Author: "Pütz B" / Publication Year Range: Last 10 years - Searchworks@Jio Institute Digital Library Search Results

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40 results on '"Pütz B"'

1. Chromosomal Region 11p14.1 is Associated with Pharmacokinetics and Pharmacodynamics of Bisoprolol

Author: Fontana V, Turner RM, Francis B, Yin P, Pütz B, Hiltunen TP, Ruotsalainen S, Kontula KK, Müller-Myhsok B, and Pirmohamed M
Subjects: bisoprolol, pharmacokinetics, genome-wide association., Therapeutics. Pharmacology, RM1-950
Abstract: Vanessa Fontana,1,2 Richard Myles Turner,1,2 Ben Francis,3 Peng Yin,3 Benno Pütz,4 Timo P Hiltunen,5 Sanni Ruotsalainen,6 Kimmo K Kontula,5 Bertam Müller-Myhsok,1,4 Munir Pirmohamed1,2,7 1The Wolfson Centre for Personalised Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK; 2MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK; 3Department of Biostatistics, Institute of Translational Medicine, University of Liverpool, Liverpool, UK; 4Max Planck Institute of Psychiatry, Munich, Germany; 5Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland; 6Institute for Molecular Medicine Finland, Helsinki Institute of Life Sciences, University of Helsinki, Helsinki, Finland; 7Royal Liverpool and Broadgreen University Hospitals NHS Trust, and Liverpool Health Partners, Liverpool, UKCorrespondence: Vanessa Fontana, MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Block A: Waterhouse Buildings, 1-5 Brownlow Street, Liverpool, L69 3GL, UK, Fax +44 151 794 5059, Email V.Fontana@liverpool.ac.ukPurpose: Bisoprolol is a widely used beta-blocker in patients with cardiovascular diseases. As with other beta-blockers, there is variability in response to bisoprolol, but the underlying reasons for this have not been clearly elucidated. Our aim was to investigate genetic factors that affect bisoprolol pharmacokinetics (PK) and pharmacodynamics (PD), and potentially the clinical outcomes.Patients and Methods: Patients with non-ST elevation acute coronary syndrome were recruited prospectively on admission to hospital and followed up for up to 2 years. Patients from this cohort who were on treatment with bisoprolol, at any dose, had bisoprolol adherence data and a plasma sample, one month after discharge from index hospitalisation were included in the study. Individual bisoprolol clearance values were estimated using population pharmacokinetic modeling. Genome-wide association analysis after genotyping was undertaken using an Illumina HumanOmniExpressExome-8 v1.0 BeadChip array, while CYP2D6 copy number variations were determined by PCR techniques and phenotypes for CYP2D6 and CYP3A were inferred from the genotype. GWAS significant SNPs were analysed for heart rate response to bisoprolol in an independent cohort of hypertensive subjects.Results: Six hundred twenty-two patients on bisoprolol underwent both PK and genome wide analysis. The mean (IQR) of the estimated clearance in this population was 13.6 (10.0– 18.0) L/h. Bisoprolol clearance was associated with rs11029955 (p=7.17× 10− 9) mapped to the region of coiled-coil domain containing 34 region (CCDC34) on chromosome 11, and with rs116702638 (p=2.54× 10− 8). Each copy of the minor allele of rs11029955 was associated with 2.2 L/h increase in clearance. In an independent cohort of hypertensive subjects, rs11029955 was associated with 24-hour heart rate response to 4-week treatment with bisoprolol (p= 9.3× 10− 5), but not with rs116702638.Conclusion: A novel locus on the chromosomal region 11p14.1 was associated with bisoprolol clearance in a real-world cohort of patients and was validated in independent cohort with a pharmacodynamic association.Keywords: bisoprolol, pharmacokinetics, genome-wide association
Published: 2022

2. The genetic architecture of the human cerebral cortex

Author: Grasby, K.L., Jahanshad, N., Painter, J.N., Colodro-Conde, L., Bralten, J., Hibar, D.P., Lind, P.A., Pizzagalli, F., Ching, C.R.K., McMahon, M.A.B., Shatokhina, N., Zsembik, L.C.P., Thomopoulos, S.I., Zhu, A.H., Strike, L.T., Agartz, I., Alhusaini, S., Almeida, M.A.A., Alnæs, D., Amlien, I.K., Andersson, M., Ard, T., Armstrong, N.J., Ashley-Koch, A., Atkins, J.R., Bernard, M., Brouwer, R.M., Buimer, E.E.L., Bülow, R., Bürger, C., Cannon, D.M., Chakravarty, M.M., Chen, Q., Cheung, J.W., Couvy-Duchesne, B., Dale, A.M., Dalvie, S., de Araujo, T.K., de Zubicaray, G.I., de Zwarte, S.M.C., den Braber, A., Doan, N.T., Dohm, K., Ehrlich, S., Engelbrecht, H-R, Erk, S., Fan, C.C., Fedko, I.O., Foley, S.F., Ford, J.M., Fukunaga, M., Garrett, M.E., Ge, T., Giddaluru, S., Goldman, A.L., Green, M.J., Groenewold, N.A., Grotegerd, D., Gurholt, T.P., Gutman, B.A., Hansell, N.K., Harris, M.A., Harrison, M.B., Haswell, C.C., Hauser, M., Herms, S., Heslenfeld, D.J., Ho, N.F., Hoehn, D., Hoffmann, P., Holleran, L., Hoogman, M., Hottenga, J-J, Ikeda, M., Janowitz, D., Jansen, I.E., Jia, T., Jockwitz, C., Kanai, R., Karama, S., Kasperaviciute, D., Kaufmann, T., Kelly, S., Kikuchi, M., Klein, M., Knapp, M., Knodt, A.R., Krämer, B., Lam, M., Lancaster, T.M., Lee, P.H., Lett, T.A., Lewis, L.B., Lopes-Cendes, I., Luciano, M., Macciardi, F., Marquand, A.F., Mathias, S.R., Melzer, T.R., Milaneschi, Y., Mirza-Schreiber, N., Moreira, J.C.V., Mühleisen, T.W., Müller-Myhsok, B., Najt, P., Nakahara, S., Nho, K., Olde Loohuis, L.M., Orfanos, D.P., Pearson, J.F., Pitcher, T.L., Pütz, B., Quidé, Y., Ragothaman, A., Rashid, F.M., Reay, W.R., Redlich, R., Reinbold, C.S., Repple, J., Richard, G., Riedel, B.C., Risacher, S.L., Rocha, C.S., Mota, N.R., Salminen, L., Saremi, A., Saykin, A.J., Schlag, F., Schmaal, L., Schofield, P.R., Secolin, R., Shapland, C.Y., Shen, L., Shin, J., Shumskaya, E., Sønderby, I.E., Sprooten, E., Tansey, K.E., Teumer, A., Thalamuthu, A., Tordesillas-Gutierrez, D., Turner, J.A., Uhlmann, A., Vallerga, C.L., van der Meer, D., van Donkelaar, M.M.J., van Eijk, L., Van Erp, T.G.M., van Haren, N.E.M., Van Rooij, D., van Tol, M-J, Veldink, J.H., Verhoef, E., Walton, E., Wang, M., Wang, Y., Wardlaw, J.M., Wen, W., Westlye, L.T., Whelan, C.D., Witt, S.H., Wittfeld, K., Wolf, C., Wolfers, T., Wu, J.Q., Yasuda, C.L., Zaremba, D., Zhang, Z., Zwiers, M.P., Artiges, E., Assareh, A.A., Ayesa-Arriola, R., Belger, A., Brandt, C.L., Brown, G.G., Cichon, S., Curran, J.E., Davies, G.E., Degenhardt, F., Dennis, M.F., Dietsche, B., Djurovic, S., Doherty, C.P., Espiritu, R., Garijo, D., Gil, Y., Gowland, P.A., Green, R.C., Häusler, A.N., Heindel, W., Ho, B-C., Hoffmann, W.U., Holsboer, F., Homuth, G., Hosten, N., Jack, C.R., Jang, M., Jansen, A., Kimbrel, N.A., Kolskår, K., Koops, S., Krug, A., Lim, K.O., Luykx, J.J., Mathalon, D.H., Mather, K.A., Mattay, V.S., Matthews, S., Mayoral Van Son, J., McEwen, S.C., Melle, I., Morris, D.W., Mueller, B.A., Nauck, M., Nordvik, J.E., Nöthen, M.M., O’Leary, D.S., Opel, N., Martinot, M-L.P., Pike, G.B., Preda, A., Quinlan, E.B., Rasser, P.E., Ratnakar, V., Reppermund, S., Steen, V.M., Tooney, P.A., Torres, F.R., Veltman, D.J., Voyvodic, J.T., Whelan, R., White, T., Yamamori, H., Adams, H.H.H., Bis, J.C., Debette, S., DeCarli, C., Fornage, M., Gudnason, V., Hofer, E., Ikram, M.A., Launer, L., Longstreth, W.T., Lopez, O.L., Mazoyer, B., Mosley, T.H., Roshchupkin, G.V., Satizabal, C.L., Schmidt, R., Seshadri, S., Yang, Q., Alvim, M.K.M., Ames, D., Anderson, T.J., Andreassen, O.A., Arias-Vasquez, A., Bastin, M.E., Baune, B.T., Beckham, J.C., Blangero, J., Boomsma, D.I., Brodaty, H., Brunner, H.G., Buckner, R.L., Buitelaar, J.K., Bustillo, J.R., Cahn, W., Cairns, M.J., Calhoun, V., Carr, V.J., Caseras, X., Caspers, S., Cavalleri, G.L., Cendes, F., Corvin, A., Crespo-Facorro, B., Dalrymple-Alford, J.C., Dannlowski, U., de Geus, E.J.C., Deary, I.J., Delanty, N., Depondt, C., Desrivières, S., Donohoe, G., Espeseth, T., Fernández, G., Fisher, S.E., Flor, H., Forstner, A.J., Francks, C., Franke, B., Glahn, D.C., Gollub, R.L., Grabe, H.J., Gruber, O., Håberg, A.K., Hariri, A.R., Hartman, C.A., Hashimoto, R., Heinz, A., Henskens, F.A., Hillegers, M.H.J., Hoekstra, P.J., Holmes, A.J., Hong, L.E., Hopkins, W.D., Hulshoff Pol, H.E., Jernigan, T.L., Jönsson, E.G., Kahn, R.S., Kennedy, M.A., Kircher, T.T.J., Kochunov, P., Kwok, J.B.J., Le Hellard, S., Loughland, C.M., Martin, N.G., Martinot, J-L, McDonald, C., McMahon, K.L., Meyer-Lindenberg, A., Michie, P.T., Morey, R.A., Mowry, B., Nyberg, L., Oosterlaan, J., Ophoff, R.A., Pantelis, C., Paus, T., Pausova, Z., Penninx, B.W.J.H., Polderman, T.J.C., Posthuma, D., Rietschel, M., Roffman, J.L., Rowland, L.M., Sachdev, P.S., Sämann, P.G., Schall, U., Schumann, G., Scott, R.J., Sim, K., Sisodiya, S.M., Smoller, J.W., Sommer, I.E., St Pourcain, B., Stein, D.J., Toga, A.W., Trollor, J.N., van der Wee, N.J.A., van ’t Ent, D., Völzke, H., Walter, H., Weber, B., Weinberger, D.R., Wright, M.J., Zhou, J., Stein, J.L., Thompson, P.M., Medland, S.E., Grasby, K.L., Jahanshad, N., Painter, J.N., Colodro-Conde, L., Bralten, J., Hibar, D.P., Lind, P.A., Pizzagalli, F., Ching, C.R.K., McMahon, M.A.B., Shatokhina, N., Zsembik, L.C.P., Thomopoulos, S.I., Zhu, A.H., Strike, L.T., Agartz, I., Alhusaini, S., Almeida, M.A.A., Alnæs, D., Amlien, I.K., Andersson, M., Ard, T., Armstrong, N.J., Ashley-Koch, A., Atkins, J.R., Bernard, M., Brouwer, R.M., Buimer, E.E.L., Bülow, R., Bürger, C., Cannon, D.M., Chakravarty, M.M., Chen, Q., Cheung, J.W., Couvy-Duchesne, B., Dale, A.M., Dalvie, S., de Araujo, T.K., de Zubicaray, G.I., de Zwarte, S.M.C., den Braber, A., Doan, N.T., Dohm, K., Ehrlich, S., Engelbrecht, H-R, Erk, S., Fan, C.C., Fedko, I.O., Foley, S.F., Ford, J.M., Fukunaga, M., Garrett, M.E., Ge, T., Giddaluru, S., Goldman, A.L., Green, M.J., Groenewold, N.A., Grotegerd, D., Gurholt, T.P., Gutman, B.A., Hansell, N.K., Harris, M.A., Harrison, M.B., Haswell, C.C., Hauser, M., Herms, S., Heslenfeld, D.J., Ho, N.F., Hoehn, D., Hoffmann, P., Holleran, L., Hoogman, M., Hottenga, J-J, Ikeda, M., Janowitz, D., Jansen, I.E., Jia, T., Jockwitz, C., Kanai, R., Karama, S., Kasperaviciute, D., Kaufmann, T., Kelly, S., Kikuchi, M., Klein, M., Knapp, M., Knodt, A.R., Krämer, B., Lam, M., Lancaster, T.M., Lee, P.H., Lett, T.A., Lewis, L.B., Lopes-Cendes, I., Luciano, M., Macciardi, F., Marquand, A.F., Mathias, S.R., Melzer, T.R., Milaneschi, Y., Mirza-Schreiber, N., Moreira, J.C.V., Mühleisen, T.W., Müller-Myhsok, B., Najt, P., Nakahara, S., Nho, K., Olde Loohuis, L.M., Orfanos, D.P., Pearson, J.F., Pitcher, T.L., Pütz, B., Quidé, Y., Ragothaman, A., Rashid, F.M., Reay, W.R., Redlich, R., Reinbold, C.S., Repple, J., Richard, G., Riedel, B.C., Risacher, S.L., Rocha, C.S., Mota, N.R., Salminen, L., Saremi, A., Saykin, A.J., Schlag, F., Schmaal, L., Schofield, P.R., Secolin, R., Shapland, C.Y., Shen, L., Shin, J., Shumskaya, E., Sønderby, I.E., Sprooten, E., Tansey, K.E., Teumer, A., Thalamuthu, A., Tordesillas-Gutierrez, D., Turner, J.A., Uhlmann, A., Vallerga, C.L., van der Meer, D., van Donkelaar, M.M.J., van Eijk, L., Van Erp, T.G.M., van Haren, N.E.M., Van Rooij, D., van Tol, M-J, Veldink, J.H., Verhoef, E., Walton, E., Wang, M., Wang, Y., Wardlaw, J.M., Wen, W., Westlye, L.T., Whelan, C.D., Witt, S.H., Wittfeld, K., Wolf, C., Wolfers, T., Wu, J.Q., Yasuda, C.L., Zaremba, D., Zhang, Z., Zwiers, M.P., Artiges, E., Assareh, A.A., Ayesa-Arriola, R., Belger, A., Brandt, C.L., Brown, G.G., Cichon, S., Curran, J.E., Davies, G.E., Degenhardt, F., Dennis, M.F., Dietsche, B., Djurovic, S., Doherty, C.P., Espiritu, R., Garijo, D., Gil, Y., Gowland, P.A., Green, R.C., Häusler, A.N., Heindel, W., Ho, B-C., Hoffmann, W.U., Holsboer, F., Homuth, G., Hosten, N., Jack, C.R., Jang, M., Jansen, A., Kimbrel, N.A., Kolskår, K., Koops, S., Krug, A., Lim, K.O., Luykx, J.J., Mathalon, D.H., Mather, K.A., Mattay, V.S., Matthews, S., Mayoral Van Son, J., McEwen, S.C., Melle, I., Morris, D.W., Mueller, B.A., Nauck, M., Nordvik, J.E., Nöthen, M.M., O’Leary, D.S., Opel, N., Martinot, M-L.P., Pike, G.B., Preda, A., Quinlan, E.B., Rasser, P.E., Ratnakar, V., Reppermund, S., Steen, V.M., Tooney, P.A., Torres, F.R., Veltman, D.J., Voyvodic, J.T., Whelan, R., White, T., Yamamori, H., Adams, H.H.H., Bis, J.C., Debette, S., DeCarli, C., Fornage, M., Gudnason, V., Hofer, E., Ikram, M.A., Launer, L., Longstreth, W.T., Lopez, O.L., Mazoyer, B., Mosley, T.H., Roshchupkin, G.V., Satizabal, C.L., Schmidt, R., Seshadri, S., Yang, Q., Alvim, M.K.M., Ames, D., Anderson, T.J., Andreassen, O.A., Arias-Vasquez, A., Bastin, M.E., Baune, B.T., Beckham, J.C., Blangero, J., Boomsma, D.I., Brodaty, H., Brunner, H.G., Buckner, R.L., Buitelaar, J.K., Bustillo, J.R., Cahn, W., Cairns, M.J., Calhoun, V., Carr, V.J., Caseras, X., Caspers, S., Cavalleri, G.L., Cendes, F., Corvin, A., Crespo-Facorro, B., Dalrymple-Alford, J.C., Dannlowski, U., de Geus, E.J.C., Deary, I.J., Delanty, N., Depondt, C., Desrivières, S., Donohoe, G., Espeseth, T., Fernández, G., Fisher, S.E., Flor, H., Forstner, A.J., Francks, C., Franke, B., Glahn, D.C., Gollub, R.L., Grabe, H.J., Gruber, O., Håberg, A.K., Hariri, A.R., Hartman, C.A., Hashimoto, R., Heinz, A., Henskens, F.A., Hillegers, M.H.J., Hoekstra, P.J., Holmes, A.J., Hong, L.E., Hopkins, W.D., Hulshoff Pol, H.E., Jernigan, T.L., Jönsson, E.G., Kahn, R.S., Kennedy, M.A., Kircher, T.T.J., Kochunov, P., Kwok, J.B.J., Le Hellard, S., Loughland, C.M., Martin, N.G., Martinot, J-L, McDonald, C., McMahon, K.L., Meyer-Lindenberg, A., Michie, P.T., Morey, R.A., Mowry, B., Nyberg, L., Oosterlaan, J., Ophoff, R.A., Pantelis, C., Paus, T., Pausova, Z., Penninx, B.W.J.H., Polderman, T.J.C., Posthuma, D., Rietschel, M., Roffman, J.L., Rowland, L.M., Sachdev, P.S., Sämann, P.G., Schall, U., Schumann, G., Scott, R.J., Sim, K., Sisodiya, S.M., Smoller, J.W., Sommer, I.E., St Pourcain, B., Stein, D.J., Toga, A.W., Trollor, J.N., van der Wee, N.J.A., van ’t Ent, D., Völzke, H., Walter, H., Weber, B., Weinberger, D.R., Wright, M.J., Zhou, J., Stein, J.L., Thompson, P.M., and Medland, S.E.
Abstract: INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 306 nominally genome-wide significant loci (P < 5 × 10−8) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 299 loci for which replication data were available, 241 loci influencing surface area and 14 influencing thickness remained significant after replication, with 199 loci passing multiple testing correction (P < 8.3 × 10−10; 187 influencing surface area and 12 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation (rG = −0.32, SE = 0.05, P = 6.5 × 10−12), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When co
Published: 2020

3. 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

4. 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, M., 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., Desrivières, 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-Santiañez, R., Kraemer, B., Håberg, 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, F., Janowitz, D., Carmichael, O., Haukvik, U.K., Aribisala, B.S., Schmidt, H., Strike, L.T., Cheng, C-Y, Risacher, S.L., Pütz, 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, B.W.J.H., 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., Sämann, 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., Valdés Hernández, 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., Schofield, P.R., Mühleisen, 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., Jönsson, 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, C., Longstreth, W.T., Ikram, M.K., 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., Müller-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., Völzke, H., Wright, M.J., van ‘t Ent, D., Nöthen, M.M., Ophoff, R.A., Buitelaar, J.K., Fernández, 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, S., Gudnason, V., Medland, S.E., Shulman, J.M., Thompson, P.M., Seshadri, S., Ikram, M.A., Satizabal, C.L., Adams, H.H.H., Hibar, D.P., White, C.C., Knol, M.J., Stein, J.L., Scholz, M., Sargurupremraj, M., 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., Desrivières, 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-Santiañez, R., Kraemer, B., Håberg, 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, F., Janowitz, D., Carmichael, O., Haukvik, U.K., Aribisala, B.S., Schmidt, H., Strike, L.T., Cheng, C-Y, Risacher, S.L., Pütz, 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, B.W.J.H., 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., Sämann, 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., Valdés Hernández, 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., Schofield, P.R., Mühleisen, 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., Jönsson, 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, C., Longstreth, W.T., Ikram, M.K., 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., Müller-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., Völzke, H., Wright, M.J., van ‘t Ent, D., Nöthen, M.M., Ophoff, R.A., Buitelaar, J.K., Fernández, 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, S., Gudnason, V., Medland, S.E., Shulman, J.M., Thompson, P.M., Seshadri, S., and Ikram, M.A.
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

5. Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis

Author: Schormair, B., Zhao, C., Bell, S., Tilch, E., Salminen, A., Pütz, B., Dauvilliers, Y., Stefani, A., Hoegl, B., Poewe, W., Kemlink, D., Sonka, K., Bachmann, C., Paulus, W., Trenkwalder, C., Oertel, W., Hornyak, M., Teder-Laving, M., Metspalu, A., Hadjigeorgiou, G., Polo, O., Fietze, I., Ross, O., Wszolek, Z., Butterworth, A., Soranzo, N., Ouwehand, W., Roberts, D., Danesh, J., Allen, R., Earley, C., Ondo, W., Xiong, L., Montplaisir, J., Gan-Or, Z., Perola, M., Vodicka, P., Dina, C., Franke, A., Tittmann, L., Stewart, A., Shah, S., Gieger, C., Peters, A., Rouleau, G., Berger, K., Oexle, K., Di Angelantonio, E., Hinds, D., Müller-Myhsok, B., and Winkelmann, J.
Abstract: Background Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets. Methods In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p
Published: 2017

6. Identification of novel risk loci for restless legs syndrome: A meta-analysis of genome-wide association studies in individuals of European ancestry: A meta-analysis

Author: Schormair, B., Zhao, C., Bell, S., Tilch, E., Salminen, A.V., Pütz, B., Dauvilliers, Y., Stefani, A., Högl, B., Poewe, W., Kemlink, D., Sonka, K., Bachmann, C.G., Paulus, W., Trenkwalder, C., Oertel, W.H., Hornyak, M., Teder-Laving, M., Metspalu, A., Hadjigeorgiou, G.M., Polo, O., Fietze, I., Ross, O.A., Wszolek, Z., Butterworth, A.S., Soranzo, N., Ouwehand, W.H., Roberts, D.J., Danesh, J., Allen, R.P., Earley, C.J., Ondo, W.G., Xiong, L., Montplaisir, J., Gan-Or, Z., Perola, M., Vodicka, P., Dina, C., Franke, A., Tittmann, L., Stewart, A.F.R., Shah, S.H., Gieger, C., Peters, A., Rouleau, G.A., Berger, K., Oexle, K., di Angelantonio, E., Hinds, D.A., Müller-Myhsok, B., and Winkelmann, J.
Abstract: Background Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets. Methods In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15 126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p≤5 × 10−8) were tested for replication in an independent GWAS of 30 770 cases and 286 913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest. Findings We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1·92, 95% CI 1·85–1·99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1). Interpretation Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations. &nbsp
Published: 2017

7. Novel genetic loci associated with hippocampal volume

Author: Hibar, DP, Adams, HHH, Jahanshad, N, Chauhan, G, Stein, JL, Hofer, E, Renteria, ME, Bis, JC, Arias-Vasquez, A, Ikram, MK, Desrivières, S, Vernooij, MW, Abramovic, L, Alhusaini, S, Amin, N, Andersson, M, Arfanakis, K, Aribisala, BS, Armstrong, NJ, Athanasiu, L, Axelsson, T, Beecham, AH, Beiser, A, Bernard, M, Blanton, SH, Bohlken, MM, Boks, MP, Bralten, J, Brickman, AM, Carmichael, O, Chakravarty, MM, Chen, Q, Ching, CRK, Chouraki, V, Cuellar-Partida, G, Crivello, F, Den Braber, A, Doan, NT, Ehrlich, S, Giddaluru, S, Goldman, AL, Gottesman, RF, Grimm, O, Griswold, ME, Guadalupe, T, Gutman, BA, Hass, J, Haukvik, UK, Hoehn, D, Holmes, AJ, Hoogman, M, Janowitz, D, Jia, T, Jørgensen, KN, Karbalai, N, Kasperaviciute, D, Kim, S, Klein, M, Kraemer, B, Lee, PH, Liewald, DCM, Lopez, LM, Luciano, M, MacAre, C, Marquand, AF, Matarin, M, Mather, KA, Mattheisen, M, McKay, DR, Milaneschi, Y, Muñoz Maniega, S, Nho, K, Nugent, AC, Nyquist, P, Loohuis, LMO, Oosterlaan, J, Papmeyer, M, Pirpamer, L, Pütz, B, Ramasamy, A, Richards, JS, Risacher, SL, Roiz-Santiañez, R, Rommelse, N, Ropele, S, Rose, EJ, Royle, NA, Rundek, T, Sämann, PG, Saremi, A, Satizabal, CL, Schmaal, L, Schork, AJ, Shen, L, Shin, J, Shumskaya, E, Smith, AV, Sprooten, E, Strike, LT, Teumer, A, Hibar, DP, Adams, HHH, Jahanshad, N, Chauhan, G, Stein, JL, Hofer, E, Renteria, ME, Bis, JC, Arias-Vasquez, A, Ikram, MK, Desrivières, S, Vernooij, MW, Abramovic, L, Alhusaini, S, Amin, N, Andersson, M, Arfanakis, K, Aribisala, BS, Armstrong, NJ, Athanasiu, L, Axelsson, T, Beecham, AH, Beiser, A, Bernard, M, Blanton, SH, Bohlken, MM, Boks, MP, Bralten, J, Brickman, AM, Carmichael, O, Chakravarty, MM, Chen, Q, Ching, CRK, Chouraki, V, Cuellar-Partida, G, Crivello, F, Den Braber, A, Doan, NT, Ehrlich, S, Giddaluru, S, Goldman, AL, Gottesman, RF, Grimm, O, Griswold, ME, Guadalupe, T, Gutman, BA, Hass, J, Haukvik, UK, Hoehn, D, Holmes, AJ, Hoogman, M, Janowitz, D, Jia, T, Jørgensen, KN, Karbalai, N, Kasperaviciute, D, Kim, S, Klein, M, Kraemer, B, Lee, PH, Liewald, DCM, Lopez, LM, Luciano, M, MacAre, C, Marquand, AF, Matarin, M, Mather, KA, Mattheisen, M, McKay, DR, Milaneschi, Y, Muñoz Maniega, S, Nho, K, Nugent, AC, Nyquist, P, Loohuis, LMO, Oosterlaan, J, Papmeyer, M, Pirpamer, L, Pütz, B, Ramasamy, A, Richards, JS, Risacher, SL, Roiz-Santiañez, R, Rommelse, N, Ropele, S, Rose, EJ, Royle, NA, Rundek, T, Sämann, PG, Saremi, A, Satizabal, CL, Schmaal, L, Schork, AJ, Shen, L, Shin, J, Shumskaya, E, Smith, AV, Sprooten, E, Strike, LT, and Teumer, A
Abstract: The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
Published: 2017

8. Novel genetic loci associated with hippocampal volume

Author: Hibar, D.P. (Derrek), Adams, H.H.H. (Hieab), Jahanshad, N. (Neda), Chauhan, G. (Ganesh), Stein, J.L., Hofer, E. (Edith), Rentería, M.E. (Miguel), Bis, J.C. (Joshua), Arias-Vásquez, A. (Alejandro), Ikram, M.K. (M. Kamran), Desrivières, S. (Sylvane), Vernooij, M.W. (Meike), Abramovic, L. (Lucija), Alhusaini, S. (Saud), Amin, N. (Najaf), Andersson, M. (Micael), Arfanakis, K. (Konstantinos), Aribisala, B. (Benjamin), Armstrong, N.J. (Nicola J.), Athanasiu, L. (Lavinia), Axelsson, T. (Tomas), Beecham, A.H. (Ashley), Beiser, A. (Alexa), Bernard, M. (Manon), Blanton, S.H. (Susan H.), Bohlken, M.M. (Marc M.), Boks, M.P.M. (Marco), Bralten, L.B.C. (Linda), Brickman, A.M. (Adam M.), Carmichael, O. (Owen), Chakravarty, M.M. (M. Mallar), Chen, Q. (Qiang), Ching, C.R.K. (Christopher), Chouraki, V. (Vincent), Cuellar-Partida, G. (Gabriel), Crivello, F. (Fabrice), Braber, A. (Anouk) den, Doan, N.T. (Nhat Trung), Ehrlich, S.M. (Stefan), Giddaluru, S. (Sudheer), Goldman, A.L. (Aaron L.), Gottesman, R.F. (Rebecca), Grimm, O. (Oliver), Griswold, M.D. (Michael), Guadalupe, T. (Tulio), Gutman, B.A. (Boris A.), Hass, J. (Johanna), Haukvik, U.K. (Unn), Hoehn, D. (David), Holmes, A.J. (Avram), Hoogman, M. (Martine), Janowitz, D. (Deborah), Jia, T. (Tianye), Jørgensen, K.N. (Kjetil N.), Karbalai, N. (Nazanin), Kasperaviciute, D. (Dalia), Kim, S. (Shinseog), Klein, M. (Marieke), Kraemer, B. (Bernd), Lee, P.H. (Phil), Liewald, D.C.M. (David), Lopez, L.M. (Lorna), Luciano, M. (Michelle), MacAre, C. (Christine), Marquand, A.F. (Andre F.), Matarin, M. (Mar), Mather, R., Mattheisen, M. (Manuel), McKay, D.R. (David R.), Milaneschi, Y. (Yuri), Muñoz Maniega, S. (Susana), Nho, K. (Kwangsik), Nugent, A.C. (Allison), Nyquist, P. (Paul), Loohuis, L.M.O. (Loes M. Olde), Oosterlaan, J. (Jaap), Papmeyer, M. (Martina), Pirpamer, L. (Lukas), Pütz, B. (Benno), Ramasamy, A. (Adaikalavan), Richards, J.S. (Jennifer S.), Risacher, S.L. (Shannon), Roiz-Santiañez, R. (Roberto), Rommelse, N. (Nanda), Ropele, S. (Stefan), Rose, E.J. (Emma), Royle, N.A. (Natalie), Rundek, T. (Tatjana), Sämann, P.G. (Philipp), Saremi, A. (Arvin), Satizabal, C.L. (Claudia), Schmaal, L. (Lianne), Schork, N.J. (Nicholas), Shen, L. (Li), Shin, J. (Jean), Shumskaya, E. (Elena), Smith, A.V. (Albert Vernon), Sprooten, R. (Roy), Strike, L.T. (Lachlan), Teumer, A. (Alexander), Tordesillas-Gutierrez, D. (Diana), Toro, R. (Roberto), Trabzuni, D. (Danyah), Trompet, S. (Stella), Vaidya, D. (Dhananjay), van der Grond, J. (Jeroen), Lee, S.J. (Sven) van der, Van Der Meer, D. (Dennis), Van Donkelaar, M.M.J. (Marjolein M. J.), Eijk, K.R. (Kristel) van, Erp, T.G.M. (Theo G.) van, Van Rooij, D. (Daan), Walton, E. (Esther), Westlye, L.T. (Lars), Whelan, C.D. (Christopher), Windham, B.G. (Gwen), Winkler, A.M. (Anderson), Wittfeld, K. (Katharina), Woldehawariat, G. (Girma), Björnsson, A. (Asgeir), Wolfers, T. (Thomas), Yanek, L.R. (Lisa), Yang, J. (Jingyun), Zijdenbos, A.P., Zwiers, M.P. (Marcel), Agartz, I. (Ingrid), Almasy, L. (Laura), Ames, D.J. (David), Amouyel, P. (Philippe), Andreassen, O.A. (Ole), Arepalli, S. (Sampath), Assareh, A.A., Barral, S. (Sandra), Bastin, M.E. (Mark), Becker, D.M. (Diane M.), Becker, J.T. (James), Bennett, D.A. (David A.), Blangero, J. (John), Bokhoven, H. (Hans) van, Boomsma, D.I. (Dorret), Brodaty, H. (Henry), Brouwer, R.M. (Rachel), Brunner, H.G., Buckner, M., Buitelaar, J.K. (Jan), Bulayeva, K. (Kazima), Cahn, W. (Wiepke), Calhoun, V.D. (Vince), Cannon, D.M. (Dara), Cavalleri, G. (Gianpiero), Cheng, C.-Y. (Ching-Yu), Cichon, S. (Sven), Cookson, M.R. (Mark), Corvin, A. (Aiden), Crespo-Facorro, B. (Benedicto), Curran, J.E. (Joanne), Czisch, M. (Michael), Dale, A.M. (Anders), Davies, G.E. (Gareth), Craen, A.J. (Anton) de, Geus, E.J.C. (Eco) de, Jager, P.L. (Philip) de, Zubicaray, G.I. (Greig) de, Deary, I.J. (Ian), Debette, S. (Stéphanie), DeCarli, C. (Charles), Delanty, N., Depondt, C. (Chantal), DeStefano, A.L. (Anita), Dillman, A. (Allissa), Djurovic, S. (Srdjan), Donohoe, D.J. (Dennis), Drevets, D.A. (Douglas), Duggirala, R. (Ravi), Dyer, M.D. (Matthew), Enzinger, C. (Christian), Erk, S., Espeseth, T. (Thomas), Fedko, I.O. (Iryna O.), Fernández, G. (Guillén), Ferrucci, L. (Luigi), Fisher, S.E. (Simon), Fleischman, D. (Debra), Ford, I. (Ian), Fornage, M. (Myriam), Foroud, T. (Tatiana), Fox, P.T. (Peter), Francks, C. (Clyde), Fukunaga, M. (Masaki), Gibbs, J.R. (J. Raphael), Glahn, D.C. (David), Gollub, R.L. (Randy), Göring, H.H.H. (Harald H.), Green, R.C. (Robert C.), Gruber, O. (Oliver), Gudnason, V. (Vilmundur), Guelfi, S. (Sebastian), Håberg, A.K. (Asta K.), Hansell, N.K. (Narelle), Hardy, J. (John), Hartman, C.A. (C.), Hashimoto, R. (Ryota), Hegenscheid, K. (Katrin), Heinz, J. (Judith), Le Hellard, S. (Stephanie), Hernandez, D.G. (Dena), Heslenfeld, D.J. (Dirk), Ho, B.-C. (Beng-Choon), Hoekstra, P.J. (Pieter), Hoffmann, W. (Wolfgang), Hofman, A. (Albert), Holsboer, F. (Florian), Homuth, G. (Georg), Hosten, N. (Norbert), Hottenga, J.J. (Jouke Jan), Huentelman, M.J. (Matthew), Pol, H.H., Ikeda, M. (Masashi), Jack, C.R. (Clifford R.), Jenkinson, S. (Sarah), Johnson, R. (Robert), Jönsson, E.G. (Erik G.), Jukema, J.W., Kahn, R. (René), Kanai, R. (Ryota), Kloszewska, I. (Iwona), Knopman, D.S. (David S.), Kochunov, P. (Peter), Kwok, J.B. (John B.), Lawrie, S. (Stephen), Lemaître, H. (Herve), Liu, X. (Xinmin), Longo, D.L. (Dan L.), Lopez, O.L. (Oscar L.), Lovestone, S. (Simon), Martinez, O. (Oliver), Martinot, J.-L. (Jean-Luc), Mattay, V.S. (Venkata S.), McDonald, C. (Colm), McIntosh, A.M. (Andrew), McMahon, F.J. (Francis J.), McMahon, K.L. (Katie L.), Mecocci, P. (Patrizia), Melle, I. (Ingrid), Meyer-Lindenberg, A. (Andreas), Mohnke, S. (Sebastian), Montgomery, G.W. (Grant W.), Morris, D.W. (Derek W), Mosley, T.H. (Thomas H.), Mühleisen, T.W. (Thomas), Müller-Myhsok, B. (B.), Nalls, M.A. (Michael), Nauck, M. (Matthias), Nichols, T.E. (Thomas), Niessen, W.J. (Wiro), Nöthen, M.M. (Markus), Nyberg, L. (Lars), Ohi, K. (Kazutaka), Olvera, R.L. (Rene), Ophoff, R.A. (Roel), Pandolfo, M. (Massimo), Paus, T. (Tomas), Pausova, Z. (Zdenka), Penninx, B.W.J.H. (Brenda), Pike, G.B. (G. Bruce), Potkin, S.G. (Steven), Psaty, B.M. (Bruce), Reppermund, S., Rietschel, M. (Marcella), Roffman, J.L. (Joshua), Seiferth, N. (Nina), Rotter, J.I. (Jerome I.), Ryten, M. (Mina), Sacco, R.L. (Ralph L.), Sachdev, P.S. (Perminder), Saykin, A.J. (Andrew), Schmidt, R. (Reinhold), Schmidt, H. (Helena), Schofield, C.J. (Christopher), Sigursson, S. (Sigurdur), Simmons, A. (Andrew), Singleton, A. (Andrew), Sisodiya, S.M. (Sanjay), Smith, C. (Colin), Smoller, J.W., Soininen, H. (H.), Steen, V.M. (Vidar), Stott, D.J. (David J.), Sussmann, J. (Jessika), Thalamuthu, A. (Anbupalam), Toga, A.W. (Arthur W.), Traynor, B. (Bryan), Troncoso, J.C. (Juan), Tsolaki, M. (Magda), Tzourio, C. (Christophe), Uitterlinden, A.G. (André), Hernández, M.C.V. (Maria C. Valdés), Brug, M.P. (Marcel) van der, Lugt, A. (Aad) van der, Wee, N.J. (Nic) van der, Haren, N.E.M. (Neeltje E.) van, Ent, D. (Dennis) van 't, Tol, M.J.D. (Marie-José) van, Vardarajan, B.N. (Badri), Vellas, B. (Bruno), Veltman, D.J. (Dick), Völzke, H. (Henry), Walter, H.J. (Henrik), Wardlaw, J. (Joanna), Wassink, A.M.J. (Annemarie), Weale, M.E. (Michael), Weinberger, D.R. (Daniel R.), Weiner, M.W. (Michael W.), Wen, W. (Wei), Westman, E. (Eric), White, T.J.H. (Tonya), Wong, T.Y. (Tien Y.), Wright, C.B. (Clinton B.), Zielke, R.H. (Ronald H.), Zonderman, A.B., Martin, N.G. (Nicholas), Duijn, C.M. (Cornelia) van, Wright, M.J. (Margaret), Longstreth Jr, W.T., Schumann, G. (Gunter), Grabe, H.J. (Hans Jörgen), Franke, B. (Barbara), Launer, L.J. (Lenore), Medland, S.E. (Sarah), Seshadri, S. (Sudha), Thompson, P.M. (Paul), Ikram, M.K. (Kamran), Hibar, D.P. (Derrek), Adams, H.H.H. (Hieab), Jahanshad, N. (Neda), Chauhan, G. (Ganesh), Stein, J.L., Hofer, E. (Edith), Rentería, M.E. (Miguel), Bis, J.C. (Joshua), Arias-Vásquez, A. (Alejandro), Ikram, M.K. (M. Kamran), Desrivières, S. (Sylvane), Vernooij, M.W. (Meike), Abramovic, L. (Lucija), Alhusaini, S. (Saud), Amin, N. (Najaf), Andersson, M. (Micael), Arfanakis, K. (Konstantinos), Aribisala, B. (Benjamin), Armstrong, N.J. (Nicola J.), Athanasiu, L. (Lavinia), Axelsson, T. (Tomas), Beecham, A.H. (Ashley), Beiser, A. (Alexa), Bernard, M. (Manon), Blanton, S.H. (Susan H.), Bohlken, M.M. (Marc M.), Boks, M.P.M. (Marco), Bralten, L.B.C. (Linda), Brickman, A.M. (Adam M.), Carmichael, O. (Owen), Chakravarty, M.M. (M. Mallar), Chen, Q. (Qiang), Ching, C.R.K. (Christopher), Chouraki, V. (Vincent), Cuellar-Partida, G. (Gabriel), Crivello, F. (Fabrice), Braber, A. (Anouk) den, Doan, N.T. (Nhat Trung), Ehrlich, S.M. (Stefan), Giddaluru, S. (Sudheer), Goldman, A.L. (Aaron L.), Gottesman, R.F. (Rebecca), Grimm, O. (Oliver), Griswold, M.D. (Michael), Guadalupe, T. (Tulio), Gutman, B.A. (Boris A.), Hass, J. (Johanna), Haukvik, U.K. (Unn), Hoehn, D. (David), Holmes, A.J. (Avram), Hoogman, M. (Martine), Janowitz, D. (Deborah), Jia, T. (Tianye), Jørgensen, K.N. (Kjetil N.), Karbalai, N. (Nazanin), Kasperaviciute, D. (Dalia), Kim, S. (Shinseog), Klein, M. (Marieke), Kraemer, B. (Bernd), Lee, P.H. (Phil), Liewald, D.C.M. (David), Lopez, L.M. (Lorna), Luciano, M. (Michelle), MacAre, C. (Christine), Marquand, A.F. (Andre F.), Matarin, M. (Mar), Mather, R., Mattheisen, M. (Manuel), McKay, D.R. (David R.), Milaneschi, Y. (Yuri), Muñoz Maniega, S. (Susana), Nho, K. (Kwangsik), Nugent, A.C. (Allison), Nyquist, P. (Paul), Loohuis, L.M.O. (Loes M. Olde), Oosterlaan, J. (Jaap), Papmeyer, M. (Martina), Pirpamer, L. (Lukas), Pütz, B. (Benno), Ramasamy, A. (Adaikalavan), Richards, J.S. (Jennifer S.), Risacher, S.L. (Shannon), Roiz-Santiañez, R. (Roberto), Rommelse, N. (Nanda), Ropele, S. (Stefan), Rose, E.J. (Emma), Royle, N.A. (Natalie), Rundek, T. (Tatjana), Sämann, P.G. (Philipp), Saremi, A. (Arvin), Satizabal, C.L. (Claudia), Schmaal, L. (Lianne), Schork, N.J. (Nicholas), Shen, L. (Li), Shin, J. (Jean), Shumskaya, E. (Elena), Smith, A.V. (Albert Vernon), Sprooten, R. (Roy), Strike, L.T. (Lachlan), Teumer, A. (Alexander), Tordesillas-Gutierrez, D. (Diana), Toro, R. (Roberto), Trabzuni, D. (Danyah), Trompet, S. (Stella), Vaidya, D. (Dhananjay), van der Grond, J. (Jeroen), Lee, S.J. (Sven) van der, Van Der Meer, D. (Dennis), Van Donkelaar, M.M.J. (Marjolein M. J.), Eijk, K.R. (Kristel) van, Erp, T.G.M. (Theo G.) van, Van Rooij, D. (Daan), Walton, E. (Esther), Westlye, L.T. (Lars), Whelan, C.D. (Christopher), Windham, B.G. (Gwen), Winkler, A.M. (Anderson), Wittfeld, K. (Katharina), Woldehawariat, G. (Girma), Björnsson, A. (Asgeir), Wolfers, T. (Thomas), Yanek, L.R. (Lisa), Yang, J. (Jingyun), Zijdenbos, A.P., Zwiers, M.P. (Marcel), Agartz, I. (Ingrid), Almasy, L. (Laura), Ames, D.J. (David), Amouyel, P. (Philippe), Andreassen, O.A. (Ole), Arepalli, S. (Sampath), Assareh, A.A., Barral, S. (Sandra), Bastin, M.E. (Mark), Becker, D.M. (Diane M.), Becker, J.T. (James), Bennett, D.A. (David A.), Blangero, J. (John), Bokhoven, H. (Hans) van, Boomsma, D.I. (Dorret), Brodaty, H. (Henry), Brouwer, R.M. (Rachel), Brunner, H.G., Buckner, M., Buitelaar, J.K. (Jan), Bulayeva, K. (Kazima), Cahn, W. (Wiepke), Calhoun, V.D. (Vince), Cannon, D.M. (Dara), Cavalleri, G. (Gianpiero), Cheng, C.-Y. (Ching-Yu), Cichon, S. (Sven), Cookson, M.R. (Mark), Corvin, A. (Aiden), Crespo-Facorro, B. (Benedicto), Curran, J.E. (Joanne), Czisch, M. (Michael), Dale, A.M. (Anders), Davies, G.E. (Gareth), Craen, A.J. (Anton) de, Geus, E.J.C. (Eco) de, Jager, P.L. (Philip) de, Zubicaray, G.I. (Greig) de, Deary, I.J. (Ian), Debette, S. (Stéphanie), DeCarli, C. (Charles), Delanty, N., Depondt, C. (Chantal), DeStefano, A.L. (Anita), Dillman, A. (Allissa), Djurovic, S. (Srdjan), Donohoe, D.J. (Dennis), Drevets, D.A. (Douglas), Duggirala, R. (Ravi), Dyer, M.D. (Matthew), Enzinger, C. (Christian), Erk, S., Espeseth, T. (Thomas), Fedko, I.O. (Iryna O.), Fernández, G. (Guillén), Ferrucci, L. (Luigi), Fisher, S.E. (Simon), Fleischman, D. (Debra), Ford, I. (Ian), Fornage, M. (Myriam), Foroud, T. (Tatiana), Fox, P.T. (Peter), Francks, C. (Clyde), Fukunaga, M. (Masaki), Gibbs, J.R. (J. Raphael), Glahn, D.C. (David), Gollub, R.L. (Randy), Göring, H.H.H. (Harald H.), Green, R.C. (Robert C.), Gruber, O. (Oliver), Gudnason, V. (Vilmundur), Guelfi, S. (Sebastian), Håberg, A.K. (Asta K.), Hansell, N.K. (Narelle), Hardy, J. (John), Hartman, C.A. (C.), Hashimoto, R. (Ryota), Hegenscheid, K. (Katrin), Heinz, J. (Judith), Le Hellard, S. (Stephanie), Hernandez, D.G. (Dena), Heslenfeld, D.J. (Dirk), Ho, B.-C. (Beng-Choon), Hoekstra, P.J. (Pieter), Hoffmann, W. (Wolfgang), Hofman, A. (Albert), Holsboer, F. (Florian), Homuth, G. (Georg), Hosten, N. (Norbert), Hottenga, J.J. (Jouke Jan), Huentelman, M.J. (Matthew), Pol, H.H., Ikeda, M. (Masashi), Jack, C.R. (Clifford R.), Jenkinson, S. (Sarah), Johnson, R. (Robert), Jönsson, E.G. (Erik G.), Jukema, J.W., Kahn, R. (René), Kanai, R. (Ryota), Kloszewska, I. (Iwona), Knopman, D.S. (David S.), Kochunov, P. (Peter), Kwok, J.B. (John B.), Lawrie, S. (Stephen), Lemaître, H. (Herve), Liu, X. (Xinmin), Longo, D.L. (Dan L.), Lopez, O.L. (Oscar L.), Lovestone, S. (Simon), Martinez, O. (Oliver), Martinot, J.-L. (Jean-Luc), Mattay, V.S. (Venkata S.), McDonald, C. (Colm), McIntosh, A.M. (Andrew), McMahon, F.J. (Francis J.), McMahon, K.L. (Katie L.), Mecocci, P. (Patrizia), Melle, I. (Ingrid), Meyer-Lindenberg, A. (Andreas), Mohnke, S. (Sebastian), Montgomery, G.W. (Grant W.), Morris, D.W. (Derek W), Mosley, T.H. (Thomas H.), Mühleisen, T.W. (Thomas), Müller-Myhsok, B. (B.), Nalls, M.A. (Michael), Nauck, M. (Matthias), Nichols, T.E. (Thomas), Niessen, W.J. (Wiro), Nöthen, M.M. (Markus), Nyberg, L. (Lars), Ohi, K. (Kazutaka), Olvera, R.L. (Rene), Ophoff, R.A. (Roel), Pandolfo, M. (Massimo), Paus, T. (Tomas), Pausova, Z. (Zdenka), Penninx, B.W.J.H. (Brenda), Pike, G.B. (G. Bruce), Potkin, S.G. (Steven), Psaty, B.M. (Bruce), Reppermund, S., Rietschel, M. (Marcella), Roffman, J.L. (Joshua), Seiferth, N. (Nina), Rotter, J.I. (Jerome I.), Ryten, M. (Mina), Sacco, R.L. (Ralph L.), Sachdev, P.S. (Perminder), Saykin, A.J. (Andrew), Schmidt, R. (Reinhold), Schmidt, H. (Helena), Schofield, C.J. (Christopher), Sigursson, S. (Sigurdur), Simmons, A. (Andrew), Singleton, A. (Andrew), Sisodiya, S.M. (Sanjay), Smith, C. (Colin), Smoller, J.W., Soininen, H. (H.), Steen, V.M. (Vidar), Stott, D.J. (David J.), Sussmann, J. (Jessika), Thalamuthu, A. (Anbupalam), Toga, A.W. (Arthur W.), Traynor, B. (Bryan), Troncoso, J.C. (Juan), Tsolaki, M. (Magda), Tzourio, C. (Christophe), Uitterlinden, A.G. (André), Hernández, M.C.V. (Maria C. Valdés), Brug, M.P. (Marcel) van der, Lugt, A. (Aad) van der, Wee, N.J. (Nic) van der, Haren, N.E.M. (Neeltje E.) van, Ent, D. (Dennis) van 't, Tol, M.J.D. (Marie-José) van, Vardarajan, B.N. (Badri), Vellas, B. (Bruno), Veltman, D.J. (Dick), Völzke, H. (Henry), Walter, H.J. (Henrik), Wardlaw, J. (Joanna), Wassink, A.M.J. (Annemarie), Weale, M.E. (Michael), Weinberger, D.R. (Daniel R.), Weiner, M.W. (Michael W.), Wen, W. (Wei), Westman, E. (Eric), White, T.J.H. (Tonya), Wong, T.Y. (Tien Y.), Wright, C.B. (Clinton B.), Zielke, R.H. (Ronald H.), Zonderman, A.B., Martin, N.G. (Nicholas), Duijn, C.M. (Cornelia) van, Wright, M.J. (Margaret), Longstreth Jr, W.T., Schumann, G. (Gunter), Grabe, H.J. (Hans Jörgen), Franke, B. (Barbara), Launer, L.J. (Lenore), Medland, S.E. (Sarah), Seshadri, S. (Sudha), Thompson, P.M. (Paul), and Ikram, M.K. (Kamran)
Abstract: The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
Published: 2017
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9. Fingolimod induces neuroprotective factors in human astrocytes

Author: Hoffmann, F., Hofereiter, J., Ruebsamen, H., Melms, J., Schwarz, S., Faber, H., Weber, P., Pütz, B., Loleit, V., Weber, F., Hohlfeld, R., Meinl, E., and Krumbholz, M.
Subjects: Time Factors, drug effects [Neural Stem Cells], pharmacology [Lysophospholipids], Interleukin 11, Neural Stem Cells, Sphingosine, RNA, Small Interfering, genetics [Heparin-binding EGF-like Growth Factor], NF-kappa B, Interleukin-11, cytology [Fetus], Neuroprotection, pharmacology [Fingolimod Hydrochloride], Neuroprotective Agents, Neurology, metabolism [NF-kappa B], Heparin-binding EGF-like growth factor, Astrocyte, pharmacology [Sphingosine], Heparin-binding EGF-like Growth Factor, B-cell activating factor of the TNF family/TNFSF13b, Immunology, metabolism [Interleukin-11], drug effects [Astrocytes], analogs & derivatives [Sphingosine], Enzyme-Linked Immunosorbent Assay, metabolism [Heparin-binding EGF-like Growth Factor], genetics [Interleukin-11], Cellular and Molecular Neuroscience, Fetus, Humans, MX1, ddc:610, RNA, Messenger, sphingosine 1-phosphate, Dose-Response Relationship, Drug, pharmacology [Neuroprotective Agents], Fingolimod Hydrochloride, Research, pharmacology [RNA, Small Interfering], Fingolimod, CXCL10/IP10, HBEGF protein, human, OAS2, Microarray Analysis, Corpus Striatum, genetics [Chemokine CXCL10], Chemokine CXCL10, Leukemia inhibitory factor, Astrocytes, metabolism [Chemokine CXCL10], cytology [Corpus Striatum], Lysophospholipids, genetics [NF-kappa B]
Abstract: Background Fingolimod (FTY720) is the first sphingosine-1-phosphate (S1P) receptor modulator approved for the treatment of multiple sclerosis. The phosphorylated active metabolite FTY720-phosphate (FTY-P) interferes with lymphocyte trafficking. In addition, it accumulates in the CNS and reduces brain atrophy in multiple sclerosis (MS), and neuroprotective effects are hypothesized. Methods Human primary astrocytes as well as human astrocytoma cells were stimulated with FTY-P or S1P. We analyzed gene expression by a genome-wide microarray and validated induced candidate genes by quantitative PCR (qPCR) and ELISA. To identify the S1P-receptor subtypes involved, we applied a membrane-impermeable S1P analog (dihydro-S1P), receptor subtype specific agonists and antagonists, as well as RNAi silencing. Results FTY-P induced leukemia inhibitory factor (LIF), interleukin 11 (IL11), and heparin-binding EGF-like growth factor (HBEGF) mRNA, as well as secretion of LIF and IL11 protein. In order to mimic an inflammatory milieu as observed in active MS lesions, we combined FTY-P application with tumor necrosis factor (TNF). In the presence of this key inflammatory cytokine, FTY-P synergistically induced LIF, HBEGF, and IL11 mRNA, as well as secretion of LIF and IL11 protein. TNF itself induced inflammatory, B-cell promoting, and antiviral factors (CXCL10, BAFF, MX1, and OAS2). Their induction was blocked by FTY-P. After continuous exposure of cells to FTY-P or S1P for up to 7 days, the extent of induction of neurotrophic factors and the suppression of TNF-induced inflammatory genes declined but was still detectable. The induction of neurotrophic factors was mediated via surface S1P receptors 1 (S1PR1) and 3 (S1PR3). Conclusions We identified effects of FTY-P on astrocytes, namely induction of neurotrophic mediators (LIF, HBEGF, and IL11) and inhibition of TNF-induced inflammatory genes (CXCL10, BAFF, MX1, and OAS2). This supports the view that a part of the effects of fingolimod may be mediated via astrocytes. Electronic supplementary material The online version of this article (doi:10.1186/s12974-015-0393-6) contains supplementary material, which is available to authorized users.
Published: 2015

10. New loci for restless legs syndrome map to chromosome 4q and 17p

Author: Winkelmann, J., Lichtner, P., Kemlink, D., Polo, O., Montagna, P., Högl, B., Stiasny-Kolster, K., Hadjigeorgiou, G., Pütz, B., Trenkwalder, C., Strom, T.M., Meitinger, T., and Müller-Myhsok, B.
Published: 2024
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11. Novel genetic loci underlying human intracranial volume identified through genome-wide association

Author: Adams, H.H.H., Hibar, D.P., Chouraki, V., Stein, J.L., Nyquist, P.A., Renteria, M.E., Trompet, S., Arias-Vasquez, A., Seshadri, S., Desrivières, S., Beecham, A.H., Jahanshad, N., Wittfeld, K., van der Lee, S.J., Abramovic, L., Alhusaini, S., Amin, N., Andersson, M., Arfanakis, K., Aribisala, B.S., Armstrong, N.J., Athanasiu, L., Axelsson, T., Beiser, A., Bernard, M., Bis, J.C., Blanken, L.M.E., Blanton, S.H., Bohlken, M.M., Boks, M.P., Bralten, J., Brickman, A.M., Carmichael, O., Chakravarty, M.M., Chauhan, G., Chen, Q., Ching, C.R.K., Cuellar-Partida, G., Braber, A.D., Doan, N.T., Ehrlich, S., Filippi, I., Ge, T., Giddaluru, S., Goldman, A.L., Gottesman, R.F., Greven, C.U., Grimm, O., Griswold, M.E., Guadalupe, T., Hass, J., Haukvik, U.K., Hilal, S., Hofer, E., Hoehn, D., Holmes, A.J., Hoogman, M., Janowitz, D., Jia, T., Kasperaviciute, D., Kim, S., Klein, M., Kraemer, B., Lee, P.H., Liao, J., Liewald, D.C.M., Lopez, L.M., Luciano, M., Macare, C., Marquand, A., Matarin, M., Mather, K.A., Mattheisen, M., Mazoyer, B., McKay, D.R., McWhirter, R., Milaneschi, Y., Mirza-Schreiber, N., Muetzel, R.L., Maniega, S.M., Nho, K., Nugent, A.C., Loohuis, L.M.O., Oosterlaan, J., Papmeyer, M., Pappa, I., Pirpamer, L., Pudas, S., Pütz, B., Rajan, K.B., Ramasamy, A., Richards, J.S., Risacher, S.L., Roiz-Santiañez, R., Rommelse, N., Rose, E.J., Royle, N.A., Rundek, T., Sämann, P.G., Satizabal, C.L., Schmaal, L., Schork, A.J., Shen, L., Shin, J., Shumskaya, E., Smith, A.V., Sprooten, E., Strike, L.T., Teumer, A., Thomson, R., Tordesillas-Gutierrez, D., Toro, R., Trabzuni, D., Vaidya, D., Van der Grond, J., van der Meer, D., van Donkelaar, M.M.J., van Eijk, K.R., Van Erp, T.G.M., Van Rooij, D., Walton, E., Westlye, L.T., Whelan, C.D., Windham, B.G., Winkler, A.M., Woldehawariat, G., Wolf, C., Wolfers, T., Xu, B., Yanek, L.R., Yang, J., Zijdenbos, A., Zwiers, M.P., Agartz, I., Aggarwal, N.T., Almasy, L., Ames, D., Amouyel, P., Andreassen, O.A., Arepalli, S., Assareh, A.A., Barral, S., Bastin, M.E., Becker, D.M., Becker, J.T., Bennett, D.A., Blangero, J., van Bokhoven, H., Boomsma, D.I., Brodaty, H., Brouwer, R.M., Brunner, H.G., Buckner, R.L., Buitelaar, J.K., Bulayeva, K.B., Cahn, W., Calhoun, V.D., Cannon, D.M., Cavalleri, G.L., Chen, C., Cheng, C-Y, Cichon, S., Cookson, M.R., Corvin, A., Crespo-Facorro, B., Curran, J.E., Czisch, M., Dale, A.M., Davies, G.E., De Geus, E.J.C., De Jager, P.L., de Zubicaray, G.I., Delanty, N., Depondt, C., DeStefano, A.L., Dillman, A., Djurovic, S., Donohoe, G., Drevets, W.C., Duggirala, R., Dyer, T.D., Erk, S., Espeseth, T., Evans, D.A., Fedko, I.O., Fernández, G., Ferrucci, L., Fisher, S.E., Fleischman, D.A., Ford, I., Foroud, T.M., Fox, P.T., Francks, C., Fukunaga, M., Gibbs, J.R., Glahn, D.C., Gollub, R.L., Göring, H.H.H., Grabe, H.J., Green, R.C., Gruber, O., Gudnason, V., Guelfi, S., Hansell, N.K., Hardy, J., Hartman, C.A., Hashimoto, R., Hegenscheid, K., Heinz, A., Le Hellard, S., Hernandez, D.G., Heslenfeld, D.J., Ho, B-C., Hoekstra, P.J., Hoffmann, W., Hofman, A., Holsboer, F., Homuth, G., Hosten, N., Hottenga, J-J, Pol, H.E.H., Ikeda, M., Ikram, M.K., Jack, C.R., Jenkinson, M., Johnson, R., Jönsson, E.G., Jukema, J.W., Kahn, R.S., Kanai, R., Kloszewska, I., Knopman, D.S., Kochunov, P., Kwok, J.B., Lawrie, S.M., Lemaitre, H., Liu, X., Longo, D.L., Longstreth, W.T., Lopez, O.L., Lovestone, S., Martinez, O.P., Martinot, J-L, Mattay, V.S., McDonald, C., McIntosh, A.M., McMahon, K.L., McMahon, F.J., Mecocci, P., Melle, I., Meyer-Lindenberg, A., Mohnke, S., Montgomery, G.W., Morris, D.W., Mosley, T.H., Mühleisen, T.W., Müller-Myhsok, B., Nalls, M.A., Nauck, M., Nichols, T.E., Niessen, W.J., Nöthen, M.M., Nyberg, L., Ohi, K., Olvera, R.L., Ophoff, R.A., Pandolfo, M., Paus, T., Pausova, Z., Penninx, B.W.J.H., Pike, G.B., Potkin, S.G., Psaty, B.M., Reppermund, S., Rietschel, M., Roffman, J.L., Romanczuk-Seiferth, N., Rotter, J.I., Ryten, M., Sacco, R.L., Sachdev, P.S., Saykin, A.J., Schmidt, R., Schofield, P.R., Sigurdsson, S., Simmons, A., Singleton, A., Sisodiya, S.M., Smith, C., Smoller, J.W., Soininen, H., Srikanth, V., Steen, V.M., Stott, D.J., Sussmann, J.E., Thalamuthu, A., Tiemeier, H., Toga, A.W., Traynor, B.J., Troncoso, J., Turner, J.A., Tzourio, C., Uitterlinden, A.G., Hernández, M.C.V., van der Brug, M., Van der Lugt, A., van der Wee, N.J.A., van Duijn, C.M., van Haren, N.E.M., Van′t Ent, D., van Tol, M-J, Vardarajan, B.N., Veltman, D.J., Vernooij, M.W., Volzke, H., Walter, H., Wardlaw, J.M., Wassink, T.H., Weale, M.E., Weinberger, D.R., Weiner, M.W., Wen, W., Westman, E., White, T., Wong, T.Y., Wright, C.B., Zielke, H.R., Zonderman, A.B., Deary, I.J., DeCarli, C., Schmidt, H., Martin, N.G., de Craen, A.J.M., Wright, M.J., Launer, L.J., Schumann, G., Fornage, M., Franke, B., Debette, S., Medland, S.E., Ikram, M.A., Thompson, P.M., Adams, H.H.H., Hibar, D.P., Chouraki, V., Stein, J.L., Nyquist, P.A., Renteria, M.E., Trompet, S., Arias-Vasquez, A., Seshadri, S., Desrivières, S., Beecham, A.H., Jahanshad, N., Wittfeld, K., van der Lee, S.J., Abramovic, L., Alhusaini, S., Amin, N., Andersson, M., Arfanakis, K., Aribisala, B.S., Armstrong, N.J., Athanasiu, L., Axelsson, T., Beiser, A., Bernard, M., Bis, J.C., Blanken, L.M.E., Blanton, S.H., Bohlken, M.M., Boks, M.P., Bralten, J., Brickman, A.M., Carmichael, O., Chakravarty, M.M., Chauhan, G., Chen, Q., Ching, C.R.K., Cuellar-Partida, G., Braber, A.D., Doan, N.T., Ehrlich, S., Filippi, I., Ge, T., Giddaluru, S., Goldman, A.L., Gottesman, R.F., Greven, C.U., Grimm, O., Griswold, M.E., Guadalupe, T., Hass, J., Haukvik, U.K., Hilal, S., Hofer, E., Hoehn, D., Holmes, A.J., Hoogman, M., Janowitz, D., Jia, T., Kasperaviciute, D., Kim, S., Klein, M., Kraemer, B., Lee, P.H., Liao, J., Liewald, D.C.M., Lopez, L.M., Luciano, M., Macare, C., Marquand, A., Matarin, M., Mather, K.A., Mattheisen, M., Mazoyer, B., McKay, D.R., McWhirter, R., Milaneschi, Y., Mirza-Schreiber, N., Muetzel, R.L., Maniega, S.M., Nho, K., Nugent, A.C., Loohuis, L.M.O., Oosterlaan, J., Papmeyer, M., Pappa, I., Pirpamer, L., Pudas, S., Pütz, B., Rajan, K.B., Ramasamy, A., Richards, J.S., Risacher, S.L., Roiz-Santiañez, R., Rommelse, N., Rose, E.J., Royle, N.A., Rundek, T., Sämann, P.G., Satizabal, C.L., Schmaal, L., Schork, A.J., Shen, L., Shin, J., Shumskaya, E., Smith, A.V., Sprooten, E., Strike, L.T., Teumer, A., Thomson, R., Tordesillas-Gutierrez, D., Toro, R., Trabzuni, D., Vaidya, D., Van der Grond, J., van der Meer, D., van Donkelaar, M.M.J., van Eijk, K.R., Van Erp, T.G.M., Van Rooij, D., Walton, E., Westlye, L.T., Whelan, C.D., Windham, B.G., Winkler, A.M., Woldehawariat, G., Wolf, C., Wolfers, T., Xu, B., Yanek, L.R., Yang, J., Zijdenbos, A., Zwiers, M.P., Agartz, I., Aggarwal, N.T., Almasy, L., Ames, D., Amouyel, P., Andreassen, O.A., Arepalli, S., Assareh, A.A., Barral, S., Bastin, M.E., Becker, D.M., Becker, J.T., Bennett, D.A., Blangero, J., van Bokhoven, H., Boomsma, D.I., Brodaty, H., Brouwer, R.M., Brunner, H.G., Buckner, R.L., Buitelaar, J.K., Bulayeva, K.B., Cahn, W., Calhoun, V.D., Cannon, D.M., Cavalleri, G.L., Chen, C., Cheng, C-Y, Cichon, S., Cookson, M.R., Corvin, A., Crespo-Facorro, B., Curran, J.E., Czisch, M., Dale, A.M., Davies, G.E., De Geus, E.J.C., De Jager, P.L., de Zubicaray, G.I., Delanty, N., Depondt, C., DeStefano, A.L., Dillman, A., Djurovic, S., Donohoe, G., Drevets, W.C., Duggirala, R., Dyer, T.D., Erk, S., Espeseth, T., Evans, D.A., Fedko, I.O., Fernández, G., Ferrucci, L., Fisher, S.E., Fleischman, D.A., Ford, I., Foroud, T.M., Fox, P.T., Francks, C., Fukunaga, M., Gibbs, J.R., Glahn, D.C., Gollub, R.L., Göring, H.H.H., Grabe, H.J., Green, R.C., Gruber, O., Gudnason, V., Guelfi, S., Hansell, N.K., Hardy, J., Hartman, C.A., Hashimoto, R., Hegenscheid, K., Heinz, A., Le Hellard, S., Hernandez, D.G., Heslenfeld, D.J., Ho, B-C., Hoekstra, P.J., Hoffmann, W., Hofman, A., Holsboer, F., Homuth, G., Hosten, N., Hottenga, J-J, Pol, H.E.H., Ikeda, M., Ikram, M.K., Jack, C.R., Jenkinson, M., Johnson, R., Jönsson, E.G., Jukema, J.W., Kahn, R.S., Kanai, R., Kloszewska, I., Knopman, D.S., Kochunov, P., Kwok, J.B., Lawrie, S.M., Lemaitre, H., Liu, X., Longo, D.L., Longstreth, W.T., Lopez, O.L., Lovestone, S., Martinez, O.P., Martinot, J-L, Mattay, V.S., McDonald, C., McIntosh, A.M., McMahon, K.L., McMahon, F.J., Mecocci, P., Melle, I., Meyer-Lindenberg, A., Mohnke, S., Montgomery, G.W., Morris, D.W., Mosley, T.H., Mühleisen, T.W., Müller-Myhsok, B., Nalls, M.A., Nauck, M., Nichols, T.E., Niessen, W.J., Nöthen, M.M., Nyberg, L., Ohi, K., Olvera, R.L., Ophoff, R.A., Pandolfo, M., Paus, T., Pausova, Z., Penninx, B.W.J.H., Pike, G.B., Potkin, S.G., Psaty, B.M., Reppermund, S., Rietschel, M., Roffman, J.L., Romanczuk-Seiferth, N., Rotter, J.I., Ryten, M., Sacco, R.L., Sachdev, P.S., Saykin, A.J., Schmidt, R., Schofield, P.R., Sigurdsson, S., Simmons, A., Singleton, A., Sisodiya, S.M., Smith, C., Smoller, J.W., Soininen, H., Srikanth, V., Steen, V.M., Stott, D.J., Sussmann, J.E., Thalamuthu, A., Tiemeier, H., Toga, A.W., Traynor, B.J., Troncoso, J., Turner, J.A., Tzourio, C., Uitterlinden, A.G., Hernández, M.C.V., van der Brug, M., Van der Lugt, A., van der Wee, N.J.A., van Duijn, C.M., van Haren, N.E.M., Van′t Ent, D., van Tol, M-J, Vardarajan, B.N., Veltman, D.J., Vernooij, M.W., Volzke, H., Walter, H., Wardlaw, J.M., Wassink, T.H., Weale, M.E., Weinberger, D.R., Weiner, M.W., Wen, W., Westman, E., White, T., Wong, T.Y., Wright, C.B., Zielke, H.R., Zonderman, A.B., Deary, I.J., DeCarli, C., Schmidt, H., Martin, N.G., de Craen, A.J.M., Wright, M.J., Launer, L.J., Schumann, G., Fornage, M., Franke, B., Debette, S., Medland, S.E., Ikram, M.A., and Thompson, P.M.
Abstract: Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.
Published: 2016

12. Common genetic variants influence human subcortical brain structures

Author: Hibar, DP, Stein, JL, Renteria, ME, Arias-Vasquez, A, Desrivières, S, Jahanshad, N, Toro, R, Wittfeld, K, Abramovic, L, Andersson, M, Aribisala, BS, Armstrong, NJ, Bernard, M, Bohlken, MM, Boks, MP, Bralten, J, Brown, AA, Mallar Chakravarty, M, Chen, Q, Ching, CRK, Cuellar-Partida, G, Den Braber, A, Giddaluru, S, Goldman, AL, Grimm, O, Guadalupe, T, Hass, J, Woldehawariat, G, Holmes, AJ, Hoogman, M, Janowitz, D, Jia, T, Kim, S, Klein, M, Kraemer, B, Lee, PH, Olde Loohuis, LM, Luciano, M, MacAre, C, Mather, KA, Mattheisen, M, Milaneschi, Y, Nho, K, Papmeyer, M, Ramasamy, A, Risacher, SL, Roiz-Santiañez, R, Rose, EJ, Salami, A, Sämann, PG, Schmaal, L, Schork, AJ, Shin, J, Strike, LT, Teumer, A, Van Donkelaar, MMJ, Van Eijk, KR, Walters, RK, Westlye, LT, Whelan, CD, Winkler, AM, Zwiers, MP, Alhusaini, S, Athanasiu, L, Ehrlich, S, Hakobjan, MMH, Hartberg, CB, Haukvik, UK, Heister, AJGAM, Hoehn, D, Kasperaviciute, D, Liewald, DCM, Lopez, LM, Makkinje, RRR, Matarin, M, Naber, MAM, Reese McKay, D, Needham, M, Nugent, AC, Pütz, B, Royle, NA, Shen, L, Sprooten, E, Trabzuni, D, Van Der Marel, SSL, Van Hulzen, KJE, Walton, E, Wolf, C, Almasy, L, Ames, D, Arepalli, S, Assareh, AA, Bastin, ME, Brodaty, H, Bulayeva, KB, Carless, MA, Cichon, S, Corvin, A, Curran, JE, Czisch, M, Hibar, DP, Stein, JL, Renteria, ME, Arias-Vasquez, A, Desrivières, S, Jahanshad, N, Toro, R, Wittfeld, K, Abramovic, L, Andersson, M, Aribisala, BS, Armstrong, NJ, Bernard, M, Bohlken, MM, Boks, MP, Bralten, J, Brown, AA, Mallar Chakravarty, M, Chen, Q, Ching, CRK, Cuellar-Partida, G, Den Braber, A, Giddaluru, S, Goldman, AL, Grimm, O, Guadalupe, T, Hass, J, Woldehawariat, G, Holmes, AJ, Hoogman, M, Janowitz, D, Jia, T, Kim, S, Klein, M, Kraemer, B, Lee, PH, Olde Loohuis, LM, Luciano, M, MacAre, C, Mather, KA, Mattheisen, M, Milaneschi, Y, Nho, K, Papmeyer, M, Ramasamy, A, Risacher, SL, Roiz-Santiañez, R, Rose, EJ, Salami, A, Sämann, PG, Schmaal, L, Schork, AJ, Shin, J, Strike, LT, Teumer, A, Van Donkelaar, MMJ, Van Eijk, KR, Walters, RK, Westlye, LT, Whelan, CD, Winkler, AM, Zwiers, MP, Alhusaini, S, Athanasiu, L, Ehrlich, S, Hakobjan, MMH, Hartberg, CB, Haukvik, UK, Heister, AJGAM, Hoehn, D, Kasperaviciute, D, Liewald, DCM, Lopez, LM, Makkinje, RRR, Matarin, M, Naber, MAM, Reese McKay, D, Needham, M, Nugent, AC, Pütz, B, Royle, NA, Shen, L, Sprooten, E, Trabzuni, D, Van Der Marel, SSL, Van Hulzen, KJE, Walton, E, Wolf, C, Almasy, L, Ames, D, Arepalli, S, Assareh, AA, Bastin, ME, Brodaty, H, Bulayeva, KB, Carless, MA, Cichon, S, Corvin, A, Curran, JE, and Czisch, M
Abstract: The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08×10 -33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.
Published: 2015

13. Common genetic variants influence human subcortical brain structures

Author: Hibar, D.P. (Derrek), Stein, J.L., Rentería, M.E. (Miguel), Arias-Vásquez, A. (Alejandro), Desrivières, S. (Sylvane), Jahanshad, N. (Neda), Toro, R. (Roberto), Wittfeld, K. (Katharina), Abramovic, L. (Lucija), Andersson, M. (Micael), Aribisala, B. (Benjamin), Armstrong, N.J. (Nicola J.), Bernard, M. (Manon), Bohlken, M.M. (Marc M.), Boks, M.P.M. (Marco), Bralten, L.B.C. (Linda), Brown, A.A. (Andrew), Chakravarty, M.M. (M. Mallar), Chen, Q. (Qiang), Ching, C.R.K. (Christopher), Cuellar-Partida, G. (Gabriel), Braber, A. (Anouk) den, Giddaluru, S. (Sudheer), Goldman, A.L. (Aaron L.), Grimm, O. (Oliver), Guadalupe, T. (Tulio), Hass, J. (Johanna), Woldehawariat, G. (Girma), Holmes, A.J. (Avram), Hoogman, M. (Martine), Janowitz, D. (Deborah), Jia, T. (Tianye), Kim, S. (Shinseog), Klein, M. (Marieke), Kraemer, B. (Bernd), Lee, P.H. (Phil H.), Olde Loohuis, L.M. (Loes M.), Luciano, M. (Michelle), MacAre, C. (Christine), Mather, R., Mattheisen, M. (Manuel), Milaneschi, Y. (Yuri), Nho, K. (Kwangsik), Papmeyer, M. (Martina), Ramasamy, A. (Adaikalavan), Risacher, S.L. (Shannon), Roiz-Santiañez, R. (Roberto), Rose, E.J. (Emma), Salami, A. (Alireza), Sämann, P.G. (Philipp), Schmaal, L. (Lianne), Schork, N.J. (Nicholas), Shin, J. (Jean), Strike, L.T. (Lachlan), Teumer, A. (Alexander), Van Donkelaar, M.M.J. (Marjolein M. J.), Eijk, K.R. (Kristel) van, Walters, R.K. (Raymond), Westlye, L.T. (Lars), Whelan, C.D. (Christopher), Winkler, A.M. (Anderson), Zwiers, M.P. (Marcel), Alhusaini, S. (Saud), Athanasiu, L. (Lavinia), Ehrlich, S.M. (Stefan), Hakobjan, M. (Marina), Hartberg, C.B. (Cecilie B.), Haukvik, U.K. (Unn), Heister, A.J.G.A.M. (Angelien J. G. A. M.), Hoehn, D. (David), Kasperaviciute, D. (Dalia), Liewald, D.C.M. (David), Lopez, L.M. (Lorna), Makkinje, R.R.R. (Remco R. R.), Matarin, M. (Mar), Naber, M.A.M. (Marlies A. M.), McKay, D.R. (Reese), Needham, M. (Margaret), Nugent, A.C. (Allison), Pütz, B. (Benno), Royle, N.A. (Natalie), Shen, L. (Li), Sprooten, R. (Roy), Trabzuni, D. (Danyah), Van Der Marel, S.S.L. (Saskia S. L.), Van Hulzen, K.J.E. (Kimm J. E.), Walton, E. (Esther), Björnsson, A. (Asgeir), Almasy, L. (Laura), Ames, D.J. (David), Arepalli, S. (Sampath), Assareh, A.A., Bastin, M.E. (Mark), Brodaty, H. (Henry), Bulayeva, K. (Kazima), Carless, M.A. (Melanie), Cichon, S. (Sven), Corvin, A. (Aiden), Curran, J.E. (Joanne), Czisch, M. (Michael), Zubicaray, G.I. (Greig) de, Dillman, A. (Allissa), Duggirala, A. (Aparna), Dyer, M.D. (Matthew), Erk, S., Fedko, I. (Iryna), Ferrucci, L. (Luigi), Foroud, T. (Tatiana), Fox, P.T. (Peter), Fukunaga, M. (Masaki), Raphael Gibbs, J., Göring, H.H.H. (Harald H.), Green, R.C. (Robert C.), Guelfi, S. (Sebastian), Hansell, N.K. (Narelle), Hartman, C.A. (Catharina), Hegenscheid, K. (Katrin), Heinz, J. (Judith), Hernandez, D.G. (Dena), Heslenfeld, D.J. (Dirk), Hoekstra, P.J. (Pieter), Holsboer, F., Homuth, G. (Georg), Hottenga, J.J. (Jouke Jan), Ikeda, M. (Masashi), Jack Jr., C.R. (Clifford), Jenkinson, S. (Sarah), Johnson, R. (Robert), Kanai, R. (Ryota), Keil, M. (Maria), Kent, J.W. (Jack W.), Kochunov, P. (Peter), Kwok, J.B. (John B.), Lawrie, S. (Stephen), Liu, X. (Xinmin), Longo, D.L. (Dan L.), Mcmahon, K.L. (Katie), Meisenzahl, E. (Eva), Melle, I. (Ingrid), Mohnke, S. (Sebastian), Montgomery, G.W. (Grant), Mostert, J.C. (Jeanette C.), Mühleisen, T.W. (Thomas), Nalls, M.A. (Michael), Nichols, T.E. (Thomas), Nilsson, L.G., Nöthen, M.M. (Markus), Ohi, K. (Kazutaka), Olvera, R.L. (Rene), Perez-Iglesias, R. (Rocio), Pike, G.B. (Bruce), Potkin, S.G. (Steven), Reinvang, I. (Ivar), Reppermund, S., Rietschel, M. (Marcella), Seiferth, N. (Nina), Rosen, G.D. (Glenn D.), Rujescu, D. (Dan), Schnell, K. (Kerry), Schofield, C.J. (Christopher), Smith, C. (Colin), Steen, V.M. (Vidar), Sussmann, J. (Jessika), Thalamuthu, A. (Anbupalam), Toga, A.W. (Arthur W.), Traynor, B. (Bryan), Troncoso, J.C. (Juan), Turner, J. (Jessica), Valdés Hernández, M.C. (Maria), Ent, D. (Dennis) van 't, Brug, M.P. (Marcel) van der, Wee, N.J. (Nic) van der, Tol, M.J.D. (Marie-José) van, Veltman, D.J. (Dick), Wassink, A.M.J. (Annemarie), Westman, E. (Eric), Zielke, R.H. (Ronald H.), Zonderman, A.B. (Alan B.), Ashbrook, D.G. (David G.), Hager, R. (Reinmar), Lu, L. (Lu), Mcmahon, F.J. (Francis J), Morris, D.W. (Derek W), Williams, R.W. (Robert W.), Brunner, H.G., Buckner, M., Buitelaar, J.K. (Jan K.), Cahn, W. (Wiepke), Calhoun, V.D. (Vince), Cavalleri, G. (Gianpiero), Crespo-Facorro, B. (Benedicto), Dale, A.M. (Anders), Davies, G.E. (Gareth), Delanty, N., Depondt, C. (Chantal), Djurovic, S. (Srdjan), Drevets, D.A. (Douglas), Espeseth, T. (Thomas), Gollub, R.L. (Randy), Ho, B.C. (Beng ), Hoffmann, W. (Wolfgang), Hosten, N. (Norbert), Kahn, R. (René), Le Hellard, S. (Stephanie), Meyer-Lindenberg, A., Müller-Myhsok, B. (B.), Nauck, M. (Matthias), Nyberg, L. (Lars), Pandolfo, M. (Massimo), Penninx, B.W.J.H. (Brenda), Roffman, J.L. (Joshua), Sisodiya, S.M. (Sanjay), Smoller, J.W., Bokhoven, H. (Hans) van, Haren, N.E.M. (Neeltje E.) van, Völzke, H. (Henry), Walter, H.J. (Henrik), Weiner, M.W. (Michael), Wen, W. (Wei), White, T.J.H. (Tonya), Agartz, I. (Ingrid), Andreassen, O.A. (Ole), Blangero, J. (John), Boomsma, D.I. (Dorret), Brouwer, R.M. (Rachel), Cannon, D.M. (Dara), Cookson, M.R. (Mark), Geus, E.J.C. (Eco) de, Deary, I.J. (Ian), Donohoe, D.J. (Dennis), Fernandez, G. (Guillén), Fisher, S.E. (Simon), Francks, C. (Clyde), Glahn, D.C. (David), Grabe, H.J. (Hans Jörgen), Gruber, O. (Oliver), Hardy, J. (John), Hashimoto, R. (Ryota), Hulshoff Pol, H.E. (Hilleke), Jönsson, E.G. (Erik), Kloszewska, I. (Iwona), Lovestone, S. (Simon), Mattay, V.S. (Venkata S.), Mecocci, P. (Patrizia), McDonald, C. (Colm), McIntosh, A.M. (Andrew), Ophoff, R.A. (Roel), Paus, T. (Tomas), Pausova, Z. (Zdenka), Ryten, M. (Mina), Sachdev, P.S. (Perminder), Saykin, A.J. (Andrew), Simmons, A. (Andrew), Singleton, A. (Andrew), Soininen, H. (H.), Wardlaw, J.M. (J.), Weale, M.E. (Michael), Weinberger, D.R. (Daniel), Adams, H.H.H. (Hieab), Launer, L.J. (Lenore), Seiler, S. (Stephan), Schmidt, R. (Reinhold), Chauhan, G. (Ganesh), Satizabal, C.L. (Claudia), Becker, J.T. (James), Yanek, L.R. (Lisa), Lee, S.J. (Sven) van der, Ebling, M. (Maritza), Fischl, B. (Bruce), Longstreth Jr, W.T., Greve, D. (Douglas), Nyquist, P. (Paul), Vinke, L.N. (Louis N.), Duijn, C.M. (Cornelia) van, Xue, L. (Luting), Mazoyer, B. (Bernard), Bis, J.C. (Joshua), Gudnason, V. (Vilmundur), Seshadri, S. (Sudha), Ikram, M.A. (Arfan), Martin, N.G. (Nicholas), Wright, M.J. (Margaret), Schumann, G. (Gunter), Franke, B. (Barbara), Thompson, P.M. (Paul), Medland, S.E. (Sarah), Hibar, D.P. (Derrek), Stein, J.L., Rentería, M.E. (Miguel), Arias-Vásquez, A. (Alejandro), Desrivières, S. (Sylvane), Jahanshad, N. (Neda), Toro, R. (Roberto), Wittfeld, K. (Katharina), Abramovic, L. (Lucija), Andersson, M. (Micael), Aribisala, B. (Benjamin), Armstrong, N.J. (Nicola J.), Bernard, M. (Manon), Bohlken, M.M. (Marc M.), Boks, M.P.M. (Marco), Bralten, L.B.C. (Linda), Brown, A.A. (Andrew), Chakravarty, M.M. (M. Mallar), Chen, Q. (Qiang), Ching, C.R.K. (Christopher), Cuellar-Partida, G. (Gabriel), Braber, A. (Anouk) den, Giddaluru, S. (Sudheer), Goldman, A.L. (Aaron L.), Grimm, O. (Oliver), Guadalupe, T. (Tulio), Hass, J. (Johanna), Woldehawariat, G. (Girma), Holmes, A.J. (Avram), Hoogman, M. (Martine), Janowitz, D. (Deborah), Jia, T. (Tianye), Kim, S. (Shinseog), Klein, M. (Marieke), Kraemer, B. (Bernd), Lee, P.H. (Phil H.), Olde Loohuis, L.M. (Loes M.), Luciano, M. (Michelle), MacAre, C. (Christine), Mather, R., Mattheisen, M. (Manuel), Milaneschi, Y. (Yuri), Nho, K. (Kwangsik), Papmeyer, M. (Martina), Ramasamy, A. (Adaikalavan), Risacher, S.L. (Shannon), Roiz-Santiañez, R. (Roberto), Rose, E.J. (Emma), Salami, A. (Alireza), Sämann, P.G. (Philipp), Schmaal, L. (Lianne), Schork, N.J. (Nicholas), Shin, J. (Jean), Strike, L.T. (Lachlan), Teumer, A. (Alexander), Van Donkelaar, M.M.J. (Marjolein M. J.), Eijk, K.R. (Kristel) van, Walters, R.K. (Raymond), Westlye, L.T. (Lars), Whelan, C.D. (Christopher), Winkler, A.M. (Anderson), Zwiers, M.P. (Marcel), Alhusaini, S. (Saud), Athanasiu, L. (Lavinia), Ehrlich, S.M. (Stefan), Hakobjan, M. (Marina), Hartberg, C.B. (Cecilie B.), Haukvik, U.K. (Unn), Heister, A.J.G.A.M. (Angelien J. G. A. M.), Hoehn, D. (David), Kasperaviciute, D. (Dalia), Liewald, D.C.M. (David), Lopez, L.M. (Lorna), Makkinje, R.R.R. (Remco R. R.), Matarin, M. (Mar), Naber, M.A.M. (Marlies A. M.), McKay, D.R. (Reese), Needham, M. (Margaret), Nugent, A.C. (Allison), Pütz, B. (Benno), Royle, N.A. (Natalie), Shen, L. (Li), Sprooten, R. (Roy), Trabzuni, D. (Danyah), Van Der Marel, S.S.L. (Saskia S. L.), Van Hulzen, K.J.E. (Kimm J. E.), Walton, E. (Esther), Björnsson, A. (Asgeir), Almasy, L. (Laura), Ames, D.J. (David), Arepalli, S. (Sampath), Assareh, A.A., Bastin, M.E. (Mark), Brodaty, H. (Henry), Bulayeva, K. (Kazima), Carless, M.A. (Melanie), Cichon, S. (Sven), Corvin, A. (Aiden), Curran, J.E. (Joanne), Czisch, M. (Michael), Zubicaray, G.I. (Greig) de, Dillman, A. (Allissa), Duggirala, A. (Aparna), Dyer, M.D. (Matthew), Erk, S., Fedko, I. (Iryna), Ferrucci, L. (Luigi), Foroud, T. (Tatiana), Fox, P.T. (Peter), Fukunaga, M. (Masaki), Raphael Gibbs, J., Göring, H.H.H. (Harald H.), Green, R.C. (Robert C.), Guelfi, S. (Sebastian), Hansell, N.K. (Narelle), Hartman, C.A. (Catharina), Hegenscheid, K. (Katrin), Heinz, J. (Judith), Hernandez, D.G. (Dena), Heslenfeld, D.J. (Dirk), Hoekstra, P.J. (Pieter), Holsboer, F., Homuth, G. (Georg), Hottenga, J.J. (Jouke Jan), Ikeda, M. (Masashi), Jack Jr., C.R. (Clifford), Jenkinson, S. (Sarah), Johnson, R. (Robert), Kanai, R. (Ryota), Keil, M. (Maria), Kent, J.W. (Jack W.), Kochunov, P. (Peter), Kwok, J.B. (John B.), Lawrie, S. (Stephen), Liu, X. (Xinmin), Longo, D.L. (Dan L.), Mcmahon, K.L. (Katie), Meisenzahl, E. (Eva), Melle, I. (Ingrid), Mohnke, S. (Sebastian), Montgomery, G.W. (Grant), Mostert, J.C. (Jeanette C.), Mühleisen, T.W. (Thomas), Nalls, M.A. (Michael), Nichols, T.E. (Thomas), Nilsson, L.G., Nöthen, M.M. (Markus), Ohi, K. (Kazutaka), Olvera, R.L. (Rene), Perez-Iglesias, R. (Rocio), Pike, G.B. (Bruce), Potkin, S.G. (Steven), Reinvang, I. (Ivar), Reppermund, S., Rietschel, M. (Marcella), Seiferth, N. (Nina), Rosen, G.D. (Glenn D.), Rujescu, D. (Dan), Schnell, K. (Kerry), Schofield, C.J. (Christopher), Smith, C. (Colin), Steen, V.M. (Vidar), Sussmann, J. (Jessika), Thalamuthu, A. (Anbupalam), Toga, A.W. (Arthur W.), Traynor, B. (Bryan), Troncoso, J.C. (Juan), Turner, J. (Jessica), Valdés Hernández, M.C. (Maria), Ent, D. (Dennis) van 't, Brug, M.P. (Marcel) van der, Wee, N.J. (Nic) van der, Tol, M.J.D. (Marie-José) van, Veltman, D.J. (Dick), Wassink, A.M.J. (Annemarie), Westman, E. (Eric), Zielke, R.H. (Ronald H.), Zonderman, A.B. (Alan B.), Ashbrook, D.G. (David G.), Hager, R. (Reinmar), Lu, L. (Lu), Mcmahon, F.J. (Francis J), Morris, D.W. (Derek W), Williams, R.W. (Robert W.), Brunner, H.G., Buckner, M., Buitelaar, J.K. (Jan K.), Cahn, W. (Wiepke), Calhoun, V.D. (Vince), Cavalleri, G. (Gianpiero), Crespo-Facorro, B. (Benedicto), Dale, A.M. (Anders), Davies, G.E. (Gareth), Delanty, N., Depondt, C. (Chantal), Djurovic, S. (Srdjan), Drevets, D.A. (Douglas), Espeseth, T. (Thomas), Gollub, R.L. (Randy), Ho, B.C. (Beng ), Hoffmann, W. (Wolfgang), Hosten, N. (Norbert), Kahn, R. (René), Le Hellard, S. (Stephanie), Meyer-Lindenberg, A., Müller-Myhsok, B. (B.), Nauck, M. (Matthias), Nyberg, L. (Lars), Pandolfo, M. (Massimo), Penninx, B.W.J.H. (Brenda), Roffman, J.L. (Joshua), Sisodiya, S.M. (Sanjay), Smoller, J.W., Bokhoven, H. (Hans) van, Haren, N.E.M. (Neeltje E.) van, Völzke, H. (Henry), Walter, H.J. (Henrik), Weiner, M.W. (Michael), Wen, W. (Wei), White, T.J.H. (Tonya), Agartz, I. (Ingrid), Andreassen, O.A. (Ole), Blangero, J. (John), Boomsma, D.I. (Dorret), Brouwer, R.M. (Rachel), Cannon, D.M. (Dara), Cookson, M.R. (Mark), Geus, E.J.C. (Eco) de, Deary, I.J. (Ian), Donohoe, D.J. (Dennis), Fernandez, G. (Guillén), Fisher, S.E. (Simon), Francks, C. (Clyde), Glahn, D.C. (David), Grabe, H.J. (Hans Jörgen), Gruber, O. (Oliver), Hardy, J. (John), Hashimoto, R. (Ryota), Hulshoff Pol, H.E. (Hilleke), Jönsson, E.G. (Erik), Kloszewska, I. (Iwona), Lovestone, S. (Simon), Mattay, V.S. (Venkata S.), Mecocci, P. (Patrizia), McDonald, C. (Colm), McIntosh, A.M. (Andrew), Ophoff, R.A. (Roel), Paus, T. (Tomas), Pausova, Z. (Zdenka), Ryten, M. (Mina), Sachdev, P.S. (Perminder), Saykin, A.J. (Andrew), Simmons, A. (Andrew), Singleton, A. (Andrew), Soininen, H. (H.), Wardlaw, J.M. (J.), Weale, M.E. (Michael), Weinberger, D.R. (Daniel), Adams, H.H.H. (Hieab), Launer, L.J. (Lenore), Seiler, S. (Stephan), Schmidt, R. (Reinhold), Chauhan, G. (Ganesh), Satizabal, C.L. (Claudia), Becker, J.T. (James), Yanek, L.R. (Lisa), Lee, S.J. (Sven) van der, Ebling, M. (Maritza), Fischl, B. (Bruce), Longstreth Jr, W.T., Greve, D. (Douglas), Nyquist, P. (Paul), Vinke, L.N. (Louis N.), Duijn, C.M. (Cornelia) van, Xue, L. (Luting), Mazoyer, B. (Bernard), Bis, J.C. (Joshua), Gudnason, V. (Vilmundur), Seshadri, S. (Sudha), Ikram, M.A. (Arfan), Martin, N.G. (Nicholas), Wright, M.J. (Margaret), Schumann, G. (Gunter), Franke, B. (Barbara), Thompson, P.M. (Paul), and Medland, S.E. (Sarah)
Abstract: The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, a
Published: 2015
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14. Common genetic variants influence human subcortical brain structures

Author: Hibar, D.P., Stein, J.L., Renteria, M.E., Arias-Vasquez, A., Desrivières, S., Jahanshad, N., Toro, R., Wittfeld, K., Abramovic, L., Andersson, M., Aribisala, B.S., Armstrong, N.J., Bernard, M., Bohlken, M.M., Boks, M.P., Bralten, J., Brown, A.A., Mallar Chakravarty, M., Chen, Q., Ching, C.R.K., Cuellar-Partida, G., den Braber, A., Giddaluru, S., Goldman, A.L., Grimm, O., Guadalupe, T., Hass, J., Woldehawariat, G., Holmes, A.J., Hoogman, M., Janowitz, D., Jia, T., Kim, S., Klein, M., Kraemer, B., Lee, P.H., Olde Loohuis, L.M., Luciano, M., Macare, C., Mather, K.A., Mattheisen, M., Milaneschi, Y., Nho, K., Papmeyer, M., Ramasamy, A., Risacher, S.L., Roiz-Santiañez, R., Rose, E.J., Salami, A., Sämann, P.G., Schmaal, L., Schork, A.J., Shin, J., Strike, L.T., Teumer, A., van Donkelaar, M.M.J., van Eijk, K.R., Walters, R.K., Westlye, L.T., Whelan, C.D., Winkler, A.M., Zwiers, M.P., Alhusaini, S., Athanasiu, L., Ehrlich, S., Hakobjan, M.M.H., Hartberg, C.B., Haukvik, U.K., Heister, A.J.G.A.M., Hoehn, D., Kasperaviciute, D., Liewald, D.C.M., Lopez, L.M., Makkinje, R.R.R., Matarin, M., Naber, M.A.M., Reese McKay, D., Needham, M., Nugent, A.C., Pütz, B., Royle, N.A., Shen, Li, Sprooten, E., Trabzuni, D., van der Marel, S.S.L., van Hulzen, K.J.E., Walton, E., Wolf, C., Almasy, L., Ames, D., Arepalli, S., Assareh, A.A., Bastin, M.E., Brodaty, H., Bulayeva, K.B., Carless, M.A., Cichon, S., Corvin, A., Curran, J.E., Czisch, M., de Zubicaray, G.I., Dillman, A., Duggirala, R., Dyer, T.D., Erk, S., Fedko, I.O., Ferrucci, L., Foroud, T.M., Fox, P.T., Fukunaga, M., Raphael Gibbs, J., Göring, H.H.H., Green, R.C., Guelfi, S., Hansell, N.K., Hartman, C.A., Hegenscheid, K., Heinz, A., Hernandez, D.G., Heslenfeld, D.J., Hoekstra, P.J., Holsboer, F., Homuth, G., Hottenga, J-J, Ikeda, M., Jack, C.R., Jenkinson, M., Johnson, R., Kanai, R., Keil, M., Kent, J.W., Kochunov, P., Kwok, J.B., Lawrie, S.M., Liu, X., Longo, D.L., McMahon, K.L., Meisenzahl, E., Melle, I., Mohnke, S., Montgomery, G.W., Mostert, J.C., Mühleisen, T.W., Nalls, M.A., Nichols, T.E., Nilsson, L.G., Nöthen, M.M., Ohi, K., Olvera, R.L., Perez-Iglesias, R., Bruce Pike, G., Potkin, S.G., Reinvang, I., Reppermund, S., Rietschel, M., Romanczuk-Seiferth, N., Rosen, G.D., Rujescu, D., Schnell, K., Schofield, P.R., Smith, C., Steen, V.M., Sussmann, J.E., Thalamuthu, A., Toga, A.W., Traynor, B.J., Troncoso, J., Turner, J.A., Valdés Hernández, M.C., van 't Ent, D., van der Brug, M., van der Wee, N.J.A., van Tol, M-J, Veltman, D.J., Wassink, T.H., Westman, E., Zielke, R.H., Zonderman, A.B., Ashbrook, D.G., Hager, R., Lu, L., McMahon, F.J., Morris, D.W., Williams, R.W., Brunner, H.G., Buckner, R.L., Buitelaar, J.K., Cahn, W., Calhoun, V.D., Cavalleri, G.L., Crespo-Facorro, B., Dale, A.M., Davies, G.E., Delanty, N., Depondt, C., Djurovic, S., Drevets, W.C., Espeseth, T., Gollub, R.L., Ho, B-C., Hoffmann, W., Hosten, N., Kahn, R.S., Le Hellard, S., Meyer-Lindenberg, A., Müller-Myhsok, B., Nauck, M., Nyberg, L., Pandolfo, M., Penninx, B.W.J.H., Roffman, J.L., Sisodiya, S.M., Smoller, J.W., van Bokhoven, H., van Haren, N.E.M., Völzke, H., Walter, H., Weiner, M.W., Wen, W., White, T., Agartz, I., Andreassen, O.A., Blangero, J., Boomsma, D.I., Brouwer, R.M., Cannon, D.M., Cookson, M.R., de Geus, E.J.C., Deary, I.J., Donohoe, G., Fernández, G., Fisher, S.E., Francks, C., Glahn, D.C., Grabe, H.J., Gruber, O., Hardy, J., Hashimoto, R., Hulshoff Pol, H.E., Jönsson, E.G., Kloszewska, I., Lovestone, S., Mattay, V.S., Mecocci, P., McDonald, C., McIntosh, A.M., Ophoff, R.A., Paus, T., Pausova, Z., Ryten, M., Sachdev, P.S., Saykin, A.J., Simmons, A., Singleton, A., Soininen, H., Wardlaw, J.M., Weale, M.E., Weinberger, D.R., Adams, H.H.H., Launer, L.J., Seiler, S., Schmidt, R., Chauhan, G., Satizabal, C.L., Becker, J.T., Yanek, L., van der Lee, S.J., Ebling, M., Fischl, B., Longstreth, W.T., Greve, D., Schmidt, H., Nyquist, P., Vinke, L.N., van Duijn, C.M., Xue, L., Mazoyer, B., Bis, J.C., Gudnason, V., Seshadri, S., Ikram, M.A., Martin, N.G., Wright, M.J., Schumann, G., Franke, B., Thompson, P.M., Medland, S.E., Hibar, D.P., Stein, J.L., Renteria, M.E., Arias-Vasquez, A., Desrivières, S., Jahanshad, N., Toro, R., Wittfeld, K., Abramovic, L., Andersson, M., Aribisala, B.S., Armstrong, N.J., Bernard, M., Bohlken, M.M., Boks, M.P., Bralten, J., Brown, A.A., Mallar Chakravarty, M., Chen, Q., Ching, C.R.K., Cuellar-Partida, G., den Braber, A., Giddaluru, S., Goldman, A.L., Grimm, O., Guadalupe, T., Hass, J., Woldehawariat, G., Holmes, A.J., Hoogman, M., Janowitz, D., Jia, T., Kim, S., Klein, M., Kraemer, B., Lee, P.H., Olde Loohuis, L.M., Luciano, M., Macare, C., Mather, K.A., Mattheisen, M., Milaneschi, Y., Nho, K., Papmeyer, M., Ramasamy, A., Risacher, S.L., Roiz-Santiañez, R., Rose, E.J., Salami, A., Sämann, P.G., Schmaal, L., Schork, A.J., Shin, J., Strike, L.T., Teumer, A., van Donkelaar, M.M.J., van Eijk, K.R., Walters, R.K., Westlye, L.T., Whelan, C.D., Winkler, A.M., Zwiers, M.P., Alhusaini, S., Athanasiu, L., Ehrlich, S., Hakobjan, M.M.H., Hartberg, C.B., Haukvik, U.K., Heister, A.J.G.A.M., Hoehn, D., Kasperaviciute, D., Liewald, D.C.M., Lopez, L.M., Makkinje, R.R.R., Matarin, M., Naber, M.A.M., Reese McKay, D., Needham, M., Nugent, A.C., Pütz, B., Royle, N.A., Shen, Li, Sprooten, E., Trabzuni, D., van der Marel, S.S.L., van Hulzen, K.J.E., Walton, E., Wolf, C., Almasy, L., Ames, D., Arepalli, S., Assareh, A.A., Bastin, M.E., Brodaty, H., Bulayeva, K.B., Carless, M.A., Cichon, S., Corvin, A., Curran, J.E., Czisch, M., de Zubicaray, G.I., Dillman, A., Duggirala, R., Dyer, T.D., Erk, S., Fedko, I.O., Ferrucci, L., Foroud, T.M., Fox, P.T., Fukunaga, M., Raphael Gibbs, J., Göring, H.H.H., Green, R.C., Guelfi, S., Hansell, N.K., Hartman, C.A., Hegenscheid, K., Heinz, A., Hernandez, D.G., Heslenfeld, D.J., Hoekstra, P.J., Holsboer, F., Homuth, G., Hottenga, J-J, Ikeda, M., Jack, C.R., Jenkinson, M., Johnson, R., Kanai, R., Keil, M., Kent, J.W., Kochunov, P., Kwok, J.B., Lawrie, S.M., Liu, X., Longo, D.L., McMahon, K.L., Meisenzahl, E., Melle, I., Mohnke, S., Montgomery, G.W., Mostert, J.C., Mühleisen, T.W., Nalls, M.A., Nichols, T.E., Nilsson, L.G., Nöthen, M.M., Ohi, K., Olvera, R.L., Perez-Iglesias, R., Bruce Pike, G., Potkin, S.G., Reinvang, I., Reppermund, S., Rietschel, M., Romanczuk-Seiferth, N., Rosen, G.D., Rujescu, D., Schnell, K., Schofield, P.R., Smith, C., Steen, V.M., Sussmann, J.E., Thalamuthu, A., Toga, A.W., Traynor, B.J., Troncoso, J., Turner, J.A., Valdés Hernández, M.C., van 't Ent, D., van der Brug, M., van der Wee, N.J.A., van Tol, M-J, Veltman, D.J., Wassink, T.H., Westman, E., Zielke, R.H., Zonderman, A.B., Ashbrook, D.G., Hager, R., Lu, L., McMahon, F.J., Morris, D.W., Williams, R.W., Brunner, H.G., Buckner, R.L., Buitelaar, J.K., Cahn, W., Calhoun, V.D., Cavalleri, G.L., Crespo-Facorro, B., Dale, A.M., Davies, G.E., Delanty, N., Depondt, C., Djurovic, S., Drevets, W.C., Espeseth, T., Gollub, R.L., Ho, B-C., Hoffmann, W., Hosten, N., Kahn, R.S., Le Hellard, S., Meyer-Lindenberg, A., Müller-Myhsok, B., Nauck, M., Nyberg, L., Pandolfo, M., Penninx, B.W.J.H., Roffman, J.L., Sisodiya, S.M., Smoller, J.W., van Bokhoven, H., van Haren, N.E.M., Völzke, H., Walter, H., Weiner, M.W., Wen, W., White, T., Agartz, I., Andreassen, O.A., Blangero, J., Boomsma, D.I., Brouwer, R.M., Cannon, D.M., Cookson, M.R., de Geus, E.J.C., Deary, I.J., Donohoe, G., Fernández, G., Fisher, S.E., Francks, C., Glahn, D.C., Grabe, H.J., Gruber, O., Hardy, J., Hashimoto, R., Hulshoff Pol, H.E., Jönsson, E.G., Kloszewska, I., Lovestone, S., Mattay, V.S., Mecocci, P., McDonald, C., McIntosh, A.M., Ophoff, R.A., Paus, T., Pausova, Z., Ryten, M., Sachdev, P.S., Saykin, A.J., Simmons, A., Singleton, A., Soininen, H., Wardlaw, J.M., Weale, M.E., Weinberger, D.R., Adams, H.H.H., Launer, L.J., Seiler, S., Schmidt, R., Chauhan, G., Satizabal, C.L., Becker, J.T., Yanek, L., van der Lee, S.J., Ebling, M., Fischl, B., Longstreth, W.T., Greve, D., Schmidt, H., Nyquist, P., Vinke, L.N., van Duijn, C.M., Xue, L., Mazoyer, B., Bis, J.C., Gudnason, V., Seshadri, S., Ikram, M.A., Martin, N.G., Wright, M.J., Schumann, G., Franke, B., Thompson, P.M., and Medland, S.E.
Abstract: The highly complex structure of the human brain is strongly shaped by genetic influences1. Subcortical brain regions form circuits with cortical areas to coordinate movement2, learning, memory3 and motivation4, and altered circuits can lead to abnormal behaviour and disease2. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume5 and intracranial volume6. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10−33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.
Published: 2015

15. RNA expression profiling in depressed patients suggests retinoid-related orphan receptor alpha as a biomarker for antidepressant response

Author: Hennings, J, primary, Uhr, M, additional, Klengel, T, additional, Weber, P, additional, Pütz, B, additional, Touma, C, additional, Czamara, D, additional, Ising, M, additional, Holsboer, F, additional, and Lucae, S, additional
Published: 2015
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16. RNA expression profiling in depressed patients suggests retinoid-related orphan receptor alpha as a biomarker for antidepressant response

Author: Hennings, J M, primary, Uhr, M, additional, Klengel, T, additional, Weber, P, additional, Pütz, B, additional, Touma, C, additional, Czamara, D, additional, Ising, M, additional, Holsboer, F, additional, and Lucae, S, additional
Published: 2015
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17. D* Extra Lite: A Dynamic A* With Search–Tree Cutting and Frontier–Gap Repairing

Author: Przybylski Maciej and Putz Barbara
Subjects: shortest-path planning, incremental heuristic search, mobile robot navigation, video games, Mathematics, QA1-939, Electronic computers. Computer science, QA75.5-76.95
Abstract: Searching for the shortest-path in an unknown or changeable environment is a common problem in robotics and video games, in which agents need to update maps and to perform re-planning in order to complete their missions. D* Lite is a popular incremental heuristic search algorithm (i.e., it utilizes knowledge from previous searches). Its efficiency lies in the fact that it re-expands only those parts of the search-space that are relevant to registered changes and the current state of the agent. In this paper, we propose a new D* Extra Lite algorithm that is close to a regular A*, with reinitialization of the affected search-space achieved by search-tree branch cutting. The provided worst-case complexity analysis strongly suggests that D* Extra Lite’s method of reinitialization is faster than the focused approach to reinitialization used in D* Lite. In comprehensive tests on a large number of typical two-dimensional path-planning problems, D* Extra Lite was 1.08 to 1.94 times faster than the optimized version of D* Lite. Moreover, while demonstrating that it can be particularly suitable for difficult, dynamic problems, as the problem-complexity increased, D* Extra Lite’s performance further surpassed that of D*Lite. The source code of the algorithm is available on the open-source basis.
Published: 2017
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18. Discriminative grandparental investment – the impact of grandchild’s gender and sociodemographic parameters

Author: Kirchengast Sylvia and Putz Beatrix
Subjects: grandparental investment, grandparent - grandchild relationship, grandparental solicitude, grandparent - grandchild contact, Anthropology, GN1-890
Abstract: Homo sapiens is a typical cooperative breeder and grandparents are among the most important caregivers besides the mothers. Grandparental investment however differs markedly between maternal and paternal grandparents but also between grandmothers and grandfathers. From an evolutionary viewpoint this differential grandparental investment is mainly explained as a result of paternity uncertainty. On the other hand emotional support and child care help from grandparents may also be associated with sociocultural factors. The present study focused on the impact of grandchild’s gender, but also grandparental age and occupation on discriminative grandparental investment, i.e. solicitude, contact frequency and quality of relationship. 272 adults persons between the age 18 and 35 years (x= 23.5yrs; ±3.7) were enrolled in the study. Patterns of grandparental investment during childhood as well as quality of the grandparent- grandchild relationship were collected retrospectively using a 57 item questionnaire. As to be expected maternal grandmothers showed the highest contact frequency and the highest solicitude while -as to be expected - the paternal grandfather exhibited the lowest degree of investment. Grandparental investment was independent of grandparent category mainly influenced by residential distance. Grandchild’s gender and sociodemographic characteristics of the grandparents in contrast had a minor impact on grandparental caregiving and contact frequency. Contrary, grandchild’s gender was related significantly with the quality of relationship and emotional closeness.
Published: 2016
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19. RNA expression profiling in depressed patients suggests retinoid-related orphan receptor alpha as a biomarker for antidepressant response.

Author: Hennings, J., Uhr, M., Klengel, T., Weber, P., Pütz, B., Touma, C., Darina, C., Ising, M., Holsboer, F., and Lucae, S.
Subjects: *THERAPEUTICS, *MENTAL depression, *RETINOIDS, *GENE expression profiling, *ANTIDEPRESSANTS, *BIOMARKERS, *RNA
Abstract: Gene expression profiling may be a tool to identify markers of antidepressant treatment response and new potential drug targets. In a first step, we selected 12 males, age- and severity-matched pairs of remitters and non-responders, and analyzed expression profiles in peripheral blood at admission and after 2 and 5 weeks of treatment using Illumina expression arrays. We identified 127 transcripts significantly associated with treatment response with a minimal P -value of 9.41 × 10 −4 (false discovery rate-corrected). Analysis of selected transcripts in an independent replication sample of 142 depressed inpatients confirmed that lower expression of retinoid-related orphan receptor alpha (RORa, P = 6.23 × 10 −4 ), germinal center expressed transcript 2 (GCET2, P = 2.08 × 10 −2 ) and chitinase 3-like protein 2 (CHI3L2, P = 4.45 × 10 −2 ) on admission were associated with beneficial treatment response. In addition, leukocyte-specific protein 1 (LSP1) significantly decreased after 5 weeks of treatment in responders ( P = 2.91 × 10 −2 ). Additional genetic, in vivo stress responsitivity data and murine hippocampal gene expression findings corroborate our finding of RORa as a transcriptional marker of antidepressant response. In summary, using a genome-wide transcriptomics approach and subsequent validation studies, we identified several transcripts including the circadian gene transcript RORa that may serve as biomarkers indicating antidepressant treatment response. [ABSTRACT FROM AUTHOR]
Published: 2016
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20. Genomic analysis of intracranial and subcortical brain volumes yields polygenic scores accounting for variation across ancestries.

Author: García-Marín LM, Campos AI, Diaz-Torres S, Rabinowitz JA, Ceja Z, Mitchell BL, Grasby KL, Thorp JG, Agartz I, Alhusaini S, Ames D, Amouyel P, Andreassen OA, Arfanakis K, Arias-Vasquez A, Armstrong NJ, Athanasiu L, Bastin ME, Beiser AS, Bennett DA, Bis JC, Boks MPM, Boomsma DI, Brodaty H, Brouwer RM, Buitelaar JK, Burkhardt R, Cahn W, Calhoun VD, Carmichael OT, Chakravarty M, Chen Q, Ching CRK, Cichon S, Crespo-Facorro B, Crivello F, Dale AM, Smith GD, de Geus EJC, De Jager PL, de Zubicaray GI, Debette S, DeCarli C, Depondt C, Desrivières S, Djurovic S, Ehrlich S, Erk S, Espeseth T, Fernández G, Filippi I, Fisher SE, Fleischman DA, Fletcher E, Fornage M, Forstner AJ, Francks C, Franke B, Ge T, Goldman AL, Grabe HJ, Green RC, Grimm O, Groenewold NA, Gruber O, Gudnason V, Håberg AK, Haukvik UK, Heinz A, Hibar DP, Hilal S, Himali JJ, Ho BC, Hoehn DF, Hoekstra PJ, Hofer E, Hoffmann W, Holmes AJ, Homuth G, Hosten N, Ikram MK, Ipser JC, Jack CR Jr, Jahanshad N, Jönsson EG, Kahn RS, Kanai R, Klein M, Knol MJ, Launer LJ, Lawrie SM, Hellard SL, Lee PH, Lemaître H, Li S, Liewald DCM, Lin H, Longstreth WT Jr, Lopez OL, Luciano M, Maillard P, Marquand AF, Martin NG, Martinot JL, Mather KA, Mattay VS, McMahon KL, Mecocci P, Melle I, Meyer-Lindenberg A, Mirza-Schreiber N, Milaneschi Y, Mosley TH, Mühleisen TW, Müller-Myhsok B, Maniega SM, Nauck M, Nho K, Niessen WJ, Nöthen MM, Nyquist PA, Oosterlaan J, Pandolfo M, Paus T, Pausova Z, Penninx BWJH, Pike GB, Psaty BM, Pütz B, Reppermund S, Rietschel MD, Risacher SL, Romanczuk-Seiferth N, Romero-Garcia R, Roshchupkin GV, Rotter JI, Sachdev PS, Sämann PG, Saremi A, Sargurupremraj M, Saykin AJ, Schmaal L, Schmidt H, Schmidt R, Schofield PR, Scholz M, Schumann G, Schwarz E, Shen L, Shin J, Sisodiya SM, Smith AV, Smoller JW, Soininen HS, Steen VM, Stein DJ, Stein JL, Thomopoulos SI, Toga AW, Tordesillas-Gutiérrez D, Trollor JN, Valdes-Hernandez MC, van T Ent D, van Bokhoven H, van der Meer D, van der Wee NJA, Vázquez-Bourgon J, Veltman DJ, Vernooij MW, Villringer A, Vinke LN, Völzke H, Walter H, Wardlaw JM, Weinberger DR, Weiner MW, Wen W, Westlye LT, Westman E, White T, Witte AV, Wolf C, Yang J, Zwiers MP, Ikram MA, Seshadri S, Thompson PM, Satizabal CL, Medland SE, and Rentería ME
Subjects: Humans, Female, Male, Organ Size genetics, Attention Deficit Disorder with Hyperactivity genetics, Attention Deficit Disorder with Hyperactivity pathology, Parkinson Disease genetics, Parkinson Disease pathology, Polymorphism, Single Nucleotide, Genomics methods, Adult, Genetic Predisposition to Disease, Middle Aged, White People genetics, Genome-Wide Association Study, Multifactorial Inheritance genetics, Brain pathology
Abstract: Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. Here we performed genome-wide association studies meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signaling and brain aging-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse ancestries. We observed causal genetic effects of brain volumes with Parkinson's disease and attention-deficit/hyperactivity disorder. Findings implicate specific gene expression patterns in brain development and genetic variants in comorbid neuropsychiatric disorders, which could point to a brain substrate and region of action for risk genes implicated in brain diseases., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Published: 2024
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21. Extracellular vesicle-mediated trafficking of molecular cues during human brain development.

Author: Forero A, Pipicelli F, Moser S, Baumann N, Grätz C, Gonzalez Pisfil M, Pfaffl MW, Pütz B, Kielkowski P, Cernilogar FM, Maccarrone G, Di Giaimo R, and Cappello S
Subjects: Humans, Neurons metabolism, Induced Pluripotent Stem Cells metabolism, Induced Pluripotent Stem Cells cytology, Astrocytes metabolism, Neural Stem Cells metabolism, Neural Stem Cells cytology, Organoids metabolism, YAP-Signaling Proteins metabolism, Protein Transport, Transcription Factors metabolism, Extracellular Vesicles metabolism, Brain metabolism, Brain growth & development
Abstract: Cellular crosstalk is an essential process influenced by numerous factors, including secreted vesicles that transfer nucleic acids, lipids, and proteins between cells. Extracellular vesicles (EVs) have been the center of many studies focusing on neurodegenerative disorders, but whether EVs display cell-type-specific features for cellular crosstalk during neurodevelopment is unknown. Here, using human-induced pluripotent stem cell-derived cerebral organoids, neural progenitors, neurons, and astrocytes, we identify heterogeneity in EV protein content and dynamics in a cell-type-specific and time-dependent manner. Our results support the trafficking of key molecules via EVs in neurodevelopment, such as the transcription factor YAP1, and their localization to differing cell compartments depending on the EV recipient cell type. This study sheds new light on the biology of EVs during human brain development., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Published: 2024
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22. Comprehensive risk factor predictions for 3-year survival among HIV-associated and disseminated cryptococcosis involving lungs and central nervous system.

Author: Wu L, Fu X, Pütz B, Zhang R, Liu L, Song W, Weng L, Shao Y, Zheng Z, Xun J, Han X, Wang T, Shen Y, Lu H, Müller-Myhsok B, and Chen J
Subjects: Humans, Male, Female, Adult, Risk Factors, Middle Aged, AIDS-Related Opportunistic Infections mortality, AIDS-Related Opportunistic Infections microbiology, Cohort Studies, Lung pathology, Lung microbiology, Lung Diseases, Fungal mortality, Lung Diseases, Fungal microbiology, Survival Analysis, Cryptococcosis mortality, Cryptococcosis drug therapy, HIV Infections complications, HIV Infections mortality
Abstract: Background: The global mortality rate resulting from HIV-associated cryptococcal disease is remarkably elevated, particularly in severe cases with dissemination to the lungs and central nervous system (CNS). Regrettably, there is a dearth of predictive analysis regarding long-term survival, and few studies have conducted longitudinal follow-up assessments for comparing anti-HIV and antifungal treatments., Methods: A cohort of 83 patients with HIV-related disseminated cryptococcosis involving the lung and CNS was studied for 3 years to examine survival. Comparative analysis of clinical and immunological parameters was performed between deceased and surviving individuals. Subsequently, multivariate Cox regression models were utilized to validate mortality predictions at 12, 24, and 36 months., Results: Observed plasma cytokine levels before treatment were significantly lower for IL-1RA (p < 0.001) and MCP-1 (p < 0.05) when in the survivor group. Incorporating plasma levels of IL-1RA, IL-6, and high-risk CURB-65 score demonstrated the highest area under curve (AUC) value (0.96) for predicting 1-year mortality. For 1-, 2- and 3-year predictions, the single-factor model with IL-1RA demonstrated superior performance compared to all multiple-variate models (AUC = 0.95/0.78/0.78)., Conclusions: IL-1RA is a biomarker for predicting 3-year survival. Further investigations to explore the pathogenetic role of IL-1RA in HIV-associated disseminated cryptococcosis and as a potential therapeutic target are warranted., (© 2024. The Author(s).)
Published: 2024
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23. Correction: Comprehensive risk factor predictions for 3-year survival among HIV-associated and disseminated cryptococcosis involving lungs and central nervous system.

Author: Wu L, Fu X, Pütz B, Zhang R, Liu L, Song W, Weng L, Shao Y, Zheng Z, Xun J, Han X, Wang T, Shen Y, Lu H, Müller-Myhsok B, and Chen J
Published: 2024
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24. Automatically annotated motion tracking identifies a distinct social behavioral profile following chronic social defeat stress.

Author: Bordes J, Miranda L, Reinhardt M, Narayan S, Hartmann J, Newman EL, Brix LM, van Doeselaar L, Engelhardt C, Dillmann L, Mitra S, Ressler KJ, Pütz B, Agakov F, Müller-Myhsok B, and Schmidt MV
Subjects: Mice, Male, Animals, Social Defeat, Reproducibility of Results, Stress, Psychological, Social Behavior, Rodentia, Mice, Inbred C57BL, Behavior, Animal physiology, Depressive Disorder, Major
Abstract: Severe stress exposure increases the risk of stress-related disorders such as major depressive disorder (MDD). An essential characteristic of MDD is the impairment of social functioning and lack of social motivation. Chronic social defeat stress is an established animal model for MDD research, which induces a cascade of physiological and behavioral changes. Current markerless pose estimation tools allow for more complex and naturalistic behavioral tests. Here, we introduce the open-source tool DeepOF to investigate the individual and social behavioral profile in mice by providing supervised and unsupervised pipelines using DeepLabCut-annotated pose estimation data. Applying this tool to chronic social defeat in male mice, the DeepOF supervised and unsupervised pipelines detect a distinct stress-induced social behavioral pattern, which was particularly observed at the beginning of a novel social encounter and fades with time due to habituation. In addition, while the classical social avoidance task does identify the stress-induced social behavioral differences, both DeepOF behavioral pipelines provide a clearer and more detailed profile. Moreover, DeepOF aims to facilitate reproducibility and unification of behavioral classification by providing an open-source tool, which can advance the study of rodent individual and social behavior, thereby enabling biological insights and, for example, subsequent drug development for psychiatric disorders., (© 2023. The Author(s).)
Published: 2023
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25. DiffBrainNet: Differential analyses add new insights into the response to glucocorticoids at the level of genes, networks and brain regions.

Author: Gerstner N, Krontira AC, Cruceanu C, Roeh S, Pütz B, Sauer S, Rex-Haffner M, Schmidt MV, Binder EB, and Knauer-Arloth J
Abstract: Genome-wide gene expression analyses are invaluable tools for studying biological and disease processes, allowing a hypothesis-free comparison of expression profiles. Traditionally, transcriptomic analysis has focused on gene-level effects found by differential expression. In recent years, network analysis has emerged as an important additional level of investigation, providing information on molecular connectivity, especially for diseases associated with a large number of linked effects of smaller magnitude, like neuropsychiatric disorders. Here, we describe how combined differential expression and prior-knowledge-based differential network analysis can be used to explore complex datasets. As an example, we analyze the transcriptional responses following administration of the glucocorticoid/stress receptor agonist dexamethasone in 8 mouse brain regions important for stress processing. By applying a combination of differential network- and expression-analyses, we find that these explain distinct but complementary biological mechanisms of the glucocorticoid responses. Additionally, network analysis identifies new differentially connected partners of risk genes and can be used to generate hypotheses on molecular pathways affected. With DiffBrainNet (http://diffbrainnet.psych.mpg.de), we provide an analysis framework and a publicly available resource for the study of the transcriptional landscape of the mouse brain which can identify molecular pathways important for basic functioning and response to glucocorticoids in a brain-region specific manner., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors.)
Published: 2022
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26. Systematic Review of Functional MRI Applications for Psychiatric Disease Subtyping.

Author: Miranda L, Paul R, Pütz B, Koutsouleris N, and Müller-Myhsok B
Abstract: Background: Psychiatric disorders have been historically classified using symptom information alone. Recently, there has been a dramatic increase in research interest not only in identifying the mechanisms underlying defined pathologies but also in redefining their etiology. This is particularly relevant for the field of personalized medicine, which searches for data-driven approaches to improve diagnosis, prognosis, and treatment selection for individual patients. Methods: This review aims to provide a high-level overview of the rapidly growing field of functional magnetic resonance imaging (fMRI) from the perspective of unsupervised machine learning applications for disease subtyping. Following the PRISMA guidelines for protocol reproducibility, we searched the PubMed database for articles describing functional MRI applications used to obtain, interpret, or validate psychiatric disease subtypes. We also employed the active learning framework ASReview to prioritize publications in a machine learning-guided way. Results: From the 20 studies that met the inclusion criteria, five used functional MRI data to interpret symptom-derived disease clusters, four used it to interpret clusters derived from biomarker data other than fMRI itself, and 11 applied clustering techniques involving fMRI directly. Major depression disorder and schizophrenia were the two most frequently studied pathologies (35% and 30% of the retrieved studies, respectively), followed by ADHD (15%), psychosis as a whole (10%), autism disorder (5%), and the consequences of early exposure to violence (5%). Conclusions: The increased interest in personalized medicine and data-driven disease subtyping also extends to psychiatric disorders. However, to date, this subfield is at an incipient exploratory stage, and all retrieved studies were mostly proofs of principle where further validation and increased sample sizes are craved for. Whereas results for all explored diseases are inconsistent, we believe this reflects the need for concerted, multisite data collection efforts with a strong focus on measuring the generalizability of results. Finally, whereas functional MRI is the best way of measuring brain function available to date, its low signal-to-noise ratio and elevated monetary cost make it a poor clinical alternative. Even with technology progressing and costs decreasing, this might incentivize the search for more accessible, clinically ready functional proxies in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Miranda, Paul, Pütz, Koutsouleris and Müller-Myhsok.)
Published: 2021
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27. Gene Expression in Spontaneous Experimental Autoimmune Encephalomyelitis Is Linked to Human Multiple Sclerosis Risk Genes.

Author: Faber H, Kurtoic D, Krishnamoorthy G, Weber P, Pütz B, Müller-Myhsok B, Weber F, and Andlauer TFM
Subjects: Adaptive Immunity genetics, Animals, Cytokines metabolism, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental genetics, Humans, Immunomodulation genetics, Mice, Mice, Inbred C57BL, Mice, Transgenic, Multiple Sclerosis genetics, Myelin-Oligodendrocyte Glycoprotein genetics, Myelin-Oligodendrocyte Glycoprotein immunology, Peptide Fragments genetics, Peptide Fragments immunology, Risk, Transcriptome, Encephalomyelitis, Autoimmune, Experimental immunology, Multiple Sclerosis immunology, Th1 Cells physiology
Abstract: Recent genome-wide association studies have identified over 230 genetic risk loci for multiple sclerosis. Current experimental autoimmune encephalomyelitis (EAE) models requiring active induction of disease may not be optimally suited for the characterization of the function of these genes. We have thus used gene expression profiling to study whether spontaneous opticospinal EAE (OSE) or MOG-induced EAE mirrors the genetic contribution to the pathogenesis of multiple sclerosis more faithfully. To this end, we compared gene expression in OSE and MOG EAE models and analyzed the relationship of both models to human multiple sclerosis risk genes and T helper cell biology. We observed stronger gene expression changes and an involvement of more pathways of the adaptive immune system in OSE than MOG EAE. Furthermore, we demonstrated a more extensive enrichment of human MS risk genes among transcripts differentially expressed in OSE than was the case for MOG EAE. Transcripts differentially expressed only in diseased OSE mice but not in MOG EAE were significantly enriched for T helper cell-specific transcripts. These transcripts are part of immune-regulatory pathways. The activation of the adaptive immune system and the enrichment of both human multiple sclerosis risk genes and T helper cell-specific transcripts were also observed in OSE mice showing only mild disease signs. These expression changes may, therefore, be indicative of processes at disease onset. In summary, more human multiple sclerosis risk genes were differentially expressed in OSE than was observed for MOG EAE, especially in T H 1 cells. When studying the functional role of multiple sclerosis risk genes and pathways during disease onset and their interactions with the environment, spontaneous OSE may thus show advantages over MOG-induced EAE., (Copyright © 2020 Faber, Kurtoic, Krishnamoorthy, Weber, Pütz, Müller-Myhsok, Weber and Andlauer.)
Published: 2020
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28. GDF15 promotes simultaneous astrocyte remodeling and tight junction strengthening at the blood-brain barrier.

Author: Malik VA, Zajicek F, Mittmann LA, Klaus J, Unterseer S, Rajkumar S, Pütz B, Deussing JM, Neumann ID, Rupprecht R, and Di Benedetto B
Subjects: Animals, Astrocytes drug effects, Blood-Brain Barrier diagnostic imaging, Cell Line, Tumor, Endothelial Cells drug effects, Endothelial Cells metabolism, Growth Differentiation Factor 15 pharmacology, Male, Motor Neurons drug effects, Permeability, Rats, Rats, Wistar, Tight Junctions drug effects, Astrocytes metabolism, Blood-Brain Barrier metabolism, Growth Differentiation Factor 15 metabolism, Motor Neurons metabolism, Tight Junctions metabolism
Abstract: Perivascular astrocyte processes (PAP) surround cerebral endothelial cells (ECs) and modulate the strengthening of tight junctions to influence blood-brain barrier (BBB) permeability. Morphologically altered astrocytes may affect barrier properties and trigger the onset of brain pathologies. However, astrocyte-dependent mediators of these events remain poorly studied. Here, we show a pharmacologically driven elevated expression and release of growth/differentiation factor 15 (GDF15) in rat primary astrocytes and cerebral PAP. GDF15 has been shown to possess trophic properties for motor neurons, prompting us to hypothesize similar effects on astrocytes. Indeed, its increased expression and release occurred simultaneously to morphological changes of astrocytes in vitro and PAP, suggesting modulatory effects of GDF15 on these cells, but also neighboring EC. Administration of recombinant GDF15 was sufficient to promote astrocyte remodeling and enhance barrier properties between ECs in vitro, whereas its pharmacogenetic abrogation prevented these effects. We validated our findings in male high anxiety-related behavior rats, an animal model of depressive-like behavior, with shrunk PAP associated with reduced expression of the junctional protein claudin-5, which were both restored by a pharmacologically induced increase in GDF15 expression. Thus, we identified GDF15 as an astrocyte-derived trigger of astrocyte process remodeling linked to enhanced tight junction strengthening at the BBB., (© 2020 Wiley Periodicals, Inc.)
Published: 2020
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29. The genetic architecture of the human cerebral cortex.

Author: Grasby KL, Jahanshad N, Painter JN, Colodro-Conde L, Bralten J, Hibar DP, Lind PA, Pizzagalli F, Ching CRK, McMahon MAB, Shatokhina N, Zsembik LCP, Thomopoulos SI, Zhu AH, Strike LT, Agartz I, Alhusaini S, Almeida MAA, Alnæs D, Amlien IK, Andersson M, Ard T, Armstrong NJ, Ashley-Koch A, Atkins JR, Bernard M, Brouwer RM, Buimer EEL, Bülow R, Bürger C, Cannon DM, Chakravarty M, Chen Q, Cheung JW, Couvy-Duchesne B, Dale AM, Dalvie S, de Araujo TK, de Zubicaray GI, de Zwarte SMC, den Braber A, Doan NT, Dohm K, Ehrlich S, Engelbrecht HR, Erk S, Fan CC, Fedko IO, Foley SF, Ford JM, Fukunaga M, Garrett ME, Ge T, Giddaluru S, Goldman AL, Green MJ, Groenewold NA, Grotegerd D, Gurholt TP, Gutman BA, Hansell NK, Harris MA, Harrison MB, Haswell CC, Hauser M, Herms S, Heslenfeld DJ, Ho NF, Hoehn D, Hoffmann P, Holleran L, Hoogman M, Hottenga JJ, Ikeda M, Janowitz D, Jansen IE, Jia T, Jockwitz C, Kanai R, Karama S, Kasperaviciute D, Kaufmann T, Kelly S, Kikuchi M, Klein M, Knapp M, Knodt AR, Krämer B, Lam M, Lancaster TM, Lee PH, Lett TA, Lewis LB, Lopes-Cendes I, Luciano M, Macciardi F, Marquand AF, Mathias SR, Melzer TR, Milaneschi Y, Mirza-Schreiber N, Moreira JCV, Mühleisen TW, Müller-Myhsok B, Najt P, Nakahara S, Nho K, Olde Loohuis LM, Orfanos DP, Pearson JF, Pitcher TL, Pütz B, Quidé Y, Ragothaman A, Rashid FM, Reay WR, Redlich R, Reinbold CS, Repple J, Richard G, Riedel BC, Risacher SL, Rocha CS, Mota NR, Salminen L, Saremi A, Saykin AJ, Schlag F, Schmaal L, Schofield PR, Secolin R, Shapland CY, Shen L, Shin J, Shumskaya E, Sønderby IE, Sprooten E, Tansey KE, Teumer A, Thalamuthu A, Tordesillas-Gutiérrez D, Turner JA, Uhlmann A, Vallerga CL, van der Meer D, van Donkelaar MMJ, van Eijk L, van Erp TGM, van Haren NEM, van Rooij D, van Tol MJ, Veldink JH, Verhoef E, Walton E, Wang M, Wang Y, Wardlaw JM, Wen W, Westlye LT, Whelan CD, Witt SH, Wittfeld K, Wolf C, Wolfers T, Wu JQ, Yasuda CL, Zaremba D, Zhang Z, Zwiers MP, Artiges E, Assareh AA, Ayesa-Arriola R, Belger A, Brandt CL, Brown GG, Cichon S, Curran JE, Davies GE, Degenhardt F, Dennis MF, Dietsche B, Djurovic S, Doherty CP, Espiritu R, Garijo D, Gil Y, Gowland PA, Green RC, Häusler AN, Heindel W, Ho BC, Hoffmann WU, Holsboer F, Homuth G, Hosten N, Jack CR Jr, Jang M, Jansen A, Kimbrel NA, Kolskår K, Koops S, Krug A, Lim KO, Luykx JJ, Mathalon DH, Mather KA, Mattay VS, Matthews S, Mayoral Van Son J, McEwen SC, Melle I, Morris DW, Mueller BA, Nauck M, Nordvik JE, Nöthen MM, O'Leary DS, Opel N, Martinot MP, Pike GB, Preda A, Quinlan EB, Rasser PE, Ratnakar V, Reppermund S, Steen VM, Tooney PA, Torres FR, Veltman DJ, Voyvodic JT, Whelan R, White T, Yamamori H, Adams HHH, Bis JC, Debette S, Decarli C, Fornage M, Gudnason V, Hofer E, Ikram MA, Launer L, Longstreth WT, Lopez OL, Mazoyer B, Mosley TH, Roshchupkin GV, Satizabal CL, Schmidt R, Seshadri S, Yang Q, Alvim MKM, Ames D, Anderson TJ, Andreassen OA, Arias-Vasquez A, Bastin ME, Baune BT, Beckham JC, Blangero J, Boomsma DI, Brodaty H, Brunner HG, Buckner RL, Buitelaar JK, Bustillo JR, Cahn W, Cairns MJ, Calhoun V, Carr VJ, Caseras X, Caspers S, Cavalleri GL, Cendes F, Corvin A, Crespo-Facorro B, Dalrymple-Alford JC, Dannlowski U, de Geus EJC, Deary IJ, Delanty N, Depondt C, Desrivières S, Donohoe G, Espeseth T, Fernández G, Fisher SE, Flor H, Forstner AJ, Francks C, Franke B, Glahn DC, Gollub RL, Grabe HJ, Gruber O, Håberg AK, Hariri AR, Hartman CA, Hashimoto R, Heinz A, Henskens FA, Hillegers MHJ, Hoekstra PJ, Holmes AJ, Hong LE, Hopkins WD, Hulshoff Pol HE, Jernigan TL, Jönsson EG, Kahn RS, Kennedy MA, Kircher TTJ, Kochunov P, Kwok JBJ, Le Hellard S, Loughland CM, Martin NG, Martinot JL, McDonald C, McMahon KL, Meyer-Lindenberg A, Michie PT, Morey RA, Mowry B, Nyberg L, Oosterlaan J, Ophoff RA, Pantelis C, Paus T, Pausova Z, Penninx BWJH, Polderman TJC, Posthuma D, Rietschel M, Roffman JL, Rowland LM, Sachdev PS, Sämann PG, Schall U, Schumann G, Scott RJ, Sim K, Sisodiya SM, Smoller JW, Sommer IE, St Pourcain B, Stein DJ, Toga AW, Trollor JN, Van der Wee NJA, van 't Ent D, Völzke H, Walter H, Weber B, Weinberger DR, Wright MJ, Zhou J, Stein JL, Thompson PM, and Medland SE
Subjects: Attention Deficit Disorder with Hyperactivity genetics, Brain Mapping, Cognition, Genetic Loci, Genome-Wide Association Study, Humans, Magnetic Resonance Imaging, Organ Size genetics, Parkinson Disease genetics, Cerebral Cortex anatomy & histology, Genetic Variation
Abstract: The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Published: 2020
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30. Genetic architecture of subcortical brain structures in 38,851 individuals.

Author: Satizabal CL, Adams HHH, Hibar DP, White CC, Knol MJ, Stein JL, Scholz M, Sargurupremraj M, Jahanshad N, Roshchupkin GV, Smith AV, Bis JC, Jian X, Luciano M, Hofer E, Teumer A, van der Lee SJ, Yang J, Yanek LR, Lee TV, Li S, Hu Y, Koh JY, Eicher JD, Desrivières S, Arias-Vasquez A, Chauhan G, Athanasiu L, Rentería ME, Kim S, Hoehn D, Armstrong NJ, Chen Q, Holmes AJ, 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 AK, Jones HJ, Pike GB, Stein DJ, Stevens A, Bralten J, Vernooij MW, Harris TB, Filippi I, Witte AV, Guadalupe T, Wittfeld K, Mosley TH, Becker JT, Doan NT, Hagenaars SP, Saba Y, Cuellar-Partida G, Amin N, Hilal S, Nho K, Mirza-Schreiber N, Arfanakis K, Becker DM, Ames D, Goldman AL, Lee PH, Boomsma DI, Lovestone S, Giddaluru S, Le Hellard S, Mattheisen M, Bohlken MM, Kasperaviciute D, Schmaal L, Lawrie SM, Agartz I, Walton E, Tordesillas-Gutierrez D, Davies GE, Shin J, Ipser JC, Vinke LN, Hoogman M, Jia T, Burkhardt R, Klein M, Crivello F, Janowitz D, Carmichael O, Haukvik UK, Aribisala BS, Schmidt H, Strike LT, Cheng CY, Risacher SL, Pütz B, Fleischman DA, Assareh AA, Mattay VS, Buckner RL, Mecocci P, Dale AM, Cichon S, Boks MP, Matarin M, Penninx BWJH, Calhoun VD, Chakravarty MM, Marquand AF, Macare C, Kharabian Masouleh S, Oosterlaan J, Amouyel P, Hegenscheid K, Rotter JI, Schork AJ, Liewald DCM, de Zubicaray GI, Wong TY, Shen L, Sämann PG, Brodaty H, Roffman JL, de Geus EJC, Tsolaki M, Erk S, van Eijk KR, Cavalleri GL, van der Wee NJA, McIntosh AM, Gollub RL, Bulayeva KB, Bernard M, Richards JS, Himali JJ, Loeffler M, Rommelse N, Hoffmann W, Westlye LT, Valdés Hernández MC, Hansell NK, van Erp TGM, Wolf C, Kwok JBJ, Vellas B, Heinz A, Olde Loohuis LM, Delanty N, Ho BC, Ching CRK, Shumskaya E, Singh B, Hofman A, van der Meer D, Homuth G, Psaty BM, Bastin ME, Montgomery GW, Foroud TM, Reppermund S, Hottenga JJ, Simmons A, Meyer-Lindenberg A, Cahn W, Whelan CD, van Donkelaar MMJ, Yang Q, Hosten N, Green RC, Thalamuthu A, Mohnke S, Hulshoff Pol HE, Lin H, Jack CR Jr, Schofield PR, Mühleisen TW, Maillard P, Potkin SG, Wen W, Fletcher E, Toga AW, Gruber O, Huentelman M, Davey Smith G, Launer LJ, Nyberg L, Jönsson EG, Crespo-Facorro B, Koen N, Greve DN, Uitterlinden AG, Weinberger DR, Steen VM, Fedko IO, Groenewold NA, Niessen WJ, Toro R, Tzourio C, Longstreth WT Jr, Ikram MK, Smoller JW, van Tol MJ, Sussmann JE, Paus T, Lemaître H, Schroeter ML, Mazoyer B, Andreassen OA, Holsboer F, Depondt C, Veltman DJ, Turner JA, Pausova Z, Schumann G, van Rooij D, Djurovic S, Deary IJ, McMahon KL, Müller-Myhsok B, Brouwer RM, Soininen H, Pandolfo M, Wassink TH, Cheung JW, Wolfers T, Martinot JL, Zwiers MP, Nauck M, Melle I, Martin NG, Kanai R, Westman E, Kahn RS, Sisodiya SM, White T, Saremi A, van Bokhoven H, Brunner HG, Völzke H, Wright MJ, van 't Ent D, Nöthen MM, Ophoff RA, Buitelaar JK, Fernández G, Sachdev PS, Rietschel M, van Haren NEM, Fisher SE, Beiser AS, Francks C, Saykin AJ, Mather KA, Romanczuk-Seiferth N, Hartman CA, DeStefano AL, Heslenfeld DJ, Weiner MW, Walter H, Hoekstra PJ, Nyquist PA, Franke B, Bennett DA, Grabe HJ, Johnson AD, Chen C, van Duijn CM, Lopez OL, Fornage M, Wardlaw JM, Schmidt R, DeCarli C, De Jager PL, Villringer A, Debette S, Gudnason V, Medland SE, Shulman JM, Thompson PM, Seshadri S, and Ikram MA
Subjects: Adult, Aged, Animals, Cohort Studies, Drosophila melanogaster genetics, Drosophila melanogaster growth & development, Humans, Magnetic Resonance Imaging, Middle Aged, Organ Size, Brain anatomy & histology, Brain metabolism, Drosophila melanogaster metabolism, Genetic Variation, Genome-Wide Association Study, Neurodevelopmental Disorders genetics, Neurodevelopmental Disorders pathology
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
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31. Treatment response classes in major depressive disorder identified by model-based clustering and validated by clinical prediction models.

Author: Paul R, Andlauer TFM, Czamara D, Hoehn D, Lucae S, Pütz B, Lewis CM, Uher R, Müller-Myhsok B, Ising M, and Sämann PG
Subjects: Adult, Algorithms, Clinical Decision Rules, Cluster Analysis, Depressive Disorder, Major genetics, Female, Humans, Male, Middle Aged, Models, Theoretical, Pharmacogenetics, Remission Induction, Treatment Outcome, Antidepressive Agents therapeutic use, Depressive Disorder, Major drug therapy
Abstract: The identification of generalizable treatment response classes (TRC[s]) in major depressive disorder (MDD) would facilitate comparisons across studies and the development of treatment prediction algorithms. Here, we investigated whether such stable TRCs can be identified and predicted by clinical baseline items. We analyzed data from an observational MDD cohort (Munich Antidepressant Response Signature [MARS] study, N = 1017), treated individually by psychopharmacological and psychotherapeutic means, and a multicenter, partially randomized clinical/pharmacogenomic study (Genome-based Therapeutic Drugs for Depression [GENDEP], N = 809). Symptoms were evaluated up to week 16 (or discharge) in MARS and week 12 in GENDEP. Clustering was performed on 809 MARS patients (discovery sample) using a mixed model with the integrated completed likelihood criterion for the assessment of cluster stability, and validated through a distinct MARS validation sample and GENDEP. A random forest algorithm was used to identify prediction patterns based on 50 clinical baseline items. From the clustering of the MARS discovery sample, seven TRCs emerged ranging from fast and complete response (average 4.9 weeks until discharge, 94% remitted patients) to slow and incomplete response (10% remitted patients at week 16). These proved stable representations of treatment response dynamics in both the MARS and the GENDEP validation sample. TRCs were strongly associated with established response markers, particularly the rate of remitted patients at discharge. TRCs were predictable from clinical items, particularly personality items, life events, episode duration, and specific psychopathological features. Prediction accuracy improved significantly when cluster-derived slopes were modelled instead of individual slopes. In conclusion, model-based clustering identified distinct and clinically meaningful treatment response classes in MDD that proved robust with regard to capturing response profiles of differently designed studies. Response classes were predictable from clinical baseline characteristics. Conceptually, model-based clustering is translatable to any outcome measure and could advance the large-scale integration of studies on treatment efficacy or the neurobiology of treatment response.
Published: 2019
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32. Genome-wide mapping of genetic determinants influencing DNA methylation and gene expression in human hippocampus.

Author: Schulz H, Ruppert AK, Herms S, Wolf C, Mirza-Schreiber N, Stegle O, Czamara D, Forstner AJ, Sivalingam S, Schoch S, Moebus S, Pütz B, Hillmer A, Fricker N, Vatter H, Müller-Myhsok B, Nöthen MM, Becker AJ, Hoffmann P, Sander T, and Cichon S
Subjects: Adolescent, Adult, Aged, Child, Child, Preschool, Female, Humans, Infant, Male, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait Loci genetics, Young Adult, DNA Methylation, Epilepsy, Temporal Lobe genetics, Gene Expression Profiling, Genome-Wide Association Study methods, Hippocampus metabolism
Abstract: Emerging evidence emphasizes the strong impact of regulatory genomic elements in neurodevelopmental processes and the complex pathways of brain disorders. The present genome-wide quantitative trait loci analyses explore the cis-regulatory effects of single-nucleotide polymorphisms (SNPs) on DNA methylation (meQTL) and gene expression (eQTL) in 110 human hippocampal biopsies. We identify cis-meQTLs at 14,118 CpG methylation sites and cis-eQTLs for 302 3'-mRNA transcripts of 288 genes. Hippocampal cis-meQTL-CpGs are enriched in flanking regions of active promoters, CpG island shores, binding sites of the transcription factor CTCF and brain eQTLs. Cis-acting SNPs of hippocampal meQTLs and eQTLs significantly overlap schizophrenia-associated SNPs. Correlations of CpG methylation and RNA expression are found for 34 genes. Our comprehensive maps of cis-acting hippocampal meQTLs and eQTLs provide a link between disease-associated SNPs and the regulatory genome that will improve the functional interpretation of non-coding genetic variants in the molecular genetic dissection of brain disorders.
Published: 2017
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33. Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis.

Author: Schormair B, Zhao C, Bell S, Tilch E, Salminen AV, Pütz B, Dauvilliers Y, Stefani A, Högl B, Poewe W, Kemlink D, Sonka K, Bachmann CG, Paulus W, Trenkwalder C, Oertel WH, Hornyak M, Teder-Laving M, Metspalu A, Hadjigeorgiou GM, Polo O, Fietze I, Ross OA, Wszolek Z, Butterworth AS, Soranzo N, Ouwehand WH, Roberts DJ, Danesh J, Allen RP, Earley CJ, Ondo WG, Xiong L, Montplaisir J, Gan-Or Z, Perola M, Vodicka P, Dina C, Franke A, Tittmann L, Stewart AFR, Shah SH, Gieger C, Peters A, Rouleau GA, Berger K, Oexle K, Di Angelantonio E, Hinds DA, Müller-Myhsok B, and Winkelmann J
Subjects: DNA-Binding Proteins genetics, GPI-Linked Proteins genetics, Humans, Nerve Tissue Proteins genetics, Netrins, Semaphorins genetics, Transcription Factors genetics, White People, Genetic Predisposition to Disease genetics, Genome-Wide Association Study, Restless Legs Syndrome epidemiology, Restless Legs Syndrome genetics
Abstract: Background: Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets., Methods: In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15 126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p≤5 × 10 -8 ) were tested for replication in an independent GWAS of 30 770 cases and 286 913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest., Findings: We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1·92, 95% CI 1·85-1·99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1)., Interpretation: Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations., Funding: Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München-Deutsches Forschungszentrum für Gesundheit und Umwelt, National Research Institutions, NHS Blood and Transplant, National Institute for Health Research, British Heart Foundation, European Commission, European Research Council, National Institutes of Health, National Institute of Neurological Disorders and Stroke, NIH Research Cambridge Biomedical Research Centre, and UK Medical Research Council., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
Published: 2017
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34. Genetic regulatory effects modified by immune activation contribute to autoimmune disease associations.

Author: Kim-Hellmuth S, Bechheim M, Pütz B, Mohammadi P, Nédélec Y, Giangreco N, Becker J, Kaiser V, Fricker N, Beier E, Boor P, Castel SE, Nöthen MM, Barreiro LB, Pickrell JK, Müller-Myhsok B, Lappalainen T, Schumacher J, and Hornung V
Subjects: Adolescent, Adult, Gene Expression genetics, Gene Expression immunology, Gene Expression Profiling, Gene Expression Regulation, Genetic Predisposition to Disease, Healthy Volunteers, Humans, Indicators and Reagents, Lipids, Male, Monocytes immunology, Monocytes metabolism, Quantitative Trait Loci, RNA, Messenger metabolism, Regulatory Sequences, Nucleic Acid, Young Adult, Acetylmuramyl-Alanyl-Isoglutamine pharmacology, Adjuvants, Immunologic pharmacology, Autoimmune Diseases genetics, Gene Expression drug effects, Lipopolysaccharides pharmacology, Monocytes drug effects, RNA, Double-Stranded pharmacology, RNA, Messenger drug effects
Abstract: The immune system plays a major role in human health and disease, and understanding genetic causes of interindividual variability of immune responses is vital. Here, we isolate monocytes from 134 genotyped individuals, stimulate these cells with three defined microbe-associated molecular patterns (LPS, MDP, and 5'-ppp-dsRNA), and profile the transcriptomes at three time points. Mapping expression quantitative trait loci (eQTL), we identify 417 response eQTLs (reQTLs) with varying effects between conditions. We characterize the dynamics of genetic regulation on early and late immune response and observe an enrichment of reQTLs in distal cis-regulatory elements. In addition, reQTLs are enriched for recent positive selection with an evolutionary trend towards enhanced immune response. Finally, we uncover reQTL effects in multiple GWAS loci and show a stronger enrichment for response than constant eQTLs in GWAS signals of several autoimmune diseases. This demonstrates the importance of infectious stimuli in modifying genetic predisposition to disease.Insight into the genetic influence on the immune response is important for the understanding of interindividual variability in human pathologies. Here, the authors generate transcriptome data from human blood monocytes stimulated with various immune stimuli and provide a time-resolved response eQTL map.
Published: 2017
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35. Novel genetic loci associated with hippocampal volume.

Author: Hibar DP, Adams HHH, Jahanshad N, Chauhan G, Stein JL, Hofer E, Renteria ME, Bis JC, Arias-Vasquez A, Ikram MK, Desrivières S, Vernooij MW, Abramovic L, Alhusaini S, Amin N, Andersson M, Arfanakis K, Aribisala BS, Armstrong NJ, Athanasiu L, Axelsson T, Beecham AH, Beiser A, Bernard M, Blanton SH, Bohlken MM, Boks MP, Bralten J, Brickman AM, Carmichael O, Chakravarty MM, Chen Q, Ching CRK, Chouraki V, Cuellar-Partida G, Crivello F, Den Braber A, Doan NT, Ehrlich S, Giddaluru S, Goldman AL, Gottesman RF, Grimm O, Griswold ME, Guadalupe T, Gutman BA, Hass J, Haukvik UK, Hoehn D, Holmes AJ, Hoogman M, Janowitz D, Jia T, Jørgensen KN, Karbalai N, Kasperaviciute D, Kim S, Klein M, Kraemer B, Lee PH, Liewald DCM, Lopez LM, Luciano M, Macare C, Marquand AF, Matarin M, Mather KA, Mattheisen M, McKay DR, Milaneschi Y, Muñoz Maniega S, Nho K, Nugent AC, Nyquist P, Loohuis LMO, Oosterlaan J, Papmeyer M, Pirpamer L, Pütz B, Ramasamy A, Richards JS, Risacher SL, Roiz-Santiañez R, Rommelse N, Ropele S, Rose EJ, Royle NA, Rundek T, Sämann PG, Saremi A, Satizabal CL, Schmaal L, Schork AJ, Shen L, Shin J, Shumskaya E, Smith AV, Sprooten E, Strike LT, Teumer A, Tordesillas-Gutierrez D, Toro R, Trabzuni D, Trompet S, Vaidya D, Van der Grond J, Van der Lee SJ, Van der Meer D, Van Donkelaar MMJ, Van Eijk KR, Van Erp TGM, Van Rooij D, Walton E, Westlye LT, Whelan CD, Windham BG, Winkler AM, Wittfeld K, Woldehawariat G, Wolf C, Wolfers T, Yanek LR, Yang J, Zijdenbos A, Zwiers MP, Agartz I, Almasy L, Ames D, Amouyel P, Andreassen OA, Arepalli S, Assareh AA, Barral S, Bastin ME, Becker DM, Becker JT, Bennett DA, Blangero J, van Bokhoven H, Boomsma DI, Brodaty H, Brouwer RM, Brunner HG, Buckner RL, Buitelaar JK, Bulayeva KB, Cahn W, Calhoun VD, Cannon DM, Cavalleri GL, Cheng CY, Cichon S, Cookson MR, Corvin A, Crespo-Facorro B, Curran JE, Czisch M, Dale AM, Davies GE, De Craen AJM, De Geus EJC, De Jager PL, De Zubicaray GI, Deary IJ, Debette S, DeCarli C, Delanty N, Depondt C, DeStefano A, Dillman A, Djurovic S, Donohoe G, Drevets WC, Duggirala R, Dyer TD, Enzinger C, Erk S, Espeseth T, Fedko IO, Fernández G, Ferrucci L, Fisher SE, Fleischman DA, Ford I, Fornage M, Foroud TM, Fox PT, Francks C, Fukunaga M, Gibbs JR, Glahn DC, Gollub RL, Göring HHH, Green RC, Gruber O, Gudnason V, Guelfi S, Håberg AK, Hansell NK, Hardy J, Hartman CA, Hashimoto R, Hegenscheid K, Heinz A, Le Hellard S, Hernandez DG, Heslenfeld DJ, Ho BC, Hoekstra PJ, Hoffmann W, Hofman A, Holsboer F, Homuth G, Hosten N, Hottenga JJ, Huentelman M, Hulshoff Pol HE, Ikeda M, Jack CR Jr, Jenkinson M, Johnson R, Jönsson EG, Jukema JW, Kahn RS, Kanai R, Kloszewska I, Knopman DS, Kochunov P, Kwok JB, Lawrie SM, Lemaître H, Liu X, Longo DL, Lopez OL, Lovestone S, Martinez O, Martinot JL, Mattay VS, McDonald C, McIntosh AM, McMahon FJ, McMahon KL, Mecocci P, Melle I, Meyer-Lindenberg A, Mohnke S, Montgomery GW, Morris DW, Mosley TH, Mühleisen TW, Müller-Myhsok B, Nalls MA, Nauck M, Nichols TE, Niessen WJ, Nöthen MM, Nyberg L, Ohi K, Olvera RL, Ophoff RA, Pandolfo M, Paus T, Pausova Z, Penninx BWJH, Pike GB, Potkin SG, Psaty BM, Reppermund S, Rietschel M, Roffman JL, Romanczuk-Seiferth N, Rotter JI, Ryten M, Sacco RL, Sachdev PS, Saykin AJ, Schmidt R, Schmidt H, Schofield PR, Sigursson S, Simmons A, Singleton A, Sisodiya SM, Smith C, Smoller JW, Soininen H, Steen VM, Stott DJ, Sussmann JE, Thalamuthu A, Toga AW, Traynor BJ, Troncoso J, Tsolaki M, Tzourio C, Uitterlinden AG, Hernández MCV, Van der Brug M, van der Lugt A, van der Wee NJA, Van Haren NEM, van 't Ent D, Van Tol MJ, Vardarajan BN, Vellas B, Veltman DJ, Völzke H, Walter H, Wardlaw JM, Wassink TH, Weale ME, Weinberger DR, Weiner MW, Wen W, Westman E, White T, Wong TY, Wright CB, Zielke RH, Zonderman AB, Martin NG, Van Duijn CM, Wright MJ, Longstreth WT, Schumann G, Grabe HJ, Franke B, Launer LJ, Medland SE, Seshadri S, Thompson PM, and Ikram MA
Subjects: Adolescent, Adult, Aged, Aged, 80 and over, Alzheimer Disease genetics, Alzheimer Disease physiopathology, Child, Cohort Studies, Dipeptidyl Peptidase 4 genetics, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Glycoproteins genetics, Humans, Male, Methionine Sulfoxide Reductases genetics, Microtubule-Associated Proteins genetics, Middle Aged, Nerve Tissue Proteins genetics, Organ Size, Protein Serine-Threonine Kinases genetics, Young Adult, Hippocampus growth & development
Abstract: The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r g =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
Published: 2017
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36. Novel genetic loci underlying human intracranial volume identified through genome-wide association.

Author: Adams HH, Hibar DP, Chouraki V, Stein JL, Nyquist PA, Rentería ME, Trompet S, Arias-Vasquez A, Seshadri S, Desrivières S, Beecham AH, Jahanshad N, Wittfeld K, Van der Lee SJ, Abramovic L, Alhusaini S, Amin N, Andersson M, Arfanakis K, Aribisala BS, Armstrong NJ, Athanasiu L, Axelsson T, Beiser A, Bernard M, Bis JC, Blanken LM, Blanton SH, Bohlken MM, Boks MP, Bralten J, Brickman AM, Carmichael O, Chakravarty MM, Chauhan G, Chen Q, Ching CR, Cuellar-Partida G, Braber AD, Doan NT, Ehrlich S, Filippi I, Ge T, Giddaluru S, Goldman AL, Gottesman RF, Greven CU, Grimm O, Griswold ME, Guadalupe T, Hass J, Haukvik UK, Hilal S, Hofer E, Hoehn D, Holmes AJ, Hoogman M, Janowitz D, Jia T, Kasperaviciute D, Kim S, Klein M, Kraemer B, Lee PH, Liao J, Liewald DC, Lopez LM, Luciano M, Macare C, Marquand A, Matarin M, Mather KA, Mattheisen M, Mazoyer B, McKay DR, McWhirter R, Milaneschi Y, Mirza-Schreiber N, Muetzel RL, Maniega SM, Nho K, Nugent AC, Loohuis LM, Oosterlaan J, Papmeyer M, Pappa I, Pirpamer L, Pudas S, Pütz B, Rajan KB, Ramasamy A, Richards JS, Risacher SL, Roiz-Santiañez R, Rommelse N, Rose EJ, Royle NA, Rundek T, Sämann PG, Satizabal CL, Schmaal L, Schork AJ, Shen L, Shin J, Shumskaya E, Smith AV, Sprooten E, Strike LT, Teumer A, Thomson R, Tordesillas-Gutierrez D, Toro R, Trabzuni D, Vaidya D, Van der Grond J, Van der Meer D, Van Donkelaar MM, Van Eijk KR, Van Erp TG, Van Rooij D, Walton E, Westlye LT, Whelan CD, Windham BG, Winkler AM, Woldehawariat G, Wolf C, Wolfers T, Xu B, Yanek LR, Yang J, Zijdenbos A, Zwiers MP, Agartz I, Aggarwal NT, Almasy L, Ames D, Amouyel P, Andreassen OA, Arepalli S, Assareh AA, Barral S, Bastin ME, Becker DM, Becker JT, Bennett DA, Blangero J, van Bokhoven H, Boomsma DI, Brodaty H, Brouwer RM, Brunner HG, Buckner RL, Buitelaar JK, Bulayeva KB, Cahn W, Calhoun VD, Cannon DM, Cavalleri GL, Chen C, Cheng CY, Cichon S, Cookson MR, Corvin A, Crespo-Facorro B, Curran JE, Czisch M, Dale AM, Davies GE, De Geus EJ, De Jager PL, de Zubicaray GI, Delanty N, Depondt C, DeStefano AL, Dillman A, Djurovic S, Donohoe G, Drevets WC, Duggirala R, Dyer TD, Erk S, Espeseth T, Evans DA, Fedko IO, Fernández G, Ferrucci L, Fisher SE, Fleischman DA, Ford I, Foroud TM, Fox PT, Francks C, Fukunaga M, Gibbs JR, Glahn DC, Gollub RL, Göring HH, Grabe HJ, Green RC, Gruber O, Gudnason V, Guelfi S, Hansell NK, Hardy J, Hartman CA, Hashimoto R, Hegenscheid K, Heinz A, Le Hellard S, Hernandez DG, Heslenfeld DJ, Ho BC, Hoekstra PJ, Hoffmann W, Hofman A, Holsboer F, Homuth G, Hosten N, Hottenga JJ, Hulshoff Pol HE, Ikeda M, Ikram MK, Jack CR Jr, Jenkinson M, Johnson R, Jönsson EG, Jukema JW, Kahn RS, Kanai R, Kloszewska I, Knopman DS, Kochunov P, Kwok JB, Lawrie SM, Lemaître H, Liu X, Longo DL, Longstreth WT Jr, Lopez OL, Lovestone S, Martinez O, Martinot JL, Mattay VS, McDonald C, McIntosh AM, McMahon KL, McMahon FJ, Mecocci P, Melle I, Meyer-Lindenberg A, Mohnke S, Montgomery GW, Morris DW, Mosley TH, Mühleisen TW, Müller-Myhsok B, Nalls MA, Nauck M, Nichols TE, Niessen WJ, Nöthen MM, Nyberg L, Ohi K, Olvera RL, Ophoff RA, Pandolfo M, Paus T, Pausova Z, Penninx BW, Pike GB, Potkin SG, Psaty BM, Reppermund S, Rietschel M, Roffman JL, Romanczuk-Seiferth N, Rotter JI, Ryten M, Sacco RL, Sachdev PS, Saykin AJ, Schmidt R, Schofield PR, Sigurdsson S, Simmons A, Singleton A, Sisodiya SM, Smith C, Smoller JW, Soininen H, Srikanth V, Steen VM, Stott DJ, Sussmann JE, Thalamuthu A, Tiemeier H, Toga AW, Traynor BJ, Troncoso J, Turner JA, Tzourio C, Uitterlinden AG, Hernández MC, Van der Brug M, Van der Lugt A, Van der Wee NJ, Van Duijn CM, Van Haren NE, Van T Ent D, Van Tol MJ, Vardarajan BN, Veltman DJ, Vernooij MW, Völzke H, Walter H, Wardlaw JM, Wassink TH, Weale ME, Weinberger DR, Weiner MW, Wen W, Westman E, White T, Wong TY, Wright CB, Zielke HR, Zonderman AB, Deary IJ, DeCarli C, Schmidt H, Martin NG, De Craen AJ, Wright MJ, Launer LJ, Schumann G, Fornage M, Franke B, Debette S, Medland SE, Ikram MA, and Thompson PM
Subjects: Brain growth & development, Brain pathology, Genetic Loci genetics, Humans, Oncogene Protein v-akt genetics, Parkinson Disease genetics, Phenotype, Phosphatidylinositol 3-Kinases genetics, White People, Cognition physiology, Genetic Predisposition to Disease, Genome-Wide Association Study methods, Polymorphism, Single Nucleotide genetics
Abstract: Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρ genetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (N combined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.
Published: 2016
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37. Fingolimod induces neuroprotective factors in human astrocytes.

Author: Hoffmann FS, Hofereiter J, Rübsamen H, Melms J, Schwarz S, Faber H, Weber P, Pütz B, Loleit V, Weber F, Hohlfeld R, Meinl E, and Krumbholz M
Subjects: Chemokine CXCL10 genetics, Chemokine CXCL10 metabolism, Corpus Striatum cytology, Dose-Response Relationship, Drug, Enzyme-Linked Immunosorbent Assay, Fetus cytology, Heparin-binding EGF-like Growth Factor genetics, Heparin-binding EGF-like Growth Factor metabolism, Humans, Interleukin-11 genetics, Interleukin-11 metabolism, Lysophospholipids pharmacology, Microarray Analysis, NF-kappa B genetics, NF-kappa B metabolism, RNA, Messenger, RNA, Small Interfering pharmacology, Sphingosine analogs & derivatives, Sphingosine pharmacology, Time Factors, Astrocytes drug effects, Fingolimod Hydrochloride pharmacology, Neural Stem Cells drug effects, Neuroprotective Agents pharmacology
Abstract: Background: Fingolimod (FTY720) is the first sphingosine-1-phosphate (S1P) receptor modulator approved for the treatment of multiple sclerosis. The phosphorylated active metabolite FTY720-phosphate (FTY-P) interferes with lymphocyte trafficking. In addition, it accumulates in the CNS and reduces brain atrophy in multiple sclerosis (MS), and neuroprotective effects are hypothesized., Methods: Human primary astrocytes as well as human astrocytoma cells were stimulated with FTY-P or S1P. We analyzed gene expression by a genome-wide microarray and validated induced candidate genes by quantitative PCR (qPCR) and ELISA. To identify the S1P-receptor subtypes involved, we applied a membrane-impermeable S1P analog (dihydro-S1P), receptor subtype specific agonists and antagonists, as well as RNAi silencing., Results: FTY-P induced leukemia inhibitory factor (LIF), interleukin 11 (IL11), and heparin-binding EGF-like growth factor (HBEGF) mRNA, as well as secretion of LIF and IL11 protein. In order to mimic an inflammatory milieu as observed in active MS lesions, we combined FTY-P application with tumor necrosis factor (TNF). In the presence of this key inflammatory cytokine, FTY-P synergistically induced LIF, HBEGF, and IL11 mRNA, as well as secretion of LIF and IL11 protein. TNF itself induced inflammatory, B-cell promoting, and antiviral factors (CXCL10, BAFF, MX1, and OAS2). Their induction was blocked by FTY-P. After continuous exposure of cells to FTY-P or S1P for up to 7 days, the extent of induction of neurotrophic factors and the suppression of TNF-induced inflammatory genes declined but was still detectable. The induction of neurotrophic factors was mediated via surface S1P receptors 1 (S1PR1) and 3 (S1PR3)., Conclusions: We identified effects of FTY-P on astrocytes, namely induction of neurotrophic mediators (LIF, HBEGF, and IL11) and inhibition of TNF-induced inflammatory genes (CXCL10, BAFF, MX1, and OAS2). This supports the view that a part of the effects of fingolimod may be mediated via astrocytes.
Published: 2015
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38. Connecting Anxiety and Genomic Copy Number Variation: A Genome-Wide Analysis in CD-1 Mice.

Author: Brenndörfer J, Altmann A, Widner-Andrä R, Pütz B, Czamara D, Tilch E, Kam-Thong T, Weber P, Rex-Haffner M, Bettecken T, Bultmann A, Müller-Myhsok B, Binder EE, Landgraf R, and Czibere L
Subjects: Animals, Basolateral Nuclear Complex metabolism, Central Amygdaloid Nucleus metabolism, Disease Models, Animal, Gyrus Cinguli metabolism, High-Throughput Nucleotide Sequencing methods, Mice, Paraventricular Hypothalamic Nucleus metabolism, Sequence Analysis, DNA methods, Anxiety Disorders genetics, DNA Copy Number Variations, Genetic Predisposition to Disease, Genome-Wide Association Study methods, Genotyping Techniques methods
Abstract: Genomic copy number variants (CNVs) have been implicated in multiple psychiatric disorders, but not much is known about their influence on anxiety disorders specifically. Using next-generation sequencing (NGS) and two additional array-based genotyping approaches, we detected CNVs in a mouse model consisting of two inbred mouse lines showing high (HAB) and low (LAB) anxiety-related behavior, respectively. An influence of CNVs on gene expression in the central (CeA) and basolateral (BLA) amygdala, paraventricular nucleus (PVN), and cingulate cortex (Cg) was shown by a two-proportion Z-test (p = 1.6 x 10-31), with a positive correlation in the CeA (p = 0.0062), PVN (p = 0.0046) and Cg (p = 0.0114), indicating a contribution of CNVs to the genetic predisposition to trait anxiety in the specific context of HAB/LAB mice. In order to confirm anxiety-relevant CNVs and corresponding genes in a second mouse model, we further examined CD-1 outbred mice. We revealed the distribution of CNVs by genotyping 64 CD 1 individuals using a high-density genotyping array (Jackson Laboratory). 78 genes within those CNVs were identified to show nominally significant association (48 genes), or a statistical trend in their association (30 genes) with the time animals spent on the open arms of the elevated plus-maze (EPM). Fifteen of them were considered promising candidate genes of anxiety-related behavior as we could show a significant overlap (permutation test, p = 0.0051) with genes within HAB/LAB CNVs. Thus, here we provide what is to our knowledge the first extensive catalogue of CNVs in CD-1 mice and potential corresponding candidate genes linked to anxiety-related behavior in mice.
Published: 2015
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39. Identification and characterization of HPA-axis reactivity endophenotypes in a cohort of female PTSD patients.

Author: Zaba M, Kirmeier T, Ionescu IA, Wollweber B, Buell DR, Gall-Kleebach DJ, Schubert CF, Novak B, Huber C, Köhler K, Holsboer F, Pütz B, Müller-Myhsok B, Höhne N, Uhr M, Ising M, Herrmann L, and Schmidt U
Subjects: Adrenocorticotropic Hormone metabolism, Adult, Case-Control Studies, Cohort Studies, Female, Humans, Hydrocortisone metabolism, Middle Aged, Receptors, Glucocorticoid genetics, Receptors, Mineralocorticoid genetics, Reverse Transcriptase Polymerase Chain Reaction, Stress Disorders, Post-Traumatic metabolism, Stress Disorders, Post-Traumatic psychology, Stress, Psychological metabolism, Stress, Psychological psychology, Tacrolimus Binding Proteins genetics, Transcriptome, Adult Survivors of Child Adverse Events, Endophenotypes, Hypothalamo-Hypophyseal System metabolism, Pituitary-Adrenal System metabolism, RNA, Messenger metabolism, Stress Disorders, Post-Traumatic genetics, Stress, Psychological genetics
Abstract: Analysis of the function of the hypothalamic-pituitary-adrenal (HPA)-axis in patients suffering from posttraumatic stress disorder (PTSD) has hitherto produced inconsistent findings, inter alia in the Trier Social Stress Test (TSST). To address these inconsistencies, we compared a sample of 23 female PTSD patients with either early life trauma (ELT) or adult trauma (AT) or combined ELT and AT to 18 age-matched non-traumatized female healthy controls in the TSST which was preceded by intensive baseline assessments. During the TSST, we determined a variety of clinical, psychological, endocrine and cardiovascular parameters as well as expression levels of four HPA-axis related genes. Using a previously reported definition of HPA-axis responsive versus non-responsive phenotypes, we identified for the first time two clinically and biologically distinct HPA-axis reactivity subgroups of PTSD. One subgroup ("non-responders") showed a blunted HPA-axis response and distinct clinical and biological characteristics such as a higher prevalence of trauma-related dissociative symptoms and of combined AT and ELT as well as alterations in the expression kinetics of the genes encoding for the mineralocorticoid receptor (MR) and for FK506 binding protein 51 (FKBP51). Interestingly, this non-responder subgroup largely drove the relatively diminished HPA axis response of the total cohort of PTSD patients. These findings are limited by the facts that the majority of patients was medicated, by the lack of traumatized controls and by the relatively small sample size. The here for the first time identified and characterized HPA-axis reactivity endophenotypes offer an explanation for the inconsistent reports on HPA-axis function in PTSD and, moreover, suggest that most likely other factors than HPA-axis reactivity play a decisive role in determination of PTSD core symptom severity., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
Published: 2015
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40. Common genetic variants influence human subcortical brain structures.

Author: Hibar DP, Stein JL, Renteria ME, Arias-Vasquez A, Desrivières S, Jahanshad N, Toro R, Wittfeld K, Abramovic L, Andersson M, Aribisala BS, Armstrong NJ, Bernard M, Bohlken MM, Boks MP, Bralten J, Brown AA, Chakravarty MM, Chen Q, Ching CR, Cuellar-Partida G, den Braber A, Giddaluru S, Goldman AL, Grimm O, Guadalupe T, Hass J, Woldehawariat G, Holmes AJ, Hoogman M, Janowitz D, Jia T, Kim S, Klein M, Kraemer B, Lee PH, Olde Loohuis LM, Luciano M, Macare C, Mather KA, Mattheisen M, Milaneschi Y, Nho K, Papmeyer M, Ramasamy A, Risacher SL, Roiz-Santiañez R, Rose EJ, Salami A, Sämann PG, Schmaal L, Schork AJ, Shin J, Strike LT, Teumer A, van Donkelaar MM, van Eijk KR, Walters RK, Westlye LT, Whelan CD, Winkler AM, Zwiers MP, Alhusaini S, Athanasiu L, Ehrlich S, Hakobjan MM, Hartberg CB, Haukvik UK, Heister AJ, Hoehn D, Kasperaviciute D, Liewald DC, Lopez LM, Makkinje RR, Matarin M, Naber MA, McKay DR, Needham M, Nugent AC, Pütz B, Royle NA, Shen L, Sprooten E, Trabzuni D, van der Marel SS, van Hulzen KJ, Walton E, Wolf C, Almasy L, Ames D, Arepalli S, Assareh AA, Bastin ME, Brodaty H, Bulayeva KB, Carless MA, Cichon S, Corvin A, Curran JE, Czisch M, de Zubicaray GI, Dillman A, Duggirala R, Dyer TD, Erk S, Fedko IO, Ferrucci L, Foroud TM, Fox PT, Fukunaga M, Gibbs JR, Göring HH, Green RC, Guelfi S, Hansell NK, Hartman CA, Hegenscheid K, Heinz A, Hernandez DG, Heslenfeld DJ, Hoekstra PJ, Holsboer F, Homuth G, Hottenga JJ, Ikeda M, Jack CR Jr, Jenkinson M, Johnson R, Kanai R, Keil M, Kent JW Jr, Kochunov P, Kwok JB, Lawrie SM, Liu X, Longo DL, McMahon KL, Meisenzahl E, Melle I, Mohnke S, Montgomery GW, Mostert JC, Mühleisen TW, Nalls MA, Nichols TE, Nilsson LG, Nöthen MM, Ohi K, Olvera RL, Perez-Iglesias R, Pike GB, Potkin SG, Reinvang I, Reppermund S, Rietschel M, Romanczuk-Seiferth N, Rosen GD, Rujescu D, Schnell K, Schofield PR, Smith C, Steen VM, Sussmann JE, Thalamuthu A, Toga AW, Traynor BJ, Troncoso J, Turner JA, Valdés Hernández MC, van 't Ent D, van der Brug M, van der Wee NJ, van Tol MJ, Veltman DJ, Wassink TH, Westman E, Zielke RH, Zonderman AB, Ashbrook DG, Hager R, Lu L, McMahon FJ, Morris DW, Williams RW, Brunner HG, Buckner RL, Buitelaar JK, Cahn W, Calhoun VD, Cavalleri GL, Crespo-Facorro B, Dale AM, Davies GE, Delanty N, Depondt C, Djurovic S, Drevets WC, Espeseth T, Gollub RL, Ho BC, Hoffmann W, Hosten N, Kahn RS, Le Hellard S, Meyer-Lindenberg A, Müller-Myhsok B, Nauck M, Nyberg L, Pandolfo M, Penninx BW, Roffman JL, Sisodiya SM, Smoller JW, van Bokhoven H, van Haren NE, Völzke H, Walter H, Weiner MW, Wen W, White T, Agartz I, Andreassen OA, Blangero J, Boomsma DI, Brouwer RM, Cannon DM, Cookson MR, de Geus EJ, Deary IJ, Donohoe G, Fernández G, Fisher SE, Francks C, Glahn DC, Grabe HJ, Gruber O, Hardy J, Hashimoto R, Hulshoff Pol HE, Jönsson EG, Kloszewska I, Lovestone S, Mattay VS, Mecocci P, McDonald C, McIntosh AM, Ophoff RA, Paus T, Pausova Z, Ryten M, Sachdev PS, Saykin AJ, Simmons A, Singleton A, Soininen H, Wardlaw JM, Weale ME, Weinberger DR, Adams HH, Launer LJ, Seiler S, Schmidt R, Chauhan G, Satizabal CL, Becker JT, Yanek L, van der Lee SJ, Ebling M, Fischl B, Longstreth WT Jr, Greve D, Schmidt H, Nyquist P, Vinke LN, van Duijn CM, Xue L, Mazoyer B, Bis JC, Gudnason V, Seshadri S, Ikram MA, Martin NG, Wright MJ, Schumann G, Franke B, Thompson PM, and Medland SE
Subjects: Adolescent, Adult, Aged, Aged, 80 and over, Aging genetics, Apoptosis genetics, Caudate Nucleus anatomy & histology, Child, Female, Gene Expression Regulation, Developmental genetics, Genetic Loci genetics, Hippocampus anatomy & histology, Humans, Magnetic Resonance Imaging, Male, Membrane Proteins genetics, Middle Aged, Organ Size genetics, Putamen anatomy & histology, Sex Characteristics, Skull anatomy & histology, Young Adult, Brain anatomy & histology, Genetic Variation genetics, Genome-Wide Association Study
Abstract: The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.
Published: 2015
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