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1. MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway:Role in lateral ventricles and corpus callosum volume

Author

Blokland, G. A.M., Maleki, N., Jovicich, J., Mesholam-Gately, R. I., DeLisi, L. E., Turner, J. A., Shenton, M. E., Voineskos, A. N., Kahn, R. S., Roffman, J. L., Holt, D. J., Ehrlich, S., Kikinis, Z., Dazzan, P., Murray, R. M., Lee, J., Sim, K., Lam, M., de Zwarte, S. M.C., Walton, E., Kelly, S., Picchioni, M. M., Bramon, E., Makris, N., David, A. S., Mondelli, V., Reinders, A. A.T.S., Oykhman, E., Morris, D. W., Gill, M., Corvin, A. P., Cahn, W., Ho, N., Liu, J., Gollub, R. L., Manoach, D. S., Calhoun, V. D., Sponheim, S. R., Buka, S. L., Cherkerzian, S., Thermenos, H. W., Dickie, E. W., Ciufolini, S., Reis Marques, T., Crossley, N. A., Purcell, S. M., Smoller, J. W., van Haren, N. E.M., Toulopoulou, T., Donohoe, G., Goldstein, J. M., Keshavan, M. S., Petryshen, T. L., del Re, E. C., Blokland, G. A.M., Maleki, N., Jovicich, J., Mesholam-Gately, R. I., DeLisi, L. E., Turner, J. A., Shenton, M. E., Voineskos, A. N., Kahn, R. S., Roffman, J. L., Holt, D. J., Ehrlich, S., Kikinis, Z., Dazzan, P., Murray, R. M., Lee, J., Sim, K., Lam, M., de Zwarte, S. M.C., Walton, E., Kelly, S., Picchioni, M. M., Bramon, E., Makris, N., David, A. S., Mondelli, V., Reinders, A. A.T.S., Oykhman, E., Morris, D. W., Gill, M., Corvin, A. P., Cahn, W., Ho, N., Liu, J., Gollub, R. L., Manoach, D. S., Calhoun, V. D., Sponheim, S. R., Buka, S. L., Cherkerzian, S., Thermenos, H. W., Dickie, E. W., Ciufolini, S., Reis Marques, T., Crossley, N. A., Purcell, S. M., Smoller, J. W., van Haren, N. E.M., Toulopoulou, T., Donohoe, G., Goldstein, J. M., Keshavan, M. S., Petryshen, T. L., and del Re, E. C.

Abstract

Background/Objective:Enlarged lateral ventricle (LV) volume and decreased volume in the corpus callosum (CC) are hallmarks of schizophrenia (SZ). We previously showed an inverse correlation between LV and CC volumes in SZ, with global functioning decreasing with increased LV volume. This study investigates the relationship between LV volume, CC abnormalities, and the microRNA MIR137 and its regulated genes in SZ, because of MIR137’s essential role in neurodevelopment. Methods:Participants were 1224 SZ probands and 1466 unaffected controls from the GENUS Consortium. Brain MRI scans, genotype, and clinical data were harmonized across cohorts and employed in the analyses. Results:Increased LV volumes and decreased CC central, mid-anterior, and mid-posterior volumes were observed in SZ probands. The MIR137-regulated ephrin pathway was significantly associated with CC:LV ratio, explaining a significant proportion (3.42 %) of CC:LV variance, and more than for LV and CC separately. Other pathways explained variance in either CC or LV, but not both. CC:LV ratio was also positively correlated with Global Assessment of Functioning, supporting previous subsample findings. SNP-based heritability estimates were higher for CC central:LV ratio (0.79) compared to CC or LV separately.Discussion:Our results indicate that the CC:LV ratio is highly heritable, influenced in part by variation in the MIR137-regulated ephrin pathway. Findings suggest that the CC:LV ratio may be a risk indicator in SZ that correlates with global functioning.

Published
2024

5. Genetic architecture of subcortical brain structures in 38,854 individuals worldwide

Author

Satizabal, C., Adams, H., Hibar, D., White, C., Knol, M., Stein, J., Scholz, M., Sargurupremraj, M., Jahanshad, N., Roshchupkin, G., Smith, A., Bis, J., Jian, X., Luciano, M., Hofer, E., Teumer, A., Van der Lee, S., Yang, J., Yanek, L., Lee, T., Li, S., Hu, Y., Koh, J., Eicher, J., Desrivières, S., Arias-Vasquez, A., Chauhan, G., Athanasiu, L., Renteria, M., Kim, S., Höhn, D., Armstrong, N., Chen, Q., Holmes, A., Den Braber, A., Kloszewska, I., Andersson, M., Espeseth, T., Grimm, O., Abramovic, L., Alhusaini, S., Milaneschi, Y., Papmeyer, M., Axelsson, T., Ehrlich, S., Roiz-Santiañez, R., Kraemer, B., Håberg, A., Jones, H., Pike, G., Stein, D., Stevens, A., Bralten, J., Vernooij, M., Harris, T., Filippi, I., Witte, A., Guadalupe, T., Wittfeld, K., Mosley, T., Becker, J., Doan, N., Hagenaars, S., Saba, Y., Cuellar-Partida, G., Amin, N., Hilal, S., Nho, K., Karbalai, N., Arfanakis, K., Becker, D., Ames, D., Goldman, A., Lee, P., Boomsma, D., Lovestone, S., Giddaluru, S., Le Hellard, S., Mattheisen, M., Bohlken, M., Kasperaviciute, D., Schmaal, L., Lawrie, S., Agartz, I., Walton, E., Tordesillas-Gutierrez, D., Davies, G., Shin, J., Ipser, J., Vinke, L., Hoogman, M., Jia, T., Burkhardt, R., Klein, M., Crivello, F., Janowitz, D., Carmichael, O., Haukvik, U., Aribisala, B., Schmidt, H., Strike, L., Cheng, C., Risacher, S., Pütz, B., Fleischman, D., Assareh, A., Mattay, V., Buckner, R., Mecocci, P., Dale, A., Cichon, S., Boks, M., Matarin, M., Penninx, B., Calhoun, V., Chakravarty, M., Marquand, A., Macare, C., Masouleh, S., Oosterlaan, J., Amouyel, P., Hegenscheid, K., Rotter, J., Schork, A., Liewald, D., De Zubicaray, G., Wong, T., Shen, L., Sämann, P., Brodaty, H., Roffman, J., De Geus, E., Tsolaki, M., Erk, S., Van Eijk, K., Cavalleri, G., Van der Wee, N., McIntosh, A., Gollub, R., Bulayeva, K., Bernard, M., Richards, J., Himali, J., Loeffler, M., Rommelse, N., Hoffmann, W., Westlye, L., Valdés Hernández, M., Hansell, N., Van Erp, T., Wolf, C., Kwok, J., Vellas, B., Heinz, A., Olde Loohuis, L., Delanty, N., Ho, B., Ching, C., Shumskaya, E., Singh, B., Hofman, A., Van der Meer, D., Homuth, G., Psaty, B., Bastin, M., Montgomery, G., Foroud, T., Reppermund, S., Hottenga, J., Simmons, A., Meyer-Lindenberg, A., Cahn, W., Whelan, C., Van Donkelaar, M., Yang, Q., Hosten, N., Green, R., Thalamuthu, A., Mohnke, S., Hulshoff Pol, H., Lin, H., Jack Jr., C., Schofield, P., Mühleisen, T., Maillard, P., Potkin, S., Wen, W., Fletcher, E., Toga, A., Gruber, O., Huentelman, M., Smith, G., Launer, L., Nyberg, L., Jönsson, E., Crespo-Facorro, B., Koen, N., Greve, D., Uitterlinden, A., Weinberger, D., Steen, V., Fedko, I., Groenewold, N., Niessen, W., Toro, R., Tzourio, C., Longstreth Jr., W., Ikram, M., Smoller, J., Van Tol, M., Sussmann, J., Paus, T., Lemaître, H., Schroeter, M., Mazoyer, B., Andreassen, O., Holsboer, F., Depondt, C., Veltman, D., Turner, J., Pausova, Z., Schumann, G., Van Rooij, D., Djurovic, S., Deary, I., McMahon, K., Müller-Myhsok, B., Brouwer, R., Soininen, H., Pandolfo, M., Wassink, T., Cheung, J., Wolfers, T., Martinot, J., Zwiers, M., Nauck, M., Melle, I., Martin, N., Kanai, R., Westman, E., Kahn, R., Sisodiya, S., White, T., Saremi, A., Van Bokhoven, H., Brunner, H., Völzke, H., Wright, M., Van 't Ent, D., Nöthen, M., Ophoff, R., Buitelaar, J., Fernández, G., Sachdev, P., Rietschel, M., Van Haren, N., Fisher, S., Beiser, A., Francks, C., Saykin, A., Mather, K., Romanczuk-Seiferth, N., Hartman, C., DeStefano, A., Heslenfeld, D., Weiner, M., Walter, H., Hoekstra, P., Nyquist, P., Franke, B., Bennett, D., Grabe, H., Johnson, A., Chen, C., Van Duijn, C., Lopez, O., Fornage, M., Wardlaw, J., Schmidt, R., DeCarli, C., De Jager, P., Villringer, A., Debette, S., Gudnason, V., Medland, S., Shulman, J., Thompson, P., and Seshadri, S.

Subjects
nervous system
Abstract

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

Published
2019

11. Genetic architecture of subcortical brain structures in 38,851 individuals

Author

SATIZABAL, C. L., ADAMS, H. H. H., HIBAR, D. P., WHITE, C. C., KNOL, M. J., STEIN, J. L., Scholz, M., Sargurupremraj, Muralidharan, JAHANSHAD, N., ROSHCHUPKIN, G. V., SMITH, A. V., BIS, J. C., JIAN, X., LUCIANO, M., Hofer, E., TEUMER, A., VAN DER LEE, S. J., Yang, J., YANEK, L. R., LEE, T. V., Li, S., Hu, Y., KOH, J. Y., EICHER, J. D., DESRIVIERES, S., ARIAS-VASQUEZ, A., Chauhan, G., ATHANASIU, L., RENTERIA, M. E., Kim, S., HOEHN, D., ARMSTRONG, N. J., Chen, Q., HOLMES, A. J., DEN BRABER, A., KLOSZEWSKA, I., Andersson, M., ESPESETH, T., Grimm, O., ABRAMOVIC, L., ALHUSAINI, S., MILANESCHI, Y., PAPMEYER, M., AXELSSON, T., Ehrlich, S., ROIZ-SANTIANEZ, R., KRAEMER, B., HABERG, A. K., JONES, H. J., Pike, G. B., STEIN, D. J., Stevens, A., BRALTEN, J., VERNOOIJ, M. W., HARRIS, T. B., FILIPPI, I., WITTE, A. V., Guadalupe, T., WITTFELD, K., MOSLEY, T. H., BECKER, J. T., DOAN, N. T., HAGENAARS, S. P., SABA, Y., CUELLAR-PARTIDA, G., Amin, N., HILAL, S., NHO, K., MIRZA-SCHREIBER, N., ARFANAKIS, K., BECKER, D. M., Ames, D., GOLDMAN, A. L., LEE, P. H., Boomsma, D. I., LOVESTONE, S., GIDDALURU, S., LE HELLARD, S., Mattheisen, M., BOHLKEN, M. M., KASPERAVICIUTE, D., SCHMAAL, L., LAWRIE, S. M., Agartz, I., Walton, E., TORDESILLAS-GUTIERREZ, D., DAVIES, G. E., Shin, J., IPSER, J. C., VINKE, L. N., HOOGMAN, M., Jia, T., BURKHARDT, R., Klein, M., Crivello, Fabrice, JANOWITZ, D., CARMICHAEL, O., HAUKVIK, U. K., ARIBISALA, B. S., Schmidt, H., STRIKE, L. T., CHENG, C. Y., RISACHER, S. L., PUTZ, B., FLEISCHMAN, D. A., ASSAREH, A. A., MATTAY, V. S., BUCKNER, R. L., MECOCCI, P., DALE, A. M., Cichon, S., BOKS, M. P., MATARIN, M., PENNINX, Bwjh, CALHOUN, V. D., CHAKRAVARTY, M. M., MARQUAND, A. F., MACARE, C., KHARABIAN MASOULEH, S., OOSTERLAAN, J., Amouyel, P., HEGENSCHEID, K., ROTTER, J. I., SCHORK, A. J., LIEWALD, D. C. M., DE ZUBICARAY, G. I., WONG, T. Y., Shen, L., SAMANN, P. G., BRODATY, H., ROFFMAN, J. L., DE GEUS, E. J. C., TSOLAKI, M., ERK, S., VAN EIJK, K. R., CAVALLERI, G. L., VAN DER WEE, N. J. A., MCINTOSH, A. M., GOLLUB, R. L., BULAYEVA, K. B., Bernard, M., RICHARDS, J. S., HIMALI, J. J., Loeffler, M., ROMMELSE, N., Hoffmann, W., WESTLYE, L. T., VALDES HERNANDEZ, M. C., HANSELL, N. K., VAN ERP, T. G. M., Wolf, C., KWOK, J. B. J., Vellas, B., Heinz, A., OLDE LOOHUIS, L. M., DELANTY, N., HO, B. C., CHING, C. R. K., SHUMSKAYA, E., Singh, B., Hofman, A., VAN DER MEER, D., Homuth, G., PSATY, B. M., BASTIN, M. E., MONTGOMERY, G. W., FOROUD, T. M., REPPERMUND, S., HOTTENGA, J. J., Simmons, A., Meyer-Lindenberg, A., Cahn, W., WHELAN, C. D., VAN DONKELAAR, M. M. J., Yang, Q., HOSTEN, N., GREEN, R. C., THALAMUTHU, A., MOHNKE, S., HULSHOFF POL, H. E., Lin, H., JACK, C. R., Jr., SCHOFIELD, P. R., MUHLEISEN, T. W., MAILLARD, P., POTKIN, S. G., Wen, W., FLETCHER, E., TOGA, A. W., Gruber, O., HUENTELMAN, M., DAVEY SMITH, G., LAUNER, L. J., Nyberg, L., JONSSON, E. G., CRESPO-FACORRO, B., KOEN, N., GREVE, D. N., UITTERLINDEN, A. G., WEINBERGER, D. R., STEEN, V. M., FEDKO, I. O., GROENEWOLD, N. A., Niessen, W. J., TORO, R., Tzourio, Christophe, LONGSTRETH, W. T., Jr., SMOLLER, J. W., VAN TOL, M. J., SUSSMANN, J. E., PAUS, T., Lemaitre, H., SCHROETER, M. L., Mazoyer, B., ANDREASSEN, O. A., Holsboer, F., DEPONDT, C., VELTMAN, D. J., Turner, J. A., PAUSOVA, Z., Schumann, G., Van Rooij, D., Djurovic, S., DEARY, I. J., MCMAHON, K. L., MULLER-MYHSOK, B., BROUWER, R. M., Soininen, H., Pandolfo, M., WASSINK, T. H., CHEUNG, J. W., WOLFERS, T., MARTINOT, J. L., ZWIERS, M. P., Nauck, M., Melle, I., Martin, N. G., Kanai, R., WESTMAN, E., KAHN, R. S., Sisodiya, S. M., White, T., SAREMI, A., van Bokhoven, H., Brunner, H. G., VOLZKE, H., WRIGHT, M. J., VAN 'T ENT, D., NOTHEN, M. M., OPHOFF, R. A., BUITELAAR, J. K., Fernandez, G., SACHDEV, P. S., Rietschel, M., VAN HAREN, N. E. M., Fisher, S. E., BEISER, A. S., Francks, C., SAYKIN, A. J., MATHER, K. A., ROMANCZUK-SEIFERTH, N., HARTMAN, C. A., DeStefano, A. L., HESLENFELD, D. J., WEINER, M. W., Walter, H., HOEKSTRA, P. J., NYQUIST, P. A., Franke, B., BENNETT, D. A., Grabe, H. J., JOHNSON, A. D., Chen, C., VAN DUIJN, C. M., LOPEZ, O. L., FORNAGE, M., WARDLAW, J. M., Schmidt, R., DeCarli, C., DE JAGER, P. L., VILLRINGER, A., Debette, Stephanie, GUDNASON, V., Medland, S. E., SHULMAN, J. M., THOMPSON, P. M., SESHADRI, S., IKRAM, M. K., Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Neurosciences cognitives et intégratives d'Aquitaine (INCIA), and Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-SFR Bordeaux Neurosciences-Centre National de la Recherche Scientifique (CNRS)

Subjects
nervous system, VINTAGE, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, HEALTHY
Abstract

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

Published
2019

12. Biochemical, physiological and clinical effects of l-methylfolate in schizophrenia: a randomized controlled trial

Author

Roffman, J L, primary, Petruzzi, L J, additional, Tanner, A S, additional, Brown, H E, additional, Eryilmaz, H, additional, Ho, N F, additional, Giegold, M, additional, Silverstein, N J, additional, Bottiglieri, T, additional, Manoach, D S, additional, Smoller, J W, additional, Henderson, D C, additional, and Goff, D C, additional

Published
2017
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13. Partitioning heritability analysis reveals a shared genetic basis of brain anatomy and schizophrenia

Author

Lee, P., Baker, J., Holmes, A., Jahanshad, Neda, Ge, T., Jung, J-Y., Cruz, Y., Manoach, D., Hibar, Derrek, Faskowitz, Joshua, McMahon, Katie, de Zubicaray, Greig, Martin, Nicholas, Wright, Margie, Ongur, D., Buckner, R., Roffman, J., Thompson, Paul, Smoller, J., Lee, P., Baker, J., Holmes, A., Jahanshad, Neda, Ge, T., Jung, J-Y., Cruz, Y., Manoach, D., Hibar, Derrek, Faskowitz, Joshua, McMahon, Katie, de Zubicaray, Greig, Martin, Nicholas, Wright, Margie, Ongur, D., Buckner, R., Roffman, J., Thompson, Paul, and Smoller, J.

Abstract

Schizophrenia is a devastating neurodevelopmental disorder with a complex genetic etiology. Widespread cortical gray matter loss has been observed in patients and prodromal samples. However, it remains unresolved whether schizophrenia-associated cortical structure variations arise due to disease etiology or secondary to the illness. Here we address this question using a partitioning-based heritability analysis of genome-wide single-nucleotide polymorphism (SNP) and neuroimaging data from 1750 healthy individuals. We find that schizophrenia-associated genetic variants explain a significantly enriched proportion of trait heritability in eight brain phenotypes (false discovery rate=10%). In particular, intracranial volume and left superior frontal gyrus thickness exhibit significant and robust associations with schizophrenia genetic risk under varying SNP selection conditions. Cross-disorder comparison suggests that the neurogenetic architecture of schizophrenia-associated brain regions is, at least in part, shared with other psychiatric disorders. Our study highlights key neuroanatomical correlates of schizophrenia genetic risk in the general population. These may provide fundamental insights into the complex pathophysiology of the illness, and a potential link to neurocognitive deficits shaping the disorder.

Published
2016

15. The ENIGMA Consortium: Large-scale collaborative analyses of neuroimaging and genetic data

Author

Thompson, P., Stein, J., Medland, S., Hibar, D., Vasquez, A., Renteria, M., Toro, R., Jahanshad, N., Schumann, G., Franke, B., Wright, M., Martin, N., Agartz, I., Alda, M., Alhusaini, S., Almasy, L., Almeida, J., Alpert, K., Andreasen, N., Andreassen, O., Apostolova, L., Appel, K., Armstrong, N., Aribisala, B., Bastin, M., Bauer, M., Bearden, C., Bergmann, O., Binder, E., Blangero, J., Bockholt, H., Boen, E., Bois, C., Boomsma, D., Booth, T., Bowman, I., Bralten, J., Brouwer, R., Brunner, H., Brohawn, D., Buckner, R., Buitelaar, J., Bulayeva, K., Bustillo, J., Calhoun, V., Cannon, D., Cantor, R., Carless, M., Caseras, X., Cavalleri, G., Chakravarty, M., Chang, K., Ching, C., Christoforou, A., Cichon, S., Clark, V., Conrod, P., Coppola, G., Crespo-Facorro, B., Curran, J., Czisch, M., Deary, I., de Geus, E., den Braber, A., Delvecchio, G., Depondt, C., de Haan, L., de Zubicaray, G., Dima, D., Dimitrova, R., Djurovic, S., Dong, H., Donohoe, G., Duggirala, R., Dyer, T., Ehrlich, S., Ekman, C., Elvsashagen, T., Emsell, L., Erk, S., Espeseth, T., Fagerness, J., Fears, S., Fedko, I., Fernandez, G., Fisher, S., Foroud, T., Fox, P., Francks, C., Frangou, S., Frey, E., Frodl, T., Frouin, V., Garavan, H., Giddaluru, S., Glahn, D., Godlewska, B., Goldstein, R., Gollub, R., Grabe, H., Grimm, O., Gruber, O., Guadalupe, T., Gur, R., Goering, H., Hagenaars, S., Hajek, T., Hall, G., Hall, J., Hardy, J., Hartman, C., Hass, J., Hatton, S., Haukvik, U., Hegenscheid, K., Heinz, A., Hickie, I., Ho, B., Hoehn, D., Hoekstra, P., Hollinshead, M., Holmes, A., Homuth, G., Hoogman, M., Hong, L., Hosten, N., Hottenga, J., Pol, H., Hwang, K., Jack, C., Jenkinson, M., Johnston, C., Joensson, E., Kahn, R., Kasperaviciute, D., Kelly, S., Kim, S., Kochunov, P., Koenders, L., Kraemer, B., Kwok, J., Lagopoulos, J., Laje, G., Landen, M., Landman, B., Lauriello, J., Lawrie, S., Lee, P., Le Hellard, S., Lemaitre, H., Leonardo, C., Li, C., Liberg, B., Liewald, D., Liu, X., Lopez, L., Loth, E., Lourdusamy, A., Luciano, M., Macciardi, F., Machielsen, M., MacQueen, G., Malt, U., Mandl, R., Manoach, D., Martinot, J., Matarin, M., Mather, K., Mattheisen, M., Mattingsdal, M., Meyer-Lindenberg, A., McDonald, C., McIntosh, A., McMahon, F., McMahon, K., Meisenzahl, E., Melle, I., Milaneschi, Y., Mohnke, S., Montgomery, G., Morris, D., Moses, Eric, Mueller, B., Munoz Maniega, S., Muehleisen, T., Mueller-Myhsok, B., Mwangi, B., Nauck, M., Nho, K., Nichols, T., Nilsson, L., Nugent, A., Nyberg, L., Olvera, R., Oosterlaan, J., Ophoff, R., Pandolfo, M., Papalampropoulou-Tsiridou, M., Papmeyer, M., Paus, T., Pausova, Z., Pearlson, G., Penninx, B., Peterson, C., Pfennig, A., Phillips, M., Pike, G., Poline, J., Potkin, S., Puetz, B., Ramasamy, A., Rasmussen, J., Rietschel, M., Rijpkema, M., Risacher, S., Roffman, J., Roiz-Santianez, R., Romanczuk-Seiferth, N., Rose, E., Royle, N., Rujescu, D., Ryten, M., Sachdev, P., Salami, A., Satterthwaite, T., Savitz, J., Saykin, A., Scanlon, C., Schmaal, L., Schnack, H., Schork, A., Schulz, S., Schuer, R., Seidman, L., Shen, L., Shoemaker, J., Simmons, A., Sisodiya, S., Smith, C., Smoller, J., Soares, J., Sponheim, S., Sprooten, E., Starr, J., Steen, V., Strakowski, S., Strike, L., Sussmann, J., Saemann, P., Teumer, A., Toga, A., Tordesillas-Gutierrez, D., Trabzuni, D., Trost, S., Turner, J., Van den Heuvel, M., van der Wee, N., van Eijk, K., van Erp, T., van Haren, N., van 't Ent, D., van Tol, M., Hernandez, M., Veltman, D., Versace, A., Voelzke, H., Walker, R., Walter, H., Wang, L., Wardlaw, J., Weale, M., Weiner, M., Wen, W., Westlye, L., Whalley, H., Whelan, C., White, T., Winkler, A., Wittfeld, K., Woldehawariat, G., Wolf, C., Zilles, D., Zwiers, M., Thalamuthu, A., Schofield, P., Freimer, N., Lawrence, N., Drevets, W., Thompson, P., Stein, J., Medland, S., Hibar, D., Vasquez, A., Renteria, M., Toro, R., Jahanshad, N., Schumann, G., Franke, B., Wright, M., Martin, N., Agartz, I., Alda, M., Alhusaini, S., Almasy, L., Almeida, J., Alpert, K., Andreasen, N., Andreassen, O., Apostolova, L., Appel, K., Armstrong, N., Aribisala, B., Bastin, M., Bauer, M., Bearden, C., Bergmann, O., Binder, E., Blangero, J., Bockholt, H., Boen, E., Bois, C., Boomsma, D., Booth, T., Bowman, I., Bralten, J., Brouwer, R., Brunner, H., Brohawn, D., Buckner, R., Buitelaar, J., Bulayeva, K., Bustillo, J., Calhoun, V., Cannon, D., Cantor, R., Carless, M., Caseras, X., Cavalleri, G., Chakravarty, M., Chang, K., Ching, C., Christoforou, A., Cichon, S., Clark, V., Conrod, P., Coppola, G., Crespo-Facorro, B., Curran, J., Czisch, M., Deary, I., de Geus, E., den Braber, A., Delvecchio, G., Depondt, C., de Haan, L., de Zubicaray, G., Dima, D., Dimitrova, R., Djurovic, S., Dong, H., Donohoe, G., Duggirala, R., Dyer, T., Ehrlich, S., Ekman, C., Elvsashagen, T., Emsell, L., Erk, S., Espeseth, T., Fagerness, J., Fears, S., Fedko, I., Fernandez, G., Fisher, S., Foroud, T., Fox, P., Francks, C., Frangou, S., Frey, E., Frodl, T., Frouin, V., Garavan, H., Giddaluru, S., Glahn, D., Godlewska, B., Goldstein, R., Gollub, R., Grabe, H., Grimm, O., Gruber, O., Guadalupe, T., Gur, R., Goering, H., Hagenaars, S., Hajek, T., Hall, G., Hall, J., Hardy, J., Hartman, C., Hass, J., Hatton, S., Haukvik, U., Hegenscheid, K., Heinz, A., Hickie, I., Ho, B., Hoehn, D., Hoekstra, P., Hollinshead, M., Holmes, A., Homuth, G., Hoogman, M., Hong, L., Hosten, N., Hottenga, J., Pol, H., Hwang, K., Jack, C., Jenkinson, M., Johnston, C., Joensson, E., Kahn, R., Kasperaviciute, D., Kelly, S., Kim, S., Kochunov, P., Koenders, L., Kraemer, B., Kwok, J., Lagopoulos, J., Laje, G., Landen, M., Landman, B., Lauriello, J., Lawrie, S., Lee, P., Le Hellard, S., Lemaitre, H., Leonardo, C., Li, C., Liberg, B., Liewald, D., Liu, X., Lopez, L., Loth, E., Lourdusamy, A., Luciano, M., Macciardi, F., Machielsen, M., MacQueen, G., Malt, U., Mandl, R., Manoach, D., Martinot, J., Matarin, M., Mather, K., Mattheisen, M., Mattingsdal, M., Meyer-Lindenberg, A., McDonald, C., McIntosh, A., McMahon, F., McMahon, K., Meisenzahl, E., Melle, I., Milaneschi, Y., Mohnke, S., Montgomery, G., Morris, D., Moses, Eric, Mueller, B., Munoz Maniega, S., Muehleisen, T., Mueller-Myhsok, B., Mwangi, B., Nauck, M., Nho, K., Nichols, T., Nilsson, L., Nugent, A., Nyberg, L., Olvera, R., Oosterlaan, J., Ophoff, R., Pandolfo, M., Papalampropoulou-Tsiridou, M., Papmeyer, M., Paus, T., Pausova, Z., Pearlson, G., Penninx, B., Peterson, C., Pfennig, A., Phillips, M., Pike, G., Poline, J., Potkin, S., Puetz, B., Ramasamy, A., Rasmussen, J., Rietschel, M., Rijpkema, M., Risacher, S., Roffman, J., Roiz-Santianez, R., Romanczuk-Seiferth, N., Rose, E., Royle, N., Rujescu, D., Ryten, M., Sachdev, P., Salami, A., Satterthwaite, T., Savitz, J., Saykin, A., Scanlon, C., Schmaal, L., Schnack, H., Schork, A., Schulz, S., Schuer, R., Seidman, L., Shen, L., Shoemaker, J., Simmons, A., Sisodiya, S., Smith, C., Smoller, J., Soares, J., Sponheim, S., Sprooten, E., Starr, J., Steen, V., Strakowski, S., Strike, L., Sussmann, J., Saemann, P., Teumer, A., Toga, A., Tordesillas-Gutierrez, D., Trabzuni, D., Trost, S., Turner, J., Van den Heuvel, M., van der Wee, N., van Eijk, K., van Erp, T., van Haren, N., van 't Ent, D., van Tol, M., Hernandez, M., Veltman, D., Versace, A., Voelzke, H., Walker, R., Walter, H., Wang, L., Wardlaw, J., Weale, M., Weiner, M., Wen, W., Westlye, L., Whalley, H., Whelan, C., White, T., Winkler, A., Wittfeld, K., Woldehawariat, G., Wolf, C., Zilles, D., Zwiers, M., Thalamuthu, A., Schofield, P., Freimer, N., Lawrence, N., and Drevets, W.

Abstract

The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way. © 2014 The Author(s).

Published
2014

16. Biochemical, physiological and clinical effects of l-methylfolate in schizophrenia: a randomized controlled trial

Author

Roffman, J L, Petruzzi, L J, Tanner, A S, Brown, H E, Eryilmaz, H, Ho, N F, Giegold, M, Silverstein, N J, Bottiglieri, T, Manoach, D S, Smoller, J W, Henderson, D C, and Goff, D C

Abstract

Folic acid supplementation confers modest benefit in schizophrenia, but its effectiveness is influenced by common genetic variants in the folate pathway that hinder conversion to its active form. We examined physiological and clinical effects of l-methylfolate, the fully reduced and bioactive form of folate, in schizophrenia. In this randomized, double-blind trial, outpatients with schizophrenia (n=55) received l-methylfolate 15 mg or placebo for 12 weeks. Patients were maintained on stable doses of antipsychotic medications. The pre-defined primary outcome was change in plasma methylfolate at 12 weeks. Secondary outcomes included change in symptoms (Positive and Negative Syndrome Scale (PANSS), Scale for Assessment of Negative Symptoms, Calgary Depression Scale for Schizophrenia), cognition (Measurement and Treatment Research to Improve Cognition in Schizophrenia composite) and three complementary magnetic resonance imaging measures (working memory-related activation, resting connectivity, cortical thickness). Primary, mixed model, intent-to-treat analyses covaried for six genetic variants in the folate pathway previously associated with symptom severity and/or response to folate supplementation. Analyses were repeated without covariates to evaluate dependence on genotype. Compared with placebo, l-methylfolate increased plasma methylfolate levels (d=1.00, P=0.0009) and improved PANSS Total (d=0.61, P=0.03) as well as PANSS Negative and General Psychopathology subscales. Although PANSS Total and General Psychopathology changes were influenced by genotype, significant PANSS Negative changes occurred regardless of genotype. No treatment differences were seen in other symptom rating scales or cognitive composite scores. Patients receiving l-methylfolate exhibited convergent changes in ventromedial prefrontal physiology, including increased task-induced deactivation, altered limbic connectivity and increased cortical thickness. In conclusion, l-methylfolate supplementation was associated with salutary physiological changes and selective symptomatic improvement in this study of schizophrenia patients, warranting larger clinical trials. ClinicalTrials.gov, NCT01091506.

Published
2018
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17. Identification of common variants associated with human hippocampal and intracranial volumes

Author

Stein, J., Medland, S., Vasquez, A., Hibar, D., Senstad, R., Winkler, A., Toro, R., Appel, K., Bartecek, R., Bergmann, O., Bernard, M., Brown, A., Cannon, D., Chakravarty, M., Christoforou, A., Domin, M., Grimm, O., Hollinshead, M., Holmes, A., Homuth, G., Hottenga, J., Langan, C., Lopez, L., Hansell, N., Hwang, K., Kim, S., Laje, G., Lee, P., Liu, X., Loth, E., Lourdusamy, A., Mattingsdal, M., Mohnke, S., Maniega, S., Nho, K., Nugent, A., O'Brien, C., Papmeyer, M., Putz, B., Ramasamy, A., Rasmussen, J., Rijpkema, M., Risacher, S., Roddey, J., Rose, E., Ryten, M., Shen, L., Sprooten, E., Strengman, E., Teumer, A., Trabzuni, D., Turner, J., van Eijk, K., van Erp, T., van Tol, M., Wittfeld, K., Wolf, C., Woudstra, S., Aleman, A., Alhusaini, S., Almasy, L., Binder, E., Brohawn, D., Cantor, R., Carless, M., Corvin, A., Czisch, M., Curran, J., Davies, G., de Almeida, M., Delanty, N., Depondt, C., Duggirala, R., Dyer, T., Erk, S., Fagerness, J., Fox, P., Freimer, N., Gill, M., Goering, H., Hagler, D., Hoehn, D., Holsboer, F., Hoogman, M., Hosten, N., Jahanshad, N., Johnson, M., Kasperaviciute, D., Kent, J., Kochunov, P., Lancaster, J., Lawrie, S., Liewald, D., Mandl, R., Matarin, M., Mattheisen, M., Meisenzahl, E., Melle, I., Moses, Eric, Muehleisen, T., Nauck, M., Noethen, M., Olvera, R., Pandolfo, M., Pike, G., Puls, R., Reinvang, I., Renteria, M., Rietschel, M., Roffman, J., Royle, N., Rujescu, D., Savitz, J., Schnack, H., Schnell, K., Seiferth, N., Smith, C., Steen, V., Hernandez, M., Van den Heuvel, M., van der Wee, N., Van Haren, N., Veltman, J., Voelzke, H., Walker, R., Westlye, L., Whelan, C., Agartz, I., Boomsma, D., Cavalleri, G., Dale, A., Djurovic, S., Drevets, W., Hagoort, P., Hall, J., Heinz, A., Jack, C., Foroud, T., Le Hellard, S., Macciardi, F., Montgomery, G., Poline, J., Porteous, D., Sisodiya, S., Starr, J., Sussmann, J., Toga, A., Veltman, D., Walter, H., Weiner, M., Bis, J., Ikram, M., Smith, A., Gudnason, V., Tzourio, C., Vernooij, M., Launer, L., DeCarli, C., Seshadri, S., Andreassen, O., Apostolova, L., Bastin, M., Blangero, J., Brunner, H., Buckner, R., Cichon, S., Coppola, G., de Zubicaray, G., Deary, I., Donohoe, G., de Geus, E., Espeseth, T., Fernandez, G., Glahn, D., Grabe, H., Hardy, J., Pol, H., Jenkinson, M., Kahn, R., McDonald, C., McIntosh, A., McMahon, F., McMahon, K., Meyer-Lindenberg, A., Morris, D., Mueller-Myhsok, B., Nichols, T., Ophoff, R., Paus, T., Pausova, Z., Penninx, B., Potkin, S., Saemann, P., Saykin, A., Schumann, G., Smoller, J., Wardlaw, J., Weale, M., Martin, N., Franke, B., Wright, M., Thompson, P., Stein, J., Medland, S., Vasquez, A., Hibar, D., Senstad, R., Winkler, A., Toro, R., Appel, K., Bartecek, R., Bergmann, O., Bernard, M., Brown, A., Cannon, D., Chakravarty, M., Christoforou, A., Domin, M., Grimm, O., Hollinshead, M., Holmes, A., Homuth, G., Hottenga, J., Langan, C., Lopez, L., Hansell, N., Hwang, K., Kim, S., Laje, G., Lee, P., Liu, X., Loth, E., Lourdusamy, A., Mattingsdal, M., Mohnke, S., Maniega, S., Nho, K., Nugent, A., O'Brien, C., Papmeyer, M., Putz, B., Ramasamy, A., Rasmussen, J., Rijpkema, M., Risacher, S., Roddey, J., Rose, E., Ryten, M., Shen, L., Sprooten, E., Strengman, E., Teumer, A., Trabzuni, D., Turner, J., van Eijk, K., van Erp, T., van Tol, M., Wittfeld, K., Wolf, C., Woudstra, S., Aleman, A., Alhusaini, S., Almasy, L., Binder, E., Brohawn, D., Cantor, R., Carless, M., Corvin, A., Czisch, M., Curran, J., Davies, G., de Almeida, M., Delanty, N., Depondt, C., Duggirala, R., Dyer, T., Erk, S., Fagerness, J., Fox, P., Freimer, N., Gill, M., Goering, H., Hagler, D., Hoehn, D., Holsboer, F., Hoogman, M., Hosten, N., Jahanshad, N., Johnson, M., Kasperaviciute, D., Kent, J., Kochunov, P., Lancaster, J., Lawrie, S., Liewald, D., Mandl, R., Matarin, M., Mattheisen, M., Meisenzahl, E., Melle, I., Moses, Eric, Muehleisen, T., Nauck, M., Noethen, M., Olvera, R., Pandolfo, M., Pike, G., Puls, R., Reinvang, I., Renteria, M., Rietschel, M., Roffman, J., Royle, N., Rujescu, D., Savitz, J., Schnack, H., Schnell, K., Seiferth, N., Smith, C., Steen, V., Hernandez, M., Van den Heuvel, M., van der Wee, N., Van Haren, N., Veltman, J., Voelzke, H., Walker, R., Westlye, L., Whelan, C., Agartz, I., Boomsma, D., Cavalleri, G., Dale, A., Djurovic, S., Drevets, W., Hagoort, P., Hall, J., Heinz, A., Jack, C., Foroud, T., Le Hellard, S., Macciardi, F., Montgomery, G., Poline, J., Porteous, D., Sisodiya, S., Starr, J., Sussmann, J., Toga, A., Veltman, D., Walter, H., Weiner, M., Bis, J., Ikram, M., Smith, A., Gudnason, V., Tzourio, C., Vernooij, M., Launer, L., DeCarli, C., Seshadri, S., Andreassen, O., Apostolova, L., Bastin, M., Blangero, J., Brunner, H., Buckner, R., Cichon, S., Coppola, G., de Zubicaray, G., Deary, I., Donohoe, G., de Geus, E., Espeseth, T., Fernandez, G., Glahn, D., Grabe, H., Hardy, J., Pol, H., Jenkinson, M., Kahn, R., McDonald, C., McIntosh, A., McMahon, F., McMahon, K., Meyer-Lindenberg, A., Morris, D., Mueller-Myhsok, B., Nichols, T., Ophoff, R., Paus, T., Pausova, Z., Penninx, B., Potkin, S., Saemann, P., Saykin, A., Schumann, G., Smoller, J., Wardlaw, J., Weale, M., Martin, N., Franke, B., Wright, M., and Thompson, P.

Abstract

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10 -16) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10 -12). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10 -7). © 2012 Nature America, Inc. All rights reserved.

Published
2012

23. Subcortical Volume Trajectories across the Lifespan: Data from 18,605 healthy individuals aged 3-90 years

Author

Dima, D., Papachristou, E., Modabbernia, A., Doucet, G. E., Agartz, I., Aghajani, M., Akudjedu, T. N., Albajes-Eizagirre, A., Alnæs, D., Alpert, K. I., Andersson, M., Andreasen, N., Andreassen, O. A., Asherson, P., Banaschewski, T., Bargallo, N., Baumeister, S., Baur-Streubel, R., Bertolino, A., Bonvino, A., Boomsma, D. I., Borgwardt, S., Bourque, J., Brandeis, D., Breier, A., Brodaty, H., Brouwer, R. M., Buitelaar, J. K., Busatto, G. F., Buckner, R. L., Calhoun, V., Canales-Rodríguez, E. J., Cannon, D. M., Caseras, X., Castellanos, F. X., Cervenka, S., Chaim-Avancini, T. M., Ching, C. R. K., Clark, V. P., Conrod, P., Conzelmann, A., Crespo-Facorro, B., Crivello, F., Crone, E. A. M., Dale, A. M., Davey, C., de Geus, E. J. C., de Haan, L., de Zubicaray, G. I., den Braber, A., Dickie, E. W., Di Giorgio, A., Doan, N. T., Dørum, E. S., Ehrlich, S., Erk, S., Espeseth, T., Fatouros-Bergman, H., Fisher, S. E., Fouche, J-P., Franke, B., Frodl, T., Fuentes-Claramonte, P., Glahn, D. C., Gotlib, I. H., Grabe, H-J., Grimm, O., Groenewold, N. A., Grotegerd, D., Gruber, O., Gruner, P., Gur, R. E., Gur, R. C., Harrison, B. J., Hartman, C. A., Hatton, S. N., Heinz, A., Heslenfeld, D. J., Hibar, D. P., Hickie, I. B., Ho, B-C., Hoekstra, P. J., Hohmann, S., Holmes, A. J., Hoogman, M., Hosten, N., Howells, F. M., Hulshoff Pol, H. E., Huyser, C., Jahanshad, N., James, A., Jiang, J., Jönsson, E. G., Joska, J. A., Kahn, R., Kalnin, A., Kanai, R., Kang, S., Klein, M., Klushnik, T. P., Koenders, L., Koops, S., Krämer, B., Kuntsi, J., Lagopoulos, J., Lázaro, L., Lebedeva, I., Lee, W. H., Lesch, K-P., Lochner, C., Machielsen, M. W. J., Maingault, S., Martin, N. G., Martínez-Zalacaín, I., Mataix-Cols, D., Mazoyer, B., McDonald, C., McDonald, B. C., McIntosh, A. M., McMahon, K. L., McPhilemy, G., Menchón, J. M., Medland, S. E., Meyer-Lindenberg, A., Naaijen, J., Najt, P., Nakao, T., Nordvik, J. E., Nyberg, L., Oosterlaan, J., de la Foz, V. O-G., Paloyelis, Y., Pauli, P., Pergola, G., Pomarol-Clotet, E., Portella, M. J., Potkin, S. G., Radua, J., Reif, A., Roffman, J. L., Rosa, P. G. P., Sacchet, M. D., Sachdev, P. S., Salvador, R., Sánchez-Juan, P., Sarró, S., Satterthwaite, T. D., Saykin, A. J., Serpa, M. H., Schmaal, L., Schnell, K., Schumann, G., Smoller, J. W., Sommer, I., Soriano-Mas, C., Stein, D. J., Strike, L. T., Swagerman, S. C., Tamnes, C. K., Temmingh, H. S., Thomopoulos, S. I., Tomyshev, A. S., Tordesillas-Gutiérrez, D., Trollor, J. N., Turner, J. A., Uhlmann, A., van den Heuvel, O. A., van den Meer, D., van der Wee, N. J. A., van Haren, N. E. M., van ’t Ent, D., van Erp, T. G. M., Veer, I. M., Veltman, D. J., Völzke, H., Walter, H., Walton, E., Wang, L., Wang, Y., Wassink, T. H., Weber, B., Wen, W., West, J. D., Westlye, L. T., Whalley, H., Wierenga, L. M., Williams, S. C. R., Wittfeld, K., Wolf, D. H., Worker, A., Wright, M. J., Yang, K., Yoncheva, Y., Zanetti, M. V., Ziegler, G. C., Thompson, P. M., and Frangou, S.

Subjects
nervous system, BF
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 capitalised on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine the age-related morphometric trajectories 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 early in life; the volume of the basal ganglia showed a gradual monotonic decline thereafter while the volumes of the thalamus, amygdala and the hippocampus remained largely stable (with some degree of decline in thalamus) until the sixth decade of life followed by a steep decline thereafter. The lateral ventricles showed a trajectory of continuous enlargement throughout the lifespan. Significant age-related increase in inter-individual variability was found for the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to derive risk predictions for the early identification of diverse clinical phenotypes.

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

Author

Dima, D., Modabbernia, A., Papachristou4, E., Doucet, G. E., Agartz, I., Aghajani, M., Akudjedu, Theophilus. N., Albajes-Eizagirre, A., Alnaes, D, Alpert, K. I., Andersson, M., Andreasen, N. C., Andreassen, O. A., Asherson, P., Banaschewski, T., Bargallo, N., Baumeister, S., Baur-Streubel, R., Bertolino, A., Bonvino, A., Boomsma, D. I., Borgwardt, S., Bourque, J., Brandeis, D., Breier, A., Brodaty, H., Brouwer, R. M., Buitelaar, J. K., Busatto, G. F., Buckner, R. L., Calhoun, V., Canales-Rodríguez, E. J., Cannon, D. M., Caseras, X., Castellanos, F. X., Cervenka, S, Chaim-Avancini, T. M., Ching, C. R. K., Chubar, V., Clark, V. P., Conrod, P., Conzelmann, A., Crespo-Facorro, B, Crivello, F., Crone, E. A., Dale, A. M., Davey, C., de Geus, E. J. C, de Haan, L., de Zubicaray, G. I., den Braber, A., Dickie, E. W., Di Giorgio, A., Doan, N. T., Dørum, E. S., Ehrlich, S., Erk, S., Espeseth, T., Fatouros- Bergman, H., Fisher, S. E., Fouche, J. P., Franke, B., Frodl, T., Fuentes-Claramonte, P., Glahn, D. C., Gotlib, I. H., Grabe, H. J., Grimm, O., Groenewold, N. A., Grotegerd, D., Gruber, O., Gruner, P., Gur, R. E., Gur, R. C., Harrison, B. J., Hartman, C. A., Hatton, S. N., Heinz, A., Heslenfeld, D. J., Hibar, D. P., Hickie, I. B., Ho, B. C., Hoekstra, P. J., Hohmann, S., Holmes, A. J., Hoogman, M., Hosten, N., Howells, F. M., Hulshoff Pol, H. E., Huyser, C., Jahanshad, N., James, A., Jernigan, T. L., Jiang, J., Jönsson, E. G., Joska, J. A., Kahn, R., Kalnin, A., Kanai, R., Klein, M., Klyushnik, T. P., Koenders, L., Koops, S., Krämer, B., Kuntsi, J., Lagopoulos, J., Lázaro, L., Lebedeva, I., Lee, W. H., Lesch, K. P., Lochner, C., Machielsen, M. W. J., Maingault, S., Martin, N. G., Martínez-Zalacaín, I., Mataix-Cols, D., Mazoyer, B., McDonald, C., McDonald, B. C., McIntosh, A. M., McMahon, K. L., McPhilemy, G., Menchón, J. M., Medland, S. E., Meyer-Lindenberg, A., Naaijen, J., Najt, P., Nakao, T., Nordvik, J. E., Nyberg, L., Oosterlaan, J., Ortiz-García de la Foz, V., Paloyelis, Y., Pauli, P., Pergola, G., Pomarol-Clotet, E., Portella, M. J., Potkin, S. G., Radua, J., Reif, A., Rinker, D. A., Roffman, J. L., Rosa, P. G. P., Sacchet, M. D., Sachdev, P. S., Salvador, R., Sánchez-Juan, P., Sarró, S., Satterthwaite, T. D., Saykin, A. J., Serpa, M. H., Schmaal, L., Schnell, K., Schumann, G., Sim, K., Smoller, J. W., Sommer, I., Soriano-Mas, C., Stein, D. J., Strike, L. T., Swagerman, S. C., Tamnes, C. K., Temmingh, H. S., Thomopoulos, S. I., Tomyshev, A. S., Tordesillas-Gutiérrez, D., Trollor, J. N., Turner, J. A., Uhimann, A., van den Heuvel, O. A., van den Meer, D., van der Wee, N. J. A., van Haren, N. E. M., van't Ent, D., van Erp, T. G. M., Veer, I. M., Veltman, D. J., Voineskos, A., Völzke, H., Walter, H., Walton, E., Wang, L., Wang, Y., Wassink, T. H., Weber, B., Wen, W., West, J. D., Westlye, L. T., Whalley, H., Wierenga, L. M., Williams, S. C. R., Wittfeld, K., Wolf, D. H., Worker, A., Wright, M. J., Yang, K., Yoncheva, Y., Zanetti, M. V., Ziegler, G. C., Thompson, P. M., Frangou, S., Karolinska Schizophrenia Project (KaSP), Dima, D., Modabbernia, A., Papachristou4, E., Doucet, G. E., Agartz, I., Aghajani, M., Akudjedu, Theophilus. N., Albajes-Eizagirre, A., Alnaes, D, Alpert, K. I., Andersson, M., Andreasen, N. C., Andreassen, O. A., Asherson, P., Banaschewski, T., Bargallo, N., Baumeister, S., Baur-Streubel, R., Bertolino, A., Bonvino, A., Boomsma, D. I., Borgwardt, S., Bourque, J., Brandeis, D., Breier, A., Brodaty, H., Brouwer, R. M., Buitelaar, J. K., Busatto, G. F., Buckner, R. L., Calhoun, V., Canales-Rodríguez, E. J., Cannon, D. M., Caseras, X., Castellanos, F. X., Cervenka, S, Chaim-Avancini, T. M., Ching, C. R. K., Chubar, V., Clark, V. P., Conrod, P., Conzelmann, A., Crespo-Facorro, B, Crivello, F., Crone, E. A., Dale, A. M., Davey, C., de Geus, E. J. C, de Haan, L., de Zubicaray, G. I., den Braber, A., Dickie, E. W., Di Giorgio, A., Doan, N. T., Dørum, E. S., Ehrlich, S., Erk, S., Espeseth, T., Fatouros- Bergman, H., Fisher, S. E., Fouche, J. P., Franke, B., Frodl, T., Fuentes-Claramonte, P., Glahn, D. C., Gotlib, I. H., Grabe, H. J., Grimm, O., Groenewold, N. A., Grotegerd, D., Gruber, O., Gruner, P., Gur, R. E., Gur, R. C., Harrison, B. J., Hartman, C. A., Hatton, S. N., Heinz, A., Heslenfeld, D. J., Hibar, D. P., Hickie, I. B., Ho, B. C., Hoekstra, P. J., Hohmann, S., Holmes, A. J., Hoogman, M., Hosten, N., Howells, F. M., Hulshoff Pol, H. E., Huyser, C., Jahanshad, N., James, A., Jernigan, T. L., Jiang, J., Jönsson, E. G., Joska, J. A., Kahn, R., Kalnin, A., Kanai, R., Klein, M., Klyushnik, T. P., Koenders, L., Koops, S., Krämer, B., Kuntsi, J., Lagopoulos, J., Lázaro, L., Lebedeva, I., Lee, W. H., Lesch, K. P., Lochner, C., Machielsen, M. W. J., Maingault, S., Martin, N. G., Martínez-Zalacaín, I., Mataix-Cols, D., Mazoyer, B., McDonald, C., McDonald, B. C., McIntosh, A. M., McMahon, K. L., McPhilemy, G., Menchón, J. M., Medland, S. E., Meyer-Lindenberg, A., Naaijen, J., Najt, P., Nakao, T., Nordvik, J. E., Nyberg, L., Oosterlaan, J., Ortiz-García de la Foz, V., Paloyelis, Y., Pauli, P., Pergola, G., Pomarol-Clotet, E., Portella, M. J., Potkin, S. G., Radua, J., Reif, A., Rinker, D. A., Roffman, J. L., Rosa, P. G. P., Sacchet, M. D., Sachdev, P. S., Salvador, R., Sánchez-Juan, P., Sarró, S., Satterthwaite, T. D., Saykin, A. J., Serpa, M. H., Schmaal, L., Schnell, K., Schumann, G., Sim, K., Smoller, J. W., Sommer, I., Soriano-Mas, C., Stein, D. J., Strike, L. T., Swagerman, S. C., Tamnes, C. K., Temmingh, H. S., Thomopoulos, S. I., Tomyshev, A. S., Tordesillas-Gutiérrez, D., Trollor, J. N., Turner, J. A., Uhimann, A., van den Heuvel, O. A., van den Meer, D., van der Wee, N. J. A., van Haren, N. E. M., van't Ent, D., van Erp, T. G. M., Veer, I. M., Veltman, D. J., Voineskos, A., Völzke, H., Walter, H., Walton, E., Wang, L., Wang, Y., Wassink, T. H., Weber, B., Wen, W., West, J. D., Westlye, L. T., Whalley, H., Wierenga, L. M., Williams, S. C. R., Wittfeld, K., Wolf, D. H., Worker, A., Wright, M. J., Yang, K., Yoncheva, Y., Zanetti, M. V., Ziegler, G. C., Thompson, P. M., Frangou, S., and Karolinska Schizophrenia Project (KaSP)

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.

25. Cortical Thickness across the Lifespan: Data from 17,075 healthy individuals aged 3-90 years

Author

Frangou, S., Modabbernia, A., Williams, S.C.R., Papachristou, E., Doucet, G. E., Agartz, I., Aghajani, M., Akudjedu, T.N., Albajes-Eizagirre, A., Alnæs, D., Alpert, K. I., Andersson, M., Andreasen, N. C., Andreassen, O.A., Asherson, P., Banaschewski, T., Bargallo, N., Baumeister, S., Baur-Streubel, R., Bertolino, A., Bonvino, A., Boomsma, D.I., Borgwardt, S., Bourque, J., Brandeis, D., Breier, A., Brodaty, H., Brouwer, R. M., Buitelaar, J. K., Busatto, G. F., Buckner, R. L., Calhoun, V., Canales-Rodríguez, E. J., Cannon, D.M., Caseras, X., Castellanos, F. X., Cervenka, S, Chaim-Avancini, T. M., Ching, C. R. K., Chubar, V., Clark, V.P., Conrod, P., Conzelmann, A., Crespo-Facorro, B, Crivello, F., Crone, E. A., Dale, A. M., Davey, C., de Geus, E. J. C, de Haan, L., de Zubicaray, G. I., den Braber, A., Dickie, E. W., Di Giorgio, A., Doan, N.T., Dørum, E. S., Ehrlich, S., Erk, S., Espeseth, T., Fatouros-Bergman, H., Fisher, S. E., Fouche, J. P., Franke, B., Frodl, T., Fuentes-Claramonte, P., Glahn, D. C., Gotlib, I. H., Grabe, H.J., Grimm, O., Groenewold, N. A., Grotegerd, D., Gruber, O., Gruner, P., Gur, R. E., Gur, R. C., Harrison, B. J., Hartman, C. A., Hatton, S. N., Heinz, A., Heslenfeld, D. J., Hibar, D. P., Hickie, I.B., Ho, B.C., Hoekstra, P. J., Hohmann, S., Holmes, A. J., Hoogman, M., Hosten, N., Howells, F. M., Hulshoff Pol, H. E., Huyser, C., Jahanshad, N., James, A., Jernigan, T. L., Jiang, J., Jönsson, E. G., Joska, J. A., Kahn, R., Kalnin, A., Kanai, R., Klein, M., Klyushnik, T. P., Koenders, L., Koops, S., Krämer, B., Kuntsi, J., Lagopoulos, J., Lazaro, L., Lebedeva, I., Lee, W. H., Lesch, K. P., Lochner, C., Machielsen, M. W. J., Maingault, S., Martin, N.G., Martínez-Zalacaín, I., Mataix-Cols, D., Mazoyer, B., McDonald, C., McDonald, B. C., McIntosh, A.M., McMahon, K. L., McPhilemy, G., Menchón, J.M., Medland, S. E., Meyer-Lindenberg, A., Naaijen, J., Najt, P., Nakao, T., Nordvik, J. E., Nyberg, L., Oosterlaan, J., Ortiz-García de la Foz, V., Paloyelis, Y., Pauli, P., Pergola, G., Pomarol-Clotet, E., Portella, M. J., Potkin, S. G., Radua, J., Reif, A., Rinker, D. A., Roffman, J. L., Rosa, P. G. P., Sacchet, M. D., Sachdev, P. S., Salvador, R., Sánchez-Juan, P., Sarró, S., Satterthwaite, T. D., Saykin, A. J., Serpa, M. H., Schmaal, L., Schnell, K., Schumann, G., Sim, K., Smoller, J.W., Sommer, I., Soriano-Mas, C., Stein, D.J., Strike, L.T., Swagerman, S. C., Tamnes, C. K., Temmingh, H. S., Thomopoulos, S.I., Tomyshev, A. S., Tordesillas-Gutiérrez, D., Trollor, J.N., Turner, J.A., Uhlmann, A., van den Heuvel, O. A., van den Meer, D., van der Wee, N. J. A., van Haren, N. E. M., van 't Ent, D., van Erp, T. G. M., Veer, I. M., Veltman, D. J., Voineskos, A., Völzke, H., Walter, H., Walton, E., Wang, L., Wang, Y., Wassink, T. H., Weber, B., Wen, W., West, J.D., Westlye, L. T., Whalley, H., Wierenga, L. M., Wittfeld, K., Wolf, D. H., Worker, A., Wright, M. J., Yang, K., Yoncheva, Y., Zanetti, M. V., Ziegler, G. C., Karolinska Schizophrenia Project, K.a.S.P., Thompson, P.M., Dima, D., Frangou, S., Modabbernia, A., Williams, S.C.R., Papachristou, E., Doucet, G. E., Agartz, I., Aghajani, M., Akudjedu, T.N., Albajes-Eizagirre, A., Alnæs, D., Alpert, K. I., Andersson, M., Andreasen, N. C., Andreassen, O.A., Asherson, P., Banaschewski, T., Bargallo, N., Baumeister, S., Baur-Streubel, R., Bertolino, A., Bonvino, A., Boomsma, D.I., Borgwardt, S., Bourque, J., Brandeis, D., Breier, A., Brodaty, H., Brouwer, R. M., Buitelaar, J. K., Busatto, G. F., Buckner, R. L., Calhoun, V., Canales-Rodríguez, E. J., Cannon, D.M., Caseras, X., Castellanos, F. X., Cervenka, S, Chaim-Avancini, T. M., Ching, C. R. K., Chubar, V., Clark, V.P., Conrod, P., Conzelmann, A., Crespo-Facorro, B, Crivello, F., Crone, E. A., Dale, A. M., Davey, C., de Geus, E. J. C, de Haan, L., de Zubicaray, G. I., den Braber, A., Dickie, E. W., Di Giorgio, A., Doan, N.T., Dørum, E. S., Ehrlich, S., Erk, S., Espeseth, T., Fatouros-Bergman, H., Fisher, S. E., Fouche, J. P., Franke, B., Frodl, T., Fuentes-Claramonte, P., Glahn, D. C., Gotlib, I. H., Grabe, H.J., Grimm, O., Groenewold, N. A., Grotegerd, D., Gruber, O., Gruner, P., Gur, R. E., Gur, R. C., Harrison, B. J., Hartman, C. A., Hatton, S. N., Heinz, A., Heslenfeld, D. J., Hibar, D. P., Hickie, I.B., Ho, B.C., Hoekstra, P. J., Hohmann, S., Holmes, A. J., Hoogman, M., Hosten, N., Howells, F. M., Hulshoff Pol, H. E., Huyser, C., Jahanshad, N., James, A., Jernigan, T. L., Jiang, J., Jönsson, E. G., Joska, J. A., Kahn, R., Kalnin, A., Kanai, R., Klein, M., Klyushnik, T. P., Koenders, L., Koops, S., Krämer, B., Kuntsi, J., Lagopoulos, J., Lazaro, L., Lebedeva, I., Lee, W. H., Lesch, K. P., Lochner, C., Machielsen, M. W. J., Maingault, S., Martin, N.G., Martínez-Zalacaín, I., Mataix-Cols, D., Mazoyer, B., McDonald, C., McDonald, B. C., McIntosh, A.M., McMahon, K. L., McPhilemy, G., Menchón, J.M., Medland, S. E., Meyer-Lindenberg, A., Naaijen, J., Najt, P., Nakao, T., Nordvik, J. E., Nyberg, L., Oosterlaan, J., Ortiz-García de la Foz, V., Paloyelis, Y., Pauli, P., Pergola, G., Pomarol-Clotet, E., Portella, M. J., Potkin, S. G., Radua, J., Reif, A., Rinker, D. A., Roffman, J. L., Rosa, P. G. P., Sacchet, M. D., Sachdev, P. S., Salvador, R., Sánchez-Juan, P., Sarró, S., Satterthwaite, T. D., Saykin, A. J., Serpa, M. H., Schmaal, L., Schnell, K., Schumann, G., Sim, K., Smoller, J.W., Sommer, I., Soriano-Mas, C., Stein, D.J., Strike, L.T., Swagerman, S. C., Tamnes, C. K., Temmingh, H. S., Thomopoulos, S.I., Tomyshev, A. S., Tordesillas-Gutiérrez, D., Trollor, J.N., Turner, J.A., Uhlmann, A., van den Heuvel, O. A., van den Meer, D., van der Wee, N. J. A., van Haren, N. E. M., van 't Ent, D., van Erp, T. G. M., Veer, I. M., Veltman, D. J., Voineskos, A., Völzke, H., Walter, H., Walton, E., Wang, L., Wang, Y., Wassink, T. H., Weber, B., Wen, W., West, J.D., Westlye, L. T., Whalley, H., Wierenga, L. M., Wittfeld, K., Wolf, D. H., Worker, A., Wright, M. J., Yang, K., Yoncheva, Y., Zanetti, M. V., Ziegler, G. C., Karolinska Schizophrenia Project, K.a.S.P., Thompson, P.M., 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.

27. Elevated common variant genetic risk for tourette syndrome in a densely-affected pedigree

Author

Andrew McQuillin, Dongmei Yu, Jeremiah M. Scharf, Poorva Mudgal, Matthew Halvorsen, David Mataix-Cols, James J. Crowley, Mary M. Robertson, Ashley E. Nordsletten, Manuel Mattheisen, Jin P. Szatkiewicz, Carol A. Mathews, Psychiatric Genomics Consortium TS/OCD Working Group, Aschauer, H., Atzmon, G., Barr, C., Barta, C., Barzilai, N., Batterson, J., Berlin, C., Bodmer, B., Bohnenpoll, J., Brown, L., Bruun, R., Buckner, R., Budman, C., Cath, D., Cheon, K.A., Chouinard, S., Coffey, B., Coppola, G., Cox, N., Crowley, J., Darrow, S., Davis, L., Depienne, C., Dietrich, A., Dion, Y., Elzerman, L., Fernandez, T., Freimer, N., Fremer, C., Fründt, O., Garcia-Delgar, B., Gilbert, D., Grados, M., Greenberg, E., Grice, D., Hagstrøm, J., Halvorsen, M., Hartmann, A., Hebebrand, J., Hedderly, T., Heiman, G., Heyman, I., Hinney, A., Hirschtritt, M., Hoekstra, P., Hong, H., Huang, A., Huyser, C., Ibanez-Gomez, L., Illmann, C., Jankovic, J., Kim, Y., Kim, Y.S., King, R., Knowles, J., Koh, Y.J., Konstantinidis, A., Kook, S., Kuperman, S., Kurlan, R., Leckman, J., Lee, P., Leventhal, B., Ludolph, A., Luðvigsson, P., Lyon, G., Madruga-Garrido, M., Malaty, I., Maras, A., Mataix-Cols, D., Mathews, C., Mattheisen, M., McMahon, W., McQuillin, A., Mir, P., Moessner, R., Morer, A., Mudgal, P., Mueller-Vahl, K., Murphy, T., Münchau, A., Nagy, P., Nawaz, M., Neale, B., Nordsletten, A., Nöthen, M., Okun, M., Ophoff, R., Osiecki, L., Paschou, P., Pato, C., Pato, M., Pauls, D., Plessen, K., Posthuma, D., Richer, P., Rizzo, R., Robertson, M., Roessner, V., Roffman, J., Rouleau, G., Sandor, P., Sæmundsen, E., Scharf, J., Schlögelhofer, M., Shin, E.Y., Singer, H., Smit, J., Smoller, J., Song, D.H., Song, J., Stamenkovic, M., State, M., Stefansson, H., Stefansson, K., Stuhrmann, M., Sul, J., Szatkiewicz, J., Tarnok, Z., Thorarensen, Ó., Tischfield, J., Tsetsos, F., Tübing, J., Visscher, F., Wagner, M., Wanderer, S., Wang, S., Willsey, J., Wolanczyk, T., Woods, D., Woods, M., Worbe, Y., Yu, D., Zelaya, I., Zinner, S., Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), Plastic, Reconstructive and Hand Surgery, and Complex Trait Genetics

Subjects
Genetics, Tics, Single-nucleotide polymorphism, Biology, medicine.disease, Tourette syndrome, Genome, Identity by descent, Polymorphism, Single Nucleotide, Pedigree, Cellular and Molecular Neuroscience, Psychiatry and Mental health, Risk Factors, Tic Disorders, medicine, SNP, Humans, Copy-number variation, Polymorphism, Single Nucleotide/genetics, Tourette Syndrome/genetics, Indel, Molecular Biology, Tourette Syndrome
Abstract

Tourette syndrome (TS) is a highly heritable neuropsychiatric disorder with complex patterns of genetic inheritance. Recent genetic findings in TS have highlighted both numerous common variants with small effects and a few rare variants with moderate or large effects. Here we searched for genetic causes of TS in a large, densely-affected British pedigree using a systematic genomic approach. This pedigree spans six generations and includes 122 members, 85 of whom were individually interviewed, and 53 of whom were diagnosed as "cases" (consisting of 28 with definite or probable TS, 20 with chronic multiple tics [CMT], and five with obsessive-compulsive behaviors [OCB]). A total of 66 DNA samples were available (25 TS, 15 CMT, 4 OCB cases, and 22 unaffecteds) and all were genotyped using a dense single nucleotide polymorphism (SNP) array to identify shared segments, copy number variants (CNVs), and to calculate genetic risk scores. Eight cases were also whole genome sequenced to test whether any rare variants were shared identical by descent. While we did not identify any notable CNVs, single nucleotide variants, indels or repeat expansions of near-Mendelian effect, the most distinctive feature of this family proved to be an unusually high load of common risk alleles for TS. We found that cases within this family carried a higher load of TS common variant risk similar to that previously found in unrelated TS cases. Thus far, the strongest evidence from genetic data for contribution to TS risk in this family comes from multiple common risk variants rather than one or a few variants of strong effect.

Published
2021

29. MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway: Role in lateral ventricles and corpus callosum volume.

Author

Blokland GAM, Maleki N, Jovicich J, Mesholam-Gately RI, DeLisi LE, Turner JA, Shenton ME, Voineskos AN, Kahn RS, Roffman JL, Holt DJ, Ehrlich S, Kikinis Z, Dazzan P, Murray RM, Lee J, Sim K, Lam M, de Zwarte SMC, Walton E, Kelly S, Picchioni MM, Bramon E, Makris N, David AS, Mondelli V, Reinders AATS, Oykhman E, Morris DW, Gill M, Corvin AP, Cahn W, Ho N, Liu J, Gollub RL, Manoach DS, Calhoun VD, Sponheim SR, Buka SL, Cherkerzian S, Thermenos HW, Dickie EW, Ciufolini S, Reis Marques T, Crossley NA, Purcell SM, Smoller JW, van Haren NEM, Toulopoulou T, Donohoe G, Goldstein JM, Keshavan MS, Petryshen TL, and Del Re EC

Abstract

Background/Objective. Enlarged lateral ventricle (LV) volume and decreased volume in the corpus callosum (CC) are hallmarks of schizophrenia (SZ). We previously showed an inverse correlation between LV and CC volumes in SZ, with global functioning decreasing with increased LV volume. This study investigates the relationship between LV volume, CC abnormalities, and the microRNA MIR137 and its regulated genes in SZ, because of MIR137's essential role in neurodevelopment. Methods . Participants were 1224 SZ probands and 1466 unaffected controls from the GENUS Consortium. Brain MRI scans, genotype, and clinical data were harmonized across cohorts and employed in the analyses. Results. Increased LV volumes and decreased CC central, mid-anterior, and mid-posterior volumes were observed in SZ probands. The MIR137-regulated ephrin pathway was significantly associated with CC:LV ratio, explaining a significant proportion (3.42 %) of CC:LV variance, and more than for LV and CC separately. Other pathways explained variance in either CC or LV, but not both. CC:LV ratio was also positively correlated with Global Assessment of Functioning, supporting previous subsample findings. SNP-based heritability estimates were higher for CC central:LV ratio (0.79) compared to CC or LV separately. Discussion. Our results indicate that the CC:LV ratio is highly heritable, influenced in part by variation in the MIR137-regulated ephrin pathway. Findings suggest that the CC:LV ratio may be a risk indicator in SZ that correlates with global functioning., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The author is an Editorial Board Member/Editor-in-Chief/Associate Editor/Guest Editor for International Journal of Clinical and Health Psychology and was not involved in the editorial review or the decision to publish this article., (© 2024 The Author(s).)

Published
2024
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31. Associations Between Genetic Risk for Adult Suicide Attempt and Suicidal Behaviors in Young Children in the US.

Author

Lee PH, Doyle AE, Silberstein M, Jung JY, Liu RT, Perlis RH, Roffman J, Smoller JW, Fava M, and Kessler RC

Subjects
Adolescent, Adult, Case-Control Studies, Child, Child, Preschool, Female, Genome-Wide Association Study, Humans, Longitudinal Studies, Male, Risk Factors, Suicidal Ideation, Suicide, Attempted psychology
Abstract

Importance: Suicide rates have been increasing among youth in the US. While the heritability of suicide risk is well established, there is limited understanding of how genetic risk is associated with suicidal thoughts and behaviors in young children., Objective: To examine whether genetic susceptibility to suicide attempts (SAs) is associated with suicidal thoughts and behaviors in children., Design, Setting, and Participants: This case-control study examined data from the Adolescent Brain Cognitive Development (ABCD) study, a population-based longitudinal study of 11 878 US children enrolled at age 9 and 10 years from September 2016 to November 2018. Youth reports of suicidal ideation (SI) and SAs were obtained from the Kiddie Schedule for Affective Disorder and Schizophrenia at baseline and 2 subsequent years. After conservative quality control of genotype data, this analysis focused on 4344 unrelated individuals of European ancestry. Data analysis was conducted from November 2020 to February 2022., Main Outcomes and Measures: Children's lifetime experiences of SI and SAs were assessed each year from ages 9 to 10 years to ages 11 to 12 years. Polygenic risk scores (PRSs) for SAs were calculated for ABCD study participants based on the largest genome-wide association study of SA cases and controls of European ancestry (total sample n = 518 612)., Results: Of 4344 children of European ancestry (2045 [47.08%] female; mean [SD] age, 9.93 [0.62] years), significant associations were found between children's SA PRSs and their lifetime SAs with the most robust association in the follow-up year 2 (odds ratio, 1.43 [95% CI, 1.18-1.75]; corrected P = 1.85 × 10-3; Nagelkerke pseudo R2 = 1.51%). These associations remained significant after accounting for children's sociodemographic backgrounds, psychopathology symptoms, parental histories of suicide and mental health, and PRSs for major depression and attention-deficit/hyperactivity disorder (likelihood ratio test P < .05). Children's depressive mood and aggressive behavior were the most significant partial mediators of SA genetic risk on SAs (mediation analysis P < 1 × 10-16). Children's behavioral problems, such as attention problems, rule-breaking behavior, and social problems, also partially mediated the association of SA PRSs with SAs (mediation analysis false discover rate < 0.05)., Conclusions and Relevance: This study's findings indicate that there may be genetic factors associated with SA risk across the life span and suggest behaviors and conditions through which the risk could be mediated in childhood. Further research is warranted to examine whether incorporating genetic data could improve the identification of children at risk for suicide.

Published
2022
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33. Effect of adjunctive L-methylfolate 15 mg among inadequate responders to SSRIs in depressed patients who were stratified by biomarker levels and genotype: results from a randomized clinical trial.

Author

Papakostas GI, Shelton RC, Zajecka JM, Bottiglieri T, Roffman J, Cassiello C, Stahl SM, and Fava M

Subjects
Adolescent, Adult, Aged, Biomarkers blood, Depressive Disorder, Treatment-Resistant blood, Depressive Disorder, Treatment-Resistant genetics, Drug Therapy, Combination, Female, Genotype, Humans, Male, Middle Aged, Tetrahydrofolates genetics, Young Adult, Aldehydes blood, C-Reactive Protein, Depressive Disorder, Treatment-Resistant drug therapy, S-Adenosylhomocysteine blood, S-Adenosylmethionine blood, Selective Serotonin Reuptake Inhibitors therapeutic use, Tetrahydrofolates therapeutic use
Abstract

Objective: Specific genetic or biological markers may predict inadequate response to therapy for major depressive disorder (MDD). The objective of the current post hoc analysis was to evaluate the effect of specific biological and genetic markers on the antidepressant efficacy of adjunctive L-methylfolate 15 mg versus placebo from a trial of inadequate responders to selective serotonin reuptake inhibitors (SSRIs)., Method: The double-blind, randomized, placebo-controlled trial used the sequential parallel comparison design. Outpatients with SSRI-resistant MDD (DSM-IV criteria) received L-methylfolate 15 mg/d for 60 days, placebo for 30 days followed by L-methylfolate 15 mg/d for 30 days, or placebo for 60 days. The effects of baseline levels of select biological and genetic markers individually and combined on treatment response to L-methylfolate versus placebo were evaluated; the primary response measure was the 28-Item Hamilton Depression Rating Scale (HDRS-28). The first patient was enrolled July 14, 2009, and the last patient completed April 28, 2011., Results: Seventy-five patients were enrolled. Patients with specific biological (body mass index ≥ 30 kg/m², elevated plasma levels of high-sensitivity C-reactive protein or 4-hydroxy-2-nonenal, low S-adenosylmethionine/S-adenosylhomocysteine ratio) and genetic markers at baseline had significantly (P ≤ .05) greater pooled mean change from baseline on the HDRS-28 with L-methylfolate versus placebo. Pooled mean change from baseline on the Clinical Global Impressions-Severity of Illness scale was significantly (P < .05) greater with L-methylfolate versus placebo for most genetic markers. Most combinations of baseline biological and genetic markers predicted significantly (P ≤ .05) greater reductions in pooled mean change from baseline in HDRS-28 scores with L-methylfolate versus placebo., Conclusions: Biomarkers associated with inflammation or metabolism and genomic markers associated with L-methylfolate synthesis and metabolism may identify patients with SSRI-resistant depression who are responsive to adjunctive therapy with L-methylfolate 15 mg. Confirmatory studies are needed., Trial Registration: ClinicalTrials.gov identifier: NCT00955955., (© Copyright 2014 Physicians Postgraduate Press, Inc.)

Published
2014
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35. Promoting successful youth mentoring relationships: a preliminary screening questionnaire.

Author

Rhodes J, Reddy R, Roffman J, and Grossman JB

Subjects
Adaptation, Psychological, Adolescent, Child, Factor Analysis, Statistical, Female, Humans, Male, Affect, Interpersonal Relations, Mass Screening methods, Mentors, Surveys and Questionnaires
Abstract

Youth mentoring programs are an increasingly popular intervention, and although successful mentoring relationships can promote a range of positive developmental outcomes, relationships that fail can lead to decrements in a youth's functioning and self-esteem. The present research develops and validates a youth mentoring relationship quality inventory, based on data from a national evaluation of Big Brothers Big Sisters (BBBS) mentoring programs (N = 347 youth). This tool can be administered to adolescents who have been assigned mentors in order to assess the quality of the relationship as it is forming and to identify dyads that may need additional support before those relationships fail. Implications of such a tool for mentoring interventions and research are discussed. Editors' Strategic Implications: Reliability and validity data are presented for a measure of youth's perceptions of the quality of their mentoring relationship. This measure shows promise as a tool for research and evaluation of a wide array of mentoring programs due to its brevity, demonstrated psychometrics, and straightforward focus on the mentoring relationship.

Published
2005
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37. The rhetoric and reality of youth mentoring.

Author

Rhodes JE, Grossman JB, and Roffman J

Subjects
Adolescent, Human Development, Humans, Program Development, Health Promotion methods, Health Promotion standards, Intergenerational Relations, Mentors
Abstract

Enduring and supportive mentoring relationships can powerfully influence the course and quality of adolescent lives. As mentoring continues to expand, community agencies are implementing alternatives to the traditional one-on-one mentoring mode. Such efforts may help to reach youth who might otherwise fall through the cracks.

Published
2002
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38. Digoxin and propranolol in the prophylaxis of supraventricular tachydysrhythmias after coronary artery bypass surgery.

Author

Roffman JA and Fieldman A

Subjects
Drug Therapy, Combination, Female, Humans, Male, Middle Aged, Postoperative Complications prevention & control, Tachycardia diagnosis, Coronary Artery Bypass, Digoxin administration & dosage, Propranolol administration & dosage, Tachycardia prevention & control
Abstract

Supraventricular tachydysrhythmia is a bothersome and potentially harmful occurrence after coronary artery bypass graft operation (CABG). Use of digoxin prophylaxis preoperatively has yielded conflicting results in lowering the incidence of supraventricular tachydysrhythmia. In this study, three groups of patients were formed. Group 1 served as the control; no prophylactic medication was given. Group 2 was given digoxin prophylaxis beginning immediately after operation. Group 3 received digoxin postoperatively as did Group 2, plus orally administered propranolol beginning on postoperative day 2. No difference in the incidence of supraventricular tachydysrhythmia was found between Groups 1 and 2 (28.2% versus 28.9%). However, the incidence in Group 3 was 2.2%, and this represented a statistically significant difference (p less than 0.005) compared with either Group or 2. The combined use of digoxin and propranolol postoperatively significantly reduced the incidence of supraventricular tachydysrhythmia after CABG.

Published
1981
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39. Nuclear scanning in necrotizing progressive "malignant" external otitis.

Author

Parisier SC, Lucente FE, Som PM, Hirschman SZ, Arnold LM, and Roffman JD

Subjects
Aged, Diabetes Complications, Diphosphonates, Female, Gallium Radioisotopes, Humans, Male, Middle Aged, Necrosis, Osteomyelitis drug therapy, Osteomyelitis etiology, Otitis Externa complications, Otitis Externa drug therapy, Pseudomonas Infections drug therapy, Radionuclide Imaging, Skull diagnostic imaging, Technetium, Technetium Tc 99m Medronate, Temporal Bone diagnostic imaging, Osteomyelitis diagnostic imaging, Otitis Externa diagnostic imaging, Pseudomonas Infections diagnostic imaging
Abstract

The usefulness of radionuclear scanning in the treatment of 18 patients with necrotizing progressive "malignant" external otitis is discussed. A Tc 99-m bone scan, a valuable test since results are positive in early cases of osteomyelitis of the temporal bone and base of skull, showed increased uptake in all 18 patients. In 6 patients, Ga-67 citrate scans were obtained at the start of therapy and at 5-6 week intervals thereafter. The serial gallium scans were useful in evaluating the effectiveness of therapy since the uptake decrease with control of infection.

Published
1982

41. Combined pre-operative irradiation and surgery for advanced cancer of the larynx and laryngopharynx. (A 14 year correlative statistical and histopathological study).

Author

Goldman JL and Roffman JD

Subjects
Evaluation Studies as Topic, Humans, Laryngeal Neoplasms mortality, Laryngeal Neoplasms pathology, Laryngeal Neoplasms surgery, Methods, Neck Dissection, Pharyngeal Neoplasms mortality, Pharyngeal Neoplasms pathology, Pharyngeal Neoplasms surgery, Radiotherapy Dosage, Laryngeal Neoplasms radiotherapy, Pharyngeal Neoplasms radiotherapy
Abstract

A carefully planned clinical program of combined pre-operative radiation and surgery has been conducted by the Department of Otolaryngology at The Mount Sinai Hospital for 14 years in an effort to improve the survival rate for advanced cancer of the larynx and laryngopharynx. An extensive histopathological study of resected larynges and radical neck specimens was undertaken in 1961 in order to determine the effects of pre-operative radiation. A very careful statistical analysis has been made of the survival experience of this series of cases. The three and five year survival rates have been computed by the actuarial method. The histopathological study entailed a serial section study of 26 larynges and 21 radical neck dissection specimens. These studies have been most informative as to the nature of the radiobiologic process involved in the destruction of laryngeal cancer. In addition, the study has been revealing as to the ability of radiation to sterilize cancer in the neck specimens. The clinical correlate of this histologic finding has been the observation of reduced cervical recurrences in patients treated with combined therapy. In conclusion, our statistics seem to indicate that our combined therapy method has improved the survival rates of patients with advanced cancer of the larynx and laryngopharynx.

Published
1975

43. Indirect laryngoscopy.

Author

Goldman JL and Roffman JD

Subjects
Anesthesia, Intravenous, Anesthesia, Local, Cocaine, History, 19th Century, History, 20th Century, Humans, Laryngeal Neoplasms history, Laryngeal Neoplasms surgery, Laryngoscopy history, Lidocaine, Preanesthetic Medication
Abstract

Indirect laryngoscopy is one of the procedural methods used for achieving a histopathologic diagnosis of cancer of the larynx. A chronologic historical summary of the development of mirror laryngoscopy is presented. The details of the procedure employed for obtaining a biopsy with the aid of topical anesthesia is discussed.

Published
1975
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44. Ventricular conduction defects: significance and prognosis.

Author

Roffman JA and Fieldman A

Subjects
Bundle-Branch Block physiopathology, Heart Conduction System physiopathology, Humans, Arrhythmias, Cardiac physiopathology, Electrocardiography, Heart Ventricles physiopathology
Published
1980

45. High dosage pre-operative radiation and surgery for carcinoma of the larynx and laryngopharynx. A 14-year program.

Author

Goldman JL, Silverstone SM, Roffman JD, and Birken EA

Subjects
Adult, Aged, Carcinoma, Squamous Cell surgery, Female, Humans, Laryngeal Neoplasms surgery, Male, Middle Aged, Neoplasm Recurrence, Local, Pharyngeal Neoplasms surgery, Postoperative Complications, Preoperative Care, Carcinoma, Squamous Cell radiotherapy, Laryngeal Neoplasms radiotherapy, Pharyngeal Neoplasms radiotherapy, Radiotherapy Dosage
Published
1972
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46. High dosage preoperative radiation and surgery for carcinoma of the larynx and laryngopharynx.

Author

Goldman JL, Roffman JD, Zak FG, and Birken EA

Subjects
Carcinoma pathology, Carcinoma radiotherapy, Carcinoma surgery, Cobalt Isotopes, Humans, Laryngeal Neoplasms pathology, Laryngeal Neoplasms radiotherapy, Laryngeal Neoplasms surgery, Laryngectomy, Larynx pathology, Lymph Nodes pathology, Neck Dissection, Neoplasm Metastasis, Neoplasm Recurrence, Local, Pharyngeal Neoplasms pathology, Pharyngeal Neoplasms radiotherapy, Pharyngeal Neoplasms surgery, Radioisotope Teletherapy, Radiotherapy Dosage, Carcinoma therapy, Laryngeal Neoplasms therapy, Pharyngeal Neoplasms therapy
Published
1972
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47. The presence of melanocytes in the human larynx.

Author

Goldman JL, Lawson W, Zak FG, and Roffman JD

Subjects
Adult, Autopsy, Histological Techniques, Humans, Laryngeal Neoplasms etiology, Melanoma etiology, Mucous Membrane pathology, Laryngeal Neoplasms pathology, Melanocytes, Melanoma pathology
Published
1972
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