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2. Longitudinal analyses of the DNA methylome in deployed military servicemen identify susceptibility loci for post-traumatic stress disorder

Author

Rutten, BPF, Vermetten, E, Vinkers, CH, Ursini, G, Daskalakis, NP, Pishva, E, de Nijs, L, Houtepen, LC, Eijssen, L, Jaffe, AE, Kenis, G, Viechtbauer, W, van den Hove, D, Schraut, KG, Lesch, K-P, Kleinman, JE, Hyde, TM, Weinberger, DR, Schalkwyk, L, Lunnon, K, Mill, J, Cohen, H, Yehuda, R, Baker, DG, Maihofer, AX, Nievergelt, CM, Geuze, E, and Boks, MPM

Subjects
Brain Disorders, Mental Health, Post-Traumatic Stress Disorder (PTSD), Human Genome, Genetics, Anxiety Disorders, 2.1 Biological and endogenous factors, Aetiology, Mental health, Adult, Cohort Studies, DNA Methylation, DNA-Binding Proteins, Epigenesis, Genetic, Genetic Predisposition to Disease, Genetic Testing, Humans, Immediate-Early Proteins, Longitudinal Studies, Male, Military Personnel, Prospective Studies, Repressor Proteins, Stress Disorders, Post-Traumatic, Transcription Factors, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

In order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n=93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n=98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD.

Published
2018

3. No association between peripheral serotonin-gene-related DNA methylation and brain serotonin neurotransmission in the healthy and depressed state

Author

Bruzzone, S. E.P., Ozenne, B., Fisher, P. M., Ortega, G., Jensen, P. S., Dam, V. H., Svarer, C., Knudsen, G. M., Lesch, K. P., Frokjaer, V. G., Bruzzone, S. E.P., Ozenne, B., Fisher, P. M., Ortega, G., Jensen, P. S., Dam, V. H., Svarer, C., Knudsen, G. M., Lesch, K. P., and Frokjaer, V. G.

Abstract

Background Methylation of serotonin-related genes has been proposed as a plausible gene-by-environment link which may mediate environmental stress, depressive and anxiety symptoms. DNA methylation is often measured in blood cells, but little is known about the association between this peripheral epigenetic modification and brain serotonergic architecture. Here, we evaluated the association between whole-blood-derived methylation of four CpG sites in the serotonin transporter (SLC6A4) and six CpG sites of the tryptophan hydroxylase 2 (TPH2) gene and in-vivo brain levels of serotonin transporter (5-HTT) and serotonin 4 receptor (5-HT4) in a cohort of healthy individuals (N = 254) and, for 5-HT4, in a cohort of unmedicated patients with depression (N = 90). To do so, we quantified SLC6A4/TPH2 methylation using bisulfite pyrosequencing and estimated brain 5-HT4 and 5-HTT levels using positron emission tomography. In addition, we explored the association between SLC6A4 and TPH2 methylation and measures of early life and recent stress, depressive and anxiety symptoms on 297 healthy individuals. Results We found no statistically significant association between peripheral DNA methylation and brain markers of serotonergic neurotransmission in patients with depression or in healthy individuals. In addition, although SLC6A4 CpG2 (chr17:30,236,083) methylation was marginally associated with the parental bonding inventory overprotection score in the healthy cohort, statistical significance did not remain after accounting for blood cell heterogeneity. Conclusions We suggest that findings on peripheral DNA methylation in the context of brain serotonin-related features should be interpreted with caution. More studies are needed to rule out a role of SLC6A4 and TPH2 methylation as biomarkers for environmental stress, depressive or anxiety symptoms., BACKGROUND: Methylation of serotonin-related genes has been proposed as a plausible gene-by-environment link which may mediate environmental stress, depressive and anxiety symptoms. DNA methylation is often measured in blood cells, but little is known about the association between this peripheral epigenetic modification and brain serotonergic architecture. Here, we evaluated the association between whole-blood-derived methylation of four CpG sites in the serotonin transporter (SLC6A4) and six CpG sites of the tryptophan hydroxylase 2 (TPH2) gene and in-vivo brain levels of serotonin transporter (5-HTT) and serotonin 4 receptor (5-HT4) in a cohort of healthy individuals (N = 254) and, for 5-HT4, in a cohort of unmedicated patients with depression (N = 90). To do so, we quantified SLC6A4/TPH2 methylation using bisulfite pyrosequencing and estimated brain 5-HT4 and 5-HTT levels using positron emission tomography. In addition, we explored the association between SLC6A4 and TPH2 methylation and measures of early life and recent stress, depressive and anxiety symptoms on 297 healthy individuals. RESULTS: We found no statistically significant association between peripheral DNA methylation and brain markers of serotonergic neurotransmission in patients with depression or in healthy individuals. In addition, although SLC6A4 CpG2 (chr17:30,236,083) methylation was marginally associated with the parental bonding inventory overprotection score in the healthy cohort, statistical significance did not remain after accounting for blood cell heterogeneity. CONCLUSIONS: We suggest that findings on peripheral DNA methylation in the context of brain serotonin-related features should be interpreted with caution. More studies are needed to rule out a role of SLC6A4 and TPH2 methylation as biomarkers for environmental stress, depressive or anxiety symptoms.

Published
2024

5. A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD

Author

Jain, M, Vélez, JI, Acosta, MT, Palacio, LG, Balog, J, Roessler, E, Pineda, D, Londoño, AC, Palacio, JD, Arbelaez, A, Lopera, F, Elia, J, Hakonarson, H, Seitz, C, Freitag, CM, Palmason, H, Meyer, J, Romanos, M, Walitza, S, Hemminger, U, Warnke, A, Romanos, J, Renner, T, Jacob, C, Lesch, K-P, Swanson, J, Castellanos, FX, Bailey-Wilson, JE, Arcos-Burgos, M, and Muenke, M

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical and Health Psychology, Clinical Sciences, Psychology, Neurosciences, Genetics, Attention Deficit Hyperactivity Disorder (ADHD), Mental Health, 2.1 Biological and endogenous factors, Aetiology, Aspartic Acid, Attention Deficit Disorder with Hyperactivity, Brain, Case-Control Studies, Choline, Chromosomes, Human, Pair 11, Genetic Linkage, Genetic Predisposition to Disease, Glutamine, Humans, Inositol, Magnetic Resonance Spectroscopy, Methylphenidate, Polymorphism, Single Nucleotide, Protons, Receptors, G-Protein-Coupled, Receptors, Peptide, ADHD, genetic interaction, LPHN3, NCAM1, DRD2, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract

In previous studies of a genetic isolate, we identified significant linkage of attention deficit hyperactivity disorder (ADHD) to 4q, 5q, 8q, 11q and 17p. The existence of unique large size families linked to multiple regions, and the fact that these families came from an isolated population, we hypothesized that two-locus interaction contributions to ADHD were plausible. Several analytical models converged to show significant interaction between 4q and 11q (P

Published
2012

6. Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3-90 years

Author

Dima, D, Modabbernia, A, Papachristou, E, Doucet, GE, Agartz, I, Aghajani, M, Akudjedu, TN, Albajes-Eizagirre, A, Alnaes, D, Alpert, K, Andersson, M, Andreasen, NC, Andreassen, OA, Asherson, P, Banaschewski, T, Bargallo, N, Baumeister, S, Baur-Streubel, R, Bertolino, A, Bonvino, A, Boomsma, D, Borgwardt, S, Bourque, J, Brandeis, D, Breier, A, Brodaty, H, Brouwer, RM, Buitelaar, JK, Busatto, GF, Buckner, RL, Calhoun, V, Canales-Rodriguez, EJ, Cannon, DM, Caseras, X, Castellanos, FX, Cervenka, S, Chaim-Avancini, TM, Ching, CRK, Chubar, V, Clark, VP, Conrod, P, Conzelmann, A, Crespo-Facorro, B, Crivello, F, Crone, EA, Dale, AM, Davey, C, de Geus, EJC, de Haan, L, de Zubicaray, G, den Braber, A, Dickie, EW, Di Giorgio, A, Nhat, TD, Dorum, ES, Ehrlich, S, Erk, S, Espeseth, T, Fatouros-Bergman, H, Fisher, SE, Fouche, J-P, Franke, B, Frodl, T, Fuentes-Claramonte, P, Glahn, DC, Gotlib, IH, Grabe, H-J, Grimm, O, Groenewold, NA, Grotegerd, D, Gruber, O, Gruner, P, Gur, RE, Gur, RC, Harrison, BJ, Hartman, CA, Hatton, SN, Heinz, A, Heslenfeld, DJ, Hibar, DP, Hickie, IB, Ho, B-C, Hoekstra, PJ, Hohmann, S, Holmes, AJ, Hoogman, M, Hosten, N, Howells, FM, Pol, HEH, Huyser, C, Jahanshad, N, James, A, Jernigan, TL, Jiang, J, Jonsson, EG, Joska, JA, Kahn, R, Kalnin, A, Kanai, R, Klein, M, Klyushnik, TP, Koenders, L, Koops, S, Kraemer, B, Kuntsi, J, Lagopoulos, J, Lazaro, L, Lebedeva, I, Lee, WH, Lesch, K-P, Lochner, C, Machielsen, MWJ, Maingault, S, Martin, NG, Martinez-Zalacain, I, Mataix-Cols, D, Mazoyer, B, McDonald, C, McDonald, BC, McIntosh, AM, McMahon, KL, McPhilemy, G, Menchon, JM, Medland, SE, Meyer-Lindenberg, A, Naaijen, J, Najt, P, Nakao, T, Nordvik, JE, Nyberg, L, Oosterlaan, J, Ortiz-Garcia De la Foz, V, Paloyelis, Y, Pauli, P, Pergola, G, Pomarol-Clotet, E, Portella, MJ, Potkin, SG, Radua, J, Reif, A, Rinker, DA, Roffman, JL, Rosa, PGP, Sacchet, MD, Sachdev, PS, Salvador, R, Sanchez-Juan, P, Sarro, S, Satterthwaite, TD, Saykin, AJ, Serpa, MH, Schmaal, L, Schnell, K, Schumann, G, Sim, K, Smoller, JW, Sommer, I, Soriano-Mas, C, Stein, DJ, Strike, LT, Swagerman, SC, Tamnes, CK, Temmingh, HS, Thomopoulos, S, Tomyshev, AS, Tordesillas-Gutierrez, D, Trollor, JN, Turner, JA, Uhlmann, A, van den Heuvel, OA, van den Meer, D, van der Wee, NJA, van Haren, NEM, Van't Ent, D, van Erp, TGM, Veer, IM, Veltman, DJ, Voineskos, A, Voelzke, H, Walter, H, Walton, E, Wang, L, Wang, Y, Wassink, TH, Weber, B, Wen, W, West, JD, Westlye, LT, Whalley, H, Wierenga, LM, Williams, SCR, Wittfeld, K, Wolf, DH, Worker, A, Wright, MJ, Yang, K, Yoncheva, Y, Zanetti, M, Ziegler, GC, Thompson, PM, Frangou, S, Dima, D, Modabbernia, A, Papachristou, E, Doucet, GE, Agartz, I, Aghajani, M, Akudjedu, TN, Albajes-Eizagirre, A, Alnaes, D, Alpert, K, Andersson, M, Andreasen, NC, Andreassen, OA, Asherson, P, Banaschewski, T, Bargallo, N, Baumeister, S, Baur-Streubel, R, Bertolino, A, Bonvino, A, Boomsma, D, Borgwardt, S, Bourque, J, Brandeis, D, Breier, A, Brodaty, H, Brouwer, RM, Buitelaar, JK, Busatto, GF, Buckner, RL, Calhoun, V, Canales-Rodriguez, EJ, Cannon, DM, Caseras, X, Castellanos, FX, Cervenka, S, Chaim-Avancini, TM, Ching, CRK, Chubar, V, Clark, VP, Conrod, P, Conzelmann, A, Crespo-Facorro, B, Crivello, F, Crone, EA, Dale, AM, Davey, C, de Geus, EJC, de Haan, L, de Zubicaray, G, den Braber, A, Dickie, EW, Di Giorgio, A, Nhat, TD, Dorum, ES, Ehrlich, S, Erk, S, Espeseth, T, Fatouros-Bergman, H, Fisher, SE, Fouche, J-P, Franke, B, Frodl, T, Fuentes-Claramonte, P, Glahn, DC, Gotlib, IH, Grabe, H-J, Grimm, O, Groenewold, NA, Grotegerd, D, Gruber, O, Gruner, P, Gur, RE, Gur, RC, Harrison, BJ, Hartman, CA, Hatton, SN, Heinz, A, Heslenfeld, DJ, Hibar, DP, Hickie, IB, Ho, B-C, Hoekstra, PJ, Hohmann, S, Holmes, AJ, Hoogman, M, Hosten, N, Howells, FM, Pol, HEH, Huyser, C, Jahanshad, N, James, A, Jernigan, TL, Jiang, J, Jonsson, EG, Joska, JA, Kahn, R, Kalnin, A, Kanai, R, Klein, M, Klyushnik, TP, Koenders, L, Koops, S, Kraemer, B, Kuntsi, J, Lagopoulos, J, Lazaro, L, Lebedeva, I, Lee, WH, Lesch, K-P, Lochner, C, Machielsen, MWJ, Maingault, S, Martin, NG, Martinez-Zalacain, I, Mataix-Cols, D, Mazoyer, B, McDonald, C, McDonald, BC, McIntosh, AM, McMahon, KL, McPhilemy, G, Menchon, JM, Medland, SE, Meyer-Lindenberg, A, Naaijen, J, Najt, P, Nakao, T, Nordvik, JE, Nyberg, L, Oosterlaan, J, Ortiz-Garcia De la Foz, V, Paloyelis, Y, Pauli, P, Pergola, G, Pomarol-Clotet, E, Portella, MJ, Potkin, SG, Radua, J, Reif, A, Rinker, DA, Roffman, JL, Rosa, PGP, Sacchet, MD, Sachdev, PS, Salvador, R, Sanchez-Juan, P, Sarro, S, Satterthwaite, TD, Saykin, AJ, Serpa, MH, Schmaal, L, Schnell, K, Schumann, G, Sim, K, Smoller, JW, Sommer, I, Soriano-Mas, C, Stein, DJ, Strike, LT, Swagerman, SC, Tamnes, CK, Temmingh, HS, Thomopoulos, S, Tomyshev, AS, Tordesillas-Gutierrez, D, Trollor, JN, Turner, JA, Uhlmann, A, van den Heuvel, OA, van den Meer, D, van der Wee, NJA, van Haren, NEM, Van't Ent, D, van Erp, TGM, Veer, IM, Veltman, DJ, Voineskos, A, Voelzke, H, Walter, H, Walton, E, Wang, L, Wang, Y, Wassink, TH, Weber, B, Wen, W, West, JD, Westlye, LT, Whalley, H, Wierenga, LM, Williams, SCR, Wittfeld, K, Wolf, DH, Worker, A, Wright, MJ, Yang, K, Yoncheva, Y, Zanetti, M, Ziegler, GC, Thompson, PM, and Frangou, S

Abstract

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.

Published
2022

7. Cortical thickness across the lifespan: Data from 17,075 healthy individuals aged 3-90 years

Author

Frangou, S, Modabbernia, A, Williams, SCR, Papachristou, E, Doucet, GE, Agartz, I, Aghajani, M, Akudjedu, TN, Albajes-Eizagirre, A, Alnaes, D, Alpert, K, Andersson, M, Andreasen, NC, Andreassen, OA, Asherson, P, Banaschewski, T, Bargallo, N, Baumeister, S, Baur-Streubel, R, Bertolino, A, Bonvino, A, Boomsma, D, Borgwardt, S, Bourque, J, Brandeis, D, Breier, A, Brodaty, H, Brouwer, RM, Buitelaar, JK, Busatto, GF, Buckner, RL, Calhoun, V, Canales-Rodriguez, EJ, Cannon, DM, Caseras, X, Castellanos, FX, Cervenka, S, Chaim-Avancini, TM, Ching, CRK, Chubar, V, Clark, VP, Conrod, P, Conzelmann, A, Crespo-Facorro, B, Crivello, F, Crone, EA, Dale, AM, Davey, C, de Geus, EJC, de Haan, L, de Zubicaray, G, den Braber, A, Dickie, EW, Di Giorgio, A, Nhat, TD, Dorum, ES, Ehrlich, S, Erk, S, Espeseth, T, Fatouros-Bergman, H, Fisher, SE, Fouche, J-P, Franke, B, Frodl, T, Fuentes-Claramonte, P, Glahn, DC, Gotlib, IH, Grabe, H-J, Grimm, O, Groenewold, NA, Grotegerd, D, Gruber, O, Gruner, P, Gur, RE, Gur, RC, Harrison, BJ, Hartman, CA, Hatton, SN, Heinz, A, Heslenfeld, DJ, Hibar, DP, Hickie, IB, Ho, B-C, Hoekstra, PJ, Hohmann, S, Holmes, AJ, Hoogman, M, Hosten, N, Howells, FM, Pol, HEH, Huyser, C, Jahanshad, N, James, A, Jernigan, TL, Jiang, J, Jonsson, EG, Joska, JA, Kahn, R, Kalnin, A, Kanai, R, Klein, M, Klyushnik, TP, Koenders, L, Koops, S, Kraemer, B, Kuntsi, J, Lagopoulos, J, Lazaro, L, Lebedeva, I, Lee, WH, Lesch, K-P, Lochner, C, Machielsen, MWJ, Maingault, S, Martin, NG, Martinez-Zalacain, I, Mataix-Cols, D, Mazoyer, B, McDonald, C, McDonald, BC, McIntosh, AM, McMahon, KL, McPhilemy, G, Menchon, JM, Medland, SE, Meyer-Lindenberg, A, Naaijen, J, Najt, P, Nakao, T, Nordvik, JE, Nyberg, L, Oosterlaan, J, de la Foz, VO-G, Paloyelis, Y, Pauli, P, Pergola, G, Pomarol-Clotet, E, Portella, MJ, Potkin, SG, Radua, J, Reif, A, Rinker, DA, Roffman, JL, Rosa, PGP, Sacchet, MD, Sachdev, PS, Salvador, R, Sanchez-Juan, P, Sarro, S, Satterthwaite, TD, Saykin, AJ, Serpa, MH, Schmaal, L, Schnell, K, Schumann, G, Sim, K, Smoller, JW, Sommer, I, Soriano-Mas, C, Stein, DJ, Strike, LT, Swagerman, SC, Tamnes, CK, Temmingh, HS, Thomopoulos, S, Tomyshev, AS, Tordesillas-Gutierrez, D, Trollor, JN, Turner, JA, Uhlmann, A, van den Heuvel, OA, van den Meer, D, van der Wee, NJA, van Haren, NEM, van't Ent, D, van Erp, TGM, Veer, IM, Veltman, DJ, Voineskos, A, Voelzke, H, Walter, H, Walton, E, Wang, L, Wang, Y, Wassink, TH, Weber, B, Wen, W, West, JD, Westlye, LT, Whalley, H, Wierenga, LM, Wittfeld, K, Wolf, DH, Worker, A, Wright, MJ, Yang, K, Yoncheva, Y, Zanetti, M, Ziegler, GC, Thompson, PM, Dima, D, Frangou, S, Modabbernia, A, Williams, SCR, Papachristou, E, Doucet, GE, Agartz, I, Aghajani, M, Akudjedu, TN, Albajes-Eizagirre, A, Alnaes, D, Alpert, K, Andersson, M, Andreasen, NC, Andreassen, OA, Asherson, P, Banaschewski, T, Bargallo, N, Baumeister, S, Baur-Streubel, R, Bertolino, A, Bonvino, A, Boomsma, D, Borgwardt, S, Bourque, J, Brandeis, D, Breier, A, Brodaty, H, Brouwer, RM, Buitelaar, JK, Busatto, GF, Buckner, RL, Calhoun, V, Canales-Rodriguez, EJ, Cannon, DM, Caseras, X, Castellanos, FX, Cervenka, S, Chaim-Avancini, TM, Ching, CRK, Chubar, V, Clark, VP, Conrod, P, Conzelmann, A, Crespo-Facorro, B, Crivello, F, Crone, EA, Dale, AM, Davey, C, de Geus, EJC, de Haan, L, de Zubicaray, G, den Braber, A, Dickie, EW, Di Giorgio, A, Nhat, TD, Dorum, ES, Ehrlich, S, Erk, S, Espeseth, T, Fatouros-Bergman, H, Fisher, SE, Fouche, J-P, Franke, B, Frodl, T, Fuentes-Claramonte, P, Glahn, DC, Gotlib, IH, Grabe, H-J, Grimm, O, Groenewold, NA, Grotegerd, D, Gruber, O, Gruner, P, Gur, RE, Gur, RC, Harrison, BJ, Hartman, CA, Hatton, SN, Heinz, A, Heslenfeld, DJ, Hibar, DP, Hickie, IB, Ho, B-C, Hoekstra, PJ, Hohmann, S, Holmes, AJ, Hoogman, M, Hosten, N, Howells, FM, Pol, HEH, Huyser, C, Jahanshad, N, James, A, Jernigan, TL, Jiang, J, Jonsson, EG, Joska, JA, Kahn, R, Kalnin, A, Kanai, R, Klein, M, Klyushnik, TP, Koenders, L, Koops, S, Kraemer, B, Kuntsi, J, Lagopoulos, J, Lazaro, L, Lebedeva, I, Lee, WH, Lesch, K-P, Lochner, C, Machielsen, MWJ, Maingault, S, Martin, NG, Martinez-Zalacain, I, Mataix-Cols, D, Mazoyer, B, McDonald, C, McDonald, BC, McIntosh, AM, McMahon, KL, McPhilemy, G, Menchon, JM, Medland, SE, Meyer-Lindenberg, A, Naaijen, J, Najt, P, Nakao, T, Nordvik, JE, Nyberg, L, Oosterlaan, J, de la Foz, VO-G, Paloyelis, Y, Pauli, P, Pergola, G, Pomarol-Clotet, E, Portella, MJ, Potkin, SG, Radua, J, Reif, A, Rinker, DA, Roffman, JL, Rosa, PGP, Sacchet, MD, Sachdev, PS, Salvador, R, Sanchez-Juan, P, Sarro, S, Satterthwaite, TD, Saykin, AJ, Serpa, MH, Schmaal, L, Schnell, K, Schumann, G, Sim, K, Smoller, JW, Sommer, I, Soriano-Mas, C, Stein, DJ, Strike, LT, Swagerman, SC, Tamnes, CK, Temmingh, HS, Thomopoulos, S, Tomyshev, AS, Tordesillas-Gutierrez, D, Trollor, JN, Turner, JA, Uhlmann, A, van den Heuvel, OA, van den Meer, D, van der Wee, NJA, van Haren, NEM, van't Ent, D, van Erp, TGM, Veer, IM, Veltman, DJ, Voineskos, A, Voelzke, H, Walter, H, Walton, E, Wang, L, Wang, Y, Wassink, TH, Weber, B, Wen, W, West, JD, Westlye, LT, Whalley, H, Wierenga, LM, Wittfeld, K, Wolf, DH, Worker, A, Wright, MJ, Yang, K, Yoncheva, Y, Zanetti, M, Ziegler, GC, Thompson, PM, and Dima, D

Abstract

Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.

Published
2022

8. Consortium neuroscience of attention deficit/hyperactivity disorder and autism spectrum disorder: The ENIGMA adventure

Author

Hoogman, M, van Rooij, D, Klein, M, Boedhoe, P, Ilioska, I, Li, T, Patel, Y, Postema, MC, Zhang-James, Y, Anagnostou, E, Arango, C, Auzias, G, Banaschewski, T, Bau, CHD, Behrmann, M, Bellgrove, MA, Brandeis, D, Brem, S, Busatto, GF, Calderoni, S, Calvo, R, Castellanos, FX, Coghill, D, Conzelmann, A, Daly, E, Deruelle, C, Dinstein, I, Durston, S, Ecker, C, Ehrlich, S, Epstein, JN, Fair, DA, Fitzgerald, J, Freitag, CM, Frodl, T, Gallagher, L, Grevet, EH, Haavik, J, Hoekstra, PJ, Janssen, J, Karkashadze, G, King, JA, Konrad, K, Kuntsi, J, Lazaro, L, Lerch, JP, Lesch, K-P, Louza, MR, Luna, B, Mattos, P, McGrath, J, Muratori, F, Murphy, C, Nigg, JT, Oberwelland-Weiss, E, Tuura, RLO, O'Hearn, K, Oosterlaan, J, Parellada, M, Pauli, P, Plessen, KJ, Ramos-Quiroga, JA, Reif, A, Reneman, L, Retico, A, Rosa, PGP, Rubia, K, Shaw, P, Silk, TJ, Tamm, L, Vilarroya, O, Walitza, S, Jahanshad, N, Faraone, S, Francks, C, van den Heuvel, OA, Paus, T, Thompson, PM, Buitelaar, JK, Franke, B, Hoogman, M, van Rooij, D, Klein, M, Boedhoe, P, Ilioska, I, Li, T, Patel, Y, Postema, MC, Zhang-James, Y, Anagnostou, E, Arango, C, Auzias, G, Banaschewski, T, Bau, CHD, Behrmann, M, Bellgrove, MA, Brandeis, D, Brem, S, Busatto, GF, Calderoni, S, Calvo, R, Castellanos, FX, Coghill, D, Conzelmann, A, Daly, E, Deruelle, C, Dinstein, I, Durston, S, Ecker, C, Ehrlich, S, Epstein, JN, Fair, DA, Fitzgerald, J, Freitag, CM, Frodl, T, Gallagher, L, Grevet, EH, Haavik, J, Hoekstra, PJ, Janssen, J, Karkashadze, G, King, JA, Konrad, K, Kuntsi, J, Lazaro, L, Lerch, JP, Lesch, K-P, Louza, MR, Luna, B, Mattos, P, McGrath, J, Muratori, F, Murphy, C, Nigg, JT, Oberwelland-Weiss, E, Tuura, RLO, O'Hearn, K, Oosterlaan, J, Parellada, M, Pauli, P, Plessen, KJ, Ramos-Quiroga, JA, Reif, A, Reneman, L, Retico, A, Rosa, PGP, Rubia, K, Shaw, P, Silk, TJ, Tamm, L, Vilarroya, O, Walitza, S, Jahanshad, N, Faraone, S, Francks, C, van den Heuvel, OA, Paus, T, Thompson, PM, Buitelaar, JK, and Franke, B

Abstract

Neuroimaging has been extensively used to study brain structure and function in individuals with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) over the past decades. Two of the main shortcomings of the neuroimaging literature of these disorders are the small sample sizes employed and the heterogeneity of methods used. In 2013 and 2014, the ENIGMA-ADHD and ENIGMA-ASD working groups were respectively, founded with a common goal to address these limitations. Here, we provide a narrative review of the thus far completed and still ongoing projects of these working groups. Due to an implicitly hierarchical psychiatric diagnostic classification system, the fields of ADHD and ASD have developed largely in isolation, despite the considerable overlap in the occurrence of the disorders. The collaboration between the ENIGMA-ADHD and -ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together. The outcomes of case-control studies of subcortical and cortical structures showed that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case-control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow-up analyses continue that include more imaging modalities (diffusion MRI and resting-state functional MRI), collaborations with other large databases, and samples with dual diagnoses.

Published
2022

11. Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree

Author

Lesch, K-P, Selch, S, Renner, T J, Jacob, C, Nguyen, T T, Hahn, T, Romanos, M, Walitza, S, Shoichet, S, Dempfle, A, Heine, M, Boreatti-Hümmer, A, Romanos, J, Gross-Lesch, S, Zerlaut, H, Wultsch, T, Heinzel, S, Fassnacht, M, Fallgatter, A, Allolio, B, Schäfer, H, Warnke, A, Reif, A, Ropers, H-H, and Ullmann, R

Published
2011
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12. A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication

Author

Arcos-Burgos, M, Jain, M, Acosta, M T, Shively, S, Stanescu, H, Wallis, D, Domené, S, Vélez, J I, Karkera, J D, Balog, J, Berg, K, Kleta, R, Gahl, W A, Roessler, E, Long, R, Lie, J, Pineda, D, Londoño, A C, Palacio, J D, Arbelaez, A, Lopera, F, Elia, J, Hakonarson, H, Johansson, S, Knappskog, P M, Haavik, J, Ribases, M, Cormand, B, Bayes, M, Casas, M, Ramos-Quiroga, J A, Hervas, A, Maher, B S, Faraone, S V, Seitz, C, Freitag, C M, Palmason, H, Meyer, J, Romanos, M, Walitza, S, Hemminger, U, Warnke, A, Romanos, J, Renner, T, Jacob, C, Lesch, K-P, Swanson, J, Vortmeyer, A, Bailey-Wilson, J E, Castellanos, F X, and Muenke, M

Published
2010
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17. Increased Oxidative Stress in the Prefrontal Cortex as a Shared Feature of Depressive- and PTSD-Like Syndromes: Effects of a Standardized Herbal Antioxidant

Author

de, Munter, J., Pavlov, D., Gorlova, A., Sicker, M., Proshin, A., Kalueff, A. V., Svistunov, A., Kiselev, D., Nedorubov, A., Morozov, S., Umriukhin, A., Lesch, K. -P., Strekalova, T., Schroeter, C. A., de, Munter, J., Pavlov, D., Gorlova, A., Sicker, M., Proshin, A., Kalueff, A. V., Svistunov, A., Kiselev, D., Nedorubov, A., Morozov, S., Umriukhin, A., Lesch, K. -P., Strekalova, T., and Schroeter, C. A.

Abstract

Major depression (MD) and posttraumatic stress disorder (PTSD) share common brain mechanisms and treatment strategies. Nowadays, the dramatically developing COVID-19 situation unavoidably results in stress, psychological trauma, and high incidence of MD and PTSD. Hence, the importance of the development of new treatments for these disorders cannot be overstated. Herbal medicine appears to be an effective and safe treatment with fewer side effects than classic pharmaca and that is affordable in low-income countries. Currently, oxidative stress and neuroinflammation attract increasing attention as important mechanisms of MD and PTSD. We investigated the effects of a standardized herbal cocktail (SHC), an extract of clove, bell pepper, basil, pomegranate, nettle, and other plants, that was designed as an antioxidant treatment in mouse models of MD and PTSD. In the MD model of “emotional” ultrasound stress (US), mice were subjected to ultrasound frequencies of 16–20 kHz, mimicking rodent sounds of anxiety/despair and “neutral” frequencies of 25–45 kHz, for three weeks and concomitantly treated with SHC. US-exposed mice showed elevated concentrations of oxidative stress markers malondialdehyde and protein carbonyl, increased gene and protein expression of pro-inflammatory cytokines interleukin (IL)-1β and IL-6 and other molecular changes in the prefrontal cortex as well as weight loss, helplessness, anxiety-like behavior, and neophobia that were ameliorated by the SHC treatment. In the PTSD model of the modified forced swim test (modFST), in which a 2-day swim is followed by an additional swim on day 5, mice were pretreated with SHC for 16 days. Increases in the floating behavior and oxidative stress markers malondialdehyde and protein carbonyl in the prefrontal cortex of modFST-mice were prevented by the administration of SHC. Chromatography mass spectrometry revealed bioactive constituents of SHC, including D-ribofuranose, beta-D-lactose, malic, glyceric, and citric ac

Published
2021

18. Cortical thickness across the lifespan: Data from 17,075 healthy individuals aged 3–90 years

Author

Frangou, S. (Sophia), Modabbernia, A. (Amirhossein), Williams, S.C.R. (Steven C. R.), Papachristou, E. (Efstathios), Doucet, G.E. (Gaelle E.), Agartz, I. (Ingrid), Aghajani, M. (Moji), Akudjedu, T.N. (Theophilus N.), Albajes-Eizagirre, A. (Anton), Alnæs, D. (Dag), Alpert, K. (Kathryn), Andersson, M. (Micael), Andreasen, N.C. (Nancy C.), Andreassen, O.A. (Ole), Asherson, P. (Philip), Banaschewski, T. (Tobias), Bargallo, N. (Nuria), Baumeister, S. (Sarah), Baur-Streubel, R. (Ramona), Bertolino, A. (Alessandro), Bonvino, A. (Aurora), Boomsma, D.I. (Dorret I.), Borgwardt, S. (Stefan), Bourque, J. (Josiane), Brandeis, D. (Daniel), Breier, A. (Alan), Brodaty, H. (Henry), Brouwer, R.M. (Rachel), Buitelaar, J.K. (Jan K.), Busatto, G.F. (Geraldo F.), Buckner, M., Calhoun, V.D. (Vince), Canales-Rodríguez, E.J. (Erick J.), Cannon, D.M. (Dara M.), Caseras, X. (Xavier), Castellanos, F.X. (Francisco X.), Cervenka, S. (Simon), Chaim-Avancini, T.M. (Tiffany M.), Ching, C.R.K. (Christopher), Chubar, V. (Victoria), Clark, V.P. (Vincent P.), Conrod, P. (Patricia), Conzelmann, A. (Annette), Crespo-Facorro, B. (Benedicto), Crivello, F. (Fabrice), Crone, E.A. (Eveline), Dale, A.M. (Anders), Davey, C.G. (Christopher), Geus, E.J.C. (Eco) de, Haan, L. (Lieuwe) de, Zubicaray, G.I. (Greig) de, Braber, A. (Anouk) den, Dickie, E.W. (Erin W.), Di Giorgio, A. (Annabella), Doan, N.T. (Nhat Trung), Dørum, E.S. (Erlend S.), Ehrlich, S.M. (Stefan), Erk, S., Espeseth, T. (Thomas), Fatouros-Bergman, H. (Helena), Fisher, S.E. (Simon), Fouche, J.-P. (Jean-Paul), Franke, B. (Barbara), Frodl, T. (Thomas), Fuentes-Claramonte, P. (Paola), Glahn, D.C. (David), Gotlib, I.H. (Ian H.), Grabe, H.J. (Hans Jörgen), Grimm, O. (Oliver), Groenewold, N.A. (Nynke A.), Grotegerd, D. (Dominik), Gruber, O. (Oliver), Gruner, P. (Patricia), Gur, R.E. (Rachel E.), Gur, R.C. (Ruben C.), Harrison, B.J. (Ben J.), Hartman, C.A. (Catharine A.), Hatton, W., Heinz, A. (Andreas), Heslenfeld, D.J. (Dirk), Hibar, D.P. (Derrek P.), Hickie, I.B. (Ian), Ho, B.-C. (Beng-Choon), Hoekstra, P.J. (Pieter), Hohmann, S. (Sarah), Holmes, A.J. (Avram J.), Hoogman, M. (Martine), Hosten, N. (Norbert), Howells, F.M. (Fleur M.), Hulshoff Pol, H.E. (Hilleke E.), Huyser, J. (Jochanan), Jahanshad, N. (Neda), James, A., Jernigan, T.L. (Terry L.), Jiang, J. (Jiyang), Jönsson, E.G. (Erik G.), Joska, J.A. (John A.), Kahn, R. (Rene), Kalnin, A. (Andrew), Kanai, R. (Ryota), Klein, M. (Marieke), Klyushnik, T.P. (Tatyana P.), Koenders, L. (Laura), Koops, S. (Sanne), Krämer, B. (Bernd), Kuntsi, J. (Jonna), Lagopoulos, J. (Jim), Lázaro, L. (Luisa), Lebedeva, I. (Irina), Lee, W.H. (Won Hee), Lesch, K.-P. (Klaus-Peter), Lochner, C. (Christine), Machielsen, M.W.J. (Marise), Maingault, S. (Sophie), Martin, N.G. (Nicholas G.), Martínez-Zalacaín, I. (Ignacio), Mataix-Cols, D. (David), Mazoyer, B. (Bernard), McDonald, C. (Colm), McDonald, B.C. (Brenna C.), McIntosh, A.M. (Andrew), McMahon, K.L. (Katie L.), McPhilemy, G. (Genevieve), Menchón, J.M. (José M.), Medland, S.E. (Sarah), Meyer-Lindenberg, A. (Andreas), Naaijen, J. (Jilly), Najt, P. (Pablo), Nakao, T. (Tomohiro), Nordvik, J.E. (Jan E.), Nyberg, L. (Lisa), Oosterlaan, J. (Jaap), de la Foz, V.O.-G. (Víctor Ortiz-García), Paloyelis, Y. (Yannis), Pauli, P. (Paul), Pergola, G. (Giulio), Pomarol-Clotet, E. (Edith), Portella, M.J. (Maria J.), Potkin, S.G. (Steven G.), Radua, J. (Joaquim), Reif, A. (Andreas), Rinker, D.A. (Daniel A.), Roffman, J.L. (Joshua), Rosa, P.G.P. (Pedro G. P.), Sacchet, M.D. (Matthew D.), Sachdev, P.S. (Perminder), Salvador, R. (Raymond), Sánchez-Juan, P. (Pascual), Sarró, S. (Salvador), Satterthwaite, T.D. (Theodore), Saykin, A.J. (Andrew), Serpa, M.H. (Mauricio H.), Schmaal, L. (Lianne), Schnell, K. (Kerry), Schumann, G. (Gunter), Sim, K. (Kang), Smoller, J.W., Sommer, I. (Iris), Soriano-Mas, C. (Carles), Stein, D.J. (Dan J.), Strike, L.T. (Lachlan), Swagerman, S.C. (Suzanne C.), Tamnes, C.K. (Christian K.), Temmingh, H.S. (Henk S.), Thomopoulos, S.I. (Sophia I.), Tomyshev, A.S. (Alexander S.), Tordesillas-Gutierrez, D. (Diana), Trollor, J., Turner, J.A. (Jessica A.), Uhlmann, A. (Anne), Heuvel, O.A. (Odile A.), van den Meer, D. (Dennis), Wee, N.J. (Nic) van der, van Haren, N.E.M. (Neeltje E. M.), Ent, D. (Dennis) van 't, Erp, T.G.M. (Theo G.) van, Veer, I.M. (Ilya), Veltman, D.J. (Dick), Voineskos, A. (Aristotle), Völzke, H. (Henry), Walter, H. (Henrik), Walton, E. (Esther), Wang, L. (Lei), Wang, Y. (Yang), Wassink, A.M.J. (Annemarie), Weber, B. (Bernd), Wen, W. (Wei), West, J.D. (John D.), Westlye, L.T. (Lars), Whalley, H. (Heather), Wierenga, L.M. (Lara M.), Wittfeld, K. (Katharina), Wolf, D.H. (Daniel H.), Worker, A. (Amanda), Wright, M.J. (Margaret J.), Yang, K. (Kun), Yoncheva, Y. (Yulyia), Zanetti, M.V. (Marcus V.), Ziegler, G.C. (Georg C.), Thompson, P.M. (Paul), Dima, D. (Danai), Frangou, S. (Sophia), Modabbernia, A. (Amirhossein), Williams, S.C.R. (Steven C. R.), Papachristou, E. (Efstathios), Doucet, G.E. (Gaelle E.), Agartz, I. (Ingrid), Aghajani, M. (Moji), Akudjedu, T.N. (Theophilus N.), Albajes-Eizagirre, A. (Anton), Alnæs, D. (Dag), Alpert, K. (Kathryn), Andersson, M. (Micael), Andreasen, N.C. (Nancy C.), Andreassen, O.A. (Ole), Asherson, P. (Philip), Banaschewski, T. (Tobias), Bargallo, N. (Nuria), Baumeister, S. (Sarah), Baur-Streubel, R. (Ramona), Bertolino, A. (Alessandro), Bonvino, A. (Aurora), Boomsma, D.I. (Dorret I.), Borgwardt, S. (Stefan), Bourque, J. (Josiane), Brandeis, D. (Daniel), Breier, A. (Alan), Brodaty, H. (Henry), Brouwer, R.M. (Rachel), Buitelaar, J.K. (Jan K.), Busatto, G.F. (Geraldo F.), Buckner, M., Calhoun, V.D. (Vince), Canales-Rodríguez, E.J. (Erick J.), Cannon, D.M. (Dara M.), Caseras, X. (Xavier), Castellanos, F.X. (Francisco X.), Cervenka, S. (Simon), Chaim-Avancini, T.M. (Tiffany M.), Ching, C.R.K. (Christopher), Chubar, V. (Victoria), Clark, V.P. (Vincent P.), Conrod, P. (Patricia), Conzelmann, A. (Annette), Crespo-Facorro, B. (Benedicto), Crivello, F. (Fabrice), Crone, E.A. (Eveline), Dale, A.M. (Anders), Davey, C.G. (Christopher), Geus, E.J.C. (Eco) de, Haan, L. (Lieuwe) de, Zubicaray, G.I. (Greig) de, Braber, A. (Anouk) den, Dickie, E.W. (Erin W.), Di Giorgio, A. (Annabella), Doan, N.T. (Nhat Trung), Dørum, E.S. (Erlend S.), Ehrlich, S.M. (Stefan), Erk, S., Espeseth, T. (Thomas), Fatouros-Bergman, H. (Helena), Fisher, S.E. (Simon), Fouche, J.-P. (Jean-Paul), Franke, B. (Barbara), Frodl, T. (Thomas), Fuentes-Claramonte, P. (Paola), Glahn, D.C. (David), Gotlib, I.H. (Ian H.), Grabe, H.J. (Hans Jörgen), Grimm, O. (Oliver), Groenewold, N.A. (Nynke A.), Grotegerd, D. (Dominik), Gruber, O. (Oliver), Gruner, P. (Patricia), Gur, R.E. (Rachel E.), Gur, R.C. (Ruben C.), Harrison, B.J. (Ben J.), Hartman, C.A. (Catharine A.), Hatton, W., Heinz, A. (Andreas), Heslenfeld, D.J. (Dirk), Hibar, D.P. (Derrek P.), Hickie, I.B. (Ian), Ho, B.-C. (Beng-Choon), Hoekstra, P.J. (Pieter), Hohmann, S. (Sarah), Holmes, A.J. (Avram J.), Hoogman, M. (Martine), Hosten, N. (Norbert), Howells, F.M. (Fleur M.), Hulshoff Pol, H.E. (Hilleke E.), Huyser, J. (Jochanan), Jahanshad, N. (Neda), James, A., Jernigan, T.L. (Terry L.), Jiang, J. (Jiyang), Jönsson, E.G. (Erik G.), Joska, J.A. (John A.), Kahn, R. (Rene), Kalnin, A. (Andrew), Kanai, R. (Ryota), Klein, M. (Marieke), Klyushnik, T.P. (Tatyana P.), Koenders, L. (Laura), Koops, S. (Sanne), Krämer, B. (Bernd), Kuntsi, J. (Jonna), Lagopoulos, J. (Jim), Lázaro, L. (Luisa), Lebedeva, I. (Irina), Lee, W.H. (Won Hee), Lesch, K.-P. (Klaus-Peter), Lochner, C. (Christine), Machielsen, M.W.J. (Marise), Maingault, S. (Sophie), Martin, N.G. (Nicholas G.), Martínez-Zalacaín, I. (Ignacio), Mataix-Cols, D. (David), Mazoyer, B. (Bernard), McDonald, C. (Colm), McDonald, B.C. (Brenna C.), McIntosh, A.M. (Andrew), McMahon, K.L. (Katie L.), McPhilemy, G. (Genevieve), Menchón, J.M. (José M.), Medland, S.E. (Sarah), Meyer-Lindenberg, A. (Andreas), Naaijen, J. (Jilly), Najt, P. (Pablo), Nakao, T. (Tomohiro), Nordvik, J.E. (Jan E.), Nyberg, L. (Lisa), Oosterlaan, J. (Jaap), de la Foz, V.O.-G. (Víctor Ortiz-García), Paloyelis, Y. (Yannis), Pauli, P. (Paul), Pergola, G. (Giulio), Pomarol-Clotet, E. (Edith), Portella, M.J. (Maria J.), Potkin, S.G. (Steven G.), Radua, J. (Joaquim), Reif, A. (Andreas), Rinker, D.A. (Daniel A.), Roffman, J.L. (Joshua), Rosa, P.G.P. (Pedro G. P.), Sacchet, M.D. (Matthew D.), Sachdev, P.S. (Perminder), Salvador, R. (Raymond), Sánchez-Juan, P. (Pascual), Sarró, S. (Salvador), Satterthwaite, T.D. (Theodore), Saykin, A.J. (Andrew), Serpa, M.H. (Mauricio H.), Schmaal, L. (Lianne), Schnell, K. (Kerry), Schumann, G. (Gunter), Sim, K. (Kang), Smoller, J.W., Sommer, I. (Iris), Soriano-Mas, C. (Carles), Stein, D.J. (Dan J.), Strike, L.T. (Lachlan), Swagerman, S.C. (Suzanne C.), Tamnes, C.K. (Christian K.), Temmingh, H.S. (Henk S.), Thomopoulos, S.I. (Sophia I.), Tomyshev, A.S. (Alexander S.), Tordesillas-Gutierrez, D. (Diana), Trollor, J., Turner, J.A. (Jessica A.), Uhlmann, A. (Anne), Heuvel, O.A. (Odile A.), van den Meer, D. (Dennis), Wee, N.J. (Nic) van der, van Haren, N.E.M. (Neeltje E. M.), Ent, D. (Dennis) van 't, Erp, T.G.M. (Theo G.) van, Veer, I.M. (Ilya), Veltman, D.J. (Dick), Voineskos, A. (Aristotle), Völzke, H. (Henry), Walter, H. (Henrik), Walton, E. (Esther), Wang, L. (Lei), Wang, Y. (Yang), Wassink, A.M.J. (Annemarie), Weber, B. (Bernd), Wen, W. (Wei), West, J.D. (John D.), Westlye, L.T. (Lars), Whalley, H. (Heather), Wierenga, L.M. (Lara M.), Wittfeld, K. (Katharina), Wolf, D.H. (Daniel H.), Worker, A. (Amanda), Wright, M.J. (Margaret J.), Yang, K. (Kun), Yoncheva, Y. (Yulyia), Zanetti, M.V. (Marcus V.), Ziegler, G.C. (Georg C.), Thompson, P.M. (Paul), and Dima, D. (Danai)

Abstract

Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3–90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.

Published
2021
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19. Altered Behaviour, Dopamine and Norepinephrine Regulation in Stressed Mice Heterozygous in TPH2 Gene

Author

Strekalova, T., Svirin, E., Waider, J., Gorlova, A., Cespuglio, R., Kalueff, A., Pomytkin, I., Schmitt-Boehrer, A. G., Lesch, K. -P., Anthony, D. C., Strekalova, T., Svirin, E., Waider, J., Gorlova, A., Cespuglio, R., Kalueff, A., Pomytkin, I., Schmitt-Boehrer, A. G., Lesch, K. -P., and Anthony, D. C.

Abstract

Gene-environment interaction (GxE) determines the vulnerability of an individual to a spectrum of stress-related neuropsychiatric disorders. Increased impulsivity, excessive aggression, and other behavioural characteristics are associated with variants within the tryptophan hydroxylase-2 (Tph2) gene, a key enzyme in brain serotonin synthesis. This phenotype is recapitulated in naïve mice with complete, but not with partial Tph2 inactivation. Tph2 haploinsufficiency in animals reflects allelic variation of Tph2 facilitating the elucidation of respective GxE mechanisms. Recently, we showed excessive aggression and altered serotonin brain metabolism in heterozygous Tph2-deficient male mice (Tph2+/−) after predator stress exposure. Here, we sought to extend these studies by investigating aggressive and anxiety-like behaviours, sociability, and the brain metabolism of dopamine and noradrenaline. Separately, Tph2+/− mice were examined for exploration activity in a novel environment and for the potentiation of helplessness in the modified swim test (ModFST). Predation stress procedure increased measures of aggression, dominancy, and suppressed sociability in Tph2+/− mice, which was the opposite of that observed in control mice. Anxiety-like behaviour was unaltered in the mutants and elevated in controls. Tph2+/− mice exposed to environmental novelty or to the ModFST exhibited increased novelty exploration and no increase in floating behaviour compared to controls, which is suggestive of resilience to stress and despair. High-performance liquid chromatography (HPLC) revealed significant genotype-dependent differences in the metabolism of dopamine, and norepinephrine within the brain tissue. In conclusion, environmentally challenged Tph2+/− mice exhibit behaviours that resemble the behaviour of non-stressed null mutants, which reveals how GxE interaction studies can unmask latent genetically determined predispositions. © 2020 The Authors.

Published
2021

20. Analysis of structural brain asymmetries in attention-deficit/hyperactivity disorder in 39 datasets

Author

Postema, MC, Hoogman, M, Ambrosino, S, Asherson, P, Banaschewski, T, Bandeira, CE, Baranov, A, Bau, CHD, Baumeister, S, Baur-Streubel, R, Bellgrove, MA, Biederman, J, Bralten, J, Brandeis, D, Brem, S, Buitelaar, JK, Busatto, GF, Castellanos, FX, Cercignani, M, Chaim-Avancini, TM, Chantiluke, KC, Christakou, A, Coghill, D, Conzelmann, A, Cubillo, AI, Cupertino, RB, de Zeeuw, P, Doyle, AE, Durston, S, Earl, EA, Epstein, JN, Ethofer, T, Fair, DA, Fallgatter, AJ, Faraone, SV, Frodl, T, Gabel, MC, Gogberashvili, T, Grevet, EH, Haavik, J, Harrison, NA, Hartman, CA, Heslenfeld, DJ, Hoekstra, PJ, Hohmann, S, Hovik, MF, Jernigan, TL, Kardatzki, B, Karkashadze, G, Kelly, C, Kohls, G, Konrad, K, Kuntsi, J, Lazaro, L, Lera-Miguel, S, Lesch, K-P, Louza, MR, Lundervold, AJ, Malpas, CB, Mattos, P, McCarthy, H, Namazova-Baranova, L, Nicolau, R, Nigg, JT, Novotny, SE, Oberwelland Weiss, E, O'Gorman Tuura, RL, Oosterlaan, J, Oranje, B, Paloyelis, Y, Pauli, P, Picon, FA, Plessen, KJ, Ramos-Quiroga, JA, Reif, A, Reneman, L, Rosa, PGP, Rubia, K, Schrantee, A, Schweren, LJS, Seitz, J, Shaw, P, Silk, TJ, Skokauskas, N, Soliva Vila, JC, Stevens, MC, Sudre, G, Tamm, L, Tovar-Moll, F, van Erp, TGM, Vance, A, Vilarroya, O, Vives-Gilabert, Y, von Polier, GG, Walitza, S, Yoncheva, YN, Zanetti, MV, Ziegler, GC, Glahn, DC, Jahanshad, N, Medland, SE, Thompson, PM, Fisher, SE, Franke, B, Francks, C, Postema, MC, Hoogman, M, Ambrosino, S, Asherson, P, Banaschewski, T, Bandeira, CE, Baranov, A, Bau, CHD, Baumeister, S, Baur-Streubel, R, Bellgrove, MA, Biederman, J, Bralten, J, Brandeis, D, Brem, S, Buitelaar, JK, Busatto, GF, Castellanos, FX, Cercignani, M, Chaim-Avancini, TM, Chantiluke, KC, Christakou, A, Coghill, D, Conzelmann, A, Cubillo, AI, Cupertino, RB, de Zeeuw, P, Doyle, AE, Durston, S, Earl, EA, Epstein, JN, Ethofer, T, Fair, DA, Fallgatter, AJ, Faraone, SV, Frodl, T, Gabel, MC, Gogberashvili, T, Grevet, EH, Haavik, J, Harrison, NA, Hartman, CA, Heslenfeld, DJ, Hoekstra, PJ, Hohmann, S, Hovik, MF, Jernigan, TL, Kardatzki, B, Karkashadze, G, Kelly, C, Kohls, G, Konrad, K, Kuntsi, J, Lazaro, L, Lera-Miguel, S, Lesch, K-P, Louza, MR, Lundervold, AJ, Malpas, CB, Mattos, P, McCarthy, H, Namazova-Baranova, L, Nicolau, R, Nigg, JT, Novotny, SE, Oberwelland Weiss, E, O'Gorman Tuura, RL, Oosterlaan, J, Oranje, B, Paloyelis, Y, Pauli, P, Picon, FA, Plessen, KJ, Ramos-Quiroga, JA, Reif, A, Reneman, L, Rosa, PGP, Rubia, K, Schrantee, A, Schweren, LJS, Seitz, J, Shaw, P, Silk, TJ, Skokauskas, N, Soliva Vila, JC, Stevens, MC, Sudre, G, Tamm, L, Tovar-Moll, F, van Erp, TGM, Vance, A, Vilarroya, O, Vives-Gilabert, Y, von Polier, GG, Walitza, S, Yoncheva, YN, Zanetti, MV, Ziegler, GC, Glahn, DC, Jahanshad, N, Medland, SE, Thompson, PM, Fisher, SE, Franke, B, and Francks, C

Abstract

OBJECTIVE: Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium. METHODS: We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries. RESULTS: There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen's d from -0.18 to 0.18) and would not survive study-wide correction for multiple testing. CONCLUSION: Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.

Published
2021

21. 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

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

Author

Patel, Y., Parker, N., Shin, J., Howard, D., French, L., Thomopoulos, S.I., Pozzi, E., Abe, Y., Abé, 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., Bargalló, 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., Bülow, R., Busatto, G.F., Calderoni, S., Calhoun, V.D., Calvo, R., Canales-Rodríguez, 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., Fatjó-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., Höschl, C., Høvik, 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., Krämer, B., Krug, A., Kuntsi, J., Kwon, J.S., Landén, M., Landrø, 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., Menchón, 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., García De La Foz, V.O., Overs, B.J., Paloyelis, Y., Pantelis, C., Parellada, M., Pauli, P., Picó-Pérez, M., Picon, F.A., Piras, F., Plessen, K.J., Pomarol-Clotet, E., Preda, A., Puig, O., Quidé, 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., Sarró, S., Satterthwaite, T.D., Sawa, A., Schall, U., Schofield, P.R., Schrantee, A., Seitz, J., Serpa, M.H., Setién-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-Gutiérrez, 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., Vázquez-Bourgon, J., Vecchio, D., Venkatasubramanian, G., Vieta, E., Vilarroya, O., Vives-Gilabert, Y., Voineskos, A.N., Völzke, 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., Patel, Y., Parker, N., Shin, J., Howard, D., French, L., Thomopoulos, S.I., Pozzi, E., Abe, Y., Abé, 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., Bargalló, 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., Bülow, R., Busatto, G.F., Calderoni, S., Calhoun, V.D., Calvo, R., Canales-Rodríguez, 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., Fatjó-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., Höschl, C., Høvik, 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., Krämer, B., Krug, A., Kuntsi, J., Kwon, J.S., Landén, M., Landrø, 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., Menchón, 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., García De La Foz, V.O., Overs, B.J., Paloyelis, Y., Pantelis, C., Parellada, M., Pauli, P., Picó-Pérez, M., Picon, F.A., Piras, F., Plessen, K.J., Pomarol-Clotet, E., Preda, A., Puig, O., Quidé, 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., Sarró, S., Satterthwaite, T.D., Sawa, A., Schall, U., Schofield, P.R., Schrantee, A., Seitz, J., Serpa, M.H., Setién-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-Gutiérrez, 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., Vázquez-Bourgon, J., Vecchio, D., Venkatasubramanian, G., Vieta, E., Vilarroya, O., Vives-Gilabert, Y., Voineskos, A.N., Völzke, 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., 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 (exce

Published
2021
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27. Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder

Author

Jarick, I, Volckmar, A-L, Pütter, C, Pechlivanis, S, Nguyen, T T, Dauvermann, M R, Beck, S, Albayrak, Ö, Scherag, S, Gilsbach, S, Cichon, S, Hoffmann, P, Degenhardt, F, Nöthen, M M, Schreiber, S, Wichmann, H-E, Jöckel, K-H, Heinrich, J, Tiesler, C MT, Faraone, S V, Walitza, S, Sinzig, J, Freitag, C, Meyer, J, Herpertz-Dahlmann, B, Lehmkuhl, G, Renner, T J, Warnke, A, Romanos, M, Lesch, K-P, Reif, A, Schimmelmann, B G, Hebebrand, J, Scherag, A, and Hinney, A

Published
2014
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42. Metabolic, Molecular, and Behavioral Effects of Western Diet in Serotonin Transporter-Deficient Mice: Rescue by Heterozygosity?

Author

Veniaminova, E., Cespuglio, R., Chernukha, I., Schmitt-Boehrer, A. G., Morozov, S., Kalueff, A. V., Kuznetsova, O., Anthony, D. C., Lesch, K. -P., Strekalova, T., Psychiatrie & Neuropsychologie, and RS: MHeNs - R3 - Neuroscience

Subjects
obesity, GENE KNOCKOUT, PROTEIN EXPRESSION, Sert-deficient mice, glucose tolerance, EVOLUTIONARY ADAPTATION, REDUCES FOOD-INTAKE, UNCLASSIFIED DRUG, MOUSE, NERVOUS SYSTEM INFLAMMATION, ANIMAL EXPERIMENT, AGING, TLR4 UP-REGULATION, serotonin receptors, TOLL-LIKE RECEPTOR 4 (TLR4), Western diet, BRAIN, HETEROSIS, SEROTONIN RECEPTORS, MOLECULAR BIOLOGY, WESTERN DIET, DEPRESSION, INSULIN, METABOLIC PARAMETERS, FEMALE, GENOTYPE, OBESITY, GLUCOSE TOLERANCE, EXPRESSION, UPREGULATION, HETEROZYGOSITY, SEROTONIN RECEPTOR HTR1A, SLC6A4 GENE, SEROTONIN RECEPTOR HTR1B, SERT-DEFICIENT MICE, RISK-FACTOR, 5-HT6 RECEPTOR, heterosis, NONHUMAN, ddc:610, ARTICLE, EMOTIONALITY, GENE OVEREXPRESSION, TOLL LIKE RECEPTOR 4, aging, SEROTONIN RECEPTOR HTR2A, SEROTONIN RECEPTOR HTR2C, ANIMAL BEHAVIOR, GENE, POLYMORPHISM, CONTROLLED STUDY, SEROTONIN RECEPTOR, PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA COACTIVATOR 1ALPHA, SEROTONIN TRANSPORTER, HIPPOCAMPUS, Toll-like receptor 4 (TLR4)
Abstract

Reduced function of the serotonin transporter (SERT) is associated with increased susceptibility to anxiety and depression and with type-2 diabetes, which is especially true in older women. Preference for a “Western diet” (WD), enriched with saturated fat, cholesterol, and sugars, may aggravate these conditions. In previous studies, decreased glucose tolerance, central and peripheral inflammation, dyslipidemia, emotional, cognitive, and social abnormalities were reported in WD-fed young female mice. We investigated the metabolic, molecular, and behavioral changes associated with a 3-week-long dietary regime of either the WD or control diet in 12-month-old female mice with three different Sert genotypes: homozygous (Slc6a4) gene knockout (Sert−/−: KO), heterozygous (Sert+/−: HET), or wild-type mice (Sert+/+: WT). In the WT-WD and KO-WD groups, but not in HET-WD-fed mice, most of changes induced by the WD paralleled those found in the younger mice, including brain overexpression of inflammatory marker Toll-like receptor 4 (Tlr4) and impaired hippocampus-dependent performance in the marble test. However, the 12-month-old female mice became obese. Control diet KO mice exhibited impaired hippocampal-dependent behaviors, increased brain expression of the serotonin receptors Htr2c and Htr1b, as well as increased Tlr4 and mitochondrial regulator, peroxisome proliferator-activated receptor gamma-coactivator-1a (Ppargc1a). Paradoxically, these, and other changes, were reversed in KO-WD mutants, suggesting a complex interplay between Sert deficiency and metabolic factors as well as potential compensatory molecular mechanisms that might be disrupted by the WD exposure. Most, but not all, of the changes in gene expression in the brain and liver of KO mice were not exhibited by the HET mice fed with either diet. Some of the WD-induced changes were similar in the KO-WD and HET-WD-fed mice, but the latter displayed a “rescued” phenotype in terms of diet-induced abnormalities in glucose tolerance, neuroinflammation, and hippocampus-dependent performance. Thus, complete versus partial Sert inactivation in aged mice results in distinct metabolic, molecular, and behavioral consequences in response to the WD. Our findings show that Sert+/− mice are resilient to certain environmental challenges and support the concept of heterosis as evolutionary adaptive mechanism. © Copyright © 2020 Veniaminova, Cespuglio, Chernukha, Schmitt-Boehrer, Morozov, Kalueff, Kuznetsova, Anthony, Lesch and Strekalova. 01EW1602B, 01EW1902, 602805 Deutsche Forschungsgemeinschaft, DFG: CRC TRR 58 A1/A5 Horizon 2020 Framework Programme, H2020: Eat2beNICE, 728018, 643051 Russian Science Foundation, RSF: 16-16-10073 Seventh Framework Programme, FP7 I.M. Sechenov First Moscow State Medical University, MSMU Deutsche Forschungsgemeinschaft, DFG We thank Collette Rousset and Donia Amrouni from C. Bernard University, Anna Gorlova from Sechenov University, and Anastasiya Kibitkina and Galina Tolmacheva from the Gorbatov Research Center for their valuable contribution to this work. Funding. The authors? work reported here was supported by the Deutsche Forschungsgemeinschaft (DFG: CRC TRR 58 A1/A5), the European Union?s Seventh Framework Programme (FP7/2007?2013) under Grant No. 602805 (Aggressotype), ERA-Net NEURON/RESPOND, No. 01EW1602B and ERA-Net NEURON/DECODE, No. 01EW1902 (to K-PL), the Horizon 2020 Research and Innovation Programme under Grant No. 728018 (Eat2beNICE) and Grant No. 643051 (MiND), 5-100 Russian Academic Excellence Project (to K-PL and TS), the Russian Science Foundation (RSF) Project No. 16-16-10073 (to IC and OK), and the University of W?rzburg in the funding programme Open Access Publishing (to KP-L).

Published
2020

45. Common brain disorders are associated with heritable patterns of apparent aging of the brain

Author

Kaufmann, T., van der Meer, D., Doan, N. T., Schwarz, E., Lund, M. J., Agartz, I., Alnaes, D., Barch, D. M., Baur-Streubel, R., Bertolino, A., Bettella, F., Beyer, M. K., Boen, E., Borgwardt, S., Brandt, C. L., Buitelaar, J., Celius, E. G., Cervenka, S., Conzelmann, A., Cordova-Palomera, A., Dale, A. M., de Quervain, D. J. F., Carlo, P. D., Djurovic, S., Dorum, E. S., Eisenacher, S., Elvsashagen, T., Espeseth, T., Fatouros-Bergman, H., Flyckt, L., Franke, B., Frei, O., Haatveit, B., Haberg, A. K., Harbo, H. F., Hartman, C. A., Heslenfeld, D., Hoekstra, P. J., Hogestol, E. A., Jernigan, T. L., Jonassen, R., Jonsson, E. G., Farde, L., Engberg, G., Erhardt, S., Schwieler, L., Piehl, F., Collste, K., Victorsson, P., Malmqvist, A., Hedberg, M., Orhan, F., Kirsch, P., Kloszewska, I., Kolskar, K. K., Landro, N. I., Hellard, S. L., Lesch, K. -P., Lovestone, S., Lundervold, A., Lundervold, A. J., Maglanoc, L. A., Malt, U. F., Mecocci, P., Melle, I., Meyer-Lindenberg, A., Moberget, T., Norbom, L. B., Nordvik, J. E., Nyberg, L., Oosterlaan, J., Papalino, M., Papassotiropoulos, A., Pauli, P., Pergola, G., Persson, K., Richard, G., Rokicki, J., Sanders, A. -M., Selbaek, G., Shadrin, A. A., Smeland, O. B., Soininen, H., Sowa, P., Steen, V. M., Tsolaki, M., Ulrichsen, K. M., Vellas, B., Wang, L., Westman, E., Ziegler, G. C., Zink, M., Andreassen, O. A., Westlye, L. T., Le Hellard, S., Di Carlo, P., Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), General Paediatrics, ARD - Amsterdam Reproduction and Development, Pediatric surgery, Psychiatrie & Neuropsychologie, RS: MHeNs - R3 - Neuroscience, and RS: MHeNs - R2 - Mental Health

Subjects
0301 basic medicine, Brain age gap, brain disorders, genetic architecture, pleiotropy, Male, Aging, Schizophrenia/genetics, LOCI, Genome-wide association study, Neuropsychological Tests, 0302 clinical medicine, 80 and over, Brain age gap, Aging/genetics, ALZHEIMERS, Child, Aged, 80 and over, Brain Diseases, Sex Characteristics, General Neuroscience, Mental Disorders, Brain, MULTIPLE-SCLEROSIS, brain disorders, Middle Aged, Magnetic Resonance Imaging, 3. Good health, Schizophrenia, Child, Preschool, Female, Alzheimer's disease, Neurovetenskaper, Algorithms, MRI, Adult, Adolescent, Brain Diseases/diagnostic imaging, Brain Structure and Function, Mental Disorders/diagnostic imaging, Biology, Article, 03 medical and health sciences, Young Adult, AGE, pleiotropy, Genetic architecture, Genetic Pleiotropy, medicine, Humans, Preschool, Brain disorders, Aged, Pleiotropy, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Brain age gaps, Multiple sclerosis, Neurosciences, Infant, medicine.disease, Brain/diagnostic imaging, genetic architecture, 030104 developmental biology, Pleiotropy (drugs), Neuroscience, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Common risk factors for psychiatric and other brain disorders are likely to converge on biological pathways influencing the development and maintenance of brain structure and function across life. Using structural MRI data from 45,615 individuals aged 3–96 years, we demonstrate distinct patterns of apparent brain aging in several brain disorders and reveal genetic pleiotropy between apparent brain aging in healthy individuals and common brain disorders. The author list between I.A. and M.Z. is in alphabetic order. The authors were funded by the Research Council of Norway (276082 LifespanHealth (T.K.), 213837 (O.A.A), 223273 NORMENT (O.A.A.), 204966 (L.T.W.), 229129 (O.A.A.), 249795 (L.T.W.), 273345 (L.T.W.) and 283798 SYNSCHIZ (O.A.A.)), the South-Eastern Norway Regional Health Authority (2013-123 (O.A.A.), 2014-097 (L.T.W.), 2015-073 (L.T.W.) and 2016083 (L.T.W.)), Stiftelsen Kristian Gerhard Jebsen (SKGJ-MED-008), the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (ERC Starting Grant, Grant agreement No. 802998 BRAINMINT (L.T.W.)), NVIDIA Corporation GPU Grant (T.K.), and the European Commission 7th Framework Programme (602450, IMAGEMEND (A.M.-L.)).

Published
2019
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49. DNA methylation in the 5-HTT regulatory region is associated with CO2-induced fear in panic disorder patients

Author

Leibold, N. K., Weidner, M. T., Ziegler, C., Ortega, G., Domschke, K., Lesch, K. P., Van den Hove, D. L., Schruers, K. R., Leibold, N. K., Weidner, M. T., Ziegler, C., Ortega, G., Domschke, K., Lesch, K. P., Van den Hove, D. L., and Schruers, K. R.

Abstract

A polymorphism in the gene encoding the serotonin (5-HT) transporter (5-HTT) has been shown to moderate the response to CO2 inhalation, an experimental model for panic attacks (PAs). Recurrent, unpredictable PAs represent, together with anticipatory anxiety of recurring attacks, the core feature of panic disorder (PD) and significantly interfere with patients' daily life. In addition to genetic components, accumulating evidence suggests that epigenetic mechanisms, which regulate gene expression by modifying chromatin structure, also play a fundamental role in the etiology of mental disorders. However, in PD, epigenetic mechanisms have barely been examined to date. In the present study, we investigated the relationship between methylation at the regulatory region of the gene encoding the 5-HTT and the reactivity to a 35% CO2 inhalation in PD patients. We focused on four specific CpG sites and found a significant association between the methylation level of one of these CpG sites and the fear response. This suggests that the emotional response to CO2 inhalation might be moderated by an epigenetic mechanism, and underlines the implication of the 5-HT system in PAs. Future studies are needed to further investigate epigenetic alterations in PD and their functional consequences. These insights can increase our understanding of the underlying pathophysiology and support the development of new treatment strategies. (c) 2020 Elsevier B.V. and ECNP. All rights reserved.

Published
2020

50. Stress-induced aggression in heterozygous TPH2 mutant mice is associated with alterations in serotonin turnover and expression of 5-HT6 and AMPA subunit 2A receptors

Author

Gorlova, A., Ortega, G., Waider, J., Bazhenova, N., Veniaminova, E., Proshin, A., Kalueff, A. V., Anthony, D. C., Lesch, K. -P., Strekalova, T., Gorlova, A., Ortega, G., Waider, J., Bazhenova, N., Veniaminova, E., Proshin, A., Kalueff, A. V., Anthony, D. C., Lesch, K. -P., and Strekalova, T.

Abstract

Background: The contribution of gene-environment interactions that lead to excessive aggression is poorly understood. Environmental stressors and mutations of the gene encoding tryptophan hydroxylase-2 (TPH2) are known to influence aggression. For example, TPH2 null mutant mice (Tph2−/−) are naturally highly aggressive, while heterozygous mice (Tph2+/−) lack a behavioral phenotype and are considered endophenotypically normal. Here we sought to discover whether an environmental stressor would affect the phenotype of the genetically ‘susceptible’ heterozygous mice (Tph2+/−). Methods: Tph2+/− male mice or Tph2+/+ controls were subjected to a five-day long rat exposure stress paradigm. Brain serotonin metabolism and the expression of selected genes encoding serotonin receptors, AMPA receptors, and stress markers were studied. Results: Stressed Tph2+/− mice displayed increased levels of aggression and social dominance, whereas Tph2+/+ animals became less aggressive and less dominant. Brain tissue concentrations of serotonin, its precursor hydroxytryptophan and its metabolite 5-hydroxyindoleacetic acid were significantly altered in all groups in the prefrontal cortex, striatum, amygdala, hippocampus and dorsal raphe after stress. Compared to non-stressed animals, the concentration of 5-hydroxytryptophan was elevated in the amygdala though decreased in the other brain structures. The overexpression of the AMPA receptor subunit, GluA2, and downregulation of 5-HT6 receptor, as well as overexpression of c-fos and glycogen-synthase-kinase-3β (GSK3-β), were found in most structures of the stressed Tph2+/− mice. Limitations: Rescue experiments would help to verify causal relationships of reported changes. Conclusions: The interaction of a partial TPH2 gene deficit with stress results in pathological aggression and molecular changes, and suggests that the presence of genetic susceptibility can augment aggression in seemingly resistant phenotypes. © 2020 The Authors

Published
2020

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