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2. A novel blood-based epigenetic biosignature in first-episode schizophrenia patients through automated machine learning

Author

Makrina Karaglani, Agorastos Agorastos, Maria Panagopoulou, Eleni Parlapani, Panagiotis Athanasis, Panagiotis Bitsios, Konstantina Tzitzikou, Theodosis Theodosiou, Ioannis Iliopoulos, Vasilios-Panteleimon Bozikas, and Ekaterini Chatzaki

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Schizophrenia (SCZ) is a chronic, severe, and complex psychiatric disorder that affects all aspects of personal functioning. While SCZ has a very strong biological component, there are still no objective diagnostic tests. Lately, special attention has been given to epigenetic biomarkers in SCZ. In this study, we introduce a three-step, automated machine learning (AutoML)-based, data-driven, biomarker discovery pipeline approach, using genome-wide DNA methylation datasets and laboratory validation, to deliver a highly performing, blood-based epigenetic biosignature of diagnostic clinical value in SCZ. Publicly available blood methylomes from SCZ patients and healthy individuals were analyzed via AutoML, to identify SCZ-specific biomarkers. The methylation of the identified genes was then analyzed by targeted qMSP assays in blood gDNA of 30 first-episode drug-naïve SCZ patients and 30 healthy controls (CTRL). Finally, AutoML was used to produce an optimized disease-specific biosignature based on patient methylation data combined with demographics. AutoML identified a SCZ-specific set of novel gene methylation biomarkers including IGF2BP1, CENPI, and PSME4. Functional analysis investigated correlations with SCZ pathology. Methylation levels of IGF2BP1 and PSME4, but not CENPI were found to differ, IGF2BP1 being higher and PSME4 lower in the SCZ group as compared to the CTRL group. Additional AutoML classification analysis of our experimental patient data led to a five-feature biosignature including all three genes, as well as age and sex, that discriminated SCZ patients from healthy individuals [AUC 0.755 (0.636, 0.862) and average precision 0.758 (0.690, 0.825)]. In conclusion, this three-step pipeline enabled the discovery of three novel genes and an epigenetic biosignature bearing potential value as promising SCZ blood-based diagnostics.

Published
2024
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5. 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

6. The innovative dimension of the research training programmes under H2020-MSCA-ITN: a methodological approach to track, measure and analyse innovative aspects and provide policy-feedback conclusions. [version 2; peer review: 3 approved]

Author

Riccardo Ricci, Audrey Arfi, Ioannis Bitsios, and Fabrizio Martone

Subjects
Innovation, Policy-feedback, H2020, Marie Sklodowska-Curie Actions -Innovative Training Networks (MSCA-ITN), Indicators, Methodology, eng, Medicine, Science
Abstract

Innovative research training programmes funded by the European Union are essential for the forging of highly skilled researchers to tackle, via breakthrough ideas and solutions, the challenges of our society. Being able to track, measure and analyse innovative aspects of the Marie Sklodowska-Curie Actions, Innovative Training Networks under the Horizon2020 funding scheme enables the impact assessment of such programmes, while filtering best practices and the generated knowledge that could ultimately breed and create further innovation. In parallel, it helps the identification of areas for improvement, the understanding of new needs to be accommodated and the co-design and implementation of EU funding policy activities to further promote innovation and excellence for researchers across Europe and beyond. In this study, a novel methodological approach is proposed for tracking and analysing innovation, using a representative sample of projects. Basic innovation indicators are examined and considered from the existing literature and from the applicable Multi-Annual Framework Programme Horizon2020. Additional ones are defined, complemented by questionnaires/surveys findings, to capture innovative aspects for which the standard indicators do not apply. Data mining and data visualization tools are used for the collection and processing of data. Innovation Radar 2 (IR) reports and HorizonResultsBooster 3 services are also engaged for the cross-validation of the identified innovative aspects. The study provides first-level input for policy-feedback activities, by identifying scientific domains and EU countries that may potentially require more attention for innovation generation. It highlights domains that are front-runners and can be used as examples or best practices for under-represented domains in terms of innovative outputs. Collaboration with organisations, defined as medium/high innovators, can increase innovation generation and success in future projects. Best practices are collected to serve as references for designing impactful future training programmes. The excellence of the H2020-MSCA-ITN actions is confirmed via the generated innovations.

Published
2023
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7. The innovative dimension of the research training programmes under H2020-MSCA-ITN1: a methodological approach to track, measure and analyse innovative aspects and provide policy-feedback conclusions. [version 1; peer review: 2 approved]

Author

Riccardo Ricci, Audrey Arfi, Ioannis Bitsios, and Fabrizio Martone

Subjects
Innovation, Policy-feedback, H2020, Marie Sklodowska-Curie Actions -Innovative Training Networks (MSCA-ITN), Indicators, Methodology, eng, Medicine, Science
Abstract

Background: Innovative research training programmes funded by the European Union are essential for the forging of highly skilled researchers to tackle, via breakthrough ideas and solutions, the challenges of our society. Being able to track, measure and analyse innovative aspects of the Marie Sklodowska-Curie Actions, Innovative Training Networks under the Horizon2020 funding scheme enables the impact assessment of such programmes, while filtering best practices and the generated knowledge that could ultimately breed and create further innovation. In parallel, it helps the identification of areas for improvement, the understanding of new needs to be accommodated and the co-design and implementation of EU funding policy activities to further promote innovation and excellence for researchers across Europe and beyond. Methods: In this study, a novel methodological approach is proposed for tracking and analysing innovation, using a representative sample of projects. Basic innovation indicators are examined and considered from the existing literature and from the applicable Multi-Annual Framework Programme Horizon2020. Additional ones are defined, complemented by questionnaires/surveys findings, to capture innovative aspects for which the standard indicators do not apply. Data mining and data visualization tools are used for the collection and processing of data. Innovation Radar2 (IR) reports and HorizonResultsBooster3 services are also engaged for the cross-validation of the identified innovative aspects. Results/Conclusions: The study provides first-level input for policy-feedback activities, by identifying scientific domains and EU countries that may potentially require more attention for innovation generation. It highlights domains that are front-runners and can be used as examples or best practices for under-represented domains in terms of innovative outputs. Collaboration with organisations, defined as medium/high innovators, can increase innovation generation and success in future projects. Best practices are collected to serve as references for designing impactful future training programmes. The excellence of the H2020-MSCA-ITN actions is confirmed via the generated innovations.

Published
2023
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8. 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

9. 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

10. 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

11. Erratum: GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium

Author

Trampush, JW, Yang, MLZ, Yu, J, Knowles, E, Davies, G, Liewald, DC, Starr, JM, Djurovic, S, Melle, I, Sundet, K, Christoforou, A, Reinvang, I, DeRosse, P, Lundervold, AJ, Steen, VM, Espeseth, T, Räikkönen, K, Widen, E, Palotie, A, Eriksson, JG, Giegling, I, Konte, B, Roussos, P, Giakoumaki, S, Burdick, KE, Payton, A, Ollier, W, Horan, M, Chiba-Falek, O, Attix, DK, Need, AC, Cirulli, ET, Voineskos, AN, Stefanis, NC, Avramopoulos, D, Hatzimanolis, A, Arking, DE, Smyrnis, N, Bilder, RM, Freimer, NA, Cannon, TD, London, E, Poldrack, RA, Sabb, FW, Congdon, E, Conley, ED, Scult, MA, Dickinson, D, Straub, RE, Donohoe, G, Morris, D, Corvin, A, Gill, M, Hariri, AR, Weinberger, DR, Pendleton, N, Bitsios, P, Rujescu, D, Lahti, J, Le Hellard, S, Keller, MC, Andreassen, OA, Deary, IJ, Glahn, DC, Malhotra, AK, and Lencz, T

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical and Health Psychology, Clinical Sciences, Psychology, Genetics, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract

This corrects the article DOI: 10.1038/mp.2016.244.

Published
2017

12. 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

13. GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

Author

Trampush, JW, Yang, MLZ, Yu, J, Knowles, E, Davies, G, Liewald, DC, Starr, JM, Djurovic, S, Melle, I, Sundet, K, Christoforou, A, Reinvang, I, DeRosse, P, Lundervold, AJ, Steen, VM, Espeseth, T, Räikkönen, K, Widen, E, Palotie, A, Eriksson, JG, Giegling, I, Konte, B, Roussos, P, Giakoumaki, S, Burdick, KE, Payton, A, Ollier, W, Horan, M, Chiba-Falek, O, Attix, DK, Need, AC, Cirulli, ET, Voineskos, AN, Stefanis, NC, Avramopoulos, D, Hatzimanolis, A, Arking, DE, Smyrnis, N, Bilder, RM, Freimer, NA, Cannon, TD, London, E, Poldrack, RA, Sabb, FW, Congdon, E, Conley, ED, Scult, MA, Dickinson, D, Straub, RE, Donohoe, G, Morris, D, Corvin, A, Gill, M, Hariri, AR, Weinberger, DR, Pendleton, N, Bitsios, P, Rujescu, D, Lahti, J, Le Hellard, S, Keller, MC, Andreassen, OA, Deary, IJ, Glahn, DC, Malhotra, AK, and Lencz, T

Subjects
Psychiatry, Medical and Health Sciences, Biological Sciences, Psychology and Cognitive Sciences
Abstract

This corrects the article DOI: 10.1038/mp.2016.244.

Published
2017

14. The relationship between dopamine receptor D1 and cognitive performance

Author

Tsang, Jonathan, Fullard, John F, Giakoumaki, Stella G, Katsel, Pavel, Karagiorga, Vasiliki Eirini, Greenwood, Tiffany A, Braff, David L, Siever, Larry J, Bitsios, Panos, Haroutunian, Vahram, and Roussos, Panos

Subjects
Biological Psychology, Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Psychology, Neurodegenerative, Genetics, Neurosciences, Dementia, Alzheimer's Disease, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Prevention, Aging, Schizophrenia, Mental Health, Acquired Cognitive Impairment, Aetiology, 2.1 Biological and endogenous factors, Neurological, Mental health, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract

BackgroundCognitive impairment cuts across traditional diagnostic boundaries and is one of the most typical symptoms in various psychiatric and neurobiological disorders.AimsThe objective of this study was to examine the genetic association between 94 candidate genes, including receptors and enzymes that participate in neurotransmission, with measures of cognition.MethodsThe Clinical Dementia Rating (CDR), a global measure of cognition, and genotypes derived from a custom array of 1,536 single-nucleotide polymorphisms (SNPs) in 94 genes were available for a large postmortem cohort of Caucasian cases with Alzheimer's disease (AD), schizophrenia and controls (n=727). A cohort of healthy young males (n=1,493) originating from the LOGOS project (Learning On Genetics Of Schizophrenia Spectrum) profiled across multiple cognitive domains was available for targeted SNP genotyping. Gene expression was quantified in the superior temporal gyrus of control samples (n=109). The regulatory effect on transcriptional activity was assessed using the luciferase reporter system.ResultsThe rs5326-A allele at the promoter region of dopamine receptor D1 (DRD1) locus was associated with: (i) poorer cognition (higher CDR) in the postmortem cohort (P=9.325×10(-4)); (ii) worse cognitive performance relevant to strategic planning in the LOGOS cohort (P=0.008); (iii) lower DRD1 gene expression in the superior temporal gyrus of controls (P=0.038); and (iv) decreased transcriptional activity in human neuroblastoma (SH-SY5Y) cells (P=0.026).ConclusionsAn interdisciplinary approach combining genetics with cognitive and molecular neuroscience provided a possible mechanistic link among DRD1 and alterations in cognitive performance.

Published
2015

15. Conserved Higher-Order Chromatin Regulates NMDA Receptor Gene Expression and Cognition

Author

Bharadwaj, Rahul, Peter, Cyril J, Jiang, Yan, Roussos, Panos, Vogel-Ciernia, Annie, Shen, Erica Y, Mitchell, Amanda C, Mao, Wenjie, Whittle, Catheryne, Dincer, Aslihan, Jakovcevski, Mira, Pothula, Venu, Rasmussen, Theodore P, Giakoumaki, Stella G, Bitsios, Panos, Sherif, Ajfar, Gardner, Paul D, Ernst, Patricia, Ghose, Subroto, Sklar, Pamela, Haroutunian, Vahram, Tamminga, Carol, Myers, Richard H, Futai, Kensuke, Wood, Marcelo A, and Akbarian, Schahram

Subjects
Human Genome, Neurosciences, Genetics, 1.1 Normal biological development and functioning, Underpinning research, Neurological, Aged, Aged, 80 and over, Animals, Animals, Newborn, Antipsychotic Agents, Cells, Cultured, Cerebral Cortex, Chromatin, Cognition, Female, Gene Expression Regulation, HEK293 Cells, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Neurons, Polymorphism, Single Nucleotide, Receptors, N-Methyl-D-Aspartate, Schizophrenia, Signal Transduction, Transcription Factors, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract

Three-dimensional chromosomal conformations regulate transcription by moving enhancers and regulatory elements into spatial proximity with target genes. Here we describe activity-regulated long-range loopings bypassing up to 0.5 Mb of linear genome to modulate NMDA glutamate receptor GRIN2B expression in human and mouse prefrontal cortex. Distal intronic and 3' intergenic loop formations competed with repressor elements to access promoter-proximal sequences, and facilitated expression via a "cargo" of AP-1 and NRF-1 transcription factors and TALE-based transcriptional activators. Neuronal deletion or overexpression of Kmt2a/Mll1 H3K4- and Kmt1e/Setdb1 H3K9-methyltransferase was associated with higher-order chromatin changes at distal regulatory Grin2b sequences and impairments in working memory. Genetic polymorphisms and isogenic deletions of loop-bound sequences conferred liability for cognitive performance and decreased GRIN2B expression. Dynamic regulation of chromosomal conformations emerges as a novel layer for transcriptional mechanisms impacting neuronal signaling and cognition.

Published
2014

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

Author

Gail Davies, Max Lam, Sarah E. Harris, Joey W. Trampush, Michelle Luciano, W. David Hill, Saskia P. Hagenaars, Stuart J. Ritchie, Riccardo E. Marioni, Chloe Fawns-Ritchie, David C. M. Liewald, Judith A. Okely, Ari V. Ahola-Olli, Catriona L. K. Barnes, Lars Bertram, Joshua C. Bis, Katherine E. Burdick, Andrea Christoforou, Pamela DeRosse, Srdjan Djurovic, Thomas Espeseth, Stella Giakoumaki, Sudheer Giddaluru, Daniel E. Gustavson, Caroline Hayward, Edith Hofer, M. Arfan Ikram, Robert Karlsson, Emma Knowles, Jari Lahti, Markus Leber, Shuo Li, Karen A. Mather, Ingrid Melle, Derek Morris, Christopher Oldmeadow, Teemu Palviainen, Antony Payton, Raha Pazoki, Katja Petrovic, Chandra A. Reynolds, Muralidharan Sargurupremraj, Markus Scholz, Jennifer A. Smith, Albert V. Smith, Natalie Terzikhan, Anbupalam Thalamuthu, Stella Trompet, Sven J. van der Lee, Erin B. Ware, B. Gwen Windham, Margaret J. Wright, Jingyun Yang, Jin Yu, David Ames, Najaf Amin, Philippe Amouyel, Ole A. Andreassen, Nicola J. Armstrong, Amelia A. Assareh, John R. Attia, Deborah Attix, Dimitrios Avramopoulos, David A. Bennett, Anne C. Böhmer, Patricia A. Boyle, Henry Brodaty, Harry Campbell, Tyrone D. Cannon, Elizabeth T. Cirulli, Eliza Congdon, Emily Drabant Conley, Janie Corley, Simon R. Cox, Anders M. Dale, Abbas Dehghan, Danielle Dick, Dwight Dickinson, Johan G. Eriksson, Evangelos Evangelou, Jessica D. Faul, Ian Ford, Nelson A. Freimer, He Gao, Ina Giegling, Nathan A. Gillespie, Scott D. Gordon, Rebecca F. Gottesman, Michael E. Griswold, Vilmundur Gudnason, Tamara B. Harris, Annette M. Hartmann, Alex Hatzimanolis, Gerardo Heiss, Elizabeth G. Holliday, Peter K. Joshi, Mika Kähönen, Sharon L. R. Kardia, Ida Karlsson, Luca Kleineidam, David S. Knopman, Nicole A. Kochan, Bettina Konte, John B. Kwok, Stephanie Le Hellard, Teresa Lee, Terho Lehtimäki, Shu-Chen Li, Christina M. Lill, Tian Liu, Marisa Koini, Edythe London, Will T. Longstreth, Oscar L. Lopez, Anu Loukola, Tobias Luck, Astri J. Lundervold, Anders Lundquist, Leo-Pekka Lyytikäinen, Nicholas G. Martin, Grant W. Montgomery, Alison D. Murray, Anna C. Need, Raymond Noordam, Lars Nyberg, William Ollier, Goran Papenberg, Alison Pattie, Ozren Polasek, Russell A. Poldrack, Bruce M. Psaty, Simone Reppermund, Steffi G. Riedel-Heller, Richard J. Rose, Jerome I. Rotter, Panos Roussos, Suvi P. Rovio, Yasaman Saba, Fred W. Sabb, Perminder S. Sachdev, Claudia L. Satizabal, Matthias Schmid, Rodney J. Scott, Matthew A. Scult, Jeannette Simino, P. Eline Slagboom, Nikolaos Smyrnis, Aïcha Soumaré, Nikos C. Stefanis, David J. Stott, Richard E. Straub, Kjetil Sundet, Adele M. Taylor, Kent D. Taylor, Ioanna Tzoulaki, Christophe Tzourio, André Uitterlinden, Veronique Vitart, Aristotle N. Voineskos, Jaakko Kaprio, Michael Wagner, Holger Wagner, Leonie Weinhold, K. Hoyan Wen, Elisabeth Widen, Qiong Yang, Wei Zhao, Hieab H. H. Adams, Dan E. Arking, Robert M. Bilder, Panos Bitsios, Eric Boerwinkle, Ornit Chiba-Falek, Aiden Corvin, Philip L. De Jager, Stéphanie Debette, Gary Donohoe, Paul Elliott, Annette L. Fitzpatrick, Michael Gill, David C. Glahn, Sara Hägg, Narelle K. Hansell, Ahmad R. Hariri, M. Kamran Ikram, J. Wouter Jukema, Eero Vuoksimaa, Matthew C. Keller, William S. Kremen, Lenore Launer, Ulman Lindenberger, Aarno Palotie, Nancy L. Pedersen, Neil Pendleton, David J. Porteous, Katri Räikkönen, Olli T. Raitakari, Alfredo Ramirez, Ivar Reinvang, Igor Rudan, Dan Rujescu, Reinhold Schmidt, Helena Schmidt, Peter W. Schofield, Peter R. Schofield, John M. Starr, Vidar M. Steen, Julian N. Trollor, Steven T. Turner, Cornelia M. Van Duijn, Arno Villringer, Daniel R. Weinberger, David R. Weir, James F. Wilson, Anil Malhotra, Andrew M. McIntosh, Catharine R. Gale, Sudha Seshadri, Thomas H. Mosley, Jan Bressler, Todd Lencz, and Ian J. Deary

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

Author

Gail Davies, Max Lam, Sarah E. Harris, Joey W. Trampush, Michelle Luciano, W. David Hill, Saskia P. Hagenaars, Stuart J. Ritchie, Riccardo E. Marioni, Chloe Fawns-Ritchie, David C. M. Liewald, Judith A. Okely, Ari V. Ahola-Olli, Catriona L. K. Barnes, Lars Bertram, Joshua C. Bis, Katherine E. Burdick, Andrea Christoforou, Pamela DeRosse, Srdjan Djurovic, Thomas Espeseth, Stella Giakoumaki, Sudheer Giddaluru, Daniel E. Gustavson, Caroline Hayward, Edith Hofer, M. Arfan Ikram, Robert Karlsson, Emma Knowles, Jari Lahti, Markus Leber, Shuo Li, Karen A. Mather, Ingrid Melle, Derek Morris, Christopher Oldmeadow, Teemu Palviainen, Antony Payton, Raha Pazoki, Katja Petrovic, Chandra A. Reynolds, Muralidharan Sargurupremraj, Markus Scholz, Jennifer A. Smith, Albert V. Smith, Natalie Terzikhan, Anbupalam Thalamuthu, Stella Trompet, Sven J. van der Lee, Erin B. Ware, B. Gwen Windham, Margaret J. Wright, Jingyun Yang, Jin Yu, David Ames, Najaf Amin, Philippe Amouyel, Ole A. Andreassen, Nicola J. Armstrong, Amelia A. Assareh, John R. Attia, Deborah Attix, Dimitrios Avramopoulos, David A. Bennett, Anne C. Böhmer, Patricia A. Boyle, Henry Brodaty, Harry Campbell, Tyrone D. Cannon, Elizabeth T. Cirulli, Eliza Congdon, Emily Drabant Conley, Janie Corley, Simon R. Cox, Anders M. Dale, Abbas Dehghan, Danielle Dick, Dwight Dickinson, Johan G. Eriksson, Evangelos Evangelou, Jessica D. Faul, Ian Ford, Nelson A. Freimer, He Gao, Ina Giegling, Nathan A. Gillespie, Scott D. Gordon, Rebecca F. Gottesman, Michael E. Griswold, Vilmundur Gudnason, Tamara B. Harris, Annette M. Hartmann, Alex Hatzimanolis, Gerardo Heiss, Elizabeth G. Holliday, Peter K. Joshi, Mika Kähönen, Sharon L. R. Kardia, Ida Karlsson, Luca Kleineidam, David S. Knopman, Nicole A. Kochan, Bettina Konte, John B. Kwok, Stephanie Le Hellard, Teresa Lee, Terho Lehtimäki, Shu-Chen Li, Christina M. Lill, Tian Liu, Marisa Koini, Edythe London, Will T. Longstreth, Oscar L. Lopez, Anu Loukola, Tobias Luck, Astri J. Lundervold, Anders Lundquist, Leo-Pekka Lyytikäinen, Nicholas G. Martin, Grant W. Montgomery, Alison D. Murray, Anna C. Need, Raymond Noordam, Lars Nyberg, William Ollier, Goran Papenberg, Alison Pattie, Ozren Polasek, Russell A. Poldrack, Bruce M. Psaty, Simone Reppermund, Steffi G. Riedel-Heller, Richard J. Rose, Jerome I. Rotter, Panos Roussos, Suvi P. Rovio, Yasaman Saba, Fred W. Sabb, Perminder S. Sachdev, Claudia L. Satizabal, Matthias Schmid, Rodney J. Scott, Matthew A. Scult, Jeannette Simino, P. Eline Slagboom, Nikolaos Smyrnis, Aïcha Soumaré, Nikos C. Stefanis, David J. Stott, Richard E. Straub, Kjetil Sundet, Adele M. Taylor, Kent D. Taylor, Ioanna Tzoulaki, Christophe Tzourio, André Uitterlinden, Veronique Vitart, Aristotle N. Voineskos, Jaakko Kaprio, Michael Wagner, Holger Wagner, Leonie Weinhold, K. Hoyan Wen, Elisabeth Widen, Qiong Yang, Wei Zhao, Hieab H. H. Adams, Dan E. Arking, Robert M. Bilder, Panos Bitsios, Eric Boerwinkle, Ornit Chiba-Falek, Aiden Corvin, Philip L. De Jager, Stéphanie Debette, Gary Donohoe, Paul Elliott, Annette L. Fitzpatrick, Michael Gill, David C. Glahn, Sara Hägg, Narelle K. Hansell, Ahmad R. Hariri, M. Kamran Ikram, J. Wouter Jukema, Eero Vuoksimaa, Matthew C. Keller, William S. Kremen, Lenore Launer, Ulman Lindenberger, Aarno Palotie, Nancy L. Pedersen, Neil Pendleton, David J. Porteous, Katri Räikkönen, Olli T. Raitakari, Alfredo Ramirez, Ivar Reinvang, Igor Rudan, Dan Rujescu, Reinhold Schmidt, Helena Schmidt, Peter W. Schofield, Peter R. Schofield, John M. Starr, Vidar M. Steen, Julian N. Trollor, Steven T. Turner, Cornelia M. Van Duijn, Arno Villringer, Daniel R. Weinberger, David R. Weir, James F. Wilson, Anil Malhotra, Andrew M. McIntosh, Catharine R. Gale, Sudha Seshadri, Thomas H. Mosley, Jan Bressler, Todd Lencz, and Ian J. Deary

Subjects
Science
Abstract

Cognitive function is associated with health and important life outcomes. Here, the authors perform a genome-wide association study for general cognitive function in 300,486 individuals and identify genetic loci that implicate neural and cell developmental pathways in this trait.

Published
2018
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18. Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets

Author

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

Subjects
GWAS, general cognitive ability, nootropics, gene expression, neurodevelopment, synapse, calcium channel, potassium channel, cerebellum, Biology (General), QH301-705.5
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
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19. 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 C. M., Okely, Judith A., Ahola-Olli, Ari V., Barnes, Catriona L. K., 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 L. R., Karlsson, Ida, Kleineidam, Luca, Knopman, David S., Kochan, Nicole A., Konte, Bettina, Kwok, John B., Le Hellard, Stephanie, Lee, Teresa, Lehtimäki, Terho, Li, Shu-Chen, Lill, Christina M., Liu, Tian, Koini, Marisa, London, Edythe, Longstreth, Jr, Will T., Lopez, Oscar L., Loukola, Anu, Luck, Tobias, Lundervold, Astri J., Lundquist, Anders, Lyytikäinen, Leo-Pekka, Martin, Nicholas G., Montgomery, Grant W., Murray, Alison D., Need, Anna C., Noordam, Raymond, Nyberg, Lars, Ollier, William, Papenberg, Goran, Pattie, Alison, Polasek, Ozren, Poldrack, Russell A., Psaty, Bruce M., Reppermund, Simone, Riedel-Heller, Steffi G., Rose, Richard J., Rotter, Jerome I., Roussos, Panos, Rovio, Suvi P., Saba, Yasaman, Sabb, Fred W., Sachdev, Perminder S., Satizabal, Claudia L., Schmid, Matthias, Scott, Rodney J., Scult, Matthew A., Simino, Jeannette, Slagboom, P. Eline, Smyrnis, Nikolaos, Soumaré, Aïcha, Stefanis, Nikos C., Stott, David J., Straub, Richard E., Sundet, Kjetil, Taylor, Adele M., Taylor, Kent D., Tzoulaki, Ioanna, Tzourio, Christophe, Uitterlinden, André, Vitart, Veronique, Voineskos, Aristotle N., Kaprio, Jaakko, Wagner, Michael, Wagner, Holger, Weinhold, Leonie, Wen, K. Hoyan, Widen, Elisabeth, Yang, Qiong, Zhao, Wei, Adams, Hieab H. H., Arking, Dan E., Bilder, Robert M., Bitsios, Panos, Boerwinkle, Eric, Chiba-Falek, Ornit, Corvin, Aiden, De Jager, Philip L., Debette, Stéphanie, Donohoe, Gary, Elliott, Paul, Fitzpatrick, Annette L., Gill, Michael, Glahn, David C., Hägg, Sara, Hansell, Narelle K., Hariri, Ahmad R., Ikram, M. Kamran, Jukema, J. Wouter, Vuoksimaa, Eero, Keller, Matthew C., Kremen, William S., Launer, Lenore, Lindenberger, Ulman, Palotie, Aarno, Pedersen, Nancy L., Pendleton, Neil, Porteous, David J., Räikkönen, Katri, Raitakari, Olli T., Ramirez, Alfredo, Reinvang, Ivar, Rudan, Igor, Dan Rujescu, Schmidt, Reinhold, Schmidt, Helena, Schofield, Peter W., Schofield, Peter R., Starr, John M., Steen, Vidar M., Trollor, Julian N., Turner, Steven T., Van Duijn, Cornelia M., Villringer, Arno, Weinberger, Daniel R., Weir, David R., Wilson, James F., Malhotra, Anil, McIntosh, Andrew M., Gale, Catharine R., Seshadri, Sudha, Mosley, Jr, Thomas H., Bressler, Jan, Lencz, Todd, and Deary, Ian J.

Published
2019
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21. The Student Counselling Centre at the University of Crete, Greece

Author

Panos Bitsios, Evangelos Karademas, Angeliki Mouzaki, George Manolitsis, Ourania Kapellaki, Anastasia Diacatou, Arianna Archontaki, George Mamalakis, and Theodoros Giovazolias

Subjects
Psychiatry, RC435-571
Abstract

This report describes the Student Counselling Centre (SCC) at the University of Crete. The SCS was established in 2003. Its main areas of activity are individual and group psychological support, crisis intervention, research, prevention, volunteering and awareness. Emphasis is also put on the support provided to students with special needs, which is now the second core service of the SCC.

Published
2017
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22. EFFECTS OF WORKING MEMORY TRAINING ON COGNITIVE FLEXIBILITY IN BOTH MEN AND WOMEN PARTICIPANTS

Author

V Stavroulaki, E Kazantzaki, P Bitsios, SG Giakoumaki, and K Sidiropoulou

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

OBJECTIVE: The study aims to investigate the effect of working memory training on cognitive flexibility in both men and women participants. MATERIAL – METHOD: Ninety-five healthy participants were divided into three groups (matched for demographic variables, schizotypy, impulsivity and baseline cognitive flexibility): a) fully adapted group (participants were fully trained with an executive working memory task, the Letter Number Sequencing task, for six consecutive days), b) partially adapted group (participants were partially trained with the same task for six consecutive days) and c) control group (participants did not receive cognitive training). Following training, all participants were tested in another cognitive flexibility task; the Intra-Extra Dimensional Set Shift Task (ID/EDS). RESULTS: Results showed that the fully adapted group had improved performance on the ID/EDS test, since they made fewer attempts to complete the stages of the test and marginally significantly fewer errors, compared with both the other two groups, who did not differ between each other. There were also significant correlations between the tests used. Specifically, it was found that the number of errors in the Wisconsin Card Sorting Task (WCST) was negatively correlated with the number of errors in the ID/EDS test. Also, it was observed that the Raven test correlates negatively with the number of errors in the WCST and also positively with the number of errors and trials needed to complete the stages of the ID/EDS task. CONCLUSIONS: These findings could have significant implications in the development of therapeutic approaches for the improvement of cognitive deficits in neuropsychiatric disorders.

Published
2018
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23. 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 C. M., Okely, Judith A., Ahola-Olli, Ari V., Barnes, Catriona L. K., 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 L. R., Karlsson, Ida, Kleineidam, Luca, Knopman, David S., Kochan, Nicole A., Konte, Bettina, Kwok, John B., Le Hellard, Stephanie, Lee, Teresa, Lehtimäki, Terho, Li, Shu-Chen, Lill, Christina M., Liu, Tian, Koini, Marisa, London, Edythe, Longstreth, Jr, Will T., Lopez, Oscar L., Loukola, Anu, Luck, Tobias, Lundervold, Astri J., Lundquist, Anders, Lyytikäinen, Leo-Pekka, Martin, Nicholas G., Montgomery, Grant W., Murray, Alison D., Need, Anna C., Noordam, Raymond, Nyberg, Lars, Ollier, William, Papenberg, Goran, Pattie, Alison, Polasek, Ozren, Poldrack, Russell A., Psaty, Bruce M., Reppermund, Simone, Riedel-Heller, Steffi G., Rose, Richard J., Rotter, Jerome I., Roussos, Panos, Rovio, Suvi P., Saba, Yasaman, Sabb, Fred W., Sachdev, Perminder S., Satizabal, Claudia L., Schmid, Matthias, Scott, Rodney J., Scult, Matthew A., Simino, Jeannette, Slagboom, P. Eline, Smyrnis, Nikolaos, Soumaré, Aïcha, Stefanis, Nikos C., Stott, David J., Straub, Richard E., Sundet, Kjetil, Taylor, Adele M., Taylor, Kent D., Tzoulaki, Ioanna, Tzourio, Christophe, Uitterlinden, André, Vitart, Veronique, Voineskos, Aristotle N., Kaprio, Jaakko, Wagner, Michael, Wagner, Holger, Weinhold, Leonie, Wen, K. Hoyan, Widen, Elisabeth, Yang, Qiong, Zhao, Wei, Adams, Hieab H. H., Arking, Dan E., Bilder, Robert M., Bitsios, Panos, Boerwinkle, Eric, Chiba-Falek, Ornit, Corvin, Aiden, De Jager, Philip L., Debette, Stéphanie, Donohoe, Gary, Elliott, Paul, Fitzpatrick, Annette L., Gill, Michael, Glahn, David C., Hägg, Sara, Hansell, Narelle K., Hariri, Ahmad R., Ikram, M. Kamran, Jukema, J. Wouter, Vuoksimaa, Eero, Keller, Matthew C., Kremen, William S., Launer, Lenore, Lindenberger, Ulman, Palotie, Aarno, Pedersen, Nancy L., Pendleton, Neil, Porteous, David J., Räikkönen, Katri, Raitakari, Olli T., Ramirez, Alfredo, Reinvang, Ivar, Rudan, Igor, Dan Rujescu, Schmidt, Reinhold, Schmidt, Helena, Schofield, Peter W., Schofield, Peter R., Starr, John M., Steen, Vidar M., Trollor, Julian N., Turner, Steven T., Van Duijn, Cornelia M., Villringer, Arno, Weinberger, Daniel R., Weir, David R., Wilson, James F., Malhotra, Anil, McIntosh, Andrew M., Gale, Catharine R., Seshadri, Sudha, Mosley, Jr, Thomas H., Bressler, Jan, Lencz, Todd, and Deary, Ian J.

Published
2018
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24. Genome-wide autozygosity is associated with lower general cognitive ability

Author

Howrigan, D P, Simonson, M A, Davies, G, Harris, S E, Tenesa, A, Starr, J M, Liewald, D C, Deary, I J, McRae, A, Wright, M J, Montgomery, G W, Hansell, N, Martin, N G, Payton, A, Horan, M, Ollier, W E, Abdellaoui, A, Boomsma, D I, DeRosse, P, Knowles, E E M, Glahn, D C, Djurovic, S, Melle, I, Andreassen, O A, Christoforou, A, Steen, V M, Hellard, S L, Sundet, K, Reinvang, I, Espeseth, T, Lundervold, A J, Giegling, I, Konte, B, Hartmann, A M, Rujescu, D, Roussos, P, Giakoumaki, S, Burdick, K E, Bitsios, P, Donohoe, G, Corley, R P, Visscher, P M, Pendleton, N, Malhotra, A K, Neale, B M, Lencz, T, and Keller, M C

Published
2016
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27. Descriptive Epidemiology of Somatising Tendency: Findings from the CUPID Study.

Author

Sergio Vargas-Prada, David Coggon, Georgia Ntani, Karen Walker-Bone, Keith T Palmer, Vanda E Felli, Raul Harari, Lope H Barrero, Sarah A Felknor, David Gimeno, Anna Cattrell, Matteo Bonzini, Eleni Solidaki, Eda Merisalu, Rima R Habib, Farideh Sadeghian, M Masood Kadir, Sudath S P Warnakulasuriya, Ko Matsudaira, Busisiwe Nyantumbu, Malcolm R Sim, Helen Harcombe, Ken Cox, Leila M M Sarquis, Maria H Marziale, Florencia Harari, Rocio Freire, Natalia Harari, Magda V Monroy, Leonardo A Quintana, Marianela Rojas, E Clare Harris, Consol Serra, J Miguel Martinez, George Delclos, Fernando G Benavides, Michele Carugno, Marco M Ferrario, Angela C Pesatori, Leda Chatzi, Panos Bitsios, Manolis Kogevinas, Kristel Oha, Tiina Freimann, Ali Sadeghian, Roshini J Peiris-John, Nalini Sathiakumar, A Rajitha Wickremasinghe, Noriko Yoshimura, Helen L Kelsall, Victor C W Hoe, Donna M Urquhart, Sarah Derrett, David McBride, Peter Herbison, Andrew Gray, and Eduardo J Salazar Vega

Subjects
Medicine, Science
Abstract

Somatising tendency, defined as a predisposition to worry about common somatic symptoms, is importantly associated with various aspects of health and health-related behaviour, including musculoskeletal pain and associated disability. To explore its epidemiological characteristics, and how it can be specified most efficiently, we analysed data from an international longitudinal study. A baseline questionnaire, which included questions from the Brief Symptom Inventory about seven common symptoms, was completed by 12,072 participants aged 20-59 from 46 occupational groups in 18 countries (response rate 70%). The seven symptoms were all mutually associated (odds ratios for pairwise associations 3.4 to 9.3), and each contributed to a measure of somatising tendency that exhibited an exposure-response relationship both with multi-site pain (prevalence rate ratios up to six), and also with sickness absence for non-musculoskeletal reasons. In most participants, the level of somatising tendency was little changed when reassessed after a mean interval of 14 months (75% having a change of 0 or 1 in their symptom count), although the specific symptoms reported at follow-up often differed from those at baseline. Somatising tendency was more common in women than men, especially at older ages, and varied markedly across the 46 occupational groups studied, with higher rates in South and Central America. It was weakly associated with smoking, but not with level of education. Our study supports the use of questions from the Brief Symptom Inventory as a method for measuring somatising tendency, and suggests that in adults of working age, it is a fairly stable trait.

Published
2016
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28. Work-related and psychological determinants of multisite musculoskeletal pain

Author

Eleni Solidaki, Leda Chatzi, Panos Bitsios, Irini Markatzi, Estel Plana, Francesc Castro, Keith Palmer, David Coggon, and Manolis Kogevinas

Subjects
multisite musculoskeletal pain, multisite pain, epidemiology, musculoskeletal disorder, occupational health, musculoskeletal pain, msd, psychological determinant, work-related determinant, Public aspects of medicine, RA1-1270
Abstract

OBJECTIVE: Musculoskeletal pain is associated with occupational physical activities and psychosocial risk factors. We evaluated the relative importance of work-related and psychological determinants of the number of ­anatomical sites affected by musculoskeletal pain in a cross-sectional survey. METHODS: The survey focused on musculoskeletal pain in six body regions (low-back, neck, shoulder, elbow, wrist–hand, and knee) among 224 nurses, 200 office workers and 140 postal clerks in Crete, Greece (response rate 95%). Information was collected about demographic characteristics, occupational physical load, psycho­social aspects of work, perceptions about the causes of pain, mental health, somatization, and experience of pain in the past 12 months. We used Poisson regression to assess associations of risk factors with the number of painful anatomical sites and explored interactions using classification and regression trees (CART). RESULTS: Two-thirds of the study sample reported pain in ≥2 body sites during the past 12 months, and in 23%, >3 sites were affected. The number of painful anatomical sites was strongly related to both physical load at work and somatization (with relative risks increased 5-fold or more for frequent and disabling multisite pain) and was also significantly associated with work-related psychosocial factors and beliefs about work causation. The CART analysis suggested that somatization was the leading determinant of the number of painful body sites. CONCLUSION: In the population studied, pain at multiple anatomical sites was common and strongly associated with somatization, which may have a more important influence on multisite pain than pain that is limited to a single anatomical site.

Published
2010
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30. Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT)

Author

Lencz, T, Knowles, E, Davies, G, Guha, S, Liewald, D C, Starr, J M, Djurovic, S, Melle, I, Sundet, K, Christoforou, A, Reinvang, I, Mukherjee, S, DeRosse, Pamela, Lundervold, A, Steen, V M, John, M, Espeseth, T, Räikkönen, K, Widen, E, Palotie, A, Eriksson, J G, Giegling, I, Konte, B, Ikeda, M, Roussos, P, Giakoumaki, S, Burdick, K E, Payton, A, Ollier, W, Horan, M, Donohoe, G, Morris, D, Corvin, A, Gill, M, Pendleton, N, Iwata, N, Darvasi, A, Bitsios, P, Rujescu, D, Lahti, J, Hellard, S L, Keller, M C, Andreassen, O A, Deary, I J, Glahn, D C, and Malhotra, A K

Published
2014
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32. Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics

Author

Lam, M. Chen, C.-Y. Ge, T. Xia, Y. Hill, D.W. Trampush, J.W. Yu, J. Knowles, E. Davies, G. Stahl, E.A. Huckins, L. Liewald, D.C. Djurovic, S. Melle, I. Christoforou, A. Reinvang, I. DeRosse, P. Lundervold, A.J. Steen, V.M. Espeseth, T. Räikkönen, K. Widen, E. Palotie, A. Eriksson, J.G. Giegling, I. Konte, B. Hartmann, A.M. Roussos, P. Giakoumaki, S. Burdick, K.E. Payton, A. Ollier, W. Chiba-Falek, O. Koltai, D.C. Need, A.C. Cirulli, E.T. Voineskos, A.N. Stefanis, N.C. Avramopoulos, D. Hatzimanolis, A. Smyrnis, N. Bilder, R.M. Freimer, N.B. Cannon, T.D. London, E. Poldrack, R.A. Sabb, F.W. Congdon, E. Conley, E.D. Scult, M.A. Dickinson, D. Straub, R.E. Donohoe, G. Morris, D. Corvin, A. Gill, M. Hariri, A.R. Weinberger, D.R. Pendleton, N. Bitsios, P. Rujescu, D. Lahti, J. Le Hellard, S. Keller, M.C. Andreassen, O.A. Deary, I.J. Glahn, D.C. Huang, H. Liu, C. Malhotra, A.K. Lencz, T.

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. © 2021, The Author(s).

Published
2021

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

Author

Lam, M, Chen, CY, Ge, T, Xia, Y, Hill, DW, Trampush, JW, Yu, J, Knowles, E, Davies, G, Stahl, EA, Huckins, L, Liewald, DC, Djurovic, S, Melle, I, Christoforou, A, Reinvang, I, DeRosse, P, Lundervold, AJ, Steen, VM, Espeseth, T, Räikkönen, K, Widen, E, Palotie, A, Eriksson, JG, Giegling, I, Konte, B, Hartmann, AM, Roussos, P, Giakoumaki, S, Burdick, KE, Payton, A, Ollier, W, Chiba-Falek, O, Koltai, DC, Need, AC, Cirulli, ET, Voineskos, AN, Stefanis, NC, Avramopoulos, D, Hatzimanolis, A, Smyrnis, N, Bilder, RM, Freimer, NB, Cannon, TD, London, E, Poldrack, RA, Sabb, FW, Congdon, E, Conley, ED, Scult, MA, Dickinson, D, Straub, RE, Donohoe, G, Morris, D, Corvin, A, Gill, M, Hariri, AR, Weinberger, DR, Pendleton, N, Bitsios, P, Rujescu, D, Lahti, J, Le Hellard, S, Keller, MC, Andreassen, OA, Deary, IJ, Glahn, DC, Huang, H, Liu, C, Malhotra, AK, Lencz, T, Lam, M, Chen, CY, Ge, T, Xia, Y, Hill, DW, Trampush, JW, Yu, J, Knowles, E, Davies, G, Stahl, EA, Huckins, L, Liewald, DC, Djurovic, S, Melle, I, Christoforou, A, Reinvang, I, DeRosse, P, Lundervold, AJ, Steen, VM, Espeseth, T, Räikkönen, K, Widen, E, Palotie, A, Eriksson, JG, Giegling, I, Konte, B, Hartmann, AM, Roussos, P, Giakoumaki, S, Burdick, KE, Payton, A, Ollier, W, Chiba-Falek, O, Koltai, DC, Need, AC, Cirulli, ET, Voineskos, AN, Stefanis, NC, Avramopoulos, D, Hatzimanolis, A, Smyrnis, N, Bilder, RM, Freimer, NB, Cannon, TD, London, E, Poldrack, RA, Sabb, FW, Congdon, E, Conley, ED, Scult, MA, Dickinson, D, Straub, RE, Donohoe, G, Morris, D, Corvin, A, Gill, M, Hariri, AR, Weinberger, DR, Pendleton, N, Bitsios, P, Rujescu, D, Lahti, J, Le Hellard, S, Keller, MC, Andreassen, OA, Deary, IJ, Glahn, DC, Huang, H, Liu, C, Malhotra, AK, and Lencz, T

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

37. The CUPID (Cultural and Psychosocial Influences on Disability) study: methods of data collection and characteristics of study sample.

Author

David Coggon, Georgia Ntani, Keith T Palmer, Vanda E Felli, Raul Harari, Lope H Barrero, Sarah A Felknor, David Gimeno, Anna Cattrell, Consol Serra, Matteo Bonzini, Eleni Solidaki, Eda Merisalu, Rima R Habib, Farideh Sadeghian, Masood Kadir, Sudath S P Warnakulasuriya, Ko Matsudaira, Busisiwe Nyantumbu, Malcolm R Sim, Helen Harcombe, Ken Cox, Maria H Marziale, Leila M Sarquis, Florencia Harari, Rocio Freire, Natalia Harari, Magda V Monroy, Leonardo A Quintana, Marianela Rojas, Eduardo J Salazar Vega, E Clare Harris, Sergio Vargas-Prada, J Miguel Martinez, George Delclos, Fernando G Benavides, Michele Carugno, Marco M Ferrario, Angela C Pesatori, Leda Chatzi, Panos Bitsios, Manolis Kogevinas, Kristel Oha, Tuuli Sirk, Ali Sadeghian, Roshini J Peiris-John, Nalini Sathiakumar, A Rajitha Wickremasinghe, Noriko Yoshimura, Danuta Kielkowski, Helen L Kelsall, Victor C W Hoe, Donna M Urquhart, Sarah Derrett, David McBride, and Andrew Gray

Subjects
Medicine, Science
Abstract

BackgroundThe CUPID (Cultural and Psychosocial Influences on Disability) study was established to explore the hypothesis that common musculoskeletal disorders (MSDs) and associated disability are importantly influenced by culturally determined health beliefs and expectations. This paper describes the methods of data collection and various characteristics of the study sample.Methods/principal findingsA standardised questionnaire covering musculoskeletal symptoms, disability and potential risk factors, was used to collect information from 47 samples of nurses, office workers, and other (mostly manual) workers in 18 countries from six continents. In addition, local investigators provided data on economic aspects of employment for each occupational group. Participation exceeded 80% in 33 of the 47 occupational groups, and after pre-specified exclusions, analysis was based on 12,426 subjects (92 to 1018 per occupational group). As expected, there was high usage of computer keyboards by office workers, while nurses had the highest prevalence of heavy manual lifting in all but one country. There was substantial heterogeneity between occupational groups in economic and psychosocial aspects of work; three- to five-fold variation in awareness of someone outside work with musculoskeletal pain; and more than ten-fold variation in the prevalence of adverse health beliefs about back and arm pain, and in awareness of terms such as "repetitive strain injury" (RSI).Conclusions/significanceThe large differences in psychosocial risk factors (including knowledge and beliefs about MSDs) between occupational groups should allow the study hypothesis to be addressed effectively.

Published
2012
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38. Correction: The CUPID (Cultural and Psychosocial Influences on Disability) Study: Methods of Data Collection and Characteristics of Study Sample.

Author

David Coggon, Georgia Ntani, Keith T. Palmer, Vanda E. Felli, Raul Harari, Lope H. Barrero, Sarah A. Felknor, David Gimeno, Anna Cattrell, Consol Serra, Matteo Bonzini, Eleni Solidaki, Eda Merisalu, Rima R. Habib, Farideh Sadeghian, Masood Kadir, Sudath S. P. Warnakulasuriya, Ko Matsudaira, Busisiwe Nyantumbu, Malcolm R. Sim, Helen Harcombe, Ken Cox, Maria H. Marziale, Leila M. Sarquis, Florencia Harari, Rocio Freire, Natalia Harari, Magda V. Monroy, Leonardo A. Quintana, Marianela Rojas, Eduardo J. Salazar Vega, E. Clare Harris, Sergio Vargas-Prada, J. Miguel Martinez, George Delclos, Fernando G. Benavides, Michele Carugno, Marco M. Ferrario, Angela C. Pesatori, Leda Chatzi, Panos Bitsios, Manolis Kogevinas, Kristel Oha, Tuuli Sirk, Ali Sadeghian, Roshini J. Peiris-John, Nalini Sathiakumar, A. Rajitha Wickremasinghe, Noriko Yoshimura, Danuta Kielkowski, Helen L. Kelsall, Victor C. W. Hoe, Donna M. Urquhart, Sarah Derrett, David McBride, and Andrew Gray

Subjects
Medicine, Science
Published
2012
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39. Cannabis-dependence risk relates to synergism between neuroticism and proenkephalin SNPs associated with amygdala gene expression: case-control study.

Author

Didier Jutras-Aswad, Michelle M Jacobs, Georgia Yiannoulos, Panos Roussos, Panos Bitsios, Yoko Nomura, Xun Liu, and Yasmin L Hurd

Subjects
Medicine, Science
Abstract

BACKGROUND:Many young people experiment with cannabis, yet only a subgroup progress to dependence suggesting individual differences that could relate to factors such as genetics and behavioral traits. Dopamine receptor D2 (DRD2) and proenkephalin (PENK) genes have been implicated in animal studies with cannabis exposure. Whether polymorphisms of these genes are associated with cannabis dependence and related behavioral traits is unknown. METHODOLOGY/PRINCIPAL FINDINGS:Healthy young adults (18-27 years) with cannabis dependence and without a dependence diagnosis were studied (N = 50/group) in relation to a priori-determined single nucleotide polymorphisms (SNPs) of the DRD2 and PENK genes. Negative affect, Impulsive Risk Taking and Neuroticism-Anxiety temperamental traits, positive and negative reward-learning performance and stop-signal reaction times were examined. The findings replicated the known association between the rs6277 DRD2 SNP and decisions associated with negative reinforcement outcomes. Moreover, PENK variants (rs2576573 and rs2609997) significantly related to Neuroticism and cannabis dependence. Cigarette smoking is common in cannabis users, but it was not associated to PENK SNPs as also validated in another cohort (N = 247 smokers, N = 312 non-smokers). Neuroticism mediated (15.3%-19.5%) the genetic risk to cannabis dependence and interacted with risk SNPs, resulting in a 9-fold increase risk for cannabis dependence. Molecular characterization of the postmortem human brain in a different population revealed an association between PENK SNPs and PENK mRNA expression in the central amygdala nucleus emphasizing the functional relevance of the SNPs in a brain region strongly linked to negative affect. CONCLUSIONS/SIGNIFICANCE:Overall, the findings suggest an important role for Neuroticism as an endophenotype linking PENK polymorphisms to cannabis-dependence vulnerability synergistically amplifying the apparent genetic risk.

Published
2012
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48. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function (vol 9, 2098, 2018)

Author

Davies, G., Lam, M., Harris, S.E., Trampush, J.W., Luciano, M., Hill, W.D., Hagenaars, S.P., Ritchie, S.J., Marioni, R.E., Fawns-Ritchie, C., Liewald, D.C.M., Okely, J.A., Ahola-Olli, A.V., Barnes, C.L.K., Bertram, L., Bis, J.C., Burdick, K.E., Christoforou, A., DeRosse, P., Djurovic, S., Espeseth, T., Giakoumaki, S., Giddaluru, S., Gustavson, D.E., Hayward, C., Hofer, E., Ikram, M.A., Karlsson, R., Knowles, E., Lahti, J., Leber, M., Li, S., Mather, K.A., Melle, I., Morris, D., Oldmeadow, C., Palviainen, T., Payton, A., Pazoki, R., Petrovic, K., Reynolds, C.A., Sargurupremraj, M., Scholz, M., Smith, J.A., Smith, A.V., Terzikhan, N., Thalamuthu, A., Trompet, S., Lee, S.J. van der, Ware, E.B., Windham, B.G., Wright, M.J., Yang, J.Y., Yu, J., Ames, D., Amin, N., Amouyel, P., Andreassen, O.A., Armstrong, N.J., Assareh, A.A., Attia, J.R., Attix, D., Avramopoulos, D., Bennett, D.A., Bohmer, A.C., Boyle, P.A., Brodaty, H., Campbell, H., Cannon, T.D., Cirulli, E.T., Congdon, E., Conley, E.D., Corley, J., Cox, S.R., Dale, A.M., Dehghan, A., Dick, D., Dickinson, D., Eriksson, J.G., Evangelou, E., Faul, J.D., Ford, I., Freimer, N.A., Gao, H., Giegling, I., Gillespie, N.A., Gordon, S.D., Gottesman, R.F., Griswold, M.E., Gudnason, V., Harris, T.B., Hartmann, A.M., Hatzimanolis, A., Heiss, G., Holliday, E.G., Joshi, P.K., Kahonen, M., Kardia, S.L.R., Karlsson, I., Kleineidam, L., Knopman, D.S., Kochan, N.A., Konte, B., Kwok, J.B., Hellard, S. le, Lee, T., Lehtimaki, T., Li, S.C., Lill, C.M., Liu, T., Koini, M., London, E., Longstreth, W.T., Lopez, O.L., Loukola, A., Luck, T., Lundervold, A.J., Lundquist, A., Lyytikainen, L.P., Martin, N.G., Montgomery, G.W., Murray, A.D., Need, A.C., Noordam, R., Nyberg, L., Ollier, W., Papenberg, G., Pattie, A., Polasek, O., Poldrack, R.A., Psaty, B.M., Reppermund, S., Riedel-Heller, S.G., Rose, R.J., Rotter, J.I., Roussos, P., Rovio, S.P., Saba, Y., Sabb, F.W., Sachdev, P.S., Satizabal, C.L., Schmid, M., Scott, R.J., Scult, M.A., Simino, J., Slagboom, P.E., Smyrnis, N., Soumare, A., Stefanis, N.C., Stott, D.J., Straub, R.E., Sundet, K., Taylor, A.M., Taylor, K.D., Tzoulaki, I., Tzourio, C., Uitterlinden, A., Vitart, V., Voineskos, A.N., Kaprio, J., Wagner, M., Wagner, H., Weinhold, L., Wen, K.H., Widen, E., Yang, Q., Zhao, W., Adams, H.H.H., Arking, D.E., Bilder, R.M., Bitsios, P., Boerwinkle, E., Chiba-Falek, O., Corvin, A., Jager, P.L. de, Debette, S., Donohoe, G., Elliott, P., Fitzpatrick, A.L., Gill, M., Glahn, D.C., Hagg, S., Hansell, N.K., Hariri, A.R., Ikram, M.K., Jukema, J.W., Vuoksimaa, E., Keller, M.C., Kremen, W.S., Launer, L., Lindenberger, U., Palotie, A., Pedersen, N.L., Pendleton, N., Porteous, D.J., Raikkonen, K., Raitakari, O.T., Ramirez, A., Reinvang, I., Rudan, I., Rujescu, D., Schmidt, R., Schmidt, H., Schofield, P.W., Schofield, P.R., Starr, J.M., Steen, V.M., Trollor, J.N., Turner, S.T., Duijn, C.M. van, Villringer, A., Weinberger, D.R., Weir, D.R., Wilson, J.F., Malhotra, A., McIntosh, A.M., Gale, C.R., Seshadri, S., Mosley, T.H., Bressler, J., Lencz, T., and Deary, I.J.

Published
2019

49. Author Correction: Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function (Nature Communications, (2018), 9, 1, (2098), 10.1038/s41467-018-04362-x)

Author

Davies, G. Lam, M. Harris, S.E. Trampush, J.W. Luciano, M. Hill, W.D. Hagenaars, S.P. Ritchie, S.J. Marioni, R.E. Fawns-Ritchie, C. Liewald, D.C.M. Okely, J.A. Ahola-Olli, A.V. Barnes, C.L.K. Bertram, L. Bis, J.C. Burdick, K.E. Christoforou, A. DeRosse, P. Djurovic, S. Espeseth, T. Giakoumaki, S. Giddaluru, S. Gustavson, D.E. Hayward, C. Hofer, E. Ikram, M.A. Karlsson, R. Knowles, E. Lahti, J. Leber, M. Li, S. Mather, K.A. Melle, I. Morris, D. Oldmeadow, C. Palviainen, T. Payton, A. Pazoki, R. Petrovic, K. Reynolds, C.A. Sargurupremraj, M. Scholz, M. Smith, J.A. Smith, A.V. Terzikhan, N. Thalamuthu, A. Trompet, S. van der Lee, S.J. Ware, E.B. Windham, B.G. Wright, M.J. Yang, J. Yu, J. Ames, D. Amin, N. Amouyel, P. Andreassen, O.A. Armstrong, N.J. Assareh, A.A. Attia, J.R. Attix, D. Avramopoulos, D. Bennett, D.A. Böhmer, A.C. Boyle, P.A. Brodaty, H. Campbell, H. Cannon, T.D. Cirulli, E.T. Congdon, E. Conley, E.D. Corley, J. Cox, S.R. Dale, A.M. Dehghan, A. Dick, D. Dickinson, D. Eriksson, J.G. Evangelou, E. Faul, J.D. Ford, I. Freimer, N.A. Gao, H. Giegling, I. Gillespie, N.A. Gordon, S.D. Gottesman, R.F. Griswold, M.E. Gudnason, V. Harris, T.B. Hartmann, A.M. Hatzimanolis, A. Heiss, G. Holliday, E.G. Joshi, P.K. Kähönen, M. Kardia, S.L.R. Karlsson, I. Kleineidam, L. Knopman, D.S. Kochan, N.A. Konte, B. Kwok, J.B. Le Hellard, S. Lee, T. Lehtimäki, T. Li, S.-C. Lill, C.M. Liu, T. Koini, M. London, E. Longstreth, W.T., Jr. Lopez, O.L. Loukola, A. Luck, T. Lundervold, A.J. Lundquist, A. Lyytikäinen, L.-P. Martin, N.G. Montgomery, G.W. Murray, A.D. Need, A.C. Noordam, R. Nyberg, L. Ollier, W. Papenberg, G. Pattie, A. Polasek, O. Poldrack, R.A. Psaty, B.M. Reppermund, S. Riedel-Heller, S.G. Rose, R.J. Rotter, J.I. Roussos, P. Rovio, S.P. Saba, Y. Sabb, F.W. Sachdev, P.S. Satizabal, C.L. Schmid, M. Scott, R.J. Scult, M.A. Simino, J. Slagboom, P.E. Smyrnis, N. Soumaré, A. Stefanis, N.C. Stott, D.J. Straub, R.E. Sundet, K. Taylor, A.M. Taylor, K.D. Tzoulaki, I. Tzourio, C. Uitterlinden, A. Vitart, V. Voineskos, A.N. Kaprio, J. Wagner, M. Wagner, H. Weinhold, L. Wen, K.H. Widen, E. Yang, Q. Zhao, W. Adams, H.H.H. Arking, D.E. Bilder, R.M. Bitsios, P. Boerwinkle, E. Chiba-Falek, O. Corvin, A. De Jager, P.L. Debette, S. Donohoe, G. Elliott, P. Fitzpatrick, A.L. Gill, M. Glahn, D.C. Hägg, S. Hansell, N.K. Hariri, A.R. Ikram, M.K. Jukema, J.W. Vuoksimaa, E. Keller, M.C. Kremen, W.S. Launer, L. Lindenberger, U. Palotie, A. Pedersen, N.L. Pendleton, N. Porteous, D.J. Räikkönen, K. Raitakari, O.T. Ramirez, A. Reinvang, I. Rudan, I. Dan Rujescu Schmidt, R. Schmidt, H. Schofield, P.W. Schofield, P.R. Starr, J.M. Steen, V.M. Trollor, J.N. Turner, S.T. Van Duijn, C.M. Villringer, A. Weinberger, D.R. Weir, D.R. Wilson, J.F. Malhotra, A. McIntosh, A.M. Gale, C.R. Seshadri, S. Mosley, T.H., Jr. Bressler, J. Lencz, T. Deary, I.J.

Subjects
ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries)
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. © 2019, The Author(s).

Published
2019

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

Author

Lam, M. Hill, W.D. Trampush, J.W. Yu, J. Knowles, E. Davies, G. Stahl, E. Huckins, L. Liewald, D.C. Djurovic, S. Melle, I. Sundet, K. Christoforou, A. Reinvang, I. DeRosse, P. Lundervold, A.J. Steen, V.M. Espeseth, T. Räikkönen, K. Widen, E. Palotie, A. Eriksson, J.G. Giegling, I. Konte, B. Hartmann, A.M. Roussos, P. Giakoumaki, S. Burdick, K.E. Payton, A. Ollier, W. Chiba-Falek, O. Attix, D.K. Need, A.C. Cirulli, E.T. Voineskos, A.N. Stefanis, N.C. Avramopoulos, D. Hatzimanolis, A. Arking, D.E. Smyrnis, N. Bilder, R.M. Freimer, N.A. Cannon, T.D. London, E. Poldrack, R.A. Sabb, F.W. Congdon, E. Conley, E.D. Scult, M.A. Dickinson, D. Straub, R.E. Donohoe, G. Morris, D. Corvin, A. Gill, M. Hariri, A.R. Weinberger, D.R. Pendleton, N. Bitsios, P. Rujescu, D. Lahti, J. Le Hellard, S. Keller, M.C. Andreassen, O.A. Deary, I.J. Glahn, D.C. Malhotra, A.K. Lencz, T.

Subjects
mental disorders
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. © 2019

Published
2019

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