Search

Your search keyword '"Terenius, L."' showing total 245 results
Start Over Author "Terenius, L." Search Limiters Available in Library Collection
245 results on '"Terenius, L."'

1. Common variant at 16p11.2 conferring risk of psychosis

Author

Steinberg, S, de Jong, S, Mattheisen, M, Costas, J, Demontis, D, Jamain, S, Pietiläinen, O P H, Lin, K, Papiol, S, Huttenlocher, J, Sigurdsson, E, Vassos, E, Giegling, I, Breuer, R, Fraser, G, Walker, N, Melle, I, Djurovic, S, Agartz, I, Tuulio-Henriksson, A, Suvisaari, J, Lönnqvist, J, Paunio, T, Olsen, L, Hansen, T, Ingason, A, Pirinen, M, Strengman, E, Hougaard, D M, Ørntoft, T, Didriksen, M, Hollegaard, M V, Nordentoft, M, Abramova, L, Kaleda, V, Arrojo, M, Sanjuán, J, Arango, C, Etain, B, Bellivier, F, Méary, A, Schürhoff, F, Szoke, A, Ribolsi, M, Magni, V, Siracusano, A, Sperling, S, Rossner, M, Christiansen, C, Kiemeney, L A, Franke, B, van den Berg, L H, Veldink, J, Curran, S, Bolton, P, Poot, M, Staal, W, Rehnstrom, K, Kilpinen, H, Freitag, C M, Meyer, J, Magnusson, P, Saemundsen, E, Martsenkovsky, I, Bikshaieva, I, Martsenkovska, I, Vashchenko, O, Raleva, M, Paketchieva, K, Stefanovski, B, Durmishi, N, Pejovic Milovancevic, M, Lecic Tosevski, D, Silagadze, T, Naneishvili, N, Mikeladze, N, Surguladze, S, Vincent, J B, Farmer, A, Mitchell, P B, Wright, A, Schofield, P R, Fullerton, J M, Montgomery, G W, Martin, N G, Rubino, I A, van Winkel, R, Kenis, G, De Hert, M, Réthelyi, J M, Bitter, I, Terenius, L, Jönsson, E G, Bakker, S, van Os, J, Jablensky, A, Leboyer, M, Bramon, E, Powell, J, Murray, R, Corvin, A, Gill, M, Morris, D, O'Neill, F A, Kendler, K, Riley, B, Craddock, N, Owen, M J, O'Donovan, M C, Thorsteinsdottir, U, Kong, A, Ehrenreich, H, Carracedo, A, Golimbet, V, Andreassen, O A, Børglum, A D, Mors, O, Mortensen, P B, Werge, T, Ophoff, R A, Nöthen, M M, Rietschel, M, Cichon, S, Ruggeri, M, Tosato, S, Palotie, A, St Clair, D, Rujescu, D, Collier, D A, Stefansson, H, and Stefansson, K

Published
2014
Full Text
View/download PDF

5. Expanding the range of ZNF804A variants conferring risk of psychosis

Author

Steinberg, S, Mors, O, Børglum, A D, Gustafsson, O, Werge, T, Mortensen, P B, Andreassen, O A, Sigurdsson, E, Thorgeirsson, T E, Böttcher, Y, Olason, P, Ophoff, R A, Cichon, S, Gudjonsdottir, I H, Pietiläinen, O P H, Nyegaard, M, Tuulio-Henriksson, A, Ingason, A, Hansen, T, Athanasiu, L, Suvisaari, J, Lonnqvist, J, Paunio, T, Hartmann, A, Jürgens, G, Nordentoft, M, Hougaard, D, Norgaard-Pedersen, B, Breuer, R, Möller, H-J, Giegling, I, Glenthøj, B, Rasmussen, H B, Mattheisen, M, Bitter, I, Réthelyi, J M, Sigmundsson, T, Fossdal, R, Thorsteinsdottir, U, Ruggeri, M, Tosato, S, Strengman, E, Kiemeney, L A, Melle, I, Djurovic, S, Abramova, L, Kaleda, V, Walshe, M, Bramon, E, Vassos, E, Li, T, Fraser, G, Walker, N, Toulopoulou, T, Yoon, J, Freimer, N B, Cantor, R M, Murray, R, Kong, A, Golimbet, V, Jönsson, E G, Terenius, L, Agartz, I, Petursson, H, Nöthen, M M, Rietschel, M, Peltonen, L, Rujescu, D, Collier, D A, Stefansson, H, St Clair, D, and Stefansson, K

Published
2011
Full Text
View/download PDF

7. Meta-analysis of 32 genome-wide linkage studies of schizophrenia

Author

Ng, M Y M, Levinson, D F, Faraone, S V, Suarez, B K, DeLisi, L E, Arinami, T, Riley, B, Paunio, T, Pulver, A E, Irmansyah, Holmans, P A, Escamilla, M, Wildenauer, D B, Williams, N M, Laurent, C, Mowry, B J, Brzustowicz, L M, Maziade, M, Sklar, P, Garver, D L, Abecasis, G R, Lerer, B, Fallin, M D, Gurling, H M D, Gejman, P V, Lindholm, E, Moises, H W, Byerley, W, Wijsman, E M, Forabosco, P, Tsuang, M T, Hwu, H-G, Okazaki, Y, Kendler, K S, Wormley, B, Fanous, A, Walsh, D, O'Neill, F A, Peltonen, L, Nestadt, G, Lasseter, V K, Liang, K Y, Papadimitriou, G M, Dikeos, D G, Schwab, S G, Owen, M J, O'Donovan, M C, Norton, N, Hare, E, Raventos, H, Nicolini, H, Albus, M, Maier, W, Nimgaonkar, V L, Terenius, L, Mallet, J, Jay, M, Godard, S, Nertney, D, Alexander, M, Crowe, R R, Silverman, J M, Bassett, A S, Roy, M-A, Mérette, C, Pato, C N, Pato, M T, Roos, J Louw, Kohn, Y, Amann-Zalcenstein, D, Kalsi, G, McQuillin, A, Curtis, D, Brynjolfson, J, Sigmundsson, T, Petursson, H, Sanders, A R, Duan, J, Jazin, E, Myles-Worsley, M, Karayiorgou, M, and Lewis, C M

Published
2009
Full Text
View/download PDF

8. Analysis of 10 independent samples provides evidence for association between schizophrenia and a SNP flanking fibroblast growth factor receptor 2

Author

O'Donovan, M C, Norton, N, Williams, H, Peirce, T, Moskvina, V, Nikolov, I, Hamshere, M, Carroll, L, Georgieva, L, Dwyer, S, Holmans, P, Marchini, J L, Spencer, C C A, Howie, B, Leung, H-T, Giegling, I, Hartmann, A M, Möller, H-J, Morris, D W, Shi, Y, Feng, G, Hoffmann, P, Propping, P, Vasilescu, C, Maier, W, Rietschel, M, Zammit, S, Schumacher, J, Quinn, E M, Schulze, T G, Iwata, N, Ikeda, M, Darvasi, A, Shifman, S, He, L, Duan, J, Sanders, A R, Levinson, D F, Adolfsson, R, Ösby, U, Terenius, L, Jönsson, E G, Cichon, S, Nöthen, M M, Gill, M, Corvin, A P, Rujescu, D, Gejman, P V, Kirov, G, Craddock, N, Williams, N M, and Owen, M J

Published
2009
Full Text
View/download PDF

10. A systematic genomewide linkage study in 353 sib pairs with schizophrenia

Author

Williams, N.M., Norton, N., Williams, H., Ekholm, B., Hamshere, M.L., Lindblom, Y., Chowdari, K.V., Cardno, A.G., Zammit, S., Jones, L.A., Murphy, K.C., Sanders, R.D., McCarthy, G., Gray, M.Y., Jones, G., Holmans, P., Nimgaonkar, V., Adolfson, R., Osby, U., Terenius, L., Sedvall, G., O'Dnovan, M.C., and Owen, M.J.

Subjects
Human genetics -- Research, Schizophrenia -- Research, Biological sciences
Published
2003

11. Analysis of 10 independent samples provides evidence for association between schizophrenia and a SNP flanking fibroblast growth factor receptor 2

Author

OʼDonovan, M C, Norton, N, Williams, H, Peirce, T, Moskvina, V, Nikolov, I, Hamshere, M, Carroll, L, Georgieva, L, Dwyer, S, Holmans, P, Marchini, J L, Spencer, C CA, Howie, B, Leung, H-T, Giegling, I, Hartmann, A M, Möller, H-J, Morris, D W, Shi, Y, Feng, G, Hoffmann, P, Propping, P, Vasilescu, C, Maier, W, Rietschel, M, Zammit, S, Schumacher, J, Quinn, E M, Schulze, T G, Iwata, N, Ikeda, M, Darvasi, A, Shifman, S, He, L, Duan, J, Sanders, A R, Levinson, D F, Adolfsson, R, Ösby, U, Terenius, L, Jönsson, E G, Cichon, S, Nöthen, M M, Gill, M, Corvin, A P, Rujescu, D, Gejman, P V, Kirov, G, Craddock, N, Williams, N M, and Owen, M J

Published
2009

13. Supplementary Material for: Genetic and Functional Study of L-Type Amino Acid Transporter 1 in Schizophrenia

Author

Comasco, E., Vumma, R., Toffoletto, S., Johansson, J., Flyckt, L., Lewander, T., Oreland, L., Bjerkenstedt, L., Andreou, D., Söderman, E., Terenius, L., Agartz, I., Jönsson, E.G., and Venizelos, N.

Abstract

Schizophrenia involves neural catecholaminergic dysregulation. Tyrosine is the precursor of catecholamines, and its major transporter, according to studies on fibroblasts, in the brain is the L-type amino acid transporter 1 (LAT1). The present study assessed haplotype tag single-nucleotide polymorphisms (SNPs) of the SLC7A5/LAT1 gene in 315 patients with psychosis within the schizophrenia spectrum and 233 healthy controls to investigate genetic vulnerability to the disorder as well as genetic relationships to homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), the major catecholamine metabolites in the cerebrospinal fluid (CSF). Moreover, the involvement of the different isoforms of the system L in tyrosine uptake and LAT1 tyrosine kinetics were studied in fibroblast cell lines of 10 patients with schizophrenia and 10 healthy controls. The results provide suggestive evidence of individual vulnerability to schizophrenia related to the LAT1 SNP rs9936204 genotype. A number of SNPs were nominally associated with CSF HVA and MHPG concentrations but did not survive correction for multiple testing. The LAT1 isoform was confirmed as the major tyrosine transporter in patients with schizophrenia. However, the kinetic parameters (maximal transport capacity, affinity of the binding sites, and diffusion constant of tyrosine transport through the LAT1 isoform) did not differ between patients with schizophrenia and controls. The present genetic findings call for independent replication in larger samples, while the functional study seems to exclude a role of LAT1 in the aberrant transport of tyrosine in fibroblasts of patients with schizophrenia.

Published
2017
Full Text
View/download PDF

14. Variability in Working Memory Performance Explained by Epistasis vs Polygenic Scores in the ZNF804A Pathway

Author

Nicodemus, Kk, Hargreaves, A, Morris, D, Anney, R, Gill, M, Corvin, A, Donohoe, G, Ripke, S, Sanders, Ar, Kendler, Ks, Levinson, Df, Sklar, P, Holmans, Pa, Lin, Dy, Duan, J, Ophoff, Ra, Andreassen, Oa, Scolnick, E, Cichon, S, Clair, St, D, Gurling, H, Werge, T, Rujescu, D, Blackwood, Dh, Pato, Cn, Malhotra, Ak, Purcell, S, Dudbridge, F, Neale, Bm, Rossin, L, Visscher, Pm, Posthuma, D, Ruderfer, Dm, Fanous, A, Stefansson, H, Steinberg, S, Mowry, Bj, Golimbet, V, Hert, De, M, Jönsson, Eg, Bitter, I, Pietiläinen, Op, Collier, Da, Tosato, Sarah, Agartz, I, Albus, M, Alexander, M, Amdur, Rl, Amin, F, Bass, N, Bergen, Se, Black, Dw, Børglum, Ad, Brown, Ma, Bruggeman, R, Buccola, Ng, Byerley, Wf, Cahn, W, Cantor, Rm, Carr, Vj, Catts, Sv, Choudhury, K, Cloninger, C, Cormican, P, Craddock, N, Danoy, Pa, Datta, S, Haan, De, L, Demontis, D, Dikeos, D, Djurovic, S, Donnelly, P, Duong, L, Dwyer, S, Fink Jensen, A, Freedman, R, Freimer, Nb, Friedl, M, Georgieva, L, Giegling, I, Glenthøj, B, Godard, S, Hamshere, M, Hansen, M, Hansen, T, Hartmann, Am, Henskens, Fa, Hougaard, Dm, Hultman, Cm, Ingason, A, Jablensky, Av, Jakobsen, Kd, Jay, M, Jürgens, G, Kahn, Rs, Keller, Mc, Kenis, G, Kenny, E, Kim, Y, Kirov, Gk, Konnerth, H, Konte, B, Krabbendam, L, Krasucki, R, Lasseter, Vk, Laurent, C, Lawrence, J, Lencz, T, Lerer, F, Liang, Ky, Lichtenstein, P, Lieberman, Ja, Linszen, Dh, Lönnqvist, J, Loughland, Cm, Maclean, Aw, Maher, Bs, Maier, W, Mallet, J, Malloy, P, Mattheisen, M, Mattingsdal, M, Mcghee, Ka, Mcgrath, Jj, Mcintosh, A, Mclean, De, Mcquillin, A, Melle, I, Michie, Pt, Milanova, V, Morris, Dw, Mors, O, Mortensen, Pb, Moskvina, V, Muglia, P, Myin Germeys, I, Nertney, Da, Nestadt, G, Nielsen, J, Nikolov, I, Nordentoft, M, Norton, N, Nöthen, Mm, O'Dushlaine, Ct, Olincy, A, Olsen, L, O'Neill, F, Ørntoft, Tf, Owen, Mj, Pantelis, C, Papadimitriou, G, Pato, Mt, Peltonen, L, Petursson, H, Pickard, B, Pimm, J, Pulver, Ae, Puri, V, Quested, D, Quinn, Em, Rasmussen, Hb, Réthelyi, Jm, Ribble, R, Rietschel, M, Riley, Bp, Ruggeri, Mirella, Schall, U, Schulze, Tg, Schwab, Sg, Scott, Rj, Shi, J, Sigurdsson, E, Silverman, Jm, Spencer, Cc, Stefansson, K, Strange, A, Strengman, E, Stroup, T, Suvisaari, J, Terenius, L, Thirumalai, S, Thygesen, Jh, Timm, S, Toncheva, D, Van, Den, Oord, E, Van, Os, Van, J, Winkel, R, Veldink, J, Walsh, D, Wang, Ag, Wiersma, D, Wildenauer, Db, Williams, Hj, Williams, Nm, Wormley, B, Zammit, S, Sullivan, Pf, O'Donovan, Mc, Daly, Mj, Gejman, P., Functional Genomics, Complex Trait Genetics, De Hert, Marc, Myin-Germeys, Inez, van Winkel, Ruud, Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, Amsterdam Neuroscience, and Adult Psychiatry

Subjects
epistasis, Male, Multifactorial Inheritance, polygenic, Neuropsychological Tests, involvement, 0302 clinical medicine, Neural Pathways, 2.1 Biological and endogenous factors, Psychology, schizophrenia risk, psychosis variant, Aetiology, 0303 health sciences, susceptibility gene znf804a, medicine.diagnostic_test, phenotypes, Zinc Fingers, Neuropsychological test, Single Nucleotide, Middle Aged, Serious Mental Illness, Psychiatry and Mental health, Memory, Short-Term, Mental Health, Schizophrenia, Major depressive disorder, Female, Cognitive Sciences, social and economic factors, Adult, medicine.medical_specialty, Psychosis, working memory, schizophrenia, IQ, Schizoaffective disorder, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Gene interaction, Genetic, Social cognition, Memory, Clinical Research, 2.3 Psychological, Behavioral and Social Science, medicine, Genetics, Humans, Genetic Predisposition to Disease, Bipolar disorder, Polymorphism, Psychiatry, 030304 developmental biology, Other Medical and Health Sciences, Prevention, Wellcome Trust Case Control Consortium 2, Neurosciences, Genetic Variation, Epistasis, Genetic, Schizophrenia Psychiatric Genome-wide Association Study (GWAS) Consortium, medicine.disease, attention, Brain Disorders, deficits, Short-Term, Psychotic Disorders, genome-wide association, Epistasis, healthy controls, identification, Cognition Disorders, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

IMPORTANCE We investigated the variation in neuropsychological function explained by risk alleles at the psychosis susceptibility gene ZNF804A and its interacting partners using single nucleotide polymorphisms (SNPs), polygenic scores, and epistatic analyses. Of particular importance was the relative contribution of the polygenic score vs epistasis in variation explained. OBJECTIVES To (1) assess the association between SNPs in ZNF804A and the ZNF804A polygenic score with measures of cognition in cases with psychosis and (2) assess whether epistasis within the ZNF804A pathway could explain additional variation above and beyond that explained by the polygenic score. DESIGN, SETTING, AND PARTICIPANTS Patients with psychosis (n = 424)were assessed in areas of cognitive ability impaired in schizophrenia including IQ, memory, attention, and social cognition.We used the Psychiatric GWAS Consortium 1 schizophrenia genome-wide association study to calculate a polygenic score based on identified risk variants within this genetic pathway. Cognitive measures significantly associated with the polygenic score were tested for an epistatic component using a training set (n = 170), which was used to develop linear regression models containing the polygenic score and 2-SNP interactions. The best-fitting models were tested for replication in 2 independent test sets of cases: (1) 170 individuals with schizophrenia or schizoaffective disorder and (2) 84 patients with broad psychosis (including bipolar disorder, major depressive disorder, and other psychosis). MAIN OUTCOMES AND MEASURES Participants completed a neuropsychological assessment battery designed to target the cognitive deficits of schizophrenia including general cognitive function, episodic memory, working memory, attentional control, and social cognition. RESULTS Higher polygenic scores were associated with poorer performance among patients on IQ, memory, and social cognition, explaining 1%to 3%of variation on these scores (range, P = .01 to .03). Using a narrow psychosis training set and independent test sets of narrow phenotype psychosis (schizophrenia and schizoaffective disorder), broad psychosis, and control participants (n = 89), the addition of 2 interaction terms containing 2 SNPs each increased the R2 for spatial working memory strategy in the independent psychosis test sets from 1.2%using the polygenic score only to 4.8%(P = .11 and .001, respectively) but did not explain additional variation in control participants. CONCLUSIONS AND RELEVANCE These data support a role for the ZNF804A pathway in IQ, memory, and social cognition in cases. Furthermore, we showed that epistasis increases the variation explained above the contribution of the polygenic score. © 2014 American Medical Association. All rights reserved.

Published
2014

15. Schizophrenia genetic variants are not associated with intelligence

Author

van Scheltinga, Af, Bakker, Sc, van Haren, Ne, Derks, Em, Buizer Voskamp, Je, Cahn, W, Ripke, S, Sanders, A, Kendler, K, Levinson, D, Sklar, P, Holmans, P, Lin, D., Duan, J, Ophoff, R, Andreassen, O, Scolnick, E, Cichon, S, St Clair, D, Corvin, A, Gurling, H, Werge, T, Rujescu, D, Blackwood, D, Pato, C, Malhotra, A, Purcell, S, Dudbridge, F, Neale, B, Rossin, L, Visscher, P, Posthuma, D, Ruderfer, D, Fanous, A, Stefansson, H, Steinberg, S, Mowry, B, Golimbet, V, Hert, De, M, Jonsson, E, Bitter, I, Pietilainen, O, Collier, D, Tosato, Sarah, Agartz, I, Albus, M, Alexander, M, Amdur, R, Amin, F, Bass, N, Bergen, S, Black, D, Børglum, A, Brown, M, Bruggeman, R, Buccola, N, Byerley, W, Cantor, R, Carr, V, Catts, S, Choudhury, K, Cloninger, C, Cormican, P, Craddock, N, Danoy, P, Datta, S, Haan, De, L, Demontis, D, Dikeos, D, Djurovic, S, Donnelly, P, Donohoe, G, Duong, L, Dwyer, S, Fink Jensen, A, Freedman, R, Freimer, N, Friedl, M, Georgieva, L, Giegling, I, Gill, M, Glenthøj, B, Godard, S, Hamshere, M, Hansen, M, Hansen, T, Hartmann, A, Henskens, F, Hougaard, D, Hultman, C, Ingason, A, Jablensky, A, Jakobsen, K, Jay, M, Jurgens, G, Kahn, R, Keller, M, Kenis, G, Kenny, E, Kim, Y, Kirov, G, Konnerth, H, Konte, B, Krabbendam, L, Krasucki, R, Lasseter, V, Laurent, C, Lawrence, J, Lencz, T, Lerer, F, Liang, K, Lichtenstein, P, Lieberman, J, Linszen, D, Lonnqvist, J, Loughland, C, Maclean, A, Maher, B, Maier, W, Mallet, J, Malloy, P, Mattheisen, M, Mattingsdal, M, Mcghee, K, Mcgrath, J, Mcintosh, A, Mclean, D, Mcquillin, A, Melle, I, Michie, P, Milanova, V, Morris, D, Mors, O, Mortensen, P, Moskvina, V, Muglia, P, Myin Germeys, I, Nertney, D, Nestadt, G, Nielsen, J, Nikolov, I, Nordentoft, M, Norton, N, Nothen, M, O'Dushlaine, C, Olincy, A, Olsen, L, O'Neill, F, Ørntoft, T, Owen, M, Pantelis, C, Papadimitriou, G, Pato, M, Peltonen, L, Petursson, H, Pickard, B, Pimm, J, Pulver, A, Puri, V, Quested, D, Quinn, E, Rasmussen, H, Rethelyi, Jm, Ribble, R, Rietschel, M, Riley, B, Ruggeri, Mirella, Schall, U, Schulze, T, Schwab, S, Scott, R, Shi, J, Sigurdsson, E, Silverman, J, Spencer, C, Stefansson, K, Strange, A, Strengman, E, Stroup, T, Suvisaari, J, Terenius, L, Thirumalai, S, Thygesen, J, Timm, S, Toncheva, D, van den Oord, E, van Os, J, van Winkel, R, Veldink, J, Walsh, D, Wang, A, Wiersma, D, Wildenauer, D, Williams, H, Williams, N, Wormley, B, Zammit, S, Sullivan, P, O'Donovan, M, Daly, M, Gejman, P), Ophoff, Ra, Kahn, Rs, Functional Genomics, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Psychiatrie & Neuropsychologie, RS: MHeNs School for Mental Health and Neuroscience, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, and Adult Psychiatry

Subjects
Oncology, Adult, Male, Psychosis, medicine.medical_specialty, Multifactorial Inheritance, DNA Copy Number Variations, Endophenotypes, Schizophrenia (object-oriented programming), Intelligence, SNP, Single-nucleotide polymorphism, Genome-wide association study, polygenic, Polymorphism, Single Nucleotide, behavioral disciplines and activities, Article, Cognition, Internal medicine, mental disorders, medicine, Humans, Genetic Predisposition to Disease, deletion, Cognitive decline, Applied Psychology, Genetic association, Genetics, Wechsler Scales, Wechsler Adult Intelligence Scale, medicine.disease, endophenotype, Psychiatry and Mental health, duplication, IQ, Endophenotype, Schizophrenia, Female, Psychology, cognition, schizophrenia, Genome-Wide Association Study
Abstract

BackgroundSchizophrenia is associated with lower pre-morbid intelligence (IQ) in addition to (pre-morbid) cognitive decline. Both schizophrenia and IQ are highly heritable traits. Therefore, we hypothesized that genetic variants associated with schizophrenia, including copy number variants (CNVs) and a polygenic schizophrenia (risk) score (PSS), may influence intelligence.MethodIQ was estimated with the Wechsler Adult Intelligence Scale (WAIS). CNVs were determined from single nucleotide polymorphism (SNP) data using the QuantiSNP and PennCNV algorithms. For the PSS, odds ratios for genome-wide SNP data were calculated in a sample collected by the Psychiatric Genome-Wide Association Study (GWAS) Consortium (8690 schizophrenia patients and 11 831 controls). These were used to calculate individual PSSs in our independent sample of 350 schizophrenia patients and 322 healthy controls.ResultsAlthough significantly more genes were disrupted by deletions in schizophrenia patients compared to controls (p = 0.009), there was no effect of CNV measures on IQ. The PSS was associated with disease status (R2 = 0.055, p = 2.1 × 10−7) and with IQ in the entire sample (R2 = 0.018, p = 0.0008) but the effect on IQ disappeared after correction for disease status.ConclusionsOur data suggest that rare and common schizophrenia-associated variants do not explain the variation in IQ in healthy subjects or in schizophrenia patients. Thus, reductions in IQ in schizophrenia patients may be secondary to other processes related to schizophrenia risk.

Published
2013

16. Analysis of 10 independent samples provides evidence for association between schizophrenia and a SNP flanking fibroblast growth factor receptor 2

Author

O'Donovan, MC, Norton, N, Williams, H, Peirce, T, Moskvina, V, Nikolov, I, Hamshere, M, Carroll, L, Georgieva, L, Dwyer, S, Holmans, P, Marchini, JL, Spencer, CCA, Howie, B, Leung, H-T, Giegling, I, Hartmann, AM, Möller, H-J, Morris, DW, Shi, Y, Feng, G, Hoffmann, P, Propping, P, Vasilescu, C, Maier, W, Rietschel, M, Zammit, S, Schumacher, J, Quinn, EM, Schulze, TG, Iwata, N, Ikeda, M, Darvasi, A, Shifman, S, He, L, Duan, J, Sanders, AR, Levinson, DF, Adolfsson, R, Ösby, U, Terenius, L, Jönsson, EG, Cichon, S, Nöthen, MM, Gill, M, Corvin, AP, Rujescu, D, Gejman, PV, Kirov, G, Craddock, N, Williams, NM, Owen, MJ, Buccola, NG, Mowry, BJ, Freedman, R, Amin, F, Black, DW, Silverman, JM, Byerley, WJ, and Cloninger, CR

Subjects
Adult, Male, Linkage disequilibrium, Genotype, Genome-wide association study, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Article, Cellular and Molecular Neuroscience, Young Adult, Gene Frequency, Meta-Analysis as Topic, Polymorphism (computer science), SNP, Humans, Genetic Predisposition to Disease, Allele, Receptor, Fibroblast Growth Factor, Type 2, Molecular Biology, Allele frequency, Aged, Genetics, Aged, 80 and over, Fibroblast growth factor receptor 2, Chromosomes, Human, Pair 10, Middle Aged, Psychiatry and Mental health, Schizophrenia, Female, Genome-Wide Association Study
Abstract

We and others have previously reported linkage to schizophrenia on chromosome 10q25-q26 but, to date, a susceptibility gene in the region has not been identified. We examined data from 3606 single-nucleotide polymorphisms (SNPs) mapping to 10q25-q26 that had been typed in a genome-wide association study (GWAS) of schizophrenia (479 UK cases/2937 controls). SNPs with P

Published
2016

17. Genome-wide association study identifies five new schizophrenia loci

Author

Ripke, S., Sanders, A. R., Kendler, K. S., Levinson, D. F., Sklar, P., Holmans, P. A., Lin, D., Duan, J., Ophoff, R. A., Andreassen, O. A., Scolnick, E., Cichon, S., Clair, D. S., Corvin, A., Gurling, H., Werge, T., Rujescu, D., D. H. R., Pato, C. N., Malhotra, A. K., Purcell, S., Dudbridge, F., Neale, B. M., Rossin, L., Visscher, P. M., Posthuma, D., Ruderfer, D. M., Fanous, A., Stefansson, H., Steinberg, S., Mowry, B. J., Golimbet, V., Hert, M. D., Jönsson, E. G., Bitter, I., O. P. H., Collier, D. A., Tosato, Sarah, Agartz, I., Albus, M., Alexander, M., Amdur, R. L., Amin, F., Bass, N., Bergen, S. E., Black, D. W., Børglum, A. D., Brown, M. A., Bruggeman, R., Buccola, N. G., Byerley, W. F., Cahn, W., Cantor, R. M., Carr, V. J., Catts, S. V., Choudhury, K., Cloninger, C. R., Cormican, P., Craddock, N., Danoy, P. A., Datta, S., Haan, L. d., Demontis, D., Dikeos, D., Djurovic, S., Donnelly, P., Donohoe, G., Duong, L., Dwyer, S., Fink Jensen, A., Freedman, R., Freimer, N. B., Friedl, M., Georgieva, L., Giegling, I., Gill, M., Glenthøj, B., Godard, S., Hamshere, M., Hansen, M., Hansen, T., Hartmann, A. M., Henskens, F. A., Hougaard, D. M., Hultman, C. M., Ingason, A., Jablensky, A. V., Jakobsen, K. D., Jay, M., Jürgens, G., Kahn, R. S., Keller, M. C., Kenis, G., Kenny, E., Kim, Y., Kirov, G. K., Konnerth, H., Konte, B., Krabbendam, L., Krasucki, R., Lasseter, V. K., Laurent, C., Lawrence, J., Lencz, T., Lerer, F. B., Liang, K., Lichtenstein, P., Lieberman, J. A., Linszen, D. H., Lönnqvist, J., Loughland, C. M., Maclean, A. W., Maher, B. S., Maier, W., Mallet, J., Malloy, P., Mattheisen, M., Mattingsdal, M., Mcghee, K. A., Mcgrath, J. J., Mcintosh, A., Mclean, D. E., Mcquillin, A., Melle, I., Michie, P. T., Milanova, V., Morris, D. W., Mors, O., Mortensen, P. B., Moskvina, V., Muglia, P., Myin Germeys, I., Nertney, D. A., Nestadt, G., Nielsen, J., Nikolov, I., Nordentoft, M., Norton, N., Nöthen, M. M., O'Dushlaine, C. T., Olincy, A., Olsen, L., O'Neill, F. A., Orntoft, T. F., Owen, M. J., Pantelis, C., Papadimitriou, G., Pato, M. T., Peltonen, L., Petursson, H., Pickard, B., Pimm, J., Pulver, A. E., Puri, V., Quested, D., Quinn, E. M., Rasmussen, H. B., Réthelyi, J. M., Ribble, R., Rietschel, M., Riley, B. P., Ruggeri, Mirella, Schall, U., Schulze, T. G., Schwab, S. G., Scott, R. J., Shi, J., Sigurdsson, E., Silverman, J. M., C. C. A., Stefansson, K., Strange, A., Strengman, E., Stroup, T. S., Suvisaari, J., Terenius, L., Thirumalai, S., Thygesen, J. H., Timm, S., Toncheva, D., Den, E. v., J. v., Os, Winkel, R. v., Veldink, J., Walsh, D., Wang, A. G., Wiersma, D., Wildenauer, D. B., Williams, H. J., Williams, N. M., Wormley, B., Zammit, S., Sullivan, P. F., O'Donovan, M. C., Daly, M. J., Gejman, P. V., Genome Wide, S. P., ANS - Amsterdam Neuroscience, Adult Psychiatry, Functional Genomics, Educational Neuroscience, Clinical Child and Family Studies, Neuroscience Campus Amsterdam - integrative Analysis & Modeling, Neuroscience Campus Amsterdam - Attention & Cognition, LEARN! - Brain, learning and development, Psychiatrie & Neuropsychologie, and RS: MHeNs School for Mental Health and Neuroscience

Subjects
Male, Gene Dosage, Biology, VARIANTS, SUSCEPTIBILITY, ANCESTRY, Polymorphism, Single Nucleotide, Article, Linkage Disequilibrium, White People, 03 medical and health sciences, 0302 clinical medicine, microRNA, Genetics, Humans, Genetic Predisposition to Disease, Alleles, 030304 developmental biology, 0303 health sciences, Genome, Genome, Human, HERITABILITY, MICRORNA, BIPOLAR DISORDER, 3. Good health, schizophrenia, COMMON SNPS EXPLAIN, MicroRNAs, INDIVIDUALS, Logistic Models, Gene Expression Regulation, Haplotypes, LARGE PROPORTION, Genetic Loci, Case-Control Studies, Mutation, Female, HUMAN HEIGHT, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 × 10 -11) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 × 10 -9), ANK3 (rs10994359, P = 2.5 × 10 -8) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 × 10 -9). © 2011 Nature America, Inc. All rights reserved.

Published
2011

18. All SNPs are not created equal: genome-wide association studies reveal a consistent pattern of enrichment among functionally annotated SNPs

Author

Aj, Schork, Wk, Thompson, Pham P, Torkamani A, Jc, Roddey, Pf, Sullivan, Jr, Kelsoe, Donovan Mc, O., Furberg H, Tobacco and Genetics Consortium, Bipolar Disorder Psychiatric Genomics Consortium, Schizophrenia Psychiatric Genomics Consortium, Nj, Schork, Oa, Andreassen, Am, Dale, Absher D, Agudo A, Almgren P, Ardissino D, Tl, Assimes, Bandinelli S, Barzan L, Bencko V, Benhamou S, Ej, Benjamin, Bernardinelli L, Bis J, Boehnke M, Boerwinkle E, Di, Boomsma, Brennan P, Canova C, Castellsagué X, Chanock S, Chasman D, Di, Conway, Dackor J, Ej, Geus, Duan J, Elosua R, Everett B, Fabianova E, Ferrucci L, Foretova L, Sp, Fortmann, Franceschini N, Frayling T, Furberg C, Pv, Gejman, Groop L, Gu F, Guralnik J, Se, Hankinson, Haritunians T, Healy C, Hofman A, Holcátová I, Dj, Hunter, Sj, Hwang, Jp, Ioannidis, Iribarren C, Au, Jackson, Janout V, Kaprio J, Kim Y, Kjaerheim K, Jw, Knowles, Kraft P, Ladenvall C, Lagiou P, Lanthrop M, Lerman C, Df, Levinson, Levy D, Md, Li, Dy, Lin, Eh, Lips, Lissowska J, Lowry R, Lucas G, Tv, Macfarlane, Maes H, Pm, Mannucci, Mates D, Mauri F, Ja, Mcgovern, Jd, Mckay, McKnight B, Melander O, Pa, Merlini, Milaneschi Y, Kl, Mohlke, Donnell Cj, O., Pare G, Bw, Penninx, Perry J, Posthuma D, Sr, Preis, Psaty B, Quertermous T, Vs, Ramachandran, Richiardi L, Ridker P, Rose J, Rudnai P, Salomaa V, Ar, Sanders, Sm, Schwartz, Shi J, Jh, Smit, Hm, Stringham, Szeszenia-Dabrowska N, Tanaka T, Taylor K, Thacker E, Thornton L, Tiemeier H, Tuomilehto J, Ag, Uitterlinden, Cm, Duijn, Jm, Vink, Vogelzangs N, Bf, Voight, Walter S, Willemsen G, Zaridze D, Znaor A, Akil H, Anjorin A, Backlund L, Ja, Badner, Jd, Barchas, Tb, Barrett, Bass N, Bauer M, Bellivier F, Se, Bergen, Berrettini W, Blackwood D, Cs, Bloss, Breen G, Breuer R, We, Bunner, Burmeister M, Byerley W, Caesar S, Chambert K, Cichon S, St Clair D, Da, Collier, Corvin A, Wh, Coryell, Craddock N, Dw, Craig, Daly M, Day R, Degenhardt F, Djurovic S, Dudbridge F, Hj, Edenberg, Elkin A, Etain B, Ae, Farmer, Ma, Ferreira, Ferrier I, Flickinger M, Foroud T, Frank J, Fraser C, Frisén L, Es, Gershon, Gill M, Gordon-Smith K, Ek, Green, Ta, Greenwood, Grozeva D, Guan W, Gurling H, Ó, Gustafsson, Ml, Hamshere, Hautzinger M, Herms S, Hipolito M, Pa, Holmans, Cm, Hultman, Jamain S, Eg, Jones, Jones I, Jones L, Kandaswamy R, Jl, Kennedy, Gk, Kirov, Dl, Koller, Kwan P, Landén M, Langstrom N, Lathrop M, Lawrence J, Wb, Lawson, Leboyer M, Ph, Lee, Li J, Lichtenstein P, Lin D, Liu C, Fw, Lohoff, Lucae S, Pb, Mahon, Maier W, Ng, Martin, Mattheisen M, Matthews K, Mattingsdal M, Ka, Mcghee, McGuffin P, Mg, Mcinnis, McIntosh A, McKinney R, Aw, Mclean, Fj, Mcmahon, McQuillin A, Meier S, Melle I, Meng F, Pb, Mitchell, Gw, Montgomery, Moran J, Morken G, Dw, Morris, Moskvina V, Muglia P, Tw, Mühleisen, Wj, Muir, Müller-Myhsok B, Rm, Myers, Cm, Nievergelt, Nikolov I, Nimgaonkar V, Mm, Nöthen, Ji, Nurnberger, Ea, Nwulia, O'Dushlaine C, Osby U, Óskarsson H, Mj, Owen, Petursson H, Bs, Pickard, Porgeirsson P, Jb, Potash, Propping P, Sm, Purcell, Quinn E, Raychaudhuri S, Rice J, Rietschel M, Ruderfer D, Schalling M, Af, Schatzberg, Wa, Scheftner, Pr, Schofield, Tg, Schulze, Schumacher J, Mm, Schwarz, Scolnick E, Lj, Scott, Pd, Shilling, Sigurdsson E, Sklar P, En, Smith, Stefansson H, Stefansson K, Steffens M, Steinberg S, Strauss J, Strohmaier J, Szelinger S, Rc, Thompson, Tozzi F, Treutlein J, Jb, Vincent, Sj, Watson, Tf, Wienker, Williamson R, Sh, Witt, Wright A, Xu W, Ah, Young, Pp, Zandi, Zhang P, Zöllner S, Agartz I, Albus M, Alexander M, Rl, Amdur, Amin F, Bitter I, Dw, Black, Ad, Børglum, Ma, Brown, Bruggeman R, Ng, Buccola, Wf, Byerley, Cahn W, Rm, Cantor, Vj, Carr, Sv, Catts, Choudhury K, Cloninger C, Cormican P, Pa, Danoy, Datta S, DeHert M, Demontis D, Dikeos D, Donnelly P, Donohoe G, Duong L, Dwyer S, Fanous A, Fink-Jensen A, Freedman R, Nb, Freimer, Friedl M, Georgieva L, Giegling I, Glenthøj B, Godard S, Golimbet V, de Haan L, Hansen M, Hansen T, Am, Hartmann, Fa, Henskens, Dm, Hougaard, Ingason A, Av, Jablensky, Kd, Jakobsen, Jay M, Eg, Jönsson, Jürgens G, Rs, Kahn, Mc, Keller, Ks, Kendler, Kenis G, Kenny E, Konnerth H, Konte B, Krabbendam L, Krasucki R, Vk, Lasseter, Laurent C, Lencz T, Lerer F, Ky, Liang, Ja, Lieberman, Dh, Linszen, Lönnqvist J, Cm, Loughland, Aw, Maclean, Bs, Maher, Ak, Malhotra, Mallet J, Malloy P, Jj, Mcgrath, McLean DE, Pt, Michie, Milanova V, Mors O, Pb, Mortensen, Bj, Mowry, Myin-Germeys I, Neale B, Da, Nertney, Nestadt G, Nielsen J, Nordentoft M, Norton N, O'Neill F, Olincy A, Olsen L, Ra, Ophoff, Tf, Ørntoft, van Os J, Pantelis C, Papadimitriou G, Cn, Pato, Mt, Pato, Peltonen L, Pickard B, Op, Pietiläinen, Pimm J, Ae, Pulver, Puri V, Digby Quested, Hb, Rasmussen, Jm, Réthelyi, Ribble R, Bp, Riley, Rossin L, Ruggeri M, Rujescu D, Schall U, Sg, Schwab, Rj, Scott, Jm, Silverman, Cc, Spencer, Strange A, Strengman E, Stroup T, Suvisaari J, Terenius L, Thirumalai S, Timm S, Toncheva D, Tosato S, Ej, Den Oord, Veldink J, Pm, Visscher, Walsh D, Ag, Wang, Werge T, Wiersma D, Db, Wildenauer, Hj, Williams, Nm, Williams, van Winkel R, Wormley B., Biological Psychology, Functional Genomics, Educational Neuroscience, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, LEARN! - Social cognition and learning, Biophotonics and Medical Imaging, LEARN! - Brain, learning and development, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Neuroscience Campus Amsterdam - Brain Imaging Technology, LaserLaB - Biophotonics and Microscopy, ANS - Amsterdam Neuroscience, Adult Psychiatry, Psychiatry, Human genetics, Epidemiology and Data Science, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, Psychiatrie & Neuropsychologie, RS: MHeNs School for Mental Health and Neuroscience, Gibson, Greg, Germeys, Inez, van Winkel, Ruud, and De Hert, Marc

Subjects
False discovery rate, Netherlands Twin Register (NTR), Cancer Research, Linkage disequilibrium, Genome-wide association study, Linkage Disequilibrium, 0302 clinical medicine, 2.1 Biological and endogenous factors, Aetiology, Genetics (clinical), Genetics, 0303 health sciences, Statistics, Genomics, Single Nucleotide, Genome Scans, Tobacco and Genetics Consortium, Functional Genomics, Phenotype, complex trait, Research Article, Bipolar Disorder Psychiatric Genomics Consortium, lcsh:QH426-470, SNP, Single-nucleotide polymorphism, Computational biology, Biostatistics, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, "genome-wide association study", Genome Analysis Tools, Clinical Research, Schizophrenia Psychiatric Genomics Consortium, Genome-Wide Association Studies, Humans, Genetic Predisposition to Disease, Statistical Methods, Polymorphism, Molecular Biology, Genetic Association Studies, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Genetic association, Linkage (software), Human Genome, Computational Biology, Human Genetics, Heritability, R1, schizophrenia, lcsh:Genetics, Schizophrenia, Mathematics, 030217 neurology & neurosurgery, Genome-Wide Association Study, Developmental Biology
Abstract

Recent results indicate that genome-wide association studies (GWAS) have the potential to explain much of the heritability of common complex phenotypes, but methods are lacking to reliably identify the remaining associated single nucleotide polymorphisms (SNPs). We applied stratified False Discovery Rate (sFDR) methods to leverage genic enrichment in GWAS summary statistics data to uncover new loci likely to replicate in independent samples. Specifically, we use linkage disequilibrium-weighted annotations for each SNP in combination with nominal p-values to estimate the True Discovery Rate (TDR = 1−FDR) for strata determined by different genic categories. We show a consistent pattern of enrichment of polygenic effects in specific annotation categories across diverse phenotypes, with the greatest enrichment for SNPs tagging regulatory and coding genic elements, little enrichment in introns, and negative enrichment for intergenic SNPs. Stratified enrichment directly leads to increased TDR for a given p-value, mirrored by increased replication rates in independent samples. We show this in independent Crohn's disease GWAS, where we find a hundredfold variation in replication rate across genic categories. Applying a well-established sFDR methodology we demonstrate the utility of stratification for improving power of GWAS in complex phenotypes, with increased rejection rates from 20% in height to 300% in schizophrenia with traditional FDR and sFDR both fixed at 0.05. Our analyses demonstrate an inherent stratification among GWAS SNPs with important conceptual implications that can be leveraged by statistical methods to improve the discovery of loci., Author Summary Modern genome-wide association studies (GWAS) have failed to identify large portions of the genetic basis of common, complex traits. Recent work suggested this could be because many genetic variants, each with individually small effects, compose their genetic architecture, limiting the power of GWAS. Moreover, these variants appear more abundantly in and near genes. Using genome annotations, summary statistics from several of the largest GWAS, and established statistical methods for quantifying distributions of test statistics, we show a consistency across studies. Namely, we show that, across all assessed traits, the test statistics resulting from SNPs that are related to the 5′ UTR of genes show the largest abundance of associations, while SNPs related to exons and the 3′UTR are also enriched. SNPs related to introns are only moderately enriched, and intergenic SNPs show a depletion of associations relative to the average SNP. This enrichment corresponds directly to increased replication across independent samples and can be incorporated a priori into statistical methods to improve discovery and prediction. Our results contribute to on-going debates about the functional nature of the genetic architecture of complex traits and point to avenues for leveraging existing GWAS data for discovery in future GWA and sequencing studies.

Published
2013

19. Genetic schizophrenia risk variants jointly modulate total brain and white matter volume

Author

Terwisscha van Scheltinga, Af, Bakker, Sc, van Haren, Ne, Derks, Em, Buizer Voskamp, Je, Boos, Hb, Cahn, W, Hulshoff, Pol, Ripke, S, Ophoff, Ra, Kahn, Rs, Sanders, Ar, Kendler, Ks, Levinson, Df, Sklar, P, Holmans, Pa, Lin, Dy, Duan, J, Andreassen, Oa, Scolnick, E, Cichon, S, Clair, St, D, Corvin, A, Gurling, H, Werge, T, Rujescu, D, Blackwood, Dh, Pato, Cn, Malhotra, Ak, Purcell, S, Dudbridge, F, Neale, Bm, Rossin, L, Visscher, Pm, Posthuma, D, Ruderfer, Dm, Fanous, A, Stefansson, H, Steinberg, S, Mowry, Bj, Golimbet, V, Hert, De, M, Jonsson, Eg, Bitter, I, Pietiläinen, Op, Collier, Da, Tosato, Sarah, Agartz, I, Albus, M, Alexander, M, Amdur, Rl, Amin, F, Bass, N, Bergen, Se, Black, Dw, Børglum, Ad, Brown, Ma, Bruggeman, R, Buccola, Ng, Byerley, Wf, Cantor, Rm, Carr, Vj, Catts, Sv, Choudhury, K, Cloninger, C, Cormican, P, Craddock, N, Danoy, Pa, Datta, S, Haan, De, L, Demontis, D, Dikeos, D, Djurovic, S, Donnelly, P, Donohoe, G, Duong, L, Dwyer, S, Fink Jensen, A, Freedman, R, Freimer, Nb, Friedl, M, Georgieva, L, Giegline, I, Gill, M, Glenthøj, B, Godard, S, Hamshere, M, Hansen, M, Hansen, T, Hartmann, Am, Henskens, Fa, Hougaard, Dm, Hultman, Cm, Ingason, A, Jablensky, Av, Jakobsen, Kd, Jay, M, Jürgens, G, Keller, Mc, Kenis, G, Kenny, E, Kim, Y, Kirov, Gk, Konnerth, H, Konte, B, Krabbendam, L, Krasucki, R, Lasseter, Vk, Laurent, C, Lawrence, J, Lencz, T, Lerer, F, Liang, Ky, Lichtenstein, P, Lieberman, Ja, Linszen, Dh, Lönnqvist, J, Loughland, Cm, Maclean, Aw, Maher, Bs, Maier, W, Mallet, J, Malloy, P, Mattheisen, M, Mattingsdal, M, Mcghee, Ka, Mcgrath, Jj, Mcintosh, A, Mclean, De, Mcquillin, A, Melle, I, Michie, Pt, Milanova, V, Morris, Dw, Mors, O, Mortensen, Pb, Moskvina, V, Muglia, P, Myin Germeys, I, Nertney, Da, Nestadt, G, Nielsen, J, Nikolov, I, Nordentoft, M, Norton, N, Nöthen, Mm, O'Dushlaine, C, Olincy, A, Olsen, L, O'Neill, F, Ørntoft, Tf, Owen, Mj, Pantelis, C, Papadimitriou, G, Pato, Mt, Peltonen, L, Petursson, H, Pickard, B, Pimm, J, Pulver, Ae, Puri, V, Quested, D, Quinn, Em, Rasmussen, Hb, Réthelyi, Jm, Ribble, R, Rietschel, M, Riley, Bp, Ruggeri, Mirella, Schall, U, Schulze, Tg, Schwab, Sg, Scott, Rj, Shi, J, Sigurdsson, E, Silverman, Jm, Spencer, Cc, Stefansson, K, Strange, A, Strengman, E, Stroup, Ts, Suvisaari, J, Terenius, L, Thirumalai, S, Thygesen, Jh, Timm, S, Toncheva, D, van den Oord, E, van Os, J, Van, Winkel, R, Veldink, J, Walsh, D, Wang, Ag, Wiersma, D, Wildenauer, Db, Williams, Hj, Williams, Nm, Wormley, B, Zammit, S, Sullivan, Pf, O'Donovan, Mc, Daly, Mj, Gejman, Pv, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Adult Psychiatry, Functional Genomics, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Psychiatrie & Neuropsychologie, RS: MHeNs School for Mental Health and Neuroscience, Myin-Germeys, Inez, De Hert, Marc, and van Winkel, Ruud

Subjects
Adult, Male, Psychosis, Genotype, Single-nucleotide polymorphism, Genome-wide association study, Biology, Nerve Fibers, Myelinated, Polymorphism, Single Nucleotide, Article, White matter, genome-wide, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, mental disorders, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Biological Psychiatry, structural MRI, Genetics, neuroimaging, Case-control study, Brain, imaging, medicine.disease, 030227 psychiatry, 3. Good health, schizophrenia, Endophenotype, Phenotype, medicine.anatomical_structure, psychiatric, Schizophrenia, Case-Control Studies, Female, endophenotype, Genome-Wide Association Study, SNPs, Atrophy, 030217 neurology & neurosurgery
Abstract

BACKGROUND: Thousands of common single nucleotide polymorphisms (SNPs) are weakly associated with schizophrenia. It is likely that subsets of disease-associated SNPs are associated with distinct heritable disease-associated phenotypes. Therefore, we examined the shared genetic susceptibility modulating schizophrenia and brain volume. METHODS: Odds ratios for genome-wide SNP data were calculated in the sample collected by the Psychiatric Genome-wide Association Study Consortium (8690 schizophrenia patients and 11,831 control subjects, excluding subjects from the present study). These were used to calculate individual polygenic schizophrenia (risk) scores in an independent sample of 152 schizophrenia patients and 142 healthy control subjects with available structural magnetic resonance imaging scans. RESULTS: In the entire group, the polygenic schizophrenia score was significantly associated with total brain volume (R2 = .048, p = 1.6 × 10(-4)) and white matter volume (R2 = .051, p = 8.6 × 10(-5)) equally in patients and control subjects. The number of (independent) SNPs that substantially influenced both disease risk and white matter (n = 2020) was much smaller than the entire set of SNPs that modulated disease status (n = 14,751). From the set of 2020 SNPs, a group of 186 SNPs showed most evidence for association with white matter volume and an explorative functional analysis showed that these SNPs were located in genes with neuronal functions. CONCLUSIONS: These results indicate that a relatively small subset of schizophrenia genetic risk variants is related to the (normal) development of white matter. This, in turn, suggests that disruptions in white matter growth increase the susceptibility to develop schizophrenia.

Published
2013

20. Ethanol Alters Opioid Regulation of Ca2+ Influx through L-type Ca2+ Channels in PC12 Cells

Author

Gruol, D.L., Nelson, T.E., Hao, C., Michael, S., Vukojevic, V., Ming, Y., and Terenius, L.

Subjects
Calcium Channels, L-Type, Ethanol, Receptors, Opioid, kappa, Receptors, Opioid, mu, Enkephalin, Ala(2)-MePhe(4)-Gly(5), Dynorphins, PC12 Cells, Article, Membrane Potentials, Molecular Imaging, Rats, Potassium, Animals, Calcium, Drug Interactions, Signal Transduction
Abstract

Studies at the behavioral and synaptic level show that effects of ethanol on the central nervous system can involve the opioid signaling system. These interactions may alter the function of a common downstream target. In this study, we examined Ca(2+) channel function as a potential downstream target of interactions between ethanol and μ or κ opioid receptor signaling.The studies were carried out in a model system, undifferentiated PC12 cells transfected with μ or κ opioid receptors. The PC12 cells express L-type Ca(2+) channels, which were activated by K(+) depolarization. Ca(2+) imaging was used to measure relative Ca(2+) flux during K(+) depolarization and the modulation of Ca(2+) flux by opioids and ethanol.Ethanol, μ receptor activation, and κ receptor activation all reduced the amplitude of the Ca(2+) signal produced by K(+) depolarization. Pretreatment with ethanol or combined treatment with ethanol and μ or κ receptor agonists caused a reduction in the amplitude of the Ca(2+) signal that was comparable to or smaller than that observed for the individual drugs alone, indicating an interaction by the drugs at a downstream target (or targets) that limited the modulation of Ca(2+) flux through L-type Ca(2+) channels.These studies provide evidence for a cellular mechanism that could play an important role in ethanol regulation of synaptic transmission and behavior through interactions with the opioid signaling.

Published
2011

21. Genome-wide association study identifies five new schizophrenia loci

Author

Ripke, S. Sanders, A.R. Kendler, K.S. Levinson, D.F. Sklar, P. Holmans, P.A. Lin, D.-Y. Duan, J. Ophoff, R.A. Andreassen, O.A. Scolnick, E. Cichon, S. St. Clair, D. Corvin, A. Gurling, H. Werge, T. Rujescu, D. Blackwood, D.H.R. Pato, C.N. Malhotra, A.K. Purcell, S. Dudbridge, F. Neale, B.M. Rossin, L. Visscher, P.M. Posthuma, D. Ruderfer, D.M. Fanous, A. Stefansson, H. Steinberg, S. Mowry, B.J. Golimbet, V. De Hert, M. Jönsson, E.G. Bitter, I. Pietiläinen, O.P.H. Collier, D.A. Tosato, S. Agartz, I. Albus, M. Alexander, M. Amdur, R.L. Amin, F. Bass, N. Bergen, S.E. Black, D.W. Børglum, A.D. Brown, M.A. Bruggeman, R. Buccola, N.G. Byerley, W.F. Cahn, W. Cantor, R.M. Carr, V.J. Catts, S.V. Choudhury, K. Cloninger, C.R. Cormican, P. Craddock, N. Danoy, P.A. Datta, S. De Haan, L. Demontis, D. Dikeos, D. Djurovic, S. Donnelly, P. Donohoe, G. Duong, L. Dwyer, S. Fink-Jensen, A. Freedman, R. Freimer, N.B. Friedl, M. Georgieva, L. Giegling, I. Gill, M. Glenthøj, B. Godard, S. Hamshere, M. Hansen, M. Hansen, T. Hartmann, A.M. Henskens, F.A. Hougaard, D.M. Hultman, C.M. Ingason, A. Jablensky, A.V. Jakobsen, K.D. Jay, M. Jürgens, G. Kahn, R.S. Keller, M.C. Kenis, G. Kenny, E. Kim, Y. Kirov, G.K. Konnerth, H. Konte, B. Krabbendam, L. Krasucki, R. Lasseter, V.K. Laurent, C. Lawrence, J. Lencz, T. Lerer, F.B. Liang, K.-Y. Lichtenstein, P. Lieberman, J.A. Linszen, D.H. Lönnqvist, J. Loughland, C.M. MacLean, A.W. Maher, B.S. Maier, W. Mallet, J. Malloy, P. Mattheisen, M. Mattingsdal, M. McGhee, K.A. McGrath, J.J. McIntosh, A. McLean, D.E. McQuillin, A. Melle, I. Michie, P.T. Milanova, V. Morris, D.W. Mors, O. Mortensen, P.B. Moskvina, V. Muglia, P. Myin-Germeys, I. Nertney, D.A. Nestadt, G. Nielsen, J. Nikolov, I. Nordentoft, M. Norton, N. Nöthen, M.M. O'Dushlaine, C.T. Olincy, A. Olsen, L. O'Neill, F.A. Ørntoft, T.F. Owen, M.J. Pantelis, C. Papadimitriou, G. Pato, M.T. Peltonen, L. Petursson, H. Pickard, B. Pimm, J. Pulver, A.E. Puri, V. Quested, D. Quinn, E.M. Rasmussen, H.B. Réthelyi, J.M. Ribble, R. Rietschel, M. Riley, B.P. Ruggeri, M. Schall, U. Schulze, T.G. Schwab, S.G. Scott, R.J. Shi, J. Sigurdsson, E. Silverman, J.M. Spencer, C.C.A. Stefansson, K. Strange, A. Strengman, E. Stroup, T.S. Suvisaari, J. Terenius, L. Thirumalai, S. Thygesen, J.H. Timm, S. Toncheva, D. Van Den Oord, E. Van Os, J. Van Winkel, R. Veldink, J. Walsh, D. Wang, A.G. Wiersma, D. Wildenauer, D.B. Williams, H.J. Williams, N.M. Wormley, B. Zammit, S. Sullivan, P.F. O'Donovan, M.C. Daly, M.J. Gejman, P.V.

Abstract

We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 × 10 -11) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 × 10 -9), ANK3 (rs10994359, P = 2.5 × 10 -8) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 × 10 -9). © 2011 Nature America, Inc. All rights reserved.

Published
2011

22. Common variants at VRK2 and TCF4 conferring risk of schizophrenia

Author

Steinberg, S., Jong, S. d., Genomics, I. S., Andreassen, O. A., Werge, T., Børglum, A. D., Mors, O., Mortensen, P. B., Gustafsson, O., Costas, J., O. P. H., Demontis, D., Papiol, S., Huttenlocher, J., Mattheisen, M., Breuer, R., Vassos, E., Giegling, I., Fraser, G., Walker, N., Tuulio Henriksson, A., Suvisaari, J., Lönnqvist, J., Paunio, T., Agartz, I., Melle, I., Djurovic, S., Strengman, E., G. R. O., Jürgens, G., Glenthøj, B., Terenius, L., Hougaard, D. M., Orntoft, T., Wiuf, C., Didriksen, M., Hollegaard, M. V., Nordentoft, M., Winkel, R. v., Kenis, G., Abramova, L., Kaleda, V., Arrojo, M., Sanjuán, J., Arango, C., Sperling, S., Rossner, M., Ribolsi, M., Magni, V., Siracusano, A., Christiansen, C., Kiemeney, L. A., Veldink, J., Den, L. v., Ingason, A., Muglia, P., Murray, R., Nöthen, M. M., Sigurdsson, E., Petursson, H., Thorsteinsdottir, U., Kong, A., Rubino, I. A., Hert, M. D., Réthelyi, J. M., Bitter, I., Jönsson, E. G., Golimbet, V., Carracedo, A., Ehrenreich, H., Craddock, N., Owen, M. J., O'Donovan, M. C., Case, W. T., Ruggeri, Mirella, Tosato, Sarah, Peltonen, L., Ophoff, R. A., Collier, D. A., Clair, D. S., Rietschel, M., Cichon, S., Stefansson, H., Rujescu, D., Stefansson, K., Psychiatrie & Neuropsychologie, RS: MHeNs School for Mental Health and Neuroscience, Amsterdam Neuroscience, Adult Psychiatry, and deCODE Genetics, IS-101 Reykjavik, Iceland.

Subjects
schizophrenia, sequence variants, TCF4, Genome-wide association study, Transcription Factor 4, 0302 clinical medicine, VRK2 protein, human, Polymorphism (computer science), Genotype, genetics [Schizophrenia], Neurogranin, Genetics (clinical), Schizophrenia, Risk, Alleles, Polymorphism, Single Nucleotide, Transcription Factors, Humans, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Genetic Predisposition to Disease, Protein-Serine-Threonine Kinases, Genome-Wide Association Study, Genetics, 0303 health sciences, Association Studies Articles, Single Nucleotide, General Medicine, genetics [Transcription Factors], 3. Good health, Protein Serine-Threonine Kinases, Biology, genetics [Protein-Serine-Threonine Kinases], Molecular epidemiology [NCEBP 1], 03 medical and health sciences, ddc:570, Polymorphism, Allele, genetics [Basic Helix-Loop-Helix Leucine Zipper Transcription Factors], Settore MED/25 - Psichiatria, Molecular Biology, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], 030304 developmental biology, Intron, Odds ratio, Molecular biology, TCF4 protein, human, 030217 neurology & neurosurgery
Abstract

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field. Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) [odds ratio (OR) = 1.09, P = 1.9 × 10(-9)] and rs4309482[A], between coiled-coiled domain containing 68 (CCDC68) and TCF4, about 400 kb from the previously described risk allele, but not accounted for by its association (OR = 1.09, P = 7.8 × 10(-9)). European Union LSHM-CT-2006-037761 PIAP-GA-2008-218251 HEALTH-F2-2009-223423 National Genome Research Network of the German Federal Ministry of Education and Research (BMBF) 01GS08144 01GS08147 National Institute of Mental Health R01 MH078075 N01 MH900001 MH074027 Centre of Excellence for Complex Disease Genetics of the Academy of Finland 213506 129680 Biocentrum Helsinki Foundation Faculty of Medicine, University of Helsinki Stanley Medical Research Institute Danish Council for Strategic Research 2101-07-0059 H. Lundbeck A/S Research Council of Norway 163070/V50 South-East Norway Health Authority 2004-123 Medical Research Council Ministerio de Sanidad y Consumo, Spain PI081522 Xunta de Galicia 08CSA005208PR Swedish Research Council Wellcome Trust 083948/Z/07/Z Max Planck Society Eli Lilly and Company info:eu-repo/grantAgreement/EC/FP7/218251

Published
2011

23. Common variant at 16p11.2 conferring risk of psychosis

Author

Steinberg, S., Jong, S. de, Mattheisen, M., Costas, J., Demontis, D., Jamain, S., Pietilainen, O.P.H., Lin, K., Papiol, S., Huttenlocher, J., Sigurdsson, E., Vassos, E., Giegling, I., Breuer, R., Fraser, G., Walker, N., Melle, I., Djurovic, S., Agartz, I., Tuulio-Henriksson, A., Suvisaari, J., Lonnqvist, J., Paunio, T., Olsen, L., Hansen, T., Ingason, A., Pirinen, M., Strengman, E., Hougaard, D.M., Orntoft, T., Didriksen, M., Hollegaard, M.V., Nordentoft, M., Abramova, L.I., Kaleda, V., Arrojo, M., Sanjuan, J., Arango, C., Etain, B., Bellivier, F., Meary, A., Schurhoff, F., Szoke, A., Ribolsi, M., Magni, V., Siracusano, A., Sperling, S., Rossner, M., Christiansen, C., Kiemeney, B., Franke, B., Berg, L.H. van den, Veldink, J., Curran, S., Bolton, P., Poot, M., Staal, W., Rehnstrom, K., Kilpinen, H., Freitag, C.M., Meyer, J., Magnusson, P., Saemundsen, E., Martsenkovsky, I., Bikshaieva, I., Martsenkovska, I., Vashchenko, O., Raleva, M., Paketchieva, K., Stefanovski, B., Durmishi, N., Milovancevic, M.P., Tosevski, D.L., Silagadze, T., Naneishvili, N., Mikeladze, N., Surguladze, S., Vincent, J.B., Farmer, A., Mitchell, P.B., Wright, A., Schofield, P.R., Fullerton, J.M., Montgomery, G.W., Martin, N.G., Rubino, I.A., Winkel, R. van, Kenis, G., Hert, M. de, Rethelyi, J.M., Bitter, I., Terenius, L., Jonsson, E.G., Bakker, S., Os, J. van, Jablensky, A., Leboyer, M., Bramon, E., et al., Steinberg, S., Jong, S. de, Mattheisen, M., Costas, J., Demontis, D., Jamain, S., Pietilainen, O.P.H., Lin, K., Papiol, S., Huttenlocher, J., Sigurdsson, E., Vassos, E., Giegling, I., Breuer, R., Fraser, G., Walker, N., Melle, I., Djurovic, S., Agartz, I., Tuulio-Henriksson, A., Suvisaari, J., Lonnqvist, J., Paunio, T., Olsen, L., Hansen, T., Ingason, A., Pirinen, M., Strengman, E., Hougaard, D.M., Orntoft, T., Didriksen, M., Hollegaard, M.V., Nordentoft, M., Abramova, L.I., Kaleda, V., Arrojo, M., Sanjuan, J., Arango, C., Etain, B., Bellivier, F., Meary, A., Schurhoff, F., Szoke, A., Ribolsi, M., Magni, V., Siracusano, A., Sperling, S., Rossner, M., Christiansen, C., Kiemeney, B., Franke, B., Berg, L.H. van den, Veldink, J., Curran, S., Bolton, P., Poot, M., Staal, W., Rehnstrom, K., Kilpinen, H., Freitag, C.M., Meyer, J., Magnusson, P., Saemundsen, E., Martsenkovsky, I., Bikshaieva, I., Martsenkovska, I., Vashchenko, O., Raleva, M., Paketchieva, K., Stefanovski, B., Durmishi, N., Milovancevic, M.P., Tosevski, D.L., Silagadze, T., Naneishvili, N., Mikeladze, N., Surguladze, S., Vincent, J.B., Farmer, A., Mitchell, P.B., Wright, A., Schofield, P.R., Fullerton, J.M., Montgomery, G.W., Martin, N.G., Rubino, I.A., Winkel, R. van, Kenis, G., Hert, M. de, Rethelyi, J.M., Bitter, I., Terenius, L., Jonsson, E.G., Bakker, S., Os, J. van, Jablensky, A., Leboyer, M., Bramon, E., and et al.

Abstract

Item does not contain fulltext, Epidemiological and genetic data support the notion that schizophrenia and bipolar disorder share genetic risk factors. In our previous genome-wide association study, meta-analysis and follow-up (totaling as many as 18 206 cases and 42 536 controls), we identified four loci showing genome-wide significant association with schizophrenia. Here we consider a mixed schizophrenia and bipolar disorder (psychosis) phenotype (addition of 7469 bipolar disorder cases, 1535 schizophrenia cases, 333 other psychosis cases, 808 unaffected family members and 46 160 controls). Combined analysis reveals a novel variant at 16p11.2 showing genome-wide significant association (rs4583255[T]; odds ratio=1.08; P=6.6 x 10(-11)). The new variant is located within a 593-kb region that substantially increases risk of psychosis when duplicated. In line with the association of the duplication with reduced body mass index (BMI), rs4583255[T] is also associated with lower BMI (P=0.0039 in the public GIANT consortium data set; P=0.00047 in 22 651 additional Icelanders).

Published
2014

24. Common variants conferring risk of schizophrenia

Author

Stefansson, H., Ophoff, R. A., Steinberg, S., Andreassen, O. A., Chichon, S., Rujescu, D., Werge, T., Pietilainen, O. P., Mors, O., Mortensen, P. B., Sigurdsson, E., Gustafsson, O., Nyegaard, M., Tuulio Henriksson, A., Ingason, A., Hansen, T., Suvisaari, J., Lonnqvist, J., Paunio, T., Borglum, A. D., Hartmann, A., Fink Jensen, A., Nordentoft, M., Hougaard, D., Norgaard Petersen, B., Bottcher, J., Olesen, J., Breuer, R., Moller, H. J., Giegling, I., Rasmussen, H. B., Timm, S., Mattheisen, M., Bitter, I., Rethelyi, J. M., Magnusdottir, B. B., Sigmundsson, T., Olason, P. I., Masson, G., Gulcher, J. R., Haraldsson, M., Fossdal, R., Thorgeirsson, T. E., Thorsteinsdottir, U., Ruggeri, Mirella, Tosato, Sarah, Franke, B., Strengman, E., Kiemeney, L. A., Group, Melle, I., Djurovic, S., Abramova, I., Kaleda, V., Sanjuan, J., de Frutos, R., Bramon, E., Vassos, E., Fraser, G., Ettinger, U., Picchioni, M., Walker, N., Toulopoulou, T., Need, A. C., Ge, D., Lim Yoon, J., Shianna, K. V., Freimer, N. B., Cator, R. M., Murray, R., Kong, A., Golimbet, V., Carracedo, A., Arango, C., Costas, J., Jonsson, E. G., Terenius, L., Agartz, I., Petursson, H., Nothen, M. M., Rietschel, M., Matthews, P. M., Muglia, P., Peltonen, L., St Clair, D., Goldstein, D. B., Collier, D., Genetic, Risk, Outcome in Psychosis, Kahn, R. S., Linszen, D. H., Van Os, J., Wiersma, D., Bruggeman, R., Cahn, H., de Haan, L., Krabbendam, L., Myin Germeys, I., ANS - Amsterdam Neuroscience, Adult Psychiatry, deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland., Clinical Child and Family Studies, LEARN! - Brain, learning and development, and Germeys, Inez

Subjects
Pair 6/genetics, Genetics and epigenetic pathways of disease [NCMLS 6], Genome-wide association study, Aetiology, screening and detection [ONCOL 5], 1Q21.1, Major Histocompatibility Complex/genetics, Major Histocompatibility Complex, Transcription Factor 4, 0302 clinical medicine, Chemicals And Cas Registry Numbers, Perception and Action [DCN 1], Copy-number variation, POPULATION, Genetics, Pair 18/genetics, 0303 health sciences, education.field_of_study, Genome, Human/genetics, Multidisciplinary, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Schizophrenia/*genetics/immunology, Genetic Predisposition to Disease/*genetics, 3. Good health, DNA-Binding Proteins, Neurogranin/genetics, DISEASES, Chromosomes, Human, Pair 6, Single Nucleotide/*genetics, Functional Neurogenomics [DCN 2], Zinc finger protein 804A, Human, Genetic Markers, Psychosis, Genotype, Population, Transcription Factors/genetics, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Chromosomes, Pair 11/genetics, Article, DNA-Binding Proteins/genetics, Genetic Markers/genetics, Genome-Wide Association Study, Humans, Polymorphism, Genomic disorders and inherited multi-system disorders [IGMD 3], Molecular epidemiology [NCEBP 1], 03 medical and health sciences, Translational research [ONCOL 3], medicine, SNP, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, education, 030304 developmental biology, Genetic association, Hereditary cancer and cancer-related syndromes [ONCOL 1], Genome, Human, Chromosomes, Human, Pair 11, MEMORY, medicine.disease, GENE, NEUROGRANIN, DELETIONS, Schizophrenia, biology.protein, Neurogranin, Chromosomes, Human, Pair 18, MENTAL-RETARDATION, SCAN, 030217 neurology & neurosurgery, Transcription Factors
Abstract

Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the ĝ€ genomic disordersĝ€™, have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition. © 2009 Macmillan Publishers Limited., link_to_OA_fulltext

Published
2009

25. Expanding the range of ZNF804A variants conferring risk of psychosis

Author

Steinberg, S., Mors, O., Borglum, A.D., Gustafsson, O., Werge, T., Mortensen, P.B., Andreassen, O.A., Sigurdsson, E., Thorgeirsson, T.E., Bottcher, Y., Olason, P., Ophoff, R.A., Cichon, S., Gudjonsdottir, I.H., Pietilainen, O.P.H., Nyegaard, M., Tuulio-Henriksson, A., Ingason, A., Hansen, T., Athanasiu, L., Suvisaari, J., Lonnqvist, J., Paunio, T., Hartmann, A., Jurgens, G., Nordentoft, M., Hougaard, D., Norgaard-Pedersen, B., Breuer, R., Moller, H.J., Giegling, I., Glenthoj, B., Rasmussen, H.B., Mattheisen, M., Bitter, I., Rethelyi, J.M., Sigmundsson, T., Fossdal, R., Thorsteinsdottir, U., Ruggeri, M., Tosato, S., Strengman, E., Kiemeney, L.A.L.M., Melle, I., Djurovic, S., Abramova, L.I., Kaleda, V., Walshe, M., Bramon, E., Vassos, E., Li, T., Fraser, G., Walker, N., Toulopoulou, T., Yoon, J., Freimer, N.B., Cantor, R.M., Murray, R., Kong, A., Golimbet, V., Jonsson, E.G., Terenius, L., Agartz, I., Petursson, H., Nothen, Markus, Rietschel, M., Peltonen, L., Rujescu, D., Collier, D.A., Stefansson, H., St Clair, D., Stefansson, K., Steinberg, S., Mors, O., Borglum, A.D., Gustafsson, O., Werge, T., Mortensen, P.B., Andreassen, O.A., Sigurdsson, E., Thorgeirsson, T.E., Bottcher, Y., Olason, P., Ophoff, R.A., Cichon, S., Gudjonsdottir, I.H., Pietilainen, O.P.H., Nyegaard, M., Tuulio-Henriksson, A., Ingason, A., Hansen, T., Athanasiu, L., Suvisaari, J., Lonnqvist, J., Paunio, T., Hartmann, A., Jurgens, G., Nordentoft, M., Hougaard, D., Norgaard-Pedersen, B., Breuer, R., Moller, H.J., Giegling, I., Glenthoj, B., Rasmussen, H.B., Mattheisen, M., Bitter, I., Rethelyi, J.M., Sigmundsson, T., Fossdal, R., Thorsteinsdottir, U., Ruggeri, M., Tosato, S., Strengman, E., Kiemeney, L.A.L.M., Melle, I., Djurovic, S., Abramova, L.I., Kaleda, V., Walshe, M., Bramon, E., Vassos, E., Li, T., Fraser, G., Walker, N., Toulopoulou, T., Yoon, J., Freimer, N.B., Cantor, R.M., Murray, R., Kong, A., Golimbet, V., Jonsson, E.G., Terenius, L., Agartz, I., Petursson, H., Nothen, Markus, Rietschel, M., Peltonen, L., Rujescu, D., Collier, D.A., Stefansson, H., St Clair, D., and Stefansson, K.

Abstract

Contains fulltext : 95884.pdf (publisher's version ) (Closed access), A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 x 10(-8)) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 x 10(-7), and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0 x 10(-8). In this study, using 5164 schizophrenia cases and 20,709 controls, we replicated the association with schizophrenia (odds ratio OR = 1.08, P = 0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N = 609, OR = 1.09, P = 0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]-common and with low relative risk-may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39,481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P = 0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P = 0.0016 for association with the larger set of psychiatric disorders).

Published
2011

26. Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and age of onset in schizophrenia: a combined analysis of independent samples

Author

Saetre, P., Vares, M., Werge, T., Andreassen, O.A., Arinami, T., Ishiguro, H., Nanko, S., Tan, E., Han, D.H., Roffman, J.L., Muntjewerff, J.W., Jagodzinski, P.P., Kempisty, B., Hauser, J., Vilella, E., Betcheva, E., Nakamura, Y., Regland, B., Agartz, I., Hall, H., Terenius, L., Jonsson, E.G., Saetre, P., Vares, M., Werge, T., Andreassen, O.A., Arinami, T., Ishiguro, H., Nanko, S., Tan, E., Han, D.H., Roffman, J.L., Muntjewerff, J.W., Jagodzinski, P.P., Kempisty, B., Hauser, J., Vilella, E., Betcheva, E., Nakamura, Y., Regland, B., Agartz, I., Hall, H., Terenius, L., and Jonsson, E.G.

Abstract

Item does not contain fulltext, Methylenetetrahydrofolate reductase (MTHFR) is involved in the one-carbon cycle, which is of importance for nucleotide synthesis and methylation of DNA, membranes, proteins and lipids. The MTHFR gene includes two common polymorphisms (rs1801133 or C677T; rs1801131 or A1298C) which both alter enzyme activity. The T-allele of the C677T polymorphism has recently been associated with earlier age at onset of schizophrenia. In the present study we examined the association between the MTHFR C677T and A1298C polymorphisms and age at onset of schizophrenia in twelve samples consisting of 3,213 unrelated schizophrenia patients, including the original Scandinavian sample. There was no consistent relationship between MTHFR C677T, A1298C or combined 677T/1298C carriers and age of onset in schizophrenia when the results of each study were combined using meta-analysis. The present results suggest that the investigated MTHFR polymorphisms do not influence age of onset in schizophrenia.

Published
2011

27. Two methylenetetrahydrofolate reductase gene (MTHFR) polymorphisms, schizophrenia and bipolar disorder: An association study

Author

Jonsson, E.G., Larsson, K., Vares, M., Hansen, T., Djurovic, S., Ronningen, K.S., Andreassen, O.A., Agartz, I., Werge, T., Terenius, L., Hall, H., Wang, August Gabriel, Jonsson, E.G., Larsson, K., Vares, M., Hansen, T., Djurovic, S., Ronningen, K.S., Andreassen, O.A., Agartz, I., Werge, T., Terenius, L., Hall, H., and Wang, August Gabriel

Abstract

Udgivelsesdato: 2008

Published
2008

28. Dysregulation of dynorphins in Alzheimer disease

Author

Yakovleva, Tatjana, Marinova, Z., Kuzmin, A., Seidah, N. G., Haroutunian, V., Terenius, L., Bakalkin, G., Yakovleva, Tatjana, Marinova, Z., Kuzmin, A., Seidah, N. G., Haroutunian, V., Terenius, L., and Bakalkin, G.

Abstract

The opioid peptides dynorphins may be involved in pathogenesis of Alzheimer disease (AD) by inducing neurodegeneration or cognitive impairment. To test this hypothesis, the dynorphin system was analyzed in postmortem samples from AD and control subjects, and subjects with Parkinson or cerebro-vascular diseases for comparison. Dynorphin A, dynorphin B and related neuropeptide nociceptin were determined in the Brodmann area 7 by radioimmunoassay. The precursor protein prodynorphin, processing convertase PC2 and the neuroendocrine pro7B2 and 7B2 proteins required for PC2 maturation were analyzed by Western blot. AD subjects displayed robustly elevated levels of dynorphin A and no differences in dynorphin B and nociceptin compared to controls. Subjects with Parkinson or cerebro-vascular diseases did not differ from controls with respect to any of the three peptides. PC2 levels were also increased, whereas, those of prodynorphin and pro7B2/7B2 were not changed in AD. Dynorphin A levels correlated with the neuritic plaque density. These results along with the known non-opioid ability of dynorphin A to induce neurodegeneration suggest a role for this neuropeptide in AD neuropathology.

Published
2007
Full Text
View/download PDF

29. Translocation of dynorphin neuropeptides across the plasma membrane : A putative mechanism of signal transmission.

Author

Marinova, Z, Vukojevic, V, Surcheva, S, Yakovleva, T, Cebers, G, Pasikova, N, Usynin, I, Hugonin, L, Fang, W, Hallberg, M, Hirschberg, D, Bergman, T, Langel, U, Hauser, KF, Pramanik, A, Aldrich, JV, Graslund, A, Terenius, L, Bakalkin, G, Marinova, Z, Vukojevic, V, Surcheva, S, Yakovleva, T, Cebers, G, Pasikova, N, Usynin, I, Hugonin, L, Fang, W, Hallberg, M, Hirschberg, D, Bergman, T, Langel, U, Hauser, KF, Pramanik, A, Aldrich, JV, Graslund, A, Terenius, L, and Bakalkin, G

Published
2005

30. Dopamine D2 receptor gene Ser311Cys variant and schizophrenia: Association study and meta-analysis

Author

Jönsson, E G, Sillén, A, Vares, M, Ekholm, B, Terenius, L, Sedvall, G C, Jönsson, E G, Sillén, A, Vares, M, Ekholm, B, Terenius, L, and Sedvall, G C

Abstract

An association has been reported between a dopamine D(2) receptor gene (DRD2) Ser311Cys variant and schizophrenia. In a replication attempt, Swedish patients with schizophrenia (n = 173) and control subjects (n = 236) were assessed for the DRD2 Ser311Cys variant. Schizophrenic patients displayed higher Cys311 allele frequencies than control subjects (4.0 vs. 0.8%, chi(2) = 9.49, df = 1, P = 0.002; odds ratio (OR) 4.93, 95% confidence interval (95% CI) 1.61-15.12). The association was detected only in men. The results were supported by a meta-analysis of all published case-control studies comprising a total of 9,152 subjects (chi(2) = 11.37, df = 1, P < 0.001; OR 1.43, 95% CI 1.16-1.78). The present results support the involvement of the DRD2 gene in the pathogenesis of schizophrenia. Copyright 2003 Wiley-Liss, Inc.

Published
2003
Full Text
View/download PDF

31. A systematic genomewide linkage study in 353 sib pairs with schizophrenia.

Author

Williams, N M, Norton, N, Williams, H, Ekholm, B, Hamshere, M L, Lindblom, Y, Chowdari, K V, Cardno, A G, Zammit, S, Jones, L A, Murphy, K C, Sanders, R D, McCarthy, G, Gray, M Y, Jones, G, Holmans, P, Nimgaonkar, V, Adolfson, R, Osby, U, Terenius, L, Sedvall, G, O'Donovan, M C, Owen, M J, Williams, N M, Norton, N, Williams, H, Ekholm, B, Hamshere, M L, Lindblom, Y, Chowdari, K V, Cardno, A G, Zammit, S, Jones, L A, Murphy, K C, Sanders, R D, McCarthy, G, Gray, M Y, Jones, G, Holmans, P, Nimgaonkar, V, Adolfson, R, Osby, U, Terenius, L, Sedvall, G, O'Donovan, M C, and Owen, M J

Abstract

We undertook a genomewide linkage study in a total of 353 affected sib pairs (ASPs) with schizophrenia. Our sample consisted of 179 ASPs from the United Kingdom, 134 from Sweden, and 40 from the United States. We typed 372 microsatellite markers at approximately 10-cM intervals. Our strongest finding was a LOD score of 3.87 on chromosome 10q25.3-q26.3, with positive results being contributed by all three samples and a LOD-1 interval of 15 cM. This finding achieved genomewide significance (P<.05), on the basis of simulation studies. We also found two regions, 17p11.2-q25.1 (maximum LOD score [MLS] = 3.35) and 22q11 (MLS = 2.29), in which the evidence for linkage was highly suggestive. Linkage to all of these regions has been supported by other studies. Moreover, we found strong evidence for linkage (genomewide P<.02) to 17p11.2-q25.1 in a single pedigree with schizophrenia. In our view, the evidence is now sufficiently compelling to undertake detailed mapping studies of these three regions.

Published
2003
Full Text
View/download PDF

35. Amyloid beta-peptide polymerization studied using fluorescence correlation spectroscopy

Author

Tjernberg, L O, Pramanik, A, Björling, S, Thyberg, P, Thyberg, J, Nordstedt, C, Berndt, Kurt D, Terenius, L, Rigler, R, Tjernberg, L O, Pramanik, A, Björling, S, Thyberg, P, Thyberg, J, Nordstedt, C, Berndt, Kurt D, Terenius, L, and Rigler, R

Abstract

Background: The accumulation of fibrillar deposits of amyloid beta-peptide (A beta) in brain parenchyma and cerebromeningeal blood vessels is a key step in the pathogenesis of Alzheimer's disease. In this report, polymerization of A beta was studied using fluorescence correlation spectroscopy (FCS), a technique capable of detecting small molecules and large aggregates simultaneously in solution. Results: The polymerization of A beta dissolved in Tris-buffered saline, pH 7.4, occurred above a critical concentration of 50 mu M and proceeded from monomers/dimers into two discrete populations of large aggregates, without any detectable amount of oligomers. The aggregation showed very high cooperativity and reached a maximum after 40 min, followed by an increase in the amount of monomers/dimers and a decrease in the size of the large aggregates. Electron micrographs of samples prepared at the time for maximum aggregation showed a mixture of an amorphous network and short diffuse fibrils, whereas only mature amyloid fibrils were detected after one day of incubation. The aggregation was reduced when A beta was incubated in the presence of A beta ligands, oligopeptides previously shown to inhibit fibril formation, and aggregates were partly dissociated after the addition of the ligands. Conclusions: The polymerization of A beta is a highly cooperative process in which the formation of very large aggregates precedes the formation of fibrils. The entire process can be inhibited and, at least in early stages, partly reversed by A beta ligands., Times Cited: 30 Article English Cited References Count: 58 235wa

Published
1999
Full Text
View/download PDF

36. Intrathecal administration of p-hydroxymercuribenzoate or phosphoramidon/bestatin-combined induces antinociceptive effects through different opioid mechanisms

Author

Tan No, K, Taira, A, Inoue, M, Ohshima, K, Sakurada, T, Sakurada, C, Nylander, Ingrid, Demuth, H-U, Silberring, J, Terenius, L, Tadano, T, Kisara, K, Tan No, K, Taira, A, Inoue, M, Ohshima, K, Sakurada, T, Sakurada, C, Nylander, Ingrid, Demuth, H-U, Silberring, J, Terenius, L, Tadano, T, and Kisara, K

Abstract

The antinociceptive effect of intrathecally (i.t.) administered protease inhibitors was tested against capsaicin (800 ng) injected into the dorsal surface of a hindpaw. Both p-hydroxymercuribenzoate (2-8 nmol), a cysteine protease inhibitor, and phosphoramidon (1-4 nmol), an endopeptidase 24.11 inhibitor in the presence of bestatin (0.25 nmol) an aminopeptidase inhibitor, administered i.t. 60 min prior to the injection of capsaicin produced a dose-dependent reduction of the capsaicin-induced paw licking and biting response. p-Hydroxymercuribenzoate (4 nmol)-induced antinociception was significantly antagonized by nor-binaltorphimine, a selective kappa-opioid receptor antagonist, but not by naltrindole, a selective delta-opioid receptor antagonist. On the other hand, phosphoramidon (4 nmol) /bestatin-induced antinociception was significantly antagonized by naltrindole, but not by nor-binaltorphimine. The results indicate that the antinociceptive effect of p-hydroxymercuribenzoate may be due to the inhibition of a cysteine protease degrading endogenous dynorphins whereas phosphoramidon in the presence of bestatin blocks the degradation of enkephalins.

Published
1998
Full Text
View/download PDF

37. Hippocampal dynorphin B injections impair spatial learning in rats : a kappa-opioid receptor-mediated effect

Author

Sandin, J, Nylander, Ingrid, Georgieva, J, Schött, P A, Ögren, O, Terenius, L, Sandin, J, Nylander, Ingrid, Georgieva, J, Schött, P A, Ögren, O, and Terenius, L

Abstract

The hippocampus plays a central role in the acquisition and storage of information. Long-term potentiation in the mossy fibre pathway to the CA3 region in the hippocampus, an animal model of memory acquisition, is modulated by dynorphin peptides. This study investigated the possible role of hippocampal dynorphin in spatial learning. Male rats were trained in the Morris Water Task after microinjection with different doses of dynorphin B (1, 3.3 or 10 nmol/rat) or artificial cerebrospinal fluid (as control) into the CA3 region of the dorsal hippocampus. Dynorphin B was found to impair spatial learning at all tested doses. The synthetic kappa1-selective opiate receptor antagonist nor-binaltorphimine (2 nmol) also given into the hippocampus fully blocked the acquisition impairment caused by dynorphin B (10 nmol), while nor-binaltorphimine alone did not affect learning performance. These findings suggest that dynorphin peptides could play a modulatory role in hippocampal plasticity by acting on hippocampal kappa-receptors and thereby impair spatial learning.

Published
1998
Full Text
View/download PDF

38. A comparison of microwave irradiation and decapitation. Basal levels of dynorphin and enkephalin peptides and the effect of morphine treatment on dynorphin peptides

Author

Nylander, Ingrid, Stenfors, C, Tan No, K, Mathe, A A, Terenius, L, Nylander, Ingrid, Stenfors, C, Tan No, K, Mathe, A A, and Terenius, L

Abstract

Opioid peptides were analysed in tissue extracts of various brain structures and the pituitary gland from rats sacrificed by microwave irradiation, and compared with peptide levels in tissue extracts from decapitated rats. Dynorphin A, dynorphin B and Leu-enkephalinArg6, derived from prodynorphin, and Met-enkephalinArg6Phe7 from proenkephalin, were measured. Basal immunoreactive levels of dynorphin A and B were consistently higher in extracts from microwave-irradiated rats, whereas in these extracts immunoreactive levels of Leu-enkephalinArg6, an endogenous metabolite of dynorphin peptides, were either lower than, the same as or higher than in decapitated rats. Immunoreactive levels of Met-enkephalinArg6Phe7 were higher in microwave-irradiated rats. Effects of morphine treatment on prodynorphin peptide levels were evaluated and compared with previous findings in decapitated rats. Dynorphin immunoreactive levels were higher in the nucleus accumbens and striatum of morphine-tolerant rats than in corresponding areas in saline-treated rats. These results indicate tissue-specific metabolism of prodynorphin peptides and show that metabolism of opioid peptides occurs during the dissection procedure after decapitation of the rat even though precautions are taken to minimize degradation.

Published
1997
Full Text
View/download PDF

39. Modulation of neurotransmitter release by cholecystokinin in neostriatum and substantia nigra of the rat : regional and receptor specificity

Author

You, Z-B, Herrera-Marschitz, M, Pettersson, E, Nylander, Ingrid, Goiny, M, Shou, H.-Z, Kehr, J, Godukhin, O, Hokfelt, T, Terenius, L, Ungerstedt, U, You, Z-B, Herrera-Marschitz, M, Pettersson, E, Nylander, Ingrid, Goiny, M, Shou, H.-Z, Kehr, J, Godukhin, O, Hokfelt, T, Terenius, L, and Ungerstedt, U

Abstract

The effect of cholecystokinin peptides on the release of dynorphin B, aspartate, glutamate, dopamine and GABA in the neostriatum and substantia nigra of the rat was investigated using in vivo microdialysis. Sulphated cholecystokinin-8S in the dialysis perfusate (1-100 microM) induced a concentration-dependent increase in extracellular dynorphin B and aspartate levels, both in the neostriatum and substantia nigra. Striatal dopamine levels were only increased by 100 microM of cholecystokinin-8S, while in the substantia nigra they were increased by 10-100 microM of cholecystokinin-8S. Extracellular GABA and glutamate levels were increased following 100 microM of cholecystokinin-8S only. Striatal cholecystokinin-8S administration also produced a significant increase in nigral dynorphin B levels. Local cholecystokinin-4 (100 microM) produced a moderate, but significant, increase of extracellular dynorphin B and aspartate levels in the neostriatum and substantia nigra. No effect was observed on the other neurotransmitters investigated. A 6-hydroxydopamine lesion of the nigrostriatal dopamine pathway did not affect the increases in dynorphin B and aspartate levels produced by local administration of cholecystokinin-8S. Basal extracellular GABA levels were increased significantly in both the neostriatum and substantia nigra ipsilateral to the lesion. Nigral glutamate and aspartate levels were also increased in the lesioned substantia nigra, but in the lesioned neostriatum aspartate levels were decreased. The cholecystokinin-B antagonist L-365,260 (20 mg/kg, s.c.), but not the cholecystokinin-A antagonist L-364,718 (devazepide; 20 mg/kg, s.c.), significantly inhibited the effect of cholecystokinin-8S on striatal dynorphin B and aspartate levels. In the substantia nigra, however, the effect of cholecystokinin-8S on dynorphin B and aspartate levels was inhibited to a similar extent by both L-365,260 and L-364,718. Pretreatment with L-364,718, but not with L-365.260, prevented

Published
1996
Full Text
View/download PDF

40. On the origin of extracellular glutamate levels monitored in the basal ganglia of the rat by in vivo microdialysis

Author

Herrera-Marschitz, M, You, Z-B, Goiny, M, Meana, J J, Silveira, R, Godukhin, O V, Chen, Y, Espinoza, S, Pettersson, E, Loidl, C F, Lubec, G, Andersson, K, Nylander, Ingrid, Terenius, L, Ungerstedt, U, Herrera-Marschitz, M, You, Z-B, Goiny, M, Meana, J J, Silveira, R, Godukhin, O V, Chen, Y, Espinoza, S, Pettersson, E, Loidl, C F, Lubec, G, Andersson, K, Nylander, Ingrid, Terenius, L, and Ungerstedt, U

Abstract

Several putative neurotransmitters and metabolites were monitored simultaneously in the extracellular space of neostriatum, substantia nigra, and cortex and in subcutaneous tissue of the rat by in vivo microdialysis. Glutamate (Glu) and aspartate (Asp) were at submicromolar and gamma-aminobutyric acid (GABA) was at nanomolar concentrations in all brain regions. The highest concentration of dopamine (DA) was in the neostriatum. Dynorphin B (Dyn B) was in the picomolar range in all brain regions. Although no GABA, DA, or Dyn B could be detected in subcutaneous tissue, Glu and Asp levels were 5 and approximately 5 and approximately 0.4 microM, respectively. Lactate and pyruvate concentrations were approximately 200 and approximately 10 microM in all regions. The following criteria were applied to ascertain the neuronal origin of substances quantified by microdialysis: sensitivity to (a) K+ depolarization, (b) Na+ channel blockade, (c) removal of extracellular Ca2+, and (d) depletion of presynaptic vesicles by local administration of alpha-latrotoxin. DA, Dyn B, and GABA largely satisfied all these criteria. In contrast, Glu and Asp levels were not greatly affected by K+ depolarization and were increased by perfusing with tetrodotoxin or with Ca2+-free medium, arguing against a neuronal origin. However, Glu and Asp, as well as DA and GABA, levels were decreased under both basal and K+-depolarizing conditions by alpha-latrotoxin. Because the effect of K+ depolarization on Glu and Asp could be masked by reuptake into nerve terminals and glial cells, the reuptake blocker dihydrokainic acid (DHKA) or L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) was included in the microdialysis perfusion medium. The effect of K+ depolarization on Glu and Asp levels was increased by DHKA, but GABA levels were also affected. In contrast, PDC increased only Glu levels. It is concluded that there is pool of releasable Glu and Asp in the rat brain. However, extracellular levels of amino acids

Published
1996
Full Text
View/download PDF

41. Dopamine-related genes and their relationships to monoamine metabolites in CSF

Author

Jonsson, E, Sedvall, G, Brene, S, Gustavsson, P, Geijer, T, Terenius, L, Crocq, M-A, Lannfelt, L, Tylec, A, Sokoloff, P, Schwartz, J.C., Wiesel, F-A, Jonsson, E, Sedvall, G, Brene, S, Gustavsson, P, Geijer, T, Terenius, L, Crocq, M-A, Lannfelt, L, Tylec, A, Sokoloff, P, Schwartz, J.C., and Wiesel, F-A

Published
1996

48. A molecular model of Alzheimer amyloid beta-peptide fibril formation.

Author

Tjernberg, L O, Callaway, D J, Tjernberg, A, Hahne, S, Lilliehöök, C, Terenius, L, Thyberg, J, and Nordstedt, C

Abstract

Polymerization of the amyloid beta (Abeta) peptide into protease-resistant fibrils is a significant step in the pathogenesis of Alzheimer's disease. It has not been possible to obtain detailed structural information about this process with conventional techniques because the peptide has limited solubility and does not form crystals. In this work, we present experimental results leading to a molecular level model for fibril formation. Systematically selected Abeta-fragments containing the Abeta16-20 sequence, previously shown essential for Abeta-Abeta binding, were incubated in a physiological buffer. Electron microscopy revealed that the shortest fibril-forming sequence was Abeta14-23. Substitutions in this decapeptide impaired fibril formation and deletion of the decapeptide from Abeta1-42 inhibited fibril formation completely. All studied peptides that formed fibrils also formed stable dimers and/or tetramers. Molecular modeling of Abeta14-23 oligomers in an antiparallel beta-sheet conformation displayed favorable hydrophobic interactions stabilized by salt bridges between all charged residues. We propose that this decapeptide sequence forms the core of Abeta-fibrils, with the hydrophobic C terminus folding over this core. The identification of this fundamental sequence and the implied molecular model could facilitate the design of potential inhibitors of amyloidogenesis.

Published
1999

50. Coexistence and gene expression of phenylethanolamine N-methyltransferase, tyrosine hydroxylase, and neuropeptide tyrosine in the rat and bovine adrenal gland: effects of reserpine.

Author

Schalling, M, Dagerlind, A, Brené, S, Hallman, H, Djurfeldt, M, Persson, H, Terenius, L, Goldstein, M, Schlesinger, D, and Hökfelt, T

Abstract

Expression and regulation of the catecholamine-synthesizing enzymes phenylethanolamine N-methyltransferase (PNMTase; S-adenosyl-L-methionine:phenylethanolamine N-methyltransferase, EC 2.1.1.28) and tyrosine hydroxylase [TyrOHase; tyrosine 3-monooxygenase, L-tyrosine, tetrahydropteridine:oxygen oxidoreductase (3-hydroxylating), EC 1.14.16.2] and the coexisting neuropeptide tyrosine (NPY) were studied in rat and bovine adrenal medulla. By using both immunohistochemistry and in situ hybridization, PNMTase- and NPY-positive cells exhibited a close overlap in bovine medulla and were preferentially localized in the outer two-thirds of the medulla. Although TyrOHase and its mRNA were observed in virtually all medullary gland cells, TyrOHase mRNA levels were much higher in the PNMTase- and NPY-positive cells. After administration of the catecholamine-depleting drug reserpine to rats, a brief increase, followed by a dramatic decrease, in the level of PNMTase mRNA was observed in the adrenal medulla. In contrast, mRNA for both TyrOHase and NPY only exhibited an increase, whereby the TyrOHase mRNA peak preceded that of NPY mRNA. Different regulatory mechanisms may thus operate for these three compounds coexisting in the adrenal medulla.

Published
1988
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results