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3. Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers

Author

Boen, R, Kaufmann, T, van der Meer, D, Frei, O, Agartz, I, Ames, D, Andersson, M, Armstrong, NJ, Artiges, E, Atkins, JR, Bauer, J, Benedetti, F, Boomsma, DI, Brodaty, H, Brosch, K, Buckner, RL, Cairns, MJ, Calhoun, V, Caspers, S, Cichon, S, Corvin, AP, Crespo-Facorro, B, Dannlowski, U, David, FS, de Geus, EJC, de Zubicaray, GI, Desrivieres, S, Doherty, JL, Donohoe, G, Ehrlich, S, Eising, E, Espeseth, T, Fisher, SE, Forstner, AJ, Fortaner-Uya, L, Frouin, V, Fukunaga, M, Ge, T, Glahn, DC, Goltermann, J, Grabe, HJ, Green, MJ, Groenewold, NA, Grotegerd, D, Grontvedt, GR, Hahn, T, Hashimoto, R, Hehir-Kwa, JY, Henskens, FA, Holmes, AJ, Haberg, AK, Haavik, J, Jacquemont, S, Jansen, A, Jockwitz, C, Joensson, EG, Kikuchi, M, Kircher, T, Kumar, K, Le Hellard, S, Leu, C, Linden, DE, Liu, J, Loughnan, R, Mather, KA, Mcmahon, KL, Mcrae, AF, Medland, SE, Meinert, S, Moreau, CA, Morris, DW, Mowry, BJ, Muehleisen, TW, Nenadic, I, Noethen, MM, Nyberg, L, Ophoff, RA, Owen, MJ, Pantelis, C, Paolini, M, Paus, T, Pausova, Z, Persson, K, Quide, Y, Marques, TR, Sachdev, PS, Sando, SB, Schall, U, Scott, RJ, Selbaek, G, Shumskaya, E, Silva, AI, Sisodiya, SM, Stein, F, Stein, DJ, Straube, B, Streit, F, Strike, LT, Teumer, A, Teutenberg, L, Thalamuthu, A, Tooney, PA, Tordesillas-Gutierrez, D, Trollor, JN, Van't Ent, D, van den Bree, MBM, van Haren, NEM, Vazquez-Bourgon, J, Voelzke, H, Wen, W, Wittfeld, K, Ching, CRK, Westlye, LT, Thompson, PM, Bearden, CE, Selmer, KK, Alnaes, D, Andreassen, OA, Sonderby, IE, Boen, R, Kaufmann, T, van der Meer, D, Frei, O, Agartz, I, Ames, D, Andersson, M, Armstrong, NJ, Artiges, E, Atkins, JR, Bauer, J, Benedetti, F, Boomsma, DI, Brodaty, H, Brosch, K, Buckner, RL, Cairns, MJ, Calhoun, V, Caspers, S, Cichon, S, Corvin, AP, Crespo-Facorro, B, Dannlowski, U, David, FS, de Geus, EJC, de Zubicaray, GI, Desrivieres, S, Doherty, JL, Donohoe, G, Ehrlich, S, Eising, E, Espeseth, T, Fisher, SE, Forstner, AJ, Fortaner-Uya, L, Frouin, V, Fukunaga, M, Ge, T, Glahn, DC, Goltermann, J, Grabe, HJ, Green, MJ, Groenewold, NA, Grotegerd, D, Grontvedt, GR, Hahn, T, Hashimoto, R, Hehir-Kwa, JY, Henskens, FA, Holmes, AJ, Haberg, AK, Haavik, J, Jacquemont, S, Jansen, A, Jockwitz, C, Joensson, EG, Kikuchi, M, Kircher, T, Kumar, K, Le Hellard, S, Leu, C, Linden, DE, Liu, J, Loughnan, R, Mather, KA, Mcmahon, KL, Mcrae, AF, Medland, SE, Meinert, S, Moreau, CA, Morris, DW, Mowry, BJ, Muehleisen, TW, Nenadic, I, Noethen, MM, Nyberg, L, Ophoff, RA, Owen, MJ, Pantelis, C, Paolini, M, Paus, T, Pausova, Z, Persson, K, Quide, Y, Marques, TR, Sachdev, PS, Sando, SB, Schall, U, Scott, RJ, Selbaek, G, Shumskaya, E, Silva, AI, Sisodiya, SM, Stein, F, Stein, DJ, Straube, B, Streit, F, Strike, LT, Teumer, A, Teutenberg, L, Thalamuthu, A, Tooney, PA, Tordesillas-Gutierrez, D, Trollor, JN, Van't Ent, D, van den Bree, MBM, van Haren, NEM, Vazquez-Bourgon, J, Voelzke, H, Wen, W, Wittfeld, K, Ching, CRK, Westlye, LT, Thompson, PM, Bearden, CE, Selmer, KK, Alnaes, D, Andreassen, OA, and Sonderby, IE

Abstract

BACKGROUND: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure. METHODS: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual's regional difference and global difference, were used to test for regional differences that diverge from the global difference. RESULTS: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness. CONCLUSIONS: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment.

Published
2024

4. Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium

Author

Constantinides, C, Han, LKM, Alloza, C, Antonucci, LA, Arango, C, Ayesa-Arriola, R, Banaj, N, Bertolino, A, Borgwardt, S, Bruggemann, J, Bustillo, J, Bykhovski, O, Calhoun, V, Carr, V, Catts, S, Chung, Y-C, Crespo-Facorro, B, Diaz-Caneja, CM, Donohoe, G, Du Plessis, S, Edmond, J, Ehrlich, S, Emsley, R, Eyler, LT, Fuentes-Claramonte, P, Georgiadis, F, Green, M, Guerrero-Pedraza, A, Ha, M, Hahn, T, Henskens, FA, Holleran, L, Homan, S, Homan, P, Jahanshad, N, Janssen, J, Ji, E, Kaiser, S, Kaleda, V, Kim, M, Kim, W-S, Kirschner, M, Kochunov, P, Kwak, YB, Kwon, JS, Lebedeva, I, Liu, J, Mitchie, P, Michielse, S, Mothersill, D, Mowry, B, de la Foz, VO-G, Pantelis, C, Pergola, G, Piras, F, Pomarol-Clotet, E, Preda, A, Quide, Y, Rasser, PE, Rootes-Murdy, K, Salvador, R, Sangiuliano, M, Sarro, S, Schall, U, Schmidt, A, Scott, RJ, Selvaggi, P, Sim, K, Skoch, A, Spalletta, G, Spaniel, F, Thomopoulos, S, Tomecek, D, Tomyshev, AS, Tordesillas-Gutierrez, D, van Amelsvoort, T, Vazquez-Bourgon, J, Vecchio, D, Voineskos, A, Weickert, CS, Weickert, T, Thompson, PM, Schmaal, L, van Erp, TGM, Turner, J, Cole, JH, Dima, D, Walton, E, Constantinides, C, Han, LKM, Alloza, C, Antonucci, LA, Arango, C, Ayesa-Arriola, R, Banaj, N, Bertolino, A, Borgwardt, S, Bruggemann, J, Bustillo, J, Bykhovski, O, Calhoun, V, Carr, V, Catts, S, Chung, Y-C, Crespo-Facorro, B, Diaz-Caneja, CM, Donohoe, G, Du Plessis, S, Edmond, J, Ehrlich, S, Emsley, R, Eyler, LT, Fuentes-Claramonte, P, Georgiadis, F, Green, M, Guerrero-Pedraza, A, Ha, M, Hahn, T, Henskens, FA, Holleran, L, Homan, S, Homan, P, Jahanshad, N, Janssen, J, Ji, E, Kaiser, S, Kaleda, V, Kim, M, Kim, W-S, Kirschner, M, Kochunov, P, Kwak, YB, Kwon, JS, Lebedeva, I, Liu, J, Mitchie, P, Michielse, S, Mothersill, D, Mowry, B, de la Foz, VO-G, Pantelis, C, Pergola, G, Piras, F, Pomarol-Clotet, E, Preda, A, Quide, Y, Rasser, PE, Rootes-Murdy, K, Salvador, R, Sangiuliano, M, Sarro, S, Schall, U, Schmidt, A, Scott, RJ, Selvaggi, P, Sim, K, Skoch, A, Spalletta, G, Spaniel, F, Thomopoulos, S, Tomecek, D, Tomyshev, AS, Tordesillas-Gutierrez, D, van Amelsvoort, T, Vazquez-Bourgon, J, Vecchio, D, Voineskos, A, Weickert, CS, Weickert, T, Thompson, PM, Schmaal, L, van Erp, TGM, Turner, J, Cole, JH, Dima, D, and Walton, E

Abstract

Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18-72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18-73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.55 years (95% CI: 2.91, 4.19; I2 = 57.53%) compared to controls, after adjusting for age, sex and site (Cohen's d = 0.48). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions.

Published
2023

5. Large- scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium

Author

Schijven, D, Postema, MC, Fukunaga, M, Matsumoto, J, Miura, K, de Zwarte, SMC, van Haren, NEM, Cahn, W, Pol, HEH, Kahn, RS, Ayesa-Arriola, R, de la Foz, VO-G, Tordesillas-Gutierrez, D, Vazquez-Bourgon, J, Crespo-Facorro, B, Alnaes, D, Dahl, A, Westlye, LT, Agartz, I, Andreassen, OA, Jonsson, EG, Kochunov, P, Bruggemann, JM, Catts, SV, Michie, PT, Mowry, BJ, Quide, Y, Rasser, PE, Schall, U, Scott, RJ, Carr, VJ, Green, MJ, Henskens, FA, Loughland, CM, Pantelis, C, Weickert, CS, Weickert, TW, De Haan, L, Brosch, K, Pfarr, J-K, Ringwald, KG, Stein, F, Jansen, A, Kircher, TTJ, Nenadic, I, Kramer, B, Gruber, O, Satterthwaite, TD, Bustillo, J, Mathalon, DH, Preda, A, Calhoun, VD, Ford, JM, Potkin, SG, Chen, J, Tan, Y, Wang, Z, Xiang, H, Fan, F, Bernardoni, F, Ehrlich, S, Fuentes-Claramonte, P, Garcia-Leon, MA, Guerrero-Pedraza, A, Salvador, R, Sarro, S, Pomarol-Clotet, E, Ciullo, V, Piras, F, Vecchio, D, Banaj, N, Spalletta, G, Michielse, S, van Amelsvoort, T, Dickie, EW, Voineskos, AN, Sim, K, Ciufolini, S, Dazzan, P, Murray, RM, Kim, W-S, Chung, Y-C, Andreou, C, Schmidt, A, Borgwardt, S, McIntosh, AM, Whalley, HC, Lawrie, SM, Du Plessis, S, Luckhoff, HK, Scheffler, F, Emsley, R, Grotegerd, D, Lencer, R, Dannlowski, U, Edmond, JT, Rootes-Murdy, K, Stephen, JM, Mayer, AR, Antonucci, LA, Fazio, L, Pergola, G, Bertolino, A, Diaz-Caneja, CM, Janssen, J, Lois, NG, Arango, C, Tomyshev, AS, Lebedeva, I, Cervenkav, S, Sellgrenv, CM, Georgiadis, F, Kirschner, M, Kaiser, S, Hajek, T, Skoch, A, Spaniel, F, Kim, M, Bin Kwak, Y, Oh, S, Kwon, JS, James, A, Bakker, G, Knochel, C, Stablein, M, Oertel, V, Uhlmann, A, Howells, FM, Stein, DJ, Temmingh, HS, Diaz-Zuluaga, AM, Pineda-Zapata, JA, Lopez-Jaramillo, C, Homan, S, Ji, E, Surbeck, W, Homan, P, Fishera, SE, Franke, B, Glahn, DC, Gur, RC, Hashimoto, R, Jahanshad, N, Luders, E, Medland, SE, Thompson, PM, Turner, JA, van Erp, TGM, Francks, C, Schijven, D, Postema, MC, Fukunaga, M, Matsumoto, J, Miura, K, de Zwarte, SMC, van Haren, NEM, Cahn, W, Pol, HEH, Kahn, RS, Ayesa-Arriola, R, de la Foz, VO-G, Tordesillas-Gutierrez, D, Vazquez-Bourgon, J, Crespo-Facorro, B, Alnaes, D, Dahl, A, Westlye, LT, Agartz, I, Andreassen, OA, Jonsson, EG, Kochunov, P, Bruggemann, JM, Catts, SV, Michie, PT, Mowry, BJ, Quide, Y, Rasser, PE, Schall, U, Scott, RJ, Carr, VJ, Green, MJ, Henskens, FA, Loughland, CM, Pantelis, C, Weickert, CS, Weickert, TW, De Haan, L, Brosch, K, Pfarr, J-K, Ringwald, KG, Stein, F, Jansen, A, Kircher, TTJ, Nenadic, I, Kramer, B, Gruber, O, Satterthwaite, TD, Bustillo, J, Mathalon, DH, Preda, A, Calhoun, VD, Ford, JM, Potkin, SG, Chen, J, Tan, Y, Wang, Z, Xiang, H, Fan, F, Bernardoni, F, Ehrlich, S, Fuentes-Claramonte, P, Garcia-Leon, MA, Guerrero-Pedraza, A, Salvador, R, Sarro, S, Pomarol-Clotet, E, Ciullo, V, Piras, F, Vecchio, D, Banaj, N, Spalletta, G, Michielse, S, van Amelsvoort, T, Dickie, EW, Voineskos, AN, Sim, K, Ciufolini, S, Dazzan, P, Murray, RM, Kim, W-S, Chung, Y-C, Andreou, C, Schmidt, A, Borgwardt, S, McIntosh, AM, Whalley, HC, Lawrie, SM, Du Plessis, S, Luckhoff, HK, Scheffler, F, Emsley, R, Grotegerd, D, Lencer, R, Dannlowski, U, Edmond, JT, Rootes-Murdy, K, Stephen, JM, Mayer, AR, Antonucci, LA, Fazio, L, Pergola, G, Bertolino, A, Diaz-Caneja, CM, Janssen, J, Lois, NG, Arango, C, Tomyshev, AS, Lebedeva, I, Cervenkav, S, Sellgrenv, CM, Georgiadis, F, Kirschner, M, Kaiser, S, Hajek, T, Skoch, A, Spaniel, F, Kim, M, Bin Kwak, Y, Oh, S, Kwon, JS, James, A, Bakker, G, Knochel, C, Stablein, M, Oertel, V, Uhlmann, A, Howells, FM, Stein, DJ, Temmingh, HS, Diaz-Zuluaga, AM, Pineda-Zapata, JA, Lopez-Jaramillo, C, Homan, S, Ji, E, Surbeck, W, Homan, P, Fishera, SE, Franke, B, Glahn, DC, Gur, RC, Hashimoto, R, Jahanshad, N, Luders, E, Medland, SE, Thompson, PM, Turner, JA, van Erp, TGM, and Francks, C

Abstract

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

Published
2023

10. Genetic variants associated with longitudinal changes in brain structure across the lifespan

Author

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, 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, and Hulshoff Pol, HE

Abstract

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.

Published
2022

11. The psychosis metabolic risk calculator (PsyMetRiC) for young people with psychosis: International external validation and site-specific recalibration in two independent European samples.

Author

Perry, BI, Vandenberghe, F, Garrido-Torres, N, Osimo, EF, Piras, M, Vazquez-Bourgon, J, Upthegrove, R, Grosu, C, De La Foz, VO-G, Jones, PB, Laaboub, N, Ruiz-Veguilla, M, Stochl, J, Dubath, C, Canal-Rivero, M, Mallikarjun, P, Delacrétaz, A, Ansermot, N, Fernandez-Egea, E, Crettol, S, Gamma, F, Plessen, KJ, Conus, P, Khandaker, GM, Murray, GK, Eap, CB, Crespo-Facorro, B, Perry, BI, Vandenberghe, F, Garrido-Torres, N, Osimo, EF, Piras, M, Vazquez-Bourgon, J, Upthegrove, R, Grosu, C, De La Foz, VO-G, Jones, PB, Laaboub, N, Ruiz-Veguilla, M, Stochl, J, Dubath, C, Canal-Rivero, M, Mallikarjun, P, Delacrétaz, A, Ansermot, N, Fernandez-Egea, E, Crettol, S, Gamma, F, Plessen, KJ, Conus, P, Khandaker, GM, Murray, GK, Eap, CB, and Crespo-Facorro, B

Abstract

BACKGROUND: Cardiometabolic dysfunction is common in young people with psychosis. Recently, the Psychosis Metabolic Risk Calculator (PsyMetRiC) was developed and externally validated in the UK, predicting up-to six-year risk of metabolic syndrome (MetS) from routinely collected data. The full-model includes age, sex, ethnicity, body-mass index, smoking status, prescription of metabolically-active antipsychotic medication, high-density lipoprotein, and triglyceride concentrations; the partial-model excludes biochemical predictors. METHODS: To move toward a future internationally-useful tool, we externally validated PsyMetRiC in two independent European samples. We used data from the PsyMetab (Lausanne, Switzerland) and PAFIP (Cantabria, Spain) cohorts, including participants aged 16-35y without MetS at baseline who had 1-6y follow-up. Predictive performance was assessed primarily via discrimination (C-statistic), calibration (calibration plots), and decision curve analysis. Site-specific recalibration was considered. FINDINGS: We included 1024 participants (PsyMetab n=558, male=62%, outcome prevalence=19%, mean follow-up=2.48y; PAFIP n=466, male=65%, outcome prevalence=14%, mean follow-up=2.59y). Discrimination was better in the full- compared with partial-model (PsyMetab=full-model C=0.73, 95% C.I., 0.68-0.79, partial-model C=0.68, 95% C.I., 0.62-0.74; PAFIP=full-model C=0.72, 95% C.I., 0.66-0.78; partial-model C=0.66, 95% C.I., 0.60-0.71). As expected, calibration plots revealed varying degrees of miscalibration, which recovered following site-specific recalibration. PsyMetRiC showed net benefit in both new cohorts, more so after recalibration. INTERPRETATION: The study provides evidence of PsyMetRiC's generalizability in Western Europe, although further local and international validation studies are required. In future, PsyMetRiC could help clinicians internationally to identify young people with psychosis who are at higher cardiometabolic risk, so interventions c

Published
2022

12. Virtual Ontogeny of Cortical Growth Preceding Mental Illness

Author

Patel, Y, Shin, J, Abe, C, Agartz, I, Alloza, C, Alnaes, D, Ambrogi, S, Antonucci, LA, Arango, C, Arolt, V, Auzias, G, Ayesa-Arriola, R, Banaj, N, Banaschewski, T, Bandeira, C, Basgoze, Z, Cupertino, RB, Bau, CHD, Bauer, J, Baumeister, S, Bernardoni, F, Bertolino, A, del Mar Bonnin, C, Brandeis, D, Brem, S, Bruggemann, J, Bulow, R, Bustillo, JR, Calderoni, S, Calvo, R, Canales-Rodriguez, EJ, Cannon, DM, Carmona, S, Carr, VJ, Catts, SV, Chenji, S, Chew, QH, Coghill, D, Connolly, CG, Conzelmann, A, Craven, AR, Crespo-Facorro, B, Cullen, K, Dahl, A, Dannlowski, U, Davey, CG, Deruelle, C, Diaz-Caneja, CM, Dohm, K, Ehrlich, S, Epstein, J, Erwin-Grabner, T, Eyler, LT, Fedor, J, Fitzgerald, J, Foran, W, Ford, JM, Fortea, L, Fuentes-Claramonte, P, Fullerton, J, Furlong, L, Gallagher, L, Gao, B, Gao, S, Goikolea, JM, Gotlib, I, Goya-Maldonado, R, Grabe, HJ, Green, M, Grevet, EH, Groenewold, NA, Grotegerd, D, Gruber, O, Haavik, J, Hahn, T, Harrison, BJ, Heindel, W, Henskens, F, Heslenfeld, DJ, Hilland, E, Hoekstra, PJ, Hohmann, S, Holz, N, Howells, FM, Ipser, JC, Jahanshad, N, Jakobi, B, Jansen, A, Janssen, J, Jonassen, R, Kaiser, A, Kaleda, V, Karantonis, J, King, JA, Kircher, T, Kochunov, P, Koopowitz, S-M, Landen, M, Landro, NI, Lawrie, S, Lebedeva, I, Luna, B, Lundervold, AJ, MacMaster, FP, Maglanoc, LA, Mathalon, DH, McDonald, C, McIntosh, A, Meinert, S, Michie, PT, Mitchell, P, Moreno-Alcazar, A, Mowry, B, Muratori, F, Nabulsi, L, Nenadic, I, Tuura, RO, Oosterlaan, J, Overs, B, Pantelis, C, Parellada, M, Pariente, JC, Pauli, P, Pergola, G, Piarulli, FM, Picon, F, Piras, F, Pomarol-Clotet, E, Pretus, C, Quide, Y, Radua, J, Ramos-Quiroga, JA, Rasser, PE, Reif, A, Retico, A, Roberts, G, Rossell, S, Rovaris, DL, Rubia, K, Sacchet, M, Salavert, J, Salvador, R, Sarro, S, Sawa, A, Schall, U, Scott, R, Selvaggi, P, Silk, T, Sim, K, Skoch, A, Spalletta, G, Spaniel, F, Stein, DJ, Steinstrater, O, Stolicyn, A, Takayanagi, Y, Tamm, L, Tavares, M, Teumer, A, Thiel, K, Thomopoulos, SI, Tomecek, D, Tomyshev, AS, Tordesillas-Gutierrez, D, Tosetti, M, Uhlmann, A, Van Rheenen, T, Vazquez-Bourgon, J, Vernooij, MW, Vieta, E, Vilarroya, O, Weickert, C, Weickert, T, Westlye, LT, Whalley, H, Willinger, D, Winter, A, Wittfeld, K, Yang, TT, Yoncheva, Y, Zijlmans, JL, Hoogman, M, Franke, B, van Rooij, D, Buitelaar, J, Ching, CRK, Andreassen, OA, Pozzi, E, Veltman, D, Schmaal, L, van Erp, TGM, Turner, J, Castellanos, FX, Pausova, Z, Thompson, P, Paus, T, Patel, Y, Shin, J, Abe, C, Agartz, I, Alloza, C, Alnaes, D, Ambrogi, S, Antonucci, LA, Arango, C, Arolt, V, Auzias, G, Ayesa-Arriola, R, Banaj, N, Banaschewski, T, Bandeira, C, Basgoze, Z, Cupertino, RB, Bau, CHD, Bauer, J, Baumeister, S, Bernardoni, F, Bertolino, A, del Mar Bonnin, C, Brandeis, D, Brem, S, Bruggemann, J, Bulow, R, Bustillo, JR, Calderoni, S, Calvo, R, Canales-Rodriguez, EJ, Cannon, DM, Carmona, S, Carr, VJ, Catts, SV, Chenji, S, Chew, QH, Coghill, D, Connolly, CG, Conzelmann, A, Craven, AR, Crespo-Facorro, B, Cullen, K, Dahl, A, Dannlowski, U, Davey, CG, Deruelle, C, Diaz-Caneja, CM, Dohm, K, Ehrlich, S, Epstein, J, Erwin-Grabner, T, Eyler, LT, Fedor, J, Fitzgerald, J, Foran, W, Ford, JM, Fortea, L, Fuentes-Claramonte, P, Fullerton, J, Furlong, L, Gallagher, L, Gao, B, Gao, S, Goikolea, JM, Gotlib, I, Goya-Maldonado, R, Grabe, HJ, Green, M, Grevet, EH, Groenewold, NA, Grotegerd, D, Gruber, O, Haavik, J, Hahn, T, Harrison, BJ, Heindel, W, Henskens, F, Heslenfeld, DJ, Hilland, E, Hoekstra, PJ, Hohmann, S, Holz, N, Howells, FM, Ipser, JC, Jahanshad, N, Jakobi, B, Jansen, A, Janssen, J, Jonassen, R, Kaiser, A, Kaleda, V, Karantonis, J, King, JA, Kircher, T, Kochunov, P, Koopowitz, S-M, Landen, M, Landro, NI, Lawrie, S, Lebedeva, I, Luna, B, Lundervold, AJ, MacMaster, FP, Maglanoc, LA, Mathalon, DH, McDonald, C, McIntosh, A, Meinert, S, Michie, PT, Mitchell, P, Moreno-Alcazar, A, Mowry, B, Muratori, F, Nabulsi, L, Nenadic, I, Tuura, RO, Oosterlaan, J, Overs, B, Pantelis, C, Parellada, M, Pariente, JC, Pauli, P, Pergola, G, Piarulli, FM, Picon, F, Piras, F, Pomarol-Clotet, E, Pretus, C, Quide, Y, Radua, J, Ramos-Quiroga, JA, Rasser, PE, Reif, A, Retico, A, Roberts, G, Rossell, S, Rovaris, DL, Rubia, K, Sacchet, M, Salavert, J, Salvador, R, Sarro, S, Sawa, A, Schall, U, Scott, R, Selvaggi, P, Silk, T, Sim, K, Skoch, A, Spalletta, G, Spaniel, F, Stein, DJ, Steinstrater, O, Stolicyn, A, Takayanagi, Y, Tamm, L, Tavares, M, Teumer, A, Thiel, K, Thomopoulos, SI, Tomecek, D, Tomyshev, AS, Tordesillas-Gutierrez, D, Tosetti, M, Uhlmann, A, Van Rheenen, T, Vazquez-Bourgon, J, Vernooij, MW, Vieta, E, Vilarroya, O, Weickert, C, Weickert, T, Westlye, LT, Whalley, H, Willinger, D, Winter, A, Wittfeld, K, Yang, TT, Yoncheva, Y, Zijlmans, JL, Hoogman, M, Franke, B, van Rooij, D, Buitelaar, J, Ching, CRK, Andreassen, OA, Pozzi, E, Veltman, D, Schmaal, L, van Erp, TGM, Turner, J, Castellanos, FX, Pausova, Z, Thompson, P, and Paus, T

Abstract

BACKGROUND: Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life. METHODS: Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed. RESULTS: Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth. CONCLUSIONS: Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from t

Published
2022

14. Virtual Histology of Cortical Thickness and Shared Neurobiology in 6 Psychiatric Disorders

Author

Patel, Y, Parker, N, Shin, J, Howard, D, French, L, Thomopoulos, SI, Pozzi, E, Abe, Y, Abe, C, Anticevic, A, Alda, M, Aleman, A, Alloza, C, Alonso-Lana, S, Ameis, SH, Anagnostou, E, McIntosh, AA, Arango, C, Arnold, PD, Asherson, P, Assogna, F, Auzias, G, Ayesa-Arriola, R, Bakker, G, Banaj, N, Banaschewski, T, Bandeira, CE, Baranov, A, Bargallo, N, Bau, CHD, Baumeister, S, Baune, BT, Bellgrove, MA, Benedetti, F, Bertolino, A, Boedhoe, PSW, Boks, M, Bollettini, I, del Mar Bonnin, C, Borgers, T, Borgwardt, S, Brandeis, D, Brennan, BP, Bruggemann, JM, Bulow, R, Busatto, GF, Calderoni, S, Calhoun, VD, Calvo, R, Canales-Rodriguez, EJ, Cannon, DM, Carr, VJ, Cascella, N, Cercignani, M, Chaim-Avancini, TM, Christakou, A, Coghill, D, Conzelmann, A, Crespo-Facorro, B, Cubillo, AI, Cullen, KR, Cupertino, RB, Daly, E, Dannlowski, U, Davey, CG, Denys, D, Deruelle, C, Di Giorgio, A, Dickie, EW, Dima, D, Dohm, K, Ehrlich, S, Ely, BA, Erwin-Grabner, T, Ethofer, T, Fair, DA, Fallgatter, AJ, Faraone, SV, Fatjo-Vilas, M, Fedor, JM, Fitzgerald, KD, Ford, JM, Frodl, T, Fu, CHY, Fullerton, JM, Gabel, MC, Glahn, DC, Roberts, G, Gogberashvili, T, Goikolea, JM, Gotlib, IH, Goya-Maldonado, R, Grabe, HJ, Green, MJ, Grevet, EH, Groenewold, NA, Grotegerd, D, Gruber, O, Gruner, P, Guerrero-Pedraza, A, Gur, RE, Gur, RC, Haar, S, Haarman, BCM, Haavik, J, Hahn, T, Hajek, T, Harrison, BJ, Harrison, NA, Hartman, CA, Whalley, HC, Heslenfeld, DJ, Hibar, DP, Hilland, E, Hirano, Y, Ho, TC, Hoekstra, PJ, Hoekstra, L, Hohmann, S, Hong, LE, Hoschl, C, Hovik, MF, Howells, FM, Nenadic, I, Jalbrzikowski, M, James, AC, Janssen, J, Jaspers-Fayer, F, Xu, J, Jonassen, R, Karkashadze, G, King, JA, Kircher, T, Kirschner, M, Koch, K, Kochunov, P, Kohls, G, Konrad, K, Kramer, B, Krug, A, Kuntsi, J, Kwon, JS, Landen, M, Landro, NI, Lazaro, L, Lebedeva, IS, Leehr, EJ, Lera-Miguel, S, Lesch, K-P, Lochner, C, Louza, MR, Luna, B, Lundervold, AJ, MacMaster, FP, Maglanoc, LA, Malpas, CB, Portella, MJ, Marsh, R, Martyn, FM, Mataix-Cols, D, Mathalon, DH, McCarthy, H, McDonald, C, McPhilemy, G, Meinert, S, Menchon, JM, Minuzzi, L, Mitchell, PB, Moreno, C, Morgado, P, Muratori, F, Murphy, CM, Murphy, D, Mwangi, B, Nabulsi, L, Nakagawa, A, Nakamae, T, Namazova, L, Narayanaswamy, J, Jahanshad, N, Nguyen, DD, Nicolau, R, O'Gorman Tuura, RL, O'Hearn, K, Oosterlaan, J, Opel, N, Ophoff, RA, Oranje, B, Garcia de la Foz, VO, Overs, BJ, Paloyelis, Y, Pantelis, C, Parellada, M, Pauli, P, Pico-Perez, M, Picon, FA, Piras, F, Plessen, KJ, Pomarol-Clotet, E, Preda, A, Puig, O, Quide, Y, Radua, J, Ramos-Quiroga, JA, Rasser, PE, Rauer, L, Reddy, J, Redlich, R, Reif, A, Reneman, L, Repple, J, Retico, A, Richarte, V, Richter, A, Rosa, PGP, Rubia, KK, Hashimoto, R, Sacchet, MD, Salvador, R, Santonja, J, Sarink, K, Sarro, S, Satterthwaite, TD, Sawa, A, Schall, U, Schofield, PR, Schrantee, A, Seitz, J, Serpa, MH, Setien-Suero, E, Shaw, P, Shook, D, Silk, TJ, Sim, K, Simon, S, Simpson, HB, Singh, A, Skoch, A, Skokauskas, N, Soares, JC, Soreni, N, Soriano-Mas, C, Spalletta, G, Spaniel, F, Lawrie, SM, Stern, ER, Stewart, SE, Takayanagi, Y, Temmingh, HS, Tolin, DF, Tomecek, D, Tordesillas-Gutierrez, D, Tosetti, M, Uhlmann, A, van Amelsvoort, T, van der Wee, NJA, van der Werff, SJA, van Haren, NEM, van Wingen, GA, Vance, A, Vazquez-Bourgon, J, Vecchio, D, Venkatasubramanian, G, Vieta, E, Vilarroya, O, Vives-Gilabert, Y, Voineskos, AN, Volzke, H, von Polier, GG, Walton, E, Weickert, TW, Weickert, CS, Weideman, AS, Wittfeld, K, Wolf, DH, Wu, M-J, Yang, TT, Yang, K, Yoncheva, Y, Yun, J-Y, Cheng, Y, Zanetti, MV, Ziegler, GC, Franke, B, Hoogman, M, Buitelaar, JK, van Rooij, D, Andreassen, OA, Ching, CRK, Veltman, DJ, Schmaal, L, Stein, DJ, van den Heuvel, OA, Turner, JA, van Erp, TGM, Pausova, Z, Thompson, PM, Paus, T, Patel, Y, Parker, N, Shin, J, Howard, D, French, L, Thomopoulos, SI, Pozzi, E, Abe, Y, Abe, C, Anticevic, A, Alda, M, Aleman, A, Alloza, C, Alonso-Lana, S, Ameis, SH, Anagnostou, E, McIntosh, AA, Arango, C, Arnold, PD, Asherson, P, Assogna, F, Auzias, G, Ayesa-Arriola, R, Bakker, G, Banaj, N, Banaschewski, T, Bandeira, CE, Baranov, A, Bargallo, N, Bau, CHD, Baumeister, S, Baune, BT, Bellgrove, MA, Benedetti, F, Bertolino, A, Boedhoe, PSW, Boks, M, Bollettini, I, del Mar Bonnin, C, Borgers, T, Borgwardt, S, Brandeis, D, Brennan, BP, Bruggemann, JM, Bulow, R, Busatto, GF, Calderoni, S, Calhoun, VD, Calvo, R, Canales-Rodriguez, EJ, Cannon, DM, Carr, VJ, Cascella, N, Cercignani, M, Chaim-Avancini, TM, Christakou, A, Coghill, D, Conzelmann, A, Crespo-Facorro, B, Cubillo, AI, Cullen, KR, Cupertino, RB, Daly, E, Dannlowski, U, Davey, CG, Denys, D, Deruelle, C, Di Giorgio, A, Dickie, EW, Dima, D, Dohm, K, Ehrlich, S, Ely, BA, Erwin-Grabner, T, Ethofer, T, Fair, DA, Fallgatter, AJ, Faraone, SV, Fatjo-Vilas, M, Fedor, JM, Fitzgerald, KD, Ford, JM, Frodl, T, Fu, CHY, Fullerton, JM, Gabel, MC, Glahn, DC, Roberts, G, Gogberashvili, T, Goikolea, JM, Gotlib, IH, Goya-Maldonado, R, Grabe, HJ, Green, MJ, Grevet, EH, Groenewold, NA, Grotegerd, D, Gruber, O, Gruner, P, Guerrero-Pedraza, A, Gur, RE, Gur, RC, Haar, S, Haarman, BCM, Haavik, J, Hahn, T, Hajek, T, Harrison, BJ, Harrison, NA, Hartman, CA, Whalley, HC, Heslenfeld, DJ, Hibar, DP, Hilland, E, Hirano, Y, Ho, TC, Hoekstra, PJ, Hoekstra, L, Hohmann, S, Hong, LE, Hoschl, C, Hovik, MF, Howells, FM, Nenadic, I, Jalbrzikowski, M, James, AC, Janssen, J, Jaspers-Fayer, F, Xu, J, Jonassen, R, Karkashadze, G, King, JA, Kircher, T, Kirschner, M, Koch, K, Kochunov, P, Kohls, G, Konrad, K, Kramer, B, Krug, A, Kuntsi, J, Kwon, JS, Landen, M, Landro, NI, Lazaro, L, Lebedeva, IS, Leehr, EJ, Lera-Miguel, S, Lesch, K-P, Lochner, C, Louza, MR, Luna, B, Lundervold, AJ, MacMaster, FP, Maglanoc, LA, Malpas, CB, Portella, MJ, Marsh, R, Martyn, FM, Mataix-Cols, D, Mathalon, DH, McCarthy, H, McDonald, C, McPhilemy, G, Meinert, S, Menchon, JM, Minuzzi, L, Mitchell, PB, Moreno, C, Morgado, P, Muratori, F, Murphy, CM, Murphy, D, Mwangi, B, Nabulsi, L, Nakagawa, A, Nakamae, T, Namazova, L, Narayanaswamy, J, Jahanshad, N, Nguyen, DD, Nicolau, R, O'Gorman Tuura, RL, O'Hearn, K, Oosterlaan, J, Opel, N, Ophoff, RA, Oranje, B, Garcia de la Foz, VO, Overs, BJ, Paloyelis, Y, Pantelis, C, Parellada, M, Pauli, P, Pico-Perez, M, Picon, FA, Piras, F, Plessen, KJ, Pomarol-Clotet, E, Preda, A, Puig, O, Quide, Y, Radua, J, Ramos-Quiroga, JA, Rasser, PE, Rauer, L, Reddy, J, Redlich, R, Reif, A, Reneman, L, Repple, J, Retico, A, Richarte, V, Richter, A, Rosa, PGP, Rubia, KK, Hashimoto, R, Sacchet, MD, Salvador, R, Santonja, J, Sarink, K, Sarro, S, Satterthwaite, TD, Sawa, A, Schall, U, Schofield, PR, Schrantee, A, Seitz, J, Serpa, MH, Setien-Suero, E, Shaw, P, Shook, D, Silk, TJ, Sim, K, Simon, S, Simpson, HB, Singh, A, Skoch, A, Skokauskas, N, Soares, JC, Soreni, N, Soriano-Mas, C, Spalletta, G, Spaniel, F, Lawrie, SM, Stern, ER, Stewart, SE, Takayanagi, Y, Temmingh, HS, Tolin, DF, Tomecek, D, Tordesillas-Gutierrez, D, Tosetti, M, Uhlmann, A, van Amelsvoort, T, van der Wee, NJA, van der Werff, SJA, van Haren, NEM, van Wingen, GA, Vance, A, Vazquez-Bourgon, J, Vecchio, D, Venkatasubramanian, G, Vieta, E, Vilarroya, O, Vives-Gilabert, Y, Voineskos, AN, Volzke, H, von Polier, GG, Walton, E, Weickert, TW, Weickert, CS, Weideman, AS, Wittfeld, K, Wolf, DH, Wu, M-J, Yang, TT, Yang, K, Yoncheva, Y, Yun, J-Y, Cheng, Y, Zanetti, MV, Ziegler, GC, Franke, B, Hoogman, M, Buitelaar, JK, van Rooij, D, Andreassen, OA, Ching, CRK, Veltman, DJ, Schmaal, L, Stein, DJ, van den Heuvel, OA, Turner, JA, van Erp, TGM, Pausova, Z, Thompson, PM, and Paus, T

Abstract

IMPORTANCE: Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood. OBJECTIVE: To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia. DESIGN, SETTING, AND PARTICIPANTS: Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244. MAIN OUTCOMES AND MEASURES: Interregional profiles of group difference in cortical thickness between cases and controls. RESULTS: A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene

Published
2021

20. Virtual Histology of Cortical Thickness and Shared Neurobiology in 6 Psychiatric Disorders

Author

Committee, Writing, Disorder, Autism Spectrum, French, Leon, Grevet, Eugenio H, Groenewold, Nynke A, Grotegerd, Dominik, Gruber, Oliver, Gruner, Patricia, Guerrero-Pedraza, Amalia, Gur, Raquel E, Gur, Ruben C, Haar, Shlomi, Haarman, Bartholomeus C M, Thomopoulos, Sophia I, Haavik, Jan, Hahn, Tim, Hajek, Tomas, Harrison, Benjamin J, Harrison, Neil A, Hartman, Catharina A, Whalley, Heather C, Heslenfeld, Dirk J, Hibar, Derrek P, Hilland, Eva, Pozzi, Elena, Hirano, Yoshiyuki, Ho, Tiffany C, Hoekstra, Pieter J, Hoekstra, Liesbeth, Hohmann, Sarah, Hong, L. E., Höschl, Cyril, Høvik, Marie F, Howells, Fleur M, Nenadic, Igor, Abe, Yoshinari, Jalbrzikowski, Maria, James, Anthony C, Janssen, Joost, Jaspers-Fayer, Fern, Xu, Jian, Jonassen, Rune, Karkashadze, Georgii, King, Joseph A, Kircher, Tilo, Kirschner, Matthias, Abé, Christoph, Koch, Kathrin, Kochunov, Peter, Kohls, Gregor, Konrad, Kerstin, Krämer, Bernd, Krug, Axel, Kuntsi, Jonna, Kwon, Jun Soo, Landén, Mikael, Landrø, Nils I, Anticevic, Alan, Lazaro, Luisa, Lebedeva, Irina S, Leehr, Elisabeth J, Lera-Miguel, Sara, Lesch, Klaus-Peter, Lochner, Christine, Louza, Mario R, Luna, Beatriz, Lundervold, Astri J, MacMaster, Frank P, Alda, Martin, Maglanoc, Luigi A, Malpas, Charles B, Portella, Maria J, Marsh, Rachel, Martyn, Fiona M, Mataix-Cols, David, Mathalon, Daniel H, McCarthy, Hazel, McDonald, Colm, McPhilemy, Genevieve, Aleman, Andre, Meinert, Susanne, Menchón, José M, Minuzzi, Luciano, Mitchell, Philip B, Moreno, Carmen, Morgado, Pedro, Muratori, Filippo, Murphy, Clodagh M, Murphy, Declan, Mwangi, Benson, Alloza, Clara, Nabulsi, Leila, Nakagawa, Akiko, Nakamae, Takashi, Namazova, Leyla, Narayanaswamy, Janardhanan, Jahanshad, Neda, Nguyen, Danai D, Nicolau, Rosa, O'Gorman Tuura, Ruth L, O'Hearn, Kirsten, Alonso-Lana, Silvia, Oosterlaan, Jaap, Opel, Nils, Ophoff, Roel A, Oranje, Bob, García de la Foz, Victor Ortiz, Overs, Bronwyn J, Paloyelis, Yannis, Pantelis, Christos, Parellada, Mara, Pauli, Paul, Disorder, Bipolar, Ameis, Stephanie H, Picó-Pérez, Maria, Picon, Felipe A, Piras, Fabrizio, Piras, Federica, Plessen, Kerstin J, Pomarol-Clotet, Edith, Preda, Adrian, Puig, Olga, Quidé, Yann, Radua, Joaquim, Anagnostou, Evdokia, Ramos-Quiroga, J Antoni, Rasser, Paul E, Rauer, Lisa, Reddy, Janardhan, Redlich, Ronny, Reif, Andreas, Reneman, Liesbeth, Repple, Jonathan, Retico, Alessandra, Richarte, Vanesa, McIntosh, Andrew A, Richter, Anja, Rosa, Pedro G P, Rubia, Katya K, Hashimoto, Ryota, Sacchet, Matthew D, Salvador, Raymond, Santonja, Javier, Sarink, Kelvin, Sarró, Salvador, Satterthwaite, Theodore D, Arango, Celso, Sawa, Akira, Schall, Ulrich, Schofield, Peter R, Schrantee, Anouk, Seitz, Jochen, Serpa, Mauricio H, Setién-Suero, Esther, Shaw, Philip, Shook, Devon, Silk, Tim J, Arnold, Paul D, Sim, Kang, Simon, Schmitt, Simpson, Helen Blair, Singh, Aditya, Skoch, Antonin, Skokauskas, Norbert, Soares, Jair C, Soreni, Noam, Soriano-Mas, Carles, Spalletta, Gianfranco, Asherson, Philip, Spaniel, Filip, Lawrie, Stephen M, Stern, Emily R, Stewart, S Evelyn, Takayanagi, Yoichiro, Temmingh, Henk S, Tolin, David F, Tomecek, David, Tordesillas-Gutiérrez, Diana, Tosetti, Michela, Assogna, Francesca, Uhlmann, Anne, van Amelsvoort, Therese, van der Wee, Nic J A, van der Werff, Steven J A, van Haren, Neeltje E M, van Wingen, Guido A, Vance, Alasdair, Vázquez-Bourgon, Javier, Vecchio, Daniela, Venkatasubramanian, Ganesan, Auzias, Guillaume, Vieta, Eduard, Vilarroya, Oscar, Vives-Gilabert, Yolanda, Voineskos, Aristotle N, Völzke, Henry, von Polier, Georg G, Walton, Esther, Weickert, Thomas W, Weickert, Cynthia Shannon, Weideman, Andrea S, Ayesa-Arriola, Rosa, Wittfeld, Katharina, Wolf, Daniel H, Wu, Mon-Ju, Yang, T. T., Yang, Sikun, Yoncheva, Yuliya, Yun, Je-Yeon, Cheng, Yuqi, Zanetti, Marcus V, Ziegler, Georg C, Bakker, Geor, Franke, Barbara, Hoogman, Martine, Buitelaar, Jan K, van Rooij, Daan, Andreassen, Ole A, Ching, Christopher R K, Veltman, Dick J, Schmaal, Lianne, Stein, Dan J, van den Heuvel, Odile A, Disorder, Major Depressive, Banaj, Nerisa, Turner, Jessica A, van Erp, Theo G M, Pausova, Zdenka, Thompson, Paul M, Paus, Tomáš, Attention-Deficit/Hyperactivity Disorder, Banaschewski, Tobias, Bandeira, Cibele E, Baranov, Alexandr, Bargalló, Núria, Bau, Claiton H D, Baumeister, Sarah, Baune, Bernhard T, Bellgrove, Mark A, Benedetti, Francesco, Disorder, Obsessive-Compulsive, Bertolino, Alessandro, Boedhoe, Premika S W, Boks, Marco, Bollettini, Irene, Del Mar Bonnin, Caterina, Borgers, Tiana, Borgwardt, Stefan, Brandeis, Daniel, Brennan, Brian P, Bruggemann, Jason M, Groups, Schizophrenia ENIGMA Working, Bülow, Robin, Busatto, Geraldo F, Calderoni, Sara, Calhoun, Vince D, Calvo, Rosa, Canales-Rodríguez, Erick J, Cannon, Dara M, Carr, Vaughan J, Cascella, Nicola, Cercignani, Mara, Patel, Yash, Chaim-Avancini, Tiffany M, Christakou, Anastasia, Coghill, David, Conzelmann, Annette, Crespo-Facorro, Benedicto, Cubillo, Ana I, Cullen, Kathryn R, Cupertino, Renata B, Daly, Eileen, Dannlowski, Udo, Parker, Nadine, Davey, Christopher G, Denys, Damiaan, Deruelle, Christine, Di Giorgio, Annabella, Dickie, Erin W, Dima, Danai, Dohm, Katharina, Ehrlich, Stefan, Ely, Benjamin A, Erwin-Grabner, Tracy, Shin, Jean, Ethofer, Thomas, Fair, Damien A, Fallgatter, Andreas, Faraone, Stephen V, Fatjó-Vilas, Mar, Fedor, Jennifer M, Fitzgerald, Kate D, Ford, Judith M, Frodl, Thomas, Fu, Cynthia H Y, Howard, Derek, Fullerton, Janice M, Gabel, Matt C, Glahn, David C, Roberts, Gloria, Gogberashvili, Tinatin, Goikolea, Jose M, Gotlib, Ian H, Goya-Maldonado, Roberto, Grabe, Hans, Green, Melissa J, Patel, Y., Parker, N., Shin, J., Howard, D., French, L., Thomopoulos, S. I., Pozzi, E., Abe, Y., Abe, C., Anticevic, A., Alda, M., Aleman, A., Alloza, C., Alonso-Lana, S., Ameis, S. H., Anagnostou, E., Mcintosh, A. A., Arango, C., Arnold, P. D., Asherson, P., Assogna, F., Auzias, G., Ayesa-Arriola, R., Bakker, G., Banaj, N., Banaschewski, T., Bandeira, C. E., Baranov, A., Bargallo, N., Bau, C. H. D., Baumeister, S., Baune, B. T., Bellgrove, M. A., Benedetti, F., Bertolino, A., Boedhoe, P. S. W., Boks, M., Bollettini, I., Del Mar Bonnin, C., Borgers, T., Borgwardt, S., Brandeis, D., Brennan, B. P., Bruggemann, J. M., Bulow, R., Busatto, G. F., Calderoni, S., Calhoun, V. D., Calvo, R., Canales-Rodriguez, E. J., Cannon, D. M., Carr, V. J., Cascella, N., Cercignani, M., Chaim-Avancini, T. M., Christakou, A., Coghill, D., Conzelmann, A., Crespo-Facorro, B., Cubillo, A. I., Cullen, K. R., Cupertino, R. B., Daly, E., Dannlowski, U., Davey, C. G., Denys, D., Deruelle, C., Di Giorgio, A., Dickie, E. W., Dima, D., Dohm, K., Ehrlich, S., Ely, B. A., Erwin-Grabner, T., Ethofer, T., Fair, D. A., Fallgatter, A. J., Faraone, S. V., Fatjo-Vilas, M., Fedor, J. M., Fitzgerald, K. D., Ford, J. M., Frodl, T., Fu, C. H. Y., Fullerton, J. M., Gabel, M. C., Glahn, D. C., Roberts, G., Gogberashvili, T., Goikolea, J. M., Gotlib, I. H., Goya-Maldonado, R., Grabe, H. J., Green, M. J., Grevet, E. H., Groenewold, N. A., Grotegerd, D., Gruber, O., Gruner, P., Guerrero-Pedraza, A., Gur, R. E., Gur, R. C., Haar, S., Haarman, B. C. M., Haavik, J., Hahn, T., Hajek, T., Harrison, B. J., Harrison, N. A., Hartman, C. A., Whalley, H. C., Heslenfeld, D. J., Hibar, D. P., Hilland, E., Hirano, Y., Ho, T. C., Hoekstra, P. J., Hoekstra, L., Hohmann, S., Hong, L. E., Hoschl, C., Hovik, M. F., Howells, F. M., Nenadic, I., Jalbrzikowski, M., James, A. C., Janssen, J., Jaspers-Fayer, F., Xu, J., Jonassen, R., Karkashadze, G., King, J. A., Kircher, T., Kirschner, M., Koch, K., Kochunov, P., Kohls, G., Konrad, K., Kramer, B., Krug, A., Kuntsi, J., Kwon, J. S., Landen, M., Landro, N. I., Lazaro, L., Lebedeva, I. S., Leehr, E. J., Lera-Miguel, S., Lesch, K. -P., Lochner, C., Louza, M. R., Luna, B., Lundervold, A. J., Macmaster, F. P., Maglanoc, L. A., Malpas, C. B., Portella, M. J., Marsh, R., Martyn, F. M., Mataix-Cols, D., Mathalon, D. H., Mccarthy, H., Mcdonald, C., Mcphilemy, G., Meinert, S., Menchon, J. M., Minuzzi, L., Mitchell, P. B., Moreno, C., Morgado, P., Muratori, F., Murphy, C. M., Murphy, D., Mwangi, B., Nabulsi, L., Nakagawa, A., Nakamae, T., Namazova, L., Narayanaswamy, J., Jahanshad, N., Nguyen, D. D., Nicolau, R., O'Gorman Tuura, R. L., O'Hearn, K., Oosterlaan, J., Opel, N., Ophoff, R. A., Oranje, B., Garcia De La Foz, V. O., Overs, B. J., Paloyelis, Y., Pantelis, C., Parellada, M., Pauli, P., Pico-Perez, M., Picon, F. A., Piras, F., Plessen, K. J., Pomarol-Clotet, E., Preda, A., Puig, O., Quide, Y., Radua, J., Ramos-Quiroga, J. A., Rasser, P. E., Rauer, L., Reddy, J., Redlich, R., Reif, A., Reneman, L., Repple, J., Retico, A., Richarte, V., Richter, A., Rosa, P. G. P., Rubia, K. K., Hashimoto, R., Sacchet, M. D., Salvador, R., Santonja, J., Sarink, K., Sarro, S., Satterthwaite, T. D., Sawa, A., Schall, U., Schofield, P. R., Schrantee, A., Seitz, J., Serpa, M. H., Setien-Suero, E., Shaw, P., Shook, D., Silk, T. J., Sim, K., Simon, S., Simpson, H. B., Singh, A., Skoch, A., Skokauskas, N., Soares, J. C., Soreni, N., Soriano-Mas, C., Spalletta, G., Spaniel, F., Lawrie, S. M., Stern, E. R., Stewart, S. E., Takayanagi, Y., Temmingh, H. S., Tolin, D. F., Tomecek, D., Tordesillas-Gutierrez, D., Tosetti, M., Uhlmann, A., Van Amelsvoort, T., Van Der Wee, N. J. A., Van Der Werff, S. J. A., Van Haren, N. E. M., Van Wingen, G. A., Vance, A., Vazquez-Bourgon, J., Vecchio, D., Venkatasubramanian, G., Vieta, E., Vilarroya, O., Vives-Gilabert, Y., Voineskos, A. N., Volzke, H., Von Polier, G. G., Walton, E., Weickert, T. W., Weickert, C. S., Weideman, A. S., Wittfeld, K., Wolf, D. H., Wu, M. -J., Yang, T. T., Yang, K., Yoncheva, Y., Yun, J. -Y., Cheng, Y., Zanetti, M. V., Ziegler, G. C., Franke, B., Hoogman, M., Buitelaar, J. K., Van Rooij, D., Andreassen, O. A., Ching, C. R. K., Veltman, D. J., Schmaal, L., Stein, D. J., Van Den Heuvel, O. A., Turner, J. A., Van Erp, T. G. M., Pausova, Z., Thompson, P. M., Paus, T., Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Pediatric surgery, Radiology and nuclear medicine, Anatomy and neurosciences, Psychiatry, Amsterdam Neuroscience - Brain Imaging, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Amsterdam Neuroscience - Neurodegeneration, Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, MUMC+: MA Med Staf Spec Psychiatrie (9), Adult Psychiatry, ANS - Compulsivity, Impulsivity & Attention, General Paediatrics, ARD - Amsterdam Reproduction and Development, Radiology and Nuclear Medicine, APH - Personalized Medicine, ANS - Brain Imaging, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, University of Zurich, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Clinical Neuropsychology, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Child and Adolescent Psychiatry / Psychology, IBBA, and Cognitive Psychology

Subjects
Male, Obsessive-Compulsive Disorder, Bipolar Disorder, Autism Spectrum Disorder, Autism, [SDV]Life Sciences [q-bio], Gene Expression, cytology [Cerebral Cortex], Cohort Studies, Fetal Development, physiology [Gene Expression], 2738 Psychiatry and Mental Health, 0302 clinical medicine, diagnostic imaging [Cerebral Cortex], SCHIZOPHRENIA, BRAIN, Child, Obsessive-compulsive disorder (OCD), Original Investigation, Aged, 80 and over, Cerebral Cortex, 0303 health sciences, pathology [Depressive Disorder, Major], Principal Component Analysis, Adolescent psychiatry, 10058 Department of Child and Adolescent Psychiatry, Middle Aged, diagnostic imaging [Obsessive-Compulsive Disorder], REGIONS, Magnetic Resonance Imaging, 3. Good health, FALSE DISCOVERY RATE, Psychiatry and Mental health, Autism spectrum disorder, Schizophrenia, growth & development [Cerebral Cortex], Child, Preschool, Major depressive disorder, diagnostic imaging [Schizophrenia], Esquizofrènia, Female, Psiquiatria infantil, Psiquiatria de l'adolescència, diagnostic imaging [Autism Spectrum Disorder], Adult, medicine.medical_specialty, Adolescent, Human Development, 610 Medicine & health, diagnostic imaging [Bipolar Disorder], pathology [Autism Spectrum Disorder], diagnostic imaging [Depressive Disorder, Major], 03 medical and health sciences, Young Adult, All institutes and research themes of the Radboud University Medical Center, Neuroimaging, SDG 3 - Good Health and Well-being, CEREBRAL-CORTEX, Child psychiatry, medicine, Attention deficit hyperactivity disorder, Humans, Bipolar disorder, ddc:610, Psychiatry, pathology [Schizophrenia], 030304 developmental biology, Aged, Depressive Disorder, Major, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, DENDRITE, Computational Biology, Correction, pathology [Attention Deficit Disorder with Hyperactivity], physiology [Fetal Development], medicine.disease, PATHOLOGY, pathology [Bipolar Disorder], pathology [Obsessive-Compulsive Disorder], 10036 Medical Clinic, Attention Deficit Disorder with Hyperactivity, 10054 Clinic for Psychiatry, Psychotherapy, and Psychosomatics, Case-Control Studies, DENSITY, ORIGINS, HIPPOCAMPUS, diagnostic imaging [Attention Deficit Disorder with Hyperactivity], pathology [Cerebral Cortex], Autisme, business, Neuroscience, 030217 neurology & neurosurgery, physiology [Human Development]
Abstract

[Importance] Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood., [Objective] To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia., [Design, Setting, and Participants] Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244., [Main Outcomes and Measures] Interregional profiles of group difference in cortical thickness between cases and controls., [Results] A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene-expression profiles of the 3 cell types explain between 25% and 54% of variance in interregional profiles of group differences in cortical thickness. Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression (explaining 56% of interregional variation). Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders., [Conclusions and Relevance] In this study, shared neurobiologic processes were associated with differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders.

Published
2021
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21. Longitudinal trajectories in negative symptoms and changes in brain cortical thickness: 10-year follow-up study.

Author

Canal-Rivero M, Ruiz-Veguilla M, Ortiz-García de la Foz V, López-Díaz A, Garrido-Torres N, Ayesa-Arriola R, Vazquez-Bourgon J, Mayoral-van Son J, Brambilla P, Kircher T, Romero-García R, and Crespo-Facorro B

Subjects
Humans, Follow-Up Studies, Longitudinal Studies, Frontal Lobe, Magnetic Resonance Imaging, Brain Cortical Thickness, Psychotic Disorders diagnostic imaging, Psychotic Disorders complications
Abstract

Background: Understanding the evolution of negative symptoms in first-episode psychosis (FEP) requires long-term longitudinal study designs that capture the progression of this condition and the associated brain changes., Aims: To explore the factors underlying negative symptoms and their association with long-term abnormal brain trajectories., Method: We followed up 357 people with FEP over a 10-year period. Factor analyses were conducted to explore negative symptom dimensionality. Latent growth mixture modelling (LGMM) was used to identify the latent classes. Analysis of variance (ANOVA) was conducted to investigate developmental trajectories of cortical thickness. Finally, the resulting ANOVA maps were correlated with a wide set of regional molecular profiles derived from public databases., Results: Three trajectories (stable, decreasing and increasing) were found in each of the three factors (expressivity, experiential and attention) identified by the factor analyses. Patients with an increasing trajectory in the expressivity factor showed cortical thinning in caudal middle frontal, pars triangularis, rostral middle frontal and superior frontal regions from the third to the tenth year after the onset of the psychotic disorder. The F -statistic map of cortical thickness expressivity differences was associated with a receptor density map derived from positron emission tomography data., Conclusions: Stable and decreasing were the most common trajectories. Additionally, cortical thickness abnormalities found at relatively late stages of FEP onset could be exploited as a biomarker of poor symptom outcome in the expressivity dimension. Finally, the brain areas with less density of receptors spatially overlap areas that discriminate the trajectories of the expressivity dimension.

Published
2023
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22. The psychosis metabolic risk calculator (PsyMetRiC) for young people with psychosis: International external validation and site-specific recalibration in two independent European samples.

Author

Perry BI, Vandenberghe F, Garrido-Torres N, Osimo EF, Piras M, Vazquez-Bourgon J, Upthegrove R, Grosu C, De La Foz VO, Jones PB, Laaboub N, Ruiz-Veguilla M, Stochl J, Dubath C, Canal-Rivero M, Mallikarjun P, Delacrétaz A, Ansermot N, Fernandez-Egea E, Crettol S, Gamma F, Plessen KJ, Conus P, Khandaker GM, Murray GK, Eap CB, and Crespo-Facorro B

Abstract

Background: Cardiometabolic dysfunction is common in young people with psychosis. Recently, the Psychosis Metabolic Risk Calculator (PsyMetRiC) was developed and externally validated in the UK, predicting up-to six-year risk of metabolic syndrome (MetS) from routinely collected data. The full-model includes age, sex, ethnicity, body-mass index, smoking status, prescription of metabolically-active antipsychotic medication, high-density lipoprotein, and triglyceride concentrations; the partial-model excludes biochemical predictors., Methods: To move toward a future internationally-useful tool, we externally validated PsyMetRiC in two independent European samples. We used data from the PsyMetab (Lausanne, Switzerland) and PAFIP (Cantabria, Spain) cohorts, including participants aged 16-35y without MetS at baseline who had 1-6y follow-up. Predictive performance was assessed primarily via discrimination (C-statistic), calibration (calibration plots), and decision curve analysis. Site-specific recalibration was considered., Findings: We included 1024 participants (PsyMetab n= 558, male=62%, outcome prevalence=19%, mean follow-up=2.48y; PAFIP n =466, male=65%, outcome prevalence=14%, mean follow-up=2.59y). Discrimination was better in the full- compared with partial-model (PsyMetab=full-model C=0.73, 95% C.I., 0.68-0.79, partial-model C=0.68, 95% C.I., 0.62-0.74; PAFIP=full-model C=0.72, 95% C.I., 0.66-0.78; partial-model C=0.66, 95% C.I., 0.60-0.71). As expected, calibration plots revealed varying degrees of miscalibration, which recovered following site-specific recalibration. PsyMetRiC showed net benefit in both new cohorts, more so after recalibration., Interpretation: The study provides evidence of PsyMetRiC's generalizability in Western Europe, although further local and international validation studies are required. In future, PsyMetRiC could help clinicians internationally to identify young people with psychosis who are at higher cardiometabolic risk, so interventions can be directed effectively to reduce long-term morbidity and mortality., Funding: NIHR Cambridge Biomedical Research Centre (BRC-1215-20014); The Wellcome Trust (201486/Z/16/Z); Swiss National Research Foundation (320030-120686, 324730- 144064, and 320030-173211); The Carlos III Health Institute (CM20/00015, FIS00/3095, PI020499, PI050427, and PI060507); IDIVAL (INT/A21/10 and INT/A20/04); The Andalusian Regional Government (A1-0055-2020 and A1-0005-2021); SENY Fundacion Research (2005-0308007); Fundacion Marques de Valdecilla (A/02/07, API07/011); Ministry of Economy and Competitiveness and the European Fund for Regional Development (SAF2016-76046-R and SAF2013-46292-R).For the Spanish and French translation of the abstract see Supplementary Materials section., Competing Interests: RU has in the past 3 years received honoraria for speaking events from Oktuska, Synovion and Vyalife; has participated as a Chair TSC for an NIHR-funded clinical trial on antipsychotic medication for treatment resistant depression, and as an Expert Member for an NIHR-funded clinical trial on psychological therapies for common mental disorders; is honorary general secretary for the British Association of Psychopharmacology and a Deputy Editor for British Journal of Psychiatry. PBJ is Chair of the MQ Mental Health Sciences Council and has participated in an advisory board for MSD on an unrelated mental health topic. FV received in the past 3 years honoraria for conferences or teaching CME courses from Forum für MedizinischeFortbildung and Sysmex Suisse AG. NA received in the past 3 years honoraria for a conference from Sysmex Suisse AG. SC received in the past 3 years honoraria for teaching CME courses from Forum pour la formation médicale, Barr Switzerland and for consultancy from the Swiss Health Observatory (Obsan) of the Swiss Federal Office of Public Health. CBE received in the past 3 years honoraria for conferences or teaching CME courses from Janssen-Cilag, Lundbeck, Otsuka, Sandoz, Servier, Sunovion, Sysmex Suisse AG, Takeda, Vifor-Pharma and Zeller. All other authors declare no potential conflicts of interest., (© 2022 The Author(s).)

Published
2022
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23. A network analysis approach to functioning problems in first psychotic episodes and their relationship with duration of untreated illness: Findings from the PAFIP cohort.

Author

Izquierdo A, Cabello M, de la Torre-Luque A, Ayesa-Arriola R, Setien-Suero E, Mayoral-van-Son J, Vazquez-Bourgon J, Ayuso-Mateos JL, and Crespo-Facorro B

Subjects
Humans, Time Factors, Psychotic Disorders epidemiology, Psychotic Disorders therapy
Abstract

Background: The domains of functioning affected by first episode of psychosis (FEP) could be analysed as forming a network of interacting or even reinforcing elements. The reasons why longer duration of untreated psychosis (DUP) might be related to higher disability are not still clear. The aim of the present study is to evaluate how different areas of functioning are inter-related according to the length of DUP in patients with FEP, with a particular focus on studying the relative influence of each other according to lengthy delays in initial treatment., Method: 441 participants in an epidemiological and intervention program of first episode psychosis (PAFIP) were included in our study. Functioning problems at baseline were assessed with the WHO Disability Assessment Schedule (DAS). Three networks of functioning domains have been estimated according to the length of DUP., Results: All the DAS items took part in the different networks. We have not found differences across the edge weights in the short, medium and long DUP groups. The domains "social withdrawal", "participation in the household activities", "general interest and information", and "low level of activity" seem to act as bridge items with other areas of functioning in people with longer DUP., Conclusions: Our results could have clinical implications for patients with longer DUP, in which case, social withdrawal, household activities, level of activity and general interest in the world around them, could be high-priority target areas of treatment, since they seem to be mediating the relation between others areas of functioning., (Copyright © 2020. Published by Elsevier Ltd.)

Published
2021
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24. Expression and Functionality Study of 9 Toll-Like Receptors in 33 Drug-Naïve Non-Affective First Episode Psychosis Individuals: A 3-Month Study.

Author

Juncal-Ruiz M, Riesco-Davila L, Vazquez-Bourgon J, Ortiz-Garcia de la Foz V, Mayoral-Van Son J, Ayesa-Arriola R, Setien-Suero E, Leza JC, Lopez-Hoyos M, and Crespo-Facorro B

Subjects
Adult, Antipsychotic Agents therapeutic use, B-Lymphocytes metabolism, Case-Control Studies, Female, Humans, Male, Prospective Studies, Psychotic Disorders drug therapy, T-Lymphocytes metabolism, Young Adult, Leukocytes, Mononuclear metabolism, Psychotic Disorders metabolism, Toll-Like Receptor 5 metabolism, Toll-Like Receptor 8 metabolism
Abstract

Toll-like receptors (TLRs) are a pivotal component of the innate immune system that seem to have a role in the pathogenesis of psychosis. The purpose of this work was to compare the expression and functionality of 9 TLRs in three peripheral blood mononuclear cells (PBMCs) (monocytes, B cells, and T cells) between 33 drug-naïve first-episode psychosis (FEP) individuals and 26 healthy volunteers, at baseline and after 3-month of antipsychotic treatment. The expression of TLRs 1-9 were assessed by flow cytometry. For the assessment of the TLR functionality, cells collected in sodium heparin tubes were polyclonally stimulated for 18 h, with different agonists for human TLR1-9. The results of our study highlight the role that TLR5 and TLR8 might play in the pathophysiology of psychosis. We found a lower expression of these receptors in FEP individuals, regarding healthy volunteers at baseline and after 3-month of treatment on the three PBMCs subsets. Most TLRs showed a lower functionality (especially reduced intracellular levels of TNF-α) in patients than in healthy volunteers. These results, together with previous evidence, suggest that individuals with psychosis might show a pattern of TLR expression that differs from that of healthy volunteers, which could vary according to the intensity of immune/inflammatory response.

Published
2020
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25. Schizophrenia Polygenic Risk Score as a Predictor of Antipsychotic Efficacy in First-Episode Psychosis.

Author

Zhang JP, Robinson D, Yu J, Gallego J, Fleischhacker WW, Kahn RS, Crespo-Facorro B, Vazquez-Bourgon J, Kane JM, Malhotra AK, and Lencz T

Subjects
Adult, Episode of Care, Female, Genome-Wide Association Study, Humans, Male, Multifactorial Inheritance, Predictive Value of Tests, Prognosis, Psychopathology, Schizophrenic Psychology, Treatment Outcome, Antipsychotic Agents therapeutic use, Psychotic Disorders diagnosis, Psychotic Disorders drug therapy, Psychotic Disorders etiology, Psychotic Disorders psychology, Risk Assessment methods, Schizophrenia diagnosis, Schizophrenia drug therapy
Abstract

Objective: Pharmacogenomic studies of antipsychotics have typically examined effects of individual polymorphisms. By contrast, polygenic risk scores (PRSs) derived from genome-wide association studies (GWAS) can quantify the influence of thousands of common alleles of small effect in a single measure. The authors examined whether PRSs for schizophrenia were predictive of antipsychotic efficacy in four independent cohorts of patients with first-episode psychosis (total N=510)., Method: All study subjects received initial treatment with antipsychotic medication for first-episode psychosis, and all were genotyped on standard single-nucleotide polymorphism (SNP) arrays imputed to the 1000 Genomes Project reference panel. PRS was computed based on the results of the large-scale schizophrenia GWAS reported by the Psychiatric Genomics Consortium. Symptoms were measured by using total symptom rating scales at baseline and at week 12 or at the last follow-up visit before dropout., Results: In the discovery cohort, higher PRS significantly predicted higher symptom scores at the 12-week follow-up (controlling for baseline symptoms, sex, age, and ethnicity). The PRS threshold set at a p value <0.01 gave the strongest result in the discovery cohort and was used to replicate the findings in the other three cohorts. Higher PRS significantly predicted greater posttreatment symptoms in the combined replication analysis and was individually significant in two of the three replication cohorts. Across the four cohorts, PRS was significantly predictive of adjusted 12-week symptom scores (pooled partial r=0.18; 3.24% of variance explained). Patients with low PRS were more likely to be treatment responders than patients with high PRS (odds ratio=1.91 in the two Caucasian samples)., Conclusions: Patients with higher PRS for schizophrenia tended to have less improvement with antipsychotic drug treatment. PRS burden may have potential utility as a prognostic biomarker.

Published
2019
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26. Recovery of long-term paresis following resection of WHO grade II gliomas infiltrating the pyramidal pathway.

Author

Martino J, Caballero H, DE Lucas EM, DA Silva-Freitas R, Velasquez C, Gomez E, Vazquez-Bourgon J, and Vázquez-Barquero A

Subjects
Adult, Brain Mapping methods, Brain Neoplasms diagnosis, Glioma diagnosis, Humans, Male, Monitoring, Intraoperative methods, Motor Cortex physiopathology, Motor Cortex surgery, Neoplasm Grading methods, Neuronavigation methods, Paresis physiopathology, Quality of Life, Time, Brain Neoplasms surgery, Glioma surgery, Paresis surgery, Pyramidal Tracts surgery, Recovery of Function physiology
Abstract

Recent publications had reported high rates of preoperative neurological impairments in WHO grade II gliomas (GIIG) that significantly affect the quality of life. Consequently, one step further in the analysis of surgical outcome in GIIG is to evaluate if surgery is capable to improve preoperative deficits. Here are reported two cases of GIIG infiltrating the primary motor cortex and pyramidal pathway that had a long-term paresis before surgery. Both patients were operated with intraoperative electrical stimulation mapping, with identification and preservation of the primary motor cortex and pyramidal tract. Despite the long-lasting paresis, both cases had a significant improvement of motor function after surgery. Knowledge of this potential recovery before surgery is of major significance for planning the surgical strategy in GIIG. Two possible predictors of motor recovery were analyzed: 1) reconstruction of the corticospinal tract with diffusion tensor imaging tractography is indicative of anatomo-functional integrity, despite tract deviation and infiltration; 2) intraoperative identification of motor response by electrostimulation confirms the presence of an intact peritumoral tract. Thus, resection should stop at this boundary even in cases of long lasting preoperative hemiplegia.

Published
2017

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