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Start Over Author "Olde Loohuis, Loes M." Topic schizophrenia
12 results on '"Olde Loohuis, Loes M."'

1. Meta-analysis of epigenetic aging in schizophrenia reveals multifaceted relationships with age, sex, illness duration, and polygenic risk.

Author

Ori APS, Olde Loohuis LM, Guintivano J, Hannon E, Dempster E, St Clair D, Bass NJ, McQuillin A, Mill J, Sullivan PF, Kahn RS, Horvath S, and Ophoff RA

Subjects
Adult, Female, Humans, Male, Young Adult, Aging genetics, Cellular Senescence, Epigenesis, Genetic, DNA Methylation, Schizophrenia genetics
Abstract

Background: The study of biological age acceleration may help identify at-risk individuals and reduce the rising global burden of age-related diseases. Using DNA methylation (DNAm) clocks, we investigated biological aging in schizophrenia (SCZ), a mental illness that is associated with an increased prevalence of age-related disabilities and morbidities. In a whole blood DNAm sample of 1090 SCZ cases and 1206 controls across four European cohorts, we performed a meta-analysis of differential aging using three DNAm clocks (i.e., Hannum, Horvath, and Levine). To dissect how DNAm aging contributes to SCZ, we integrated information on duration of illness and SCZ polygenic risk, as well as stratified our analyses by chronological age and biological sex., Results: We found that blood-based DNAm aging is significantly altered in SCZ independent from duration of the illness since onset. We observed sex-specific and nonlinear age effects that differed between clocks and point to possible distinct age windows of altered aging in SCZ. Most notably, intrinsic cellular age (Horvath clock) is decelerated in SCZ cases in young adulthood, while phenotypic age (Levine clock) is accelerated in later adulthood compared to controls. Accelerated phenotypic aging was most pronounced in women with SCZ carrying a high polygenic burden with an age acceleration of + 3.82 years (CI 2.02-5.61, P = 1.1E-03). Phenotypic aging and SCZ polygenic risk contributed additively to the illness and together explained up to 14.38% of the variance in disease status., Conclusions: Our study contributes to the growing body of evidence of altered DNAm aging in SCZ and points to intrinsic age deceleration in younger adulthood and phenotypic age acceleration in later adulthood in SCZ. Since increased phenotypic age is associated with increased risk of all-cause mortality, our findings indicate that specific and identifiable patient groups are at increased mortality risk as measured by the Levine clock. Our study did not find that DNAm aging could be explained by the duration of illness of patients, but we did observe age- and sex-specific effects that warrant further investigation. Finally, our results show that combining genetic and epigenetic predictors can improve predictions of disease outcomes and may help with disease management in schizophrenia., (© 2024. The Author(s).)

Published
2024
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2. The Relationship Between Polygenic Risk Scores and Cognition in Schizophrenia.

Author

Richards AL, Pardiñas AF, Frizzati A, Tansey KE, Lynham AJ, Holmans P, Legge SE, Savage JE, Agartz I, Andreassen OA, Blokland GAM, Corvin A, Cosgrove D, Degenhardt F, Djurovic S, Espeseth T, Ferraro L, Gayer-Anderson C, Giegling I, van Haren NE, Hartmann AM, Hubert JJ, Jönsson EG, Konte B, Lennertz L, Olde Loohuis LM, Melle I, Morgan C, Morris DW, Murray RM, Nyman H, Ophoff RA, van Os J, Petryshen TL, Quattrone D, Rietschel M, Rujescu D, Rutten BPF, Streit F, Strohmaier J, Sullivan PF, Sundet K, Wagner M, Escott-Price V, Owen MJ, Donohoe G, O'Donovan MC, and Walters JTR

Subjects
Datasets as Topic, Humans, Multifactorial Inheritance, Bipolar Disorder genetics, Depressive Disorder, Major genetics, Educational Status, Genome-Wide Association Study, Intelligence genetics, Psychotic Disorders genetics, Schizophrenia genetics
Abstract

Background: Cognitive 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., Methods: We 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., Results: PRS 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., Conclusions: Cognition 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., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Published
2020
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3. Candidate CSPG4 mutations and induced pluripotent stem cell modeling implicate oligodendrocyte progenitor cell dysfunction in familial schizophrenia.

Author

de Vrij FM, Bouwkamp CG, Gunhanlar N, Shpak G, Lendemeijer B, Baghdadi M, Gopalakrishna S, Ghazvini M, Li TM, Quadri M, Olgiati S, Breedveld GJ, Coesmans M, Mientjes E, de Wit T, Verheijen FW, Beverloo HB, Cohen D, Kok RM, Bakker PR, Nijburg A, Spijker AT, Haffmans PMJ, Hoencamp E, Bergink V, Vorstman JA, Wu T, Olde Loohuis LM, Amin N, Langen CD, Hofman A, Hoogendijk WJ, van Duijn CM, Ikram MA, Vernooij MW, Tiemeier H, Uitterlinden AG, Elgersma Y, Distel B, Gribnau J, White T, Bonifati V, and Kushner SA

Subjects
Adult, Antigens genetics, Cell Differentiation physiology, Chondroitin Sulfate Proteoglycans metabolism, Diffusion Tensor Imaging, Family, Female, Humans, Induced Pluripotent Stem Cells metabolism, Male, Membrane Proteins metabolism, Mutation genetics, Oligodendrocyte Precursor Cells physiology, Oligodendroglia metabolism, Pedigree, Proteoglycans genetics, Schizophrenia metabolism, White Matter metabolism, Chondroitin Sulfate Proteoglycans genetics, Membrane Proteins genetics, Oligodendrocyte Precursor Cells metabolism, Schizophrenia genetics
Abstract

Schizophrenia is highly heritable, yet its underlying pathophysiology remains largely unknown. Among the most well-replicated findings in neurobiological studies of schizophrenia are deficits in myelination and white matter integrity; however, direct etiological genetic and cellular evidence has thus far been lacking. Here, we implement a family-based approach for genetic discovery in schizophrenia combined with functional analysis using induced pluripotent stem cells (iPSCs). We observed familial segregation of two rare missense mutations in Chondroitin Sulfate Proteoglycan 4 (CSPG4) (c.391G > A [p.A131T], MAF 7.79 × 10 -5 and c.2702T > G [p.V901G], MAF 2.51 × 10 -3 ). The CSPG4 A131T mutation was absent from the Swedish Schizophrenia Exome Sequencing Study (2536 cases, 2543 controls), while the CSPG4 V901G mutation was nominally enriched in cases (11 cases vs. 3 controls, P = 0.026, OR 3.77, 95% CI 1.05-13.52). CSPG4/NG2 is a hallmark protein of oligodendrocyte progenitor cells (OPCs). iPSC-derived OPCs from CSPG4 A131T mutation carriers exhibited abnormal post-translational processing (P = 0.029), subcellular localization of mutant NG2 (P = 0.007), as well as aberrant cellular morphology (P = 3.0 × 10 -8 ), viability (P = 8.9 × 10 -7 ), and myelination potential (P = 0.038). Moreover, transfection of healthy non-carrier sibling OPCs confirmed a pathogenic effect on cell survival of both the CSPG4 A131T (P = 0.006) and CSPG4 V901G (P = 3.4 × 10 -4 ) mutations. Finally, in vivo diffusion tensor imaging of CSPG4 A131T mutation carriers demonstrated a reduction of brain white matter integrity compared to unaffected sibling and matched general population controls (P = 2.2 × 10 -5 ). Together, our findings provide a convergence of genetic and functional evidence to implicate OPC dysfunction as a candidate pathophysiological mechanism of familial schizophrenia.

Published
2019
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4. A Longitudinal Model of Human Neuronal Differentiation for Functional Investigation of Schizophrenia Polygenic Risk.

Author

Ori APS, Bot MHM, Molenhuis RT, Olde Loohuis LM, and Ophoff RA

Subjects
Humans, Longitudinal Studies, Risk, Cell Differentiation, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Models, Neurological, Multifactorial Inheritance, Neural Stem Cells, Schizophrenia genetics
Abstract

Background: Common psychiatric disorders are characterized by complex disease architectures with many small genetic effects that contribute and complicate biological understanding of their etiology. There is therefore a pressing need for in vitro experimental systems that allow for interrogation of polygenic psychiatric disease risk to study the underlying biological mechanisms., Methods: We have developed an analytical framework that integrates genome-wide disease risk from genome-wide association studies with longitudinal in vitro gene expression profiles of human neuronal differentiation., Results: We demonstrate that the cumulative impact of risk loci of specific psychiatric disorders is significantly associated with genes that are differentially expressed and upregulated during differentiation. We find the strongest evidence for schizophrenia, a finding that we replicate in an independent dataset. A longitudinal gene cluster involved in synaptic function primarily drives the association with schizophrenia risk., Conclusions: These findings reveal that in vitro human neuronal differentiation can be used to translate the polygenic architecture of schizophrenia to biologically relevant pathways that can be modeled in an experimental system. Overall, this work emphasizes the use of longitudinal in vitro transcriptomic signatures as a cellular readout and the application to the genetics of complex traits., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Published
2019
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5. Double hits in schizophrenia.

Author

Vorstman JAS, Olde Loohuis LM, Kahn RS, and Ophoff RA

Subjects
Case-Control Studies, Female, Humans, Male, Phenotype, Polymorphism, Single Nucleotide, Sequence Deletion, DNA Copy Number Variations, Point Mutation, Schizophrenia genetics
Abstract

The co-occurrence of a copy number variant (CNV) and a functional variant on the other allele may be a relevant genetic mechanism in schizophrenia. We hypothesized that the cumulative burden of such double hits-in particular those composed of a deletion and a coding single-nucleotide variation (SNV)-is increased in patients with schizophrenia. We combined CNV data with coding variants data in 795 patients with schizophrenia and 474 controls. To limit false CNV-detection, only CNVs called by two algorithms were included. CNV-affected genes were subsequently examined for coding SNVs, which we termed "CNV-SNVs." Correcting for total queried sequence, we assessed the CNV-SNV-burden and the combined predicted deleterious effect. We estimated P-values by permutation of the phenotype. We detected 105 CNV-SNVs; 67 in duplicated and 38 in deleted genic sequence. Although the difference in CNV-SNVs rates was not significant, the combined deleteriousness inferred by CNV-SNVs in deleted sequence was almost 4-fold higher in cases compared with controls (nominal P = 0.009). This effect may be driven by a higher number of CNV-SNVs and/or by a higher degree of predicted deleteriousness of CNV-SNVs. No such effect was observed for duplications. We provide early evidence that deletions co-occurring with a functional variant may be relevant, albeit of modest impact, for the genetic etiology of schizophrenia. Large-scale consortium studies are required to validate our findings. Sequence-based analyses would provide the best resolution for detection of CNVs as well as coding variants genome-wide., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Published
2018
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6. Transcriptome analysis in whole blood reveals increased microbial diversity in schizophrenia.

Author

Olde Loohuis LM, Mangul S, Ori APS, Jospin G, Koslicki D, Yang HT, Wu T, Boks MP, Lomen-Hoerth C, Wiedau-Pazos M, Cantor RM, de Vos WM, Kahn RS, Eskin E, and Ophoff RA

Subjects
Adult, Amyotrophic Lateral Sclerosis blood, Amyotrophic Lateral Sclerosis microbiology, Bipolar Disorder blood, Bipolar Disorder microbiology, Female, Gene Expression Profiling, Humans, Male, Middle Aged, Sequence Analysis, RNA, Young Adult, Microbiota, Schizophrenia blood, Schizophrenia microbiology
Abstract

The role of the human microbiome in health and disease is increasingly appreciated. We studied the composition of microbial communities present in blood across 192 individuals, including healthy controls and patients with three disorders affecting the brain: schizophrenia, amyotrophic lateral sclerosis, and bipolar disorder. By using high-quality unmapped RNA sequencing reads as candidate microbial reads, we performed profiling of microbial transcripts detected in whole blood. We were able to detect a wide range of bacterial and archaeal phyla in blood. Interestingly, we observed an increased microbial diversity in schizophrenia patients compared to the three other groups. We replicated this finding in an independent schizophrenia case-control cohort. This increased diversity is inversely correlated with estimated cell abundance of a subpopulation of CD8 + memory T cells in healthy controls, supporting a link between microbial products found in blood, immunity and schizophrenia.

Published
2018
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7. 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

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

9. Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults

Author

Hofer, Edith, Roshchupkin, Gennady V, Bernard, Manon, Grasby, Katrina L, Jahanshad, Neda, Painter, Jodie N, Colodro-Conde, Lucía, Bralten, Janita, Hibar, Derrek P, Lind, Penelope A, Pizzagalli, Fabrizio, Ching, Christopher R K, McMahon, Mary Agnes B, Bis, Joshua C, Shatokhina, Natalia, Zsembik, Leo C P, Agartz, Ingrid, Alhusaini, Saud, Almeida, Marcio A A, Alnæs, Dag, Amlien, Inge K, Andersson, Micael, Ard, Tyler, Armstrong, Nicola J, Gillespie, Nathan A, Ashley-Koch, Allison, Brouwer, Rachel M, Buimer, Elizabeth E L, Bülow, Robin, Bürger, Christian, Cannon, Dara M, Chakravarty, Mallar, Chen, Qiang, Cheung, Joshua W, Luciano, Michelle, Couvy-Duchesne, Baptiste, Dale, Anders M, Dalvie, Shareefa, de Araujo, Tânia K, de Zubicaray, Greig I, de Zwarte, Sonja M C, den Braber, Anouk, Doan, Nhat Trung, Dohm, Katharina, Ehrlich, Stefan, Mishra, Aniket, Engelbrecht, Hannah-Ruth, Erk, Susanne, Fan, Chun Chieh, Fedko, Iryna O, Foley, Sonya F, Ford, Judith M, Fukunaga, Masaki, Garrett, Melanie E, Ge, Tian, Giddaluru, Sudheer, Scholz, Markus, Goldman, Aaron L, Groenewold, Nynke A, Grotegerd, Dominik, Gurholt, Tiril P, Gutman, Boris A, Hansell, Narelle K, Harris, Mathew A, Harrison, Marc B, Haswell, Courtney C, Hauser, Michael, Teumer, Alexander, Herms, Stefan, Heslenfeld, Dirk J, Ho, New Fei, Hoehn, David, Hoffmann, Per, Holleran, Laurena, Hoogman, Martine, Hottenga, Jouke-Jan, Ikeda, Masashi, Janowitz, Deborah, Xia, Rui, Jansen, Iris E, Jia, Tianye, Jockwitz, Christiane, Kanai, Ryota, Karama, Sherif, Kasperaviciute, Dalia, Kaufmann, Tobias, Kelly, Sinead, Kikuchi, Masataka, Klein, Marieke, Jian, Xueqiu, Knapp, Michael, Knodt, Annchen R, Krämer, Bernd, Lam, Max, Lancaster, Thomas M, Lee, Phil H, Lett, Tristram A, Lewis, Lindsay B, Lopes-Cendes, Iscia, Mosley, Thomas H, Macciardi, Fabio, Marquand, Andre F, Mathias, Samuel R, Melzer, Tracy R, Milaneschi, Yuri, Mirza-Schreiber, Nazanin, Moreira, Jose C V, Mühleisen, Thomas W, Müller-Myhsok, Bertram, Najt, Pablo, Adams, Hieab H H, Saba, Yasaman, Nakahara, Soichiro, Nho, Kwangsik, Olde Loohuis, Loes M, Orfanos, Dimitri Papadopoulos, Pearson, John F, Pitcher, Toni L, Pütz, Benno, Ragothaman, Anjanibhargavi, Rashid, Faisal M, Redlich, Ronny, Pirpamer, Lukas, Reinbold, Céline S, Repple, Jonathan, Richard, Geneviève, Riedel, Brandalyn C, Risacher, Shannon L, Rocha, Cristiane S, Mota, Nina Roth, Salminen, Lauren, Saremi, Arvin, Saykin, Andrew J, Seiler, Stephan, Schlag, Fenja, Schmaal, Lianne, Schofield, Peter R, Secolin, Rodrigo, Shapland, Chin Yang, Shen, Li, Shin, Jean, Shumskaya, Elena, Sønderby, Ida E, Sprooten, Emma, Becker, James T, Strike, Lachlan T, Tansey, Katherine E, Thalamuthu, Anbupalam, Thomopoulos, Sophia I, Tordesillas-Gutiérrez, Diana, Turner, Jessica A, Uhlmann, Anne, Vallerga, Costanza Ludovica, van der Meer, Dennis, Carmichael, Owen, van Donkelaar, Marjolein M J, van Eijk, Liza, van Erp, Theo G M, van Haren, Neeltje E M, van Rooij, Daan, van Tol, Marie-José, Veldink, Jan H, Verhoef, Ellen, Walton, Esther, Wang, Mingyuan, Rotter, Jerome I, Wang, Yunpeng, Wardlaw, Joanna M, Wen, Wei, Westlye, Lars T, Whelan, Christopher D, Witt, Stephanie H, Wittfeld, Katharina, Wolf, Christiane, Wolfers, Thomas, Yasuda, Clarissa L, Psaty, Bruce M, Zaremba, Dario, Zhang, Zuo, Zhu, Alyssa H, Zwiers, Marcel P, Artiges, Eric, Assareh, Amelia A, Ayesa-Arriola, Rosa, Belger, Aysenil, Brandt, Christine L, Brown, Gregory G, Lopez, Oscar L, Cichon, Sven, Curran, Joanne E, Davies, Gareth E, Degenhardt, Franziska, Dietsche, Bruno, Djurovic, Srdjan, Doherty, Colin P, Espiritu, Ryan, Garijo, Daniel, Gil, Yolanda, Amin, Najaf, Gowland, Penny A, Green, Robert C, Häusler, Alexander N, Heindel, Walter, Ho, Beng-Choon, Hoffmann, Wolfgang U, Holsboer, Florian, Homuth, Georg, Hosten, Norbert, Jack, Clifford R, van der Lee, Sven J, Jang, MiHyun, Jansen, Andreas, Kolskår, Knut, Koops, Sanne, Krug, Axel, Lim, Kelvin O, Luykx, Jurjen J, Mathalon, Daniel H, Mather, Karen A, Mattay, Venkata S, Knol, Maria J, Yang, Qiong, Matthews, Sarah, Son, Jaqueline Mayoral Van, McEwen, Sarah C, Melle, Ingrid, Morris, Derek W, Mueller, Bryon A, Nauck, Matthias, Nordvik, Jan E, Nöthen, Markus M, O'Leary, Daniel S, Himali, Jayandra J, Opel, Nils, Martinot, Marie -Laure Paillère, Pike, G Bruce, Preda, Adrian, Quinlan, Erin B, Ratnakar, Varun, Reppermund, Simone, Steen, Vidar M, Torres, Fábio R, Veltman, Dick J, Maillard, Pauline, Voyvodic, James T, Whelan, Robert, White, Tonya, Yamamori, Hidenaga, Alvim, Marina K M, Ames, David, Anderson, Tim J, Andreassen, Ole A, Arias-Vasquez, Alejandro, Bastin, Mark E, Beiser, Alexa S, Baune, Bernhard T, Blangero, John, Boomsma, Dorret I, Brodaty, Henry, Brunner, Han G, Buckner, Randy L, Buitelaar, Jan K, Bustillo, Juan R, Cahn, Wiepke, Calhoun, Vince, DeCarli, Charles, Caseras, Xavier, Caspers, Svenja, Cavalleri, Gianpiero L, Cendes, Fernando, Corvin, Aiden, Crespo-Facorro, Benedicto, Dalrymple-Alford, John C, Dannlowski, Udo, de Geus, Eco J C, Deary, Ian J, Delanty, Norman, Depondt, Chantal, Desrivières, Sylvane, Donohoe, Gary, Espeseth, Thomas, Fernández, Guillén, Fisher, Simon E, Flor, Herta, Forstner, Andreas J, Francks, Clyde, Lewis, Lindsay, Franke, Barbara, Glahn, David C, Gollub, Randy L, Grabe, Hans J, Gruber, Oliver, Håberg, Asta K, Hariri, Ahmad R, Hartman, Catharina A, Hashimoto, Ryota, Heinz, Andreas, Harris, Mat, Hillegers, Manon H J, Hoekstra, Pieter J, Holmes, Avram J, Hong, L Elliot, Hopkins, William D, Hulshoff Pol, Hilleke E, Jernigan, Terry L, Jönsson, Erik G, Kahn, René S, Kennedy, Martin A, Kircher, Tilo T J, Kochunov, Peter, Kwok, John B J, Hellard, Stephanie Le, Martin, Nicholas G, Martinot, Jean -Luc, McDonald, Colm, McMahon, Katie L, Meyer-Lindenberg, Andreas, Morey, Rajendra A, Nyberg, Lars, Oosterlaan, Jaap, Ophoff, Roel A, Paus, Tomáš, Pausova, Zdenka, Penninx, Brenda W J H, Polderman, Tinca J C, Posthuma, Danielle, Rietschel, Marcella, Roffman, Joshua L, Lin, Honghuang, Veronica Witte, A., Rowland, Laura M, Sachdev, Perminder S, Sämann, Philipp G, Schumann, Gunter, Sim, Kang, Sisodiya, Sanjay M, Smoller, Jordan W, Sommer, Iris E, Pourcain, Beate St, Stein, Dan J, Beyer, Frauke, Toga, Arthur W, Trollor, Julian N, Van der Wee, Nic J A, van 't Ent, Dennis, Völzke, Henry, Walter, Henrik, Weber, Bernd, Weinberger, Daniel R, Wright, Margaret J, Zhou, Juan, Loeffler, Markus, Stein, Jason L, Thompson, Paul M, Medland, Sarah E, Kwok, John B, Trollor, Julian, Li, Shuo, Jiang, Jiyang, Vernooij, Meike W, Hofman, Albert, Uitterlinden, André G, Niessen, Wiro J, Völker, Uwe, Zare, Habil, Bruce Pike, G., Maingault, Sophie, Crivello, Fabrice, Tzourio, Christophe, Amouyel, Philippe, Mazoyer, Bernard, Neale, Michael C, Franz, Carol E, Lyons, Michael J, Ahmad, Shahzad, Panizzon, Matthew S, Logue, Mark, consortium, ENIGMA, Kremen, William S, Villringer, Arno, Satizabal, Claudia L, van Duijn, Cornelia M, Grabe, Hans, Longstreth, William T, Fornage, Myriam, Paus, Tomas, Debette, Stephanie, Ikram, M Arfan, Schmidt, Helena, Schmidt, Reinhold, Seshadri, Sudha, University of Graz, Medical University Graz, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), School of Public Health [Boston], University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), The University of Texas at San Antonio (UTSA), Murdoch University, The Hospital for sick children [Toronto] (SickKids), University of Washington [Seattle], Virginia Commonwealth University (VCU), QIMR Berghofer Medical Research Institute, University of Edinburgh, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Leipzig [Leipzig], Universität Greifswald - University of Greifswald, University of Mississippi Medical Center (UMMC), University of California [Davis] (UC Davis), University of California, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Pennington Biomedical Research Center, Louisiana State University (LSU), Los Angeles Biomedical Research Institute (LA BioMed), McGill University = Université McGill [Montréal, Canada], Max Planck Institute for Human Cognitive and Brain Sciences [Leipzig] (IMPNSC), Max-Planck-Gesellschaft, University of New South Wales [Sydney] (UNSW), Neuroscience Research Australia (NeuRA), The University of Sydney, University of Queensland [Brisbane], The Royal Melbourne Hospital, University of Melbourne, Harvard T.H. Chan School of Public Health, Delft University of Technology (TU Delft), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), University of Toronto, University of Calgary, Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), CHU Bordeaux [Bordeaux], Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Réseau International des Instituts Pasteur (RIIP), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of California [San Diego] (UC San Diego), University of Oslo (UiO), Oslo University Hospital [Oslo], VA Boston Healthcare System, University of Southern California (USC), Radboud University Medical Center [Nijmegen], Radboud university [Nijmegen], Janssen Research & Development, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Prince of Wales Hospital, University Hospital Leipzig, University of Oxford [Oxford], Holland Bloorview Kids Rehabilitation Hospital [Toronto, ON, Canada], Epidemiology, Medical Informatics, Radiology & Nuclear Medicine, Neurology, Complex Trait Genetics, Biological Psychology, Cognitive Psychology, IBBA, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, APH - Mental Health, APH - Methodology, Clinical Neuropsychology, Clinical Developmental Psychology, Amsterdam Neuroscience - Complex Trait Genetics, Movement Disorder (MD), Clinical Cognitive Neuropsychiatry Research Program (CCNP), General Paediatrics, ARD - Amsterdam Reproduction and Development, Karl-Franzens-Universität Graz, Universität Leipzig, University of California (UC), Radboud University [Nijmegen], University of Oxford, Psychiatry, Anatomy and neurosciences, Pediatric surgery, Human genetics, APH - Digital Health, and Karl-Franzens-Universität [Graz, Autriche]

Subjects
0301 basic medicine, Male, Genetics of the nervous system, Aging, General Physics and Astronomy, Genome-wide association study, Disease, VARIANTS, genetics [Mental Disorders], Genome-wide association studies, 0302 clinical medicine, Cognition, PARKINSONS-DISEASE, SCHIZOPHRENIA, 80 and over, 2.1 Biological and endogenous factors, Aetiology, lcsh:Science, Aged, 80 and over, education.field_of_study, Multidisciplinary, ENIGMA consortium, Mental Disorders, Brain, Neurodegenerative Diseases, Genomics, Single Nucleotide, Middle Aged, Biobank, ALZHEIMERS-DISEASE, Phenotype, VINTAGE, Neurology, Chromosome Structures, Schizophrenia, genetics [Aging], Neurological, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, ddc:500, Biotechnology, Adult, Science, geentics of the nervous system, 1.1 Normal biological development and functioning, Population, SURFACE-AREA, ORGANIZATION, Biology, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Underpinning research, THICKNESS, medicine, Genetics, Humans, Polymorphism, education, HEALTHY, METAANALYSIS, Aged, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Genetic heterogeneity, neurology, Human Genome, Neurosciences, General Chemistry, Heritability, medicine.disease, Brain Disorders, INDIVIDUALS, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Evolutionary biology, genetics [Neurodegenerative Diseases], VOLUME, genome-wide association studies, lcsh:Q, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging., Cortex morphology varies with age, cognitive function, and in neurological and psychiatric diseases. Here the authors report 160 genome-wide significant associations with thickness, surface area and volume of the total cortex and 34 cortical regions from a GWAS meta-analysis in 22,824 adults.

Published
2020
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10. Double hits in schizophrenia

Author

Vorstman, Jacob AS, Olde Loohuis, Loes M, GROUP Investigators, Kahn, René S, Ophoff, Roel A, and GROUP investigators

Subjects
Male, Genetics & Heredity, DNA Copy Number Variations, Human Genome, Single Nucleotide, Biological Sciences, Medical and Health Sciences, Brain Disorders, Phenotype, Mental Health, Case-Control Studies, Schizophrenia, Genetics, Humans, Point Mutation, 2.1 Biological and endogenous factors, Female, GROUP Investigators, Polymorphism, Aetiology, Sequence Deletion
Abstract

The co-occurrence of a copy number variant (CNV) and a functional variant on the other allele may be a relevant genetic mechanism in schizophrenia. We hypothesized that the cumulative burden of such double hits-in particular those composed of a deletion and a coding single-nucleotide variation (SNV)-is increased in patients with schizophrenia. We combined CNV data with coding variants data in 795 patients with schizophrenia and 474 controls. To limit false CNV-detection, only CNVs called by two algorithms were included. CNV-affected genes were subsequently examined for coding SNVs, which we termed "CNV-SNVs." Correcting for total queried sequence, we assessed the CNV-SNV-burden and the combined predicted deleterious effect. We estimated P-values by permutation of the phenotype. We detected 105 CNV-SNVs; 67 in duplicated and 38 in deleted genic sequence. Although the difference in CNV-SNVs rates was not significant, the combined deleteriousness inferred by CNV-SNVs in deleted sequence was almost 4-fold higher in cases compared with controls (nominal P = 0.009). This effect may be driven by a higher number of CNV-SNVs and/or by a higher degree of predicted deleteriousness of CNV-SNVs. No such effect was observed for duplications. We provide early evidence that deletions co-occurring with a functional variant may be relevant, albeit of modest impact, for the genetic etiology of schizophrenia. Large-scale consortium studies are required to validate our findings. Sequence-based analyses would provide the best resolution for detection of CNVs as well as coding variants genome-wide.

Published
2018

11. Structural Brain Alterations in Youth With Psychosis and Bipolar Spectrum Symptoms.

Author

Jalbrzikowski, Maria, Freedman, David, Hegarty, Catherine E., Mennigen, Eva, Karlsgodt, Katherine H., Olde Loohuis, Loes M., Ophoff, Roel A., Gur, Raquel E., and Bearden, Carrie E.

Subjects
*PSYCHIATRIC diagnosis, *PSYCHOSES, *BRAIN abnormalities, *ADOLESCENCE, *MAGNETIC resonance, *22Q11 deletion syndrome
Abstract

Objective: Adults with established diagnoses of serious mental illness (bipolar disorder and schizophrenia) exhibit structural brain abnormalities, yet less is known about how such abnormalities manifest earlier in development.Method: Cross-sectional data publicly available from the Philadelphia Neurodevelopmental Cohort (PNC) were analyzed. Structural magnetic resonance neuroimaging data were collected on a subset of the PNC (N = 989; 9-22 years old). Cortical thickness, surface area (SA), and subcortical volumes were calculated. Study participants were assessed for psychiatric symptomatology using a structured interview and the following groups were created: typically developing (n = 376), psychosis spectrum (PS; n = 113), bipolar spectrum (BP; n = 117), and BP + PS (n = 109). Group and developmental differences in structural magnetic resonance neuroimaging measures were examined. In addition, the extent to which any structural aberration was related to neurocognition, global functioning, and clinical symptomatology was examined.Results: Compared with other groups, PS youth exhibited significantly decreased SA in the orbitofrontal, cingulate, precentral, and postcentral regions. PS youth also exhibited deceased thalamic volume compared with all other groups. The strongest effects for precentral and posterior cingulate SA decreases were seen during early adolescence (13-15 years old) in PS youth. The strongest effects for decreases in thalamic volume and orbitofrontal and postcentral SA were observed in mid-adolescence (16-18 years) in PS youth. Across groups, better overall functioning was associated with increased lateral orbitofrontal SA. Increased postcentral SA was associated with better executive cognition and less severe negative symptoms in the entire sample.Conclusion: In a community-based sample, decreased cortical SA and thalamic volume were present early in adolescent development in youth with PS symptoms, but not in youth with BP symptoms or with BP and PS symptoms. These findings point to potential biological distinctions between PS and BP conditions, which could suggest additional biomarkers relevant to early identification. [ABSTRACT FROM AUTHOR]

Published
2019
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12. The Relationship Between Polygenic Risk Scores and Cognition in Schizophrenia

Author

Laura Ferraro, Michael John Owen, Tracey L. Petryshen, Franziska Degenhardt, Derek W. Morris, Alexander Richards, Aura Frizzati, Ingrid Agartz, Leonhard Lennertz, Ingrid Melle, Fabian Streit, Jim van Os, Bart P. F. Rutten, Bettina Konte, Valentina Escott-Price, Annette M. Hartmann, Håkan Nyman, Ole A. Andreassen, Jana Strohmaier, Diego Quattrone, John Hubert, Gary Donohoe, Sophie E. Legge, Roel A. Ophoff, Loes M. Olde Loohuis, Amy Lynham, Dan Rujescu, Gabriëlla A.M. Blokland, James T.R. Walters, Jeanne E. Savage, Peter Holmans, Craig Morgan, Erik G. Jönsson, Robin M. Murray, Neeltje E.M. van Haren, Kjetil Sundet, Charlotte Gayer-Anderson, Antonio F. Pardiñas, Donna Cosgrove, Michael Wagner, Marcella Rietschel, Michael Conlon O'Donovan, Aiden Corvin, Patrick F. Sullivan, Thomas Espeseth, Ina Giegling, Katherine E. Tansey, Srdjan Djurovic, Child and Adolescent Psychiatry / Psychology, Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, MUMC+: Hersen en Zenuw Centrum (3), MUMC+: MA Psychiatrie (3), RS: MHeNs - R3 - Neuroscience, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, 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 A M, Corvin, Aiden, Cosgrove, Donna, Degenhardt, Franziska, Djurovic, Srdjan, Espeseth, Thoma, 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 P F, 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 T R

Subjects
Multifactorial Inheritance, Bipolar Disorder, Datasets as Topic, INTELLIGENCE, Genome-wide association study, 0302 clinical medicine, genetics [Schizophrenia], education.field_of_study, HERITABILITY, COMMON VARIANTS, Cognition, bioinformatics, intelligence, psychiatry, ABILITY, Psychiatry and Mental health, Schizophrenia, Major depressive disorder, Educational Status, psychiatry, genomics, intelligence, bioinformatics, Clinical psychology, Population, genetics [Psychotic Disorders], behavioral disciplines and activities, 03 medical and health sciences, mental disorders, genomics, medicine, Humans, Bipolar disorder, ddc:610, GENOME-WIDE ASSOCIATION, education, Settore MED/25 - Psichiatria, METAANALYSIS, Genetic association, Depressive Disorder, Major, ENDOPHENOTYPES, business.industry, MEMORY, CONSORTIUM, genetics [Depressive Disorder, Major], PERFORMANCE, medicine.disease, 030227 psychiatry, Psychotic Disorders, genetics [Intelligence], Endophenotype, business, 030217 neurology & neurosurgery, genetics [Bipolar Disorder], Regular Articles, Genome-Wide Association Study
Abstract

Background Cognitive 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. Methods We 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. Results PRS 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. Conclusions Cognition 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
2019
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