleiotropy, psychiatric disorders, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.

Published
2019

13. Brain Imaging of the Cortex in ADHD: A Coordinated Analysis of Large-Scale Clinical and Population-Based Samples

Author

Hoogman, Martine, Muetzel, Ryan, Guimaraes, Joao P, Shumskaya, Elena, Mennes, Maarten, Zwiers, Marcel P, Jahanshad, Neda, Sudre, Gustavo, Wolfers, Thomas, Earl, Eric A, Soliva Vila, Juan Carlos, Vives-Gilabert, Yolanda, Khadka, Sabin, Novotny, Stephanie E, Hartman, Catharina A, Heslenfeld, Dirk J, Schweren, Lizanne JS, Ambrosino, Sara, Oranje, Bob, de Zeeuw, Patrick, Chaim-Avancini, Tiffany M, Rosa, Pedro GP, Zanetti, Marcus V, Malpas, Charles B, Kohls, Gregor, von Polier, Georg G, Seitz, Jochen, Biederman, Joseph, Doyle, Alysa E, Dale, Anders M, van Erp, Theo GM, Epstein, Jeffery N, Jernigan, Terry L, Baur-Streubel, Ramona, Ziegler, Georg C, Zierhut, Kathrin C, Schrantee, Anouk, Høvik, Marie F, Lundervold, Astri J, Kelly, Clare, McCarthy, Hazel, Skokauskas, Norbert, O’Gorman Tuura, Ruth L, Calvo, Anna, Lera-Miguel, Sara, Nicolau, Rosa, Chantiluke, Kaylita C, Christakou, Anastasia, Vance, Alasdair, Cercignani, Mara, Gabel, Matt C, Asherson, Philip, Baumeister, Sarah, Brandeis, Daniel, Hohmann, Sarah, Bramati, Ivanei E, Tovar-Moll, Fernanda, Fallgatter, Andreas J, Kardatzki, Bernd, Schwarz, Lena, Anikin, Anatoly, Baranov, Alexandr, Gogberashvili, Tinatin, Kapilushniy, Dmitry, Solovieva, Anastasia, El Marroun, Hanan, White, Tonya, Karkashadze, Georgii, Namazova-Baranova, Leyla, Ethofer, Thomas, Mattos, Paulo, Banaschewski, Tobias, Coghill, David, Plessen, Kerstin J, Kuntsi, Jonna, Mehta, Mitul A, Paloyelis, Yannis, Harrison, Neil A, Bellgrove, Mark A, Silk, Tim J, Cubillo, Ana I, Rubia, Katya, Lazaro, Luisa, Brem, Silvia, Walitza, Susanne, Frodl, Thomas, Zentis, Mariam, Castellanos, Francisco X, Yoncheva, Yuliya N, Haavik, Jan, Reneman, Liesbeth, Conzelmann, Annette, Lesch, Klaus-Peter, Pauli, Paul, Reif, Andreas, Tamm, Leanne, Konrad, Kerstin, Oberwelland Weiss, Eileen, Busatto, Geraldo F, and Louza, Mario R

Subjects
Pediatric, Neurosciences, Mental Health, Attention Deficit Hyperactivity Disorder (ADHD), Behavioral and Social Science, Clinical Research, Brain Disorders, Pediatric Research Initiative, Aetiology, 2.1 Biological and endogenous factors, Mental health, Adolescent, Adult, Age Factors, Attention Deficit Disorder with Hyperactivity, Case-Control Studies, Cerebral Cortex, Child, Child, Preschool, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Neuroimaging, Psychiatric Status Rating Scales, Sex Factors, Young Adult, Attention Deficit Hyperactivity Disorder, Cortical Surface Area, Cortical Thickness, Imaging, Meta-Analysis, Neuroanatomy, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

ObjectiveNeuroimaging studies show structural alterations of various brain regions in children and adults with attention deficit hyperactivity disorder (ADHD), although nonreplications are frequent. The authors sought to identify cortical characteristics related to ADHD using large-scale studies.MethodsCortical thickness and surface area (based on the Desikan-Killiany atlas) were compared between case subjects with ADHD (N=2,246) and control subjects (N=1,934) for children, adolescents, and adults separately in ENIGMA-ADHD, a consortium of 36 centers. To assess familial effects on cortical measures, case subjects, unaffected siblings, and control subjects in the NeuroIMAGE study (N=506) were compared. Associations of the attention scale from the Child Behavior Checklist with cortical measures were determined in a pediatric population sample (Generation-R, N=2,707).ResultsIn the ENIGMA-ADHD sample, lower surface area values were found in children with ADHD, mainly in frontal, cingulate, and temporal regions; the largest significant effect was for total surface area (Cohen's d=-0.21). Fusiform gyrus and temporal pole cortical thickness was also lower in children with ADHD. Neither surface area nor thickness differences were found in the adolescent or adult groups. Familial effects were seen for surface area in several regions. In an overlapping set of regions, surface area, but not thickness, was associated with attention problems in the Generation-R sample.ConclusionsSubtle differences in cortical surface area are widespread in children but not adolescents and adults with ADHD, confirming involvement of the frontal cortex and highlighting regions deserving further attention. Notably, the alterations behave like endophenotypes in families and are linked to ADHD symptoms in the population, extending evidence that ADHD behaves as a continuous trait in the population. Future longitudinal studies should clarify individual lifespan trajectories that lead to nonsignificant findings in adolescent and adult groups despite the presence of an ADHD diagnosis.

Published
2019

14. Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder.

Author

Demontis, Ditte, Walters, Raymond K, Martin, Joanna, Mattheisen, Manuel, Als, Thomas D, Agerbo, Esben, Baldursson, Gísli, Belliveau, Rich, Bybjerg-Grauholm, Jonas, Bækvad-Hansen, Marie, Cerrato, Felecia, Chambert, Kimberly, Churchhouse, Claire, Dumont, Ashley, Eriksson, Nicholas, Gandal, Michael, Goldstein, Jacqueline I, Grasby, Katrina L, Grove, Jakob, Gudmundsson, Olafur O, Hansen, Christine S, Hauberg, Mads Engel, Hollegaard, Mads V, Howrigan, Daniel P, Huang, Hailiang, Maller, Julian B, Martin, Alicia R, Martin, Nicholas G, Moran, Jennifer, Pallesen, Jonatan, Palmer, Duncan S, Pedersen, Carsten Bøcker, Pedersen, Marianne Giørtz, Poterba, Timothy, Poulsen, Jesper Buchhave, Ripke, Stephan, Robinson, Elise B, Satterstrom, F Kyle, Stefansson, Hreinn, Stevens, Christine, Turley, Patrick, Walters, G Bragi, Won, Hyejung, Wright, Margaret J, ADHD Working Group of the Psychiatric Genomics Consortium (PGC), Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium, 23andMe Research Team, Andreassen, Ole A, Asherson, Philip, Burton, Christie L, Boomsma, Dorret I, Cormand, Bru, Dalsgaard, Søren, Franke, Barbara, Gelernter, Joel, Geschwind, Daniel, Hakonarson, Hakon, Haavik, Jan, Kranzler, Henry R, Kuntsi, Jonna, Langley, Kate, Lesch, Klaus-Peter, Middeldorp, Christel, Reif, Andreas, Rohde, Luis Augusto, Roussos, Panos, Schachar, Russell, Sklar, Pamela, Sonuga-Barke, Edmund JS, Sullivan, Patrick F, Thapar, Anita, Tung, Joyce Y, Waldman, Irwin D, Medland, Sarah E, Stefansson, Kari, Nordentoft, Merete, Hougaard, David M, Werge, Thomas, Mors, Ole, Mortensen, Preben Bo, Daly, Mark J, Faraone, Stephen V, Børglum, Anders D, and Neale, Benjamin M

Subjects
ADHD Working Group of the Psychiatric Genomics Consortium, Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium, 23andMe Research Team, Brain, Humans, Genetic Predisposition to Disease, Risk, Cohort Studies, Attention Deficit Disorder with Hyperactivity, Gene Expression Regulation, Polymorphism, Single Nucleotide, Adolescent, Child, Child, Preschool, Female, Male, Genome-Wide Association Study, Genetic Loci, Clinical Research, Mental Health, Human Genome, Pediatric, Prevention, Genetics, Brain Disorders, Attention Deficit Hyperactivity Disorder (ADHD), Behavioral and Social Science, Aetiology, 2.1 Biological and endogenous factors, Mental health, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.

Published
2019

15. Novel Loci Associated With Attention-Deficit/Hyperactivity Disorder Are Revealed by Leveraging Polygenic Overlap With Educational Attainment.

Author

Shadrin, Alexey A, Smeland, Olav B, Zayats, Tetyana, Schork, Andrew J, Frei, Oleksandr, Bettella, Francesco, Witoelar, Aree, Li, Wen, Eriksen, Jon A, Krull, Florian, Djurovic, Srdjan, Faraone, Stephen V, Reichborn-Kjennerud, Ted, Thompson, Wesley K, Johansson, Stefan, Haavik, Jan, Dale, Anders M, Wang, Yunpeng, and Andreassen, Ole A

Subjects
Humans, Genetic Predisposition to Disease, Attention Deficit Disorder with Hyperactivity, Multifactorial Inheritance, Phenotype, Polymorphism, Single Nucleotide, Child, Educational Status, Female, Male, Genome-Wide Association Study, Jumonji Domain-Containing Histone Demethylases, attention-deficit/hyperactivity disorder, conditional/conjunctional false discovery rate, educational attainment, genetic overlap, Genetics, Brain Disorders, Pediatric, Attention Deficit Hyperactivity Disorder (ADHD), Mental Health, Human Genome, Biotechnology, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Mental health, Medical and Health Sciences, Psychology and Cognitive Sciences, Developmental & Child Psychology
Abstract

OBJECTIVE:Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable psychiatric condition. By exploiting the reported relationship between ADHD and educational attainment (EA), we aimed to improve discovery of ADHD-associated genetic variants and to investigate genetic overlap between these phenotypes. METHOD:A conditional/conjunctional false discovery rate (condFDR/conjFDR) method was applied to genome-wide association study (GWAS) data on ADHD (2,064 trios, 896 cases, and 2,455 controls) and EA (n=328,917) to identify ADHD-associated loci and loci overlapping between ADHD and EA. Identified single nucleotide polymorphisms (SNPs) were tested for association in an independent population-based study of ADHD symptoms (n=17,666). Genetic correlation between ADHD and EA was estimated using LD score regression and Pearson correlation. RESULTS:At levels of condFDR10-fold mutual enrichment of SNPs associated with both traits. CONCLUSION:We identified 5 novel loci associated with ADHD and provided evidence for a shared genetic basis between ADHD and EA. These findings could aid understanding of the genetic risk architecture of ADHD and its relation to EA.

Published
2018

16. Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: a cross-sectional mega-analysis

Author

Hoogman, Martine, Bralten, Janita, Hibar, Derrek P, Mennes, Maarten, Zwiers, Marcel P, Schweren, Lizanne SJ, van Hulzen, Kimm JE, Medland, Sarah E, Shumskaya, Elena, Jahanshad, Neda, de Zeeuw, Patrick, Szekely, Eszter, Sudre, Gustavo, Wolfers, Thomas, Onnink, Alberdingk MH, Dammers, Janneke T, Mostert, Jeanette C, Vives-Gilabert, Yolanda, Kohls, Gregor, Oberwelland, Eileen, Seitz, Jochen, Schulte-Rüther, Martin, Ambrosino, Sara, Doyle, Alysa E, Høvik, Marie F, Dramsdahl, Margaretha, Tamm, Leanne, van Erp, Theo GM, Dale, Anders, Schork, Andrew, Conzelmann, Annette, Zierhut, Kathrin, Baur, Ramona, McCarthy, Hazel, Yoncheva, Yuliya N, Cubillo, Ana, Chantiluke, Kaylita, Mehta, Mitul A, Paloyelis, Yannis, Hohmann, Sarah, Baumeister, Sarah, Bramati, Ivanei, Mattos, Paulo, Tovar-Moll, Fernanda, Douglas, Pamela, Banaschewski, Tobias, Brandeis, Daniel, Kuntsi, Jonna, Asherson, Philip, Rubia, Katya, Kelly, Clare, Di Martino, Adriana, Milham, Michael P, Castellanos, Francisco X, Frodl, Thomas, Zentis, Mariam, Lesch, Klaus-Peter, Reif, Andreas, Pauli, Paul, Jernigan, Terry L, Haavik, Jan, Plessen, Kerstin J, Lundervold, Astri J, Hugdahl, Kenneth, Seidman, Larry J, Biederman, Joseph, Rommelse, Nanda, Heslenfeld, Dirk J, Hartman, Catharina A, Hoekstra, Pieter J, Oosterlaan, Jaap, von Polier, Georg, Konrad, Kerstin, Vilarroya, Oscar, Ramos-Quiroga, Josep Antoni, Soliva, Joan Carles, Durston, Sarah, Buitelaar, Jan K, Faraone, Stephen V, Shaw, Philip, Thompson, Paul M, and Franke, Barbara

Subjects
Brain Disorders, Neurosciences, Attention Deficit Hyperactivity Disorder (ADHD), Clinical Research, Mental Health, Pediatric, Biomedical Imaging, 2.1 Biological and endogenous factors, Aetiology, Mental health, Good Health and Well Being, Adolescent, Adult, Attention Deficit Disorder with Hyperactivity, Brain, Case-Control Studies, Child, Child, Preschool, Cross-Sectional Studies, Female, Humans, Linear Models, Longitudinal Studies, Magnetic Resonance Imaging, Male, Middle Aged, Neuroimaging, Young Adult, Clinical Sciences, Public Health and Health Services, Psychology
Abstract

BackgroundNeuroimaging studies have shown structural alterations in several brain regions in children and adults with attention deficit hyperactivity disorder (ADHD). Through the formation of the international ENIGMA ADHD Working Group, we aimed to address weaknesses of previous imaging studies and meta-analyses, namely inadequate sample size and methodological heterogeneity. We aimed to investigate whether there are structural differences in children and adults with ADHD compared with those without this diagnosis.MethodsIn this cross-sectional mega-analysis, we used the data from the international ENIGMA Working Group collaboration, which in the present analysis was frozen at Feb 8, 2015. Individual sites analysed structural T1-weighted MRI brain scans with harmonised protocols of individuals with ADHD compared with those who do not have this diagnosis. Our primary outcome was to assess case-control differences in subcortical structures and intracranial volume through pooling of all individual data from all cohorts in this collaboration. For this analysis, p values were significant at the false discovery rate corrected threshold of p=0·0156.FindingsOur sample comprised 1713 participants with ADHD and 1529 controls from 23 sites with a median age of 14 years (range 4-63 years). The volumes of the accumbens (Cohen's d=-0·15), amygdala (d=-0·19), caudate (d=-0·11), hippocampus (d=-0·11), putamen (d=-0·14), and intracranial volume (d=-0·10) were smaller in individuals with ADHD compared with controls in the mega-analysis. There was no difference in volume size in the pallidum (p=0·95) and thalamus (p=0·39) between people with ADHD and controls. Exploratory lifespan modelling suggested a delay of maturation and a delay of degeneration, as effect sizes were highest in most subgroups of children (21 years): in the accumbens (Cohen's d=-0·19 vs -0·10), amygdala (d=-0·18 vs -0·14), caudate (d=-0·13 vs -0·07), hippocampus (d=-0·12 vs -0·06), putamen (d=-0·18 vs -0·08), and intracranial volume (d=-0·14 vs 0·01). There was no difference between children and adults for the pallidum (p=0·79) or thalamus (p=0·89). Case-control differences in adults were non-significant (all p>0·03). Psychostimulant medication use (all p>0·15) or symptom scores (all p>0·02) did not influence results, nor did the presence of comorbid psychiatric disorders (all p>0·5).InterpretationWith the largest dataset to date, we add new knowledge about bilateral amygdala, accumbens, and hippocampus reductions in ADHD. We extend the brain maturation delay theory for ADHD to include subcortical structures and refute medication effects on brain volume suggested by earlier meta-analyses. Lifespan analyses suggest that, in the absence of well powered longitudinal studies, the ENIGMA cross-sectional sample across six decades of ages provides a means to generate hypotheses about lifespan trajectories in brain phenotypes.FundingNational Institutes of Health.

Published
2017

17. Effects of ECT in treatment of depression: study protocol for a prospective neuroradiological study of acute and longitudinal effects on brain structure and function

Author

Oltedal, Leif, Kessler, Ute, Ersland, Lars, Grüner, Renate, Andreassen, Ole A, Haavik, Jan, Hoff, Per Ivar, Hammar, Åsa, Dale, Anders M, Hugdahl, Kenneth, and Oedegaard, Ketil J

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Clinical Sciences, Psychology, Clinical Research, Clinical Trials and Supportive Activities, Depression, Cardiovascular, Biomedical Imaging, Heart Disease, Brain Disorders, Mental Health, Neurosciences, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Mental health, Adolescent, Adult, Biomarkers, Brain, Clinical Protocols, Depressive Disorder, Major, Electroconvulsive Therapy, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Neuroimaging, Neuropsychological Tests, Prospective Studies, Treatment Outcome, Young Adult, Electroconvulsive therapy, Public Health and Health Services, Psychiatry, Clinical sciences, Epidemiology, Clinical and health psychology
Abstract

BackgroundMajor depression can be a serious and debilitating condition. For some patients in a treatment resistant depressive episode, electroconvulsive treatment (ECT) is the only treatment that is effective. Although ECT has shown efficacy in randomized controlled trials, the treatment is still controversial and stigmatized. This can in part be attributed to our lack of knowledge of the mechanisms of action. Some reports also suggest potential harmful effects of ECT treatment and memory related side effects have been documented.Methods/designThe present study will apply state of the art radiology through advanced magnetic resonance imaging (MRI) techniques to investigate structural and functional brain effects of ECT. As a multi-disciplinary collaboration, imaging findings will be correlated to psychiatric response parameters, neuropsychological functioning as well as neurochemical and genetic biomarkers that can elucidate the underlying mechanisms. The aim is to document both treatment effects and potential harmful effects of ECT.Samplen = 40 patients in a major depressive episode (bipolar and major depressive disorder). Two control groups with n = 15 in each group: age and gender matched healthy volunteers not receiving ECT and patients undergoing electrical cardioversion (ECV) for atrial fibrillation (AF). Observation time: six months.DiscussionThe study will contribute to our understanding of the pathophysiology of major depression as well as mechanisms of action for the most effective treatment for the disorder; ECT.

Published
2015

18. Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains

Author

Demontis, Ditte, Walters, G. Bragi, Athanasiadis, Georgios, Walters, Raymond, Therrien, Karen, Nielsen, Trine Tollerup, Farajzadeh, Leila, Voloudakis, Georgios, Bendl, Jaroslav, Zeng, Biau, Zhang, Wen, Grove, Jakob, Als, Thomas D., Duan, Jinjie, Satterstrom, F. Kyle, Bybjerg-Grauholm, Jonas, Bækved-Hansen, Marie, Gudmundsson, Olafur O., Magnusson, Sigurdur H., Baldursson, Gisli, Davidsdottir, Katrin, Haraldsdottir, Gyda S., Agerbo, Esben, Hoffman, Gabriel E., Dalsgaard, Søren, Martin, Joanna, Ribasés, Marta, Boomsma, Dorret I., Soler Artigas, Maria, Roth Mota, Nina, Howrigan, Daniel, Medland, Sarah E., Zayats, Tetyana, Rajagopal, Veera M., Havdahl, Alexandra, Doyle, Alysa, Reif, Andreas, Thapar, Anita, Cormand, Bru, Liao, Calwing, Burton, Christie, Bau, Claiton H. D., Rovaris, Diego Luiz, Sonuga-Barke, Edmund, Corfield, Elizabeth, Grevet, Eugenio Horacio, Larsson, Henrik, Gizer, Ian R., Waldman, Irwin, Brikell, Isabell, Haavik, Jan, Crosbie, Jennifer, McGough, James, Kuntsi, Jonna, Glessner, Joseph, Langley, Kate, Lesch, Klaus-Peter, Rohde, Luis Augusto, Hutz, Mara H., Klein, Marieke, Bellgrove, Mark, Tesli, Martin, O’Donovan, Michael C., Andreassen, Ole Andreas, Leung, Patrick W. L., Pan, Pedro M., Joober, Ridha, Schachar, Russel, Loo, Sandra, Witt, Stephanie H., Reichborn-Kjennerud, Ted, Banaschewski, Tobias, Hawi, Ziarih, Daly, Mark J., Mors, Ole, Nordentoft, Merete, Hougaard, David M., Mortensen, Preben Bo, Faraone, Stephen V., Stefansson, Hreinn, Roussos, Panos, Franke, Barbara, Werge, Thomas, Neale, Benjamin M., Stefansson, Kari, Børglum, Anders D., APH - Methodology, APH - Mental Health, Amsterdam Reproduction & Development, and Biological Psychology

Subjects
Cognition, All institutes and research themes of the Radboud University Medical Center, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], SDG 3 - Good Health and Well-being, Genetics, Brain, Humans, Genetic Predisposition to Disease, Attention Deficit Disorder with Hyperactivity/genetics, Genome-Wide Association Study
Abstract

Contains fulltext : 290804.pdf (Publisher’s version ) (Closed access) Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder with a major genetic component. Here, we present a genome-wide association study meta-analysis of ADHD comprising 38,691 individuals with ADHD and 186,843 controls. We identified 27 genome-wide significant loci, highlighting 76 potential risk genes enriched among genes expressed particularly in early brain development. Overall, ADHD genetic risk was associated with several brain-specific neuronal subtypes and midbrain dopaminergic neurons. In exome-sequencing data from 17,896 individuals, we identified an increased load of rare protein-truncating variants in ADHD for a set of risk genes enriched with probable causal common variants, potentially implicating SORCS3 in ADHD by both common and rare variants. Bivariate Gaussian mixture modeling estimated that 84-98% of ADHD-influencing variants are shared with other psychiatric disorders. In addition, common-variant ADHD risk was associated with impaired complex cognition such as verbal reasoning and a range of executive functions, including attention. 01 februari 2023

Published
2023

19. Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality

Author

Oddsson, Asmundur, Sulem, Patrick, Sveinbjornsson, Gardar, Arnadottir, Gudny A, Steinthorsdottir, Valgerdur, Halldorsson, Gisli H, Atlason, Bjarni A, Oskarsson, Gudjon R, Helgason, Hannes, Nielsen, Henriette Svarre, Westergaard, David, Karjalainen, Juha M, Katrinardottir, Hildigunnur, Fridriksdottir, Run, Jensson, Brynjar O, Tragante, Vinicius, Ferkingstad, Egil, Jonsson, Hakon, Gudjonsson, Sigurjon A, Beyter, Doruk, Moore, Kristjan H S, Thordardottir, Helga B, Kristmundsdottir, Snaedis, Stefansson, Olafur A, Rantapää-Dahlqvist, Solbritt, Sonderby, Ida Elken, Didriksen, Maria, Stridh, Pernilla, Haavik, Jan, Tryggvadottir, Laufey, Frei, Oleksandr, Walters, G Bragi, Kockum, Ingrid, Hjalgrim, Henrik, Olafsdottir, Thorunn A, Selbaek, Geir, Nyegaard, Mette, Erikstrup, Christian, Brodersen, Thorsten, Saevarsdottir, Saedis, Olsson, Tomas, Nielsen, Kaspar Rene, Haraldsson, Asgeir, Bruun, Mie Topholm, Hansen, Thomas Folkmann, Steingrimsdottir, Thora, Jacobsen, Rikke Louise, Lie, Rolv T, Djurovic, Srdjan, Alfredsson, Lars, Lopez de Lapuente Portilla, Aitzkoa, Brunak, Soren, Melsted, Pall, Halldorsson, Bjarni V, Saemundsdottir, Jona, Magnusson, Olafur Th, Padyukov, Leonid, Banasik, Karina, Rafnar, Thorunn, Askling, Johan, Klareskog, Lars, Pedersen, Ole Birger, Masson, Gisli, Havdahl, Alexandra, Nilsson, Bjorn, Andreassen, Ole A, Daly, Mark, Ostrowski, Sisse Rye, Jonsdottir, Ingileif, Stefansson, Hreinn, Holm, Hilma, Helgason, Agnar, Thorsteinsdottir, Unnur, Stefansson, Kari, and Gudbjartsson, Daniel F

Subjects
Mice, Genotype, Homozygote, Proteins/genetics, Animals, Humans, Genes, Recessive
Abstract

Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.

Published
2023

20. Polygenic risk score-based phenome-wide association study identifies novel associations for Tourette syndrome

Author

Jain, Pritesh, Miller-Fleming, Tyne, Topaloudi, Apostolia, Yu, Dongmei, Drineas, Petros, Georgitsi, Marianthi, Yang, Zhiyu, Rizzo, Renata, Müller-Vahl, Kirsten R., Tumer, Zeynep, Mol Debes, Nanette, Hartmann, Andreas, Depienne, Christel, Worbe, Yulia, Mir, Pablo, Cath, Danielle C., Boomsma, Dorret I., Roessner, Veit, Wolanczyk, Tomasz, Janik, Piotr, Szejko, Natalia, Zekanowski, Cezary, Barta, Csaba, Nemoda, Zsofia, Tarnok, Zsanett, Buxbaum, Joseph D., Grice, Dorothy, Glennon, Jeffrey, Stefansson, Hreinn, Hengerer, Bastian, Benaroya-Milshtein, Noa, Cardona, Francesco, Hedderly, Tammy, Heyman, Isobel, Huyser, Chaim, Morer, Astrid, Mueller, Norbert, Munchau, Alexander, Plessen, Kerstin J., Porcelli, Cesare, Walitza, Susanne, Schrag, Anette, Martino, Davide, Dietrich, Andrea, Mathews, Carol A., Scharf, Jeremiah M., Hoekstra, Pieter J., Davis, Lea K., Paschou, Peristera, Als, Thomas D., Aschauer, Harald, Atzmon, Gil, Bækvad-Hansen, Matie, Barr, Cathy L., Barzilai, Nir, Batterson, James R., Batterson, Robert, Benarroch, Fortu, Berlin, Cheston, Boberg, Julia, Bodmer, Benjamin, Bohnenpoll, Julia, Børglum, Anders D., Brown, Lawrence W., Bruun, Ruth, Budman, Cathy L., Buckner, Randy L., Bybjerg-Grauholm, Jonas, Cheon, Keun-Ah, Chouinard, Sylvain, Coffey, Barbara J., Coppola, Giovanni, Crowley, James J., Dahl, Niklas, Darrow, Sabrina M., Daly, Mark J., De Rubeis, Silvia, Dion, Yves, Djurfeldt, Diana R., Domenech-Salgado, Laura, Eapen, Valsamma, Elzerman, Lonneke, Fernandez, Thomas V., Freimer Carolin Fremer, Nelson B., Garcia-Delgar, Blanca, Garrido, Marcos, Gilbert, Donald L., Giusti-Rodriguez, Paola, Grados, Marco, Greenberg, Erica, Grove, Jakob, Hagstrom, Julie, Halvorsen, Matt, Hansen, Bjarne, Haavik, Jan, Hebebrand, Johannes, Heiman, Gary A., Herrera, Luis, Hinney, Anke, Hirschtritt, Matthew E., Sul, Jae Hoon, Hong, Hyun Ju, Hougaard, David M., Huang, Alden Y., Ibanez-Gomez, Laura, Ivankovic, Franjo, Jankovic, Joseph, Karlsson, Elinor K., Kaprio, Jakko A., Kim, Young Key, Kim, Young-Shin, King, Robert A., Knowles, James A., Koh, Yun-Joo, Kook, Sodham, Khalifa, Najah, Konstantinidis, Anastasios, Kuperman, Samuel, Kurlan, Roger, Kvale, Gerd, Leckman, James, Lee, Paul C., Leventhal, Bennett, Lichtenstein, Paul, Lindbald-Toh, Kerstin, Lowe, Thomas, Ludolph, Andrea, da Silva, Claudia Luhrs, Luðvigsson, Pétur, Luykx, Jurjen, Lyon, Gholson J., Mahjani, Behrang, Maras, Athanasios, Mataix-Cols, David, Mattheisen, Manuel, Malaty, Irene A., McMahon, William M., McQuillin, Andrew, Meier, Sandra M., Moessner, Rainald, Mortensen, Preben B., Mors, Ole, Mudgal, Poorva, Nagy, Peter, Naarden, Allan, Neale, Benjamin M., Nawaz, Muhammad S., Nissen, Judith Becker, Nöthen Merete Nordentoft, Markus M., Nordsletten, Ashley E., Okun, Michael S., Ophoff, Roel, Osiecki, Lisa, Palotie, Aarno, Palviainen, Teemu P., Pato Michele T. Pato, Carlos N., Pittenger, Christopher, Pollak, Yehuda, Posthuma, Danielle, Ramos, Eliana, Reichert, Jennifer, Robertson, Mary M., Roffman, Joshua L., Rouleau, Guy, Rück, Christian, Sæmundsen, Evald, Samuels, Jack, Sandin, Sven, Sandor, Paul, Schlögelhofer, Monika, Shin, Eun-Young, Singer, Harvey S., Smit, Jan, Smoller, Jordan W., State, Matthew, Solem, Stian, Song, Dong-Ho, Song, Jungeun, Stamenkovic, Mara, Stefansson, Kári, Strom, Nora, Stuhrmann, Manfred, Szatkiewicz, Jin, Szymanska, Urszula, Tischfield, Jay A., Tsetsos, Fotis, Thorarensen, Ólafur, Tubing, Jennifer, Visscher, Frank, Wagner, Michael, Wanderer, Sina, Wang, Sheng, Werge, Thomas, Willsey, Jeremy A., Wolancyk, Tomasz, Woods, Douglas W., Woods, Martin, Zelaya, Ivette, Zinner, Samuel H., Apter, Alan, Ball, Juliane, Bognar, Emese, Buse, Judith, Vela, Marta Correa, Fremer, Carolin, Gulisano, Mariangela, Hagen, Annelieke, Hagstrøm, Julie, Madruga-Garrido, Marcos, Pellico, Alessandra, Ruhrman, Daphna, Schnell, Jaana, Silvestri, Paola Rosaria, Skov, Liselotte, Steinberg, Tamar, Gloor, Friederike Tagwerker, Turner, Victoria L., Weidinger, Elif, Alexander, John, Aranyi, Tamas, Buisman, Wim R., Buitelaar, Jan K., Driessen, Nicole, Fan, Siyan, Forde, Natalie J., Gerasch, Sarah, van den Heuvel, Odile A., Jespersgaard, Cathrine, Kanaan, Ahmad S., Möller, Harald E., Nespoli, Ester, Pagliaroli, Luca, Poelmans, Geert, Pouwels, Petra J. W., Rizzo, Francesca, Veltman, Dick J., van der Werf, Ysbrand D., Widomska, Joanna, Zilhäo, Nuno R., Biological Psychology, Amsterdam Reproduction & Development, APH - Mental Health, APH - Methodology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Dynamic Earth and Resources, and Clinical Cognitive Neuropsychiatry Research Program (CCNP)

Subjects
Male, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Medizin, Autism Spectrum Disorder/genetics, Cellular and Molecular Neuroscience, Psychiatry and Mental health, Diabetes Mellitus, Type 2, Risk Factors, Diabetes Mellitus, Tourette Syndrome/genetics, Humans, Female, Attention Deficit Disorder with Hyperactivity/genetics, Type 2, Biological Psychiatry
Abstract

Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders. Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders.

Published
2023

21. Statistical and functional convergence of common and rare genetic influences on autism at chromosome 16p

Author

Weiner, Daniel J., Ling, Emi, Erdin, Serkan, Tai, Derek J. C., Yadav, Rachita, Grove, Jakob, Fu, Jack M., Nadig, Ajay, Carey, Caitlin E., Baya, Nikolas, Bybjerg-Grauholm, Jonas, Mortensen, Preben B., Werge, Thomas, Demontis, Ditte, Mors, Ole, Nordentoft, Merete, Als, Thomas D., Baekvad-Hansen, Marie, Rosengren, Anders, Havdahl, Alexandra, Hedemand, Anne, Palotie, Aarno, Chakravarti, Aravinda, Arking, Dan, Sulovari, Arvis, Starnawska, Anna, Thiruvahindrapuram, Bhooma, de Leeuw, Christiaan, Carey, Caitlin, Ladd-Acosta, Christine, van der Merwe, Celia, Devlin, Bernie, Cook, Edwin H., Eichler, Evan, Corfield, Elisabeth, Dieleman, Gwen, Schellenberg, Gerard, Hakonarson, Hakon, Coon, Hilary, Dziobek, Isabel, Vorstman, Jacob, Girault, Jessica, Sutcliffe, James S., Duan, Jinjie, Nurnberger, John, Hallmayer, Joachim, Buxbaum, Joseph, Piven, Joseph, Weiss, Lauren, Davis, Lea, Janecka, Magdalena, Mattheisen, Manuel, State, Matthew W., Gill, Michael, Daly, Mark, Uddin, Mohammed, Andreassen, Ole, Szatmari, Peter, Lee, Phil Hyoun, Anney, Richard, Ripke, Stephan, Satterstrom, Kyle, Santangelo, Susan, Kuo, Susan, van Elst, Ludger Tebartz, Rolland, Thomas, Bougeron, Thomas, Polderman, Tinca, Turner, Tychele, Underwood, Jack, Manikandan, Veera, Pillalamarri, Vamsee, Warrier, Varun, Philipsen, Alexandra, Reif, Andreas, Hinney, Anke, Cormand, Bru, Bau, Claiton H. D., Rovaris, Diego Luiz, Sonuga-Barke, Edmund, Corfield, Elizabeth, Grevet, Eugenio Horacio, Salum, Giovanni, Larsson, Henrik, Buitelaar, Jan, Haavik, Jan, McGough, James, Kuntsi, Jonna, Elia, Josephine, Lesch, Klaus-Peter, Klein, Marieke, Bellgrove, Mark, Tesli, Martin, Leung, Patrick W. L., Pan, Pedro M., Dalsgaard, Soren, Loo, Sandra, Medland, Sarah, Faraone, Stephen V., Reichborn-Kjennerud, Ted, Banaschewski, Tobias, Hawi, Ziarih, Berretta, Sabina, Macosko, Evan Z., Sebat, Jonathan, O’Connor, Luke J., Hougaard, David M., Børglum, Anders D., Talkowski, Michael E., McCarroll, Steven A., Robinson, Elise B., Pediatrics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Hinney, Anke (Beitragende*r), Child and Adolescent Psychiatry / Psychology, Centre of Excellence in Complex Disease Genetics, Research Programs Unit, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Complex Trait Genetics, and Clinical Developmental Psychology

Subjects
Genètica humana, DNA Copy Number Variations, Autism, 3112 Neurosciences, Medizin, Chromosomes, Cromosomes, Human genetics, Genetics, Humans, Autistic Disorder, Chromosome Deletion, Chromosomes, Human, Pair 16/genetics, Autisme, Chromosomes, Human, Pair 16, Autistic Disorder/genetics
Abstract

in press, weitere Verfasser:innen aus Einrichtungen außerhalb der Universität Duisburg-Essen sind nicht aufgeführt. The canonical paradigm for converting genetic association to mechanism involves iteratively mapping individual associations to the proximal genes through which they act. In contrast, in the present study we demonstrate the feasibility of extracting biological insights from a very large region of the genome and leverage this strategy to study the genetic influences on autism. Using a new statistical approach, we identified the 33-Mb p-arm of chromosome 16 (16p) as harboring the greatest excess of autism’s common polygenic influences. The region also includes the mechanistically cryptic and autism-associated 16p11.2 copy number variant. Analysis of RNA-sequencing data revealed that both the common polygenic influences within 16p and the 16p11.2 deletion were associated with decreased average gene expression across 16p. The transcriptional effects of the rare deletion and diffuse common variation were correlated at the level of individual genes and analysis of Hi-C data revealed patterns of chromatin contact that may explain this transcriptional convergence. These results reflect a new approach for extracting biological insight from genetic association data and suggest convergence of common and rare genetic influences on autism at 16p.

Published
2022

22. Reproducibility in the absence of selective reporting : An illustration from large-scale brain asymmetry research

Author

Kong, Xiang-Zhen, Francks, Clyde, Allen, Nicholas B., Heslenfeld, Dirk, Hester, Robert, Hibar, Derrek Paul, Ho, Beng-Choon, Ho, Tiffany C., Hoekstra, Pieter J., Holst, Ruth J., Hoogman, Martine, Høvik, Marie F., Howells, Fleur M., Ames, David, Hugdahl, Kenneth, Huyser, Chaim, Ingvar, Martin, Ishikawa, Akari, James, Anthony, Jahanshad, Neda, Jernigan, Terry L., Jönsson, Erik G, Kaleda, Vasily, Kelly, Clare, Andreassen, Ole A., Kerich, Michael, Keshavan, Matcheri S., Khadka, Sabin, Kircher, Tilo, Kohls, Gregor, Konrad, Kerstin, Korucuoglu, Ozlem, Krämer, Bernd, Krug, Axel, Kuntsi, Jonna, Vasquez, Alejandro Arias, Kwon, Jun Soo, Lambregts-Rommelse, Nanda, Landén, Mikael, Lázaro, Luisa, Lebedeva, Irina, Lenroot, Rhoshel, Lesch, Klaus-Peter, Li, Qinqin, Lim, Kelvin O., Liu, Jia, Armstrong, Nicola J., Lochner, Christine, London, Edythe D., Lorenzetti, Valentina, Luciano, Michelle, Luijten, Maartje, Lundervold, Astri J., Mackey, Scott, MacMaster, Frank P., Maingault, Sophie, Malpas, Charles B., Asherson, Phil, Malt, Ulrik F., Mataix-Cols, David, Martin-Santos, Rocio, Mayer, Andrew R., McCarthy, Hazel, Medland, Sarah, Metha, Mitul, Mitchell, Philip B., Mueller, Bryon A., Maniega, Susana Muñoz, Bergo, Felipe, Mazoyer, Bernard, McDonald, Colm, McLellan, Quinn, McMahon, Katie L., McPhilemy, Genevieve, Momenan, Reza, Morales, Angelica M., Narayanaswamy, Janardhanan C., Moreira, José Carlos Vasques, Nerland, Stener, Bastin, Mark E., Nestor, Liam, Newman, Erik, Nigg, Joel T., Nordvik, Jan Egil, Novotny, Stephanie, Weiss, Eileen Oberwelland, O'Gorman, Ruth L., Oosterlaan, Jaap, Oranje, Bob, Orr, Catherine, Batalla, Albert, Overs, Bronwyn, Paloyelis, Yannis, Pauli, Paul, Paulus, Martin, Plessen, Kerstin Jessica, Polier, Georg G., Pomarol-Clotet, Edith, Portella, Maria J., Qiu, Jiang, Radua, Joaquim, Bauer, Jochen, Ramos-Quiroga, Josep Antoni, Reddy, Y. C. Janardhan, Reif, Andreas, Roberts, Gloria, Rosa, Pedro, Rubia, Katya, Sacchet, Matthew D., Sachdev, Perminder S., Salvador, Raymond, Schmaal, Lianne, Baune, Bernhard T, Schulte-Rüther, Martin, Schweren, Lizanne, Seitz, Jochen, Serpa, Mauricio Henriques, Shaw, Philip, Shumskaya, Elena, Silk, Timothy J., Simmons, Alan N., Simulionyte, Egle, Sinha, Rajita, Baur-Streubel, Ramona, Sjoerds, Zsuzsika, Smelror, Runar Elle, Soliva, Joan Carlos, Solowij, Nadia, Souza-Duran, Fabio Luisde, Sponheim, Scott R., Stein, Dan J., Stein, Elliot A., Stevens, Michael, Strike, Lachlan T., Biederman, Joseph, Sudre, Gustavo, Sui, Jing, Tamm, Leanne, Temmingh, Hendrik S., Thoma, Robert J., Tomyshev, Alexander, Tronchin, Giulia, Turner, Jessica, Uhlmann, Anne, Erp, Theo G. M., Blaine, Sara K., Heuvel, Odile A., Meer, Dennis, Eijk, Liza, Vance, Alasdair, Veer, Ilya M., Veltman, Dick J., Venkatasubramanian, Ganesan, Vilarroya, Oscar, Vives-Gilabert, Yolanda, Voineskos, Aristotle N, Boedhoe, Premika, Völzke, Henry, Vuletic, Daniella, Walitza, Susanne, Walter, Henrik, Walton, Esther, Wardlaw, Joanna M., Wen, Wei, Westlye, Lars T., Whelan, Christopher D., White, Tonya, Bøen, Erlend, Wiers, Reinout W., Wright, Margaret J., Wittfeld, Katharina, Yang, Tony T., Yasuda, Clarissa L., Yoncheva, Yuliya, Yücel, Murat, Yun, Je-Yeon, Zanetti, Marcus Vinicius, Zhen, Zonglei, Bose, Anushree, Zhu, Xing-xing, Ziegler, Georg C., Zubicaray, Greig I., Zwiers, Marcel, Project, Karolinska Schizophrenia, Glahn, David C., Crivello, Fabrice, Fisher, Simon E., Thompson, Paul M., Bralten, Janita, Farde, Lars, Flyckt, Lena, Engberg, Göran, Erhardt, Sophie, Fatouros-Bergman, Helena, Cervenka, Simon, Schwieler, Lilly, Piehl, Fredrik, Agartz, Ingrid, Collste, Karin, Brandeis, Daniel, Victorsson, Pauliina, Malmqvist, Anna, Hedberg, Mikael, Orhan, Funda, Sellgren, Carl, Brem, Silvia, Mathias, Samuel R., Brodaty, Henry, Yüksel, Dilara, Brooks, Samantha J., Buitelaar, Jan, Bürger, Christian, Bülow, Robin, Calhoun, Vince, Calvo, Anna, Canales-Rodríguez, Erick Jorge, Cannon, Dara M., Guadalupe, Tulio, Caparelli, Elisabeth C., Castellanos, Francisco X., Cendes, Fernando, Chaim-Avancini, Tiffany Moukbel, Chantiluke, Kaylita, Chen, Qun-lin, Chen, Xiayu, Cheng, Yuqi, Christakou, Anastasia, Clark, Vincent P., Abé, Christoph, Coghill, David, Connolly, Colm G., Conzelmann, Annette, Córdova-Palomera, Aldo, Cousijn, Janna, Crow, Tim, Cubillo, Ana, Dannlowski, Udo, Bruttopilo, Sara Ambrosino, Zeeuw, Patrick, Deary, Ian J., Demeter, Damion V., Di Martino, Adriana, Dickie, Erin W, Dietsche, Bruno, Doan, Nhat Trung, Doherty, Colin P., Doyle, Alysa, Durston, Sarah, Earl, Eric, Akudjedu, Theophilus N., Ehrlich, Stefan, Ekman, Carl Johan, Elvsåshagen, Torbjørn, Epstein, Jeffery N., Fair, Damien A., Faraone, Stephen V., Fernández, Guillén, Flint, Claas, Filho, Geraldo Busatto, Förster, Katharina, Aleman, Andre, Fouche, Jean-Paul, Foxe, John J., Frodl, Thomas, Fuentes-Claramonte, Paola, Fullerton, Janice M., Garavan, Hugh, Santos Garcia, Danielle, Gotlib, Ian H., Goudriaan, Anna E., Grabe, Hans Jörgen, Alhusaini, Saud, Groenewold, Nynke A., Grotegerd, Dominik, Gruber, Oliver, Gurholt, Tiril, Haavik, Jan, Hahn, Tim, Hansell, Narelle K., Harris, Mathew A., Hartman, Catharina A., Carmen Valdés Hernández, Maria, Alhusaini, Saud, Del Carmen Valdés Hernández, Maria, Heslenfeld, Dirk, Hester, Robert, Hibar, Derrek Paul, Ho, Beng-Choon, Ho, Tiffany C., Hoekstra, Pieter J., van Holst, Ruth J., Hoogman, Martine, Høvik, Marie F., Allen, Nicholas B., Howells, Fleur M., Hugdahl, Kenneth, Huyser, Chaim, Ingvar, Martin, Ishikawa, Akari, James, Anthony, Jahanshad, Neda, Jernigan, Terry L., Jönsson, Erik G., Kaleda, Vasily, Ames, David, Kelly, Clare, Kerich, Michael, Keshavan, Matcheri S., Khadka, Sabin, Kircher, Tilo, Kohls, Gregor, Konrad, Kerstin, Korucuoglu, Ozlem, Krämer, Bernd, Krug, Axel, Andreassen, Ole A., Kuntsi, Jonna, Kwon, Jun Soo, Lambregts-Rommelse, Nanda, Landén, Mikael, Lázaro, Luisa, Lebedeva, Irina, Lenroot, Rhoshel, Lesch, Klaus-Peter, Li, Qinqin, Lim, Kelvin O., Vasquez, Alejandro Arias, Liu, Jia, Lochner, Christine, London, Edythe D., Lorenzetti, Valentina, Luciano, Michelle, Luijten, Maartje, Lundervold, Astri J., Mackey, Scott, MacMaster, Frank P., Maingault, Sophie, Armstrong, Nicola J., Malpas, Charles B., Malt, Ulrik F., Mataix-Cols, David, Martin-Santos, Rocio, Mayer, Andrew R., McCarthy, Hazel, Medland, Sarah, Metha, Mitul, Mitchell, Philip B., Mueller, Bryon A., Asherson, Phil, Maniega, Susana Muñoz, Mazoyer, Bernard, McDonald, Colm, McLellan, Quinn, McMahon, Katie L., McPhilemy, Genevieve, Momenan, Reza, Morales, Angelica M., Narayanaswamy, Janardhanan C., Moreira, José Carlos Vasques, Bergo, Felipe, Nerland, Stener, Nestor, Liam, Newman, Erik, Nigg, Joel T., Nordvik, Jan Egil, Novotny, Stephanie, Weiss, Eileen Oberwelland, O'Gorman, Ruth L., Oosterlaan, Jaap, Oranje, Bob, Bastin, Mark E., Orr, Catherine, Overs, Bronwyn, Paloyelis, Yannis, Pauli, Paul, Paulus, Martin, Plessen, Kerstin Jessica, von Polier, Georg G., Pomarol-Clotet, Edith, Portella, Maria J., Qiu, Jiang, Batalla, Albert, Radua, Joaquim, Ramos-Quiroga, Josep Antoni, Reddy, Y. C. Janardhan, Reif, Andreas, Roberts, Gloria, Rosa, Pedro, Rubia, Katya, Sacchet, Matthew D., Sachdev, Perminder S., Salvador, Raymond, Bauer, Jochen, Schmaal, Lianne, Schulte-Rüther, Martin, Schweren, Lizanne, Seitz, Jochen, Serpa, Mauricio Henriques, Shaw, Philip, Shumskaya, Elena, Silk, Timothy J., Simmons, Alan N., Simulionyte, Egle, Baune, Bernhard T., Sinha, Rajita, Sjoerds, Zsuzsika, Smelror, Runar Elle, Soliva, Joan Carlos, Solowij, Nadia, Souza-Duran, Fabio Luisde, Sponheim, Scott R., Stein, Dan J., Stein, Elliot A., Stevens, Michael, Baur-Streubel, Ramona, Strike, Lachlan T., Sudre, Gustavo, Sui, Jing, Tamm, Leanne, Temmingh, Hendrik S., Thoma, Robert J., Tomyshev, Alexander, Tronchin, Giulia, Turner, Jessica, Uhlmann, Anne, Biederman, Joseph, van Erp, Theo G. M., van den Heuvel, Odile A., van der Meer, Dennis, van Eijk, Liza, Vance, Alasdair, Veer, Ilya M., Veltman, Dick J., Venkatasubramanian, Ganesan, Vilarroya, Oscar, Vives-Gilabert, Yolanda, Blaine, Sara K., Voineskos, Aristotle N., Völzke, Henry, Vuletic, Daniella, Walitza, Susanne, Walter, Henrik, Walton, Esther, Wardlaw, Joanna M., Wen, Wei, Westlye, Lars T., Whelan, Christopher D., Boedhoe, Premika, White, Tonya, Wiers, Reinout W., Wright, Margaret J., Wittfeld, Katharina, Yang, Tony T., Yasuda, Clarissa L., Yoncheva, Yuliya, Yücel, Murat, Yun, Je-Yeon, Zanetti, Marcus Vinicius, Bøen, Erlend, Zhen, Zonglei, Zhu, Xing-Xing, Ziegler, Georg C., de Zubicaray, Greig I., Zwiers, Marcel, Project, Karolinska Schizophrenia, Glahn, David C., Crivello, Fabrice, Fisher, Simon E., Thompson, Paul M., Bose, Anushree, Francks, Clyde, Farde, Lars, Flyckt, Lena, Engberg, Göran, Erhardt, Sophie, Fatouros-Bergman, Helena, Cervenka, Simon, Schwieler, Lilly, Piehl, Fredrik, Agartz, Ingrid, Bralten, Janita, Collste, Karin, Victorsson, Pauliina, Malmqvist, Anna, Hedberg, Mikael, Orhan, Funda, Sellgren, Carl, Brandeis, Daniel, Kong, Xiang-Zhen, Brem, Silvia, Brodaty, Henry, Yüksel, Dilara, Brooks, Samantha J., Buitelaar, Jan, Bürger, Christian, Bülow, Robin, Calhoun, Vince, Calvo, Anna, Canales-Rodríguez, Erick Jorge, Mathias, Samuel R., Cannon, Dara M., Caparelli, Elisabeth C., Castellanos, Francisco X., Cendes, Fernando, Chaim-Avancini, Tiffany Moukbel, Chantiluke, Kaylita, Chen, Qun-Lin, Chen, Xiayu, Cheng, Yuqi, Christakou, Anastasia, Guadalupe, Tulio, Clark, Vincent P., Coghill, David, Connolly, Colm G., Conzelmann, Annette, Córdova-Palomera, Aldo, Cousijn, Janna, Crow, Tim, Cubillo, Ana, Dannlowski, Udo, de Bruttopilo, Sara Ambrosino, Abé, Christoph, de Zeeuw, Patrick, Deary, Ian J., Demeter, Damion V., Di Martino, Adriana, Dickie, Erin W., Dietsche, Bruno, Doan, Nhat Trung, Doherty, Colin P., Doyle, Alysa, Durston, Sarah, Earl, Eric, Ehrlich, Stefan, Ekman, Carl Johan, Elvsåshagen, Torbjørn, Epstein, Jeffery N., Fair, Damien A., Faraone, Stephen V., Fernández, Guillén, Flint, Claas, Filho, Geraldo Busatto, Akudjedu, Theophilus N., Förster, Katharina, Fouche, Jean-Paul, Foxe, John J., Frodl, Thomas, Fuentes-Claramonte, Paola, Fullerton, Janice M., Garavan, Hugh, do Santos Garcia, Danielle, Gotlib, Ian H., Goudriaan, Anna E., Aleman, Andre, Grabe, Hans Jörgen, Groenewold, Nynke A., Grotegerd, Dominik, Gruber, Oliver, Gurholt, Tiril, Haavik, Jan, Hahn, Tim, Hansell, Narelle K., Harris, Mathew A., Hartman, Catharina A., Ontwikkelingspsychologie (Psychologie, FMG), Adult Psychiatry, APH - Mental Health, ANS - Compulsivity, Impulsivity & Attention, Child and Adolescent Psychiatry & Psychosocial Care, Child Psychiatry, ANS - Cellular & Molecular Mechanisms, Laboratory Genetic Metabolic Diseases, Paediatrics, General Paediatrics, ARD - Amsterdam Reproduction and Development, Paediatric Pulmonology, Graduate School, and APH - Digital Health

Subjects
P‐hacking, Datasets as Topic, Publication bias, 0302 clinical medicine, 130 000 Cognitive Neurology & Memory, Statistics, team science, Brain asymmetry, Multicenter Studies as Topic, Cervell, Research Articles, Cerebral Cortex, Radiological and Ultrasound Technology, P-hacking, 05 social sciences, Brain, Cerebral cortex, Middle Aged, Magnetic Resonance Imaging, Discoveries in science, Escorça cerebral, Neurology, Biaix de publicació, Anatomy, Psychology, Research Article, Neuroinformatics, Adult, Adolescent, Neuroimaging, Descobriments científics, 050105 experimental psychology, Statistical power, 03 medical and health sciences, Young Adult, Magnetic resonance imaging, Imatges per ressonància magnètica, multisite collaboration, Humans, 0501 psychology and cognitive sciences, Radiology, Nuclear Medicine and imaging, ddc:610, reproducibility, Aged, publication bias, Reproducibility, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Perspective (graphical), Reproducibility of Results, Brain Cortical Thickness, Research data, Sample size determination, Dades de recerca, Neurology (clinical), Scale (map), Developmental Psychopathology, 030217 neurology & neurosurgery
Abstract

The problem of poor reproducibility of scientific findings has received much attention over recent years, in a variety of fields including psychology and neuroscience. The problem has been partly attributed to publication bias and unwanted practices such as p‐hacking. Low statistical power in individual studies is also understood to be an important factor. In a recent multisite collaborative study, we mapped brain anatomical left–right asymmetries for regional measures of surface area and cortical thickness, in 99 MRI datasets from around the world, for a total of over 17,000 participants. In the present study, we revisited these hemispheric effects from the perspective of reproducibility. Within each dataset, we considered that an effect had been reproduced when it matched the meta‐analytic effect from the 98 other datasets, in terms of effect direction and significance threshold. In this sense, the results within each dataset were viewed as coming from separate studies in an “ideal publishing environment,” that is, free from selective reporting and p hacking. We found an average reproducibility rate of 63.2% (SD = 22.9%, min = 22.2%, max = 97.0%). As expected, reproducibility was higher for larger effects and in larger datasets. Reproducibility was not obviously related to the age of participants, scanner field strength, FreeSurfer software version, cortical regional measurement reliability, or regional size. These findings constitute an empirical illustration of reproducibility in the absence of publication bias or p hacking, when assessing realistic biological effects in heterogeneous neuroscience data, and given typically‐used sample sizes., Region‐wise effect sizes and reproducibility rates of hemispheric asymmetry effects. In general, effects with higher effect sizes showed higher reproducibility, given the same conditions (e.g., sample size and data heterogeneity).

Published
2022

23. Elevated body weight modulates subcortical volume change and associated clinical response following electroconvulsive therapy

Author

Opel, Nils, Narr, Katherine L., Abbott, Christopher, Argyelan, Miklos, Espinoza, Randall, Emsell, Louise, Bouckaert, Filip, Sienaert, Pascal, Vandenbulcke, Mathieu, Nordanskog, Pia, Repple, Jonathan, Kavakbasi, Erhan, Balslev Jørgensen, Martin, Paulson, Olaf B., Hanson, Lars G., Dols, Annemieke, Exel, Eric van, Oudega, Mardien L., Takamiya, Akihiro, Kishimoto, Taishiro, Ousdal, Olga Therese, Haavik, Jan, Hammar, Åsa, Oedegaard, Ketil Joachim, Kessler, Ute, Bartsch, Hauke, Dale, Anders M., Baune, Bernhard Th., Dannlowski, Udo, Oltedal, Leif, Redlich, Ronny, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Amsterdam Neuroscience - Neurodegeneration, APH - Aging & Later Life, and Universitäts- und Landesbibliothek Münster

Subjects
Psychiatry, Male, Depressive Disorder, Major, 610 Medicine and health, Body Weight, Brain, Middle Aged, behavioral disciplines and activities, Psykiatri, SDG 3 - Good Health and Well-being, Medicine and health, mental disorders, Humans, Female, ddc:610, Gray Matter, Electroconvulsive Therapy, Research Paper
Abstract

Background: Obesity is a frequent somatic comorbidity of major depression, and it has been associated with worse clinical outcomes and brain structural abnormalities. Converging evidence suggests that electroconvulsive therapy (ECT) induces both clinical improvements and increased subcortical grey matter volume in patients with depression. However, it remains unknown whether increased body weight modulates the clinical response and structural neuroplasticity that occur with ECT. Methods: To address this question, we conducted a longitudinal investigation of structural MRI data from the Global ECT-MRI Research Collaboration (GEMRIC) in 223 patients who were experiencing a major depressive episode (10 scanning sites). Structural MRI data were acquired before and after ECT, and we assessed change in subcortical grey matter volume using FreeSurfer and Quarc. Results: Higher body mass index (BMI) was associated with a significantly lower increase in subcortical grey matter volume following ECT. We observed significant negative associations between BMI and change in subcortical grey matter volume, with pronounced effects in the thalamus and putamen, where obese participants showed increases in grey matter volume that were 43.3% and 49.6%, respectively, of the increases found in participants with normal weight. As well, BMI significantly moderated the association between subcortical grey matter volume change and clinical response to ECT. We observed no significant association between BMI and clinical response to ECT. Limitations: Because only baseline BMI values were available, we were unable to study BMI changes during ECT and their potential association with clinical and grey matter volume change. Conclusion: Future studies should take into account the relevance of body weight as a modulator of structural neuroplasticity during ECT treatment and aim to further explore the functional relevance of this novel finding., Finanziert durch den Open-Access-Publikationsfonds der Westfälischen Wilhelms-Universität Münster (WWU Münster).

Published
2021

24. Risk variants and polygenic architecture of disruptive behavior disorders in the context of attention-deficit/hyperactivity disorder

Author

Demontis, Ditte, Walters, Raymond K., Rajagopal, Veera M., Waldman, Irwin D., Grove, Jakob, Als, Thomas D., Dalsgaard, Søren, Ribasas, Marta, Bybjerg-Grauholm, Jonas, Bækvad-Hansen, Maria, Werge, Thomas, Nordentoft, Merete, Mors, Ole, Mortensen, Preben Bo, (PGC), ADHD Working Group of the Psychiatric Genomics Consortium, Andreassen, Ole A., Arranz, Maria Jesús, Banaschewski, Tobias, Bau, Claiton, Bellgrove, Mark, Biederman, Joseph, Brikell, Isabell, Buitelaar, Jan K., Burton, Christie L., Casas, Miguel, Crosbie, Jennifer, Doyle, Alysa E., Ebstein, Richard P., Elia, Josephine, Elizabeth, Corfield C., Grevet, Eugenio, Grizenko, Natalie, Havdahl, Alexandra, Hawi, Ziarih, Hebebrand, Johannes, Hervas, Amaia, Hohmann, Sarah, Haavik, Jan, Joober, Ridha, Kent, Lindsey, Kuntsi, Jonna, Langley, Kate, Larsson, Henrik, Lesch, Klaus-Peter, Leung, Patrick W. L., Liao, Calwing, Loo, Sandra K., Martin, Joanna, Martin, Nicholas G., Medland, Sarah E., Miranda, Ana, Mota, Nina Roth, Oades, Robert D., Ramos-Quiroga, Josep Antoni, Reif, Andreas, Rietschel, Marcella, Roeyers, Herbert, Rohde, Luis Augusto, Rothenberger, Aribert, Rovira, Paula, Sánchez-Mora, Cristina, Schachar, Russell James, Sengupta, Sarojini, Artigas, Maria Soler, Steinhausen, Hans-Christoph, Thapar, Anita, Witt, Stephanie H., Yang, Li, Zayats, Tetyana, Zhang-James, Yanli, Cormand, Bru, Hougaard, David M., Neale, Benjamin M., Franke, Barbara, Faraone, Stephen V., Børglum, Anders D., University of St Andrews. School of Medicine, University of St Andrews. Institute of Behavioural and Neural Sciences, University of St Andrews. Cellular Medicine Division, Institut Català de la Salut, [Demontis D, Rajagopal VM, Als TD] The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark. Center for Genomics and Personalized Medicine, Aarhus, Denmark. Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, Denmark. [Walters RK] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [Waldman ID] Department of Psychology, Emory University, Atlanta, GA, USA. [Grove J] The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark. Center for Genomics and Personalized Medicine, Aarhus, Denmark. Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, Denmark. [Ribasés M] Unitat de Psiquiatria Genètica, Grup de recerca en Psiquiatria, salut mental i addiccions, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Servei de Psiquiatria, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Biomedical Network Research Center on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain. Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Catalonia, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Male, 0301 basic medicine, Multifactorial Inheritance, Trastorns per dèficit d'atenció amb hiperactivitat en els infants, Medizin, General Physics and Astronomy, Genome-wide association study, Comorbidity, Genome-wide association studies, Attention deficit disorder with hyperactivity in children, conducta y mecanismos de la conducta::conducta::conducta y mecanismos de la conducta::conducta::conducta infantil::conducta problemática [PSIQUIATRÍA Y PSICOLOGÍA], Cohort Studies, 0302 clinical medicine, Mental Disorders::Neurodevelopmental Disorders::Attention Deficit and Disruptive Behavior Disorders::Attention Deficit Disorder with Hyperactivity [PSYCHIATRY AND PSYCHOLOGY], Risk Factors, 2.1 Biological and endogenous factors, Medicine, Attention Deficit Disorder with Hyperactivity/epidemiology, Aetiology, Child, China/epidemiology, Violence Research, Pediatric, Multidisciplinary, Genetic Predisposition to Disease/genetics, Attention Deficit and Disruptive Behavior Disorders/epidemiology, Single Nucleotide, 3. Good health, Europe, Mental Health, Attention Deficit and Disruptive Behavior Disorders, Cohort, Genome-Wide Association Study/methods, Attention Deficit Disorder (ADD), Female, medicine.symptom, RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry, Clinical psychology, China, Investigative Techniques::Epidemiologic Methods::Epidemiologic Research Design::Genome-Wide Association Study [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Science, Context (language use), Locus (genetics), QH426 Genetics, Polymorphism, Single Nucleotide, behavioral disciplines and activities, Article, General Biochemistry, Genetics and Molecular Biology, Europe/epidemiology, 03 medical and health sciences, Aggressiveness in children, Behavioral and Social Science, mental disorders, Genetics, ADHD, Humans, SNP, Attention deficit hyperactivity disorder, Genetic Predisposition to Disease, Polymorphism, Author Correction, QH426, Multifactorial Inheritance/genetics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Aggression, Prevention, Human Genome, DAS, General Chemistry, Agressivitat en els infants, Heritability, medicine.disease, Attention Deficit Hyperactivity Disorder (ADHD), Behavior and Behavior Mechanisms::Behavior::Behavior and Behavior Mechanisms::Behavior::Child Behavior::Problem Behavior [PSYCHIATRY AND PSYCHOLOGY], Brain Disorders, Genòmica, ADHD Working Group of the Psychiatric Genomics Consortium, Trastorn per dèficit d'atenció amb hiperactivitat, 030104 developmental biology, Attention Deficit Disorder with Hyperactivity, técnicas de investigación::métodos epidemiológicos::diseño de la investigación epidemiológica::estudio de asociación genómica completa [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], RC0321, trastornos mentales::trastornos del desarrollo neurológico::trastornos conductuales disruptivos y déficit de atención::trastornos de déficit de atención con hiperactividad [PSIQUIATRÍA Y PSICOLOGÍA], business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). Here, we report a GWAS meta-analysis of ADHD comorbid with DBDs (ADHD + DBDs) including 3802 cases and 31,305 controls. We identify three genome-wide significant loci on chromosomes 1, 7, and 11. A meta-analysis including a Chinese cohort supports that the locus on chromosome 11 is a strong risk locus for ADHD + DBDs across European and Chinese ancestries (rs7118422, P = 3.15×10−10, OR = 1.17). We find a higher SNP heritability for ADHD + DBDs (h2SNP = 0.34) when compared to ADHD without DBDs (h2SNP = 0.20), high genetic correlations between ADHD + DBDs and aggressive (rg = 0.81) and anti-social behaviors (rg = 0.82), and an increased burden (polygenic score) of variants associated with ADHD and aggression in ADHD + DBDs compared to ADHD without DBDs. Our results suggest an increased load of common risk variants in ADHD + DBDs compared to ADHD without DBDs, which in part can be explained by variants associated with aggressive behavior., ADHD is often found to be comorbid with disruptive behavior disorders, but the genetic loci underlying this comorbidity are unknown. Here, the authors have performed a GWAS meta-analysis of ADHD with disruptive behavior disorders, finding three genome-wide significant loci in Europeans, and replicating one in a Chinese cohort.

Published
2021

25. Effects of copy number variations on brain structure and risk for psychiatric illness: Large-scale studies from the ENIGMA working groups on CNVs

Author

Sønderby, Ida E, Ching, Christopher R K, Ayesa-Arriola, Rosa, Thompson, Paul M, Bearden, Carrie E, Andreassen, Ole A, Group, ENIGMA-CNV Working, 2 Deletion Syndrome Working Group, ENIGMA 22q11., Bernard, Manon, Blackburn, Nicholas B, Bøen, Rune, de Geus, Eco, de Zwarte, Sonja M C, Bakker, Geor, Forti, Marta Di, Frei, Oleksandr, Fukunaga, Masaki, Hehir-Kwa, Jayne Y, Hillegers, Manon H J, Hoffmann, Per, Homuth, Georg, Jahanshad, Neda, Koops, Sanne, Kumar, Kuldeep, Bassett, Anne S, Kikuchi, Masataka, Le Hellard, Stephanie, Leu, Costin, Murray, Robin M, Naerland, Terje, Nyberg, Lars, Ophoff, Roel A, Pike, G Bruce, Sando, Sigrid B, Shin, Jean, Boomsma, Dorret I, Shumskaya, Elena, Sisodiya, Sanjay M, Steen, Vidar M, Teumer, Alexander, Uhlmann, Anne, Wright, Margaret J, Antshel, Kevin M, Campbell, Linda E, Crossley, Nicolas A, Crowley, T Blaine, Bülow, Robin, Daly, Eileen, Fiksinski, Ania M, Forsyth, Jennifer K, Fremont, Wanda, Goodrich-Hunsaker, Naomi J, Gudbrandsen, Maria, Jonas, Rachel K, Kates, Wendy R, Lin, Amy, McCabe, Kathryn L, Butcher, Nancy J, Moss, Hayley, Murphy, Declan G, Murphy, Kieran C, Owen, Michael J, Ruparel, Kosha, Simon, Tony J, van Amelsvoort, Therese, Vorstman, Jacob A S, Calhoun, Vince D, Caspers, Svenja, Chow, Eva W C, Cichon, Sven, Thomopoulos, Sophia I, Ciufolini, Simone, Craig, Michael C, Crespo-Facorro, Benedicto, Cunningham, Adam C, Dale, Anders M, Dazzan, Paola, de Zubicaray, Greig I, Djurovic, Srdjan, Doherty, Joanne L, Donohoe, Gary, van der Meer, Dennis, Draganski, Bogdan, Durdle, Courtney A, Ehrlich, Stefan, Emanuel, Beverly S, Espeseth, Thomas, Fisher, Simon E, Ge, Tian, Glahn, David C, Grabe, Hans J, Gur, Raquel E, Sun, Daqiang, Gutman, Boris A, Haavik, Jan, Håberg, Asta K, Hansen, Laura A, Hashimoto, Ryota, Hibar, Derrek P, Holmes, Avram J, Hottenga, Jouke-Jan, Hulshoff Pol, Hilleke E, Jalbrzikowski, Maria, Villalon-Reina, Julio E, Knowles, Emma E M, Kushan, Leila, Linden, David E J, Liu, Jingyu, Lundervold, Astri J, Martin-Brevet, Sandra, Martínez, Kenia, Mather, Karen A, Mathias, Samuel R, McDonald-McGinn, Donna M, Agartz, Ingrid, McRae, Allan F, Medland, Sarah E, Moberget, Torgeir, Modenato, Claudia, Monereo Sánchez, Jennifer, Moreau, Clara A, Mühleisen, Thomas W, Paus, Tomas, Pausova, Zdenka, Prieto, Carlos, Amunts, Katrin, Ragothaman, Anjanibhargavi, Reinbold, Céline S, Reis Marques, Tiago, Repetto, Gabriela M, Reymond, Alexandre, Roalf, David R, Rodriguez-Herreros, Borja, Rucker, James J, Sachdev, Perminder S, Schmitt, James E, Arango, Celso, Schofield, Peter R, Silva, Ana I, Stefansson, Hreinn, Stein, Dan J, Tamnes, Christian K, Tordesillas-Gutiérrez, Diana, Ulfarsson, Magnus O, Vajdi, Ariana, van 't Ent, Dennis, van den Bree, Marianne B M, Armstrong, Nicola J, Vassos, Evangelos, Vázquez-Bourgon, Javier, Vila-Rodriguez, Fidel, Walters, G Bragi, Wen, Wei, Westlye, Lars T, Wittfeld, Katharina, Zackai, Elaine H, Stefánsson, Kári, Jacquemont, Sebastien, the ENIGMA-CNV Working Group, the ENIGMA 22q11.2 Deletion Syndrome Working Group, Stochastics, Biological Psychology, APH - Mental Health, APH - Methodology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, ENIGMA-CNV Working Group, ENIGMA 22q11.2 Deletion Syndrome Working Group, and Universidad de Cantabria

Subjects
Review Article, genetics [Mental Disorders], 0302 clinical medicine, genetics-first approach, pathology [Brain], Multicenter Studies as Topic, Copy-number variation, Review Articles, education.field_of_study, brain structural imaging, Radiological and Ultrasound Technology, genetics [Neurodevelopmental Disorders], Mental Disorders, neurodevelopmental disorders, 05 social sciences, growth & development [Brain], Brain, pathology [Mental Disorders], Cognition, Human brain, diffusion tensor imaging, Magnetic Resonance Imaging, diagnostic imaging [Neurodevelopmental Disorders], medicine.anatomical_structure, psychiatric disorders, Neurology, Anatomy, medicine.medical_specialty, Brain development, DNA Copy Number Variations, Population, Neuroimaging, Biology, 050105 experimental psychology, 03 medical and health sciences, evolution, medicine, pathology [Neurodevelopmental Disorders], Humans, 0501 psychology and cognitive sciences, Radiology, Nuclear Medicine and imaging, Deletion syndrome, copy number variant, ddc:610, genetics‐first approach, education, Psychiatry, diagnostic imaging [Brain], Neurology (clinical), Working group, 030217 neurology & neurosurgery, diagnostic imaging [Mental Disorders]
Abstract

The Enhancing NeuroImaging Genetics through Meta‐Analysis copy number variant (ENIGMA‐CNV) and 22q11.2 Deletion Syndrome Working Groups (22q‐ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA‐CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q‐ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest‐ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi‐site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene‐dosage effects on distinct brain regions also emerged, providing further insight into genotype–phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This “genotype‐first” approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior., The enhancing neuroimaging genetics through meta‐analysis (ENIGMA) copy number variant (CNV) and 22q11.2 Working Groups focus on gaining insight into how rare genetic variants affect human brain development, cognition, and behavior. The two ENIGMA working groups have collated CNV and brain‐imaging data from numerous individuals, gathered by numerous international research centers, and analyzed this data with standardized processing and analysis pipelines. Future directions for the ENIGMA CNV and 22q11.2 working groups are to analyze CNVs with larger sample sizes and more imaging modalities to better understand how rare genetic variants affect the brain, and their clinical and behavioral consequences.

Published
2021

26. Virtual Histology of Cortical Thickness and Shared Neurobiology in 6 Psychiatric Disorders

Author

Committee, Writing, Disorder, Autism Spectrum, French, Leon, Grevet, Eugenio H, Groenewold, Nynke A, Grotegerd, Dominik, Gruber, Oliver, Gruner, Patricia, Guerrero-Pedraza, Amalia, Gur, Raquel E, Gur, Ruben C, Haar, Shlomi, Haarman, Bartholomeus C M, Thomopoulos, Sophia I, Haavik, Jan, Hahn, Tim, Hajek, Tomas, Harrison, Benjamin J, Harrison, Neil A, Hartman, Catharina A, Whalley, Heather C, Heslenfeld, Dirk J, Hibar, Derrek P, Hilland, Eva, Pozzi, Elena, Hirano, Yoshiyuki, Ho, Tiffany C, Hoekstra, Pieter J, Hoekstra, Liesbeth, Hohmann, Sarah, Hong, L. E., Höschl, Cyril, Høvik, Marie F, Howells, Fleur M, Nenadic, Igor, Abe, Yoshinari, Jalbrzikowski, Maria, James, Anthony C, Janssen, Joost, Jaspers-Fayer, Fern, Xu, Jian, Jonassen, Rune, Karkashadze, Georgii, King, Joseph A, Kircher, Tilo, Kirschner, Matthias, Abé, Christoph, Koch, Kathrin, Kochunov, Peter, Kohls, Gregor, Konrad, Kerstin, Krämer, Bernd, Krug, Axel, Kuntsi, Jonna, Kwon, Jun Soo, Landén, Mikael, Landrø, Nils I, Anticevic, Alan, Lazaro, Luisa, Lebedeva, Irina S, Leehr, Elisabeth J, Lera-Miguel, Sara, Lesch, Klaus-Peter, Lochner, Christine, Louza, Mario R, Luna, Beatriz, Lundervold, Astri J, MacMaster, Frank P, Alda, Martin, Maglanoc, Luigi A, Malpas, Charles B, Portella, Maria J, Marsh, Rachel, Martyn, Fiona M, Mataix-Cols, David, Mathalon, Daniel H, McCarthy, Hazel, McDonald, Colm, McPhilemy, Genevieve, Aleman, Andre, Meinert, Susanne, Menchón, José M, Minuzzi, Luciano, Mitchell, Philip B, Moreno, Carmen, Morgado, Pedro, Muratori, Filippo, Murphy, Clodagh M, Murphy, Declan, Mwangi, Benson, Alloza, Clara, Nabulsi, Leila, Nakagawa, Akiko, Nakamae, Takashi, Namazova, Leyla, Narayanaswamy, Janardhanan, Jahanshad, Neda, Nguyen, Danai D, Nicolau, Rosa, O'Gorman Tuura, Ruth L, O'Hearn, Kirsten, Alonso-Lana, Silvia, Oosterlaan, Jaap, Opel, Nils, Ophoff, Roel A, Oranje, Bob, García de la Foz, Victor Ortiz, Overs, Bronwyn J, Paloyelis, Yannis, Pantelis, Christos, Parellada, Mara, Pauli, Paul, Disorder, Bipolar, Ameis, Stephanie H, Picó-Pérez, Maria, Picon, Felipe A, Piras, Fabrizio, Piras, Federica, Plessen, Kerstin J, Pomarol-Clotet, Edith, Preda, Adrian, Puig, Olga, Quidé, Yann, Radua, Joaquim, Anagnostou, Evdokia, Ramos-Quiroga, J Antoni, Rasser, Paul E, Rauer, Lisa, Reddy, Janardhan, Redlich, Ronny, Reif, Andreas, Reneman, Liesbeth, Repple, Jonathan, Retico, Alessandra, Richarte, Vanesa, McIntosh, Andrew A, Richter, Anja, Rosa, Pedro G P, Rubia, Katya K, Hashimoto, Ryota, Sacchet, Matthew D, Salvador, Raymond, Santonja, Javier, Sarink, Kelvin, Sarró, Salvador, Satterthwaite, Theodore D, Arango, Celso, Sawa, Akira, Schall, Ulrich, Schofield, Peter R, Schrantee, Anouk, Seitz, Jochen, Serpa, Mauricio H, Setién-Suero, Esther, Shaw, Philip, Shook, Devon, Silk, Tim J, Arnold, Paul D, Sim, Kang, Simon, Schmitt, Simpson, Helen Blair, Singh, Aditya, Skoch, Antonin, Skokauskas, Norbert, Soares, Jair C, Soreni, Noam, Soriano-Mas, Carles, Spalletta, Gianfranco, Asherson, Philip, Spaniel, Filip, Lawrie, Stephen M, Stern, Emily R, Stewart, S Evelyn, Takayanagi, Yoichiro, Temmingh, Henk S, Tolin, David F, Tomecek, David, Tordesillas-Gutiérrez, Diana, Tosetti, Michela, Assogna, Francesca, Uhlmann, Anne, van Amelsvoort, Therese, van der Wee, Nic J A, van der Werff, Steven J A, van Haren, Neeltje E M, van Wingen, Guido A, Vance, Alasdair, Vázquez-Bourgon, Javier, Vecchio, Daniela, Venkatasubramanian, Ganesan, Auzias, Guillaume, Vieta, Eduard, Vilarroya, Oscar, Vives-Gilabert, Yolanda, Voineskos, Aristotle N, Völzke, Henry, von Polier, Georg G, Walton, Esther, Weickert, Thomas W, Weickert, Cynthia Shannon, Weideman, Andrea S, Ayesa-Arriola, Rosa, Wittfeld, Katharina, Wolf, Daniel H, Wu, Mon-Ju, Yang, T. T., Yang, Sikun, Yoncheva, Yuliya, Yun, Je-Yeon, Cheng, Yuqi, Zanetti, Marcus V, Ziegler, Georg C, Bakker, Geor, Franke, Barbara, Hoogman, Martine, Buitelaar, Jan K, van Rooij, Daan, Andreassen, Ole A, Ching, Christopher R K, Veltman, Dick J, Schmaal, Lianne, Stein, Dan J, van den Heuvel, Odile A, Disorder, Major Depressive, Banaj, Nerisa, Turner, Jessica A, van Erp, Theo G M, Pausova, Zdenka, Thompson, Paul M, Paus, Tomáš, Attention-Deficit/Hyperactivity Disorder, Banaschewski, Tobias, Bandeira, Cibele E, Baranov, Alexandr, Bargalló, Núria, Bau, Claiton H D, Baumeister, Sarah, Baune, Bernhard T, Bellgrove, Mark A, Benedetti, Francesco, Disorder, Obsessive-Compulsive, Bertolino, Alessandro, Boedhoe, Premika S W, Boks, Marco, Bollettini, Irene, Del Mar Bonnin, Caterina, Borgers, Tiana, Borgwardt, Stefan, Brandeis, Daniel, Brennan, Brian P, Bruggemann, Jason M, Groups, Schizophrenia ENIGMA Working, Bülow, Robin, Busatto, Geraldo F, Calderoni, Sara, Calhoun, Vince D, Calvo, Rosa, Canales-Rodríguez, Erick J, Cannon, Dara M, Carr, Vaughan J, Cascella, Nicola, Cercignani, Mara, Patel, Yash, Chaim-Avancini, Tiffany M, Christakou, Anastasia, Coghill, David, Conzelmann, Annette, Crespo-Facorro, Benedicto, Cubillo, Ana I, Cullen, Kathryn R, Cupertino, Renata B, Daly, Eileen, Dannlowski, Udo, Parker, Nadine, Davey, Christopher G, Denys, Damiaan, Deruelle, Christine, Di Giorgio, Annabella, Dickie, Erin W, Dima, Danai, Dohm, Katharina, Ehrlich, Stefan, Ely, Benjamin A, Erwin-Grabner, Tracy, Shin, Jean, Ethofer, Thomas, Fair, Damien A, Fallgatter, Andreas, Faraone, Stephen V, Fatjó-Vilas, Mar, Fedor, Jennifer M, Fitzgerald, Kate D, Ford, Judith M, Frodl, Thomas, Fu, Cynthia H Y, Howard, Derek, Fullerton, Janice M, Gabel, Matt C, Glahn, David C, Roberts, Gloria, Gogberashvili, Tinatin, Goikolea, Jose M, Gotlib, Ian H, Goya-Maldonado, Roberto, Grabe, Hans, Green, Melissa J, Patel, Y., Parker, N., Shin, J., Howard, D., French, L., Thomopoulos, S. I., Pozzi, E., Abe, Y., Abe, C., Anticevic, A., Alda, M., Aleman, A., Alloza, C., Alonso-Lana, S., Ameis, S. H., Anagnostou, E., Mcintosh, A. A., Arango, C., Arnold, P. D., Asherson, P., Assogna, F., Auzias, G., Ayesa-Arriola, R., Bakker, G., Banaj, N., Banaschewski, T., Bandeira, C. E., Baranov, A., Bargallo, N., Bau, C. H. D., Baumeister, S., Baune, B. T., Bellgrove, M. A., Benedetti, F., Bertolino, A., Boedhoe, P. S. W., Boks, M., Bollettini, I., Del Mar Bonnin, C., Borgers, T., Borgwardt, S., Brandeis, D., Brennan, B. P., Bruggemann, J. M., Bulow, R., Busatto, G. F., Calderoni, S., Calhoun, V. D., Calvo, R., Canales-Rodriguez, E. J., Cannon, D. M., Carr, V. J., Cascella, N., Cercignani, M., Chaim-Avancini, T. M., Christakou, A., Coghill, D., Conzelmann, A., Crespo-Facorro, B., Cubillo, A. I., Cullen, K. R., Cupertino, R. B., Daly, E., Dannlowski, U., Davey, C. G., Denys, D., Deruelle, C., Di Giorgio, A., Dickie, E. W., Dima, D., Dohm, K., Ehrlich, S., Ely, B. A., Erwin-Grabner, T., Ethofer, T., Fair, D. A., Fallgatter, A. J., Faraone, S. V., Fatjo-Vilas, M., Fedor, J. M., Fitzgerald, K. D., Ford, J. M., Frodl, T., Fu, C. H. Y., Fullerton, J. M., Gabel, M. C., Glahn, D. C., Roberts, G., Gogberashvili, T., Goikolea, J. M., Gotlib, I. H., Goya-Maldonado, R., Grabe, H. J., Green, M. J., Grevet, E. H., Groenewold, N. A., Grotegerd, D., Gruber, O., Gruner, P., Guerrero-Pedraza, A., Gur, R. E., Gur, R. C., Haar, S., Haarman, B. C. M., Haavik, J., Hahn, T., Hajek, T., Harrison, B. J., Harrison, N. A., Hartman, C. A., Whalley, H. C., Heslenfeld, D. J., Hibar, D. P., Hilland, E., Hirano, Y., Ho, T. C., Hoekstra, P. J., Hoekstra, L., Hohmann, S., Hong, L. E., Hoschl, C., Hovik, M. F., Howells, F. M., Nenadic, I., Jalbrzikowski, M., James, A. C., Janssen, J., Jaspers-Fayer, F., Xu, J., Jonassen, R., Karkashadze, G., King, J. A., Kircher, T., Kirschner, M., Koch, K., Kochunov, P., Kohls, G., Konrad, K., Kramer, B., Krug, A., Kuntsi, J., Kwon, J. S., Landen, M., Landro, N. I., Lazaro, L., Lebedeva, I. S., Leehr, E. J., Lera-Miguel, S., Lesch, K. -P., Lochner, C., Louza, M. R., Luna, B., Lundervold, A. J., Macmaster, F. P., Maglanoc, L. A., Malpas, C. B., Portella, M. J., Marsh, R., Martyn, F. M., Mataix-Cols, D., Mathalon, D. H., Mccarthy, H., Mcdonald, C., Mcphilemy, G., Meinert, S., Menchon, J. M., Minuzzi, L., Mitchell, P. B., Moreno, C., Morgado, P., Muratori, F., Murphy, C. M., Murphy, D., Mwangi, B., Nabulsi, L., Nakagawa, A., Nakamae, T., Namazova, L., Narayanaswamy, J., Jahanshad, N., Nguyen, D. D., Nicolau, R., O'Gorman Tuura, R. L., O'Hearn, K., Oosterlaan, J., Opel, N., Ophoff, R. A., Oranje, B., Garcia De La Foz, V. O., Overs, B. J., Paloyelis, Y., Pantelis, C., Parellada, M., Pauli, P., Pico-Perez, M., Picon, F. A., Piras, F., Plessen, K. J., Pomarol-Clotet, E., Preda, A., Puig, O., Quide, Y., Radua, J., Ramos-Quiroga, J. A., Rasser, P. E., Rauer, L., Reddy, J., Redlich, R., Reif, A., Reneman, L., Repple, J., Retico, A., Richarte, V., Richter, A., Rosa, P. G. P., Rubia, K. K., Hashimoto, R., Sacchet, M. D., Salvador, R., Santonja, J., Sarink, K., Sarro, S., Satterthwaite, T. D., Sawa, A., Schall, U., Schofield, P. R., Schrantee, A., Seitz, J., Serpa, M. H., Setien-Suero, E., Shaw, P., Shook, D., Silk, T. J., Sim, K., Simon, S., Simpson, H. B., Singh, A., Skoch, A., Skokauskas, N., Soares, J. C., Soreni, N., Soriano-Mas, C., Spalletta, G., Spaniel, F., Lawrie, S. M., Stern, E. R., Stewart, S. E., Takayanagi, Y., Temmingh, H. S., Tolin, D. F., Tomecek, D., Tordesillas-Gutierrez, D., Tosetti, M., Uhlmann, A., Van Amelsvoort, T., Van Der Wee, N. J. A., Van Der Werff, S. J. A., Van Haren, N. E. M., Van Wingen, G. A., Vance, A., Vazquez-Bourgon, J., Vecchio, D., Venkatasubramanian, G., Vieta, E., Vilarroya, O., Vives-Gilabert, Y., Voineskos, A. N., Volzke, H., Von Polier, G. G., Walton, E., Weickert, T. W., Weickert, C. S., Weideman, A. S., Wittfeld, K., Wolf, D. H., Wu, M. -J., Yang, T. T., Yang, K., Yoncheva, Y., Yun, J. -Y., Cheng, Y., Zanetti, M. V., Ziegler, G. C., Franke, B., Hoogman, M., Buitelaar, J. K., Van Rooij, D., Andreassen, O. A., Ching, C. R. K., Veltman, D. J., Schmaal, L., Stein, D. J., Van Den Heuvel, O. A., Turner, J. A., Van Erp, T. G. M., Pausova, Z., Thompson, P. M., Paus, T., Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Pediatric surgery, Radiology and nuclear medicine, Anatomy and neurosciences, Psychiatry, Amsterdam Neuroscience - Brain Imaging, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Amsterdam Neuroscience - Neurodegeneration, Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, MUMC+: MA Med Staf Spec Psychiatrie (9), Adult Psychiatry, ANS - Compulsivity, Impulsivity & Attention, General Paediatrics, ARD - Amsterdam Reproduction and Development, Radiology and Nuclear Medicine, APH - Personalized Medicine, ANS - Brain Imaging, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, University of Zurich, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Clinical Neuropsychology, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Child and Adolescent Psychiatry / Psychology, IBBA, and Cognitive Psychology

Subjects
Male, Obsessive-Compulsive Disorder, Bipolar Disorder, Autism Spectrum Disorder, Autism, [SDV]Life Sciences [q-bio], Gene Expression, cytology [Cerebral Cortex], Cohort Studies, Fetal Development, physiology [Gene Expression], 2738 Psychiatry and Mental Health, 0302 clinical medicine, diagnostic imaging [Cerebral Cortex], SCHIZOPHRENIA, BRAIN, Child, Obsessive-compulsive disorder (OCD), Original Investigation, Aged, 80 and over, Cerebral Cortex, 0303 health sciences, pathology [Depressive Disorder, Major], Principal Component Analysis, Adolescent psychiatry, 10058 Department of Child and Adolescent Psychiatry, Middle Aged, diagnostic imaging [Obsessive-Compulsive Disorder], REGIONS, Magnetic Resonance Imaging, 3. Good health, FALSE DISCOVERY RATE, Psychiatry and Mental health, Autism spectrum disorder, Schizophrenia, growth & development [Cerebral Cortex], Child, Preschool, Major depressive disorder, diagnostic imaging [Schizophrenia], Esquizofrènia, Female, Psiquiatria infantil, Psiquiatria de l'adolescència, diagnostic imaging [Autism Spectrum Disorder], Adult, medicine.medical_specialty, Adolescent, Human Development, 610 Medicine & health, diagnostic imaging [Bipolar Disorder], pathology [Autism Spectrum Disorder], diagnostic imaging [Depressive Disorder, Major], 03 medical and health sciences, Young Adult, All institutes and research themes of the Radboud University Medical Center, Neuroimaging, SDG 3 - Good Health and Well-being, CEREBRAL-CORTEX, Child psychiatry, medicine, Attention deficit hyperactivity disorder, Humans, Bipolar disorder, ddc:610, Psychiatry, pathology [Schizophrenia], 030304 developmental biology, Aged, Depressive Disorder, Major, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, DENDRITE, Computational Biology, Correction, pathology [Attention Deficit Disorder with Hyperactivity], physiology [Fetal Development], medicine.disease, PATHOLOGY, pathology [Bipolar Disorder], pathology [Obsessive-Compulsive Disorder], 10036 Medical Clinic, Attention Deficit Disorder with Hyperactivity, 10054 Clinic for Psychiatry, Psychotherapy, and Psychosomatics, Case-Control Studies, DENSITY, ORIGINS, HIPPOCAMPUS, diagnostic imaging [Attention Deficit Disorder with Hyperactivity], pathology [Cerebral Cortex], Autisme, business, Neuroscience, 030217 neurology & neurosurgery, physiology [Human Development]
Abstract

[Importance] Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood., [Objective] To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia., [Design, Setting, and Participants] Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244., [Main Outcomes and Measures] Interregional profiles of group difference in cortical thickness between cases and controls., [Results] A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene-expression profiles of the 3 cell types explain between 25% and 54% of variance in interregional profiles of group differences in cortical thickness. Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression (explaining 56% of interregional variation). Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders., [Conclusions and Relevance] In this study, shared neurobiologic processes were associated with differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders.

Published
2021

27. Gene-Environment Interactions in Attention-Deficit/Hyperactivity Disorder Symptom Dimensions: The Role of Unhealthy Food Habits

Author

Li, Lin, Taylor, Mark J., Baelter, Katarina, Xie, Tian, Solberg, Berit Skretting, Haavik, Jan, Arias Vasquez, A., Hartman, C.A., Larsson, H., and Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE)

Subjects
Adult, Male, DEFICIT HYPERACTIVITY DISORDER, MODELS, Twins, food habits, QH426-470, Article, Young Adult, All institutes and research themes of the Radboud University Medical Center, Genetics, Humans, ADHD, twin study, CONFLICT, Sweden, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], HERITABILITY, REFLECTIONS, Feeding Behavior, gene-environment interactions, Middle Aged, Attention Deficit Disorder with Hyperactivity, NUTRIGENOMICS, Female, Gene-Environment Interaction, Self Report
Abstract

Background: Dietary habits were investigated as environmental risk factors for Attention-Deficit/Hyperactivity Disorder (ADHD). However, no previous studies explored the effects of dietary factors on modifying the role of genetic factors on ADHD. Methods: Based on a Swedish population-based twin study with 1518 twin pairs aged 20–47 years, we tested whether the importance of genetic and environmental effects on ADHD varied as a function of dietary habits. Self-reported dietary habits and ADHD symptoms were collected. Twin methods were used to test the degree to which high-sugar and unhealthy food intake moderated the genetic and environmental influences on ADHD symptoms. Results: In middle-aged adults, genetic influences on inattention symptoms were statistically significantly higher among individuals with higher levels of high-sugar (45%, 95%CI: 25–54%) and unhealthy food intake (51%, 95%CI: 31–60%), compared with those with lower levels of consumption of high-sugar (36%, 95%CI: 25–47%) and unhealthy foods (30%, 95%CI: 20–41%). Similar patterns were also found for the associations between hyperactivity/impulsivity and high-sugar/unhealthy food intake, even though the moderation effects were not statistically significant. Conclusion The present study suggests that genetic factors play a more prominent role in individual differences of ADHD symptoms in the presence of the high consumption of sugar and unhealthy foods. Future longitudinal studies with multiple assessments of ADHD and dietary habits are needed to replicate our findings.

Published
2021

28. Analysis of shared heritability in common disorders of the brain

Author

Brainstorm Consortium, Anttila, Verneri, Bulik-Sullivan, Brendan, Finucane, Hilary K, Walters, Raymond K, Bras, Jose, Duncan, Laramie, Escott-Price, Valentina, Falcone, Guido J, Gormley, Padhraig, Malik, Rainer, Patsopoulos, Nikolaos A, Ripke, Stephan, Wei, Zhi, Yu, Dongmei, Lee, Phil H, Turley, Patrick, Grenier-Boley, Benjamin, Chouraki, Vincent, Kamatani, Yoichiro, Berr, Claudine, Letenneur, Luc, Hannequin, Didier, Amouyel, Philippe, Boland, Anne, Deleuze, Jean-François, Duron, Emmanuelle, Vardarajan, Badri N, Reitz, Christiane, Goate, Alison M, Huentelman, Matthew J, Kamboh, M Ilyas, Larson, Eric B, Rogaeva, Ekaterina, St George-Hyslop, Peter, Hakonarson, Hakon, Kukull, Walter A, Farrer, Lindsay A, Barnes, Lisa L, Beach, Thomas G, Demirci, F Yesim, Head, Elizabeth, Hulette, Christine M, Jicha, Gregory A, Kauwe, John SK, Kaye, Jeffrey A, Leverenz, James B, Levey, Allan I, Lieberman, Andrew P, Pankratz, Vernon S, Poon, Wayne W, Quinn, Joseph F, Saykin, Andrew J, Schneider, Lon S, Smith, Amanda G, Sonnen, Joshua A, Stern, Robert A, Van Deerlin, Vivianna M, Van Eldik, Linda J, Harold, Denise, Russo, Giancarlo, Rubinsztein, David C, Bayer, Anthony, Tsolaki, Magda, Proitsi, Petra, Fox, Nick C, Hampel, Harald, Owen, Michael J, Mead, Simon, Passmore, Peter, Morgan, Kevin, Nöthen, Markus M, Rossor, Martin, Lupton, Michelle K, Hoffmann, Per, Kornhuber, Johannes, Lawlor, Brian, McQuillin, Andrew, Al-Chalabi, Ammar, Bis, Joshua C, Ruiz, Agustin, Boada, Mercè, Seshadri, Sudha, Beiser, Alexa, Rice, Kenneth, Van Der Lee, Sven J, De Jager, Philip L, Geschwind, Daniel H, Riemenschneider, Matthias, Riedel-Heller, Steffi, Rotter, Jerome I, Ransmayr, Gerhard, Hyman, Bradley T, Cruchaga, Carlos, Alegret, Montserrat, Winsvold, Bendik, Palta, Priit, Farh, Kai-How, Cuenca-Leon, Ester, Furlotte, Nicholas, Kurth, Tobias, Ligthart, Lannie, Terwindt, Gisela M, Freilinger, Tobias, Ran, Caroline, Gordon, Scott D, Borck, Guntram, Adams, Hieab HH, Lehtimäki, Terho, Wedenoja, Juho, Buring, Julie E, Schürks, Markus, Hrafnsdottir, Maria, Hottenga, Jouke-Jan, Penninx, Brenda, Artto, Ville, Kaunisto, Mari, Vepsäläinen, Salli, Martin, Nicholas G, Montgomery, Grant W, Kurki, Mitja I, Hämäläinen, Eija, Huang, Hailiang, Huang, Jie, Sandor, Cynthia, Webber, Caleb, Muller-Myhsok, Bertram, Schreiber, Stefan, Salomaa, Veikko, Loehrer, Elizabeth, Göbel, Hartmut, Macaya, Alfons, Pozo-Rosich, Patricia, Hansen, Thomas, Werge, Thomas, Kaprio, Jaakko, Metspalu, Andres, Kubisch, Christian, Ferrari, Michel D, Belin, Andrea C, Van Den Maagdenberg, Arn MJM, Zwart, John-Anker, Boomsma, Dorret, Eriksson, Nicholas, Olesen, Jes, Chasman, Daniel I, Nyholt, Dale R, Avbersek, Andreja, Baum, Larry, Berkovic, Samuel, Bradfield, Jonathan, Buono, Russell J, Catarino, Claudia B, Cossette, Patrick, De Jonghe, Peter, Depondt, Chantal, Dlugos, Dennis, Ferraro, Thomas N, French, Jacqueline, Hjalgrim, Helle, Jamnadas-Khoda, Jennifer, Kälviäinen, Reetta, Kunz, Wolfram S, Lerche, Holger, Leu, Costin, Lindhout, Dick, Lo, Warren, Lowenstein, Daniel, McCormack, Mark, Møller, Rikke S, Molloy, Anne, Ng, Ping-Wing, Oliver, Karen, Privitera, Michael, Radtke, Rodney, Ruppert, Ann-Kathrin, Sander, Thomas, Schachter, Steven, Schankin, Christoph, Scheffer, Ingrid, Schoch, Susanne, Sisodiya, Sanjay M, Smith, Philip, Sperling, Michael, Striano, Pasquale, Surges, Rainer, Thomas, G Neil, Visscher, Frank, Whelan, Christopher D, Zara, Federico, Heinzen, Erin L, Marson, Anthony, Becker, Felicitas, Stroink, Hans, Zimprich, Fritz, Gasser, Thomas, Gibbs, Raphael, Heutink, Peter, Martinez, Maria, Morris, Huw R, Sharma, Manu, Ryten, Mina, Mok, Kin Y, Pulit, Sara, Bevan, Steve, Holliday, Elizabeth, Attia, John, Battey, Thomas, Boncoraglio, Giorgio, Thijs, Vincent, Chen, Wei-Min, Mitchell, Braxton, Rothwell, Peter, Sharma, Pankaj, Sudlow, Cathie, Vicente, Astrid, Markus, Hugh, Kourkoulis, Christina, Pera, Joana, Raffeld, Miriam, Silliman, Scott, Boraska Perica, Vesna, Thornton, Laura M, Huckins, Laura M, William Rayner, N, Lewis, Cathryn M, Gratacos, Monica, Rybakowski, Filip, Keski-Rahkonen, Anna, Raevuori, Anu, Hudson, James I, Reichborn-Kjennerud, Ted, Monteleone, Palmiero, Karwautz, Andreas, Mannik, Katrin, Baker, Jessica H, O'Toole, Julie K, Trace, Sara E, Davis, Oliver SP, Helder, Sietske G, Ehrlich, Stefan, Herpertz-Dahlmann, Beate, Danner, Unna N, Van Elburg, Annemarie A, Clementi, Maurizio, Forzan, Monica, Docampo, Elisa, Lissowska, Jolanta, Hauser, Joanna, Tortorella, Alfonso, Maj, Mario, Gonidakis, Fragiskos, Tziouvas, Konstantinos, Papezova, Hana, Yilmaz, Zeynep, Wagner, Gudrun, Cohen-Woods, Sarah, Herms, Stefan, Julià, Antonio, Rabionet, Raquel, Dick, Danielle M, Ripatti, Samuli, Andreassen, Ole A, Espeseth, Thomas, Lundervold, Astri J, Steen, Vidar M, Pinto, Dalila, Scherer, Stephen W, Aschauer, Harald, Schosser, Alexandra, Alfredsson, Lars, Padyukov, Leonid, Halmi, Katherine A, Mitchell, James, Strober, Michael, Bergen, Andrew W, Kaye, Walter, Szatkiewicz, Jin Peng, Cormand, Bru, Ramos-Quiroga, Josep Antoni, Sánchez-Mora, Cristina, Ribasés, Marta, Casas, Miguel, Hervas, Amaia, Arranz, Maria Jesús, Haavik, Jan, Zayats, Tetyana, Johansson, Stefan, Williams, Nigel, Dempfle, Astrid, Rothenberger, Aribert, Kuntsi, Jonna, Oades, Robert D, Banaschewski, Tobias, Franke, Barbara, Buitelaar, Jan K, Arias Vasquez, Alejandro, Doyle, Alysa E, Reif, Andreas, Lesch, Klaus-Peter, Freitag, Christine, Rivero, Olga, Palmason, Haukur, Romanos, Marcel, Langley, Kate, Rietschel, Marcella, Witt, Stephanie H, Dalsgaard, Soeren, Børglum, Anders D, Waldman, Irwin, Wilmot, Beth, Molly, Nikolas, Bau, Claiton HD, Crosbie, Jennifer, Schachar, Russell, Loo, Sandra K, McGough, James J, Grevet, Eugenio H, Medland, Sarah E, Robinson, Elise, Weiss, Lauren A, Bacchelli, Elena, Bailey, Anthony, Bal, Vanessa, Battaglia, Agatino, Betancur, Catalina, Bolton, Patrick, Cantor, Rita, Celestino-Soper, Patrícia, Dawson, Geraldine, De Rubeis, Silvia, Duque, Frederico, Green, Andrew, Klauck, Sabine M, Leboyer, Marion, Levitt, Pat, Maestrini, Elena, Mane, Shrikant, De-Luca, Daniel Moreno, Parr, Jeremy, Regan, Regina, Reichenberg, Abraham, Sandin, Sven, Vorstman, Jacob, Wassink, Thomas, Wijsman, Ellen, Cook, Edwin, Santangelo, Susan, Delorme, Richard, Rogé, Bernadette, Magalhaes, Tiago, Arking, Dan, Schulze, Thomas G, Thompson, Robert C, Strohmaier, Jana, Matthews, Keith, Melle, Ingrid, Morris, Derek, Blackwood, Douglas, McIntosh, Andrew, Bergen, Sarah E, Schalling, Martin, Jamain, Stéphane, Maaser, Anna, Fischer, Sascha B, Reinbold, Céline S, Fullerton, Janice M, Guzman-Parra, José, Mayoral, Fermin, Schofield, Peter R, Cichon, Sven, Mühleisen, Thomas W, Degenhardt, Franziska, Schumacher, Johannes, Bauer, Michael, Mitchell, Philip B, Gershon, Elliot S, Rice, John, Potash, James B, Zandi, Peter P, Craddock, Nick, Ferrier, I Nicol, Alda, Martin, Rouleau, Guy A, Turecki, Gustavo, Ophoff, Roel, Pato, Carlos, Anjorin, Adebayo, Stahl, Eli, Leber, Markus, Czerski, Piotr M, Cruceanu, Cristiana, Jones, Ian R, Posthuma, Danielle, Andlauer, Till FM, Forstner, Andreas J, Streit, Fabian, Baune, Bernhard T, Air, Tracy, Sinnamon, Grant, Wray, Naomi R, MacIntyre, Donald J, Porteous, David, Homuth, Georg, Rivera, Margarita, Grove, Jakob, Middeldorp, Christel M, Hickie, Ian, Pergadia, Michele, Mehta, Divya, Smit, Johannes H, Jansen, Rick, De Geus, Eco, Dunn, Erin, Li, Qingqin S, Nauck, Matthias, Schoevers, Robert A, Beekman, Aartjan Tf, Knowles, James A, Viktorin, Alexander, Arnold, Paul, Barr, Cathy L, Bedoya-Berrio, Gabriel, Bienvenu, O Joseph, Brentani, Helena, Burton, Christie, Camarena, Beatriz, Cappi, Carolina, Cath, Danielle, Cavallini, Maria, Cusi, Daniele, Darrow, Sabrina, Denys, Damiaan, Derks, Eske M, Dietrich, Andrea, Fernandez, Thomas, Figee, Martijn, Freimer, Nelson, Gerber, Gloria, Grados, Marco, Greenberg, Erica, Hanna, Gregory L, Hartmann, Andreas, Hirschtritt, Matthew E, Hoekstra, Pieter J, Huang, Alden, Huyser, Chaim, Illmann, Cornelia, Jenike, Michael, Kuperman, Samuel, Leventhal, Bennett, Lochner, Christine, Lyon, Gholson J, Macciardi, Fabio, Madruga-Garrido, Marcos, Malaty, Irene A, Maras, Athanasios, McGrath, Lauren, Miguel, Eurípedes C, Mir, Pablo, Nestadt, Gerald, Nicolini, Humberto, Okun, Michael S, Pakstis, Andrew, Paschou, Peristera, Piacentini, John, Pittenger, Christopher, Plessen, Kerstin, Ramensky, Vasily, Ramos, Eliana M, Reus, Victor, Richter, Margaret A, Riddle, Mark A, Robertson, Mary M, Roessner, Veit, Rosário, Maria, Samuels, Jack F, Sandor, Paul, Stein, Dan J, Tsetsos, Fotis, Van Nieuwerburgh, Filip, Weatherall, Sarah, Wendland, Jens R, Wolanczyk, Tomasz, Worbe, Yulia, Zai, Gwyneth, Goes, Fernando S, McLaughlin, Nicole, Nestadt, Paul S, Grabe, Hans-Jorgen, Depienne, Christel, Konkashbaev, Anuar, Lanzagorta, Nuria, Valencia-Duarte, Ana, Bramon, Elvira, Buccola, Nancy, Cahn, Wiepke, Cairns, Murray, Chong, Siow A, Cohen, David, Crespo-Facorro, Benedicto, Crowley, James, Davidson, Michael, DeLisi, Lynn, Dinan, Timothy, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Haan, Lieuwe, Hougaard, David, Karachanak-Yankova, Sena, Khrunin, Andrey, Klovins, Janis, Kučinskas, Vaidutis, Lee Chee Keong, Jimmy, Limborska, Svetlana, Loughland, Carmel, Lönnqvist, Jouko, Maher, Brion, Mattheisen, Manuel, McDonald, Colm, Murphy, Kieran C, Nenadic, Igor, Van Os, Jim, Pantelis, Christos, Pato, Michele, Petryshen, Tracey, Quested, Digby, Roussos, Panos, Sanders, Alan R, Schall, Ulrich, Schwab, Sibylle G, Sim, Kang, So, Hon-Cheong, Stögmann, Elisabeth, Subramaniam, Mythily, Toncheva, Draga, Waddington, John, Walters, James, Weiser, Mark, Cheng, Wei, Cloninger, Robert, Curtis, David, Gejman, Pablo V, Henskens, Frans, Mattingsdal, Morten, Oh, Sang-Yun, Scott, Rodney, Webb, Bradley, Breen, Gerome, Churchhouse, Claire, Bulik, Cynthia M, Daly, Mark, Dichgans, Martin, Faraone, Stephen V, Guerreiro, Rita, Holmans, Peter, Kendler, Kenneth S, Koeleman, Bobby, Mathews, Carol A, Price, Alkes, Scharf, Jeremiah, Sklar, Pamela, Williams, Julie, Wood, Nicholas W, Cotsapas, Chris, Palotie, Aarno, Smoller, Jordan W, Sullivan, Patrick, Rosand, Jonathan, Corvin, Aiden, Neale, Benjamin M, Schott, Jonathan M, Anney, Richard, Elia, Josephine, Grigoroiu-Serbanescu, Maria, Edenberg, Howard J, Murray, Robin, Massachusetts General Hospital [Boston], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], UK Dementia Research Institute (UK DRI), University College of London [London] (UCL), School of Psychology [Cardiff University], Cardiff University, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität [München]-Ludwig Maximilian University [Munich] (LMU), New Jersey Institute of Technology [Newark] (NJIT), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire de Biotechnologie et Microbiologie Appliquée (LBMA), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Gériatrie générale et aigüe [Paris], AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Columbia University [New York], Dpt of Neuroscience [New York], Icahn School of Medicine at Mount Sinai [New York] (MSSM), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), University of Washington [Seattle], Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Children’s Hospital of Philadelphia (CHOP ), University of Kentucky (UK), School of medicine, Duke University [Durham], College of medicine, Brigham Young University (BYU), Oregon Health and Science University [Portland] (OHSU), Cleveland Clinic, Department of Neurology, Emory University [Atlanta, GA], Medical School, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Health sciences center, The University of New Mexico [Albuquerque], Institute for Memory Impairments and Neurological Disorders [Irvine], University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Indiana University - Purdue University Indianapolis (IUPUI), Indiana University System, Keck School of Medicine [Los Angeles], University of Southern California (USC), University of South Florida [Tampa] (USF), University of Utah School of Medicine [Salt Lake City], Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Perelman School of Medicine, University of Pennsylvania, Dublin City University [Dublin] (DCU), Functional Genomics Center Zurich, Universität Zürich [Zürich] = University of Zurich (UZH)- Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Cambridge Institute for Medical Research (CIMR), University of Cambridge [UK] (CAM), Aristotle University of Thessaloniki, Maurice Wohl Clinical Neuroscience Institut, King‘s College London, Dementia Research Centre [London] (DRC), Groupe de recherche clinique Alzheimer Precision Medicine (GRC 21 - APM), Sorbonne Université (SU), MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council-Cardiff University, MRC Prion Unit [London], Queen's University [Belfast] (QUB), School of Life Sciences, University of Nottingham, UK (UON), Rheinische Friedrich-Wilhelms-Universität Bonn, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), QIMR Berghofer Medical Research Institute, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), School of Medicine [Dublin], Trinity College Dublin, Department of Medicine, University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), School of Public Health [Boston], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Columbia University Medical Center (CUMC), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), Saarland University [Saarbrücken], Universität Leipzig, School of Medicine [Los Angeles], Johannes Kepler Universität Linz - Johannes Kepler University Linz [Autriche] (JKU), Department of Neurology [Boston], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], School of Medecine, Washington University in Saint Louis (WUSTL), Oslo University Hospital [Oslo], Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, 23andMe Inc., Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Biological Psychology [Amsterdam], Vrije Universiteit Amsterdam [Amsterdam] (VU), Leiden University Medical Center (LUMC), Universiteit Leiden, University-Hospital Munich-Großhadern [München], Karolinska Institutet [Stockholm], Universität Ulm - Ulm University [Ulm, Allemagne], Faculty of Medicine and Life Sciences [Tampere], University of Tampere [Finland], Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Landspitali National University Hospital of Iceland, VU University Medical Center [Amsterdam], Boston VA Research Institute (BVARI), Department of Physiology, Anatomy and Genetics [Oxford], University of Oxford, Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Christian-Albrechts-Universität zu Kiel (CAU), Institute of Clinical Molecular Biology, Kiel University, National Institute for Health and Welfare [Helsinki], Harvard T.H. Chan School of Public Health, Universitat Autònoma de Barcelona (UAB), Vall d'Hebron University Hospital [Barcelona], University of Tartu, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Center for Human and Clinical Genetics, Universiteit Leiden-Universiteit Leiden, University of Copenhagen = Københavns Universitet (UCPH), Institute of Health and Biomedical Innovation (IHBI), Queensland University of Technology [Brisbane] (QUT), Discipline of Psychiatry [Dublin], Trinity College Dublin-Trinity College Dublin, Institute of Neurology [London], The University of Hong Kong (HKU), University of Melbourne, Cooper Medical School of Rowan University [Camden] (CMSRU), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), University of Antwerp (UA), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), New York University School of Medicine (NYU), New York University School of Medicine, NYU System (NYU)-NYU System (NYU), University of Eastern Finland, Universitätsklinikum Bonn (UKB), Hertie Institute for Clinical Brain Research [Tubingen], University of Tübingen, NIHR Biomedical Research Centre [London], Guy's and St Thomas' NHS Foundation Trust-King‘s College London, University Medical Center [Utrecht], Ohio State University [Columbus] (OSU), University of California [San Francisco] (UC San Francisco), University of California (UC), Royal College of Surgeons in Ireland (RCSI), University of Southern Denmark (SDU), United Christian Hospital [Hong Kong] (UCH), University of Cincinnati (UC), University of Cologne, Inselspital Bern, University of Wales, Jefferson University Hospitals, University of Liverpool, Medizinische Universität Wien = Medical University of Vienna, National Institutes of Health [Bethesda] (NIH), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Institut de Recherche en Santé Digestive (IRSD ), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Lincoln, University of Newcastle [Callaghan, Australia] (UoN), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', University of Virginia, University of Maryland [Baltimore County] (UMBC), University of Maryland System, Royal Holloway [University of London] (RHUL), University of Edinburgh, Universidade de Lisboa = University of Lisbon (ULISBOA), Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), University of Split, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Center for Genomic Regulation (CRG-UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), McLean Hospital [Belmont, Ma.], Norwegian Institute of Public Health [Oslo] (NIPH), Università degli Studi di Salerno = University of Salerno (UNISA), University of Bristol [Bristol], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Utrecht University [Utrecht], Azienda Ospedaliera di Padova, Université de Liège, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), Università degli Studi di Perugia = University of Perugia (UNIPG), Università degli studi della Campania 'Luigi Vanvitelli' = University of the Study of Campania Luigi Vanvitelli, National and Kapodistrian University of Athens (NKUA), Charles University [Prague] (CU), SURFACES, Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Flinders University [Adelaide, Australia], Virginia Commonwealth University (VCU), University of Oslo (UiO), University of Bergen (UiB), Weill Medical College of Cornell University [New York], University of North Dakota [Grand Forks] (UND), Oregon Research Institute (ORI), University of California [San Diego] (UC San Diego), Universitat de Barcelona (UB), Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Hospital Universitario Mutua de Terrassa, School of Computer Science and Communication [Stockholm], Royal Institute of Technology [Stockholm] (KTH ), Jefferson (Philadelphia University + Thomas Jefferson University), University Medical Center Göttingen (UMG), Universität Heidelberg [Heidelberg] = Heidelberg University, Radboud University Medical Center [Nijmegen], Universitätsklinikum Frankfurt, Maastricht University [Maastricht], Institute of Psychological Medicine and Clinical Neurosciences, Aarhus University [Aarhus], University of Iowa [Iowa City], Universidade Federal do Rio Grande do Sul [Porto Alegre] (UFRGS), The Hospital for sick children [Toronto] (SickKids), Hospital de Clínicas de Porto Alegre (HCPA), Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), University of British Columbia (UBC), IRCCS Fondazione Stella Maris [Pisa], Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Universidade de Coimbra [Coimbra], Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Our Lady's Children's Hospital Crumlin (OLCHC), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Children’s Hospital Los Angeles [Los Angeles], Yale University [New Haven], Brown University, Institute of Neuroscience [Newcastle] (ION), Newcastle University [Newcastle], Department of Medical Epidemiology and Biostatistics (MEB), Division of Medical Genetics [Seattle], University of Illinois [Chicago] (UIC), University of Illinois System, Maine Medical Center Research Institute (MMCRI), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre d’Etudes et de Recherches en Psychopathologie et Psychologie de la Santé (CERPPS), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Toulouse Mind & Brain Institut (TMBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Johns Hopkins University School of Medicine [Baltimore], Ludwig Maximilian University [Munich] (LMU), University of Michigan System, Department of Genetic Epidemiology in Psychiatry [Mannhein], Universität Heidelberg [Heidelberg] = Heidelberg University-Central Institute of Mental Health Mannheim, University of Dundee, National University of Ireland [Galway] (NUI Galway), University Hospital Basel [Basel], Neuroscience Research Australia (NeuRA), Forschungszentrum Jülich GmbH | Centre de recherche de Juliers, Helmholtz-Gemeinschaft = Helmholtz Association, UNSW Faculty of Medicine [Sydney], University of New South Wales [Sydney] (UNSW), University of Chicago, Johns Hopkins University (JHU), Johns Hopkins Bloomberg School of Public Health [Baltimore], Dalhousie University [Halifax], Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], State University of New York (SUNY), University Hospital of Cologne [Cologne], University of Adelaide, James Cook University (JCU), Institute for Molecular Bioscience, University of Queensland [Brisbane], Greifswald University Hospital, The University of Sydney, University Medical Center Groningen [Groningen] (UMCG), University of Calgary, University Health Network, Universidad de Antioquia = University of Antioquia [Medellín, Colombia], Universidade de São Paulo = University of São Paulo (USP), Ospedale San Raffaele, University of Amsterdam [Amsterdam] (UvA), University of Groningen [Groningen], Yale School of Medicine [New Haven, Connecticut] (YSM), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Cape Town, Cold Spring Harbor Laboratory (CSHL), Universidad de Sevilla / University of Sevilla, University of Florida [Gainesville] (UF), University of Denver, Purdue University [West Lafayette], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Moscow Institute of Physics and Technology [Moscow] (MIPT), Sunnybrook Health Sciences Centre, Federal Institute of São Paulo (IFSP), Democritus University of Thrace (DUTH), Universiteit Gent = Ghent University (UGENT), Medical University of Warsaw - Poland, Sorbonne Université - Faculté de Médecine - Département d'Enseignement et de Recherche en Médecine Générale, Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Institute of Mental Health [Singapore], Universidad de Cantabria [Santander], Tel Aviv University (TAU), University College Cork (UCC), University of Rochester [USA], Statens Serum Institut [Copenhagen], Софийски университет = Sofia University, Russian Academy of Sciences [Moscow] (RAS), Latvian Biomedical Research and Study Centre [Rīga], Vilnius University [Vilnius], Nanyang Technological University [Singapour], Department of Life Sciences, Imperial College London, Jena University Hospital [Jena], Oxford University Hospitals NHS Trust, Schizophrenia Research Institute [Sydney], Faculty of Science, Medicine and Health [Wollongong], University of Wollongong [Australia], City University of Hong Kong [Hong Kong] (CUHK), Lawrence Berkeley National Laboratory [Berkeley] (LBNL), This work was supported by grants 1R01MH10764901 and 5U01MH09443203 from the National Institute of Mental Health, as well as the Orion Farmos Research Foundation (V.A.) and the Fannie and John Hertz Foundation (H.K.F.). Consortium specific funding is detailed in the supplementary materials ('Study-specific acknowledgments')., Brainstorm Consortium, University of Kentucky, University of California [Irvine] (UCI), University of California-University of California, University of Pennsylvania [Philadelphia], Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 AMP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Universität Leipzig [Leipzig], Johannes Kepler University Linz [Linz] (JKU), University of Helsinki-University of Helsinki, University of Helsinki, University of Oxford [Oxford], University of Copenhagen = Københavns Universitet (KU), University of California [San Francisco] (UCSF), University of California, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Newcastle [Australia] (UoN), University of Virginia [Charlottesville], Universidade de Lisboa (ULISBOA), Università degli Studi di Salerno (UNISA), Rheinisch-Westfälische Technische Hochschule Aachen (RWTH), Università degli Studi di Perugia (UNIPG), Università degli studi della Campania 'Luigi Vanvitelli', Universität Heidelberg [Heidelberg], Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Universität Heidelberg [Heidelberg]-Central Institute of Mental Health Mannheim, VU University Amsterdam, Universidade de São Paulo (USP), Yale University School of Medicine, Universidad de Sevilla, Universiteit Gent = Ghent University [Belgium] (UGENT), Service de Psychiatrie de l'Enfant et de l'Adolescent [CHU Pitié-Salpêtrière] (SPEA), Tel Aviv University [Tel Aviv], University of Sofia, Anttila, Verneri, Bulik-Sullivan, Brendan, Finucane, Hilary K., Walters, Raymond K., Bras, Jose, Duncan, Laramie, Escott-Price, Valentina, Falcone, Guido J., Gormley, Padhraig, Malik, Rainer, Patsopoulos, Nikolaos A., Ripke, Stephan, Wei, Zhi, Yu, Dongmei, Lee, Phil H., Turley, Patrick, Grenier-Boley, Benjamin, Chouraki, Vincent, Kamatani, Yoichiro, Berr, Claudine, Letenneur, Luc, Hannequin, Didier, Amouyel, Philippe, Boland, Anne, Deleuze, Jean-Françoi, Duron, Emmanuelle, Vardarajan, Badri N., Reitz, Christiane, Goate, Alison M., Huentelman, Matthew J., Ilyas Kamboh, M., Larson, Eric B., Rogaeva, Ekaterina, George-Hyslop, Peter St, Hakonarson, Hakon, Kukull, Walter A., Farrer, Lindsay A., Barnes, Lisa L., Beach, Thomas G., Yesim Demirci, F., Head, Elizabeth, Hulette, Christine M., Jicha, Gregory A., Kauwe, John S.K., Kaye, Jeffrey A., Leverenz, James B., Levey, Allan I., Lieberman, Andrew P., Pankratz, Vernon S., Poon, Wayne W., Quinn, Joseph F., Saykin, Andrew J., Schneider, Lon S., Smith, Amanda G., Sonnen, Joshua A., Stern, Robert A., Van Deerlin, Vivianna M., Van Eldik, Linda J., Harold, Denise, Russo, Giancarlo, Rubinsztein, David C., Bayer, Anthony, Tsolaki, Magda, Proitsi, Petra, Fox, Nick C., Hampel, Harald, Owen, Michael J., Mead, Simon, Passmore, Peter, Morgan, Kevin, Nöthen, Markus M., Rossor, Martin, Lupton, Michelle K., Hoffmann, Per, Kornhuber, Johanne, Lawlor, Brian, McQuillin, Andrew, Al-Chalabi, Ammar, Bis, Joshua C., Ruiz, Agustin, Boada, Mercè, Seshadri, Sudha, Beiser, Alexa, Rice, Kenneth, Van Der Lee, Sven J., De Jager, Philip L., Geschwind, Daniel H., Riemenschneider, Matthia, Riedel-Heller, Steffi, Rotter, Jerome I., Ransmayr, Gerhard, Hyman, Bradley T., Cruchaga, Carlo, Alegret, Montserrat, Winsvold, Bendik, Palta, Priit, Farh, Kai-How, Cuenca-Leon, Ester, Furlotte, Nichola, Kurth, Tobia, Ligthart, Lannie, Terwindt, Gisela M., Freilinger, Tobia, Ran, Caroline, Gordon, Scott D., Borck, Guntram, Adams, Hieab H.H., Lehtimäki, Terho, Wedenoja, Juho, Buring, Julie E., Schürks, Marku, Hrafnsdottir, Maria, Hottenga, Jouke-Jan, Penninx, Brenda, Artto, Ville, Kaunisto, Mari, Vepsäläinen, Salli, Martin, Nicholas G., Montgomery, Grant W., Kurki, Mitja I., Hämäläinen, Eija, Huang, Hailiang, Huang, Jie, Sandor, Cynthia, Webber, Caleb, Muller-Myhsok, Bertram, Schreiber, Stefan, Salomaa, Veikko, Loehrer, Elizabeth, Göbel, Hartmut, Macaya, Alfon, Pozo-Rosich, Patricia, Hansen, Thoma, Werge, Thoma, Kaprio, Jaakko, Metspalu, Andre, Kubisch, Christian, Ferrari, Michel D., Belin, Andrea C., Van Den Maagdenberg, Arn M. J. M., Zwart, John-Anker, Boomsma, Dorret, Eriksson, Nichola, Olesen, Je, Chasman, Daniel I., Nyholt, Dale R., Avbersek, Andreja, Baum, Larry, Berkovic, Samuel, Bradfield, Jonathan, Buono, Russell, Catarino, Claudia B., Cossette, Patrick, De Jonghe, Peter, Depondt, Chantal, Dlugos, Denni, Ferraro, Thomas N., French, Jacqueline, Hjalgrim, Helle, Jamnadas-Khoda, Jennifer, Kälviäinen, Reetta, Kunz, Wolfram S., Lerche, Holger, Leu, Costin, Lindhout, Dick, Lo, Warren, Lowenstein, Daniel, McCormack, Mark, Møller, Rikke S., Molloy, Anne, Ng, Ping-Wing, Oliver, Karen, Privitera, Michael, Radtke, Rodney, Ruppert, Ann-Kathrin, Sander, Thoma, Schachter, Steven, Schankin, Christoph, Scheffer, Ingrid, Schoch, Susanne, Sisodiya, Sanjay M., Smith, Philip, Sperling, Michael, Striano, Pasquale, Surges, Rainer, Neil Thomas, G., Visscher, Frank, Whelan, Christopher D., Zara, Federico, Heinzen, Erin L., Marson, Anthony, Becker, Felicita, Stroink, Han, Zimprich, Fritz, Gasser, Thoma, Gibbs, Raphael, Heutink, Peter, Martinez, Maria, Morris, Huw R., Sharma, Manu, Ryten, Mina, Mok, Kin Y., Pulit, Sara, Bevan, Steve, Holliday, Elizabeth, Attia, John, Battey, Thoma, Boncoraglio, Giorgio, Thijs, Vincent, Chen, Wei-Min, Mitchell, Braxton, Rothwell, Peter, Sharma, Pankaj, Sudlow, Cathie, Vicente, Astrid, Markus, Hugh, Kourkoulis, Christina, Pera, Joana, Raffeld, Miriam, Silliman, Scott, Perica, Vesna Boraska, Thornton, Laura M., Huckins, Laura M., William Rayner, N., Lewis, Cathryn M., Gratacos, Monica, Rybakowski, Filip, Keski-Rahkonen, Anna, Raevuori, Anu, Hudson, James I., Reichborn-Kjennerud, Ted, Monteleone, Palmiero, Karwautz, Andrea, Mannik, Katrin, Baker, Jessica H., O'Toole, Julie K., Trace, Sara E., Davis, Oliver S. P., Helder, Sietske G., Ehrlich, Stefan, Herpertz-Dahlmann, Beate, Danner, Unna N., Van Elburg, Annemarie A., Clementi, Maurizio, Forzan, Monica, Docampo, Elisa, Lissowska, Jolanta, Hauser, Joanna, Tortorella, Alfonso, Maj, Mario, Gonidakis, Fragisko, Tziouvas, Konstantino, Papezova, Hana, Yilmaz, Zeynep, Wagner, Gudrun, Cohen-Woods, Sarah, Herms, Stefan, Julia, Antonio, Rabionet, Raquel, Dick, Danielle M., Ripatti, Samuli, Andreassen, Ole A., Espeseth, Thoma, Lundervold, Astri J., Steen, Vidar M., Pinto, Dalila, Scherer, Stephen W., Aschauer, Harald, Schosser, Alexandra, Alfredsson, Lar, Padyukov, Leonid, Halmi, Katherine A., Mitchell, Jame, Strober, Michael, Bergen, Andrew W., Kaye, Walter, Szatkiewicz, Jin Peng, Cormand, Bru, Ramos-Quiroga, Josep Antoni, Sánchez-Mora, Cristina, Ribasés, Marta, Casas, Miguel, Hervas, Amaia, Arranz, Maria Jesú, Haavik, Jan, Zayats, Tetyana, Johansson, Stefan, Williams, Nigel, Dempfle, Astrid, Rothenberger, Aribert, Kuntsi, Jonna, Oades, Robert D., Banaschewski, Tobia, Franke, Barbara, Buitelaar, Jan K., Vasquez, Alejandro Aria, Doyle, Alysa E., Reif, Andrea, Lesch, Klaus-Peter, Freitag, Christine, Rivero, Olga, Palmason, Haukur, Romanos, Marcel, Langley, Kate, Rietschel, Marcella, Witt, Stephanie H., Dalsgaard, Soeren, Børglum, Anders D., Waldman, Irwin, Wilmot, Beth, Molly, Nikola, Bau, Claiton H.D., Crosbie, Jennifer, Schachar, Russell, Loo, Sandra K., McGough, James J., Grevet, Eugenio H., Medland, Sarah E., Robinson, Elise, Weiss, Lauren A., Bacchelli, Elena, Bailey, Anthony, Bal, Vanessa, Battaglia, Agatino, Betancur, Catalina, Bolton, Patrick, Cantor, Rita, Celestino-Soper, Patrícia, Dawson, Geraldine, De Rubeis, Silvia, Duque, Frederico, Green, Andrew, Klauck, Sabine M., Leboyer, Marion, Levitt, Pat, Maestrini, Elena, Mane, Shrikant, Moreno-De-Luca, Daniel, Parr, Jeremy, Regan, Regina, Reichenberg, Abraham, Sandin, Sven, Vorstman, Jacob, Wassink, Thoma, Wijsman, Ellen, Cook, Edwin, Santangelo, Susan, Delorme, Richard, Roge, Bernadette, Magalhaes, Tiago, Arking, Dan, Schulze, Thomas G., Thompson, Robert C., Strohmaier, Jana, Matthews, Keith, Melle, Ingrid, Morris, Derek, Blackwood, Dougla, McIntosh, Andrew, Bergen, Sarah E., Schalling, Martin, Jamain, Stéphane, Maaser, Anna, Fischer, Sascha B., Reinbold, Céline S., Fullerton, Janice M., Guzman-Parra, José, Mayoral, Fermin, Schofield, Peter R., Cichon, Sven, Mühleisen, Thomas W., Degenhardt, Franziska, Schumacher, Johanne, Bauer, Michael, Mitchell, Philip B., Gershon, Elliot S., Rice, John, Potash, James B., Zandi, Peter P., Craddock, Nick, Nicol Ferrier, I., Alda, Martin, Rouleau, Guy A., Turecki, Gustavo, Ophoff, Roel, Pato, Carlo, Anjorin, Adebayo, Stahl, Eli, Leber, Marku, Czerski, Piotr M., Cruceanu, Cristiana, Jones, Ian R., Posthuma, Danielle, Andlauer, Till F.M., Forstner, Andreas J., Streit, Fabian, Baune, Bernhard T., Air, Tracy, Sinnamon, Grant, Wray, Naomi R., MacIntyre, Donald J., Porteous, David, Homuth, Georg, Rivera, Margarita, Grove, Jakob, Middeldorp, Christel M., Hickie, Ian, Pergadia, Michele, Mehta, Divya, Smit, Johannes H., Jansen, Rick, De Geus, Eco, Dunn, Erin, Li, Qingqin S., Nauck, Matthia, Schoevers, Robert A., Beekman, Aartjan TF, Knowles, James A., Viktorin, Alexander, Arnold, Paul, Barr, Cathy L., Bedoya-Berrio, Gabriel, Joseph Bienvenu, O., Brentani, Helena, Burton, Christie, Camarena, Beatriz, Cappi, Carolina, Cath, Danielle, Cavallini, Maria, Cusi, Daniele, Darrow, Sabrina, Denys, Damiaan, Derks, Eske M., Dietrich, Andrea, Fernandez, Thoma, Figee, Martijn, Freimer, Nelson, Gerber, Gloria, Grados, Marco, Greenberg, Erica, Hanna, Gregory L., Hartmann, Andrea, Hirschtritt, Matthew E., Hoekstra, Pieter J., Huang, Alden, Huyser, Chaim, Illmann, Cornelia, Jenike, Michael, Kuperman, Samuel, Leventhal, Bennett, Lochner, Christine, Lyon, Gholson J., Macciardi, Fabio, Madruga-Garrido, Marco, Malaty, Irene A., Maras, Athanasio, McGrath, Lauren, Miguel, Eurípedes C., Mir, Pablo, Nestadt, Gerald, Nicolini, Humberto, Okun, Michael S., Pakstis, Andrew, Paschou, Peristera, Piacentini, John, Pittenger, Christopher, Plessen, Kerstin, Ramensky, Vasily, Ramos, Eliana M., Reus, Victor, Richter, Margaret A., Riddle, Mark A., Robertson, Mary M., Roessner, Veit, Rosário, Maria, Samuels, Jack F., Sandor, Paul, Stein, Dan J., Tsetsos, Foti, Van Nieuwerburgh, Filip, Weatherall, Sarah, Wendland, Jens R., Wolanczyk, Tomasz, Worbe, Yulia, Zai, Gwyneth, Goes, Fernando S., McLaughlin, Nicole, Nestadt, Paul S., Grabe, Hans-Jorgen, Depienne, Christel, Konkashbaev, Anuar, Lanzagorta, Nuria, Valencia-Duarte, Ana, Bramon, Elvira, Buccola, Nancy, Cahn, Wiepke, Cairns, Murray, Chong, Siow A., Cohen, David, Crespo-Facorro, Benedicto, Crowley, Jame, Davidson, Michael, DeLisi, Lynn, Dinan, Timothy, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Haan, Lieuwe, Hougaard, David, Karachanak-Yankova, Sena, Khrunin, Andrey, Klovins, Jani, Kučinskas, Vaiduti, Keong, Jimmy Lee Chee, Limborska, Svetlana, Loughland, Carmel, Lönnqvist, Jouko, Maher, Brion, Mattheisen, Manuel, McDonald, Colm, Murphy, Kieran C., Nenadic, Igor, Van Os, Jim, Pantelis, Christo, Pato, Michele, Petryshen, Tracey, Quested, Digby, Roussos, Pano, Sanders, Alan R., Schall, Ulrich, Schwab, Sibylle G., Sim, Kang, So, Hon-Cheong, Stögmann, Elisabeth, Subramaniam, Mythily, Toncheva, Draga, Waddington, John, Walters, Jame, Weiser, Mark, Cheng, Wei, Cloninger, Robert, Curtis, David, Gejman, Pablo V., Henskens, Fran, Mattingsdal, Morten, Oh, Sang-Yun, Scott, Rodney, Webb, Bradley, Breen, Gerome, Churchhouse, Claire, Bulik, Cynthia M., Daly, Mark, Dichgans, Martin, Faraone, Stephen V., Guerreiro, Rita, Holmans, Peter, Kendler, Kenneth S., Koeleman, Bobby, Mathews, Carol A., Price, Alke, Scharf, Jeremiah, Sklar, Pamela, Williams, Julie, Wood, Nicholas W., Cotsapas, Chri, Palotie, Aarno, Smoller, Jordan W., Sullivan, Patrick, Rosand, Jonathan, Corvin, Aiden, Neale, Benjamin M., Epidemiology, Radiology & Nuclear Medicine, Anttila, V, Bulik-Sullivan, B, Finucane, H, Walters, R, Bras, J, Duncan, L, Escott-Price, V, Falcone, G, Gormley, P, Malik, R, Patsopoulos, N, Ripke, S, Wei, Z, Yu, D, Lee, P, Turley, P, Grenier-Boley, B, Chouraki, V, Kamatani, Y, Berr, C, Letenneur, L, Hannequin, D, Amouyel, P, Boland, A, Deleuze, J, Duron, E, Vardarajan, B, Reitz, C, Goate, A, Huentelman, M, Ilyas Kamboh, M, Larson, E, Rogaeva, E, George-Hyslop, P, Hakonarson, H, Kukull, W, Farrer, L, Barnes, L, Beach, T, Yesim Demirci, F, Head, E, Hulette, C, Jicha, G, Kauwe, J, Kaye, J, Leverenz, J, Levey, A, Lieberman, A, Pankratz, V, Poon, W, Quinn, J, Saykin, A, Schneider, L, Smith, A, Sonnen, J, Stern, R, Van Deerlin, V, Van Eldik, L, Harold, D, Russo, G, Rubinsztein, D, Bayer, A, Tsolaki, M, Proitsi, P, Fox, N, Hampel, H, Owen, M, Mead, S, Passmore, P, Morgan, K, Nöthen, M, Rossor, M, Lupton, M, Hoffmann, P, Kornhuber, J, Lawlor, B, Mcquillin, A, Al-Chalabi, A, Bis, J, Ruiz, A, Boada, M, Seshadri, S, Beiser, A, Rice, K, Van Der Lee, S, De Jager, P, Geschwind, D, Riemenschneider, M, Riedel-Heller, S, Rotter, J, Ransmayr, G, Hyman, B, Cruchaga, C, Alegret, M, Winsvold, B, Palta, P, Farh, K, Cuenca-Leon, E, Furlotte, N, Kurth, T, Ligthart, L, Terwindt, G, Freilinger, T, Ran, C, Gordon, S, Borck, G, Adams, H, Lehtimäki, T, Wedenoja, J, Buring, J, Schürks, M, Hrafnsdottir, M, Hottenga, J, Penninx, B, Artto, V, Kaunisto, M, Vepsäläinen, S, Martin, N, Montgomery, G, Kurki, M, Hämäläinen, E, Huang, H, Huang, J, Sandor, C, Webber, C, Muller-Myhsok, B, Schreiber, S, Salomaa, V, Loehrer, E, Göbel, H, Macaya, A, Pozo-Rosich, P, Hansen, T, Werge, T, Kaprio, J, Metspalu, A, Kubisch, C, Ferrari, M, Belin, A, Van Den Maagdenberg, A, Zwart, J, Boomsma, D, Eriksson, N, Olesen, J, Chasman, D, Nyholt, D, Avbersek, A, Baum, L, Berkovic, S, Bradfield, J, Buono, R, Catarino, C, Cossette, P, De Jonghe, P, Depondt, C, Dlugos, D, Ferraro, T, French, J, Hjalgrim, H, Jamnadas-Khoda, J, Kälviäinen, R, Kunz, W, Lerche, H, Leu, C, Lindhout, D, Lo, W, Lowenstein, D, Mccormack, M, Møller, R, Molloy, A, Ng, P, Oliver, K, Privitera, M, Radtke, R, Ruppert, A, Sander, T, Schachter, S, Schankin, C, Scheffer, I, Schoch, S, Sisodiya, S, Smith, P, Sperling, M, Striano, P, Surges, R, Neil Thomas, G, Visscher, F, Whelan, C, Zara, F, Heinzen, E, Marson, A, Becker, F, Stroink, H, Zimprich, F, Gasser, T, Gibbs, R, Heutink, P, Martinez, M, Morris, H, Sharma, M, Ryten, M, Mok, K, Pulit, S, Bevan, S, Holliday, E, Attia, J, Battey, T, Boncoraglio, G, Thijs, V, Chen, W, Mitchell, B, Rothwell, P, Sharma, P, Sudlow, C, Vicente, A, Markus, H, Kourkoulis, C, Pera, J, Raffeld, M, Silliman, S, Perica, V, Thornton, L, Huckins, L, William Rayner, N, Lewis, C, Gratacos, M, Rybakowski, F, Keski-Rahkonen, A, Raevuori, A, Hudson, J, Reichborn-Kjennerud, T, Monteleone, P, Karwautz, A, Mannik, K, Baker, J, O'Toole, J, Trace, S, Davis, O, Helder, S, Ehrlich, S, Herpertz-Dahlmann, B, Danner, U, Van Elburg, A, Clementi, M, Forzan, M, Docampo, E, Lissowska, J, Hauser, J, Tortorella, A, Maj, M, Gonidakis, F, Tziouvas, K, Papezova, H, Yilmaz, Z, Wagner, G, Cohen-Woods, S, Herms, S, Julia, A, Rabionet, R, Dick, D, Ripatti, S, Andreassen, O, Espeseth, T, Lundervold, A, Steen, V, Pinto, D, Scherer, S, Aschauer, H, Schosser, A, Alfredsson, L, Padyukov, L, Halmi, K, Mitchell, J, Strober, M, Bergen, A, Kaye, W, Szatkiewicz, J, Cormand, B, Ramos-Quiroga, J, Sánchez-Mora, C, Ribasés, M, Casas, M, Hervas, A, Arranz, M, Haavik, J, Zayats, T, Johansson, S, Williams, N, Dempfle, A, Rothenberger, A, Kuntsi, J, Oades, R, Banaschewski, T, Franke, B, Buitelaar, J, Vasquez, A, Doyle, A, Reif, A, Lesch, K, Freitag, C, Rivero, O, Palmason, H, Romanos, M, Langley, K, Rietschel, M, Witt, S, Dalsgaard, S, Børglum, A, Waldman, I, Wilmot, B, Molly, N, Bau, C, Crosbie, J, Schachar, R, Loo, S, Mcgough, J, Grevet, E, Medland, S, Robinson, E, Weiss, L, Bacchelli, E, Bailey, A, Bal, V, Battaglia, A, Betancur, C, Bolton, P, Cantor, R, Celestino-Soper, P, Dawson, G, De Rubeis, S, Duque, F, Green, A, Klauck, S, Leboyer, M, Levitt, P, Maestrini, E, Mane, S, Moreno-De-Luca, D, Parr, J, Regan, R, Reichenberg, A, Sandin, S, Vorstman, J, Wassink, T, Wijsman, E, Cook, E, Santangelo, S, Delorme, R, Roge, B, Magalhaes, T, Arking, D, Schulze, T, Thompson, R, Strohmaier, J, Matthews, K, Melle, I, Morris, D, Blackwood, D, Mcintosh, A, Bergen, S, Schalling, M, Jamain, S, Maaser, A, Fischer, S, Reinbold, C, Fullerton, J, Guzman-Parra, J, Mayoral, F, Schofield, P, Cichon, S, Mühleisen, T, Degenhardt, F, Schumacher, J, Bauer, M, Mitchell, P, Gershon, E, Rice, J, Potash, J, Zandi, P, Craddock, N, Nicol Ferrier, I, Alda, M, Rouleau, G, Turecki, G, Ophoff, R, Pato, C, Anjorin, A, Stahl, E, Leber, M, Czerski, P, Cruceanu, C, Jones, I, Posthuma, D, Andlauer, T, Forstner, A, Streit, F, Baune, B, Air, T, Sinnamon, G, Wray, N, Macintyre, D, Porteous, D, Homuth, G, Rivera, M, Grove, J, Middeldorp, C, Hickie, I, Pergadia, M, Mehta, D, Smit, J, Jansen, R, De Geus, E, Dunn, E, Li, Q, Nauck, M, Schoevers, R, Beekman, A, Knowles, J, Viktorin, A, Arnold, P, Barr, C, Bedoya-Berrio, G, Joseph Bienvenu, O, Brentani, H, Burton, C, Camarena, B, Cappi, C, Cath, D, Cavallini, M, Cusi, D, Darrow, S, Denys, D, Derks, E, Dietrich, A, Fernandez, T, Figee, M, Freimer, N, Gerber, G, Grados, M, Greenberg, E, Hanna, G, Hartmann, A, Hirschtritt, M, Hoekstra, P, Huang, A, Huyser, C, Illmann, C, Jenike, M, Kuperman, S, Leventhal, B, Lochner, C, Lyon, G, Macciardi, F, Madruga-Garrido, M, Malaty, I, Maras, A, Mcgrath, L, Miguel, E, Mir, P, Nestadt, G, Nicolini, H, Okun, M, Pakstis, A, Paschou, P, Piacentini, J, Pittenger, C, Plessen, K, Ramensky, V, Ramos, E, Reus, V, Richter, M, Riddle, M, Robertson, M, Roessner, V, Rosário, M, Samuels, J, Sandor, P, Stein, D, Tsetsos, F, Van Nieuwerburgh, F, Weatherall, S, Wendland, J, Wolanczyk, T, Worbe, Y, Zai, G, Goes, F, Mclaughlin, N, Nestadt, P, Grabe, H, Depienne, C, Konkashbaev, A, Lanzagorta, N, Valencia-Duarte, A, Bramon, E, Buccola, N, Cahn, W, Cairns, M, Chong, S, Cohen, D, Crespo-Facorro, B, Crowley, J, Davidson, M, Delisi, L, Dinan, T, Donohoe, G, Drapeau, E, Duan, J, Haan, L, Hougaard, D, Karachanak-Yankova, S, Khrunin, A, Klovins, J, Kučinskas, V, Keong, J, Limborska, S, Loughland, C, Lönnqvist, J, Maher, B, Mattheisen, M, Mcdonald, C, Murphy, K, Nenadic, I, Van Os, J, Pantelis, C, Pato, M, Petryshen, T, Quested, D, Roussos, P, Sanders, A, Schall, U, Schwab, S, Sim, K, So, H, Stögmann, E, Subramaniam, M, Toncheva, D, Waddington, J, Walters, J, Weiser, M, Cheng, W, Cloninger, R, Curtis, D, Gejman, P, Henskens, F, Mattingsdal, M, Oh, S, Scott, R, Webb, B, Breen, G, Churchhouse, C, Bulik, C, Daly, M, Dichgans, M, Faraone, S, Guerreiro, R, Holmans, P, Kendler, K, Koeleman, B, Mathews, C, Price, A, Scharf, J, Sklar, P, Williams, J, Wood, N, Cotsapas, C, Palotie, A, Smoller, J, Sullivan, P, Rosand, J, Corvin, A, Neale, B, Kauwe, John S. K., Mcquillin, Andrew, Adams, Hieab H. H., Mccormack, Mark, Bau, Claiton H. D., Mcgough, James J., Mcintosh, Andrew, Andlauer, Till F. M., Macintyre, Donald J., Mcgrath, Lauren, Mclaughlin, Nicole, Delisi, Lynn, Mcdonald, Colm, Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), RIKEN Center for Integrative Medical Science, Neuropsychiatrie : recherche épidémiologique et clinique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), University of South Florida (USF), University of Zürich [Zürich] (UZH)-Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology in Zürich [Zürich] (ETH Zürich), Alzheimer Precision Medicine GRC n°21 (APM), CHU Pitié-Salpêtrière [APHP], Cardiff University-Medical Research Council, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Johannes Kepler University Linz [linz] (JKU), Washington University in St Louis, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Universitat Autònoma de Barcelona [Barcelona] (UAB), Hôpital Erasme (Bruxelles), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Jagiellonian University [Krakow] (UJ), Technische Universität Dresden (TUD), National and Kapodistrian University of Athens = University of Athens (NKUA | UoA), Charles University [Prague], Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), University of Bergen (UIB), University Medicine Goettingen, Università di Bologna [Bologna] (UNIBO), Forschungszentrum Jülich GmbH, UNSW Medicine [Sydney], McGill University, Universidad de Antioquia, University of Florida [Gainesville], Universiteit Gent [Ghent], Service Psychiatrie de l'Enfant et de l'Adolescent [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], University of Wollongong, Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 APM), Anttila, Verneri [0000-0002-0073-4675], Finucane, Hilary K [0000-0003-3864-9828], Walters, Raymond K [0000-0001-8422-6530], Duncan, Laramie [0000-0003-1131-661X], Escott-Price, Valentina [0000-0003-1784-5483], Falcone, Guido J [0000-0002-6407-0302], Gormley, Padhraig [0000-0002-8908-6968], Malik, Rainer [0000-0001-9212-2520], Ripke, Stephan [0000-0003-3622-835X], Wei, Zhi [0000-0001-6059-4267], Yu, Dongmei [0000-0001-7901-4365], Lee, Phil H [0000-0003-1770-3100], Breen, Gerome [0000-0003-2053-1792], Bulik, Cynthia M [0000-0001-7772-3264], Daly, Mark [0000-0002-0949-8752], Dichgans, Martin [0000-0002-0654-387X], Faraone, Stephen V [0000-0002-9217-3982], Holmans, Peter [0000-0003-0870-9412], Koeleman, Bobby [0000-0001-7749-182X], Mathews, Carol A [0000-0003-2208-7058], Sklar, Pamela [0000-0001-9715-4943], Williams, Julie [0000-0002-4069-0259], Wood, Nicholas W [0000-0002-9500-3348], Cotsapas, Chris [0000-0002-7772-5910], Smoller, Jordan W [0000-0002-0381-6334], Sullivan, Patrick [0000-0002-6619-873X], Rosand, Jonathan [0000-0002-1014-9138], Corvin, Aiden [0000-0001-6717-4089], Neale, Benjamin M [0000-0003-1513-6077], and Apollo - University of Cambridge Repository

Subjects
Etiology, [SDV]Life Sciences [q-bio], MESH: Brain Diseases, body-mass index, genetics [Mental Disorders], Disorders of the Brain, Risks factors, classification [Mental Disorders], MESH: Quantitative Trait, Heritable, MESH: Risk Factors, Risk Factors, MESH: Genetic Variation, alzheimers-disease, 610 Medicine & health, bipolar disorder, Brain Diseases, deficit hyperactivity disorder, Multidisciplinary, Mental Disorders, genetics [Brain Diseases], Brain Disease, Brain, Genetic Variation, Genome-Wide Association Study, Humans, Phenotype, Quantitative Trait, Heritable, Psychiatric Disorders, anorexia-nervosa, Mental Disorder, Psychiatric Genomics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], long-term survival, Engineering sciences. Technology, Human, General Science & Technology, population-based twin, diagnosis [Mental Disorders], MESH: Phenotype, Neurological Disorders, Quantitative Trait, MD Multidisciplinary, MESH: Mental Disorders, diagnosis [Brain Diseases], Heritable, genetic correlations, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, major depressive disorder, Risk Factor, Brain Diseases/classification, Brain Diseases/diagnosis, Brain Diseases/genetics, Mental Disorders/classification, Mental Disorders/diagnosis, Mental Disorders/genetics, classification [Brain Diseases], Perturbações do Desenvolvimento Infantil e Saúde Mental, ddc:320, MESH: Genome-Wide Association Study, genome-wide association, Brainstorm Consortium, Genetic Factors, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities’ assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer’s disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important “scaffolding” to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders.

Published
2018

29. Identification of genetic loci shared between ADHD, intelligence and educational attainment

Author

O’Connell, Kevin S, Shadrin, Alexey, Smeland, Olav B, Bahrami, Shahram, Frei, Oleksandr, Bettella, Francesco, Krull, Florian, Fan, Chun C, Askeland, Ragna B., Knudsen, Gun Peggy S., Halmøy, Anne, Steen, Nils Eiel, Ueland, Torill, Walters, G. Bragi, Davíðsdóttir, Katrín, Haraldsdóttir, Gyða S., Guðmundsson, Ólafur Ó., Stefánsson, Hreinn, Reichborn-Kjennerud, Ted, Haavik, Jan, Dale, Anders M, Stefánsson, Kári, Djurovic, Srdjan, and Andreassen, Ole A

Subjects
Academic Success, Attention Deficit Disorder with Hyperactivity, Genetic Loci, mental disorders, Intelligence, Humans, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Article, Genome-Wide Association Study
Abstract

Background Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that is consistently associated with lower levels of educational attainment. A recent large genome-wide association study identified common gene variants associated with ADHD, but most of the genetic architecture remains unknown. Methods We analyzed independent genome-wide association study summary statistics for ADHD (19,099 cases and 34,194 controls), educational attainment ( N = 842,499), and general intelligence ( N = 269,867) using a conditional/conjunctional false discovery rate (FDR) statistical framework that increases power of discovery by conditioning the FDR on overlapping associations. The genetic variants identified were characterized in terms of function, expression, and biological processes. Results We identified 58 linkage disequilibrium–independent ADHD-associated loci (conditional FDR < 0.01), of which 30 were shared between ADHD and educational attainment or general intelligence (conjunctional FDR < 0.01) and 46 were novel risk loci for ADHD. Conclusions These results expand on previous genetic and epidemiological studies and support the hypothesis of a shared genetic basis between these phenotypes. Although the clinical utility of the identified loci remains to be determined, they can be used as resources to guide future studies aiming to disentangle the complex etiologies of ADHD, educational attainment, and general intelligence.

Published
2019

30. Mapping cortical brain asymmetry in 17,141 healthy individuals worldwide via the ENIGMA Consortium

Author

Kong, Xiang-Zhen, Mathias, Samuel R, Francks, Clyde, Grabe, Hans, Groenewold, Nynke A, Grotegerd, Dominik, Gruber, Oliver, Gurholt, Tiril, Haavik, Jan, Hahn, Tim, Hansell, Narelle K, Harris, Mathew A, Hartman, Catharina A, Hernández, Maria Del Carmen Valdés, Heslenfeld, Dirk, Hester, Robert, Hibar, Derrek Paul, Ho, Beng-Choon, Ho, Tiffany C, Hoekstra, Pieter J, van Holst, Ruth J, Hoogman, Martine, Høvik, Marie F, Howells, Fleur M, Hugdahl, Kenneth, Huyser, Chaim, Ingvar, Martin, Irwin, Lourdes, Ishikawa, Akari, James, Anthony, Jahanshad, Neda, Jernigan, Terry L, Jönsson, Erik G, Guadalupe, Tulio, Kähler, Claas, Kaleda, Vasily, Kelly, Clare, Kerich, Michael, Keshavan, Matcheri S, Khadka, Sabin, Kircher, Tilo, Kohls, Gregor, Konrad, Kerstin, Korucuoglu, Ozlem, Abé, Christoph, Krämer, Bernd, Krug, Axel, Kwon, Jun Soo, Lambregts-Rommelse, Nanda, Landén, Mikael, Lázaro, Luisa, Lebedeva, Irina, Lenroot, Rhoshel, Lesch, Klaus-Peter, Li, Qinqin, Agartz, Ingrid, Lim, Kelvin O, Liu, Jia, Lochner, Christine, London, Edythe D, Lonning, Vera, Lorenzetti, Valentina, Luciano, Michelle, Luijten, Maartje, Lundervold, Astri J, Mackey, Scott, Akudjedu, Theophilus N, MacMaster, Frank P, Maingault, Sophie, Malpas, Charles B, Malt, Ulrik F, Mataix-Cols, David, Martin-Santos, Rocio, Mayer, Andrew R, McCarthy, Hazel, Mitchell, Philip B, Mueller, Bryon A, Aleman, Andre, Maniega, Susana Muñoz, Mazoyer, Bernard, McDonald, Colm, McLellan, Quinn, McMahon, Katie L, McPhilemy, Genevieve, Momenan, Reza, Morales, Angelica M, Narayanaswamy, Janardhanan C, Moreira, José Carlos Vasques, Alhusaini, Saud, Nerland, Stener, Nestor, Liam, Newman, Erik, Nigg, Joel T, Nordvik, Jan Egil, Novotny, Stephanie, Weiss, Eileen Oberwelland, O'Gorman, Ruth L, Oosterlaan, Jaap, Oranje, Bob, Allen, Nicholas B, Orr, Catherine, Overs, Bronwyn, Pauli, Paul, Paulus, Martin, Plessen, Kerstin Jessica, von Polier, Georg G, Pomarol-Clotet, Edith, Portella, Maria J, Qiu, Jiang, Radua, Joaquim, Ames, David, Ramos-Quiroga, Josep Antoni, Reddy, Y C Janardhan, Reif, Andreas, Roberts, Gloria, Rosa, Pedro, Rubia, Katya, Sacchet, Matthew D, Sachdev, Perminder S, Salvador, Raymond, Schmaal, Lianne, Andreassen, Ole A, Schulte-Rüther, Martin, Schweren, Lizanne, Seidman, Larry, Seitz, Jochen, Serpa, Mauricio Henriques, Shaw, Philip, Shumskaya, Elena, Silk, Timothy J, Simmons, Alan N, Simulionyte, Egle, Vasquez, Alejandro Arias, Sinha, Rajita, Sjoerds, Zsuzsika, Smelror, Runar Elle, Soliva, Joan Carlos, Solowij, Nadia, Souza-Duran, Fabio Luisde, Sponheim, Scott R, Stein, Dan J, Stein, Elliot A, Stevens, Michael, Armstrong, Nicola J, Strike, Lachlan T, Sudre, Gustavo, Sui, Jing, Tamm, Leanne, Temmingh, Hendrik S, Thoma, Robert J, Tomyshev, Alexander, Tronchin, Giulia, Turner, Jessica, Uhlmann, Anne, Bergo, Felipe, van Erp, Theo G M, van den Heuvel, Odile A, van der Meer, Dennis, van Eijk, Liza, Vance, Alasdair, Veer, Ilya M, Veltman, Dick J, Venkatasubramanian, Ganesan, Vilarroya, Oscar, Vives-Gilabert, Yolanda, Bastin, Mark E, Voineskos, Aristotle N, Völzke, Henry, Vuletic, Daniella, Walitza, Susanne, Walter, Henrik, Walton, Esther, Wardlaw, Joanna M, Wen, Wei, Westlye, Lars T, Whelan, Christopher D, Batalla, Albert, White, Tonya, Wiers, Reinout W, Wright, Margaret J, Wittfeld, Katharina, Yang, Tony T, Yasuda, Clarissa L, Yoncheva, Yuliya, Yücel, Murat, Yun, Je-Yeon, Zanetti, Marcus Vinicius, Bauer, Jochen, Zhen, Zonglei, Zhu, Xing-Xing, Ziegler, Georg C, Zierhut, Kathrin, de Zubicaray, Greig I, Zwiers, Marcel, Glahn, David C, Franke, Barbara, Crivello, Fabrice, Tzourio-Mazoyer, Nathalie, Baune, Bernhard T, Fisher, Simon E, Thompson, Paul M, Farde, Lars, Flyckt, Lena, Engberg, Göran, Erhardt, Sophie, Fatouros-Bergman, Helena, Cervenka, Simon, Schwieler, Lilly, Baur-Streubel, Ramona, Piehl, Fredrik, Collste, Karin, Victorsson, Pauliina, Malmqvist, Anna, Hedberg, Mikael, Orhan, Funda, Group, ENIGMA Laterality Working, Biederman, Joseph, Blaine, Sara K, Boedhoe, Premika, Bøen, Erlend, Bose, Anushree, Bralten, Janita, Brandeis, Daniel, Brem, Silvia, Brodaty, Henry, Yüksel, Dilara, Brooks, Samantha J, Buitelaar, Jan, Bürger, Christian, Bülow, Robin, Calhoun, Vince, Calvo, Anna, Canales-Rodríguez, Erick Jorge, Canive, Jose M, Cannon, Dara M, Caparelli, Elisabeth C, Castellanos, Francisco X, Cavalleri, Gianpiero L, Cendes, Fernando, Chaim-Avancini, Tiffany Moukbel, Chantiluke, Kaylita, Chen, Qun-Lin, Chen, Xiayu, Cheng, Yuqi, Christakou, Anastasia, Clark, Vincent P, Coghill, David, Connolly, Colm G, Conzelmann, Annette, Córdova-Palomera, Aldo, Cousijn, Janna, Crow, Tim, Cubillo, Ana, Dale, Anders, Dannlowski, Udo, Ambrosino de Bruttopilo, Sara, de Zeeuw, Patrick, Deary, Ian J, Delanty, Norman, Demeter, Damion V, Di Martino, Adriana, Dickie, Erin W, Dietsche, Bruno, Doan, N Trung, Doherty, Colin P, Doyle, Alysa, Durston, Sarah, Earl, Eric, Ehrlich, Stefan, Ekman, Carl Johan, Elvsåshagen, Torbjørn, Epstein, Jeffery N, Fair, Damien A, Faraone, Stephen V, Fernández, Guillén, Filho, Geraldo Busatto, Förster, Katharina, Fouche, Jean-Paul, Foxe, John J, Frodl, Thomas, Fuentes-Claramonte, Paola, Fullerton, Janice, Garavan, Hugh, Garcia, Danielle do Santos, Gotlib, Ian H, Goudriaan, Anna E, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Stochastics, Clinical Neuropsychology, Cognitive Psychology, IBBA, APH - Mental Health, Ontwikkelingspsychologie (Psychologie, FMG), Anatomy and neurosciences, Psychiatry, Pediatric surgery, Amsterdam Neuroscience - Brain Imaging, Child Psychiatry, Adult Psychiatry, ANS - Brain Imaging, AGEM - Endocrinology, metabolism and nutrition, Graduate School, AGEM - Inborn errors of metabolism, ARD - Amsterdam Reproduction and Development, General Paediatrics, APH - Digital Health, Radiology & Nuclear Medicine, Child and Adolescent Psychiatry / Psychology, and Universitat de Barcelona

Subjects
Dominància cerebral, Male, Databases, Factual, Planum temporale, Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13], 0302 clinical medicine, Transverse temporal gyrus, 130 000 Cognitive Neurology & Memory, diagnostic imaging [Cerebral Cortex], 80 and over, Brain asymmetry, Neuroimaging/methods, Child, ENIGMA Laterality Working Group, Aged, 80 and over, Cerebral Cortex, Multidisciplinary, Laterality, 05 social sciences, Human brain, Middle Aged, Databases, Factual/statistics & numerical data, medicine.anatomical_structure, Mental Health, PNAS Plus, Lateralitat, Child, Preschool, Brain size, Neurological, Biomedical Imaging, Female, ddc:500, methods [Neuroimaging], Parahippocampal gyrus, Neuroinformatics, Adult, statistics & numerical data [Databases, Factual], Adolescent, Cerebral Cortex/diagnostic imaging, 1.1 Normal biological development and functioning, BF, Inferior frontal gyrus, Neuroimaging, and over, Biology, 050105 experimental psychology, Lateralization of brain function, 03 medical and health sciences, Databases, Young Adult, All institutes and research themes of the Radboud University Medical Center, Clinical Research, Underpinning research, Journal Article, medicine, Humans, lateralization, 0501 psychology and cognitive sciences, General, Preschool, Factual, Aged, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], [SCCO.NEUR]Cognitive science/Neuroscience, Neurosciences, Infant, surface area, cortical thickness, Brain Disorders, meta-analysis, Cerebral dominance, brain asymmetry, Neuroscience, Developmental Psychopathology, 030217 neurology & neurosurgery
Abstract

Hemispheric asymmetry is a cardinal feature of human brain organization. Altered brain asymmetry has also been linked to some cognitive and neuropsychiatric disorders. Here the ENIGMA consortium presents the largest ever analysis of cerebral cortical asymmetry and its variability across individuals. Cortical thickness and surface area were assessed in MRI scans of 17,141 healthy individuals from 99 datasets worldwide. Results revealed widespread asymmetries at both hemispheric and regional levels, with a generally thicker cortex but smaller surface area in the left hemisphere relative to the right. Regionally, asymmetries of cortical thickness and/or surface area were found in the inferior frontal gyrus, transverse temporal gyrus, parahippocampal gyrus, and entorhinal cortex. These regions are involved in lateralized functions, including language and visuospatial processing. In addition to population-level asymmetries, variability in brain asymmetry was related to sex, age, and brain size (indexed by intracranial volume). Interestingly, we did not find significant associations between asymmetries and handedness. Finally, with two independent pedigree datasets (N = 1,443 and 1,113, respectively), we found several asymmetries showing modest but highly reliable heritability. The structural asymmetries identified, and their variabilities and heritability provide a reference resource for future studies on the genetic basis of brain asymmetry and altered laterality in cognitive, neurological, and psychiatric disorders.Significance StatementLeft-right asymmetry is a key feature of the human brain's structure and function. It remains unclear which cortical regions are asymmetrical on average in the population, and how biological factors such as age, sex and genetic variation affect these asymmetries. Here we describe by far the largest ever study of cerebral cortical brain asymmetry, based on data from 17,141 participants. We found a global anterior-posterior 'torque' pattern in cortical thickness, together with various regional asymmetries at the population level, which have not been previously described, as well as effects of age, sex, and heritability estimates. From these data, we have created an on-line resource that will serve future studies of human brain anatomy in health and disease.

Published
2018

31. Expanding the toolbox of ADHD genetics. How can we make sense of parent of origin effects in ADHD and related behavioral phenotypes?

Author

Zayats, Tetyana, Johansson, Stefan, and Haavik, Jan

Subjects
Male, Parents, Sex Chromosomes, Maternal effects, Maternal Health, Sex chromosomes, Parent-of-origin effects, Imprinting, Review, Mitochondrial DNA, Behavioral Neuroscience, Genomic Imprinting, Attention Deficit Disorder with Hyperactivity, Medisinske Fag: 700 [VDP], Genome, Mitochondrial, Humans, ADHD, Female, Genetic Predisposition to Disease, Epigenetics, Biological Psychiatry
Abstract

Genome-wide association (GWA) studies have shown that many different genetic variants cumulatively contribute to the risk of psychiatric disorders. It has also been demonstrated that various parent-of-origin effects (POE) may differentially influence the risk of these disorders. Together, these observations have provided important new possibilities to uncover the genetic underpinnings of such complex phenotypes. As POE so far have received little attention in neuropsychiatric disorders, there is still much progress to be made. Here, we mainly focus on the new and emerging role of POE in attention-deficit hyperactivity disorder (ADHD). We review the current evidence that POE play an imperative role in vulnerability to ADHD and related disorders. We also discuss how POE can be assessed using statistical genetics tools, expanding the resources of modern psychiatric genetics. We propose that better comprehension and inspection of POE may offer new insight into the molecular basis of ADHD and related phenotypes, as well as the potential for preventive and therapeutic interventions. publishedVersion

Published
2015

32. Genome wide association study identifies variants in NBEA associated with migraine in bipolar disorder

Author

Jacobsen, Kaya K, Nievergelt, Caroline M, Zayats, Tetyana, Greenwood, Tiffany A, Anttila, Verneri, Akiskal, Hagop S, BiGS Consortium, IHG Consortium, Haavik, Jan, Bernt Fasmer, Ole, Kelsoe, John R, Johansson, Stefan, and Oedegaard, Ketil J

Subjects
Adult, Male, Bipolar Disorder, Migraine Disorders, Nerve Tissue Proteins, Comorbidity, Medical and Health Sciences, Migraines, 2.3 Psychological, Genetics, Humans, Genetic Predisposition to Disease, Polymorphism, Aetiology, IHG Consortium, Migraine, Psychiatry, Headaches, Human Genome, Pain Research, Psychology and Cognitive Sciences, Neurosciences, Single Nucleotide, Neurobeachin, NBEA, Brain Disorders, Mental Health, Female, social and economic factors, Carrier Proteins, BiGS Consortium, Genome-Wide Association Study
Abstract

BackgroundMigraine is a common comorbidity among individuals with bipolar disorder, but the underlying mechanisms for this co-occurrence are poorly understood. The aim of this study was to investigate the genetic background of bipolar patients with and without migraine.MethodsWe performed a genome-wide association analysis contrasting 460 bipolar migraneurs with 914 bipolar patients without migraine from the Bipolar Genome Study (BiGS).ResultsWe identified one genome-wide significant association between migraine in bipolar disorder patients and rs1160720, an intronic single nucleotide polymorphism (SNP) in the NBEA gene (P=2.97 × 10(-8), OR: 1.82, 95% CI: 1.47-2.25), although this was not replicated in a smaller sample of 289 migraine cases.LimitationsOur study is based on self-reported migraine.ConclusionsNBEA encodes neurobeachin, a scaffolding protein primarily expressed in the brain and involved in trafficking of vesicles containing neurotransmitter receptors. This locus has not previously been implicated in migraine per se. We found no evidence of association in data from the GWAS migraine meta-analysis consortium (n=118,710 participants) suggesting that the association might be specific to migraine co-morbid with bipolar disorder.

Published
2015

33. Common variants in the ARC gene are not associated withcognitive abilities

Author

Myrum, Craig, Giddaluru, Sudheer, Jacobsen, Kaya Kvarme, Espeseth, Thomas, Nyberg, Lars, Lundervold, Astri, Haavik, Jan, Nilsson, Lars-Göran, Reinvang, Ivar, Steen, Vidar Martin, Johansson, Stefan, Wibrand, Karin, Le Hellard, Stephanie, and Bramham, Clive R.

Subjects
Adult, Male, cognition, Genotype, single‐nucleotide polymorphism, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, memory, Humans, Genetic Predisposition to Disease, genetics, Matematikk og Naturvitenskap: 400 [VDP], Original Research, Aged, Activity‐regulated cytoskeleton‐associated protein, Neuronal Plasticity, synaptic plasticity, Genetic Variation, Activity-regulated cytoskeleton-associated protein, Middle Aged, single-nucleotide polymorphism, Cytoskeletal Proteins, Attention Deficit Disorder with Hyperactivity, Female, Cognition Disorders, Genome-Wide Association Study
Abstract

Introduction: The Activity-Regulated Cytoskeleton-associated (ARC) gene encodes a protein that is critical for the consolidation of synaptic plasticity and long-term memory formation. Given ARC's key role in synaptic plasticity, we hypothesized that genetic variations in ARC may contribute to interindividual variability in human cognitive abilities or to attention-deficit hyperactivity disorder (ADHD) susceptibility, where cognitive impairment often accompanies the disorder. Methods: We tested whether ARC variants are associated with six measures of cognitive functioning in 670 healthy subjects in the Norwegian Cognitive NeuroGenetics (NCNG) by extracting data from its Genome-Wide Association Study (GWAS). In addition, the Swedish Betula sample of 1800 healthy subjects who underwent similar cognitive testing was also tested for association with 19 tag SNPs. Results: No ARC variants show association at the study-wide level, but several markers show a trend toward association with human cognitive functions. We also tested for association between ARC SNPs and ADHD in a Norwegian sample of cases and controls, but found no significant associations. Conclusion: This study suggests that common genetic variants located in ARC do not account for variance in human cognitive abilities, though small effects cannot be ruled out. publishedVersion

Published
2015

34. Phosphorylation dependence and stoichiometry of the complex formed by tyrosine hydroxylase and 14-3-3γ

Author

Kleppe, Rune, Rosati, Sara, Jorge-Finnigan, Ana, Alvira, Sara, Ghorbani, Sadaf, Haavik, Jan, Valpuesta, José María, Heck, Albert J R, Martinez, Aurora, Sub Biomol.Mass Spectrometry & Proteom., Sub Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Molecular Pharmacy, Sub Biomol.Mass Spectrometry & Proteom., Sub Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, and Molecular Pharmacy

Subjects
Tyrosine 3-Monooxygenase, Stereochemistry, Dimer, Population, Biochemistry, Mass Spectrometry, Analytical Chemistry, Dephosphorylation, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Tetramer, Serine, Humans, Phosphorylation, Binding site, education, Molecular Biology, 030304 developmental biology, 0303 health sciences, education.field_of_study, Binding Sites, Tyrosine hydroxylase, Articles, Surface Plasmon Resonance, Receptor–ligand kinetics, Kinetics, 14-3-3 Proteins, chemistry, Protein Multimerization, 030217 neurology & neurosurgery
Abstract

Phosphorylated tyrosine hydroxylase (TH) can form complexes with 14-3-3 proteins, resulting in enzyme activation and stabilization. Although TH was among the first binding partners identified for these ubiquitous regulatory proteins, the binding stoichiometry and the activation mechanism remain unknown. To address this, we performed native mass spectrometry analyses of human TH (nonphosphorylated or phosphorylated on Ser19 (TH-pS19), Ser40 (TH-pS40), or Ser19 and Ser40 (TH-pS19pS40)) alone and together with 14-3-3γ. Tetrameric TH-pS19 (224 kDa) bound 14-3-3γ (58.3 kDa) with high affinity (Kd = 3.2 nM), generating complexes containing either one (282.4 kDa) or two (340.8 kDa) dimers of 14-3-3. Electron microscopy also revealed one major population of an asymmetric complex, consistent with one TH tetramer and one 14-3-3 dimer, and a minor population of a symmetric complex of one TH tetramer with two 14-3-3 dimers. Lower phosphorylation stoichiometries (0.15-0.54 phosphate/monomer) produced moderate changes in binding kinetics, but native MS detected much less of the symmetric TH:14-3-3γ complex. Interestingly, dephosphorylation of [(32)P]-TH-pS19 was mono-exponential for low phosphorylation stoichiometries (0.18-0.52), and addition of phosphatase accelerated the dissociation of the TH-pS19:14-3-3γ complex 3- to 4-fold. All together this is consistent with a model in which the pS19 residues in the TH tetramer contribute differently in the association to 14-3-3γ. Complex formation between TH-pS40 and 14-3-3γ was not detected via native MS, and surface plasmon resonance showed that the interaction was very weak. Furthermore, TH-pS19pS40 behaved similarly to TH-pS19 in terms of binding stoichiometry and affinity (Kd = 2.1 nM). However, we found that 14-3-3γ inhibited the phosphorylation rate of TH-pS19 by PKA (3.5-fold) on Ser40. We therefore conclude that Ser40 does not significantly contribute to the binding of 14-3-3γ, and rather has reduced accessibility in the TH:14-3-3γ complex. This adds to our understanding of the fine-tuned physiological regulation of TH, including hierarchical phosphorylation at multiple sites.

Published
2014

35. Characterizing neuroanatomic heterogeneity in people with and without ADHD based on subcortical brain volumes

Author

Li, Ting, Rooij, Daan, Roth Mota, Nina, Buitelaar, Jan K., Hoogman, Martine, Arias Vasquez, Alejandro, Franke, Barbara, Ambrosino, Sara, Banaschewski, Tobias, Bandeira, Cibele E., Bau, Claiton H.D., Baumeister, Sarah, Baur‐Streubel, Ramona, Bellgrove, Mark A., Biederman, Joseph, Bralten, Janita, Bramati, Ivanei E., Brandeis, Daniel, Berm, Silvia, Busatto, Geraldo F., Calvo, Anna, Castellanos, Francisco X., Cercignani, Mara, Chantiluke, Kaylita C., Christakou, Anastasia, Coghill, David, Conzelmann, Annette, Cubillo, Ana I., Cupertino, Renata B., Zeeuw, Parick, Durston, Sarah, Earl, Eric A., Epstein, Jeffery N., Ethofer, Thomas, Fallgatter, Andreas J., Fair, Damien A., Faraone, Stephen V., Frodl, Thomas, Gabel, Matt C., Gogberashvili, Tinatin, Grevet, Eugenio H., Haavik, Jan, Harrison, Neil A., Hartman, Catharina A., Heslenfeld, Dirk J., Hoekstra, Pieter J., Høvik, Marie F., Jahanshad, Neda, Kardatzki, Bernd, Karkashadze, Georgii, Kelly, Clare, Kohls, Gregor, Konrad, Kerstin, Kuntsi, Jonna, Lazaro, Luisa, Lera‐Miguel, Sara, Lesch, Klaus‐Peter, Louza, Mario R., Lundervold, Astri J., Malpas, Charles B., Mattos, Paulo, McCarthy, Hazel, Nicolau, Rosa, Nigg, Joel T., O'Gorman Tuura, Ruth L., Oosterlaan, Jaap, Oranje, Bob, Paloyelis, Yannis, Pauli, Paul, Picon, Felipe A., Plessen, Kerstin J., Ramos‐Quiroga, J. Antoni, Reif, Andreas, Reneman, Liesbeth, Rosa, Pedro G.P., Rubia, Katya, Schrantee, Anouk, Schweren, Lizanne J.S., Seitz, Jochen, Shaw, Philip, Silk, Tim J., Skokauskas, Norbert, Carlos Soliva Vila, Juan, Soloveva, Anastasiia, Stevens, Michael C., Sudre, Gustavo, Tamm, Leanne, Thompson, Paul M., Tovar‐Moll, Fernanda, Erp, Theo GM, Vance, Alasdair, Vilarroya, Oscar, Vives‐Gilabert, Yolanda, Polier, Georg G., Walitza, Susanne, Yoncheva, Yuliya N., Zanetti, Marcus V., Ziegler, Georg C., Anikin, Anatoly, Asherson, Philip, Baranov, Alexandr, Chaim‐Avanicini, Tiffany, Dale, Anders M., Doyle, Alysa E., Jernigan, Terry, Hohmann, Sarah, Kapilushniy, Dmitry, Mehta, Mitul, Namazova‐Baranova, Leyla, Novotny, Stephanie E., Oberwelland Weiss, Eileen, Schwarz, Lena, General Paediatrics, ARD - Amsterdam Reproduction and Development, Radiology and Nuclear Medicine, APH - Mental Health, APH - Personalized Medicine, ANS - Brain Imaging, ANS - Compulsivity, Impulsivity & Attention, ENIGMA ADHD Working Group, Ambrosino, S., Banaschewski, T., Bandeira, C.E., Bau, CHD, Baumeister, S., Baur-Streubel, R., Bellgrove, M.A., Biederman, J., Bralten, J., Bramati, I.E., Brandeis, D., Berm, S., Busatto, G.F., Calvo, A., Castellanos, F.X., Cercignani, M., Chantiluke, K.C., Christakou, A., Coghill, D., Conzelmann, A., Cubillo, A.I., Cupertino, R.B., de Zeeuw, P., Durston, S., Earl, E.A., Epstein, J.N., Ethofer, T., Fallgatter, A.J., Fair, D.A., Faraone, S.V., Frodl, T., Gabel, M.C., Gogberashvili, T., Grevet, E.H., Haavik, J., Harrison, N.A., Hartman, C.A., Heslenfeld, D.J., Hoekstra, P.J., Høvik, M.F., Jahanshad, N., Kardatzki, B., Karkashadze, G., Kelly, C., Kohls, G., Konrad, K., Kuntsi, J., Lazaro, L., Lera-Miguel, S., Lesch, K.P., Louza, M.R., Lundervold, A.J., Malpas, C.B., Mattos, P., McCarthy, H., Nicolau, R., Nigg, J.T., O'Gorman Tuura, R.L., Oosterlaan, J., Oranje, B., Paloyelis, Y., Pauli, P., Picon, F.A., Plessen, K.J., Ramos-Quiroga, J.A., Reif, A., Reneman, L., Rosa, PGP, Rubia, K., Schrantee, A., Schweren, LJS, Seitz, J., Shaw, P., Silk, T.J., Skokauskas, N., Carlos Soliva Vila, J., Soloveva, A., Stevens, M.C., Sudre, G., Tamm, L., Thompson, P.M., Tovar-Moll, F., van Erp, T.G., Vance, A., Vilarroya, O., Vives-Gilabert, Y., von Polier, G.G., Walitza, S., Yoncheva, Y.N., Zanetti, M.V., Ziegler, G.C., Anikin, A., Asherson, P., Baranov, A., Chaim-Avanicini, T., Dale, A.M., Doyle, A.E., L Jernigan, T., Hohmann, S., Kapilushniy, D., Mehta, M., Namazova-Baranova, L., Novotny, S.E., Oberwelland Weiss, E., and Schwarz, L.

Subjects
Adult, Attention Deficit Disorder with Hyperactivity/diagnostic imaging, Attention Deficit Disorder with Hyperactivity/epidemiology, Brain/diagnostic imaging, Case-Control Studies, Female, Humans, Magnetic Resonance Imaging, Male, Thalamus/diagnostic imaging, ADHD, community detection, effect sizes, neuroanatomic heterogeneity, subcortical volume, INCREASED EFFECT, 0302 clinical medicine, Limbic system, Neurodevelopmental disorder, Thalamus, 130 000 Cognitive Neurology & Memory, Basal ganglia, Developmental and Educational Psychology, Psychology, Pediatric, 0303 health sciences, 05 social sciences, Brain, Exploratory factor analysis, Psychiatry and Mental health, Mental Health, medicine.anatomical_structure, Attention Deficit Disorder (ADD), Cognitive Sciences, Original Article, 050104 developmental & child psychology, Clinical psychology, Clinical Sciences, Patient subgroups, Developmental & Child Psychology, 03 medical and health sciences, ENIGMA ADHD Working Group, Clinical Research, mental disorders, medicine, In patient, 0501 psychology and cognitive sciences, ddc:610, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Neurosciences, Case-control study, Original Articles, medicine.disease, Attention Deficit Hyperactivity Disorder (ADHD), Brain Disorders, Attention Deficit Disorder with Hyperactivity, Sample size determination, Pediatrics, Perinatology and Child Health, Etiology, business, 030217 neurology & neurosurgery
Abstract

The journal of child psychology and psychiatry 62(9), 1140-1149 (2021). doi:10.1111/jcpp.13384, Published by Wiley-Blackwell, Oxford

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36. Attention-deficit/hyperactivity disorder and smoking habits in pregnant women

Author

Andersson, Anneli, Hegvik, Tor-Arne, Chen, Qi, Rosenqvist, Mina A., Kvalvik, Liv Grimstvedt, Almqvist, Catarina, D’Onofrio, Brian M., Hartman, Catharina, Klungsøyr, Kari, Haavik, Jan, Tuvblad, Catherine, Larsson, Henrik, and Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE)

Subjects
European People, Pulmonology, Maternal Health, CHILDHOOD, Social Sciences, Geographical locations, Cohort Studies, Habits, Labor and Delivery, Pregnancy, Risk Factors, ADOLESCENTS, Medicine and Health Sciences, Smoking Habits, Psychology, Ethnicities, Public and Occupational Health, MATERNAL SMOKING, RISK, Norway, Obstetrics and Gynecology, PREVALENCE, Europe, Neurology, Medicine, Female, Research Article, GENES, Norwegian People, Substance-Related Disorders, Science, Pregnancy Trimester, Third, Neuropsychiatric Disorders, BEHAVIORS, Developmental Neuroscience, mental disorders, Mental Health and Psychiatry, Tobacco Smoking, Humans, European Union, Sweden, Behavior, Siblings, Biology and Life Sciences, Smoking Related Disorders, Pregnancy Trimester, First, Neurodevelopmental Disorders, Attention Deficit Disorder with Hyperactivity, Birth, Women's Health, Adhd, Population Groupings, Smoking Cessation, CIGARETTE-SMOKING, People and places, Neuroscience
Abstract

BackgroundAttention-deficit/hyperactivity disorder (ADHD) has been associated with an increased risk of tobacco smoking, and more difficulties with smoking cessation compared to non-ADHD individuals. Women with ADHD may therefore show elevated rates of smoking during pregnancy.AimsTo examine the association between ADHD and smoking habits among pregnant women in Sweden and Norway.MethodsWomen pregnant for the first time were identified in Sweden (n = 622,037), and Norway (n = 293,383), of which 1.2% (n = 7,444), and 1.7% (n = 4,951) were defined as having ADHD, respectively. Data on smoking habits were collected early and late in pregnancy.ResultsIn Sweden, ADHD was associated with an increased risk of smoking early in pregnancy, adjusted risk ratio (adjRR) 2.69 (95% confidence interval, 2.58-2.81), and late in pregnancy, adjRR 2.95 (2.80-3.10). Similar findings were observed in the Norwegian data, early in pregnancy, adjRR 2.31 (2.21-2.40), and late in pregnancy, adjRR 2.56 (2.42-2.70). Women with ADHD were more likely to continue smoking during pregnancy, compared to women without ADHD, both in Sweden adjRR 1.13 (1.10-1.17), and in Norway, adjRR 1.16 (1.12-1.20). Having a sibling diagnosed with ADHD was associated with an increased risk of smoking early and late in pregnancy, in both Sweden and Norway.ConclusionsWomen with ADHD are considerably more likely to smoke early and late in (their first) pregnancy and are less likely to stop smoking between the two time points. Smoking, early and late in pregnancy, co-aggregates in families with ADHD. Smoking prevention and intervention programs should be targeted towards women with ADHD, specifically during their childbearing years, to ensure better mother and child outcomes.

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37. Virtual Ontogeny of Cortical Growth Preceding Mental Illness

Author

Yash Patel, Jean Shin, Christoph Abé, Ingrid Agartz, Clara Alloza, Dag Alnæs, Sonia Ambrogi, Linda A. Antonucci, Celso Arango, Volker Arolt, Guillaume Auzias, Rosa Ayesa-Arriola, Nerisa Banaj, Tobias Banaschewski, Cibele Bandeira, Zeynep Başgöze, Renata Basso Cupertino, Claiton H.D. Bau, Jochen Bauer, Sarah Baumeister, Fabio Bernardoni, Alessandro Bertolino, Caterina del Mar Bonnin, Daniel Brandeis, Silvia Brem, Jason Bruggemann, Robin Bülow, Juan R. Bustillo, Sara Calderoni, Rosa Calvo, Erick J. Canales-Rodríguez, Dara M. Cannon, Susanna Carmona, Vaughan J. Carr, Stanley V. Catts, Sneha Chenji, Qian Hui Chew, David Coghill, Colm G. Connolly, Annette Conzelmann, Alexander R. Craven, Benedicto Crespo-Facorro, Kathryn Cullen, Andreas Dahl, Udo Dannlowski, Christopher G. Davey, Christine Deruelle, Covadonga M. Díaz-Caneja, Katharina Dohm, Stefan Ehrlich, Jeffery Epstein, Tracy Erwin-Grabner, Lisa T. Eyler, Jennifer Fedor, Jacqueline Fitzgerald, William Foran, Judith M. Ford, Lydia Fortea, Paola Fuentes-Claramonte, Janice Fullerton, Lisa Furlong, Louise Gallagher, Bingchen Gao, Si Gao, Jose M. Goikolea, Ian Gotlib, Roberto Goya-Maldonado, Hans J. Grabe, Melissa Green, Eugenio H. Grevet, Nynke A. Groenewold, Dominik Grotegerd, Oliver Gruber, Jan Haavik, Tim Hahn, Ben J. Harrison, Walter Heindel, Frans Henskens, Dirk J. Heslenfeld, Eva Hilland, Pieter J. Hoekstra, Sarah Hohmann, Nathalie Holz, Fleur M. Howells, Jonathan C. Ipser, Neda Jahanshad, Babette Jakobi, Andreas Jansen, Joost Janssen, Rune Jonassen, Anna Kaiser, Vasiliy Kaleda, James Karantonis, Joseph A. King, Tilo Kircher, Peter Kochunov, Sheri-Michelle Koopowitz, Mikael Landén, Nils Inge Landrø, Stephen Lawrie, Irina Lebedeva, Beatriz Luna, Astri J. Lundervold, Frank P. MacMaster, Luigi A. Maglanoc, Daniel H. Mathalon, Colm McDonald, Andrew McIntosh, Susanne Meinert, Patricia T. Michie, Philip Mitchell, Ana Moreno-Alcázar, Bryan Mowry, Filippo Muratori, Leila Nabulsi, Igor Nenadić, Ruth O'Gorman Tuura, Jaap Oosterlaan, Bronwyn Overs, Christos Pantelis, Mara Parellada, Jose C. Pariente, Paul Pauli, Giulio Pergola, Francesco Maria Piarulli, Felipe Picon, Fabrizio Piras, Edith Pomarol-Clotet, Clara Pretus, Yann Quidé, Joaquim Radua, J. Antoni Ramos-Quiroga, Paul E. Rasser, Andreas Reif, Alessandra Retico, Gloria Roberts, Susan Rossell, Diego Luiz Rovaris, Katya Rubia, Matthew D. Sacchet, Josep Salavert, Raymond Salvador, Salvador Sarró, Akira Sawa, Ulrich Schall, Rodney Scott, Pierluigi Selvaggi, Tim Silk, Kang Sim, Antonin Skoch, Gianfranco Spalletta, Filip Spaniel, Dan J. Stein, Olaf Steinsträter, Aleks Stolicyn, Yoichiro Takayanagi, Leanne Tamm, Maria Tavares, Alexander Teumer, Katharina Thiel, Sophia I. Thomopoulos, David Tomecek, Alexander S. Tomyshev, Diana Tordesillas-Gutiérrez, Michela Tosetti, Anne Uhlmann, Tamsyn Van Rheenen, Javier Vazquez-Bourgón, Meike W. Vernooij, Eduard Vieta, Oscar Vilarroya, Cynthia Weickert, Thomas Weickert, Lars T. Westlye, Heather Whalley, David Willinger, Alexandra Winter, Katharina Wittfeld, Tony T. Yang, Yuliya Yoncheva, Jendé L. Zijlmans, Martine Hoogman, Barbara Franke, Daan van Rooij, Jan Buitelaar, Christopher R.K. Ching, Ole A. Andreassen, Elena Pozzi, Dick Veltman, Lianne Schmaal, Theo G.M. van Erp, Jessica Turner, F. Xavier Castellanos, Zdenka Pausova, Paul Thompson, Tomas Paus, Pediatric surgery, Anatomy and neurosciences, Psychiatry, Amsterdam Neuroscience - Brain Imaging, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, General Paediatrics, ARD - Amsterdam Reproduction and Development, Paediatrics, Radiology & Nuclear Medicine, Epidemiology, Clinical Cognitive Neuropsychiatry Research Program (CCNP), German Research Foundation, University of Münster, National Health and Medical Research Council (Australia), University of Cape Town, National Research Foundation (South Africa), Swinburne Universit, Jack Brockhoff Foundation, University of Melbourne, Barbara Dicker Brain Sciences Foundation, Rebecca L. Cooper Foundation, Society of Mental Health Research, Swedish Research Council, Swedish Foundation for Strategic Research, Swedish Brain Foundation, Health Research Board (Ireland), Russian Foundation for Basic Research, University of Zurich, Pratt Foundation, Ramsay Health Care, Viertel Charitable Foundation, Schizophrenia Research Institute, European Commission, Australian Research Council, Instituto de Salud Carlos III, National Institute for Health and Care Research (US), National Institute for Health Research (UK), Ministry of Health of the Czech Republic, Bill & Melinda Gates Foundation, South African Medical Research Council, Carnegie Corporation of New York, Wellcome Trust, Medical Research Council (UK), Medical Research Scotland, Netherlands Organization for Scientific Research, Ambrogi, Sonia, Banaschewski, Tobias, Bandeira, Cibele Edom, Cupertino, Renata, Calderoni, Sara, Cannon, Dara, Carr, Vaughan, Chew, Qian Hui, Coghill, David, Cullen, Kathryn, Dahl, Andreas, Epstein, Jeffery, Foran, William, Fortea, Lydia, Fuentes-Claramonte, Paola, Fullerton, Janice M., Furlong, Lisa, Gallagher, Louise, Gao, Si, Gotlib, Ian, Haavik, Jan, Henskens, Frans, Hilland, Eva, Hoekstra, Pieter J, Howells, Fleur M, Ipser, Jonathan, Jørgensen, Jes Kristian, Karantonis, James A., Lawrie, Stephen, Research Institute of the Hospital for Sick Children and University of Toronto, University of Toronto, Departments of Physiology and Nutritional Sciences, University of Toronto, Toronto, Canada, KG Jebsen Centre for Psychosis Research, University of Oslo (UiO)-Institute of Clinical Medicine-Oslo University Hospital [Oslo], Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Mental Health Sciences Unit, University College of London [London] (UCL), Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Clinical and Behavioral Neurology - Neuroscienze e riabilitazione, IRCCS Fondazione Santa Lucia [Roma], Heidelberg University, Universidade Federal do Rio Grande do Sul [Porto Alegre] (UFRGS), Universität Heidelberg [Heidelberg] = Heidelberg University, Clinical Neuropsychology, IBBA, APH - Mental Health, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Hospital Sant Joan de Déu [Barcelona], and Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM)

Subjects
Bipolar Disorder, Autism Spectrum Disorder, [SDV]Life Sciences [q-bio], Neurogenesis, pathology [Premature Birth], Neurodevelopment, Cortical surface area, pathology [Autism Spectrum Disorder], Cortical growth, methods [Magnetic Resonance Imaging], SDG 3 - Good Health and Well-being, Pregnancy, 130 000 Cognitive Neurology & Memory, Humans, ddc:610, Child, Biological Psychiatry, Cerebral Cortex, pathology [Depressive Disorder, Major], Depressive Disorder, Major, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Infant, Newborn, Magnetic Resonance Imaging, Mental illness, Attention Deficit Disorder with Hyperactivity, Premature Birth, genetics [Autism Spectrum Disorder], Female, Psychiatric disorders, 170 000 Motivational & Cognitive Control
Abstract

[Background]: Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life., [Methods]: Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed., [Results]: Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth., [Conclusions]: Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy., This work was supported by the German Research Foundation (DFG Grant Nos. HA7070/2-2, HA7070/3, HA7070/4 [to TH]) and IZKF of the medical faculty of Münster (Grants No. Dan3/012/17 [to UD] and MzH 3/020/20 [to TH]), and NHMRC projects (Grant No. 1064643 [to BJH] and 1024570 [to CGD]). The CIAM study was supported by the University of Cape Town Research Committee, South African National Research Foundation, and the South African Medical Research Council (principal investigator [PI], Fleur M. Howells) and Grant No. R01MH117601 (to NJ). This work was funded by the German Research Foundation (Grant Nos. FOR2107 JA 1890/7-1 and FOR2107 JA 1890/7-2 [to AJ]) and Swinburne University scholarship/Australian Postgraduate Award (to JK). Collection of the COGSBD cohort was funded by the Jack Brockhoff Foundation, University of Melbourne, Barbara Dicker Brain Sciences Foundation, Rebecca L Cooper Foundation, and the Society of Mental Health Research (to JK). This work was funded by the German Research Foundation (Grant Nos. FOR2107 KI588/14-1 and FOR2107 KI588/14-2 [to TK]). The St. Göran study was supported by grants from the Swedish Research Council (Grant No. 2018-02653 [to ML]), the Swedish foundation for Strategic Research (Grant No. KF10-0039 [to ML]), the Swedish Brain foundation (Grant No. FO2020-0261 [to ML]), and the Swedish Government under the LUA/ALF agreement (Grant Nos. ALF 20170019 and ALFGBG-716801 [to ML]). This work was supported by RFBR (Grant No. 20-013-00748 [to IL, AST]) and funded by the Health Research Board (Grant No. HRA_POR/2011/100 [to CM]). The Australian Schizophrenia Research Bank (ASRB) was supported by the NHMRC (Enabling Grant No. 386500), the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation, and the Schizophrenia Research Institute. Chief investigators for ASRB were VC, US, RSc, AJ, BM, PTM, SVC, FH, and CPa. This work was supported by Deutsche Forschungsgemeinschaft (Grant Nos. DFG NE 2254/2-1, NE 2254/3-1, NE2254/4-1 [to IN]), the University Research Priority Program “Integrative Human Physiology” at the University of Zurich (to ROT), an NHMRC Senior Principal Research Fellowship (Grant No. 1105825 [to CPa]), an NHMRC L3 Investigator Grant (Grant No. 1196508 [to CPa]), and NHMRC Program Grant (Grant No. 1150083 [to CPa]). ASRB was supported by the NHMRC (Enabling Grant No. 386500), the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation and the Schizophrenia Research Institute. Chief investigators for ASRB were VC, US, RSc, AJ, BM, PTM, SVC, FH, and CPa. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant (Agreement No. 798181 [to GP]). ASRB was supported by the NHMRC (Enabling Grant, ID 386500), the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation and the Schizophrenia Research Institute. Chief investigators for ASRB were VC, US, RSc, AJ, BM, PTM, SVC, FH, and CPa. The Imaging Genetics in Psychosis study was funded by Project Grants from the NHMRC (Grant Nos. APP630471 and APP1081603 [to YQ]) and the Macquarie University’s Australian Research Council (ARC) Centre of Excellence in Cognition and its Disorders (Grant No. CE110001021 [to YQ]). This work was supported by the Spanish Ministry of Science, Innovation and Universities/Economy and Competitiveness/Instituto de Salud Carlos III (Grant Nos. PI11/01766 and CPII19/00009 [to JR]), co-financed by European Regional Development Fund funds from the European Commission (“A Way of Making Europe”). ASRB was supported by the NHMRC (Enabling Grant No. 386500), the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation, and the Schizophrenia Research Institute. Chief investigators for ASRB were VC, US, RSc, AJ, BM, PTM, SVC, FH, and CPa. SR was supported by an NHMRC Senior Fellowship (Grant No. GNT1154651). Collection of the COGSBD cohort was funded by the Jack Brockhoff Foundation, University of Melbourne, Barbara Dicker Brain Sciences Foundation, Rebecca L Cooper Foundation, and the Society of Mental Health Research (to SR). This work was supported by NIHR; MRC (to KR), NIH (Grant Nos. MH-094268, MH-105660, and MH-107730 [to ASS]). The Neuroimaging of the Children's Attention Project cohort was funded by NHMRC, Australia (Grant No. 1065895). Earlier funding for the cohort as also provided by NHMRC (Grant No. 1008522) and a grant from the Collier Foundation. The ACPU cohort was funded by NHMRC, Australia (Project Grant Nos. 384419 and 569533 [to TS]). This work was supported by research grants from the National Healthcare Group, Singapore (Grant Nos. SIG/05004, SIG/05028, and SIG /1103), and the Singapore Bioimaging Consortium (RP C009/2006 [to KS]), and the Ministry of Health, Czech Republic - conceptual development of research organization (“Institute for Clinical and Experimental Medicine - IKEM, IN 00023001” [to ASk]). This study was supported by the Italian Ministry of Health (Grant No. RC/17-18-19-20-21/A [to GS]) and Ministry of Health of the Czech Republic (Grant No. NU20-04-00393 [to FS]). The Drakenstein Child Health Study (DCHS) cohort is funded by the Bill and Melinda Gates Foundation (Grant No. OPP 1017641) and the South African Medical Research Council. This DCHS contribution was made possible in part by a grant from Carnegie Corporation of New York. The statements made and views expressed are solely the responsibility of the author (DJS). STRADL study was supported and funded by the Wellcome Trust Strategic Award “Stratifying Resilience and Depression Longitudinally” (Grant No. 104036/Z/14/Z), and the Medical Research Council Mental Health Pathfinder Award “Leveraging routinely collected and linked research data to study the causes and consequences of common mental disorders” (MRC, Grant No. MC_PC_17209). Scottish Bipolar Family Study (SBFS) was supported by National Health Service Research Scotland, through the Scottish Mental Health Research Network (www.smhrn.org.uk), who provided assistance with subject recruitment and assessments. SBFS was conducted at the Brain Research Imaging Centre (http://www.bric.ed.ac.uk), which is supported by SINAPSE (Scottish Imaging Network, a Platform for Scientific Excellence, http://www.sinapse.ac.uk). Processing of the datasets used the resources provided by the Edinburgh Compute and Data Facility (http://www.ecdf.ed.ac.uk/) (ASt). TVR was supported by an NHMRC Early Career Fellowship (Grant No. GNT1088785). Collection of the COGSBD cohort was funded by the Jack Brockhoff Foundation, University of Melbourne, Barbara Dicker Brain Sciences Foundation, Rebecca L Cooper Foundation, and the Society of Mental Health Research (to TVR). EV was supported by the Spanish Ministry of Science and Innovation (PI18/00805) integrated into the Plan Nacional de I+D+I and co-financed by the ISCIII-Subdirección General de Evaluación and the FEDER; the Instituto de Salud Carlos III; the CIBERSAM (Centro de Investigación Biomédica en Red de Salud Mental); by the CERCA Programme/Generalitat de Catalunya and the Secretaria d’Universitats i Recerca del Departament d’Economia I Coneixement (Grant No. 2017SGR1355). This study was also supported by the Departament de Salut de la Generalitat de Catalunya, Pla Estratègic de Recerca i Innovació en Salut (PERIS) 2016-2020 (Grant No. SLT006/17/00345) and the European Union Horizon 2020 research and innovation program (EU.3.1.1. Understanding health, wellbeing and disease: Grant Nos. 754907 and EU.3.1.3 [to EB]; Treating and managing disease: Grant No. 945151 [to EV]). This study was supported by the National Center for Complementary and Integrative Health (Grant Nos. R21AT009173 and R61AT009864 [to TTY]); by the National Center for Advancing Translational Sciences (CTSI), National Institutes of Health, through UCSF-CTSI (Grant No. UL1TR001872 [to TTY]); by the American Foundation for Suicide Prevention (Grant No. SRG-1-141-18 [to TTY]); by UCSF Research Evaluation and Allocation Committee (REAC) and J. Jacobson Fund (to TTY); by the NIMH (Grant No. R01MH085734 [to TTY]); and by the Brain and Behavior Research Foundation (formerly NARSAD) (to TTY). This work was supported by a personal Veni grant to MH from the Netherlands Organization for Scientific Research (NWO, Grant No. 91619115 [to MH]) and European Community’s Horizon 2020 Programme (H2020/2014 – 2020) (Grant Agreements Nos. 667302 [CoCA], 728018 [Eat2beNICE], and 847879 [PRIME] [to BF]). JBu has been supported by the EU-AIMS (European Autism Interventions) and AIMS-2-TRIALS programmes, which receive support from Innovative Medicines Initiative Joint Undertaking Grant Nos. 115300 and 777394, the resources of which are composed of financial contributions from the European Union’s FP7 and Horizon 2020 Programmes, and from the European Federation of Pharmaceutical Industries and Associations companies’ in-kind contributions, and AUTISM SPEAKS, Autistica and SFARI; and by the Horizon 2020–supported programme CANDY (Grant No. 847818 [to JBu]). This work is supported by Grant No. NIA T32AG058507 and NIH Grant No. U54EB020403 from the Big Data to Knowledge (BD2K) Program (to CRKC). ENIGMA MDD work is supported by NIH (Grant Nos. U54 EB020403 [to PT], R01 MH116147 [to PT], and R01 MH117601 [to NJ and LS]). LS was supported by an NHMRC Career Development Fellowship (Grant No. 1140764). This work was supported by the National Center for Research Resources at the NIH (Grant Nos. NIH 1 U24 RR021992 [Function Biomedical Informatics Research Network], NIH 1 U24 RR025736-01 [Biomedical Informatics Research Network Coordinating Center; http://www.birncommunity.org]). TGMvE is supported by ENIGMA’s NIH BD2K initiative (Grant No. U54 EB020403), ENIGMA Sex Differences (Grant No. R01MH116147), and ENIGMA-COINSTAC: Advanced Worldwide Transdiagnostic Analysis of Valence System Brain Circuits (Grant No. R01MH121246). This work was supported by the NIH (Grant No. R01MH121246 [to JT, Calhoun, and TGMvE]). This work was supported in part by NIH (Grant No. U54 EB020403 [to PT]).

Published
2022

38. Genetic association study of childhood aggression across raters, instruments, and age

Author

Nicholas G. Martin, S. Alexandra Burt, Louise Arseneault, Fazil Aliev, Luke M. Evans, Hill F. Ip, Beate St Pourcain, Michel G. Nivard, William E. Copeland, Rebecca K. Vinding, Scott Gordon, Koen Bolhuis, Christian J. Hopfer, Gun Peggy Knudsen, Stefan Johansson, Avshalom Caspi, Richard Border, Chandra A. Reynolds, Pål R. Njølstad, Liisa Keltikangas-Järvinen, Dorret I. Boomsma, Klaus Bønnelykke, Teemu Palviainen, Marta Ribasés, Alina Rodriguez, Catharina A. Hartman, Ilkka Seppälä, Christel M. Middeldorp, Rosa Bosch, Jan Haavik, Gail M. Williams, Andrea G. Allegrini, Ruth Ks, John R. B. Perry, Hadi Zafarmand, Chang Jiang, Elizabeth J. Costello, Camiel M. van der Laan, Olli T. Raitakari, Miquel Casas, Isabell Brikell, William G. Iacono, Jaakko Kaprio, John K. Hewitt, Andrew C. Heath, Eero Vuoksimaa, Xiaoran Tong, Gemma Español, Erik A. Ehli, Richie Poulton, Gareth E. Davies, Albertine J. Oldehinkel, Hans Bisgaard, Naomi R. Wray, Ted Reichborn-Kjennerud, Robert Plomin, Michael C. Stallings, Qing Lu, Jackob M. Najman, Daniel E. Adkins, Yi Lu, Harold Snieder, Sally J. Wadsworth, Alexander Neumann, Alexandra Havdahl, Karen Sugden, Kelly L. Klump, Andrew Smolen, Henrik Larsson, Toos C. E. M. van Beijsterveldt, Kenneth Krauter, Tarunveer S. Ahluwalia, Tellervo Korhonen, Andrey A. Shabalin, Joachim Heinrich, Anke R. Hammerschlag, Shelby Marrington, Lærke Sass, Pamela A. F. Madden, Henning Tiemeier, Tanja Vrijkotte, Paul Lichtenstein, Terho Lehtimäki, Ville Karhunen, Cristina Sánchez-Mora, Robin P. Corley, Anna A. E. Vinkhuyzen, Richard J. Rose, Per Magnus, Sabrina Llop, Ilja M. Nolte, S.A. Brown, Christian Hakulinen, Anjali K. Henders, Marie Standl, Silvia Alemany, Gretchen R.B. Saunders, Jouke-Jan Hottenga, Eveline L. de Zeeuw, Meike Bartels, Elisabeth Thiering, José J. Morosoli, Fiona A. Hagenbeek, Laura Pulkki-Råback, Frank C. Verhulst, Martin A. Kennedy, Craig E. Pennell, Eva Krapohl, Kaili Rimfeld, Tetyana Zayats, Lucía Colodro-Conde, Judith B.M. Ensink, André G. Uitterlinden, Natalia Vilor-Tejedor, Felix R. Day, Jennifer R. Harris, George Davey Smith, Qi Chen, Sebastian Lundström, Marjo-Riitta Järvelin, Alyce M. Whipp, Katrina L. Grasby, L. John Horwood, John Pearson, Judy L. Silberg, Paula Rovira, Hermine H. Maes, Carol A. Wang, Roseann E. Peterson, Tamara L. Wall, Andrew J. O. Whitehouse, Maria-Jose Lopez-Espinosa, Najaf Amin, Jess Tyrrell, Danielle M. Dick, Sarah E. Medland, Allison L. Miller, Øyvind Helgeland, Josep Antoni Ramos Quiroga, Joseph M. Boden, Abdullah Mamun, James Scott, María Soler Artigas, Joseph A. Prinz, Lindon J. Eaves, Terrie E. Moffitt, Matt McGue, Jordi Sunyer, Joanna Martin, Tampere University, Clinical Medicine, Department of Clinical Chemistry, Apollo-University Of Cambridge Repository, Ip, Hill F [0000-0003-1991-5019], Sánchez-Mora, Cristina [0000-0003-4211-1107], Nolte, Ilja M [0000-0001-5047-4077], St Pourcain, Beate [0000-0002-4680-3517], Palviainen, Teemu [0000-0002-7847-8384], Colodro-Conde, Lucía [0000-0002-9004-364X], Gordon, Scott [0000-0001-7623-328X], Aliev, Fazil [0000-0001-8357-4699], Karhunen, Ville [0000-0001-6064-1588], Border, Richard [0000-0002-6293-2968], Ahluwalia, Tarunveer S [0000-0002-7464-3354], Day, Felix R [0000-0003-3789-7651], Hottenga, Jouke-Jan [0000-0002-5668-2368], Rimfeld, Kaili [0000-0001-5139-065X], Lu, Yi [0000-0001-9933-3654], Soler Artigas, María [0000-0002-3213-1107], Bosch, Rosa [0000-0002-7596-183X], Ramos Quiroga, Josep Antoni [0000-0003-1622-0350], Neumann, Alexander [0000-0001-6653-3203], Grasby, Katrina [0000-0001-8539-0228], Middeldorp, Christel [0000-0002-6218-0428], Evans, Luke M [0000-0002-7458-1720], Alemany, Silvia [0000-0002-7925-6767], Sass, Lærke [0000-0002-5217-7014], Ruth, Kate [0000-0003-4966-9170], Ehli, Erik A [0000-0002-7865-3015], Hagenbeek, Fiona A [0000-0002-8773-0430], Snieder, Harold [0000-0003-1949-2298], Uitterlinden, André G [0000-0002-7276-3387], Haavik, Jan [0000-0001-7865-2808], Johansson, Stefan [0000-0002-2298-7008], Knudsen, Gun Peggy S [0000-0002-6193-4291], Njolstad, Pal Rasmus [0000-0003-0304-6728], Rodriguez, Alina [0000-0003-1209-8802], Brown, Sandy [0000-0001-8780-0323], Miller, Allison [0000-0003-3816-2251], Keltikangas-Järvinen, Liisa [0000-0002-7977-3852], Havdahl, Alexandra [0000-0002-9268-0423], Perry, John RB [0000-0001-6483-3771], Lehtimäki, Terho [0000-0002-2555-4427], Arseneault, Louise [0000-0002-2938-2191], Boden, Joseph [0000-0003-1502-1608], Pearson, John [0000-0001-5607-4517], Kennedy, Martin [0000-0002-6445-8526], Poulton, Richie [0000-0002-1052-4583], Copeland, William E [0000-0002-1348-7781], Wray, Naomi [0000-0001-7421-3357], Järvelin, Marjo-Riitta [0000-0002-2149-0630], McGue, Matt [0000-0002-5580-1433], Pennell, Craig E [0000-0002-0937-6165], Dick, Danielle M [0000-0002-1636-893X], Martin, Nicholas G [0000-0003-4069-8020], Medland, Sarah E [0000-0003-1382-380X], Kaprio, Jaakko [0000-0002-3716-2455], Tiemeier, Henning [0000-0002-4395-1397], Davey Smith, George [0000-0002-1407-8314], Oldehinkel, Albertine J [0000-0003-3925-3913], Ribasés, Marta [0000-0003-1039-1116], Lichtenstein, Paul [0000-0003-3037-5287], Plomin, Robert [0000-0002-0756-3629], Bartels, Meike [0000-0002-9667-7555], Nivard, Michel G [0000-0003-2015-1888], Boomsma, Dorret I [0000-0002-7099-7972], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Child and Adolescent Psychiatry / Psychology, Epidemiology, Internal Medicine, Institute for Molecular Medicine Finland, Genetic Epidemiology, Helsinki Institute of Life Science HiLIFE, University of Helsinki, Tellervo Korhonen / Principal Investigator, Cognitive and Brain Aging, Faculty Common Matters (Faculty of Medicine), Medicum, Doctoral Programme in Cognition, Learning, Instruction and Communication, Department of Psychology and Logopedics, Helsinki Inequality Initiative (INEQ), Faculty Common Matters (Faculty of Education), Psychosocial factors and health, Behavioural Sciences, Department of Public Health, Adult Psychiatry, Epidemiology and Data Science, APH - Aging & Later Life, APH - Methodology, ARD - Amsterdam Reproduction and Development, Graduate School, Child Psychiatry, ACS - Pulmonary hypertension & thrombosis, ANS - Cellular & Molecular Mechanisms, ANS - Compulsivity, Impulsivity & Attention, Public and occupational health, APH - Health Behaviors & Chronic Diseases, Institut Català de la Salut, [Ip HF] Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. [van der Laan CM] Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. Netherlands Institute for the Study of Crime and Law Enforcement, Amsterdam, The Netherlands. [Krapohl EML] Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK. [Brikell I] Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. [Sánchez-Mora C, Soler Artigas M, Rovira P, Ribasés M] Servei de Psiquiatria, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Barcelona, Spain. Unitat de Genètica Psiquiàtrica, Grup de Recerca en Psiquiatria, Salut Mental i Addicció, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Nolte IM] Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. [Bosch R] Servei de Psiquiatria, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Barcelona, Spain. Servei de Psiquiatria i Medicina Legal, Universitat Autònoma de Barcelona, Bellaterra, Spain. [Español G] Servei de Psiquiatria, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Ramos Quiroga JA, Ribasés M] Servei de Psiquiatria, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Barcelona, Spain. Unitat de Genètica Psiquiàtrica, Grup de Recerca en Psiquiatria, Salut Mental i Addicció, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Servei de Psiquiatria i Medicina Legal, Universitat Autònoma de Barcelona, Bellaterra, Spain, Vall d'Hebron Barcelona Hospital Campus, Biological Psychology, APH - Personalized Medicine, APH - Mental Health, Amsterdam Reproduction & Development, Perry, John R B [0000-0001-6483-3771], Ip, Hill F. [0000-0003-1991-5019], Nolte, Ilja M. [0000-0001-5047-4077], Ahluwalia, Tarunveer S. [0000-0002-7464-3354], Day, Felix R. [0000-0003-3789-7651], Evans, Luke M. [0000-0002-7458-1720], Ehli, Erik A. [0000-0002-7865-3015], Hagenbeek, Fiona A. [0000-0002-8773-0430], Uitterlinden, André G. [0000-0002-7276-3387], Knudsen, Gun Peggy S. [0000-0002-6193-4291], Perry, John R. B. [0000-0001-6483-3771], Copeland, William E. [0000-0002-1348-7781], Pennell, Craig E. [0000-0002-0937-6165], Dick, Danielle M. [0000-0002-1636-893X], Martin, Nicholas G. [0000-0003-4069-8020], Medland, Sarah E. [0000-0003-1382-380X], Oldehinkel, Albertine J. [0000-0003-3925-3913], Nivard, Michel G. [0000-0003-2015-1888], and Boomsma, Dorret I. [0000-0002-7099-7972]

Subjects
0301 basic medicine, DISORDER, 45/43, Genome-wide association study, 3124 Neurology and psychiatry, 0302 clinical medicine, Child, Psychiatry, 0303 health sciences, trastornos mentales [PSIQUIATRÍA Y PSICOLOGÍA], HERITABILITY, Mental Disorders, Cognition, Genomics, Explained variation, Justice and Strong Institutions, Aggression, Psychiatry and Mental health, Meta-analysis, ADOLESCENCE, Child, Preschool, conducta y mecanismos de la conducta::conducta::síntomas conductuales::agresión [PSIQUIATRÍA Y PSICOLOGÍA], 631/208/212, Female, Biological psychiatry, medicine.symptom, Life Sciences & Biomedicine, Investigative Techniques::Genetic Techniques::Genetic Association Studies [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], BEHAVIOR, RC321-571, Childhood aggression, Clinical psychology, SDG 16 - Peace, Adolescent, Mental Disorders [PSYCHIATRY AND PSYCHOLOGY], Neurosciences. Biological psychiatry. Neuropsychiatry, Single-nucleotide polymorphism, Biology, 3121 Internal medicine, Malalties mentals - Aspectes genètics, Genetic correlation, Article, 1117 Public Health and Health Services, Cellular and Molecular Neuroscience, 03 medical and health sciences, 631/477/2811, SDG 3 - Good Health and Well-being, Human behaviour, medicine, SNP, Humans, GENOME-WIDE ASSOCIATION, Biological Psychiatry, Genetic Association Studies, 030304 developmental biology, Genetic association, Retrospective Studies, técnicas de investigación::técnicas genéticas::estudios de asociación genética [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Science & Technology, SDG 16 - Peace, Justice and Strong Institutions, Infant, Behavior and Behavior Mechanisms::Behavior::Behavioral Symptoms::Aggression [PSYCHIATRY AND PSYCHOLOGY], 1103 Clinical Sciences, Agressivitat en els infants, Heritability, 030104 developmental biology, 1701 Psychology, ORIGINS, Research Programm of Donders Centre for Neuroscience, 3111 Biomedicine, TRAJECTORIES, 030217 neurology & neurosurgery, Demography, Genome-Wide Association Study
Abstract

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E–06), PCDH7 (P = 2.0E–06), and IPO13 (P = 2.5E–06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg = 0.46 between self- and teacher-assessment to rg = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range $$\left| {r_g} \right|$$ r g : 0.19–1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg = ~−0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range $$\left| {r_g} \right|$$ r g : 0.46–0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.

Published
2021

39. Subcortical brain volume, regional cortical thickness, and cortical surface area across disorders:Findings from the ENIGMA ADHD, ASD, and OCD working groups

Author

Pedro Moreira, Ruth O'Gorman Tuura, Mara Cercignani, Philip Aherson, Maria Jalbrzikowski, Kate D. Fitzgerald, Declan G. Murphy, Bernd Kardatzki, Christine Ecker, David F. Tolin, Fern Jaspers-Fayer, Pedro Morgado, Juan Carlos Soliva Vila, Kang Ik K. Cho, Kathrin Koch, Timothy J. Silk, Philip R. Szeszko, Thomas Frodl, Mara Parellada, Shlomi Haar, Eileen Daly, Bob Oranje, Anouk Schrantee, Leyla Namazova-Baranova, Joseph A. King, Beatriz Luna, Silvia Brem, Eric Earl, Alasdair Vance, Michela Tosetti, Christine Deruelle, Ramona Baur-Streubel, Jackie Fitzgerald, Kirsten O'Hearn, Michael C. Stevens, Yoshiyuki Hirano, J. Antoni Ramos-Quiroga, Erika L. Nurmi, Kaylita Chantiluke, Joseph O'Neill, Kerstin Kohls, Olga Puig, Devon Shook, Clodagh M. Murphy, Gustavo Sudre, Marlene Behrmann, Jaap Oosterlaan, Tinatin Gogberashvili, Lianne Schmaal, Carles Soriano-Mas, Liesbeth Hoekstra, Ignacio Martínez-Zalacaín, Noam Soreni, Marcel P. Zwiers, Paulo Mattos, Gregor Kohls, Andreas J. Fallgatter, Tiffany M. Chaim-Avancini, Alexander Baranov, S. Evelyn Stewart, Sara Dallaspezia, Gianfranco Spalletta, Jonna Kuntsi, Lizanne J. S. Schweren, Joel T. Nigg, Leanne Tamm, Premika S.W. Boedhoe, Adriana Di Martino, Jane McGrath, Marcelo C. Batistuzzo, Norbert Skokauskas, Filippo Muratori, John Piacentini, Jean-Paul Fouche, Sarah Baumeister, Alan Anticevic, Neil A. Harrison, Christine M. Freitag, Pedro G.P. Rosa, Stephen V. Faraone, Ana Cubillo, David Mataix-Cols, Yuki Sakai, Stefan Ehrlich, Eileen Oberwelland Weiss, Fabrizio Piras, Dirk J. Heslenfeld, Je-Yeon Yun, Paul Pauli, Catharina A. Hartman, Ganesan Venkatasubramanian, Janardhanan C. Narayanaswamy, Charles B Malpas, Jan C. Beucke, José M. Menchón, Egill A. Fridgeirsson, Margot J. Taylor, Mauricio Moller Martinho, H. Blair Simpson, Jan K. Buitelaar, Gerd Kvale, Ivanei E. Bramati, Aki Tsuchiyagaito, Susanne Walitza, Irene Bollettini, Jeffery N. Epstein, Anders M. Dale, Thomas Ethofer, Terry L. Jernigan, David Coghill, Rachel Marsh, Andreas Reif, Astri J. Lundervold, Pieter J. Hoekstra, Oana Georgiana Rus, Damiaan Denys, Gregory L. Wallace, Matt C. Gabel, Hazel McCarthy, Sarah Hohmann, Rosa Nicolau, Stephanie H. Ameis, Neda Jahanshad, Takashi Nakamae, Xin Feng, Emily R. Stern, Georg G. von Polier, Yanni Liu, Paulo Marques, Anushree Bose, Hao Hu, Sara Lera-Miguel, Deniz A. Gürsel, Jochen Seitz, Jos W. R. Twisk, Mario Rodrigues Louzã, Clare Kelly, Annette Conzelmann, Alysa E. Doyle, Odile A. van den Heuvel, Anthony A. James, Chris Perriello, Joost Janssen, Damien A. Fair, Norbert Kathmann, Francisco X. Castellanos, Paul D. Arnold, Oscar Vilarroya, Geraldo F. Busatto, Federica Piras, Pino Alonso, Akiko Nakagawa, Sarah Durston, Lena Schwarz, Mitul A. Mehta, Dan J. Stein, Celso Arango, Daan van Rooij, Ilan Dinstein, Anastasia Christakou, Klaus-Peter Lesch, Kerstin J. Plessen, Jennifer Fedor, Yolanda Vives-Gilabert, Ilaria Gori, Louise Gallagher, Brian P. Brennan, Yuqi Cheng, Barbara Franke, Sabin Khadka, Stephanie E. Novotny, Martine Hoogman, Georgii Karkashadze, Georg C. Ziegler, Yuliya N. Yoncheva, Rosa Calvo, Thomas Wolfers, Marcelo Q. Hoexter, Benjamin A. Ely, Masaru Kuno, Alessandra Retico, Yoshinari Abe, Geoffrey B. Hall, Tobias Banaschewski, Anatoly Anikin, Christine Lochner, Astrid Morer, Guido van Wingen, Jan Haavik, Joseph Biederman, Luisa Lázaro, Francesco Benedetti, Fengfeng Zhou, Guillaume Auzias, Daniel Brandeis, Dmitry Kapilushniy, Katya Rubia, Philip Shaw, Christian Kaufmann, Sara Calderoni, Marcus V. Zanetti, Anastasia Solovieva, Zhen Wang, Francesca Assogna, Jamie D. Feusner, Chaim Huyser, Fernanda Tovar-Moll, Theo G.M. van Erp, Y.C. Janardhan Reddy, Jun Soo Kwon, Yannis Paloyelis, Anna Calvo, Patricia Gruner, Kathrin C. Zierhut, Liesbeth Reneman, Tomohiro Nakao, Janita Bralten, Marie F. Høvik, Mark A. Bellgrove, Maarten Mennes, Paul M. Thompson, Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Epidemiology and Data Science, Pediatric surgery, Radiology and nuclear medicine, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Psychiatry, APH - Methodology, APH - Health Behaviors & Chronic Diseases, Boedhoe, Premika S W, van Rooij, Daan, Hoogman, Martine, Twisk, Jos W R, Schmaal, Lianne, Abe, Yoshinari, Alonso, Pino, Ameis, Stephanie H, Anikin, Anatoly, Anticevic, Alan, Arango, Celso, Arnold, Paul D, Asherson, Philip, Assogna, Francesca, Auzias, Guillaume, Banaschewski, Tobia, Baranov, Alexander, Batistuzzo, Marcelo C, Baumeister, Sarah, Baur-Streubel, Ramona, Behrmann, Marlene, Bellgrove, Mark A, Benedetti, Francesco, Beucke, Jan C, Biederman, Joseph, Bollettini, Irene, Bose, Anushree, Bralten, Janita, Bramati, Ivanei E, Brandeis, Daniel, Brem, Silvia, Brennan, Brian P, Busatto, Geraldo F, Calderoni, Sara, Calvo, Anna, Calvo, Rosa, Castellanos, Francisco X, Cercignani, Mara, Chaim-Avancini, Tiffany M, Chantiluke, Kaylita C, Cheng, Yuqi, Cho, Kang Ik K, Christakou, Anastasia, Coghill, David, Conzelmann, Annette, Cubillo, Ana I, Dale, Anders M, Dallaspezia, Sara, Daly, Eileen, Denys, Damiaan, Deruelle, Christine, Di Martino, Adriana, Dinstein, Ilan, Doyle, Alysa E, Durston, Sarah, Earl, Eric A, Ecker, Christine, Ehrlich, Stefan, Ely, Benjamin A, Epstein, Jeffrey N, Ethofer, Thoma, Fair, Damien A, Fallgatter, Andreas J, Faraone, Stephen V, Fedor, Jennifer, Feng, Xin, Feusner, Jamie D, Fitzgerald, Jackie, Fitzgerald, Kate D, Fouche, Jean-Paul, Freitag, Christine M, Fridgeirsson, Egill A, Frodl, Thoma, Gabel, Matt C, Gallagher, Louise, Gogberashvili, Tinatin, Gori, Ilaria, Gruner, Patricia, Gürsel, Deniz A, Haar, Shlomi, Haavik, Jan, Hall, Geoffrey B, Harrison, Neil A, Hartman, Catharina A, Heslenfeld, Dirk J, Hirano, Yoshiyuki, Hoekstra, Pieter J, Hoexter, Marcelo Q, Hohmann, Sarah, Høvik, Marie F, Hu, Hao, Huyser, Chaim, Jahanshad, Neda, Jalbrzikowski, Maria, James, Anthony, Janssen, Joost, Jaspers-Fayer, Fern, Jernigan, Terry L, Kapilushniy, Dmitry, Kardatzki, Bernd, Karkashadze, Georgii, Kathmann, Norbert, Kaufmann, Christian, Kelly, Clare, Khadka, Sabin, King, Joseph A, Koch, Kathrin, Kohls, Gregor, Konrad, Kerstin, Kuno, Masaru, Kuntsi, Jonna, Kvale, Gerd, Kwon, Jun Soo, Lázaro, Luisa, Lera-Miguel, Sara, Lesch, Klaus-Peter, Hoekstra, Liesbeth, Liu, Yanni, Lochner, Christine, Louza, Mario R, Luna, Beatriz, Lundervold, Astri J, Malpas, Charles B, Marques, Paulo, Marsh, Rachel, Martínez-Zalacaín, Ignacio, Mataix-Cols, David, Mattos, Paulo, Mccarthy, Hazel, Mcgrath, Jane, Mehta, Mitul A, Menchón, José M, Mennes, Maarten, Martinho, Mauricio Moller, Moreira, Pedro S, Morer, Astrid, Morgado, Pedro, Muratori, Filippo, Murphy, Clodagh M, Murphy, Declan G M, Nakagawa, Akiko, Nakamae, Takashi, Nakao, Tomohiro, Namazova-Baranova, Leyla, Narayanaswamy, Janardhanan C, Nicolau, Rosa, Nigg, Joel T, Novotny, Stephanie E, Nurmi, Erika L, Weiss, Eileen Oberwelland, O'Gorman Tuura, Ruth L, O'Hearn, Kirsten, O'Neill, Joseph, Oosterlaan, Jaap, Oranje, Bob, Paloyelis, Yanni, Parellada, Mara, Pauli, Paul, Perriello, Chri, Piacentini, John, Piras, Fabrizio, Piras, Federica, Plessen, Kerstin J, Puig, Olga, Ramos-Quiroga, J Antoni, Reddy, Y C Janardhan, Reif, Andrea, Reneman, Liesbeth, Retico, Alessandra, Rosa, Pedro G P, Rubia, Katya, Rus, Oana Georgiana, Sakai, Yuki, Schrantee, Anouk, Schwarz, Lena, Schweren, Lizanne J S, Seitz, Jochen, Shaw, Philip, Shook, Devon, Silk, Tim J, Simpson, H Blair, Skokauskas, Norbert, Soliva Vila, Juan Carlo, Solovieva, Anastasia, Soreni, Noam, Soriano-Mas, Carle, Spalletta, Gianfranco, Stern, Emily R, Stevens, Michael C, Stewart, S Evelyn, Sudre, Gustavo, Szeszko, Philip R, Tamm, Leanne, Taylor, Margot J, Tolin, David F, Tosetti, Michela, Tovar-Moll, Fernanda, Tsuchiyagaito, Aki, van Erp, Theo G M, van Wingen, Guido A, Vance, Alasdair, Venkatasubramanian, Ganesan, Vilarroya, Oscar, Vives-Gilabert, Yolanda, von Polier, Georg G, Walitza, Susanne, Wallace, Gregory L, Wang, Zhen, Wolfers, Thoma, Yoncheva, Yuliya N, Yun, Je-Yeon, Zanetti, Marcus V, Zhou, Fengfeng, Ziegler, Georg C, Zierhut, Kathrin C, Zwiers, Marcel P, Thompson, Paul M, Stein, Dan J, Buitelaar, Jan, Franke, Barbara, van den Heuvel, Odile A, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Adult Psychiatry, ANS - Compulsivity, Impulsivity & Attention, Graduate School, Child Psychiatry, General Paediatrics, ARD - Amsterdam Reproduction and Development, Radiology and Nuclear Medicine, APH - Personalized Medicine, and APH - Mental Health

Subjects
Male, Research Report, Obsessive-Compulsive Disorder, Frontal cortex, Systems Analysis, Attention Deficit Hyperactivity Disorder, Autism Spectrum Disorder, [SDV]Life Sciences [q-bio], Hippocampal formation, Audiology, 0302 clinical medicine, 130 000 Cognitive Neurology & Memory, Child, Obsessive-compulsive disorder (OCD), ComputingMilieux_MISCELLANEOUS, Intelligence quotient, Psychopathology, ATTENTION-DEFICIT/HYPERACTIVITY DISORDER, ABNORMALITIES, ENIGMA, Organ Size, 3. Good health, Psychiatry and Mental health, Autism spectrum disorder, Brain size, Cohort, Female, MRI, Adult, medicine.medical_specialty, CORTEX, Adolescent, DEFICIT HYPERACTIVITY DISORDER, Human Development, Neuroimaging, behavioral disciplines and activities, Article, 03 medical and health sciences, FIELD-STRENGTH, mental disorders, medicine, MEGA-ANALYSIS, Attention deficit hyperactivity disorder, Humans, Cortical surface, Structural MRI, Attention Deficit Disorder with Hyperactivity, Cerebrum, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, medicine.disease, 030227 psychiatry, VOXEL, Autism, business, 030217 neurology & neurosurgery
Abstract

ObjectiveAttention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. We aimed to directly compare all three disorders. The ENIGMA consortium is ideally positioned to investigate structural brain alterations across these disorders.MethodsStructural T1-weighted whole-brain MRI of controls (n=5,827) and patients with ADHD (n=2,271), ASD (n=1,777), and OCD (n=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. We examined subcortical volume, cortical thickness and surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults using linear mixed-effects models adjusting for age, sex and site (and ICV for subcortical and surface area measures).ResultsWe found no shared alterations among all three disorders, while shared alterations between any two disorders did not survive multiple comparisons correction. Children with ADHD compared to those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller ICV than controls and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared to adult controls and other clinical groups. No OCD-specific alterations across different age-groups and surface area alterations among all disorders in childhood and adulthood were observed.ConclusionOur findings suggest robust but subtle alterations across different age-groups among ADHD, ASD, and OCD. ADHD-specific ICV and hippocampal alterations in children and adolescents, and ASD-specific cortical thickness alterations in the frontal cortex in adults support previous work emphasizing neurodevelopmental alterations in these disorders.

Published
2020

40. Long-term efficacy and safety of treatment with stimulants and atomoxetine in adult ADHD: A review of controlled and naturalistic studies.

Author

Fredriksen, Mats, Halmøy, Anne, Faraone, Stephen V., and Haavik, Jan

Subjects
*STIMULANTS, *ATOMOXETINE, *DRUG efficacy, *MEDICATION safety, *ATTENTION-deficit hyperactivity disorder, *METHYLPHENIDATE
Abstract

Abstract: Attention-deficit/hyperactivity disorder (ADHD) is a common disorder of childhood that often persists into adulthood. Although stimulant medications are recommended as the first-line treatment for ADHD because of their documented short-term effects in children and adults, less is known about their effects on long-term outcome in adults. Here we review the long-term efficacy and safety of the stimulant drugs methylphenidate and amphetamine, as well as the related compound atomoxetine. We performed a systematic review to identify direct and indirect effects of stimulant therapy on long-term outcome in adults. Five randomized controlled trials (RCTs), and 10 open-label extension studies of initial short-term RCTs, with total follow-up of at least 24weeks, were identified. All these RCTs found that medication was significantly more efficacious than placebo in treating ADHD in adults, and the extension studies showed that this favorable effect of medication was maintained during the open-label follow-up period. However, since the maximum duration of these pharmacological trials was 4years, we also reviewed 18 defined naturalistic longitudinal and cross-sectional studies, to provide more information about longer term functional outcomes, side effects and complications. These observational studies also showed positive correlations between early recognition of the disorder, stimulant treatment during childhood and favorable long-term outcome in adult ADHD patients. In conclusion, stimulant therapy of ADHD has long-term beneficial effects and is well tolerated. However, more longitudinal studies of long duration should be performed. In addition, the ethical issues involved in performing double blind RCTs of many years duration should be further explored. [Copyright &y& Elsevier]

Published
2013
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