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32 results on '"Corvin, Aiden"'

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

Author

Holleran L, Kelly S, Alloza C, Agartz I, Andreassen OA, Arango C, Banaj N, Calhoun V, Cannon D, Carr V, Corvin A, Glahn DC, Gur R, Hong E, Hoschl C, Howells FM, James A, Janssen J, Kochunov P, Lawrie SM, Liu J, Martinez C, McDonald C, Morris D, Mothersill D, Pantelis C, Piras F, Potkin S, Rasser PE, Roalf D, Rowland L, Satterthwaite T, Schall U, Spalletta G, Spaniel F, Stein DJ, Uhlmann A, Voineskos A, Zalesky A, van Erp TGM, Turner JA, Deary IJ, Thompson PM, Jahanshad N, and Donohoe G

Subjects
Adult, Anisotropy, Brain diagnostic imaging, Case-Control Studies, Diffusion Tensor Imaging, Factor Analysis, Statistical, Female, Healthy Volunteers, Humans, Male, Middle Aged, Neural Pathways diagnostic imaging, Principal Component Analysis, Schizophrenia physiopathology, Wechsler Scales, Cognition physiology, Intelligence, Schizophrenia diagnostic imaging, Schizophrenic Psychology, White Matter diagnostic imaging
Abstract

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

Published
2020
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2. Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition.

Author

van der Meer D, Sønderby IE, Kaufmann T, Walters GB, Abdellaoui A, Ames D, Amunts K, Andersson M, Armstrong NJ, Bernard M, Blackburn NB, Blangero J, Boomsma DI, Brodaty H, Brouwer RM, Bülow R, Cahn W, Calhoun VD, Caspers S, Cavalleri GL, Ching CRK, Cichon S, Ciufolini S, Corvin A, Crespo-Facorro B, Curran JE, Dalvie S, Dazzan P, de Geus EJC, de Zubicaray GI, de Zwarte SMC, Delanty N, den Braber A, Desrivieres S, Di Forti M, Doherty JL, Donohoe G, Ehrlich S, Eising E, Espeseth T, Fisher SE, Fladby T, Frei O, Frouin V, Fukunaga M, Gareau T, Glahn DC, Grabe HJ, Groenewold NA, Gústafsson Ó, Haavik J, Haberg AK, Hashimoto R, Hehir-Kwa JY, Hibar DP, Hillegers MHJ, Hoffmann P, Holleran L, Hottenga JJ, Hulshoff Pol HE, Ikeda M, Jacquemont S, Jahanshad N, Jockwitz C, Johansson S, Jönsson EG, Kikuchi M, Knowles EEM, Kwok JB, Le Hellard S, Linden DEJ, Liu J, Lundervold A, Lundervold AJ, Martin NG, Mather KA, Mathias SR, McMahon KL, McRae AF, Medland SE, Moberget T, Moreau C, Morris DW, Mühleisen TW, Murray RM, Nordvik JE, Nyberg L, Olde Loohuis LM, Ophoff RA, Owen MJ, Paus T, Pausova Z, Peralta JM, Pike B, Prieto C, Quinlan EB, Reinbold CS, Reis Marques T, Rucker JJH, Sachdev PS, Sando SB, Schofield PR, Schork AJ, Schumann G, Shin J, Shumskaya E, Silva AI, Sisodiya SM, Steen VM, Stein DJ, Strike LT, Tamnes CK, Teumer A, Thalamuthu A, Tordesillas-Gutiérrez D, Uhlmann A, Úlfarsson MÖ, van 't Ent D, van den Bree MBM, Vassos E, Wen W, Wittfeld K, Wright MJ, Zayats T, Dale AM, Djurovic S, Agartz I, Westlye LT, Stefánsson H, Stefánsson K, Thompson PM, and Andreassen OA

Subjects
Brain Cortical Thickness, Cerebral Cortex diagnostic imaging, Cerebral Cortex physiology, Chromosome Breakpoints, DNA Copy Number Variations physiology, Female, Genetic Association Studies, Heterozygote, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Neuroimaging, Neuropsychological Tests, Organ Size genetics, Cerebral Cortex anatomy & histology, Chromosomes, Human, Pair 15 genetics, Cognition, DNA Copy Number Variations genetics
Abstract

Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities., Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance., Design, Setting, and Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019., Main Outcomes and Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort., Results: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks., Conclusions and Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.

Published
2020
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3. Moral cognition, the missing link between psychotic symptoms and acts of violence: a cross-sectional national forensic cohort study.

Author

O'Reilly K, O'Connell P, O'Sullivan D, Corvin A, Sheerin J, O'Flynn P, Donohoe G, McCarthy H, Ambrosh D, O'Donnell M, Ryan A, and Kennedy HG

Subjects
Adult, Cohort Studies, Cross-Sectional Studies, Female, Homicide psychology, Humans, Male, Middle Aged, Cognition, Morals, Psychotic Disorders psychology, Violence psychology
Abstract

Background: People with schizophrenia are ten times more likely to commit homicide than a member of the general population. The relationship between symptoms of schizophrenia and acts of violence is unclear. There has also been limited research on what determines the seriousness and form of violence, such as reactive or instrumental violence. Moral cognition may play a paradoxical role in acts of violence for people with schizophrenia. Thoughts which have moral content arising from psychotic symptoms may be a cause of serious violence., Method: We investigated if psychotic symptoms and moral cognitions at the time of a violent act were associated with acts of violence using a cross-sectional national forensic cohort (n = 55). We examined whether moral cognitions were associated with violence when controlling for neurocognition and violence proneness. We explored the association between all psychotic symptoms present at the time of the violent act, psychotic symptoms judged relevant to the violent act and moral cognitions present at that time. Using mediation analysis, we examined whether moral cognitions were the missing link between symptoms and the relevance of symptoms for violence. We also investigated if specific moral cognitions mediated the relationship between specific psychotic symptoms, the seriousness of violence (including homicide), and the form of violence., Results: Psychotic symptoms generally were not associated with the seriousness or form of violence. However, specific moral cognitions were associated with the seriousness and form of violence even when controlling for neurocognition and violence proneness. Specific moral cognitions were associated with specific psychotic symptoms present and relevant to violence. Moral cognitions mediated the relationship between the presence of specific psychotic symptoms and their relevance for violence, homicide, seriousness of violence, and the form of violence., Conclusions: Moral cognitions including the need to reduce suffering, responding to an act of injustice or betrayal, the desire to comply with authority, or the wish to punish impure or disgusting behaviour, may be a key mediator explaining the relationship between psychotic symptoms and acts of violence. Our findings may have important implications for risk assessment, treatment and violence prevention.

Published
2019
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4. Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.

Author

Lam M, Hill WD, Trampush JW, Yu J, Knowles E, Davies G, Stahl E, Huckins L, Liewald DC, 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, Hartmann AM, Roussos P, Giakoumaki S, Burdick KE, Payton A, Ollier W, 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
Adult, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Neurodevelopmental Disorders pathology, Cognition physiology, Cognition Disorders physiopathology, Educational Status, Neurodevelopmental Disorders etiology, Polymorphism, Single Nucleotide, Schizophrenia physiopathology, Synaptic Transmission
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., (Copyright © 2019. Published by Elsevier Inc.)

Published
2019
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5. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.

Author

Davies G, Lam M, Harris SE, Trampush JW, Luciano M, Hill WD, Hagenaars SP, Ritchie SJ, Marioni RE, Fawns-Ritchie C, Liewald DCM, Okely JA, Ahola-Olli AV, Barnes CLK, Bertram L, Bis JC, Burdick KE, Christoforou A, DeRosse P, Djurovic S, Espeseth T, Giakoumaki S, Giddaluru S, Gustavson DE, Hayward C, Hofer E, Ikram MA, Karlsson R, Knowles E, Lahti J, Leber M, Li S, Mather KA, Melle I, Morris D, Oldmeadow C, Palviainen T, Payton A, Pazoki R, Petrovic K, Reynolds CA, Sargurupremraj M, Scholz M, Smith JA, Smith AV, Terzikhan N, Thalamuthu A, Trompet S, van der Lee SJ, Ware EB, Windham BG, Wright MJ, Yang J, Yu J, Ames D, Amin N, Amouyel P, Andreassen OA, Armstrong NJ, Assareh AA, Attia JR, Attix D, Avramopoulos D, Bennett DA, Böhmer AC, Boyle PA, Brodaty H, Campbell H, Cannon TD, Cirulli ET, Congdon E, Conley ED, Corley J, Cox SR, Dale AM, Dehghan A, Dick D, Dickinson D, Eriksson JG, Evangelou E, Faul JD, Ford I, Freimer NA, Gao H, Giegling I, Gillespie NA, Gordon SD, Gottesman RF, Griswold ME, Gudnason V, Harris TB, Hartmann AM, Hatzimanolis A, Heiss G, Holliday EG, Joshi PK, Kähönen M, Kardia SLR, Karlsson I, Kleineidam L, Knopman DS, Kochan NA, Konte B, Kwok JB, Le Hellard S, Lee T, Lehtimäki T, Li SC, Lill CM, Liu T, Koini M, London E, Longstreth WT Jr, Lopez OL, Loukola A, Luck T, Lundervold AJ, Lundquist A, Lyytikäinen LP, Martin NG, Montgomery GW, Murray AD, Need AC, Noordam R, Nyberg L, Ollier W, Papenberg G, Pattie A, Polasek O, Poldrack RA, Psaty BM, Reppermund S, Riedel-Heller SG, Rose RJ, Rotter JI, Roussos P, Rovio SP, Saba Y, Sabb FW, Sachdev PS, Satizabal CL, Schmid M, Scott RJ, Scult MA, Simino J, Slagboom PE, Smyrnis N, Soumaré A, Stefanis NC, Stott DJ, Straub RE, Sundet K, Taylor AM, Taylor KD, Tzoulaki I, Tzourio C, Uitterlinden A, Vitart V, Voineskos AN, Kaprio J, Wagner M, Wagner H, Weinhold L, Wen KH, Widen E, Yang Q, Zhao W, Adams HHH, Arking DE, Bilder RM, Bitsios P, Boerwinkle E, Chiba-Falek O, Corvin A, De Jager PL, Debette S, Donohoe G, Elliott P, Fitzpatrick AL, Gill M, Glahn DC, Hägg S, Hansell NK, Hariri AR, Ikram MK, Jukema JW, Vuoksimaa E, Keller MC, Kremen WS, Launer L, Lindenberger U, Palotie A, Pedersen NL, Pendleton N, Porteous DJ, Räikkönen K, Raitakari OT, Ramirez A, Reinvang I, Rudan I, Dan Rujescu, Schmidt R, Schmidt H, Schofield PW, Schofield PR, Starr JM, Steen VM, Trollor JN, Turner ST, Van Duijn CM, Villringer A, Weinberger DR, Weir DR, Wilson JF, Malhotra A, McIntosh AM, Gale CR, Seshadri S, Mosley TH Jr, Bressler J, Lencz T, and Deary IJ

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Genetic Loci genetics, Genetic Predisposition to Disease, Humans, Middle Aged, Polymorphism, Single Nucleotide genetics, Reaction Time genetics, Young Adult, Cognition physiology, Mental Disorders genetics, Multifactorial Inheritance genetics, Neurodegenerative Diseases genetics, Neurodevelopmental Disorders genetics
Abstract

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10 -8 ) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

Published
2018
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6. Cognitive Characterization of Schizophrenia Risk Variants Involved in Synaptic Transmission: Evidence of CACNA1C's Role in Working Memory.

Author

Cosgrove D, Mothersill O, Kendall K, Konte B, Harold D, Giegling I, Hartmann A, Richards A, Mantripragada K, Owen MJ, O'Donovan MC, Gill M, Rujescu D, Walters J, Corvin A, Morris DW, and Donohoe G

Subjects
Adult, Brain diagnostic imaging, Brain physiology, Brain Mapping, Female, Genetic Loci, Genome-Wide Association Study, Humans, Magnetic Resonance Imaging, Male, Neural Pathways diagnostic imaging, Neural Pathways physiology, Neuropsychological Tests, Polymorphism, Single Nucleotide, Psychotic Disorders genetics, Calcium Channels, L-Type genetics, Cognition, Genetic Predisposition to Disease, Memory, Short-Term physiology, Schizophrenia genetics, Synaptic Transmission genetics
Abstract

With >100 common variants associated with schizophrenia risk, establishing their biological significance is a priority. We sought to establish cognitive effects of risk variants at loci implicated in synaptic transmission by (1) identifying GWAS schizophrenia variants whose associated gene function is related to synaptic transmission, and (2) testing for association between these and measures of neurocognitive function. We selected variants, reported in the largest GWAS to date, associated with genes involved in synaptic transmission. Associations between genotype and cognitive test score were analyzed in a discovery sample (988 Irish participants, including 798 with psychosis), and replication samples (528 UK patients with schizophrenia/schizoaffective disorder; 921 German participants including 362 patients with schizophrenia). Three loci showed significant associations with neuropsychological performance in the discovery samples. This included an association between the rs2007044 (risk allele G) within CACNA1C and poorer working memory performance (increased errors B (95% CI)=0.635-4.535, p=0.012), an effect driven mainly by the psychosis groups. In an fMRI analysis of working memory performance (n=84 healthy participants, a subset of the discovery sample), we further found evidence that the same CACNA1C allele was associated with decreased functional connectivity between the right dorsolateral prefrontal cortex and right superior occipital gyrus/cuneus and anterior cingulate cortex. In conclusion, these data provide evidence to suggest that the CACNA1C risk variant rs2007044 is associated with poorer memory function that may result from risk carriers' difficulty with top-down initiated responses caused by dysconnectivity between the right DLPFC and several cortical regions.

Published
2017
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7. Novel genetic loci underlying human intracranial volume identified through genome-wide association.

Author

Adams HH, Hibar DP, Chouraki V, Stein JL, Nyquist PA, Rentería ME, Trompet S, Arias-Vasquez A, Seshadri S, Desrivières S, Beecham AH, Jahanshad N, Wittfeld K, Van der Lee SJ, Abramovic L, Alhusaini S, Amin N, Andersson M, Arfanakis K, Aribisala BS, Armstrong NJ, Athanasiu L, Axelsson T, Beiser A, Bernard M, Bis JC, Blanken LM, Blanton SH, Bohlken MM, Boks MP, Bralten J, Brickman AM, Carmichael O, Chakravarty MM, Chauhan G, Chen Q, Ching CR, Cuellar-Partida G, Braber AD, Doan NT, Ehrlich S, Filippi I, Ge T, Giddaluru S, Goldman AL, Gottesman RF, Greven CU, Grimm O, Griswold ME, Guadalupe T, Hass J, Haukvik UK, Hilal S, Hofer E, Hoehn D, Holmes AJ, Hoogman M, Janowitz D, Jia T, Kasperaviciute D, Kim S, Klein M, Kraemer B, Lee PH, Liao J, Liewald DC, Lopez LM, Luciano M, Macare C, Marquand A, Matarin M, Mather KA, Mattheisen M, Mazoyer B, McKay DR, McWhirter R, Milaneschi Y, Mirza-Schreiber N, Muetzel RL, Maniega SM, Nho K, Nugent AC, Loohuis LM, Oosterlaan J, Papmeyer M, Pappa I, Pirpamer L, Pudas S, Pütz B, Rajan KB, Ramasamy A, Richards JS, Risacher SL, Roiz-Santiañez R, Rommelse N, Rose EJ, Royle NA, Rundek T, Sämann PG, Satizabal CL, Schmaal L, Schork AJ, Shen L, Shin J, Shumskaya E, Smith AV, Sprooten E, Strike LT, Teumer A, Thomson R, Tordesillas-Gutierrez D, Toro R, Trabzuni D, Vaidya D, Van der Grond J, Van der Meer D, Van Donkelaar MM, Van Eijk KR, Van Erp TG, Van Rooij D, Walton E, Westlye LT, Whelan CD, Windham BG, Winkler AM, Woldehawariat G, Wolf C, Wolfers T, Xu B, Yanek LR, Yang J, Zijdenbos A, Zwiers MP, Agartz I, Aggarwal NT, Almasy L, Ames D, Amouyel P, Andreassen OA, Arepalli S, Assareh AA, Barral S, Bastin ME, Becker DM, Becker JT, Bennett DA, Blangero J, van Bokhoven H, Boomsma DI, Brodaty H, Brouwer RM, Brunner HG, Buckner RL, Buitelaar JK, Bulayeva KB, Cahn W, Calhoun VD, Cannon DM, Cavalleri GL, Chen C, Cheng CY, Cichon S, Cookson MR, Corvin A, Crespo-Facorro B, Curran JE, Czisch M, Dale AM, Davies GE, De Geus EJ, De Jager PL, de Zubicaray GI, Delanty N, Depondt C, DeStefano AL, Dillman A, Djurovic S, Donohoe G, Drevets WC, Duggirala R, Dyer TD, Erk S, Espeseth T, Evans DA, Fedko IO, Fernández G, Ferrucci L, Fisher SE, Fleischman DA, Ford I, Foroud TM, Fox PT, Francks C, Fukunaga M, Gibbs JR, Glahn DC, Gollub RL, Göring HH, Grabe HJ, Green RC, Gruber O, Gudnason V, Guelfi S, Hansell NK, Hardy J, Hartman CA, Hashimoto R, Hegenscheid K, Heinz A, Le Hellard S, Hernandez DG, Heslenfeld DJ, Ho BC, Hoekstra PJ, Hoffmann W, Hofman A, Holsboer F, Homuth G, Hosten N, Hottenga JJ, Hulshoff Pol HE, Ikeda M, Ikram MK, Jack CR Jr, Jenkinson M, Johnson R, Jönsson EG, Jukema JW, Kahn RS, Kanai R, Kloszewska I, Knopman DS, Kochunov P, Kwok JB, Lawrie SM, Lemaître H, Liu X, Longo DL, Longstreth WT Jr, Lopez OL, Lovestone S, Martinez O, Martinot JL, Mattay VS, McDonald C, McIntosh AM, McMahon KL, McMahon FJ, Mecocci P, Melle I, Meyer-Lindenberg A, Mohnke S, Montgomery GW, Morris DW, Mosley TH, Mühleisen TW, Müller-Myhsok B, Nalls MA, Nauck M, Nichols TE, Niessen WJ, Nöthen MM, Nyberg L, Ohi K, Olvera RL, Ophoff RA, Pandolfo M, Paus T, Pausova Z, Penninx BW, Pike GB, Potkin SG, Psaty BM, Reppermund S, Rietschel M, Roffman JL, Romanczuk-Seiferth N, Rotter JI, Ryten M, Sacco RL, Sachdev PS, Saykin AJ, Schmidt R, Schofield PR, Sigurdsson S, Simmons A, Singleton A, Sisodiya SM, Smith C, Smoller JW, Soininen H, Srikanth V, Steen VM, Stott DJ, Sussmann JE, Thalamuthu A, Tiemeier H, Toga AW, Traynor BJ, Troncoso J, Turner JA, Tzourio C, Uitterlinden AG, Hernández MC, Van der Brug M, Van der Lugt A, Van der Wee NJ, Van Duijn CM, Van Haren NE, Van T Ent D, Van Tol MJ, Vardarajan BN, Veltman DJ, Vernooij MW, Völzke H, Walter H, Wardlaw JM, Wassink TH, Weale ME, Weinberger DR, Weiner MW, Wen W, Westman E, White T, Wong TY, Wright CB, Zielke HR, Zonderman AB, Deary IJ, DeCarli C, Schmidt H, Martin NG, De Craen AJ, Wright MJ, Launer LJ, Schumann G, Fornage M, Franke B, Debette S, Medland SE, Ikram MA, and Thompson PM

Subjects
Brain growth & development, Brain pathology, Genetic Loci genetics, Humans, Oncogene Protein v-akt genetics, Parkinson Disease genetics, Phenotype, Phosphatidylinositol 3-Kinases genetics, White People, Cognition physiology, Genetic Predisposition to Disease, Genome-Wide Association Study methods, Polymorphism, Single Nucleotide genetics
Abstract

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρ genetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (N combined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.

Published
2016
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8. Independent evidence for an association between general cognitive ability and a genetic locus for educational attainment.

Author

Trampush JW, Lencz T, Knowles E, Davies G, Guha S, Pe'er I, Liewald DC, Starr JM, Djurovic S, Melle I, Sundet K, Christoforou A, Reinvang I, Mukherjee S, DeRosse P, Lundervold A, Steen VM, John M, Espeseth T, Räikkönen K, Widen E, Palotie A, Eriksson JG, Giegling I, Konte B, Ikeda M, Roussos P, Giakoumaki S, Burdick KE, Payton A, Ollier W, Horan M, Scult M, Dickinson D, Straub RE, Donohoe G, Morris D, Corvin A, Gill M, Hariri A, Weinberger DR, Pendleton N, Iwata N, Darvasi A, Bitsios P, Rujescu D, Lahti J, Le Hellard S, Keller MC, Andreassen OA, Deary IJ, Glahn DC, and Malhotra AK

Subjects
Adult, Aged, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Middle Aged, Cognition physiology, Cognition Disorders genetics, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide genetics
Abstract

Cognitive deficits and reduced educational achievement are common in psychiatric illness; understanding the genetic basis of cognitive and educational deficits may be informative about the etiology of psychiatric disorders. A recent, large genome-wide association study (GWAS) reported a genome-wide significant locus for years of education, which subsequently demonstrated association to general cognitive ability ("g") in overlapping cohorts. The current study was designed to test whether GWAS hits for educational attainment are involved in general cognitive ability in an independent, large-scale collection of cohorts. Using cohorts in the Cognitive Genomics Consortium (COGENT; up to 20,495 healthy individuals), we examined the relationship between g and variants associated with educational attainment. We next conducted meta-analyses with 24,189 individuals with neurocognitive data from the educational attainment studies, and then with 53,188 largely independent individuals from a recent GWAS of cognition. A SNP (rs1906252) located at chromosome 6q16.1, previously associated with years of schooling, was significantly associated with g (P = 1.47 × 10(-4) ) in COGENT. The first joint analysis of 43,381 non-overlapping individuals for this a priori-designated locus was strongly significant (P = 4.94 × 10(-7) ), and the second joint analysis of 68,159 non-overlapping individuals was even more robust (P = 1.65 × 10(-9) ). These results provide independent replication, in a large-scale dataset, of a genetic locus associated with cognitive function and education. As sample sizes grow, cognitive GWAS will identify increasing numbers of associated loci, as has been accomplished in other polygenic quantitative traits, which may be relevant to psychiatric illness., (© 2015 Wiley Periodicals, Inc.)

Published
2015
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9. A NOS1 variant implicated in cognitive performance influences evoked neural responses during a high density EEG study of early visual perception.

Author

O'Donoghue T, Morris DW, Fahey C, Da Costa A, Foxe JJ, Hoerold D, Tropea D, Gill M, Corvin A, and Donohoe G

Subjects
Adolescent, Adult, Child, Female, Humans, Male, Photic Stimulation methods, Psychomotor Performance physiology, Young Adult, Cognition physiology, Electroencephalography methods, Evoked Potentials, Visual physiology, Genetic Variation genetics, Nitric Oxide Synthase Type I genetics, Visual Perception physiology
Abstract

Background: The nitric oxide synthasase-1 gene (NOS1) has been implicated in mental disorders including schizophrenia and variation in cognition. The NOS1 variant rs6490121 identified in a genome wide association study of schizophrenia has recently been associated with variation in general intelligence and working memory in both patients and healthy participants. Whether this variant is also associated with variation in early sensory processing remains unclear., Methods: We investigated differences in the P1 visual evoked potential in a high density EEG study of 54 healthy participants. Given both NOS1's association with cognition and recent evidence that cognitive performance and P1 response are correlated, we investigated whether NOS1's effect on P1 response was independent of its effects on cognition using CANTAB's spatial working memory (SWM) task., Results: We found that carriers of the previously identified risk "G" allele showed significantly lower P1 responses than non-carriers. We also found that while P1 response and SWM performance were correlated, NOS1 continued to explain a significant proportion of variation in P1 response even when its effects on cognition were accounted for., Conclusion: The schizophrenia implicated NOS1 variants rs6490121 influences visual sensory processing as measured by the P1 response, either as part of the gene's pleiotropic effects on multiple aspects of brain function, or because of a primary influence on sensory processing that mediates the effects already seen in higher cognitive processes., (Copyright © 2011 Wiley-Liss, Inc.)

Published
2012
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10. Variance in neurocognitive performance is associated with dysbindin-1 in schizophrenia: a preliminary study.

Author

Donohoe G, Morris DW, Clarke S, McGhee KA, Schwaiger S, Nangle JM, Garavan H, Robertson IH, Gill M, and Corvin A

Subjects
Adolescent, Adult, Attention physiology, Dysbindin, Dystrophin-Associated Proteins, Female, Genotype, Haplotypes, Heterozygote, Humans, Male, Memory, Short-Term physiology, Middle Aged, Psychiatric Status Rating Scales, Wechsler Scales, Carrier Proteins genetics, Cognition physiology, Psychomotor Performance physiology, Schizophrenia genetics, Schizophrenic Psychology
Abstract

Susceptibility genes for schizophrenia have been hypothesised to mediate liability for the disorder at least partly by influencing cognitive performance. We investigated the association between genotype and cognitive performance for a Dysbindin risk haplotype which is associated with schizophrenia in our sample. Fifty-two patients with schizophrenia or schizoaffective disorder (24 risk haplotypes carriers versus 28 non-risk haplotype carriers) were assessed in areas of cognition showing evidence of familial deficits in schizophrenia. Verbal and spatial memory, working memory, and attentional control was assessed using selected measures from the Weschler memory scale (WMS), Cambridge automated test battery (CANTAB), continuous performance test (CPT), and a simple go/no-go task. Pre-morbid IQ was also assessed using the Weschler Test of Adult Reading (WTAR). Patients carrying the Dysbindin risk haplotype showed significantly lower spatial working memory performance than patients who were non-risk carriers, with genotype explaining 12% of variance in performance. Our study suggests that the increased risk for schizophrenia associated with dysbindin may be partly mediated by its influence on pre-frontal function.

Published
2007
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11. 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

12. 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

13. 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

15. 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

16. The genetic architecture of the human cerebral cortex

Author

Grasby, Katrina L, Jahanshad, Neda, Shatokhina, Natalia, Mirza-Schreiber, Nazanin, Moreira, Jose C V, Mühleisen, Thomas W, Müller-Myhsok, Bertram, Najt, Pablo, Nakahara, Soichiro, Nho, Kwangsik, Olde Loohuis, Loes M, Orfanos, Dimitri Papadopoulos, Pearson, John F, Zsembik, Leo C P, Pitcher, Toni L, Pütz, Benno, Quidé, Yann, Ragothaman, Anjanibhargavi, Rashid, Faisal M, Reay, William R, Redlich, Ronny, Reinbold, Céline S, Repple, Jonathan, Richard, Geneviève, Thomopoulos, Sophia I, Riedel, Brandalyn C, Risacher, Shannon L, Rocha, Cristiane S, Mota, Nina Roth, Salminen, Lauren, Saremi, Arvin, Saykin, Andrew J, Schlag, Fenja, Schmaal, Lianne, Schofield, Peter R, Zhu, Alyssa H, Secolin, Rodrigo, Shapland, Chin Yang, Shen, Li, Shin, Jean, Shumskaya, Elena, Sønderby, Ida E, Sprooten, Emma, Tansey, Katherine E, Teumer, Alexander, Thalamuthu, Anbupalam, Strike, Lachlan T, Tordesillas-Gutiérrez, Diana, Turner, Jessica A, Uhlmann, Anne, Vallerga, Costanza Ludovica, van der Meer, Dennis, van Donkelaar, Marjolein M J, van Eijk, Liza, van Erp, Theo G M, van Haren, Neeltje E M, van Rooij, Daan, Agartz, Ingrid, van Tol, Marie-José, Veldink, Jan H, Verhoef, Ellen, Walton, Esther, Wang, Mingyuan, Wang, Yunpeng, Wardlaw, Joanna M, Wen, Wei, Westlye, Lars T, Whelan, Christopher D, Alhusaini, Saud, Witt, Stephanie H, Wittfeld, Katharina, Wolf, Christiane, Wolfers, Thomas, Wu, Jing Qin, Yasuda, Clarissa L, Zaremba, Dario, Zhang, Zuo, Zwiers, Marcel P, Artiges, Eric, Almeida, Marcio A A, Assareh, Amelia A, Ayesa-Arriola, Rosa, Belger, Aysenil, Brandt, Christine L, Brown, Gregory G, Cichon, Sven, Curran, Joanne E, Davies, Gareth E, Degenhardt, Franziska, Dennis, Michelle F, Alnæs, Dag, Dietsche, Bruno, Djurovic, Srdjan, Doherty, Colin P, Espiritu, Ryan, Garijo, Daniel, Gil, Yolanda, Gowland, Penny A, Green, Robert C, Häusler, Alexander N, Heindel, Walter, Amlien, Inge K, Ho, Beng-Choon, Hoffmann, Wolfgang U, Holsboer, Florian, Homuth, Georg, Hosten, Norbert, Jack, Clifford R, Jang, MiHyun, Jansen, Andreas, Kimbrel, Nathan A, Kolskår, Knut, Painter, Jodie N, Andersson, Micael, Koops, Sanne, Krug, Axel, Lim, Kelvin O, Luykx, Jurjen J, Mathalon, Daniel H, Mather, Karen A, Mattay, Venkata S, Matthews, Sarah, Mayoral Van Son, Jaqueline, McEwen, Sarah C, Ard, Tyler, Melle, Ingrid, Morris, Derek W, Mueller, Bryon A, Nauck, Matthias, Nordvik, Jan E, Nöthen, Markus M, O'Leary, Daniel S, Opel, Nils, Martinot, Marie-Laure Paillère, Pike, G Bruce, Armstrong, Nicola J, Preda, Adrian, Quinlan, Erin B, Rasser, Paul E, Ratnakar, Varun, Reppermund, Simone, Steen, Vidar M, Tooney, Paul A, Torres, Fábio R, Veltman, Dick J, Voyvodic, James T, Ashley-Koch, Allison, Whelan, Robert, White, Tonya, Yamamori, Hidenaga, Adams, Hieab H H, Bis, Joshua C, Debette, Stephanie, Decarli, Charles, Fornage, Myriam, Gudnason, Vilmundur, Hofer, Edith, Atkins, Joshua R, Ikram, M Arfan, Launer, Lenore, Longstreth, W. T., Lopez, Oscar L, Mazoyer, Bernard, Mosley, Thomas H, Roshchupkin, Gennady V, Satizabal, Claudia L, Schmidt, Reinhold, Seshadri, Sudha, Bernard, Manon, Yang, Qiong, Initiative, Alzheimer’s Disease Neuroimaging, Consortium, CHARGE, Consortium, EPIGEN, Consortium, IMAGEN, Consortium, SYS, Initiative, Parkinson’s Progression Markers, Alvim, Marina K M, Ames, David, Anderson, Tim J, Brouwer, Rachel M, Andreassen, Ole A, Arias-Vasquez, Alejandro, Bastin, Mark E, Baune, Bernhard T, Beckham, Jean C, Blangero, John, Boomsma, Dorret I, Brodaty, Henry, Brunner, Han G, Buckner, Randy L, Buimer, Elizabeth E L, Buitelaar, Jan K, Bustillo, Juan R, Cahn, Wiepke, Cairns, Murray J, Calhoun, Vince, Carr, Vaughan J, Caseras, Xavier, Caspers, Svenja, Cavalleri, Gianpiero L, Cendes, Fernando, Bülow, Robin, 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, Bürger, Christian, Espeseth, Thomas, Fernández, Guillén, Fisher, Simon E, Flor, Herta, Forstner, Andreas J, Francks, Clyde, Franke, Barbara, Glahn, David C, Gollub, Randy L, Grabe, Hans J, Colodro-Conde, Lucía, Cannon, Dara M, Gruber, Oliver, Håberg, Asta K, Hariri, Ahmad R, Hartman, Catharina A, Hashimoto, Ryota, Heinz, Andreas, Henskens, Frans A, Hillegers, Manon H J, Hoekstra, Pieter J, Holmes, Avram J, Chakravarty, Mallar, 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, Chen, Qiang, Le Hellard, Stephanie, Loughland, Carmel M, Martin, Nicholas G, Martinot, Jean-Luc, McDonald, Colm, McMahon, Katie L, Meyer-Lindenberg, Andreas, Michie, Patricia T, Morey, Rajendra A, Mowry, Bryan, Cheung, Joshua W, Nyberg, Lars, Oosterlaan, Jaap, Ophoff, Roel A, Pantelis, Christos, Paus, Tomas, Pausova, Zdenka, Penninx, Brenda W J H, Polderman, Tinca J C, Posthuma, Danielle, Rietschel, Marcella, Couvy-Duchesne, Baptiste, Roffman, Joshua L, Rowland, Laura M, Sachdev, Perminder S, Sämann, Philipp G, Schall, Ulrich, Schumann, Gunter, Scott, Rodney J, Sim, Kang, Sisodiya, Sanjay M, Smoller, Jordan W, Dale, Anders M, Sommer, Iris E, St Pourcain, Beate, Stein, Dan J, Toga, Arthur W, Trollor, Julian N, Van der Wee, Nic J A, van 't Ent, Dennis, Völzke, Henry, Walter, Henrik, Weber, Bernd, Dalvie, Shareefa, Weinberger, Daniel R, Wright, Margaret J, Zhou, Juan, Stein, Jason L, Thompson, Paul M, Medland, Sarah E, Consortium, Enhancing NeuroImaging Genetics through Meta-Analysis, Witte, A Veronica, Darin, Abigail, Fleisher, Adam, de Araujo, Tânia K, Pierce, Aimee, Mintz, Akiva, Lerner, Alan, Reith, Alastair D, Hofman, Albert, Espay, Alberto, Ihlenfeld, Albrecht, Ing, Alex, Iranzo, Alex, Beiser, Alexa S, de Zubicaray, Greig I, Norbash, Alexander, Barbot, Alexis, Rudolph, Alice, Portillo, Alicia, Chalker, Alison, Levey, Allan I, Rosen, Allyson, Smith, Amanda, Catafau, Ana, de Zwarte, Sonja M C, Ulysse, Anaztasia, Uitterlinden, André G, Becker, Andreas, Budson, Andrew E, Kertesz, Andrew, Siderowf, Andrew, Bralten, Janita, den Braber, Anouk, Singleton, Andrew, James, Angela, Oliver, Angela, Mishra, Aniket, Hake, Ann Marie, Burke, Anna, Sarrael, Antero, Porsteinsson, Anton P, Stringaris, Argyris, McCoy, Arita, Doan, Nhat Trung, Villringer, Arno, Lenahan, Art, Toga, Arthur, Bokde, Arun, Rawlins, Ashlee, Lamb, Ashley, Lee, Athena, Raj, Balebail Ashok, Tran, Baochan, Dohm, Katharina, Ruggeri, Barbara, Saba, Barbara, Lane, Barton, Yanez, Beatriz, Ances, Beau, Dunlop, Becky, Mudge, Benita, Ravina, Bernard, Ittermann, Bernd, Ehrlich, Stefan, van Noort, Betteke, Lind, Betty, Shah, Bina, Stefanovic, Bojana, Goldstein, Bonnie S, Bonakdarpour, Borna, Matthews, Brandy R, Borowski, Bret, Ott, Brian R, Reynolds, Brigid, Engelbrecht, Hannah-Ruth, Mollenhauer, Brit, Miller, Bruce L, Psaty, Bruce M, Spann, Bryan M, Sadowsky, Carl, Linder, Carly, Franz, Carol E, Tanner, Caroline, Kopil, Catherine, Thomas, Cathi-Ann, Erk, Susanne, Ward, Chad, Bernick, Charles, Smith, Charles D, DeCarli, Charles, Caspell, Chelsea, Deeley, Cheryl, Riordan, Cheryl, Mathis, Chet, Onyike, Chiadi, Heyn, Chris Chinthaka, Fan, Chun Chieh, Hosein, Chris, Leach, Christi, Bÿchel, Christian, Gigliotti, Christina, Hunter, Christine, Belden, Christine M, Tzourio, Christophe, Coffey, Christopher, van Dyck, Christopher H, Clark, Christopher M, Fedko, Iryna O, Wu, Chuang-Kuo, Albers, Colleen S, Chu, Congying, Brand, Connie, Isensee, Corinna, van Duijn, Cornelia M, Bishop, Courtney, Bodge, Courtney, Foley, Sonya F, Tatsuoka, Curtis, Casaceli, Cynthia, Carlsson, Cynthia M, Mathews, Dana, D'Agostino, Daniel, Silverman, Daniel H S, Marson, Daniel, Berg, Daniela, Harvey, Danielle, Jennings, Danna, Ford, Judith M, Wolk, David A, Goldstein, David B, Bachman, David, Brooks, David, Clark, David, Geldmacher, David, Hart, David, Holtzman, David, Jones, David, Hibar, Derrek P, Fukunaga, Masaki, Knopman, David, Hewitt, David L, Perry, David, Russell, David, Standaert, David, Winkfield, David, Green, Davis Robert C, Fontaine, Deborah, Miller, Delwyn D, Gessert, Devon, Garrett, Melanie E, Kerwin, Diana, Willeke, Diana, Drost, Dick, Papadopoulos, Dimitri, Rowe, Dominic, Simpson, Donna M, Muni, Donna, Galasko, Douglas, Scharre, Douglas W, Fillmer, Ariane, Ge, Tian, Bartha, Rob, Celmins, Dzintra, Zimmerman, Earl A, Teng, Edmond, Tolosa, Eduardo, Coleman, Edward, Zamrini, Edward, Mitsis, Effie, Finger, Elizabeth, Giddaluru, Sudheer, Oates, Elizabeth, Sosa, Elizabeth, Woo, Ellen, Rogalski, Emily, Lethbridge, Emma, Dooley, Eoin, Foster, Eric, Reiman, Eric M, Quinlan, Erin Burke, Goldman, Aaron L, Franklin, Erin, Heinzen, Erin L, Fletcher, Evan, Sprenger, Fabienne, Crivello, Fabrice, Biondo, Francesca, Parfitt, Francine, Hefti, Franz, Beyer, Frauke, Nees, Frauke, Green, Melissa J, Leonard, Gabriel, Robert, Gabriel, Thai, Gaby, Marshall, Gad A, Barker, Gareth, Conrad, Gary, Tremont, Geoffrey, Bartzokis, George, Groenewold, Nynke A, Hsiung, Ging-Yuek Robin, Malferrari, Giulia, Chiang, Gloria, Pearlson, Godfrey D, Liang, Grace, Jicha, Greg, Sorensen, Greg, Todd, Gretchen, Jimenez, Gustavo, Grotegerd, Dominik, Zare, Habil, Grabe, Hans Jörgen, Vanderswag, Helen, Schmidt, Helena, Venkov, Heli, Lemaitre, Hervé, Gurholt, Tiril P, Grossman, Hillel, Shill, Holly, Soares, Holly, Lin, Honghuang, Capote, Horacio, Bergman, Howard, Chertkow, Howard, Feldman, Howard, Fillit, Howard, Rosen, Howard J, Gutman, Boris A, Koleva, Hristina, Fernandez, Hubert, Garavan, Hugh, Shim, Hyungsub, Grachev, Igor D, Richard, Irene, Filippi, Irina, Rachinsky, Irina, Wurster, Isabel, Lind, Penelope A, Hansell, Narelle K, Mintzer, Jacobo, Ziolkowski, Jaimie, Brewer, James, Lah, James J, Leverenz, James, Becker, James T, Tetrud, James, Singleton-Garvin, Jamika, Egebjerg, Jan, Cellar, Janet S, Harris, Mathew A, Pentilla, Jani, Brosch, Jared R, Tinklenberg, Jared, Karlawish, Jason H, Meyer, Javier Villanueva, Himali, Jayandra J, Poline, Jean-Baptiste, Gunter, Jeff, Kaye, Jeffrey A, Harrison, Marc B, Dalley, Jeffrey, Burns, Jeffrey M, Petrella, Jeffrey R, Mule, Jennifer, Salazar, Jennifer, Rotter, Jerome I, Yesavage, Jerome, Cedarbaum, Jesse, Jiang, Jiyang, Haswell, Courtney C, Allard, Joanne, Lord, Joanne L, Hetelle, Joel, Kwok, John B, Brockington, John, Morris, John C, Hsiao, John, Morris, John, Olichney, John, Trojanowki, John Q, Hauser, Michael, Rogers, John, Seibyl, John, Yankey, Jon, Dubow, Jordan S, Jankovic, Joseph, Quinn, Joseph, Kass, Joseph S, Taylor, Joy L, Heidebrink, Judith L, Herms, Stefan, Trollor, Julian, Fröhner, Juliane, Anderson, Karen, Blank, Karen, Crawford, Karen, Smith, Karen Ekstam, Bell, Karen L, Williams, Karen, Kieburtz, Karl, Heslenfeld, Dirk J, Gauss, Katharina, Gloer, Katherine, Johnson, Kathleen, Tingus, Kathleen, DeMarco, Kathryn, Sink, Kaycee M, Hawkins, Keith A, Johnson, Keith A, Kantarci, Kejal, Ho, New Fei, Faber, Kelley, Harless, Kelly, Makino, Kelly M, Marek, Kenneth, Spicer, Kenneth, Shianna, Kevin, Chen, Kewei, Nam, Ki Won, Martin, Kim, Poki-Walker, Kim, Hoehn, David, Seppi, Klaus, Johnson, Kris, Fargher, Kristin, Lipowski, Kristine, Espay, Kristy, Womack, Kyle, Chahine, Lama, Flashman, Laura A, Daedelow, Laura, Hoffmann, Per, Leary, Laura, Beckett, Laurel, Honig, Lawrence S, Thal, Leon, Shaw, Leslie M, Kuller, Lew, Apostolova, Liana, Teodoro, Liberty, Rees, Linda, Pizzagalli, Fabrizio, Holleran, Laurena, Lewis, Lindsay, Hergesheimer, Lindsey, Silbert, Lisa C, Ravdin, Lisa, Taylor-Reinwald, Lisa, Uribe, Liz, Schneider, Lon S, Daiello, Lori A, Richer, Louis, Poustka, Luise, Hoogman, Martine, Pirpamer, Lukas, Mesulam, M Marcel, Ismail, M Saleem, Ranola, Madelaine, Korecka, Magdalena, Raichle, Marc, Seltzer, Marc, van der Brug, Marcel, Hottenga, Jouke-Jan, Mesulam, Marek-Marsel, Carrillo, Maria, Carroll, Maria, Knol, Maria J, Kataki, Maria, Greig-Custo, Maria T, Paillere, Marie-Laure, Albert, Marilyn, Love, Marissa Natelson, Ikeda, Masashi, Mintun, Mark A, Frasier, Mark, Logue, Mark, Minton, Mark, Loeffler, Markus, Scholz, Markus, Baca, Marne, Farlow, Martin R, Sadowski, Martin, Janowitz, Deborah, Creech, Mary L, Hynes, Mary L, Quiceno, Mary, Oakley, MaryAnn, Harris, Mat, Senjem, Matt, Bernstein, Matthew, Panizzon, Matthew S, Stern, Matthew, Becerra, Mauricio, Jansen, Iris E, Witbracht, Megan, Vernooij, Meike W, Brandabur, Melanie, Keltz, Melanie, Lamar, Melissa, Yang, Mia, Ahlijanian, Michael, Borrie, Michael, Neale, Michael C, Donohue, Michael, Jia, Tianye, Lyons, Michael J, Lin, Michael, Rapp, Michael, Smolka, Michael, Weiner, Michael W, Weiner, Michael, Figurski, Michal, Perron, Michel, Assaly, Michele, Luciano, Michelle, Jockwitz, Christiane, Rainka, Michelle, Dang, Mimi, Sheikh, Mohammed O, Ghanbari, Mohsen, Gaikwad, Mrunalini, Chowdhury, Munir, Trncic, Nadira, Amin, Najaf, Johnson, Nancy, Kanai, Ryota, Kowalksi, Nancy, Monahan, Nancy, Gillespie, Nathan A, Pacini, Nathaniel, Buckholtz, Neil, Kowall, Neil, Graff-Radford, Neill R, Fox, Nick, Pavese, Nicola, Karama, Sherif, Cairns, Nigel J, Schuff, Norbert, Foster, Norm, Relkin, Norman, Oyonumo, Ntekim E, Pomara, Nunzio, James, Olga, Ogunlana, Olu, Ching, Christopher R K, Kasperaviciute, Dalia, Carmichael, Owen, Doraiswamy, P Murali, Casalin, Paola, Barone, Paolo, Fatica, Parianne, Conrod, Patricia, Johnson, Patricia Lynn, Samuels, Patricia, Aisen, Paul, Malloy, Paul, Kaufmann, Tobias, Thompson, Paul, Ogrocki, Paula, Bezivin-Frere, Pauline, Maillard, Pauline, Fontoura, Paulo, Taylor, Peggy, Hogarth, Penelope, Gowland, Penny, Davies, Peter, Kelly, Sinead, Hardy, Peter, Snyder, Peter J, Snyder, Peter, Amouyel, Philippe, Muglia, Pierandrea, Tariot, Pierre, Lu, Po H, Varma, Pradeep, Vemuri, Prashanthi, Kikuchi, Masataka, Doody, Rachelle S, Carter, Raina, Shah, Raj C, Griffith, Randall, Yeh, Randy, Duara, Ranjan, Tarawneh, Rawan, James, Raymond, Turner, Raymond Scott, Klein, Marieke, Hernando, Raymundo, Silverstein, Rebecca, Sperling, Reisa A, Wilson, Renee, Carson, Richard E, Frank, Richard, El Khouli, Riham, Koeppe, Robert A, Santulli, Robert B, Knapp, Michael, Hauser, Robert, Umek, Robert, Radtke, Rodney, Killiany, Ronald, Petersen, Ronald, Rodriguez, Rosemarie, Miranda, Ruben, Knodt, Annchen R, Bruehl, Ruediger, Xia, Rui, Swerdlow, Russell H, Ottmann, Ruth, Millenet, Sabina, Borges-Neto, Salvador, Frank, Samuel, Black, Sandra, Weintraub, Sandra, Obradov, Sanja, Krämer, Bernd, Asthana, Sanjay, Vaishnavi, Sanjeev, Dolen, Sara, Mason, Sara S, Hohmann, Sarah, Kremen, Sarah, Miller, Sarah, Walter, Sarah, Herring, Scott, Neu, Scott, Lam, Max, Aydin, Semiha, Ahmad, Shahzad, Harlan, Sherry, Sirrel, Sherye A, Lasch, Shirley, Hu, Shu-Ching, Li, Shuo, Kittur, Smita, Chowdhury, Sohini, Lancaster, Thomas M, Pawluczyk, Sonia, Maingault, Sophie, Schneider, Stacy, Seiler, Stephan, Guthrie, Stephanie, Kielb, Stephanie, Reeder, Stephanie, Correia, Stephen, Pasternak, Stephen, McMahon, Mary Agnes B, Lee, Phil H, Salloway, Stephen, Johnson, Sterling, Williams, Steve, Chao, Steven, Arnold, Steven E, Paul, Steven, Potkin, Steven, Factor, Stewart, Isaacson, Stuart, Lett, Tristram A, Kim, Sungeun, Ainscough, Susan, Schultz, Susan K, Landau, Susan, Mendick, Susan, Rountree, Susan, Ostrowizki, Suzanne, Veillette, Suzanne, van der Lee, Sven J, Desrivieres, Sylvane, Lewis, Lindsay B, Lee, T-Y, Simuni, Tanya, Foroud, Tatiana, Foroud, Tatiana M, Wong, Terence Z, Villena, Teresa, Comery, Thomas, Obisesan, Thomas O, Lopes-Cendes, Iscia, Banaschewski, Tobias, Sherer, Todd, Montine, Tom, Paus, Tomáš, Robbins, Trevor, Bromberg, Uli, Völker, Uwe, Pavlik, Valory, Arnedo, Vanessa, Kiyasova, Vera, Bates, Vernice, Logovinsky, Veronika, Sossi, Vesna, Shibley, Victoria, Frouin, Vincent, Lee, Virginia, Poewe, Werner, Jagust, William, Brooks, William M, Macciardi, Fabio, Pavlosky, William, Potter, William, Kremen, William S, Longstreth, William T, Niessen, Wiro J, Jian, Xueqiu, Stern, Yaakov, Saba, Yasaman, Cabrera, Yuliana, Grimmer, Yvonne, Marquand, Andre F, Khachaturian, Zaven, Mari, Zoltan, Mathias, Samuel R, Melzer, Tracy R, Milaneschi, Yuri, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Movement Disorder (MD), Alzheimer’s Disease Neuroimaging Initiative, CHARGE Consortium, EPIGEN Consortium, IMAGEN Consortium, SYS Consortium, Parkinson’s Progression Markers Initiative, Stochastics, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, Science and Society, Cognitive Psychology, IBBA, APH - Personalized Medicine, Complex Trait Genetics, APH - Methodology, Clinical Neuropsychology, Sociology and Social Gerontology, Amsterdam Neuroscience - Complex Trait Genetics, RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA Klinische Genetica (5), Neurology, Psychiatry, Pediatric surgery, Amsterdam Reproduction & Development (AR&D), Human genetics, APH - Digital Health, Psychology, Precision Medicine Institute of Psychiatry, Child and Adolescent Psychiatry / Psychology, Radiology & Nuclear Medicine, Clinical Genetics, Epidemiology, Medical Informatics, Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Neurodegeneratives Diseases Institute (IMN-UMR CNRS 5293), Centre National de la Recherche Scientifique (CNRS), General Paediatrics, ARD - Amsterdam Reproduction and Development, Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), [SDV]Life Sciences [q-bio], LOCI, Genome-wide association study, Brain mapping, 0302 clinical medicine, Cognition, Cortex (anatomy), ComputingMilieux_MISCELLANEOUS, Cerebral Cortex, 0303 health sciences, Brain Mapping, Multidisciplinary, COMMON VARIANTS, Parkinson Disease, Organ Size, Central sulcus, Magnetic Resonance Imaging, medicine.anatomical_structure, Cerebral cortex, Neuroinformatics, EXPRESSION, endocrine system, central sulcus, SURFACE-AREA, Biology, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetic variation, medicine, Attention deficit hyperactivity disorder, Humans, General, Gene, METAANALYSIS, 030304 developmental biology, Progenitor, CORTICAL SULCI, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Genetic variants, Genetic Variation, Attention Deficit Disorder with Hyperactivity, Genetic Loci, Genome-Wide Association Study, functional annotation, medicine.disease, Genetic architecture, 030104 developmental biology, Evolutionary biology, OBSERVER-INDEPENDENT CHARACTERIZATION, Multiple comparisons problem, ddc:320, genome-wide association, Neuroscience, 030217 neurology & neurosurgery
Abstract

Enhancing NeuroImaging Genetics through Meta-Analysis Consortium (ENIGMA)—Genetics working group., The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.

Published
2020

17. Changes in Default-Mode Network Associated With Childhood Trauma in Schizophrenia.

Author

Dauvermann, Maria R, Mothersill, David, Rokita, Karolina I, King, Sinead, Holleran, Laurena, Kane, Ruan, McKernan, Declan P, Kelly, John P, Morris, Derek W, Corvin, Aiden, Hallahan, Brian, McDonald, Colm, and Donohoe, Gary

Subjects
ADVERSE childhood experiences, THOUGHT & thinking, NEURAL pathways, SCHIZOPHRENIA, HISTORICAL trauma, EMOTIONAL trauma, MAGNETIC resonance imaging, CASE-control method, COGNITION, COMPUTED tomography
Abstract

Background There is considerable evidence of dysconnectivity within the default-mode network (DMN) in schizophrenia, as measured during resting-state functional MRI (rs-fMRI). History of childhood trauma (CT) is observed at a higher frequency in schizophrenia than in the general population, but its relationship to DMN functional connectivity has yet to be investigated. Methods CT history and rs-fMRI data were collected in 65 individuals with schizophrenia and 132 healthy controls. Seed-based functional connectivity between each of 4 a priori defined seeds of the DMN (medial prefrontal cortex, right and left lateral parietal lobes, and the posterior cingulate cortex) and all other voxels of the brain were compared across groups. Effects of CT on functional connectivity were examined using multiple regression analyses. Where significant associations were observed, regression analyses were further used to determine whether variance in behavioral measures of Theory of Mind (ToM), previously associated with DMN recruitment, were explained by these associations. Results Seed-based analyses revealed evidence of widespread reductions in functional connectivity in patients vs controls, including between the left/right parietal lobe (LP) and multiple other regions, including the parietal operculum bilaterally. Across all subjects, increased CT scores were associated with reduced prefrontal-parietal connectivity and, in patients, with increased prefrontal-cerebellar connectivity also. These CT-associated differences in DMN connectivity also predicted variation in behavioral measures of ToM. Conclusions These findings suggest that CT history is associated with variation in DMN connectivity during rs-fMRI in patients with schizophrenia and healthy participants, which may partly mediate associations observed between early life adversity and cognitive performance. [ABSTRACT FROM AUTHOR]

Published
2021
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18. Genetic Determinants of Cortical Structure (Thickness, Surface Area and Volumes) among Disease Free Adults in the CHARGE Consortium

Author

Hofer, Edith, Roshchupkin, Gennady V., Adams, Hieab H. H., Knol, Maria J., Lin, Honghuang, Li, Shuo, Zare, Habil, Ahmad, Shahzad, Armstrong, Nicola J., Satizabal, Claudia L., Bernard, Manon, Bis, Joshua C., Gillespie, Nathan A., Luciano, Michelle, Mishra, Aniket, Scholz, Markus, Teumer, Alexander, Xia, Rui, Jian, Xueqiu, Mosley, Thomas H., Saba, Yasaman, Pirpamer, Lukas, Seiler, Stephan, Becker, James T., Carmichael, Owen, Rotter, Jerome I., Psaty, Bruce M., Lopez, Oscar L., Amin, Najaf, van der Lee, Sven J., Yang, Qiong, Himali, Jayandra J., Maillard, Pauline, Beiser, Alexa S., DeCarli, Charles, Karama, Sherif, Lewis, Lindsay, Harris, Mat, Bastin, Mark E., Deary, Ian J., Witte, A.Veronica, Beyer, Frauke, Loeffler, Markus, Mather, Karen A., Schofield, Peter R., Thalamuthu, Anbupalam, Kwok, John B., Wright, Margaret J., Ames, David, Trollor, Julian, Jiang, Jiyang, Brodaty, Henry, Wen, Wei, Vernooij, Meike W, Hofman, Albert, Uitterlinden, André G., Niessen, Wiro J., Wittfeld, Katharina, Bülow, Robin, Völker, Uwe, Pausova, Zdenka, Pike, G. Bruce, Maingault, Sophie, Crivello, Fabrice, Tzourio, Christophe, Amouye, Philippe, Mazoyer, Bernard, Neale, Michael C., Franz, Carol E., Lyons, Michael J., Panizzon, Matthew S., Andreassen, Ole A., Dale, Anders M., Logue, Mark, Grasby, Katrina L., Jahanshad, Neda, Painter, Jodie N., Colodro-Conde, Lucía, Bralten, Janita, Hibar, Derrek P., Lind, Penelope A., Pizzagalli, Fabrizio, Stein, Jason L., Thompson, Paul M., Medland, Sarah E., Ching Christopher, R.K., McMahon Mary Agnes, B., Shatokhina, Natalia, Zsembik, Leo C.P., Agartz, Ingrid, Alhusaini, Saud, Almeida, Marcio A.A., Alnæs, Dag, Amlien, Inge K., Andersson, Micael, Ard, Tyler, Ashley-Koch, Allison, Brouwer, Rachel M., Buimer, Elizabeth E.L., Bürger, Christian, Cannon, Dara M., Chakravarty, Mallar, Chen, Qiang, Cheung, Joshua W., Couvy-Duchesne, Baptiste, Dalvie, Shareefa, de Araujo, Tânia K., de Zubicaray, Greig I., de Zwarte, Sonja M.C., Braber, Anouk den, Doan, Nhat Trung, Dohm, Katharina, Ehrlich, Stefan, 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, 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, Herms, Stefan, Heslenfeld, Dirk J., Ho, New Fei, Hoehn, David, Hoffmann, Per, Holleran, Laurena, Hoogman, Martine, Hottenga, Jouke-Jan, Ikeda, Masashi, Janowitz, Deborah, Jansen, Iris E., Jia, Tianye, Jockwitz, Christiane, Kanai, Ryota, Kasperaviciute, Dalia, Kaufmann, Tobias, Kelly, Sinead, Kikuchi, Masataka, Klein, Marieke, Knapp, Michael, Knodt, Annchen R., Krämer, Bernd, Lam, Max, Lancaster, Thomas M., Lee, Phil H., Lett, Tristram A., Lewis, Lindsay B., Lopes-Cendes, Iscia, 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, Nakahara, Soichiro, Nho, Kwangsik, Olde Loohuis, Loes M., Orfanos, Dimitri Papadopoulos, Pearson, John F., Pitcher, Toni L., Pütz, Benno, Ragothaman, Anjanibhargavi, Rashid, Faisal M., Ronny, Redlich, 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., Schlag, Fenja, Schmaal, Lianne, Secolin, Rodrigo, Shapland, Chin Yang, Shen, Li, Shin, Jean, Shumskaya, Elena, Sønderby, Ida E., Sprooten, Emma, Strike, Lachlan T., Tansey, Katherine E., Thomopoulos, Sophia I., Tordesillas-Gutiérrez, Diana, Turner, Jessica A., Uhlmann, Anne, Vallerga, Costanza Ludovica, der Meer, Dennis van, van Donkelaar, Marjolein M.J., Eijk, Liza van, van Erp, Theo G.M., van Haren, Neeltje E.M., Rooij, Daan van, van Tol, Marie-José, Veldink, Jan H., Verhoef, Ellen, Walton, Esther, Wang, Mingyuan, Wang, Yunpeng, Wardlaw, Joanna M., Westlye, Lars T., Whelan, Christopher D., Witt, Stephanie H., Wolf, Christiane, Wolfers, Thomas, Yasuda, Clarissa L., 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., Cichon, Sven, Curran, Joanne E., Davies, Gareth E., Degenhardt, Franziska, Dietsche, Bruno, Djurovic, Srdjan, Doherty, Colin P., Espiritu, Ryan, Garijo, Daniel, Gil, Yolanda, Gowland, Penny A., Green, Robert C., Häusler, Alexander N., Heindel, Walter, Ho, Beng-Choon, Hoffmann, Wolfgang U., Holsboer, Florian, Homuth, Georg, Hosten, Norbert, Jack Jr., Clifford R., Jang, MiHyun, Jansen, Andreas, Kolskår, Knut, Koops, Sanne, Krug, Axel, Lim, Kelvin O., Luykx, Jurjen J., Mathalon, Daniel H., Mattay, Venkata S., Matthews, Sarah, Van Son, Jaqueline Mayoral, McEwen, Sarah C., Melle, Ingrid, Morris, Derek W., Mueller, Bryon A., Nauck, Matthias, Nordvik, Jan E., Nöthen, Markus M., O’Leary, Daniel S., Opel, Nils, Paillère Martinot, Marie-Laure, Preda, Adrian, Quinlan, Erin B., Ratnakar, Varun, Reppermund, Simone, Steen, Vidar M., Torres, Fábio R., Veltman, Dick J., Voyvodic, James T., Whelan, Robert, White, Tonya, Yamamori, Hidenaga, Alvim, Marina K.M., Anderson, Tim J., Arias-Vasquez, Alejandro, Baune, Bernhard T., Blangero, John, Boomsma, Dorret I., Brunner, Han G., Buckner, Randy L., Buitelaar, Jan K., Bustillo, Juan R., Cahn, Wiepke, Calhoun, Vince, 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., Delanty, Norman, Depondt, Chantal, Desrivières, Sylvane, Donohoe, Gary, Espeseth, Thomas, Fernández, Guillén, Fisher, Simon E., Flor, Herta, Forstner, Andreas J., Francks, Clyde, 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, 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, Penninx, Brenda W.J.H., Polderman, Tinca J.C., Posthuma, Danielle, Rietschel, Marcella, Roffman, Joshua L., 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., Toga, Arthur W., Trollor, Julian N., Van der Wee, Nic J.A., Ent, Dennis van’t, Völzke, Henry, Walter, Henrik, Weber, Bernd, Weinberger, Daniel R., Zhou, Juan, Kremen, William S., Villringer, Arno, Duijn, Cornelia M. van, Jörgen Grabe, Hans, Longstreth Jr, William T., Fornage, Myriam, Paus, Tomas, Debette, Stephanie, Ikram, M. Arfan, Schmidt, Helena, Schmidt, Reinhold, Seshadri, Sudha, and ENIGMA consortium

Subjects
0303 health sciences, biology, Genetic heterogeneity, Cognition, Hindbrain, Disease, Heritability, Biobank, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Evolutionary biology, Cortex (anatomy), biology.protein, medicine, Sonic hedgehog, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Cortical thickness, surface area and volumes (MRI cortical measures) vary with age and cognitive function, and in neurological and psychiatric diseases. We examined heritability, genetic correlations and genome-wide associations of cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprised 22,822 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the United Kingdom Biobank. Significant associations were replicated in the Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium, and their biological implications explored using bioinformatic annotation and pathway analyses. We identified genetic heterogeneity between cortical measures and brain regions, and 161 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There was 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.

Published
2018

19. MiR-137-derived polygenic risk: effects on cognitive performance in patients with schizophrenia and controls

Author

Cosgrove, D, Harold, D, Mothersill, O, Anney, Richard, Hill, Martin, Bray, Nicholas, Blokland, G, Petryshen, T, Donnelly, Peter, Bates, Lesley, Barroso, Ines, Blackwell, Jenefer M, Bramon, Elvira, Brown, Matthew A, Casas, Juan P, Corvin, Aiden, Deloukas, Panos, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S, Mathew, Christopher G, Palmer, Colin N A, Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J, Trembath, Richard C, Viswanathan, Ananth C, Wood, Nicholas W, Spencer, Chris C A, Band, Gavin, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Giannoulatou, Eleni, Hopkins, Lucinda, Pirinen, Matti, Pearson, Richard, Strange, Amy, Su, Zhan, Vukcevic, Damjan, Langford, Cordelia, Hunt, Sarah E, Edkins, Sarah, Gwilliam, Rhian, Blackburn, Hannah, Bumpstead, Suzannah J, Dronov, Serge, Gillman, Matthew, Gray, Emma, Hammond, Naomi, Jayakumar, Alagurevathi, McCann, Owen T, Liddle, Jennifer, Potter, Simon C, Ravindrarajah, Radhi, Ricketts, Michelle, Waller, Matthew, Weston, PaulWeston, Widaa, SaraWidaa, Whittaker, Pamela, Richards, Alexander, Mantripragada, Kiran, Owen, Michael, O'Donovan, Michael, Gill, M, Corvin, A, Morris, D W, Donohoe, G, Broad Institute of MIT and Harvard, and Petryshen, Tracey

Subjects
0301 basic medicine, Adult, Male, Multifactorial Inheritance, Memory, Episodic, BF, Bioinformatics, Spatial memory, Polymorphism, Single Nucleotide, 03 medical and health sciences, Cellular and Molecular Neuroscience, Young Adult, 0302 clinical medicine, Cognition, Memory, Task Performance and Analysis, medicine, Humans, Effects of sleep deprivation on cognitive performance, Episodic memory, Biological Psychiatry, Intelligence quotient, Working memory, Memoria, Functional Neuroimaging, Brain, Middle Aged, medicine.disease, R1, Magnetic Resonance Imaging, Psychiatry and Mental health, MicroRNAs, 030104 developmental biology, Memory, Short-Term, Schizophrenia, Case-Control Studies, Original Article, Female, Schizophrenic Psychology, Psychology, Facial Recognition, 030217 neurology & neurosurgery, Clinical psychology
Abstract

Variants at microRNA-137 (MIR137), one of the most strongly associated schizophrenia risk loci identified to date, have been associated with poorer cognitive performance. As microRNA-137 is known to regulate the expression of ~1900 other genes, including several that are independently associated with schizophrenia, we tested whether this gene set was also associated with variation in cognitive performance. Our analysis was based on an empirically derived list of genes whose expression was altered by manipulation of MIR137 expression. This list was cross-referenced with genome-wide schizophrenia association data to construct individual polygenic scores. We then tested, in a sample of 808 patients and 192 controls, whether these risk scores were associated with altered performance on cognitive functions known to be affected in schizophrenia. A subgroup of healthy participants also underwent functional imaging during memory (n=108) and face processing tasks (n=83). Increased polygenic risk within the empirically derived miR-137 regulated gene score was associated with significantly lower performance on intelligence quotient, working memory and episodic memory. These effects were observed most clearly at a polygenic threshold of P=0.05, although significant results were observed at all three thresholds analyzed. This association was found independently for the gene set as a whole, excluding the schizophrenia-associated MIR137 SNP itself. Analysis of the spatial working memory fMRI task further suggested that increased risk score (thresholded at P=10−5) was significantly associated with increased activation of the right inferior occipital gyrus. In conclusion, these data are consistent with emerging evidence that MIR137 associated risk for schizophrenia may relate to its broader downstream genetic effects.

Published
2016

20. Genome-wide estimates of inbreeding in unrelated individuals and their association with cognitive ability

Author

Power, Robert A, Nagoshi, Craig, DeFries, John C, Donnelly, Peter, Barroso, Ines, Blackwell, Jenefer M, Bramon, Elvira, Brown, Matthew A, Casas, Juan P, Corvin, Aiden, Deloukas, Panos, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S, Mathew, Christopher G, Palmer, Colin NA, Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J, Trembath, Richard C, Viswanathan, Ananth C, Wood, Nicholas W, Spencer, Chris C A, Band, Gavin, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Giannoulatou, Eleni, Pirinen, Matti, Pearson, Richard, Strange, Amy, Su, Zhan, Vukcevic, Damjan, Langford, Cordelia, Hunt, Sarah E, Edkins, Sarah, Gwilliam, Rhian, Blackburn, Hannah, Bumpstead, Suzannah J, Dronov, Serge, Gillman, Matthew, Gray, Emma, Hammond, Naomi, Jayakumar, Alagurevathi, McCann, Owen T, Liddle, Jennifer, Potter, Simon C, Ravindrarajah, Radhi, Ricketts, Michelle, Waller, Matthew, Weston, Paul, Widaa, Sara, and Whittaker, Pamela

Subjects
Adult, Male, Intelligence, Population, Genome-wide association study, Single-nucleotide polymorphism, Biology, Runs of Homozygosity, Polymorphism, Single Nucleotide, Article, Consanguinity, 03 medical and health sciences, Cognition, 0302 clinical medicine, Genetics, Humans, Child, education, Genetic Association Studies, Genetics (clinical), 030304 developmental biology, 0303 health sciences, education.field_of_study, Genome, Human, Homozygote, Assortative mating, Minor allele frequency, Case-Control Studies, Female, Inbreeding, 030217 neurology & neurosurgery
Abstract

The consequence of reduced cognitive ability from inbreeding has long been investigated, mainly restricted to cousin-cousin marriages. Molecular genetic techniques now allow us to test the relationship between increased ancestral inbreeding and cognitive ability in a population of traditionally unrelated individuals. In a representative UK sample of 2329 individuals, we used genome-wide SNP data to estimate the percentage of the genome covered by runs of homozygous SNPs (ROH). This was tested for association with general cognitive ability, as well as measures of verbal and non-verbal ability. Further, association was tested between these traits and specific ROH. Burden of ROH was not associated with cognitive ability after correction for multiple testing, although burden of ROH was nominally associated with increased non-verbal cognitive ability (P=0.03). Moreover, although no individual ROH was significantly associated with cognitive ability, there was a significant bias towards increased cognitive ability in carriers of ROH (P=0.002). A potential explanation for these results is increased positive assortative mating in spouses with higher cognitive ability, although we found no evidence in support of this hypothesis in a separate sample. Reduced minor allele frequency across the genome was associated with higher cognitive ability, which could contribute to an apparent increase in ROH. This may reflect minor alleles being more likely to be deleterious.

Published
2013

21. Independent Evidence for an Association between General Cognitive Ability and a Genetic Locus for Educational Attainment

Author

Trampush, Joey W., Lencz, Todd, Knowles, Emma, Davies, Gail, Guha, Saurav, Pe’er, Itsik, Liewald, David C., Starr, John M., Djurovic, Srdjan, Melle, Ingrid, Sundet, Kjetil, Christoforou, Andrea, Reinvang, Ivar, Mukherjee, Semanti, DeRosse, Pamela, Lundervold, Astri, Steen, Vidar M., John, Majnu, Espeseth, Thomas, Räikkönen, Katri, Widen, Elisabeth, Palotie, Aarno, Eriksson, Johan G., Giegling, Ina, Konte, Bettina, Ikeda, Masashi, Roussos, Panos, Giakoumaki, Stella, Burdick, Katherine E., Payton, Antony, Ollier, William, Horan, Mike, Scult, Matthew, Dickinson, Dwight, Straub, Richard E., Donohoe, Gary, Morris, Derek, Corvin, Aiden, Gill, Michael, Hariri, Ahmad, Weinberger, Daniel R., Pendleton, Neil, Iwata, Nakao, Darvasi, Ariel, Bitsios, Panos, Rujescu, Dan, Lahti, Jari, Le Hellard, Stephanie, Keller, Matthew C., Andreassen, Ole A., Deary, Ian J., Glahn, David C., and Malhotra, Anil K.

Subjects
Adult, Male, Cognition, Genetic Loci, Humans, Female, Genetic Predisposition to Disease, Middle Aged, Cognition Disorders, Polymorphism, Single Nucleotide, Article, Aged, Genome-Wide Association Study
Abstract

Cognitive deficits and reduced educational achievement are common in psychiatric illness; understanding the genetic basis of cognitive and educational deficits may be informative about the etiology of psychiatric disorders. A recent, large genome-wide association study (GWAS) reported a genome-wide significant locus for years of education, which subsequently demonstrated association to general cognitive ability ("g") in overlapping cohorts. The current study was designed to test whether GWAS hits for educational attainment are involved in general cognitive ability in an independent, large-scale collection of cohorts. Using cohorts in the Cognitive Genomics Consortium (COGENT; up to 20,495 healthy individuals), we examined the relationship between g and variants associated with educational attainment. We next conducted meta-analyses with 24,189 individuals with neurocognitive data from the educational attainment studies, and then with 53,188 largely independent individuals from a recent GWAS of cognition. A SNP (rs1906252) located at chromosome 6q16.1, previously associated with years of schooling, was significantly associated with g (P = 1.47 × 10(-4) ) in COGENT. The first joint analysis of 43,381 non-overlapping individuals for this a priori-designated locus was strongly significant (P = 4.94 × 10(-7) ), and the second joint analysis of 68,159 non-overlapping individuals was even more robust (P = 1.65 × 10(-9) ). These results provide independent replication, in a large-scale dataset, of a genetic locus associated with cognitive function and education. As sample sizes grow, cognitive GWAS will identify increasing numbers of associated loci, as has been accomplished in other polygenic quantitative traits, which may be relevant to psychiatric illness.

Published
2015

22. The Role of the Major Histocompatibility Complex Region in Cognition and Brain Structure: A Schizophrenia GWAS Follow-Up.

Author

Walters, James T. R., Rujescu, Dan, Franke, Barbara, Giegling, Ina, Arias Vásquez, Alejandro, Hargreaves, April, Russo, Giancarlo, Morris, Derek W., Hoogman, Martine, Da Costa, Andrea, Moskvina, Valentina, Fernández, Guillén, Gill, Michael, Corvin, Aiden, O'Donovan, Michael C., Donohoe, Gary, and Owen, Michael J.

Subjects
MAJOR histocompatibility complex, COGNITION, SCHIZOPHRENIA, HIPPOCAMPUS (Brain), SINGLE nucleotide polymorphisms, PATHOLOGICAL physiology
Abstract

Objective: The authors investigated the effects of recently identified genome-wide significant schizophrenia genetic risk var- iants on cognition and brain structure. Method: A panel of six single-nucleotide polymorphisms (SNPs) was selected to represent genome-wide significant loci from three recent genome-wide associa- tion studies (GWAS) for schizophrenia and was tested for association with cognitive measures in 346 patients with schizophrenia and 2,342 healthy comparison subjects. Nominally significant results were evaluated for replication in an independent case-control sample. For SNP5 showing evidence of association with cognition, associations with brain structural volumes were investigated in a large independent healthy comparison sample. Results: Five of the six SNPs showed no significant association with any cognitive measure. One marker in the major histocompatibility complex (MHC) region, rs6904071, showed independent, replicated evidence of association with delayed episodic memory and was significant when both samples were combined. In the combined sample of up to 3,100 individuals, this SNP was associated with widespread effects across cognitive domains, although these additional associations were no longer significant after adjusting for delayed episodic memory. In the large independent structural imaging sample, the same SNP was also associated with decreased hippocampal volume. Conclusions: The authors identified a SNP in the MHC region that was associated with cognitive performance in patients with schizophrenia. and healthy comparison subjects. This SNP, rs6904071, showed a replicated association with episodic memory and hippocampal volume. These findings implicate the MHC region in hippocampal structure and functioning, consistent with the role of MHC proteins in synaptic development and function. Follow-up of these results has the potential to provide insights into the pathophysiology of schizophrenia and cognition. [ABSTRACT FROM AUTHOR]

Published
2013
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23. Is "clinical" insight the same as "cognitive" insight in schizophrenia?

Author

Donohoe, Gary, Hayden, Judy, Mcglade, Nicola, O'Gráda, Cara, Burke, Teresa, Barry, Sandra, Behan, Caragh, Dinan, Timothy G., O'Callaghan, Eadbhard, Gill, Michael, and Corvin, Aiden P.

Subjects
SCHIZOPHRENIA, PSYCHOSES, COGNITION disorders, MENTAL illness, NEUROPSYCHOLOGICAL tests
Abstract

Poor insight is associated with impaired cognitive function in psychosis. Whether poor clinical insight overlaps with other aspects of self-awareness in schizophrenia, such as cognitive self-awareness, is unclear. We investigated whether awareness of clinical state ("clinical insight") and awareness of cognitive deficits ("cognitive insight") overlap in schizophrenia in a sample of 51 stabilized patients with chronic schizophrenia. Cognitive insight was assessed in terms of the agreement between subjective self-report and neuropsychological assessment. Patients who show good cognitive insight did not necessarily show good clinical insight. By contrast, self-report and objective neuropsychological assessment only correlated for patients in the intact clinical insight group and not for those in the impairment clinical insight group. We conclude that while good cognitive insight may not be necessary for good clinical insight, good cognitive awareness is at least partly reliant on the processes involved in clinical insight. [ABSTRACT FROM AUTHOR]

Published
2009
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24. Evidence that specific executive functions predict symptom variance among schizophrenia patients with a predominantly negative symptom profile.

Author

Donohoe, Gary, Corvin, Aiden, and Robertson, Ian H.

Subjects
*SCHIZOPHRENIA, *PEOPLE with schizophrenia, *PSYCHOSES, *MEMORY, *COGNITION, *SHORT-term memory
Abstract

Introduction . Although deficits in executive functioning in schizophrenia have been consistently reported, their precise relationship to symptomatology remains unclear. Recent approaches to executive functioning in nonschizophrenia studies have aimed to “fractionate” the individual cognitive processes involved. In this study, we hypothesised that if these processes are fractionable, then particular symptom syndromes may be selectively related to executive deficits. In particular, it was hoped that this approach could clarify whether negative and positive symptoms of schizophrenia are differentially related to particular aspects of executive/attentional functions. Methods . A total of 32 patients with schizophrenia and 16 matched controls were assessed on a series of tasks designed to tap the theoretically derived executive functions of Inhibition, Shifting set, Working memory, and Sustained attention. Results . Negative symptoms were significantly predicted by performance on an “Inhibition” task (Stroop), and not by performance on any other task. Furthermore, for a subgroup of patients with predominantly negative symptoms variance in positive symptoms was only significantly predicted by performance on a set-shifting task (Visual Elevator), and not by performance on other tasks, including inhibition. Conclusions . Our results support the contention that negative symptoms can, at least partly, be conceived of as cognitive behaviours expressing specific executive deficits. Specifically, we discuss the possibility that negative symptoms may, in part, express a failure in response monitoring. We further suggest that the disordered metacognition resulting in positive symptoms may be mediated by cognitive flexibility in patients with a predominantly negative symptom profile. [ABSTRACT FROM AUTHOR]

Published
2006
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25. Beyond C4: Analysis of the complement gene pathway shows enrichment for IQ in patients with psychotic disorders and healthy controls.

Author

Holland, Jessica F., Cosgrove, Donna, Whitton, Laura, Harold, Denise, Corvin, Aiden, Gill, Michael, Mothersill, David O., Morris, Derek W., and Donohoe, Gary

Subjects
PSYCHOSES, 22Q11 deletion syndrome, INTELLIGENCE levels, INTELLECT, STATISTICAL association, REGRESSION analysis, COMPLEMENT receptors
Abstract

Variation in cognitive performance, which strongly predicts functional outcome in schizophrenia (SZ), has been associated with multiple immune‐relevant genetic loci. These loci include complement component 4 (C4A), structural variation at which was recently associated with SZ risk and synaptic pruning during neurodevelopment and cognitive function. Here, we test whether this genetic association with cognition and SZ risk is specific to C4A, or extends more broadly to genes related to the complement system. Using a gene‐set with an identified role in "complement" function (excluding C4A), we used MAGMA to test if this gene‐set was enriched for genes associated with human intelligence and SZ risk, using genome‐wide association summary statistics (IQ; N = 269 867, SZ; N = 105 318). We followed up this gene‐set analysis with a complement gene‐set polygenic score (PGS) regression analysis in an independent data set of patients with psychotic disorders and healthy participants with cognitive and genomic data (N = 1000). Enrichment analysis suggested that genes within the complement pathway were significantly enriched for genes associated with IQ, but not SZ. In a gene‐based analysis of 90 genes, SERPING1 was the most enriched gene for the phenotype of IQ. In a PGS regression analysis, we found that a complement pathway PGS associated with IQ genome‐wide association studies statistics also predicted variation in IQ in our independent sample. This association (observed across both patients and controls) remained significant after controlling for the relationship between C4A and cognition. These results suggest a robust association between the complement system and cognitive function, extending beyond structural variation at C4A. [ABSTRACT FROM AUTHOR]

Published
2019
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26. Rare Copy Number Variants Are Associated With Poorer Cognition in Schizophrenia.

Author

Hubbard, Leon, Rees, Elliott, Morris, Derek W., Lynham, Amy J., Richards, Alex L., Pardiñas, Antonio F., Legge, Sophie E., Harold, Denise, Zammit, Stanley, Corvin, Aiden C., Gill, Michael G., Hall, Jeremy, Holmans, Peter, O'Donovan, Michael C., Owen, Michael J., Donohoe, Gary, Kirov, George, Pocklington, Andrew, and Walters, James T.R.

Subjects
*DNA copy number variations, *WECHSLER Adult Intelligence Scale, *COGNITION disorders, *SCHIZOPHRENIA, *META-analysis, *COGNITIVE ability
Abstract

Cognitive impairment in schizophrenia is a major contributor to poor outcomes, yet its causes are poorly understood. Some rare copy number variants (CNVs) are associated with schizophrenia risk and affect cognition in healthy populations, but their contribution to cognitive impairment in schizophrenia has not been investigated. We examined the effect of 12 schizophrenia CNVs on cognition in those with schizophrenia. General cognitive ability was measured using the Measurement and Treatment Research to Improve Cognition in Schizophrenia composite z score in 875 patients with schizophrenia and in a replication sample of 519 patients with schizophrenia using Wechsler Adult Intelligence Scale Full Scale IQ. Using linear regression, we tested for association between cognition and schizophrenia CNV status, covarying for age and sex. In addition, we tested whether CNVs hitting genes in schizophrenia-enriched gene sets (loss-of-function intolerant and synaptic gene sets) were associated with cognitive impairment. A total of 23 schizophrenia CNV carriers were identified. Schizophrenia CNV carriers had lower general cognitive ability than nonschizophrenia CNV carriers in discovery (β = −0.66, 95% confidence interval [CI] = −1.31 to −0.01) and replication samples (β = −0.91, 95% CI = −1.71 to −0.11) and after meta-analysis (β = −0.76, 95% CI = −1.26 to −0.25, p =.003). CNVs hitting loss-of-function intolerant genes were associated with lower cognition (β = −0.15, 95% CI = −0.29 to −0.001, p =.048). In those with schizophrenia, cognitive ability in schizophrenia CNV carriers is 0.5–1.0 standard deviations below non-CNV carriers, which may have implications for clinical assessment and management. We also demonstrate that rare CNVs hitting genes intolerant to loss-of-function variation lead to more severe cognitive impairment, above and beyond the effect of known schizophrenia CNVs. [ABSTRACT FROM AUTHOR]

Published
2021
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27. Does the ability to sustain attention underlie symptom severity in schizophrenia?

Author

O’Gráda, Cara, Barry, Sandra, McGlade, Nicola, Behan, Caragh, Haq, Farhan, Hayden, Judy, O’Donoghue, Therese, Peel, Rosie, Morris, Derek W., O’Callaghan, Eadbhard, Gill, Michael, Corvin, Aiden P., Dinan, Timothy G., and Donohoe, Gary

Subjects
*COGNITION disorders, *PEOPLE with schizophrenia, *SHORT-term memory, *DISABILITIES, *SCHIZOPHRENIA, *DISEASES
Abstract

Abstract: An association between deficits in executive control, particularly inhibitory control, and more severe negative and disorganised symptoms of schizophrenia has been widely reported. The importance of more basic aspects of attention, often referred to as ‘vigilant’ or ‘sustained’ attention, to this relationship remains unclear. This study examined the contribution of sustained attention to symptom severity using the Sustained Attention to Response Task (SART) in 69 patients with schizophrenia. We found that negative and disorganised symptom severity scores were correlated with sustained attention, working memory, and psychomotor speed. The ability to sustain attention significantly predicted variance in negative symptom severity but not disorganised symptoms, which were instead predicted by working memory performance. These data suggest that this component of attention at least partly explains variance in negative symptoms. [Copyright &y& Elsevier]

Published
2009
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28. 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

29. SU121GENETIC VARIATION RELATED TO IMMUNE FUNCTION AND SCHIZOPHRENIA RISK: EVIDENCE FOR EFFECTS ON COGNITION.

Author

Donohoe, Gary, Holland, Jessica, Mothersill, David, Corvin, Aiden, Gill, Michael, Cosgrove, Donna, and Morris, Derek

Subjects
*SCHIZOPHRENIA, *COGNITION, *COGNITIVE ability, *EVIDENCE, *EPISODIC memory, *COMPLEMENT receptors
Abstract

Highlights from the article: Su121genetic variation related to immune function and schizophrenia risk: evidence for effects on cognition We further investigated immune gene-set enrichment analysis in three datasets (PGC, ENIGMA, and UK Biobank). B Discussion: b Based on these findings we conclude that schizophrenia risk associated with variation within immune related genes is likely to be conferred at least partly via effects on cognition, and that genetic variation within the complement system may have a particularly important role.

Published
2019
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30. 43RARE COPY NUMBER VARIATIONS ARE ASSOCIATED WITH POORER COGNITION IN SCHIZOPHRENIA.

Author

Hubbard, Leon, Rees, Elliott, Morris, Derek, Lynham, Amy, Legge, Sophie, Harold, Denise, Zammit, Stanley, Corvin, Aiden, Gill, Michael, O'Donovan, Michael, Owen, Michael, Donohoe, Gary, Kirov, George, Pocklington, Andrew, and Walters, James T.R.

Subjects
*SCHIZOPHRENIA, *META-analysis, *COGNITION, *SCHIZOAFFECTIVE disorders
Abstract

Highlights from the article: B Background: b Rare copy number variations (CNVs) are associated with increased risk of neuropsychiatric disorders and lower cognitive ability in healthy individuals. B Results: b In CardiffCOGS, individuals with a schizophrenia CNV (N=8) performed over one standard deviation below cases without a schizophrenia CNV (N=471) on the MATRICS composite z-score ( =-1.16., 95%CI = -2.06 to -0.25, p=0.011). B Discussion: b In the largest combined schizophrenia sample to date with cognition data, we have demonstrated that individuals with the disorder who are carriers of schizophrenia CNVs display clinically important levels of cognitive impairment.

Published
2019
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31. SA108 - THE IMMUNE 8: IMPAIRED COGNITION IN SCHIZOPHRENIA RELATED TO GENETIC, ENVIRONMENTAL, AND IMMUNE INTERACTIONS IN IRISH AND UK COHORTS.

Author

Holland, Jessica, Morris, Derek, Cosgrove, Donna, Harold, Denise, David Mothershill, Omar, Corvin, Aiden, and Donohoe, Gary

Subjects
*22Q11 deletion syndrome, *SCHIZOPHRENIA, *SOCIAL perception, *MAJOR histocompatibility complex, *PARENT-child relationships, *COGNITION
Abstract

The aim of this study is to characterise the effects of 8 already identified genetic risk variants on social cognitive deficits in schizophrenia. Although the aetiology of schizophrenia is largely unknown, it is increasingly clear that genetic and environmental interactions contribute to cognitive deficits associated with this disorder. The 'Immune Hypothesis' suggests that schizophrenia is often predicted by early environmentally-driven immune challenges, and genetically driven sub-optimal immune responsiveness. In the largest genetic study of schizophrenia to date, recent Genome-Wide Association Studies (GWAS) have established the strongest association with schizophrenia was found at a region of the genome that is synonymous with immune function- the major histocompatibility complex, or MHC. Social cognitive deficits are core features of Schizophrenia, which relate to genetic risk. The current study analyses the effects of immune challenge (genetic and environmental) on social cognition, examining a set of genes related to immune function and schizophrenia risk, as well as environmental factors that may contribute to cognitive deficit. To test if genetic variants related to immune function impair cognition, 8 genes were selected by cross referencing "Immunology" Gene Ontology lists with the most recent list of genes implicated in GWAS for schizophrenia. 1013 participants were genotyped and cognitively assessed in an Irish population of schizophrenia sufferers and healthy controls, and this cohort was used for primary analysis of a gene-cognition relationship. A separate cohort of already collected data was also examined from the Avon Longitudinal Study of Parents and Children (ALSPAC) for replication of results and mediation analysis, consisting of ~5000 participants. Block regression analysis using SPSS statistical software was performed, testing a relationship between genetic risk levels and cognitive deficits. In a second element to the study, environmental factors were examined as possible mediators of the relationship between genetic risk variants and cognitive impairment (PROCESS mediation, SPSS) in the ALSPAC sample. Regression analysis suggests that 7 of 8 genetic variants selected contribute to impairments in cognition across an Irish sample, and these findings were replicated in the ALSPAC sample. Cognitive deficits overlapped for the majority of genes examined, across domains of social cognition, IQ and episodic memory. In examining ALSPAC as a replication sample, many of the same genetic variants also showed negative effects on social cognition, as well as more generalized effects of these genes on various cognitive domains. In mediation analysis, environmental factors such as childhood abuse were also found to impact on this gene-cognition relationship. The "Immune 8" may serve as significant risk markers for schizophrenia, and further elucidate aetiology of this disorder. Future studies on neurobiology of social cognition, and greater knowledge of genetic risk may establish targets for interventions. Childhood abuse was also found to be significantly related to cognitive deficit. The role of environmental stressors contributing to genetic risk and immune function is an interesting avenue for future research in schizophrenia. [ABSTRACT FROM AUTHOR]

Published
2019
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32. Genetic Risk Variants Interacting With MIR137: Effects On Cognition, Brain Structure And Brain Function In Patients And Healthy Participants.

Author

Donohoe, Gary, Cosgrove, Donna, Motherills, David, Harold, Denise, Kelly, Sinead, Holleran, Laurena, Holland, Jessica, Wellcome Trust CCC, Anney, Richard, Richards, Alexander, Owen, Michael, O'Donovan, Michael, Gill, Michael, Corvin, Aiden, and Morris, Derek

Subjects
*VOXEL-based morphometry, *22Q11 deletion syndrome, *EPISODIC memory, *SPATIAL memory, *COGNITION, *SHORT-term memory, *GENE regulatory networks
Abstract

Variants at microRNA-137 (MIR137), one of the most strongly associated schizophrenia risk loci identified to date, are associated with poorer cognitive performance. As microRNA-137 is known to regulate the expression of ~1900 other genes, including several that are independently associated with schizophrenia, we tested whether this gene set was also associated with variation in cognition, brain structure and brain function. Our analysis was based on an empirically derived list of genes whose expression was altered by manipulation of MIR137 expression. This list was cross-referenced with genome-wide schizophrenia association data to construct individual polygenic scores. In a sample of 808 patients and 192 controls, we tested whether these risk scores were associated with altered performance on cognitive functions known to be affected in schizophrenia. A subgroup of healthy participants also underwent functional imaging during memory performance, and brain volume and cortical thickness and shape analysis was carried out in n=216 patients and healthy participants. Increased polygenic risk within the empirically derived miR-137 regulated gene score was associated with significantly lower performance measures of IQ, working memory and episodic memory. Analysis of the spatial working memory fMRI task further suggested that increased risk score (thresholded at P=10-5) was significantly associated with increased activation of the right inferior occipital gyrus. Finally, the MiR137 gene network was not associated with variation in cortical thickness or shape, nor was it associated with variation in hippocampal volume. While polygenic risk scores were associated with reduced whole brain volume, this finding did not survive correction for multiple testing. In conclusion, these data are consistent with emerging evidence that MIR137 associated risk for schizophrenia may relate, in part, to its broader downstream genetic effects on neurocognitive function. [ABSTRACT FROM AUTHOR]

Published
2019
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