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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. Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia

Author

Palmer, Duncan S, Howrigan, Daniel P, Chapman, Sinéad B, Adolfsson, Rolf, Bass, Nick, Blackwood, Douglas, Boks, Marco PM, Chen, Chia-Yen, Churchhouse, Claire, Corvin, Aiden P, Craddock, Nicholas, Curtis, David, Di Florio, Arianna, Dickerson, Faith, Freimer, Nelson B, Goes, Fernando S, Jia, Xiaoming, Jones, Ian, Jones, Lisa, Jonsson, Lina, Kahn, Rene S, Landén, Mikael, Locke, Adam E, McIntosh, Andrew M, McQuillin, Andrew, Morris, Derek W, O’Donovan, Michael C, Ophoff, Roel A, Owen, Michael J, Pedersen, Nancy L, Posthuma, Danielle, Reif, Andreas, Risch, Neil, Schaefer, Catherine, Scott, Laura, Singh, Tarjinder, Smoller, Jordan W, Solomonson, Matthew, Clair, David St, Stahl, Eli A, Vreeker, Annabel, Walters, James TR, Wang, Weiqing, Watts, Nicholas A, Yolken, Robert, Zandi, Peter P, and Neale, Benjamin M

Subjects
Biotechnology, Human Genome, Clinical Research, Serious Mental Illness, Schizophrenia, Brain Disorders, Bipolar Disorder, Mental Health, Genetics, 2.1 Biological and endogenous factors, Aetiology, Mental health, A Kinase Anchor Proteins, Exome, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Exome Sequencing, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

We report results from the Bipolar Exome (BipEx) collaboration analysis of whole-exome sequencing of 13,933 patients with bipolar disorder (BD) matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in patients with BD among genes under strong evolutionary constraint in both major BD subtypes. We find enrichment of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from genome-wide association studies (GWASs) of BD, however, are not significantly enriched for ultra-rare PTVs. Combining gene-level results with SCHEMA, AKAP11 emerges as a definitive risk gene (odds ratio (OR) = 7.06, P = 2.83 × 10-9). At the protein level, AKAP-11 interacts with GSK3B, the hypothesized target of lithium, a primary treatment for BD. Our results lend support to BD's polygenicity, demonstrating a role for rare coding variation as a significant risk factor in BD etiology.

Published
2022

3. Rare coding variants in ten genes confer substantial risk for schizophrenia.

Author

Singh, Tarjinder, Poterba, Timothy, Curtis, David, Akil, Huda, Al Eissa, Mariam, Barchas, Jack D, Bass, Nicholas, Bigdeli, Tim B, Breen, Gerome, Bromet, Evelyn J, Buckley, Peter F, Bunney, William E, Bybjerg-Grauholm, Jonas, Byerley, William F, Chapman, Sinéad B, Chen, Wei J, Churchhouse, Claire, Craddock, Nicholas, Cusick, Caroline M, DeLisi, Lynn, Dodge, Sheila, Escamilla, Michael A, Eskelinen, Saana, Fanous, Ayman H, Faraone, Stephen V, Fiorentino, Alessia, Francioli, Laurent, Gabriel, Stacey B, Gage, Diane, Gagliano Taliun, Sarah A, Ganna, Andrea, Genovese, Giulio, Glahn, David C, Grove, Jakob, Hall, Mei-Hua, Hämäläinen, Eija, Heyne, Henrike O, Holi, Matti, Hougaard, David M, Howrigan, Daniel P, Huang, Hailiang, Hwu, Hai-Gwo, Kahn, René S, Kang, Hyun Min, Karczewski, Konrad J, Kirov, George, Knowles, James A, Lee, Francis S, Lehrer, Douglas S, Lescai, Francesco, Malaspina, Dolores, Marder, Stephen R, McCarroll, Steven A, McIntosh, Andrew M, Medeiros, Helena, Milani, Lili, Morley, Christopher P, Morris, Derek W, Mortensen, Preben Bo, Myers, Richard M, Nordentoft, Merete, O'Brien, Niamh L, Olivares, Ana Maria, Ongur, Dost, Ouwehand, Willem H, Palmer, Duncan S, Paunio, Tiina, Quested, Digby, Rapaport, Mark H, Rees, Elliott, Rollins, Brandi, Satterstrom, F Kyle, Schatzberg, Alan, Scolnick, Edward, Scott, Laura J, Sharp, Sally I, Sklar, Pamela, Smoller, Jordan W, Sobell, Janet L, Solomonson, Matthew, Stahl, Eli A, Stevens, Christine R, Suvisaari, Jaana, Tiao, Grace, Watson, Stanley J, Watts, Nicholas A, Blackwood, Douglas H, Børglum, Anders D, Cohen, Bruce M, Corvin, Aiden P, Esko, Tõnu, Freimer, Nelson B, Glatt, Stephen J, Hultman, Christina M, McQuillin, Andrew, Palotie, Aarno, Pato, Carlos N, Pato, Michele T, Pulver, Ann E, and St Clair, David

Subjects
Humans, Genetic Predisposition to Disease, Receptors, N-Methyl-D-Aspartate, Case-Control Studies, Schizophrenia, Mutation, Exome, Neurodevelopmental Disorders, Human Genome, Biotechnology, Mental Health, Neurosciences, Brain Disorders, Genetics, Serious Mental Illness, Aetiology, 2.1 Biological and endogenous factors, Mental health, Neurological, General Science & Technology
Abstract

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3-50, P

Published
2022

5. A meta‐analysis of deep brain structural shape and asymmetry abnormalities in 2,833 individuals with schizophrenia compared with 3,929 healthy volunteers via the ENIGMA Consortium

Author

Gutman, Boris A, Erp, Theo GM, Alpert, Kathryn, Ching, Christopher RK, Isaev, Dmitry, Ragothaman, Anjani, Jahanshad, Neda, Saremi, Arvin, Zavaliangos‐Petropulu, Artemis, Glahn, David C, Shen, Li, Cong, Shan, Alnæs, Dag, Andreassen, Ole Andreas, Doan, Nhat Trung, Westlye, Lars T, Kochunov, Peter, Satterthwaite, Theodore D, Wolf, Daniel H, Huang, Alexander J, Kessler, Charles, Weideman, Andrea, Nguyen, Dana, Mueller, Bryon A, Faziola, Lawrence, Potkin, Steven G, Preda, Adrian, Mathalon, Daniel H, Bustillo, Juan, Calhoun, Vince, Ford, Judith M, Walton, Esther, Ehrlich, Stefan, Ducci, Giuseppe, Banaj, Nerisa, Piras, Fabrizio, Piras, Federica, Spalletta, Gianfranco, Canales‐Rodríguez, Erick J, Fuentes‐Claramonte, Paola, Pomarol‐Clotet, Edith, Radua, Joaquim, Salvador, Raymond, Sarró, Salvador, Dickie, Erin W, Voineskos, Aristotle, Tordesillas‐Gutiérrez, Diana, Crespo‐Facorro, Benedicto, Setién‐Suero, Esther, Son, Jacqueline Mayoral, Borgwardt, Stefan, Schönborn‐Harrisberger, Fabienne, Morris, Derek, Donohoe, Gary, Holleran, Laurena, Cannon, Dara, McDonald, Colm, Corvin, Aiden, Gill, Michael, Filho, Geraldo Busatto, Rosa, Pedro GP, Serpa, Mauricio H, Zanetti, Marcus V, Lebedeva, Irina, Kaleda, Vasily, Tomyshev, Alexander, Crow, Tim, James, Anthony, Cervenka, Simon, Sellgren, Carl M, Fatouros‐Bergman, Helena, Agartz, Ingrid, Howells, Fleur, Stein, Dan J, Temmingh, Henk, Uhlmann, Anne, Zubicaray, Greig I, McMahon, Katie L, Wright, Margie, Cobia, Derin, Csernansky, John G, Thompson, Paul M, Turner, Jessica A, and Wang, Lei

Subjects
Brain Disorders, Mental Health, Neurosciences, Schizophrenia, Mental health, Good Health and Well Being, Amygdala, Corpus Striatum, Hippocampus, Humans, Multicenter Studies as Topic, Neuroimaging, Thalamus, schizophrenia, structure, subcortical shape, Cognitive Sciences, Experimental Psychology
Abstract

Schizophrenia is associated with widespread alterations in subcortical brain structure. While analytic methods have enabled more detailed morphometric characterization, findings are often equivocal. In this meta-analysis, we employed the harmonized ENIGMA shape analysis protocols to collaboratively investigate subcortical brain structure shape differences between individuals with schizophrenia and healthy control participants. The study analyzed data from 2,833 individuals with schizophrenia and 3,929 healthy control participants contributed by 21 worldwide research groups participating in the ENIGMA Schizophrenia Working Group. Harmonized shape analysis protocols were applied to each site's data independently for bilateral hippocampus, amygdala, caudate, accumbens, putamen, pallidum, and thalamus obtained from T1-weighted structural MRI scans. Mass univariate meta-analyses revealed more-concave-than-convex shape differences in the hippocampus, amygdala, accumbens, and thalamus in individuals with schizophrenia compared with control participants, more-convex-than-concave shape differences in the putamen and pallidum, and both concave and convex shape differences in the caudate. Patterns of exaggerated asymmetry were observed across the hippocampus, amygdala, and thalamus in individuals with schizophrenia compared to control participants, while diminished asymmetry encompassed ventral striatum and ventral and dorsal thalamus. Our analyses also revealed that higher chlorpromazine dose equivalents and increased positive symptom levels were associated with patterns of contiguous convex shape differences across multiple subcortical structures. Findings from our shape meta-analysis suggest that common neurobiological mechanisms may contribute to gray matter reduction across multiple subcortical regions, thus enhancing our understanding of the nature of network disorganization in schizophrenia.

Published
2022

9. Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics.

Author

Lam, Max, Chen, Chia-Yen, Ge, Tian, Xia, Yan, Hill, David W, Trampush, Joey W, Yu, Jin, Knowles, Emma, Davies, Gail, Stahl, Eli A, Huckins, Laura, Liewald, David C, Djurovic, Srdjan, Melle, Ingrid, Christoforou, Andrea, Reinvang, Ivar, DeRosse, Pamela, Lundervold, Astri J, Steen, Vidar M, Espeseth, Thomas, Räikkönen, Katri, Widen, Elisabeth, Palotie, Aarno, Eriksson, Johan G, Giegling, Ina, Konte, Bettina, Hartmann, Annette M, Roussos, Panos, Giakoumaki, Stella, Burdick, Katherine E, Payton, Antony, Ollier, William, Chiba-Falek, Ornit, Koltai, Deborah C, Need, Anna C, Cirulli, Elizabeth T, Voineskos, Aristotle N, Stefanis, Nikos C, Avramopoulos, Dimitrios, Hatzimanolis, Alex, Smyrnis, Nikolaos, Bilder, Robert M, Freimer, Nelson B, Cannon, Tyrone D, London, Edythe, Poldrack, Russell A, Sabb, Fred W, Congdon, Eliza, Conley, Emily Drabant, Scult, Matthew A, Dickinson, Dwight, Straub, Richard E, Donohoe, Gary, Morris, Derek, Corvin, Aiden, Gill, Michael, Hariri, Ahmad R, Weinberger, Daniel R, Pendleton, Neil, Bitsios, Panos, Rujescu, Dan, Lahti, Jari, Le Hellard, Stephanie, Keller, Matthew C, Andreassen, Ole A, Deary, Ian J, Glahn, David C, Huang, Hailiang, Liu, Chunyu, Malhotra, Anil K, and Lencz, Todd

Subjects
Humans, Nootropic Agents, Cognition, Schizophrenia, Genome-Wide Association Study, Transcriptome, Psychiatry, Medical and Health Sciences, Psychology and Cognitive Sciences
Abstract

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.

Published
2021

10. Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder.

Author

Jia, Xiaoming, Goes, Fernando S, Locke, Adam E, Palmer, Duncan, Wang, Weiqing, Cohen-Woods, Sarah, Genovese, Giulio, Jackson, Anne U, Jiang, Chen, Kvale, Mark, Mullins, Niamh, Nguyen, Hoang, Pirooznia, Mehdi, Rivera, Margarita, Ruderfer, Douglas M, Shen, Ling, Thai, Khanh, Zawistowski, Matthew, Zhuang, Yongwen, Abecasis, Gonçalo, Akil, Huda, Bergen, Sarah, Burmeister, Margit, Chapman, Sinéad, DelaBastide, Melissa, Juréus, Anders, Kang, Hyun Min, Kwok, Pui-Yan, Li, Jun Z, Levy, Shawn E, Monson, Eric T, Moran, Jennifer, Sobell, Janet, Watson, Stanley, Willour, Virginia, Zöllner, Sebastian, Adolfsson, Rolf, Blackwood, Douglas, Boehnke, Michael, Breen, Gerome, Corvin, Aiden, Craddock, Nick, DiFlorio, Arianna, Hultman, Christina M, Landen, Mikael, Lewis, Cathryn, McCarroll, Steven A, Richard McCombie, W, McGuffin, Peter, McIntosh, Andrew, McQuillin, Andrew, Morris, Derek, Myers, Richard M, O'Donovan, Michael, Ophoff, Roel, Boks, Marco, Kahn, Rene, Ouwehand, Willem, Owen, Michael, Pato, Carlos, Pato, Michele, Posthuma, Danielle, Potash, James B, Reif, Andreas, Sklar, Pamela, Smoller, Jordan, Sullivan, Patrick F, Vincent, John, Walters, James, Neale, Benjamin, Purcell, Shaun, Risch, Neil, Schaefer, Catherine, Stahl, Eli A, Zandi, Peter P, and Scott, Laura J

Subjects
Humans, Genetic Predisposition to Disease, Bipolar Disorder, Schizophrenia, Polymorphism, Single Nucleotide, Genetic Variation, Genome-Wide Association Study, Exome, Brain Disorders, Prevention, Clinical Research, Human Genome, Serious Mental Illness, Genetics, Mental Health, 2.1 Biological and endogenous factors, Mental health, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3-2.8, one-sided p = 6.0 × 10-4), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ.

Published
2021

12. 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
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

13. Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

Author

Marshall, Christian R., Merico, Daniele, Thiruvahindrapuram, Bhooma, Wang, Zhouzhi, Scherer, Stephen W., Howrigan, Daniel P, Ripke, Stephan, Bulik-Sullivan, Brendan, Farh, Kai-How, Fromer, Menachem, Goldstein, Jacqueline I., Huang, Hailiang, Lee, Phil, Daly, Mark J., Neale, Benjamin M., Belliveau, Richard A., Jr., Bergen, Sarah E., Bevilacqua, Elizabeth, Chambert, Kimberley D., O'Dushlaine, Colm, Scolnick, Edward M., Smoller, Jordan W., Moran, Jennifer L., Palotie, Aarno, Petryshen, Tracey L., Wu, Wenting, Greer, Douglas S., Antaki, Danny, Shetty, Aniket, Gujral, Madhusudan, Brandler, William M., Malhotra, Dheeraj, Fuentes Fajarado, Karin V., Maile, Michelle S., Holmans, Peter A., Carrera, Noa, Craddock, Nick, Escott-Price, Valentina, Georgieva, Lyudmila, Hamshere, Marian L., Kavanagh, David, Legge, Sophie E., Pocklington, Andrew J., Richards, Alexander L., Ruderfer, Douglas M., Williams, Nigel M., Kirov, George, Owen, Michael J., Pinto, Dalila, Cai, Guiqing, Davis, Kenneth L., Drapeau, Elodie, Friedman, Joseph I, Haroutunian, Vahram, Parkhomenko, Elena, Reichenberg, Abraham, Silverman, Jeremy M., Buxbaum, Joseph D., Domenici, Enrico, Agartz, Ingrid, Djurovic, Srdjan, Mattingsdal, Morten, Melle, Ingrid, Andreassen, Ole A., Jönsson, Erik G., Söderman, Erik, Albus, Margot, Alexander, Madeline, Laurent, Claudine, Levinson, Douglas F., Amin, Farooq, Atkins, Joshua, Cairns, Murray J., Scott, Rodney J., Tooney, Paul A., Wu, Jing Qin, Bacanu, Silviu A., Bigdeli, Tim B., Reimers, Mark A., Webb, Bradley T., Wolen, Aaron R., Wormley, Brandon K., Kendler, Kenneth S., Riley, Brien P., Kähler, Anna K., Magnusson, Patrik K.E., Hultman, Christina M., Bertalan, Marcelo, Hansen, Thomas, Olsen, Line, Rasmussen, Henrik B., Werge, Thomas, Mattheisen, Manuel, Black, Donald W., Bruggeman, Richard, Buccola, Nancy G., Buckner, Randy L., Roffman, Joshua L., Byerley, William, Cahn, Wiepke, Kahn, René S, Strengman, Eric, Ophoff, Roel A., Carr, Vaughan J., Catts, Stanley V., Henskens, Frans A., Loughland, Carmel M., Michie, Patricia T., Pantelis, Christos, Schall, Ulrich, Jablensky, Assen V., Kelly, Brian J., Campion, Dominique, Cantor, Rita M., Cheng, Wei, Cloninger, C. Robert, Svrakic, Dragan M, Cohen, David, Cormican, Paul, Donohoe, Gary, Morris, Derek W., Corvin, Aiden, Gill, Michael, Crespo-Facorro, Benedicto, Crowley, James J., Farrell, Martilias S., Giusti-Rodríguez, Paola, Kim, Yunjung, Szatkiewicz, Jin P., Williams, Stephanie, Curtis, David, Pimm, Jonathan, Gurling, Hugh, McQuillin, Andrew, Davidson, Michael, Weiser, Mark, Degenhardt, Franziska, Forstner, Andreas J., Herms, Stefan, Hoffmann, Per, Hofman, Andrea, Cichon, Sven, Nöthen, Markus M., Del Favero, Jurgen, DeLisi, Lynn E., McCarley, Robert W., Levy, Deborah L., Mesholam-Gately, Raquelle I., Seidman, Larry J., Dikeos, Dimitris, Papadimitriou, George N., Dinan, Timothy, Duan, Jubao, Sanders, Alan R., Gejman, Pablo V., Gershon, Elliot S., Dudbridge, Frank, Eichhammer, Peter, Eriksson, Johan, Salomaa, Veikko, Essioux, Laurent, Fanous, Ayman H., Knowles, James A., Pato, Michele T., Pato, Carlos N., Frank, Josef, Meier, Sandra, Schulze, Thomas G., Strohmaier, Jana, Witt, Stephanie H., Rietschel, Marcella, Franke, Lude, Karjalainen, Juha, Freedman, Robert, Olincy, Ann, Freimer, Nelson B., Purcell, Shaun M., Roussos, Panos, Stahl, Eli A., Sklar, Pamela, Giegling, Ina, Hartmann, Annette M., Konte, Bettina, Rujescu, Dan, Godard, Stephanie, Hirschhorn, Joel N., Pers, Tune H., Price, Alkes, Esko, Tõnu, Gratten, Jacob, Lee, S. Hong, Visscher, Peter M., Wray, Naomi R., Mowry, Bryan J., de Haan, Lieuwe, Meijer, Carin J., Hansen, Mark, Ikeda, Masashi, Iwata, Nakao, Joa, Inge, Kalaydjieva, Luba, Keller, Matthew C., Kennedy, James L., Zai, Clement C., Knight, Jo, Lerer, Bernard, Liang, Kung-Yee, Lieberman, Jeffrey, Stroup, T. Scott, Lönnqvist, Jouko, Suvisaari, Jaana, Maher, Brion S., Maier, Wolfgang, Mallet, Jacques, McDonald, Colm, McIntosh, Andrew M., Blackwood, Douglas H.R., Metspalu, Andres, Milani, Lili, Milanova, Vihra, Mokrab, Younes, Collier, David A., Müller-Myhsok, Bertram, Murphy, Kieran C., Murray, Robin M., Powell, John, Myin-Germeys, Inez, Van Os, Jim, Nenadic, Igor, Nertney, Deborah A., Nestadt, Gerald, Pulver, Ann E., Nicodemus, Kristin K., Nisenbaum, Laura, Nordin, Annelie, Adolfsson, Rolf, O'Callaghan, Eadbhard, Oh, Sang-Yun, O'Neill, F. Anthony, Paunio, Tiina, Pietiläinen, Olli, Perkins, Diana O., Quested, Digby, Savitz, Adam, Li, Qingqin S., Schwab, Sibylle G., Shi, Jianxin, Spencer, Chris C.A., Thirumalai, Srinivas, Veijola, Juha, Waddington, John, Walsh, Dermot, Wildenauer, Dieter B., Bramon, Elvira, Darvasi, Ariel, Posthuma, Danielle, St. Clair, David, Shanta, Omar, Klein, Marieke, Park, Peter J., Weinberger, Daniel, Moran, John V., Gage, Fred H., Vaccarino, Flora M., Gleeson, Joseph, Mathern, Gary, Courchesne, Eric, Roy, Subhojit, Bizzotto, Sara, Coulter, Michael, Dias, Caroline, D'Gama, Alissa, Ganz, Javier, Hill, Robert, Huang, August Yue, Khoshkhoo, Sattar, Kim, Sonia, Lodato, Michael, Miller, Michael, Borges-Monroy, Rebeca, Rodin, Rachel, Zhou, Zinan, Bohrson, Craig, Chu, Chong, Cortes-Ciriano, Isidro, Dou, Yanmei, Galor, Alon, Gulhan, Doga, Kwon, Minseok, Luquette, Joe, Viswanadham, Vinay, Jones, Attila, Rosenbluh, Chaggai, Cho, Sean, Langmead, Ben, Thorpe, Jeremy, Erwin, Jennifer, Jaffe, Andrew, McConnell, Michael, Narurkar, Rujuta, Paquola, Apua, Shin, Jooheon, Straub, Richard, Abyzov, Alexej, Bae, Taejeong, Jang, Yeongjun, Wang, Yifan, Gage, Fred, Linker, Sara, Reed, Patrick, Wang, Meiyan, Urban, Alexander, Zhou, Bo, Zhu, Xiaowei, Pattni, Reenal, Amero, Aitor Serres, Juan, David, Lobon, Irene, Marques-Bonet, Tomas, Moruno, Manuel Solis, Perez, Raquel Garcia, Povolotskaya, Inna, Soriano, Eduardo, Averbuj, Dan, Ball, Laurel, Breuss, Martin, Yang, Xiaoxu, Chung, Changuk, Emery, Sarah B., Flasch, Diane A., Kidd, Jeffrey M., Kopera, Huira C., Kwan, Kenneth Y., Mills, Ryan E., Moldovan, John B., Sun, Chen, Zhao, Xuefang, Zhou, Weichen, Frisbie, Trenton J., Cherskov, Adriana, Fasching, Liana, Jourdon, Alexandre, Pochareddy, Sirisha, Scuderi, Soraya, Sestan, Nenad, Maury, Eduardo A., Sherman, Maxwell A., Genovese, Giulio, Gilgenast, Thomas G., Kamath, Tushar, Burris, S.J., Rajarajan, Prashanth, Flaherty, Erin, Akbarian, Schahram, Chess, Andrew, McCarroll, Steven A., Loh, Po-Ru, Phillips-Cremins, Jennifer E., Brennand, Kristen J., Macosko, Evan Z., Walters, James T.R., O’Donovan, Michael, Sullivan, Patrick, Sebat, Jonathan, Lee, Eunjung A., and Walsh, Christopher A.

Published
2023
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14. Using brain cell-type-specific protein interactomes to interpret neurodevelopmental genetic signals in schizophrenia

Author

Ripke, Stephan, Neale, Benjamin M., Corvin, Aiden, Walters, James T.R., Farh, Kai-How, Holmans, Peter A., Lee, Phil, Bulik-Sullivan, Brendan, Collier, David A., Huang, Hailiang, Pers, Tune H., Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A., Begemann, Martin, Belliveau, Richard A., Jr., Bene, Judit, Bergen, Sarah E., Bevilacqua, Elizabeth, Bigdeli, Tim B., Black, Donald W., Bruggeman, Richard, Buccola, Nancy G., Buckner, Randy L., Byerley, William, Cahn, Wiepke, Cai, Guiqing, Campion, Dominique, Cantor, Rita M., Carr, Vaughan J., Carrera, Noa, Catts, Stanley V., Chambert, Kimberley D., Chan, Raymond C.K., Chan, Ronald Y.L., Chen, Eric Y.H., Cheng, Wei, Cheung, Eric FC., Chong, Siow Ann, Cloninger, C. Robert, Cohen, David, Cohen, Nadine, Cormican, Paul, Craddock, Nick, Crowley, James J., Curtis, David, Davidson, Michael, Davis, Kenneth L., Degenhardt, Franziska, Del Favero, Jurgen, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Durmishi, Naser, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H., Farrell, Martilias S., Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B., Friedl, Marion, Friedman, Joseph I., Fromer, Menachem, Genovese, Giulio, Georgieva, Lyudmila, Giegling, Ina, Giusti-Rodríguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I., Golimbet, Vera, Gopal, Srihari, Gratten, Jacob, de Haan, Lieuwe, Hammer, Christian, Hamshere, Marian L., Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M., Henskens, Frans A., Herms, Stefan, Hirschhorn, Joel N., Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V., Hougaard, David M., Ikeda, Masashi, Joa, Inge, Julià, Antonio, Kahn, René S., Kalaydjieva, Luba, Karachanak-Yankova, Sena, Karjalainen, Juha, Kavanagh, David, Keller, Matthew C., Kennedy, James L., Khrunin, Andrey, Kim, Yunjung, Klovins, Janis, Knowles, James A., Konte, Bettina, Kucinskas, Vaidutis, Kucinskiene, Zita Ausrele, Kuzelova-Ptackova, Hana, Kähler, Anna K., Laurent, Claudine, Lee, Jimmy, Lee, S. Hong, Legge, Sophie E., Lerer, Bernard, Li, Miaoxin, Li, Tao, Liang, Kung-Yee, Lieberman, Jeffrey, Limborska, Svetlana, Loughland, Carmel M., Lubinski, Jan, Lönnqvist, Jouko, Macek, Milan, Magnusson, Patrik K.E., Maher, Brion S., Maier, Wolfgang, Mallet, Jacques, Marsal, Sara, Mattheisen, Manuel, Mattingsdal, Morten, McCarley, Robert W., McDonald, Colm, McIntosh, Andrew M., Meier, Sandra, Meijer, Carin J., Melegh, Bela, Melle, Ingrid, Mesholam-Gately, Raquelle I., Metspalu, Andres, Michie, Patricia T., Milani, Lili, Milanova, Vihra, Mokrab, Younes, Morris, Derek W., Mors, Ole, Murphy, Kieran C., Murray, Robin M., Myin-Germeys, Inez, Müller-Myhsok, Bertram, Nelis, Mari, Nenadic, Igor, Nertney, Deborah A., Nestadt, Gerald, Nicodemus, Kristin K., Nikitina-Zake, Liene, Nisenbaum, Laura, Nordin, Annelie, O'Callaghan, Eadbhard, O'Dushlaine, Colm, O'Neill, F. Anthony, Oh, Sang-Yun, Olincy, Ann, Olsen, Line, Van Os, Jim, Pantelis, Christos, Papadimitriou, George N., Papiol, Sergi, Parkhomenko, Elena, Pato, Michele T., Paunio, Tiina, Pejovic-Milovancevic, Milica, Perkins, Diana O., Pietiläinen, Olli, Pimm, Jonathan, Pocklington, Andrew J., Powell, John, Price, Alkes, Pulver, Ann E., Purcell, Shaun M., Quested, Digby, Rasmussen, Henrik B., Reichenberg, Abraham, Reimers, Mark A., Richards, Alexander L., Roffman, Joshua L., Roussos, Panos, Ruderfer, Douglas M., Salomaa, Veikko, Sanders, Alan R., Schall, Ulrich, Schubert, Christian R., Schulze, Thomas G., Schwab, Sibylle G., Scolnick, Edward M., Scott, Rodney J., Seidman, Larry J., Shi, Jianxin, Sigurdsson, Engilbert, Silagadze, Teimuraz, Silverman, Jeremy M., Sim, Kang, Slominsky, Petr, Smoller, Jordan W., So, Hon-Cheong, Spencer, Chris C.A., Stahl, Eli A., Stefansson, Hreinn, Steinberg, Stacy, Stogmann, Elisabeth, Straub, Richard E., Strengman, Eric, Strohmaier, Jana, Stroup, T Scott, Subramaniam, Mythily, Suvisaari, Jaana, Svrakic, Dragan M., Szatkiewicz, Jin P., Söderman, Erik, Thirumalai, Srinivas, Toncheva, Draga, Tosato, Sarah, Veijola, Juha, Waddington, John, Walsh, Dermot, Wang, Dai, Wang, Qiang, Webb, Bradley T., Weiser, Mark, Wildenauer, Dieter B., Williams, Nigel M., Williams, Stephanie, Witt, Stephanie H., Wolen, Aaron R., Wong, Emily H.M., Wormley, Brandon K., Xi, Hualin Simon, Zai, Clement C., Zheng, Xuebin, Zimprich, Fritz, Wray, Naomi R., Stefansson, Kari, Visscher, Peter M., Adolfsson, Rolf, Andreassen, Ole A., Blackwood, Douglas H.R., Bramon, Elvira, Buxbaum, Joseph D., Børglum, Anders D., Cichon, Sven, Darvasi, Ariel, Domenici, Enrico, Ehrenreich, Hannelore, Esko, Tõnu, Gejman, Pablo V., Gill, Michael, Gurling, Hugh, Hultman, Christina M., Iwata, Nakao, Jablensky, Assen V., Jönsson, Erik G., Kendler, Kenneth S., Kirov, George, Knight, Jo, Lencz, Todd, Levinson, Douglas F., Li, Qingqin S., Liu, Jianjun, Malhotra, Anil K., McCarroll, Steven A., McQuillin, Andrew, Moran, Jennifer L., Mortensen, Preben B., Mowry, Bryan J., Nöthen, Markus M., Ophoff, Roel A., Owen, Michael J., Palotie, Aarno, Pato, Carlos N., Petryshen, Tracey L., Posthuma, Danielle, Rietschel, Marcella, Riley, Brien P., Rujescu, Dan, Sham, Pak C., Sklar, Pamela, St Clair, David, Weinberger, Daniel R., Wendland, Jens R., Werge, Thomas, Daly, Mark J., Sullivan, Patrick F., O'Donovan, Michael C., Qin, Shengying, Sawa, Akira, Kahn, Rene, Hong, Kyung Sue, Shi, Wenzhao, Tsuang, Ming, Itokawa, Masanari, Feng, Gang, Glatt, Stephen J., Ma, Xiancang, Tang, Jinsong, Ruan, Yunfeng, Liu, Ruize, Zhu, Feng, Horiuchi, Yasue, Lee, Byung Dae, Joo, Eun-Jeong, Myung, Woojae, Ha, Kyooseob, Won, Hong-Hee, Baek, Ji Hyung, Chung, Young Chul, Kim, Sung-Wan, Kusumawardhani, Agung, Chen, Wei J., Hwu, Hai-Gwo, Hishimoto, Akitoyo, Otsuka, Ikuo, Sora, Ichiro, Toyota, Tomoko, Yoshikawa, Takeo, Kunugi, Hiroshi, Hattori, Kotaro, Ishiwata, Sayuri, Numata, Shusuke, Ohmori, Tetsuro, Arai, Makoto, Ozeki, Yuji, Fujii, Kumiko, Kim, Se Joo, Lee, Heon-Jeong, Ahn, Yong Min, Kim, Se Hyun, Akiyama, Kazufumi, Shimoda, Kazutaka, Kinoshita, Makoto, Hsu, Yu-Han H., Pintacuda, Greta, Nacu, Eugeniu, Kim, April, Tsafou, Kalliopi, Petrossian, Natalie, Crotty, William, Suh, Jung Min, Riseman, Jackson, Martin, Jacqueline M., Biagini, Julia C., Mena, Daya, Ching, Joshua K.T., Malolepsza, Edyta, Li, Taibo, Singh, Tarjinder, Ge, Tian, Egri, Shawn B., Tanenbaum, Benjamin, Stanclift, Caroline R., Apffel, Annie M., Carr, Steven A., Schenone, Monica, Jaffe, Jake, Fornelos, Nadine, Eggan, Kevin C., and Lage, Kasper

Published
2023
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16. The Relationship Between White Matter Microstructure and General Cognitive Ability in Patients With Schizophrenia and Healthy Participants in the ENIGMA Consortium

Author

Holleran, Laurena, Kelly, Sinead, Alloza, Clara, Agartz, Ingrid, Andreassen, Ole A, Arango, Celso, Banaj, Nerisa, Calhoun, Vince, Cannon, Dara, Carr, Vaughan, Corvin, Aiden, Glahn, David C, Gur, Ruben, Hong, Elliot, Hoschl, Cyril, Howells, Fleur M, James, Anthony, Janssen, Joost, Kochunov, Peter, Lawrie, Stephen M, Liu, Jingyu, Martinez, Covadonga, McDonald, Colm, Morris, Derek, Mothersill, David, Pantelis, Christos, Piras, Fabrizio, Potkin, Steven, Rasser, Paul E, Roalf, David, Rowland, Laura, Satterthwaite, Theodore, Schall, Ulrich, Spalletta, Gianfranco, Spaniel, Filip, Stein, Dan J, Uhlmann, Anne, Voineskos, Aristotle, Zalesky, Andrew, van Erp, Theo GM, Turner, Jessica A, Deary, Ian J, Thompson, Paul M, Jahanshad, Neda, and Donohoe, Gary

Subjects
Biological Psychology, Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Psychology, Prevention, Neurosciences, Behavioral and Social Science, Clinical Research, Brain Disorders, Serious Mental Illness, Schizophrenia, Mental Health, Mental health, Adult, Anisotropy, Brain, Case-Control Studies, Cognition, Diffusion Tensor Imaging, Factor Analysis, Statistical, Female, Healthy Volunteers, Humans, Intelligence, Male, Middle Aged, Neural Pathways, Principal Component Analysis, Schizophrenic Psychology, Wechsler Scales, White Matter, ENIGMA, Meta-Analysis, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Clinical and health psychology
Abstract

ObjectiveSchizophrenia has recently been associated with widespread white matter microstructural abnormalities, but the functional effects of these abnormalities remain unclear. Widespread heterogeneity of results from studies published to date preclude any definitive characterization of the relationship between white matter and cognitive performance in schizophrenia. Given the relevance of deficits in cognitive function to predicting social and functional outcomes in schizophrenia, the authors carried out a meta-analysis of available data through the ENIGMA Consortium, using a common analysis pipeline, to elucidate the relationship between white matter microstructure and a measure of general cognitive performance, IQ, in patients with schizophrenia and healthy participants.MethodsThe meta-analysis included 760 patients with schizophrenia and 957 healthy participants from 11 participating ENIGMA Consortium sites. For each site, principal component analysis was used to calculate both a global fractional anisotropy component (gFA) and a fractional anisotropy component for six long association tracts (LA-gFA) previously associated with cognition.ResultsMeta-analyses of regression results indicated that gFA accounted for a significant amount of variation in cognition in the full sample (effect size [Hedges' g]=0.27, CI=0.17-0.36), with similar effects sizes observed for both the patient (effect size=0.20, CI=0.05-0.35) and healthy participant groups (effect size=0.32, CI=0.18-0.45). Comparable patterns of association were also observed between LA-gFA and cognition for the full sample (effect size=0.28, CI=0.18-0.37), the patient group (effect size=0.23, CI=0.09-0.38), and the healthy participant group (effect size=0.31, CI=0.18-0.44).ConclusionsThis study provides robust evidence that cognitive ability is associated with global structural connectivity, with higher fractional anisotropy associated with higher IQ. This association was independent of diagnosis; while schizophrenia patients tended to have lower fractional anisotropy and lower IQ than healthy participants, the comparable size of effect in each group suggested a more general, rather than disease-specific, pattern of association.

Published
2020

17. 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

18. Correction: 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
16p11.2 European Consortium, for the ENIGMA-CNV working group, Neurosciences, Psychiatry, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences
Abstract

Prior to and following the publication of this article the authors noted that the complete list of authors was not included in the main article and was only present in Supplementary Table 1. The author list in the original article has now been updated to include all authors, and Supplementary Table 1 has been removed. All other supplementary files have now been updated accordingly. Furthermore, in Table 1 of this Article, the replication cohort for the row Close relative in data set, n (%) was incorrect. All values have now been corrected to 0(0%). The publishers would like to apologise for this error and the inconvenience it may have caused.

Published
2020

19. The Relationship Between Polygenic Risk Scores and Cognition in Schizophrenia

Author

Richards, Alexander L, Pardiñas, Antonio F, Frizzati, Aura, Tansey, Katherine E, Lynham, Amy J, Holmans, Peter, Legge, Sophie E, Savage, Jeanne E, Agartz, Ingrid, Andreassen, Ole A, Blokland, Gabriella AM, Corvin, Aiden, Cosgrove, Donna, Degenhardt, Franziska, Djurovic, Srdjan, Espeseth, Thomas, Ferraro, Laura, Gayer-Anderson, Charlotte, Giegling, Ina, van Haren, Neeltje E, Hartmann, Annette M, Hubert, John J, Jönsson, Erik G, Konte, Bettina, Lennertz, Leonhard, Olde Loohuis, Loes M, Melle, Ingrid, Morgan, Craig, Morris, Derek W, Murray, Robin M, Nyman, Håkan, Ophoff, Roel A, van Os, Jim, Petryshen, Tracey L, Quattrone, Diego, Rietschel, Marcella, Rujescu, Dan, Rutten, Bart PF, Streit, Fabian, Strohmaier, Jana, Sullivan, Patrick F, Sundet, Kjetil, Wagner, Michael, Escott-Price, Valentina, Owen, Michael J, Donohoe, Gary, O’Donovan, Michael C, and Walters, James TR

Subjects
Genetics, Prevention, Schizophrenia, Depression, Behavioral and Social Science, Mental Health, Brain Disorders, Serious Mental Illness, Human Genome, 2.1 Biological and endogenous factors, Aetiology, 2.3 Psychological, social and economic factors, Mental health, Bipolar Disorder, Datasets as Topic, Depressive Disorder, Major, Educational Status, Genome-Wide Association Study, Humans, Intelligence, Multifactorial Inheritance, Psychotic Disorders, psychiatry, genomics, intelligence, bioinformatics, GROUP Investigators, EUGEI WP2 Group, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

BackgroundCognitive impairment is a clinically important feature of schizophrenia. Polygenic risk score (PRS) methods have demonstrated genetic overlap between schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), educational attainment (EA), and IQ, but very few studies have examined associations between these PRS and cognitive phenotypes within schizophrenia cases.MethodsWe combined genetic and cognitive data in 3034 schizophrenia cases from 11 samples using the general intelligence factor g as the primary measure of cognition. We used linear regression to examine the association between cognition and PRS for EA, IQ, schizophrenia, BD, and MDD. The results were then meta-analyzed across all samples. A genome-wide association studies (GWAS) of cognition was conducted in schizophrenia cases.ResultsPRS for both population IQ (P = 4.39 × 10-28) and EA (P = 1.27 × 10-26) were positively correlated with cognition in those with schizophrenia. In contrast, there was no association between cognition in schizophrenia cases and PRS for schizophrenia (P = .39), BD (P = .51), or MDD (P = .49). No individual variant approached genome-wide significance in the GWAS.ConclusionsCognition in schizophrenia cases is more strongly associated with PRS that index cognitive traits in the general population than PRS for neuropsychiatric disorders. This suggests the mechanisms of cognitive variation within schizophrenia are at least partly independent from those that predispose to schizophrenia diagnosis itself. Our findings indicate that this cognitive variation arises at least in part due to genetic factors shared with cognitive performance in populations and is not solely due to illness or treatment-related factors, although our findings are consistent with important contributions from these factors.

Published
2020

21. Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Author

Trubetskoy, Vassily, Pardiñas, Antonio F., Qi, Ting, Panagiotaropoulou, Georgia, Awasthi, Swapnil, Bigdeli, Tim B., Bryois, Julien, Chen, Chia-Yen, Dennison, Charlotte A., Hall, Lynsey S., Lam, Max, Watanabe, Kyoko, Frei, Oleksandr, Ge, Tian, Harwood, Janet C., Koopmans, Frank, Magnusson, Sigurdur, Richards, Alexander L., Sidorenko, Julia, Wu, Yang, Zeng, Jian, Grove, Jakob, Kim, Minsoo, Li, Zhiqiang, Voloudakis, Georgios, Zhang, Wen, Adams, Mark, Agartz, Ingrid, Atkinson, Elizabeth G., Agerbo, Esben, Al Eissa, Mariam, Albus, Margot, Alexander, Madeline, Alizadeh, Behrooz Z., Alptekin, Köksal, Als, Thomas D., Amin, Farooq, Arolt, Volker, Arrojo, Manuel, Athanasiu, Lavinia, Azevedo, Maria Helena, Bacanu, Silviu A., Bass, Nicholas J., Begemann, Martin, Belliveau, Richard A., Bene, Judit, Benyamin, Beben, Bergen, Sarah E., Blasi, Giuseppe, Bobes, Julio, Bonassi, Stefano, Braun, Alice, Bressan, Rodrigo Affonseca, Bromet, Evelyn J., Bruggeman, Richard, Buckley, Peter F., Buckner, Randy L., Bybjerg-Grauholm, Jonas, Cahn, Wiepke, Cairns, Murray J., Calkins, Monica E., Carr, Vaughan J., Castle, David, Catts, Stanley V., Chambert, Kimberley D., Chan, Raymond C. K., Chaumette, Boris, Cheng, Wei, Cheung, Eric F. C., Chong, Siow Ann, Cohen, David, Consoli, Angèle, Cordeiro, Quirino, Costas, Javier, Curtis, Charles, Davidson, Michael, Davis, Kenneth L., de Haan, Lieuwe, Degenhardt, Franziska, DeLisi, Lynn E., Demontis, Ditte, Dickerson, Faith, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Duan, Jubao, Ducci, Giuseppe, Dudbridge, Frank, Eriksson, Johan G., Fañanás, Lourdes, Faraone, Stephen V., Fiorentino, Alessia, Forstner, Andreas, Frank, Josef, Freimer, Nelson B., Fromer, Menachem, Frustaci, Alessandra, Gadelha, Ary, Genovese, Giulio, Gershon, Elliot S., Giannitelli, Marianna, Giegling, Ina, Giusti-Rodríguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I., González Peñas, Javier, González-Pinto, Ana, Gopal, Srihari, Gratten, Jacob, Green, Michael F., Greenwood, Tiffany A., Guillin, Olivier, Gülöksüz, Sinan, Gur, Raquel E., Gur, Ruben C., Gutiérrez, Blanca, Hahn, Eric, Hakonarson, Hakon, Haroutunian, Vahram, Hartmann, Annette M., Harvey, Carol, Hayward, Caroline, Henskens, Frans A., Herms, Stefan, Hoffmann, Per, Howrigan, Daniel P., Ikeda, Masashi, Iyegbe, Conrad, Joa, Inge, Julià, Antonio, Kähler, Anna K., Kam-Thong, Tony, Kamatani, Yoichiro, Karachanak-Yankova, Sena, Kebir, Oussama, Keller, Matthew C., Kelly, Brian J., Khrunin, Andrey, Kim, Sung-Wan, Klovins, Janis, Kondratiev, Nikolay, Konte, Bettina, Kraft, Julia, Kubo, Michiaki, Kučinskas, Vaidutis, Kučinskiene, Zita Ausrele, Kusumawardhani, Agung, Kuzelova-Ptackova, Hana, Landi, Stefano, Lazzeroni, Laura C., Lee, Phil H., Legge, Sophie E., Lehrer, Douglas S., Lencer, Rebecca, Lerer, Bernard, Li, Miaoxin, Lieberman, Jeffrey, Light, Gregory A., Limborska, Svetlana, Liu, Chih-Min, Lönnqvist, Jouko, Loughland, Carmel M., Lubinski, Jan, Luykx, Jurjen J., Lynham, Amy, Macek, Jr, Milan, Mackinnon, Andrew, Magnusson, Patrik K. E., Maher, Brion S., Maier, Wolfgang, Malaspina, Dolores, Mallet, Jacques, Marder, Stephen R., Marsal, Sara, Martin, Alicia R., Martorell, Lourdes, Mattheisen, Manuel, McCarley, Robert W., McDonald, Colm, McGrath, John J., Medeiros, Helena, Meier, Sandra, Melegh, Bela, Melle, Ingrid, Mesholam-Gately, Raquelle I., Metspalu, Andres, Michie, Patricia T., Milani, Lili, Milanova, Vihra, Mitjans, Marina, Molden, Espen, Molina, Esther, Molto, María Dolores, Mondelli, Valeria, Moreno, Carmen, Morley, Christopher P., Muntané, Gerard, Murphy, Kieran C., Myin-Germeys, Inez, Nenadić, Igor, Nestadt, Gerald, Nikitina-Zake, Liene, Noto, Cristiano, Nuechterlein, Keith H., O’Brien, Niamh Louise, O’Neill, F. Anthony, Oh, Sang-Yun, Olincy, Ann, Ota, Vanessa Kiyomi, Pantelis, Christos, Papadimitriou, George N., Parellada, Mara, Paunio, Tiina, Pellegrino, Renata, Periyasamy, Sathish, Perkins, Diana O., Pfuhlmann, Bruno, Pietiläinen, Olli, Pimm, Jonathan, Porteous, David, Powell, John, Quattrone, Diego, Quested, Digby, Radant, Allen D., Rampino, Antonio, Rapaport, Mark H., Rautanen, Anna, Reichenberg, Abraham, Roe, Cheryl, Roffman, Joshua L., Roth, Julian, Rothermundt, Matthias, Rutten, Bart P. F., Saker-Delye, Safaa, Salomaa, Veikko, Sanjuan, Julio, Santoro, Marcos Leite, Savitz, Adam, Schall, Ulrich, Scott, Rodney J., Seidman, Larry J., Sharp, Sally Isabel, Shi, Jianxin, Siever, Larry J., Sigurdsson, Engilbert, Sim, Kang, Skarabis, Nora, Slominsky, Petr, So, Hon-Cheong, Sobell, Janet L., Söderman, Erik, Stain, Helen J., Steen, Nils Eiel, Steixner-Kumar, Agnes A., Stögmann, Elisabeth, Stone, William S., Straub, Richard E., Streit, Fabian, Strengman, Eric, Stroup, T. Scott, Subramaniam, Mythily, Sugar, Catherine A., Suvisaari, Jaana, Svrakic, Dragan M., Swerdlow, Neal R., Szatkiewicz, Jin P., Ta, Thi Minh Tam, Takahashi, Atsushi, Terao, Chikashi, Thibaut, Florence, Toncheva, Draga, Tooney, Paul A., Torretta, Silvia, Tosato, Sarah, Tura, Gian Battista, Turetsky, Bruce I., Üçok, Alp, Vaaler, Arne, van Amelsvoort, Therese, van Winkel, Ruud, Veijola, Juha, Waddington, John, Walter, Henrik, Waterreus, Anna, Webb, Bradley T., Weiser, Mark, Williams, Nigel M., Witt, Stephanie H., Wormley, Brandon K., Wu, Jing Qin, Xu, Zhida, Yolken, Robert, Zai, Clement C., Zhou, Wei, Zhu, Feng, Zimprich, Fritz, Atbaşoğlu, Eşref Cem, Ayub, Muhammad, Benner, Christian, Bertolino, Alessandro, Black, Donald W., Bray, Nicholas J., Breen, Gerome, Buccola, Nancy G., Byerley, William F., Chen, Wei J., Cloninger, C. Robert, Crespo-Facorro, Benedicto, Donohoe, Gary, Freedman, Robert, Galletly, Cherrie, Gandal, Michael J., Gennarelli, Massimo, Hougaard, David M., Hwu, Hai-Gwo, Jablensky, Assen V., McCarroll, Steven A., Moran, Jennifer L., Mors, Ole, Mortensen, Preben B., Müller-Myhsok, Bertram, Neil, Amanda L., Nordentoft, Merete, Pato, Michele T., Petryshen, Tracey L., Pirinen, Matti, Pulver, Ann E., Schulze, Thomas G., Silverman, Jeremy M., Smoller, Jordan W., Stahl, Eli A., Tsuang, Debby W., Vilella, Elisabet, Wang, Shi-Heng, Xu, Shuhua, Adolfsson, Rolf, Arango, Celso, Baune, Bernhard T., Belangero, Sintia Iole, Børglum, Anders D., Braff, David, Bramon, Elvira, Buxbaum, Joseph D., Campion, Dominique, Cervilla, Jorge A., Cichon, Sven, Collier, David A., Corvin, Aiden, Curtis, David, Forti, Marta Di, Domenici, Enrico, Ehrenreich, Hannelore, Escott-Price, Valentina, Esko, Tõnu, Fanous, Ayman H., Gareeva, Anna, Gawlik, Micha, Gejman, Pablo V., Gill, Michael, Glatt, Stephen J., Golimbet, Vera, Hong, Kyung Sue, Hultman, Christina M., Hyman, Steven E., Iwata, Nakao, Jönsson, Erik G., Kahn, René S., Kennedy, James L., Khusnutdinova, Elza, Kirov, George, Knowles, James A., Krebs, Marie-Odile, Laurent-Levinson, Claudine, Lee, Jimmy, Lencz, Todd, Levinson, Douglas F., Li, Qingqin S., Liu, Jianjun, Malhotra, Anil K., Malhotra, Dheeraj, McIntosh, Andrew, McQuillin, Andrew, Menezes, Paulo R., Morgan, Vera A., Morris, Derek W., Mowry, Bryan J., Murray, Robin M., Nimgaonkar, Vishwajit, Nöthen, Markus M., Ophoff, Roel A., Paciga, Sara A., Palotie, Aarno, Pato, Carlos N., Qin, Shengying, Rietschel, Marcella, Riley, Brien P., Rivera, Margarita, Rujescu, Dan, Saka, Meram C., Sanders, Alan R., Schwab, Sibylle G., Serretti, Alessandro, Sham, Pak C., Shi, Yongyong, St Clair, David, Stefánsson, Hreinn, Stefansson, Kari, Tsuang, Ming T., van Os, Jim, Vawter, Marquis P., Weinberger, Daniel R., Werge, Thomas, Wildenauer, Dieter B., Yu, Xin, Yue, Weihua, Holmans, Peter A., Pocklington, Andrew J., Roussos, Panos, Vassos, Evangelos, Verhage, Matthijs, Visscher, Peter M., Yang, Jian, Posthuma, Danielle, Andreassen, Ole A., Kendler, Kenneth S., Owen, Michael J., Wray, Naomi R., Daly, Mark J., Huang, Hailiang, Neale, Benjamin M., Sullivan, Patrick F., Ripke, Stephan, Walters, James T. R., and O’Donovan, Michael C.

Published
2022
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22. Genetic variants associated with longitudinal changes in brain structure across the lifespan

Author

Brouwer, Rachel M., Klein, Marieke, Grasby, Katrina L., Schnack, Hugo G., Jahanshad, Neda, Teeuw, Jalmar, Thomopoulos, Sophia I., Sprooten, Emma, Franz, Carol E., Gogtay, Nitin, Kremen, William S., Panizzon, Matthew S., Olde Loohuis, Loes M., Whelan, Christopher D., Aghajani, Moji, Alloza, Clara, Alnæs, Dag, Artiges, Eric, Ayesa-Arriola, Rosa, Barker, Gareth J., Bastin, Mark E., Blok, Elisabet, Bøen, Erlend, Breukelaar, Isabella A., Bright, Joanna K., Buimer, Elizabeth E. L., Bülow, Robin, Cannon, Dara M., Ciufolini, Simone, Crossley, Nicolas A., Damatac, Christienne G., Dazzan, Paola, de Mol, Casper L., de Zwarte, Sonja M. C., Desrivières, Sylvane, Díaz-Caneja, Covadonga M., Doan, Nhat Trung, Dohm, Katharina, Fröhner, Juliane H., Goltermann, Janik, Grigis, Antoine, Grotegerd, Dominik, Han, Laura K. M., Harris, Mathew A., Hartman, Catharina A., Heany, Sarah J., Heindel, Walter, Heslenfeld, Dirk J., Hohmann, Sarah, Ittermann, Bernd, Jansen, Philip R., Janssen, Joost, Jia, Tianye, Jiang, Jiyang, Jockwitz, Christiane, Karali, Temmuz, Keeser, Daniel, Koevoets, Martijn G. J. C., Lenroot, Rhoshel K., Malchow, Berend, Mandl, René C. W., Medel, Vicente, Meinert, Susanne, Morgan, Catherine A., Mühleisen, Thomas W., Nabulsi, Leila, Opel, Nils, de la Foz, Víctor Ortiz-García, Overs, Bronwyn J., Paillère Martinot, Marie-Laure, Redlich, Ronny, Marques, Tiago Reis, Repple, Jonathan, Roberts, Gloria, Roshchupkin, Gennady V., Setiaman, Nikita, Shumskaya, Elena, Stein, Frederike, Sudre, Gustavo, Takahashi, Shun, Thalamuthu, Anbupalam, Tordesillas-Gutiérrez, Diana, van der Lugt, Aad, van Haren, Neeltje E. M., Wardlaw, Joanna M., Wen, Wei, Westeneng, Henk-Jan, Wittfeld, Katharina, Zhu, Alyssa H., Zugman, Andre, Armstrong, Nicola J., Bonfiglio, Gaia, Bralten, Janita, Dalvie, Shareefa, Davies, Gail, Di Forti, Marta, Ding, Linda, Donohoe, Gary, Forstner, Andreas J., Gonzalez-Peñas, Javier, Guimaraes, Joao P. O. F. T., Homuth, Georg, Hottenga, Jouke-Jan, Knol, Maria J., Kwok, John B. J., Le Hellard, Stephanie, Mather, Karen A., Milaneschi, Yuri, Morris, Derek W., Nöthen, Markus M., Papiol, Sergi, Rietschel, Marcella, Santoro, Marcos L., Steen, Vidar M., Stein, Jason L., Streit, Fabian, Tankard, Rick M., Teumer, Alexander, van ‘t Ent, Dennis, van der Meer, Dennis, van Eijk, Kristel R., Vassos, Evangelos, Vázquez-Bourgon, Javier, Witt, Stephanie H., Adams, Hieab H. H., Agartz, Ingrid, Ames, David, Amunts, Katrin, Andreassen, Ole A., Arango, Celso, Banaschewski, Tobias, Baune, Bernhard T., Belangero, Sintia I., Bokde, Arun L. W., Boomsma, Dorret I., Bressan, Rodrigo A., Brodaty, Henry, Buitelaar, Jan K., Cahn, Wiepke, Caspers, Svenja, Cichon, Sven, Crespo-Facorro, Benedicto, Cox, Simon R., Dannlowski, Udo, Elvsåshagen, Torbjørn, Espeseth, Thomas, Falkai, Peter G., Fisher, Simon E., Flor, Herta, Fullerton, Janice M., Garavan, Hugh, Gowland, Penny A., Grabe, Hans J., Hahn, Tim, Heinz, Andreas, Hillegers, Manon, Hoare, Jacqueline, Hoekstra, Pieter J., Ikram, Mohammad A., Jackowski, Andrea P., Jansen, Andreas, Jönsson, Erik G., Kahn, Rene S., Kircher, Tilo, Korgaonkar, Mayuresh S., Krug, Axel, Lemaitre, Herve, Malt, Ulrik F., Martinot, Jean-Luc, McDonald, Colm, Mitchell, Philip B., Muetzel, Ryan L., Murray, Robin M., Nees, Frauke, Nenadić, Igor, Oosterlaan, Jaap, Ophoff, Roel A., Pan, Pedro M., Penninx, Brenda W. J. H., Poustka, Luise, Sachdev, Perminder S., Salum, Giovanni A., Schofield, Peter R., Schumann, Gunter, Shaw, Philip, Sim, Kang, Smolka, Michael N., Stein, Dan J., Trollor, Julian N., van den Berg, Leonard H., Veldink, Jan H., Walter, Henrik, Westlye, Lars T., Whelan, Robert, White, Tonya, Wright, Margaret J., Medland, Sarah E., Franke, Barbara, Thompson, Paul M., and Hulshoff Pol, Hilleke E.

Published
2022
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23. Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.

Author

Lam, Max, Hill, W David, Trampush, Joey W, Yu, Jin, Knowles, Emma, Davies, Gail, Stahl, Eli, Huckins, Laura, Liewald, David C, Djurovic, Srdjan, Melle, Ingrid, Sundet, Kjetil, Christoforou, Andrea, Reinvang, Ivar, DeRosse, Pamela, Lundervold, Astri J, Steen, Vidar M, Espeseth, Thomas, Räikkönen, Katri, Widen, Elisabeth, Palotie, Aarno, Eriksson, Johan G, Giegling, Ina, Konte, Bettina, Hartmann, Annette M, Roussos, Panos, Giakoumaki, Stella, Burdick, Katherine E, Payton, Antony, Ollier, William, Chiba-Falek, Ornit, Attix, Deborah K, Need, Anna C, Cirulli, Elizabeth T, Voineskos, Aristotle N, Stefanis, Nikos C, Avramopoulos, Dimitrios, Hatzimanolis, Alex, Arking, Dan E, Smyrnis, Nikolaos, Bilder, Robert M, Freimer, Nelson A, Cannon, Tyrone D, London, Edythe, Poldrack, Russell A, Sabb, Fred W, Congdon, Eliza, Conley, Emily Drabant, Scult, Matthew A, Dickinson, Dwight, Straub, Richard E, Donohoe, Gary, Morris, Derek, Corvin, Aiden, Gill, Michael, Hariri, Ahmad R, Weinberger, Daniel R, Pendleton, Neil, Bitsios, Panos, Rujescu, Dan, Lahti, Jari, Le Hellard, Stephanie, Keller, Matthew C, Andreassen, Ole A, Deary, Ian J, Glahn, David C, Malhotra, Anil K, and Lencz, Todd

Subjects
Humans, Genetic Predisposition to Disease, Cognition, Cognition Disorders, Schizophrenia, Synaptic Transmission, Polymorphism, Single Nucleotide, Adult, Educational Status, Genome-Wide Association Study, Neurodevelopmental Disorders, GWAS, cognitive ability, educational attainment, genetic correlation, pathways, pleiotropy, schizophrenia, Serious Mental Illness, Neurosciences, Biotechnology, Mental Health, Genetics, Brain Disorders, Prevention, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Mental health, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected ("concordant") direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive ("discordant") relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10-8. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms-early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways-that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness.

Published
2019

24. Author Correction: Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.

Author

Davies, Gail, Lam, Max, Harris, Sarah E, Trampush, Joey W, Luciano, Michelle, Hill, W David, Hagenaars, Saskia P, Ritchie, Stuart J, Marioni, Riccardo E, Fawns-Ritchie, Chloe, Liewald, David CM, Okely, Judith A, Ahola-Olli, Ari V, Barnes, Catriona LK, Bertram, Lars, Bis, Joshua C, Burdick, Katherine E, Christoforou, Andrea, DeRosse, Pamela, Djurovic, Srdjan, Espeseth, Thomas, Giakoumaki, Stella, Giddaluru, Sudheer, Gustavson, Daniel E, Hayward, Caroline, Hofer, Edith, Ikram, M Arfan, Karlsson, Robert, Knowles, Emma, Lahti, Jari, Leber, Markus, Li, Shuo, Mather, Karen A, Melle, Ingrid, Morris, Derek, Oldmeadow, Christopher, Palviainen, Teemu, Payton, Antony, Pazoki, Raha, Petrovic, Katja, Reynolds, Chandra A, Sargurupremraj, Muralidharan, Scholz, Markus, Smith, Jennifer A, Smith, Albert V, Terzikhan, Natalie, Thalamuthu, Anbupalam, Trompet, Stella, van der Lee, Sven J, Ware, Erin B, Windham, B Gwen, Wright, Margaret J, Yang, Jingyun, Yu, Jin, Ames, David, Amin, Najaf, Amouyel, Philippe, Andreassen, Ole A, Armstrong, Nicola J, Assareh, Amelia A, Attia, John R, Attix, Deborah, Avramopoulos, Dimitrios, Bennett, David A, Böhmer, Anne C, Boyle, Patricia A, Brodaty, Henry, Campbell, Harry, Cannon, Tyrone D, Cirulli, Elizabeth T, Congdon, Eliza, Conley, Emily Drabant, Corley, Janie, Cox, Simon R, Dale, Anders M, Dehghan, Abbas, Dick, Danielle, Dickinson, Dwight, Eriksson, Johan G, Evangelou, Evangelos, Faul, Jessica D, Ford, Ian, Freimer, Nelson A, Gao, He, Giegling, Ina, Gillespie, Nathan A, Gordon, Scott D, Gottesman, Rebecca F, Griswold, Michael E, Gudnason, Vilmundur, Harris, Tamara B, Hartmann, Annette M, Hatzimanolis, Alex, Heiss, Gerardo, Holliday, Elizabeth G, Joshi, Peter K, Kähönen, Mika, Kardia, Sharon LR, Karlsson, Ida, and Kleineidam, Luca

Abstract

Christina M. Lill, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this article. This has now been corrected in both the PDF and HTML versions of the article.

Published
2019

25. Cortical Brain Abnormalities in 4474 Individuals With Schizophrenia and 5098 Control Subjects via the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) Consortium.

Author

van Erp, Theo GM, Walton, Esther, Hibar, Derrek P, Schmaal, Lianne, Jiang, Wenhao, Glahn, David C, Pearlson, Godfrey D, Yao, Nailin, Fukunaga, Masaki, Hashimoto, Ryota, Okada, Naohiro, Yamamori, Hidenaga, Bustillo, Juan R, Clark, Vincent P, Agartz, Ingrid, Mueller, Bryon A, Cahn, Wiepke, de Zwarte, Sonja MC, Hulshoff Pol, Hilleke E, Kahn, René S, Ophoff, Roel A, van Haren, Neeltje EM, Andreassen, Ole A, Dale, Anders M, Doan, Nhat Trung, Gurholt, Tiril P, Hartberg, Cecilie B, Haukvik, Unn K, Jørgensen, Kjetil N, Lagerberg, Trine V, Melle, Ingrid, Westlye, Lars T, Gruber, Oliver, Kraemer, Bernd, Richter, Anja, Zilles, David, Calhoun, Vince D, Crespo-Facorro, Benedicto, Roiz-Santiañez, Roberto, Tordesillas-Gutiérrez, Diana, Loughland, Carmel, Carr, Vaughan J, Catts, Stanley, Cropley, Vanessa L, Fullerton, Janice M, Green, Melissa J, Henskens, Frans A, Jablensky, Assen, Lenroot, Rhoshel K, Mowry, Bryan J, Michie, Patricia T, Pantelis, Christos, Quidé, Yann, Schall, Ulrich, Scott, Rodney J, Cairns, Murray J, Seal, Marc, Tooney, Paul A, Rasser, Paul E, Cooper, Gavin, Shannon Weickert, Cynthia, Weickert, Thomas W, Morris, Derek W, Hong, Elliot, Kochunov, Peter, Beard, Lauren M, Gur, Raquel E, Gur, Ruben C, Satterthwaite, Theodore D, Wolf, Daniel H, Belger, Aysenil, Brown, Gregory G, Ford, Judith M, Macciardi, Fabio, Mathalon, Daniel H, O'Leary, Daniel S, Potkin, Steven G, Preda, Adrian, Voyvodic, James, Lim, Kelvin O, McEwen, Sarah, Yang, Fude, Tan, Yunlong, Tan, Shuping, Wang, Zhiren, Fan, Fengmei, Chen, Jingxu, Xiang, Hong, Tang, Shiyou, Guo, Hua, Wan, Ping, Wei, Dong, Bockholt, Henry J, Ehrlich, Stefan, Wolthusen, Rick PF, King, Margaret D, Shoemaker, Jody M, Sponheim, Scott R, De Haan, Lieuwe, and Koenders, Laura

Subjects
Karolinska Schizophrenia Project, Brain, Frontal Lobe, Prefrontal Cortex, Temporal Lobe, Humans, Magnetic Resonance Imaging, Severity of Illness Index, Linear Models, Case-Control Studies, Schizophrenia, Age of Onset, Adolescent, Adult, Aged, Middle Aged, Child, Female, Male, Young Adult, Neuroimaging, Cortical, Imaging, Meta-analysis, Surface area, Thickness, Serious Mental Illness, Biomedical Imaging, Mental Health, Clinical Research, Neurosciences, Brain Disorders, Mental health, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

BackgroundThe profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group.MethodsThe study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide.ResultsCompared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset.ConclusionsThe findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia.

Published
2018

26. Multi-Trait Analysis of GWAS and Biological Insights Into Cognition: A Response to Hill (2018)

Author

Lam, Max, Trampush, Joey W, Yu, Jin, Knowles, Emma, Djurovic, Srdjan, Melle, Ingrid, Sundet, Kjetil, Christoforou, Andrea, Reinvang, Ivar, DeRosse, Pamela, Lundervold, Astri J, Steen, Vidar M, Espeseth, Thomas, Räikkönen, Katri, Widen, Elisabeth, Palotie, Aarno, Eriksson, Johan G, Giegling, Ina, Konte, Bettina, Roussos, Panos, Giakoumaki, Stella, Burdick, Katherine E, Payton, Antony, Ollier, William, Chiba-Falek, Ornit, Attix, Deborah K, Need, Anna C, Cirulli, Elizabeth T, Voineskos, Aristotle N, Stefanis, Nikos C, Avramopoulos, Dimitrios, Hatzimanolis, Alex, Arking, Dan E, Smyrnis, Nikolaos, Bilder, Robert M, Freimer, Nelson A, Cannon, Tyrone D, London, Edythe, Poldrack, Russell A, Sabb, Fred W, Congdon, Eliza, Conley, Emily Drabant, Scult, Matthew A, Dickinson, Dwight, Straub, Richard E, Donohoe, Gary, Morris, Derek, Corvin, Aiden, Gill, Michael, Hariri, Ahmad R, Weinberger, Daniel R, Pendleton, Neil, Bitsios, Panos, Rujescu, Dan, Lahti, Jari, Le Hellard, Stephanie, Keller, Matthew C, Andreassen, Ole A, Glahn, David C, Malhotra, Anil K, and Lencz, Todd

Subjects
Reproductive Medicine, Biomedical and Clinical Sciences, Clinical Sciences, Human Genome, Genetics, Mental Health, Aetiology, 2.1 Biological and endogenous factors, Cognition, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Nootropic Agents, Polymorphism, Single Nucleotide, GWAS, general cognitive ability, nootropics, gene expression, neurodevelopment, synapse, calcium channel, potassium channel, cerebellum, Paediatrics and Reproductive Medicine, Cognitive Sciences, Genetics & Heredity, Clinical sciences, Reproductive medicine
Abstract

Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88) presented a critique of our recently published paper in Cell Reports entitled 'Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets' (Lam et al., Cell Reports, Vol. 21, 2017, 2597-2613). Specifically, Hill offered several interrelated comments suggesting potential problems with our use of a new analytic method called Multi-Trait Analysis of GWAS (MTAG) (Turley et al., Nature Genetics, Vol. 50, 2018, 229-237). In this brief article, we respond to each of these concerns. Using empirical data, we conclude that our MTAG results do not suffer from 'inflation in the FDR [false discovery rate]', as suggested by Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88), and are not 'more relevant to the genetic contributions to education than they are to the genetic contributions to intelligence'.

Published
2018

27. Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence

Author

Savage, Jeanne E, Jansen, Philip R, Stringer, Sven, Watanabe, Kyoko, Bryois, Julien, de Leeuw, Christiaan A, Nagel, Mats, Awasthi, Swapnil, Barr, Peter B, Coleman, Jonathan RI, Grasby, Katrina L, Hammerschlag, Anke R, Kaminski, Jakob A, Karlsson, Robert, Krapohl, Eva, Lam, Max, Nygaard, Marianne, Reynolds, Chandra A, Trampush, Joey W, Young, Hannah, Zabaneh, Delilah, Hägg, Sara, Hansell, Narelle K, Karlsson, Ida K, Linnarsson, Sten, Montgomery, Grant W, Muñoz-Manchado, Ana B, Quinlan, Erin B, Schumann, Gunter, Skene, Nathan G, Webb, Bradley T, White, Tonya, Arking, Dan E, Avramopoulos, Dimitrios, Bilder, Robert M, Bitsios, Panos, Burdick, Katherine E, Cannon, Tyrone D, Chiba-Falek, Ornit, Christoforou, Andrea, Cirulli, Elizabeth T, Congdon, Eliza, Corvin, Aiden, Davies, Gail, Deary, Ian J, DeRosse, Pamela, Dickinson, Dwight, Djurovic, Srdjan, Donohoe, Gary, Conley, Emily Drabant, Eriksson, Johan G, Espeseth, Thomas, Freimer, Nelson A, Giakoumaki, Stella, Giegling, Ina, Gill, Michael, Glahn, David C, Hariri, Ahmad R, Hatzimanolis, Alex, Keller, Matthew C, Knowles, Emma, Koltai, Deborah, Konte, Bettina, Lahti, Jari, Le Hellard, Stephanie, Lencz, Todd, Liewald, David C, London, Edythe, Lundervold, Astri J, Malhotra, Anil K, Melle, Ingrid, Morris, Derek, Need, Anna C, Ollier, William, Palotie, Aarno, Payton, Antony, Pendleton, Neil, Poldrack, Russell A, Räikkönen, Katri, Reinvang, Ivar, Roussos, Panos, Rujescu, Dan, Sabb, Fred W, Scult, Matthew A, Smeland, Olav B, Smyrnis, Nikolaos, Starr, John M, Steen, Vidar M, Stefanis, Nikos C, Straub, Richard E, Sundet, Kjetil, Tiemeier, Henning, Voineskos, Aristotle N, Weinberger, Daniel R, Widen, Elisabeth, Yu, Jin, Abecasis, Goncalo, Andreassen, Ole A, Breen, Gerome, and Christiansen, Lene

Subjects
Biological Sciences, Genetics, Brain Disorders, Mental Health, Human Genome, Biotechnology, Neurosciences, Underpinning research, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Aetiology, Mental health, Neurological, Adolescent, Brain, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Intelligence, Male, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.

Published
2018

28. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.

Author

Davies, Gail, Lam, Max, Harris, Sarah E, Trampush, Joey W, Luciano, Michelle, Hill, W David, Hagenaars, Saskia P, Ritchie, Stuart J, Marioni, Riccardo E, Fawns-Ritchie, Chloe, Liewald, David CM, Okely, Judith A, Ahola-Olli, Ari V, Barnes, Catriona LK, Bertram, Lars, Bis, Joshua C, Burdick, Katherine E, Christoforou, Andrea, DeRosse, Pamela, Djurovic, Srdjan, Espeseth, Thomas, Giakoumaki, Stella, Giddaluru, Sudheer, Gustavson, Daniel E, Hayward, Caroline, Hofer, Edith, Ikram, M Arfan, Karlsson, Robert, Knowles, Emma, Lahti, Jari, Leber, Markus, Li, Shuo, Mather, Karen A, Melle, Ingrid, Morris, Derek, Oldmeadow, Christopher, Palviainen, Teemu, Payton, Antony, Pazoki, Raha, Petrovic, Katja, Reynolds, Chandra A, Sargurupremraj, Muralidharan, Scholz, Markus, Smith, Jennifer A, Smith, Albert V, Terzikhan, Natalie, Thalamuthu, Anbupalam, Trompet, Stella, van der Lee, Sven J, Ware, Erin B, Windham, B Gwen, Wright, Margaret J, Yang, Jingyun, Yu, Jin, Ames, David, Amin, Najaf, Amouyel, Philippe, Andreassen, Ole A, Armstrong, Nicola J, Assareh, Amelia A, Attia, John R, Attix, Deborah, Avramopoulos, Dimitrios, Bennett, David A, Böhmer, Anne C, Boyle, Patricia A, Brodaty, Henry, Campbell, Harry, Cannon, Tyrone D, Cirulli, Elizabeth T, Congdon, Eliza, Conley, Emily Drabant, Corley, Janie, Cox, Simon R, Dale, Anders M, Dehghan, Abbas, Dick, Danielle, Dickinson, Dwight, Eriksson, Johan G, Evangelou, Evangelos, Faul, Jessica D, Ford, Ian, Freimer, Nelson A, Gao, He, Giegling, Ina, Gillespie, Nathan A, Gordon, Scott D, Gottesman, Rebecca F, Griswold, Michael E, Gudnason, Vilmundur, Harris, Tamara B, Hartmann, Annette M, Hatzimanolis, Alex, Heiss, Gerardo, Holliday, Elizabeth G, Joshi, Peter K, Kähönen, Mika, Kardia, Sharon LR, Karlsson, Ida, and Kleineidam, Luca

Subjects
Humans, Neurodegenerative Diseases, Genetic Predisposition to Disease, Cognition, Reaction Time, Mental Disorders, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Adolescent, Adult, Aged, Aged, 80 and over, Middle Aged, Young Adult, Genetic Loci, Neurodevelopmental Disorders, Prevention, Behavioral and Social Science, Mental Health, Neurosciences, Biotechnology, Genetics, Human Genome, Neurological, Mental health
Abstract

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P

Published
2018

29. Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets

Author

Lam, Max, Trampush, Joey W, Yu, Jin, Knowles, Emma, Davies, Gail, Liewald, David C, Starr, John M, Djurovic, Srdjan, Melle, Ingrid, Sundet, Kjetil, Christoforou, Andrea, Reinvang, Ivar, DeRosse, Pamela, Lundervold, Astri J, Steen, Vidar M, Espeseth, Thomas, Räikkönen, Katri, Widen, Elisabeth, Palotie, Aarno, Eriksson, Johan G, Giegling, Ina, Konte, Bettina, Roussos, Panos, Giakoumaki, Stella, Burdick, Katherine E, Payton, Antony, Ollier, William, Chiba-Falek, Ornit, Attix, Deborah K, Need, Anna C, Cirulli, Elizabeth T, Voineskos, Aristotle N, Stefanis, Nikos C, Avramopoulos, Dimitrios, Hatzimanolis, Alex, Arking, Dan E, Smyrnis, Nikolaos, Bilder, Robert M, Freimer, Nelson A, Cannon, Tyrone D, London, Edythe, Poldrack, Russell A, Sabb, Fred W, Congdon, Eliza, Conley, Emily Drabant, Scult, Matthew A, Dickinson, Dwight, Straub, Richard E, Donohoe, Gary, Morris, Derek, Corvin, Aiden, Gill, Michael, Hariri, Ahmad R, Weinberger, Daniel R, Pendleton, Neil, Bitsios, Panos, Rujescu, Dan, Lahti, Jari, Le Hellard, Stephanie, Keller, Matthew C, Andreassen, Ole A, Deary, Ian J, Glahn, David C, Malhotra, Anil K, and Lencz, Todd

Subjects
Biological Sciences, Genetics, Mental Health, Aging, Brain Disorders, Biotechnology, Autoimmune Disease, Neurosciences, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Underpinning research, 1.1 Normal biological development and functioning, Mental health, Neurological, Cefotaxime, Cognition, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Nootropic Agents, Polymorphism, Single Nucleotide, Synapses, GWAS, calcium channel, cerebellum, gene expression, general cognitive ability, neurodevelopment, nootropics, potassium channel, synapse, Biochemistry and Cell Biology, Medical Physiology, Biological sciences
Abstract

Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth.

Published
2017

30. Human subcortical brain asymmetries in 15,847 people worldwide reveal effects of age and sex.

Author

Guadalupe, Tulio, Mathias, Samuel R, vanErp, Theo GM, Whelan, Christopher D, Zwiers, Marcel P, Abe, Yoshinari, Abramovic, Lucija, Agartz, Ingrid, Andreassen, Ole A, Arias-Vásquez, Alejandro, Aribisala, Benjamin S, Armstrong, Nicola J, Arolt, Volker, Artiges, Eric, Ayesa-Arriola, Rosa, Baboyan, Vatche G, Banaschewski, Tobias, Barker, Gareth, Bastin, Mark E, Baune, Bernhard T, Blangero, John, Bokde, Arun LW, Boedhoe, Premika SW, Bose, Anushree, Brem, Silvia, Brodaty, Henry, Bromberg, Uli, Brooks, Samantha, Büchel, Christian, Buitelaar, Jan, Calhoun, Vince D, Cannon, Dara M, Cattrell, Anna, Cheng, Yuqi, Conrod, Patricia J, Conzelmann, Annette, Corvin, Aiden, Crespo-Facorro, Benedicto, Crivello, Fabrice, Dannlowski, Udo, de Zubicaray, Greig I, de Zwarte, Sonja MC, Deary, Ian J, Desrivières, Sylvane, Doan, Nhat Trung, Donohoe, Gary, Dørum, Erlend S, Ehrlich, Stefan, Espeseth, Thomas, Fernández, Guillén, Flor, Herta, Fouche, Jean-Paul, Frouin, Vincent, Fukunaga, Masaki, Gallinat, Jürgen, Garavan, Hugh, Gill, Michael, Suarez, Andrea Gonzalez, Gowland, Penny, Grabe, Hans J, Grotegerd, Dominik, Gruber, Oliver, Hagenaars, Saskia, Hashimoto, Ryota, Hauser, Tobias U, Heinz, Andreas, Hibar, Derrek P, Hoekstra, Pieter J, Hoogman, Martine, Howells, Fleur M, Hu, Hao, Hulshoff Pol, Hilleke E, Huyser, Chaim, Ittermann, Bernd, Jahanshad, Neda, Jönsson, Erik G, Jurk, Sarah, Kahn, Rene S, Kelly, Sinead, Kraemer, Bernd, Kugel, Harald, Kwon, Jun Soo, Lemaitre, Herve, Lesch, Klaus-Peter, Lochner, Christine, Luciano, Michelle, Marquand, Andre F, Martin, Nicholas G, Martínez-Zalacaín, Ignacio, Martinot, Jean-Luc, Mataix-Cols, David, Mather, Karen, McDonald, Colm, McMahon, Katie L, Medland, Sarah E, Menchón, José M, Morris, Derek W, Mothersill, Omar, Maniega, Susana Munoz, and Mwangi, Benson

Subjects
Brain, Humans, Magnetic Resonance Imaging, Organ Size, Aging, Sex Characteristics, Quantitative Trait, Heritable, Adolescent, Adult, Aged, Middle Aged, Female, Male, Functional Laterality, Meta-Analysis as Topic, Young Adult, Age, Enigma, Handedness, Heritability, Meta-analysis, Sex, Subcortical brain asymmetry, Quantitative Trait, Heritable, Medical and Health Sciences, Psychology and Cognitive Sciences, Experimental Psychology
Abstract

The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders.

Published
2017

35. Mir137 Polygenic Risk for Schizophrenia and Ephrin-Regulated Pathway: Role in Lateral Ventricles and Corpus Callosum Volume

Author

Blokland, Gabriëlla Antonina Maria, primary, Maleki, Nasim, additional, Jovicich, Jorge, additional, Mesholam-Gately, Raquelle, additional, DeLisi, Lynn E., additional, Turner, Jessica A., additional, Shenton, Martha E., additional, Voineskos, Aristotle, additional, Kahn, Rene S., additional, Roffman, Joshua L., additional, Holt, Daphne J., additional, Ehrlich, Stefan, additional, Kikinis, Zora, additional, Dazzan, Paola, additional, Murray, Robin, additional, Lee, Jimmy, additional, Sim, Kang, additional, Lam, Max, additional, de Zwarte, Sonja M. C., additional, Walton, Esther, additional, Kelly, Sinead, additional, Picchioni, Marco M., additional, Bramon, Elvira, additional, Makris, Nikos, additional, David, Anthony S., additional, Mondelli, Valeria, additional, Reinders, Antje ATS, additional, Oykhman, Efim, additional, Morris, Derek W., additional, Gill, Michael, additional, Corvin, Aiden, additional, Cahn, Wiepke, additional, Ho, New Fei, additional, Liu, Jianjun, additional, Gollub, Randy L., additional, Manoach, Dara S., additional, Calhoun, Vince D., additional, Sponheim, Scott R., additional, Buka, Stephen, additional, Cherkerzian, Sara, additional, Thermenos, Heidi W., additional, Dickie, Erin W., additional, Ciufolini, Simone, additional, Reis Marques, Tiago, additional, Crossley, Nicolas A., additional, Purcell, Shaun M., additional, Smoller, Jordan W., additional, van Haren, Neeltje E.M., additional, Toulopoulou, Timothea, additional, Donohoe, Gary, additional, Goldstein, Jill M., additional, Keshavan, Matcheri S., additional, Petryshen, Tracey L., additional, and del Re, Elisabetta Claudia, additional

Published
2024
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36. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Author

Mullins, Niamh, Forstner, Andreas J., O’Connell, Kevin S., Coombes, Brandon, Coleman, Jonathan R. I., Qiao, Zhen, Als, Thomas D., Bigdeli, Tim B., Børte, Sigrid, Bryois, Julien, Charney, Alexander W., Drange, Ole Kristian, Gandal, Michael J., Hagenaars, Saskia P., Ikeda, Masashi, Kamitaki, Nolan, Kim, Minsoo, Krebs, Kristi, Panagiotaropoulou, Georgia, Schilder, Brian M., Sloofman, Laura G., Steinberg, Stacy, Trubetskoy, Vassily, Winsvold, Bendik S., Won, Hong-Hee, Abramova, Liliya, Adorjan, Kristina, Agerbo, Esben, Al Eissa, Mariam, Albani, Diego, Alliey-Rodriguez, Ney, Anjorin, Adebayo, Antilla, Verneri, Antoniou, Anastasia, Awasthi, Swapnil, Baek, Ji Hyun, Bækvad-Hansen, Marie, Bass, Nicholas, Bauer, Michael, Beins, Eva C., Bergen, Sarah E., Birner, Armin, Bøcker Pedersen, Carsten, Bøen, Erlend, Boks, Marco P., Bosch, Rosa, Brum, Murielle, Brumpton, Ben M., Brunkhorst-Kanaan, Nathalie, Budde, Monika, Bybjerg-Grauholm, Jonas, Byerley, William, Cairns, Murray, Casas, Miquel, Cervantes, Pablo, Clarke, Toni-Kim, Cruceanu, Cristiana, Cuellar-Barboza, Alfredo, Cunningham, Julie, Curtis, David, Czerski, Piotr M., Dale, Anders M., Dalkner, Nina, David, Friederike S., Degenhardt, Franziska, Djurovic, Srdjan, Dobbyn, Amanda L., Douzenis, Athanassios, Elvsåshagen, Torbjørn, Escott-Price, Valentina, Ferrier, I. Nicol, Fiorentino, Alessia, Foroud, Tatiana M., Forty, Liz, Frank, Josef, Frei, Oleksandr, Freimer, Nelson B., Frisén, Louise, Gade, Katrin, Garnham, Julie, Gelernter, Joel, Giørtz Pedersen, Marianne, Gizer, Ian R., Gordon, Scott D., Gordon-Smith, Katherine, Greenwood, Tiffany A., Grove, Jakob, Guzman-Parra, José, Ha, Kyooseob, Haraldsson, Magnus, Hautzinger, Martin, Heilbronner, Urs, Hellgren, Dennis, Herms, Stefan, Hoffmann, Per, Holmans, Peter A., Huckins, Laura, Jamain, Stéphane, Johnson, Jessica S., Kalman, Janos L., Kamatani, Yoichiro, Kennedy, James L., Kittel-Schneider, Sarah, Knowles, James A., Kogevinas, Manolis, Koromina, Maria, Kranz, Thorsten M., Kranzler, Henry R., Kubo, Michiaki, Kupka, Ralph, Kushner, Steven A., Lavebratt, Catharina, Lawrence, Jacob, Leber, Markus, Lee, Heon-Jeong, Lee, Phil H., Levy, Shawn E., Lewis, Catrin, Liao, Calwing, Lucae, Susanne, Lundberg, Martin, MacIntyre, Donald J., Magnusson, Sigurdur H., Maier, Wolfgang, Maihofer, Adam, Malaspina, Dolores, Maratou, Eirini, Martinsson, Lina, Mattheisen, Manuel, McCarroll, Steven A., McGregor, Nathaniel W., McGuffin, Peter, McKay, James D., Medeiros, Helena, Medland, Sarah E., Millischer, Vincent, Montgomery, Grant W., Moran, Jennifer L., Morris, Derek W., Mühleisen, Thomas W., O’Brien, Niamh, O’Donovan, Claire, Olde Loohuis, Loes M., Oruc, Lilijana, Papiol, Sergi, Pardiñas, Antonio F., Perry, Amy, Pfennig, Andrea, Porichi, Evgenia, Potash, James B., Quested, Digby, Raj, Towfique, Rapaport, Mark H., DePaulo, J. Raymond, Regeer, Eline J., Rice, John P., Rivas, Fabio, Rivera, Margarita, Roth, Julian, Roussos, Panos, Ruderfer, Douglas M., Sánchez-Mora, Cristina, Schulte, Eva C., Senner, Fanny, Sharp, Sally, Shilling, Paul D., Sigurdsson, Engilbert, Sirignano, Lea, Slaney, Claire, Smeland, Olav B., Smith, Daniel J., Sobell, Janet L., Søholm Hansen, Christine, Soler Artigas, Maria, Spijker, Anne T., Stein, Dan J., Strauss, John S., Świątkowska, Beata, Terao, Chikashi, Thorgeirsson, Thorgeir E., Toma, Claudio, Tooney, Paul, Tsermpini, Evangelia-Eirini, Vawter, Marquis P., Vedder, Helmut, Walters, James T. R., Witt, Stephanie H., Xi, Simon, Xu, Wei, Yang, Jessica Mei Kay, Young, Allan H., Young, Hannah, Zandi, Peter P., Zhou, Hang, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Alda, Martin, Alfredsson, Lars, Babadjanova, Gulja, Backlund, Lena, Baune, Bernhard T., Bellivier, Frank, Bengesser, Susanne, Berrettini, Wade H., Blackwood, Douglas H. R., Boehnke, Michael, Børglum, Anders D., Breen, Gerome, Carr, Vaughan J., Catts, Stanley, Corvin, Aiden, Craddock, Nicholas, Dannlowski, Udo, Dikeos, Dimitris, Esko, Tõnu, Etain, Bruno, Ferentinos, Panagiotis, Frye, Mark, Fullerton, Janice M., Gawlik, Micha, Gershon, Elliot S., Goes, Fernando S., Green, Melissa J., Grigoroiu-Serbanescu, Maria, Hauser, Joanna, Henskens, Frans, Hillert, Jan, Hong, Kyung Sue, Hougaard, David M., Hultman, Christina M., Hveem, Kristian, Iwata, Nakao, Jablensky, Assen V., Jones, Ian, Jones, Lisa A., Kahn, René S., Kelsoe, John R., Kirov, George, Landén, Mikael, Leboyer, Marion, Lewis, Cathryn M., Li, Qingqin S., Lissowska, Jolanta, Lochner, Christine, Loughland, Carmel, Martin, Nicholas G., Mathews, Carol A., Mayoral, Fermin, McElroy, Susan L., McIntosh, Andrew M., McMahon, Francis J., Melle, Ingrid, Michie, Patricia, Milani, Lili, Mitchell, Philip B., Morken, Gunnar, Mors, Ole, Mortensen, Preben Bo, Mowry, Bryan, Müller-Myhsok, Bertram, Myers, Richard M., Neale, Benjamin M., Nievergelt, Caroline M., Nordentoft, Merete, Nöthen, Markus M., O’Donovan, Michael C., Oedegaard, Ketil J., Olsson, Tomas, Owen, Michael J., Paciga, Sara A., Pantelis, Chris, Pato, Carlos, Pato, Michele T., Patrinos, George P., Perlis, Roy H., Posthuma, Danielle, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Reininghaus, Eva Z., Ribasés, Marta, Rietschel, Marcella, Ripke, Stephan, Rouleau, Guy A., Saito, Takeo, Schall, Ulrich, Schalling, Martin, Schofield, Peter R., Schulze, Thomas G., Scott, Laura J., Scott, Rodney J., Serretti, Alessandro, Shannon Weickert, Cynthia, Smoller, Jordan W., Stefansson, Hreinn, Stefansson, Kari, Stordal, Eystein, Streit, Fabian, Sullivan, Patrick F., Turecki, Gustavo, Vaaler, Arne E., Vieta, Eduard, Vincent, John B., Waldman, Irwin D., Weickert, Thomas W., Werge, Thomas, Wray, Naomi R., Zwart, John-Anker, Biernacka, Joanna M., Nurnberger, John I., Cichon, Sven, Edenberg, Howard J., Stahl, Eli A., McQuillin, Andrew, Di Florio, Arianna, Ophoff, Roel A., and Andreassen, Ole A.

Published
2021
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37. Neuroharmony: A new tool for harmonizing volumetric MRI data from unseen scanners

Author

Garcia-Dias, Rafael, Scarpazza, Cristina, Baecker, Lea, Vieira, Sandra, Pinaya, Walter H.L., Corvin, Aiden, Redolfi, Alberto, Nelson, Barnaby, Crespo-Facorro, Benedicto, McDonald, Colm, Tordesillas-Gutiérrez, Diana, Cannon, Dara, Mothersill, David, Hernaus, Dennis, Morris, Derek, Setien-Suero, Esther, Donohoe, Gary, Frisoni, Giovanni, Tronchin, Giulia, Sato, João, Marcelis, Machteld, Kempton, Matthew, van Haren, Neeltje E.M., Gruber, Oliver, McGorry, Patrick, Amminger, Paul, McGuire, Philip, Gong, Qiyong, Kahn, René S., Ayesa-Arriola, Rosa, van Amelsvoort, Therese, Ortiz-García de la Foz, Victor, Calhoun, Vince, Cahn, Wiepke, and Mechelli, Andrea

Published
2020
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38. The Genetics of the Mood Disorder Spectrum: Genome-wide Association Analyses of More Than 185,000 Cases and 439,000 Controls

Author

Byrne, Enda M., Forstner, Andreas J., Holmans, Peter A., de Leeuw, Christiaan A., Mattheisen, Manuel, McQuillin, Andrew, Whitehead Pavlides, Jennifer M., Pers, Tune H., Ripke, Stephan, Stahl, Eli A., Steinberg, Stacy, Trubetskoy, Vassily, Trzaskowski, Maciej, Wang, Yunpeng, Abbott, Liam, Abdellaoui, Abdel, Adams, Mark J., Adolfsson, Annelie Nordin, Agerbo, Esben, Akil, Huda, Albani, Diego, Alliey-Rodriguez, Ney, Als, Thomas D., Andlauer, Till F.M., Anjorin, Adebayo, Antilla, Verneri, Van der Auwera, Sandra, Awasthi, Swapnil, Bacanu, Silviu-Alin, Badner, Judith A., Bækvad-Hansen, Marie, Barchas, Jack D., Bass, Nicholas, Bauer, Michael, Beekman, Aartjan T.F., Belliveau, Richard, Bergen, Sarah E., Bigdeli, Tim B., Binder, Elisabeth B., Bøen, Erlend, Boks, Marco, Boocock, James, Budde, Monika, Bunney, William, Burmeister, Margit, Buttenschøn, Henriette N., Bybjerg-Grauholm, Jonas, Byerley, William, Cai, Na, Casas, Miquel, Castelao, Enrique, Cerrato, Felecia, Cervantes, Pablo, Chambert, Kimberly, Charney, Alexander W., Chen, Danfeng, Christensen, Jane Hvarregaard, Churchhouse, Claire, St Clair, David, Clarke, Toni-Kim, Colodro-Conde, Lucía, Coryell, William, Couvy-Duchesne, Baptiste, Craig, David W., Crawford, Gregory E., Cruceanu, Cristiana, Czerski, Piotr M., Dale, Anders M., Davies, Gail, Deary, Ian J., Degenhardt, Franziska, Del-Favero, Jurgen, DePaulo, J Raymond, Derks, Eske M., Direk, Nese, Djurovic, Srdjan, Dobbyn, Amanda L., Dolan, Conor V., Dumont, Ashley, Dunn, Erin C., Eley, Thalia C., Elvsåshagen, Torbjørn, Escott-Price, Valentina, Fan, Chun Chieh, Finucane, Hilary K., Fischer, Sascha B., Flickinger, Matthew, Foo, Jerome C., Foroud, Tatiana M., Forty, Liz, Frank, Josef, Fraser, Christine, Freimer, Nelson B., Frisén, Louise, Gade, Katrin, Gage, Diane, Garnham, Julie, Giambartolomei, Claudia, Goes, Fernando S., Goldstein, Jaqueline, Gordon, Scott D., Gordon-Smith, Katherine, Green, Elaine K., Green, Melissa J., Greenwood, Tiffany A., Grove, Jakob, Guan, Weihua, Hall, Lynsey S., Hamshere, Marian L., Hansen, Christine Søholm, Hansen, Thomas F., Hautzinger, Martin, Heilbronner, Urs, van Hemert, Albert M., Herms, Stefan, Hickie, Ian B., Hipolito, Maria, Hoffmann, Per, Holland, Dominic, Homuth, Georg, Horn, Carsten, Hottenga, Jouke-Jan, Huckins, Laura, Ising, Marcus, Jamain, Stéphane, Jansen, Rick, Johnson, Jessica S., de Jong, Simone, Jorgenson, Eric, Juréus, Anders, Kandaswamy, Radhika, Karlsson, Robert, Kennedy, James L., Hassan Kiadeh, Farnush Farhadi, Kittel-Schneider, Sarah, Knowles, James A., Kogevinas, Manolis, Kohane, Isaac S., Koller, Anna C., Kraft, Julia, Kretzschmar, Warren W., Krogh, Jesper, Kupka, Ralph, Kutalik, Zoltán, Lavebratt, Catharina, Lawrence, Jacob, Lawson, William B., Leber, Markus, Lee, Phil H., Levy, Shawn E., Li, Jun Z., Li, Yihan, Lind, Penelope A., Liu, Chunyu, Olde Loohuis, Loes M., Maaser, Anna, MacIntyre, Donald J., MacKinnon, Dean F., Mahon, Pamela B., Maier, Wolfgang, Maier, Robert M., Marchini, Jonathan, Martinsson, Lina, Mbarek, Hamdi, McCarroll, Steve, McGrath, Patrick, McGuffin, Peter, McInnis, Melvin G., McKay, James D., Medeiros, Helena, Medland, Sarah E., Mehta, Divya, Meng, Fan, Middeldorp, Christel M., Mihailov, Evelin, Milaneschi, Yuri, Milani, Lili, Mirza, Saira Saeed, Mondimore, Francis M., Montgomery, Grant W., Morris, Derek W., Mostafavi, Sara, Mühleisen, Thomas W., Mullins, Niamh, Nauck, Matthias, Ng, Bernard, Nguyen, Hoang, Nievergelt, Caroline M., Nivard, Michel G., Nwulia, Evaristus A., Nyholt, Dale R., O'Donovan, Claire, O'Reilly, Paul F., Ori, Anil P.S., Oruc, Lilijana, Ösby, Urban, Oskarsson, Hogni, Painter, Jodie N., Parra, José Guzman, Pedersen, Carsten Bøcker, Pedersen, Marianne Giørtz, Perry, Amy, Peterson, Roseann E., Pettersson, Erik, Peyrot, Wouter J., Pfennig, Andrea, Pistis, Giorgio, Purcell, Shaun M., Quiroz, Jorge A., Qvist, Per, Regeer, Eline J., Reif, Andreas, Reinbold, Céline S., Rice, John P., Riley, Brien P., Rivas, Fabio, Rivera, Margarita, Roussos, Panos, Ruderfer, Douglas M., Ryu, Euijung, Sánchez-Mora, Cristina, Schatzberg, Alan F., Scheftner, William A., Schoevers, Robert, Schork, Nicholas J., Schulte, Eva C., Shehktman, Tatyana, Shen, Ling, Shi, Jianxin, Shilling, Paul D., Shyn, Stanley I., Sigurdsson, Engilbert, Slaney, Claire, Smeland, Olav B., Smit, Johannes H., Smith, Daniel J., Sobell, Janet L., Spijker, Anne T., Steffens, Michael, Strauss, John S., Streit, Fabian, Strohmaier, Jana, Szelinger, Szabolcs, Tansey, Katherine E., Teismann, Henning, Teumer, Alexander, Thompson, Robert C., Thompson, Wesley, Thomson, Pippa A., Thorgeirsson, Thorgeir E., Traylor, Matthew, Treutlein, Jens, Uitterlinden, André G., Umbricht, Daniel, Vedder, Helmut, Viktorin, Alexander, Visscher, Peter M., Wang, Weiqing, Watson, Stanley J., Webb, Bradley T., Weickert, Cynthia Shannon, Weickert, Thomas W., Weinsheimer, Shantel Marie, Wellmann, Jürgen, Willemsen, Gonneke, Witt, Stephanie H., Wu, Yang, Xi, Hualin S., Xu, Wei, Yang, Jian, Young, Allan H., Zandi, Peter, Zhang, Peng, Zhang, Futao, Zollner, Sebastian, Adolfsson, Rolf, Agartz, Ingrid, Alda, Martin, Arolt, Volker, Backlund, Lena, Baune, Bernhard T., Bellivier, Frank, Berger, Klaus, Berrettini, Wade H., Biernacka, Joanna M., Blackwood, Douglas H.R., Boehnke, Michael, Boomsma, Dorret I., Corvin, Aiden, Craddock, Nicholas, Daly, Mark J., Dannlowski, Udo, Domenici, Enrico, Domschke, Katharina, Esko, Tõnu, Etain, Bruno, Frye, Mark, Fullerton, Janice M., Gershon, Elliot S., de Geus, E.J.C., Gill, Michael, Goes, Fernando, Grabe, Hans J., Grigoroiu-Serbanescu, Maria, Hamilton, Steven P., Hauser, Joanna, Hayward, Caroline, Heath, Andrew C., Hougaard, David M., Hultman, Christina M., Jones, Ian, Jones, Lisa A., Kahn, René S., Kendler, Kenneth S., Kirov, George, Kloiber, Stefan, Landén, Mikael, Leboyer, Marion, Lewis, Glyn, Li, Qingqin S., Lissowska, Jolanta, Lucae, Susanne, Madden, Pamela A.F., Magnusson, Patrik K., Martin, Nicholas G., Mayoral, Fermin, McElroy, Susan L., McIntosh, Andrew M., McMahon, Francis J., Melle, Ingrid, Metspalu, Andres, Mitchell, Philip B., Morken, Gunnar, Mors, Ole, Mortensen, Preben Bo, Müller-Myhsok, Bertram, Myers, Richard M., Neale, Benjamin M., Nimgaonkar, Vishwajit, Nordentoft, Merete, Nöthen, Markus M., O'Donovan, Michael C., Oedegaard, Ketil J., Owen, Michael J., Paciga, Sara A., Pato, Carlos, Pato, Michele T., Pedersen, Nancy L., Penninx, Brenda W.J. H., Perlis, Roy H., Porteous, David J., Posthuma, Danielle, Potash, James B., Preisig, Martin, Ramos-Quiroga, Josep Antoni, Ribasés, Marta, Rietschel, Marcella, Rouleau, Guy A., Schaefer, Catherine, Schalling, Martin, Schofield, Peter R., Schulze, Thomas G., Serretti, Alessandro, Smoller, Jordan W., Stefansson, Hreinn, Stefansson, Kari, Stordal, Eystein, Tiemeier, Henning, Turecki, Gustavo, Uher, Rudolf, Vaaler, Arne E., Vieta, Eduard, Vincent, John B., Völzke, Henry, Weissman, Myrna M., Werge, Thomas, Andreassen, Ole A., Børglum, Anders D., Cichon, Sven, Edenberg, Howard J., Di Florio, Arianna, Kelsoe, John, Levinson, Douglas F., Lewis, Cathryn M., Nurnberger, John I., Ophoff, Roel A., Scott, Laura J., Sklar, Pamela, Sullivan, Patrick F., Wray, Naomi R., Coleman, Jonathan R.I., Gaspar, Héléna A., Bryois, Julien, and Breen, Gerome

Published
2020
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39. Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women

Author

Mehta, Divya, Tropf, Felix C, Gratten, Jacob, Bakshi, Andrew, Zhu, Zhihong, Bacanu, Silviu-Alin, Hemani, Gibran, Magnusson, Patrik KE, Barban, Nicola, Esko, Tõnu, Metspalu, Andres, Snieder, Harold, Mowry, Bryan J, Kendler, Kenneth S, Yang, Jian, Visscher, Peter M, McGrath, John J, Mills, Melinda C, Wray, Naomi R, Lee, S Hong, Andreassen, Ole A, Bramon, Elvira, Bruggeman, Richard, Buxbaum, Joseph D, Cairns, Murray J, Cantor, Rita M, Cloninger, C Robert, Cohen, David, Crespo-Facorro, Benedicto, Darvasi, Ariel, DeLisi, Lynn E, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Escott-Price, Valentina, Freimer, Nelson B, Georgieva, Lyudmila, de Haan, Lieuwe, Henskens, Frans A, Joa, Inge, Julià, Antonio, Khrunin, Andrey, Lerer, Bernard, Limborska, Svetlana, Loughland, Carmel M, Macek, Milan, Marsal, Sara, McCarley, Robert W, McIntosh, Andrew M, McQuillin, Andrew, Melegh, Bela, Michie, Patricia T, Morris, Derek W, Murphy, Kieran C, Myin-Germeys, Inez, Olincy, Ann, Van Os, Jim, Pantelis, Christos, Posthuma, Danielle, Quested, Digby, Schall, Ulrich, Scott, Rodney J, Seidman, Larry J, Toncheva, Draga, Tooney, Paul A, Waddington, John, Weinberger, Daniel R, Weiser, Mark, and Wu, Jing Qin

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Epidemiology, Health Sciences, Human Genome, Prevention, Brain Disorders, Serious Mental Illness, Mental Health, Schizophrenia, Clinical Research, Mental health, Adult, Alleles, Birth Order, Cohort Studies, Denmark, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Maternal Age, Phenotype, Pregnancy, Risk, Schizophrenia Working Group of the Psychiatric Genomics Consortium, LifeLines Cohort Study, and TwinsUK, Other Medical and Health Sciences, Psychology, Cognitive Sciences, Clinical sciences, Clinical and health psychology
Abstract

ImportanceA recently published study of national data by McGrath et al in 2014 showed increased risk of schizophrenia (SCZ) in offspring associated with both early and delayed parental age, consistent with a U-shaped relationship. However, it remains unclear if the risk to the child is due to psychosocial factors associated with parental age or if those at higher risk for SCZ tend to have children at an earlier or later age.ObjectiveTo determine if there is a genetic association between SCZ and age at first birth (AFB) using genetically informative but independently ascertained data sets.Design, setting, and participantsThis investigation used multiple independent genome-wide association study data sets. The SCZ sample comprised 18 957 SCZ cases and 22 673 controls in a genome-wide association study from the second phase of the Psychiatric Genomics Consortium, and the AFB sample comprised 12 247 genotyped women measured for AFB from the following 4 community cohorts: Estonia (Estonian Genome Center Biobank, University of Tartu), the Netherlands (LifeLines Cohort Study), Sweden (Swedish Twin Registry), and the United Kingdom (TwinsUK). Schizophrenia genetic risk for each woman in the AFB community sample was estimated using genetic effects inferred from the SCZ genome-wide association study.Main outcomes and measuresWe tested if SCZ genetic risk was a significant predictor of response variables based on published polynomial functions that described the relationship between maternal age and SCZ risk in offspring in Denmark. We substituted AFB for maternal age in these functions, one of which was corrected for the age of the father, and found that the fit was superior for the model without adjustment for the father's age.ResultsWe observed a U-shaped relationship between SCZ risk and AFB in the community cohorts, consistent with the previously reported relationship between SCZ risk in offspring and maternal age when not adjusted for the age of the father. We confirmed that SCZ risk profile scores significantly predicted the response variables (coefficient of determination R2 = 1.1E-03, P = 4.1E-04), reflecting the published relationship between maternal age and SCZ risk in offspring by McGrath et al in 2014.Conclusions and relevanceThis study provides evidence for a significant overlap between genetic factors associated with risk of SCZ and genetic factors associated with AFB. It has been reported that SCZ risk associated with increased maternal age is explained by the age of the father and that de novo mutations that occur more frequently in the germline of older men are the underlying causal mechanism. This explanation may need to be revised if, as suggested herein and if replicated in future studies, there is also increased genetic risk of SCZ in older mothers.

Published
2016

41. Direct targets of MEF2C are enriched for genes associated with schizophrenia and cognitive function and are involved in neurogenesis and mitochondrial function

Author

Ali, Deema, primary, Laighneach, Aodán, additional, Corley, Emma, additional, Patlola, Saahithh Redddi, additional, Holleran, Laurena, additional, McKernan, Declan P., additional, Kelly, John P., additional, Corvin, Aiden P., additional, Hallahan, Brian, additional, McDonald, Colm, additional, Donohoe, Gary, additional, and Morris, Derek W, additional

Published
2023
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43. Corpus callosum microstructural organization mediates the effects of physical neglect on social cognition in schizophrenia

Author

Corley, Emma, primary, Gleeson, Christina, additional, Godfrey, Emmet, additional, Cowman, Megan, additional, Patlola, Saahithh Redddi, additional, Cannon, Dara M., additional, McKernan, Declan P., additional, Kelly, John P., additional, Hallahan, Brian, additional, McDonald, Colm, additional, Morris, Derek W., additional, Burke, Tom, additional, and Donohoe, Gary, additional

Published
2023
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44. New data and an old puzzle: the negative association between schizophrenia and rheumatoid arthritis

Author

Lee, S Hong, Byrne, Enda M, Hultman, Christina M, Kähler, Anna, Vinkhuyzen, Anna AE, Ripke, Stephan, Andreassen, Ole A, Frisell, Thomas, Gusev, Alexander, Hu, Xinli, Karlsson, Robert, Mantzioris, Vasilis X, McGrath, John J, Mehta, Divya, Stahl, Eli A, Zhao, Qiongyi, Kendler, Kenneth S, Sullivan, Patrick F, Price, Alkes L, O’Donovan, Michael, Okada, Yukinori, Mowry, Bryan J, Raychaudhuri, Soumya, Wray, Naomi R, Byerley, William, Cahn, Wiepke, Cantor, Rita M, Cichon, Sven, Cormican, Paul, Curtis, David, Djurovic, Srdjan, Escott-Price, Valentina, Gejman, Pablo V, Georgieva, Lyudmila, Giegling, Ina, Hansen, Thomas F, Ingason, Andrés, Kim, Yunjung, Konte, Bettina, Lee, Phil H, McIntosh, Andrew, McQuillin, Andrew, Morris, Derek W, Nöthen, Markus M, O’Dushlaine, Colm, Olincy, Ann, Olsen, Line, Pato, Carlos N, Pato, Michele T, Pickard, Benjamin S, Posthuma, Danielle, Rasmussen, Henrik B, Rietschel, Marcella, Rujescu, Dan, Schulze, Thomas G, Silverman, Jeremy M, Thirumalai, Srinivasa, Werge, Thomas, Agartz, Ingrid, Amin, Farooq, Azevedo, Maria H, Bass, Nicholas, Black, Donald W, Blackwood, Douglas HR, Bruggeman, Richard, Buccola, Nancy G, Choudhury, Khalid, Cloninger, Robert C, Corvin, Aiden, Craddock, Nicholas, Daly, Mark J, Datta, Susmita, Donohoe, Gary J, Duan, Jubao, Dudbridge, Frank, Fanous, Ayman, Freedman, Robert, Freimer, Nelson B, Friedl, Marion, Gill, Michael, Gurling, Hugh, De Haan, Lieuwe, Hamshere, Marian L, Hartmann, Annette M, Holmans, Peter A, Kahn, René S, Keller, Matthew C, Kenny, Elaine, Kirov, George K, Krabbendam, Lydia, Krasucki, Robert, Lawrence, Jacob, Lencz, Todd, Levinson, Douglas F, Lieberman, Jeffrey A, Lin, Dan-Yu, Linszen, Don H, Magnusson, Patrik KE, Maier, Wolfgang, and Malhotra, Anil K

Subjects
Epidemiology, Health Sciences, Human Genome, Mental Health, Brain Disorders, Autoimmune Disease, Schizophrenia, Clinical Research, Arthritis, Serious Mental Illness, Genetics, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Mental health, Adolescent, Adult, Arthritis, Rheumatoid, Cohort Studies, Cross-Sectional Studies, Female, Gene-Environment Interaction, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Young Adult, Schizophrenia Working Group of the Psychiatric Genomics Consortium and Rheumatoid Arthritis Consortium International, Schizophrenia Working Group of the Psychiatric Genomics Consortium Authors, Schizophrenia Working Group of the Psychiatric Genomics Consortium Collaborators, Rheumatoid Arthritis Consortium International Authors, Rheumatoid Arthritis Consortium International Collaborators, Statistics, Public Health and Health Services, Public health
Abstract

BackgroundA long-standing epidemiological puzzle is the reduced rate of rheumatoid arthritis (RA) in those with schizophrenia (SZ) and vice versa. Traditional epidemiological approaches to determine if this negative association is underpinned by genetic factors would test for reduced rates of one disorder in relatives of the other, but sufficiently powered data sets are difficult to achieve. The genomics era presents an alternative paradigm for investigating the genetic relationship between two uncommon disorders.MethodsWe use genome-wide common single nucleotide polymorphism (SNP) data from independently collected SZ and RA case-control cohorts to estimate the SNP correlation between the disorders. We test a genotype X environment (GxE) hypothesis for SZ with environment defined as winter- vs summer-born.ResultsWe estimate a small but significant negative SNP-genetic correlation between SZ and RA (-0.046, s.e. 0.026, P = 0.036). The negative correlation was stronger for the SNP set attributed to coding or regulatory regions (-0.174, s.e. 0.071, P = 0.0075). Our analyses led us to hypothesize a gene-environment interaction for SZ in the form of immune challenge. We used month of birth as a proxy for environmental immune challenge and estimated the genetic correlation between winter-born and non-winter born SZ to be significantly less than 1 for coding/regulatory region SNPs (0.56, s.e. 0.14, P = 0.00090).ConclusionsOur results are consistent with epidemiological observations of a negative relationship between SZ and RA reflecting, at least in part, genetic factors. Results of the month of birth analysis are consistent with pleiotropic effects of genetic variants dependent on environmental context.

Published
2015

49. Targeted Sequencing of 10,198 Samples Confirms Abnormalities in Neuronal Activity and Implicates Voltage-Gated Sodium Channels in Schizophrenia Pathogenesis

Author

Alizadeh, Behrooz Z., van Amelsvoort, Therese, Bartels-Velthuis, Agna A., van Beveren, Nico J., Bruggeman, Richard, Cahn, Wiepke, de Haan, Lieuwe, Delespaul, Philippe, Meijer, Carin J., Myin-Germeys, Inez, Kahn, Rene S., Schirmbeck, Frederike, Simons, Claudia J.P., van Haren, Neeltje E., van Os, Jim, van Winkel, Ruud, Luykx, Jurjen J., Rees, Elliott, Carrera, Noa, Morgan, Joanne, Hambridge, Kirsty, Escott-Price, Valentina, Pocklington, Andrew J., Richards, Alexander L., Pardiñas, Antonio F., McDonald, Colm, Donohoe, Gary, Morris, Derek W., Kenny, Elaine, Kelleher, Eric, Gill, Michael, Corvin, Aiden, Kirov, George, Walters, James T.R., Holmans, Peter, Owen, Michael J., and O’Donovan, Michael C.

Published
2019
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50. Variability in Working Memory Performance Explained by Epistasis vs Polygenic Scores in the ZNF804A Pathway

Author

Nicodemus, Kristin K, Hargreaves, April, Morris, Derek, Anney, Richard, Gill, Michael, Corvin, Aiden, and Donohoe, Gary

Subjects
Mental Health, Schizophrenia, Serious Mental Illness, Genetics, Clinical Research, Behavioral and Social Science, Neurosciences, Brain Disorders, Prevention, 2.3 Psychological, social and economic factors, 2.1 Biological and endogenous factors, Aetiology, Mental health, Adult, Cognition Disorders, Epistasis, Genetic, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Male, Memory, Short-Term, Middle Aged, Multifactorial Inheritance, Neural Pathways, Neuropsychological Tests, Polymorphism, Single Nucleotide, Psychotic Disorders, Zinc Fingers, Schizophrenia Psychiatric Genome-wide Association Study (GWAS) Consortium, Wellcome Trust Case Control Consortium 2, Other Medical and Health Sciences, Psychology, Cognitive Sciences
Abstract

ImportanceWe investigated the variation in neuropsychological function explained by risk alleles at the psychosis susceptibility gene ZNF804A and its interacting partners using single nucleotide polymorphisms (SNPs), polygenic scores, and epistatic analyses. Of particular importance was the relative contribution of the polygenic score vs epistasis in variation explained.ObjectivesTo (1) assess the association between SNPs in ZNF804A and the ZNF804A polygenic score with measures of cognition in cases with psychosis and (2) assess whether epistasis within the ZNF804A pathway could explain additional variation above and beyond that explained by the polygenic score.Design, setting, and participantsPatients with psychosis (n = 424) were assessed in areas of cognitive ability impaired in schizophrenia including IQ, memory, attention, and social cognition. We used the Psychiatric GWAS Consortium 1 schizophrenia genome-wide association study to calculate a polygenic score based on identified risk variants within this genetic pathway. Cognitive measures significantly associated with the polygenic score were tested for an epistatic component using a training set (n = 170), which was used to develop linear regression models containing the polygenic score and 2-SNP interactions. The best-fitting models were tested for replication in 2 independent test sets of cases: (1) 170 individuals with schizophrenia or schizoaffective disorder and (2) 84 patients with broad psychosis (including bipolar disorder, major depressive disorder, and other psychosis).Main outcomes and measuresParticipants completed a neuropsychological assessment battery designed to target the cognitive deficits of schizophrenia including general cognitive function, episodic memory, working memory, attentional control, and social cognition.ResultsHigher polygenic scores were associated with poorer performance among patients on IQ, memory, and social cognition, explaining 1% to 3% of variation on these scores (range, P = .01 to .03). Using a narrow psychosis training set and independent test sets of narrow phenotype psychosis (schizophrenia and schizoaffective disorder), broad psychosis, and control participants (n = 89), the addition of 2 interaction terms containing 2 SNPs each increased the R2 for spatial working memory strategy in the independent psychosis test sets from 1.2% using the polygenic score only to 4.8% (P = .11 and .001, respectively) but did not explain additional variation in control participants.Conclusions and relevanceThese data support a role for the ZNF804A pathway in IQ, memory, and social cognition in cases. Furthermore, we showed that epistasis increases the variation explained above the contribution of the polygenic score.

Published
2014

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