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    Cortisol Levels in Childhood Associated with Emergence of Attenuated Psychotic Symptoms in Early Adulthood
    Cullen, AE ; Fisher, HL ; Gullet, N ; Fraser, ER ; Roberts, RE ; Zahid, U ; To, M ; Yap, N ; Zunszain, PA ; Pariante, CM ; Wood, SJ ; McGuire, P ; Murray, RM ; Mondelli, V ; Laurens, KR (PERGAMON-ELSEVIER SCIENCE LTD, 2021-09)
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    Cognitive functioning throughout adulthood and illness stages in individuals with psychotic disorders and their unaffected siblings
    Velthorst, E ; Mollon, J ; Murray, RM ; de Haan, L ; Germeys, IM ; Glahn, DC ; Arango, C ; van der Ven, E ; Di Forti, M ; Bernardo, M ; Guloksuz, S ; Delespaul, P ; Mezquida, G ; Amoretti, S ; Bobes, J ; Saiz, PA ; Garcia-Portilla, MP ; Santos, JL ; Jimenez-Lopez, E ; Sanjuan, J ; Aguilar, EJ ; Arrojo, M ; Carracedo, A ; Lopez, G ; Gonzalez-Penas, J ; Parellada, M ; Atbasoglu, C ; Saka, MC ; Ucok, A ; Alptekin, K ; Akdede, B ; Binbay, T ; Altinyazar, V ; Ulas, H ; Yalincetin, B ; Gumus-Akay, G ; Beyaz, BC ; Soygur, H ; Cankurtaran, ES ; Kaymak, SU ; Maric, NP ; Mihaljevic, MM ; Petrovic, SA ; Mirjanic, T ; Del-Ben, CM ; Ferraro, L ; Gayer-Anderson, C ; Jones, PB ; Jongsma, HE ; Kirkbride, JB ; La Cascia, C ; Lasalvia, A ; Tosato, S ; Llorca, P-M ; Menezes, PR ; Morgan, C ; Quattrone, D ; Menchetti, M ; Selten, J-P ; Szoke, A ; Tarricone, I ; Tortelli, A ; McGuire, P ; Valmaggia, L ; Kempton, MJ ; van der Gaag, M ; Riecher-Rossler, A ; Bressan, RA ; Barrantes-Vidal, N ; Nelson, B ; McGorry, P ; Pantelis, C ; Krebs, M-O ; Ruhrmann, S ; Sachs, G ; Rutten, BPF ; van Os, J ; Alizadeh, BZ ; van Amelsvoort, T ; Bartels-Velthuis, AA ; Bruggeman, R ; van Beveren, NJ ; Luykx, JJ ; Cahn, W ; Simons, CJP ; Kahn, RS ; Schirmbeck, F ; van Winkel, R ; Reichenberg, A (SPRINGERNATURE, 2021-08)
    Important questions remain about the profile of cognitive impairment in psychotic disorders across adulthood and illness stages. The age-associated profile of familial impairments also remains unclear, as well as the effect of factors, such as symptoms, functioning, and medication. Using cross-sectional data from the EU-GEI and GROUP studies, comprising 8455 participants aged 18 to 65, we examined cognitive functioning across adulthood in patients with psychotic disorders (n = 2883), and their unaffected siblings (n = 2271), compared to controls (n = 3301). An abbreviated WAIS-III measured verbal knowledge, working memory, visuospatial processing, processing speed, and IQ. Patients showed medium to large deficits across all functions (ES range = -0.45 to -0.73, p < 0.001), while siblings showed small deficits on IQ, verbal knowledge, and working memory (ES = -0.14 to -0.33, p < 0.001). Magnitude of impairment was not associated with participant age, such that the size of impairment in older and younger patients did not significantly differ. However, first-episode patients performed worse than prodromal patients (ES range = -0.88 to -0.60, p < 0.001). Adjusting for cannabis use, symptom severity, and global functioning attenuated impairments in siblings, while deficits in patients remained statistically significant, albeit reduced by half (ES range = -0.13 to -0.38, p < 0.01). Antipsychotic medication also accounted for around half of the impairment in patients (ES range = -0.21 to -0.43, p < 0.01). Deficits in verbal knowledge, and working memory may specifically index familial, i.e., shared genetic and/or shared environmental, liability for psychotic disorders. Nevertheless, potentially modifiable illness-related factors account for a significant portion of the cognitive impairment in psychotic disorders.
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    1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans
    Sonderby, IE ; van der Meer, D ; Moreau, C ; Kaufmann, T ; Walters, GB ; Ellegaard, M ; Abdellaoui, A ; Ames, D ; Amunts, K ; Andersson, M ; Armstrong, NJ ; Bernard, M ; Blackburn, NB ; Blangero, J ; Boomsma, DI ; Brodaty, H ; Brouwer, RM ; Buelow, R ; Boen, R ; Cahn, W ; Calhoun, VD ; Caspers, S ; Ching, CRK ; Cichon, S ; Ciufolini, S ; Crespo-Facorro, B ; Curran, JE ; Dale, AM ; Dalvie, S ; Dazzan, P ; de Geus, EJC ; de Zubicaray, GI ; de Zwarte, SMC ; Desrivieres, S ; Doherty, JL ; Donohoe, G ; Draganski, B ; Ehrlich, S ; Eising, E ; Espeseth, T ; Fejgin, K ; Fisher, SE ; Fladby, T ; Frei, O ; Frouin, V ; Fukunaga, M ; Gareau, T ; Ge, T ; Glahn, DC ; Grabe, HJ ; Groenewold, NA ; Gustafsson, O ; Haavik, J ; Haberg, AK ; Hall, J ; Hashimoto, R ; Hehir-Kwa, JY ; Hibar, DP ; Hillegers, MHJ ; Hoffmann, P ; Holleran, L ; Holmes, AJ ; Homuth, G ; Hottenga, J-J ; Hulshoff Pol, HE ; Ikeda, M ; Jahanshad, N ; Jockwitz, C ; Johansson, S ; Joensson, EG ; Jorgensen, NR ; Kikuchi, M ; Knowles, EEM ; Kumar, K ; Le Hellard, S ; Leu, C ; Linden, DEJ ; Liu, J ; Lundervold, A ; Lundervold, AJ ; Maillard, AM ; Martin, NG ; Martin-Brevet, S ; Mather, KA ; Mathias, SR ; McMahon, KL ; McRae, AF ; Medland, SE ; Meyer-Lindenberg, A ; Moberget, T ; Modenato, C ; Sanchez, JM ; Morris, DW ; Muehleisen, TW ; Murray, RM ; Nielsen, J ; Nordvik, JE ; Nyberg, L ; Loohuis, LMO ; Ophoff, RA ; Owen, MJ ; Paus, T ; Pausova, Z ; Peralta, JM ; Pike, GB ; Prieto, C ; Quinlan, EB ; Reinbold, CS ; Marques, TR ; 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 ; Suzuki, IK ; Tamnes, CK ; Teumer, A ; Thalamuthu, A ; Tordesillas-Gutierrez, D ; Uhlmann, A ; Ulfarsson, MO ; van 't Ent, D ; van den Bree, MBM ; Vanderhaeghen, P ; Vassos, E ; Wen, W ; Wittfeld, K ; Wright, MJ ; Agartz, I ; Djurovic, S ; Westlye, LT ; Stefansson, H ; Stefansson, K ; Jacquemont, S ; Thompson, PM ; Andreassen, OA (SPRINGERNATURE, 2021-03-22)
    Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
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    Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants With Treatment Resistance in Schizophrenia
    Pardinas, AF ; Smart, SE ; Willcocks, IR ; Holmans, PA ; Dennison, CA ; Lynham, AJ ; Legge, SE ; Baune, BT ; Bigdeli, TB ; Cairns, MJ ; Corvin, A ; Fanous, AH ; Frank, J ; Kelly, B ; McQuillin, A ; Melle, I ; Mortensen, PB ; Mowry, BJ ; Pato, CN ; Periyasamy, S ; Rietschel, M ; Rujescu, D ; Simonsen, C ; St Clair, D ; Tooney, P ; Wu, JQ ; Andreassen, OA ; Kowalec, K ; Sullivan, PF ; Murray, RM ; Owen, MJ ; MacCabe, JH ; O'Donovan, MC ; Walters, JTR (AMER MEDICAL ASSOC, 2022-03)
    IMPORTANCE: About 20% to 30% of people with schizophrenia have psychotic symptoms that do not respond adequately to first-line antipsychotic treatment. This clinical presentation, chronic and highly disabling, is known as treatment-resistant schizophrenia (TRS). The causes of treatment resistance and their relationships with causes underlying schizophrenia are largely unknown. Adequately powered genetic studies of TRS are scarce because of the difficulty in collecting data from well-characterized TRS cohorts. OBJECTIVE: To examine the genetic architecture of TRS through the reassessment of genetic data from schizophrenia studies and its validation in carefully ascertained clinical samples. DESIGN, SETTING, AND PARTICIPANTS: Two case-control genome-wide association studies (GWASs) of schizophrenia were performed in which the case samples were defined as individuals with TRS (n = 10 501) and individuals with non-TRS (n = 20 325). The differences in effect sizes for allelic associations were then determined between both studies, the reasoning being such differences reflect treatment resistance instead of schizophrenia. Genotype data were retrieved from the CLOZUK and Psychiatric Genomics Consortium (PGC) schizophrenia studies. The output was validated using polygenic risk score (PRS) profiling of 2 independent schizophrenia cohorts with TRS and non-TRS: a prevalence sample with 817 individuals (Cardiff Cognition in Schizophrenia [CardiffCOGS]) and an incidence sample with 563 individuals (Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances [STRATA-G]). MAIN OUTCOMES AND MEASURES: GWAS of treatment resistance in schizophrenia. The results of the GWAS were compared with complex polygenic traits through a genetic correlation approach and were used for PRS analysis on the independent validation cohorts using the same TRS definition. RESULTS: The study included a total of 85 490 participants (48 635 [56.9%] male) in its GWAS stage and 1380 participants (859 [62.2%] male) in its PRS validation stage. Treatment resistance in schizophrenia emerged as a polygenic trait with detectable heritability (1% to 4%), and several traits related to intelligence and cognition were found to be genetically correlated with it (genetic correlation, 0.41-0.69). PRS analysis in the CardiffCOGS prevalence sample showed a positive association between TRS and a history of taking clozapine (r2 = 2.03%; P = .001), which was replicated in the STRATA-G incidence sample (r2 = 1.09%; P = .04). CONCLUSIONS AND RELEVANCE: In this GWAS, common genetic variants were differentially associated with TRS, and these associations may have been obscured through the amalgamation of large GWAS samples in previous studies of broadly defined schizophrenia. Findings of this study suggest the validity of meta-analytic approaches for studies on patient outcomes, including treatment resistance.
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    Genetic variants associated with longitudinal changes in brain structure across the lifespan
    Brouwer, RM ; Klein, M ; Grasby, KL ; Schnack, HG ; Jahanshad, N ; Teeuw, J ; Thomopoulos, SI ; Sprooten, E ; Franz, CE ; Gogtay, N ; Kremen, WS ; Panizzon, MS ; Olde Loohuis, LM ; Whelan, CD ; Aghajani, M ; Alloza, C ; Alanaes, D ; Artiges, E ; Ayesa-Arriola, R ; Barker, GJ ; Bastin, ME ; Blok, E ; Boen, E ; Breukelaar, IA ; Bright, JK ; Buimer, EEL ; Bulow, R ; Cannon, DM ; Ciufolini, S ; Crossley, NA ; Damatac, CG ; Dazzan, P ; de Mol, CL ; de Zwarte, SMC ; Desrivieres, S ; Diaz-Caneja, CM ; Doan, NT ; Dohm, K ; Froehner, JH ; Goltermann, J ; Grigis, A ; Grotegerd, D ; Han, LKM ; Harris, MA ; Hartman, CA ; Heany, SJ ; Heindel, W ; Heslenfeld, DJ ; Hohmann, S ; Ittermann, B ; Jansen, PR ; Janssen, J ; Jia, T ; Jiang, J ; Jockwitz, C ; Karali, T ; Keeser, D ; Koevoets, MGJC ; Lenroot, RK ; Malchow, B ; Mandl, RCW ; Medel, V ; Meinert, S ; Morgan, CA ; Muehleisen, TW ; Nabulsi, L ; Opel, N ; de la Foz, VO-G ; Overs, BJ ; Paillere Martinot, M-L ; Redlich, R ; Marques, TR ; Repple, J ; Roberts, G ; Roshchupkin, GV ; Setiaman, N ; Shumskaya, E ; Stein, F ; Sudre, G ; Takahashi, S ; Thalamuthu, A ; Tordesillas-Gutierrez, D ; van der Lugt, A ; van Haren, NEM ; Wardlaw, JM ; Wen, W ; Westeneng, H-J ; Wittfeld, K ; Zhu, AH ; Zugman, A ; Armstrong, NJ ; Bonfiglio, G ; Bralten, J ; Dalvie, S ; Davies, G ; Di Forti, M ; Ding, L ; Donohoe, G ; Forstner, AJ ; Gonzalez-Penas, J ; Guimaraes, JPOFT ; Homuth, G ; Hottenga, J-J ; Knol, MJ ; Kwok, JBJ ; Le Hellard, S ; Mather, KA ; Milaneschi, Y ; Morris, DW ; Noethen, MM ; Papiol, S ; Rietschel, M ; Santoro, ML ; Steen, VM ; Stein, JL ; Streit, F ; Tankard, RM ; Teumer, A ; van 't Ent, D ; van der Meer, D ; van Eijk, KR ; Vassos, E ; Vazquez-Bourgon, J ; Witt, SH ; Adams, HHH ; Agartz, I ; Ames, D ; Amunts, K ; Andreassen, OA ; Arango, C ; Banaschewski, T ; Baune, BT ; Belangero, SI ; Bokde, ALW ; Boomsma, DI ; Bressan, RA ; Brodaty, H ; Buitelaar, JK ; Cahn, W ; Caspers, S ; Cichon, S ; Crespo-Facorro, B ; Cox, SR ; Dannlowski, U ; Elvsashagen, T ; Espeseth, T ; Falkai, PG ; Fisher, SE ; Flor, H ; Fullerton, JM ; Garavan, H ; Gowland, PA ; Grabe, HJ ; Hahn, T ; Heinz, A ; Hillegers, M ; Hoare, J ; Hoekstra, PJ ; Ikram, MA ; Jackowski, AP ; Jansen, A ; Jonsson, EG ; Kahn, RS ; Kircher, T ; Korgaonkar, MS ; Krug, A ; Lemaitre, H ; Malt, UF ; Martinot, J-L ; McDonald, C ; Mitchell, PB ; Muetzel, RL ; Murray, RM ; Nees, F ; Nenadic, I ; Oosterlaan, J ; Ophoff, RA ; Pan, PM ; Penninx, BWJH ; Poustka, L ; Sachdev, PS ; Salum, GA ; Schofield, PR ; Schumann, G ; Shaw, P ; Sim, K ; Smolka, MN ; Stein, DJ ; Trollor, JN ; van den Berg, LH ; Veldink, JH ; Walter, H ; Westlye, LT ; Whelan, R ; White, T ; Wright, MJ ; Medland, SE ; Franke, B ; Thompson, PM ; Hulshoff Pol, HE (NATURE PORTFOLIO, 2022-04)
    Human brain structure changes throughout the lifespan. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental and neurodegenerative diseases. In this study, we identified common genetic variants that affect rates of brain growth or atrophy in what is, to our knowledge, the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal magnetic resonance imaging data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genes GPR139, DACH1 and APOE are associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and aging.
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    Vitamin D supplementation compared to placebo in people with First Episode psychosis-Neuroprotection Design (DFEND): a protocol for a randomised, double-blind, placebo-controlled, parallel-group trial
    Gaughran, F ; Stringer, D ; Berk, M ; Smith, S ; Taylor, D ; Whiskey, E ; Landau, S ; Murray, R ; McGuire, P ; Gardner-Sood, P ; Wojewodka, G ; Ciufolini, S ; Jordan, H ; Clarke, J ; Allen, L ; Krivoy, A ; Stubbs, B ; Lowe, P ; Arbuthnott, M ; Rathod, S ; Boardman, A ; Firdosi, M ; McGrath, JJ (BMC, 2020-01-06)
    BACKGROUND: People experiencing their first episode of psychosis are often deficient in vitamin D. Observational studies have reported an association between low vitamin D concentrations and poorer subsequent health outcomes in psychosis. A vitamin D deficiency in neonates and children has been linked to a later increased risk of schizophrenia and psychotic-like experiences. This trial aims to examine the effect of high-dose vitamin D supplementation on outcomes in early psychosis. We hypothesise that vitamin D supplementation will be associated with better mental health outcomes. METHODS/DESIGN: The DFEND study is a multicentre double-blind placebo-controlled parallel-group trial of vitamin D supplementation in people with early psychosis. Patients with an ICD-10 diagnosis of functional psychosis will be randomised in a 1:1 ratio to receive either 120,000 IU/month of vitamin D (cholecalciferol) or a matched placebo for 6 months. The primary outcome is the total Positive and Negative Syndrome Scale (PANSS) score at the 6-month follow-up for all patients. Secondary outcomes include assessment of mood (Calgary Depression Scale), general function (Global Assessment of Functioning), cardiovascular risk (body mass index, waist circumference, C-reactive protein, cholesterol and HbA1c) and vitamin D levels at the 6-month follow-up. Additionally, 3- and 6-month total PANSS scores will be analysed for those with inadequate vitamin D levels at the baseline. DISCUSSION: The DFEND study is the first trial to examine whether vitamin D supplementation in early psychosis is associated with better mental health outcomes. The findings of this study may help to resolve the clinical equipoise regarding the benefits and cost-effectiveness of routine vitamin D supplementation in people with psychosis. TRIAL REGISTRATION: ISRCTN, ISRCTN12424842. Registered on 25 February 2015.