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1. Analysis of exome sequence in 604 trios for recessive genotypes in schizophrenia.

Author

Rees, E, Kirov, G, Walters, JT, Richards, AL, Howrigan, D, Kavanagh, DH, Pocklington, AJ, Fromer, M, Ruderfer, DM, Georgieva, L, Carrera, N, Gormley, P, Palta, P, Williams, H, Dwyer, S, Johnson, JS, Roussos, P, Barker, DD, Banks, E, Milanova, V, Rose, SA, Chambert, K, Mahajan, M, Scolnick, EM, Moran, JL, Tsuang, MT, Glatt, SJ, Chen, WJ, Hwu, H-G, Taiwanese Trios Exome Sequencing Consortium, Neale, BM, Palotie, A, Sklar, P, Purcell, SM, McCarroll, SA, Holmans, P, Owen, MJ, and O'Donovan, MC

Subjects
Taiwanese Trios Exome Sequencing Consortium, Humans, Genetic Predisposition to Disease, Case-Control Studies, Family, Schizophrenia, Gene Frequency, Genotype, Heterozygote, Homozygote, Genes, Recessive, Female, Male, Exome, Voltage-Gated Sodium Channels, Genes, Recessive, Clinical Sciences, Public Health and Health Services, Psychology
Abstract

Genetic associations involving both rare and common alleles have been reported for schizophrenia but there have been no systematic scans for rare recessive genotypes using fully phased trio data. Here, we use exome sequencing in 604 schizophrenia proband-parent trios to investigate the role of recessive (homozygous or compound heterozygous) nonsynonymous genotypes in the disorder. The burden of recessive genotypes was not significantly increased in probands at either a genome-wide level or in any individual gene after adjustment for multiple testing. At a system level, probands had an excess of nonsynonymous compound heterozygous genotypes (minor allele frequency, MAF ⩽ 1%) in voltage-gated sodium channels (VGSCs; eight in probands and none in parents, P = 1.5 × 10(-)(4)). Previous findings of multiple de novo loss-of-function mutations in this gene family, particularly SCN2A, in autism and intellectual disability provide biological and genetic plausibility for this finding. Pointing further to the involvement of VGSCs in schizophrenia, we found that these genes were enriched for nonsynonymous mutations (MAF ⩽ 0.1%) in cases genotyped using an exome array, (5585 schizophrenia cases and 8103 controls), and that in the trios data, synaptic proteins interacting with VGSCs were also enriched for both compound heterozygosity (P = 0.018) and de novo mutations (P = 0.04). However, we were unable to replicate the specific association with compound heterozygosity at VGSCs in an independent sample of Taiwanese schizophrenia trios (N = 614). We conclude that recessive genotypes do not appear to make a substantial contribution to schizophrenia at a genome-wide level. Although multiple lines of evidence, including several from this study, suggest that rare mutations in VGSCs contribute to the disorder, in the absence of replication of the original findings regarding compound heterozygosity, this conclusion requires evaluation in a larger sample of trios.

Published
2015

3. A splicing-regulatory polymorphism in DRD2 disrupts ZRANB2 binding, impairs cognitive functioning and increases risk for schizophrenia in six Han Chinese samples

Author

Cohen, O S, Weickert, T W, Hess, J L, Paish, L M, McCoy, S Y, Rothmond, D A, Galletly, C, Liu, D, Weinberg, D D, Huang, X-F, Xu, Q, Shen, Y, Zhang, D, Yue, W, Yan, J, Wang, L, Lu, T, He, L, Shi, Y, Xu, M, Che, R, Tang, W, Chen, C-H, Chang, W-H, Hwu, H-G, Liu, C-M, Liu, Y-L, Wen, C-C, Fann, C S-J, Chang, C-C, Kanazawa, T, Middleton, F A, Duncan, T M, Faraone, S V, Weickert, C S, Tsuang, M T, and Glatt, S J

Published
2016
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4. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Author

Mullins, N, Kang, J, Campos, A, Coleman, JR, Edwards, AC, Galfalvy, H, Levey, DF, Lori, A, Shabalin, A, Starnawska, A, Su, M-H, Watson, HJ, Adams, M, Awasthi, S, Ganda, M, Hafferty, JD, Hishimoto, A, Kim, M, Okazaki, S, Otsuka, I, Ripke, S, Ware, EB, Bergen, AW, Berrettini, WH, Bohus, M, Brandt, H, Chang, X, Chen, WJ, Chen, H-C, Crawford, S, Crow, S, DiBlasi, E, Duriez, P, Fernandez-Aranda, F, Fichter, MM, Gallinger, S, Glatt, SJ, Gorwood, P, Guo, Y, Hakonarson, H, Halmi, KA, Hwu, H-G, Jain, S, Jamain, S, Jimenez-Murcia, S, Johnson, C, Kaplan, AS, Kaye, WH, Keel, PK, Kennedy, JL, Klump, KL, Li, D, Liao, S-C, Lieb, K, Lilenfeld, L, Liu, C-M, Magistretti, PJ, Marshall, CR, Mitchell, JE, Monson, ET, Myers, RM, Pinto, D, Powers, A, Ramoz, N, Roepke, S, Rozanov, V, Scherer, SW, Schmahl, C, Sokolowski, M, Strober, M, Thornton, LM, Treasure, J, Tsuang, MT, Witt, SH, Woodside, DB, Yilmaz, Z, Zillich, L, Adolfsson, R, Agartz, I, Air, TM, Alda, M, Alfredsson, L, Andreassen, OA, Anjorin, A, Appadurai, V, Artigas, MS, Van der Auwera, S, Azevedo, MH, Bass, N, Bau, CHD, Baune, BT, Bellivier, F, Berger, K, Biernacka, JM, Bigdeli, TB, Binder, EB, Boehnke, M, Boks, MP, Bosch, R, Braff, DL, Bryant, R, Budde, M, Byrne, EM, Cahn, W, Casas, M, Castelao, E, Cervilla, JA, Chaumette, B, Cichon, S, Corvin, A, Craddock, N, Craig, D, Degenhardt, F, Djurovic, S, Edenberg, HJ, Fanous, AH, Foo, JC, Forstner, AJ, Frye, M, Fullerton, JM, Gatt, JM, Gejman, P, Giegling, I, Grabe, HJ, Green, MJ, Grevet, EH, Grigoroiu-Serbanescu, M, Gutierrez, B, Guzman-Parra, J, Hamilton, SP, Hamshere, ML, Hartmann, A, Hauser, J, Heilmann-Heimbach, S, Hoffmann, P, Ising, M, Jones, I, Jones, LA, Jonsson, L, Kahn, RS, Kelsoe, JR, Kendler, KS, Kloiber, S, Koenen, KC, Kogevinas, M, Konte, B, Krebs, M-O, Lander, M, Lawrence, J, Leboyer, M, Lee, PH, Levinson, DF, Liao, C, Lissowska, J, Lucae, S, Mayoral, F, McElroy, SL, McGrath, P, McGuffin, P, McQuillin, A, Medland, SE, Mehta, D, Melle, I, Milaneschi, Y, Mitchell, PB, Molina, E, Morken, G, Mortensen, PB, Mueller-Myhsok, B, Nievergelt, C, Nimgaonkar, V, Noethen, MM, O'Donovan, MC, Ophoff, RA, Owen, MJ, Pato, C, Pato, MT, Penninx, BWJH, Pimm, J, Pistis, G, Potash, JB, Power, RA, Preisig, M, Quested, D, Ramos-Quiroga, JA, Reif, A, Ribases, M, Richarte, V, Rietschel, M, Rivera, M, Roberts, A, Roberts, G, Rouleau, GA, Rovaris, DL, Rujescu, D, Sanchez-Mora, C, Sanders, AR, Schofield, PR, Schulze, TG, Scott, LJ, Serretti, A, Shi, J, Shyn, S, Sirignano, L, Sklar, P, Smeland, OB, Smoller, JW, Sonuga-Barke, EJS, Spalletta, G, Strauss, JS, Swiatkowska, B, Trzaskowski, M, Turecki, G, Vilar-Ribo, L, Vincent, JB, Voelzke, H, Walters, JTR, Weickert, CS, Weickert, TW, Weissman, MM, Williams, LM, Wray, NR, Zai, CC, Ashley-Koch, AE, Beckham, JC, Hauser, ER, Hauser, MA, Kimbrel, NA, Lindquist, JH, McMahon, B, Oslin, DW, Qin, X, Agerbo, E, Borglum, AD, Breen, G, Erlangsen, A, Esko, T, Gelernter, J, Hougaard, DM, Kessler, RC, Kranzler, HR, Li, QS, Martin, NG, McIntosh, AM, Mors, O, Nordentoft, M, Olsen, CM, Porteous, D, Ursano, RJ, Wasserman, D, Werge, T, Whiteman, DC, Bulik, CM, Coon, H, Demontis, D, Docherty, AR, Kuo, P-H, Lewis, CM, Mann, JJ, Renteria, ME, Smith, DJ, Stahl, EA, Stein, MB, Streit, F, Willour, V, Ruderfer, DM, Mullins, N, Kang, J, Campos, A, Coleman, JR, Edwards, AC, Galfalvy, H, Levey, DF, Lori, A, Shabalin, A, Starnawska, A, Su, M-H, Watson, HJ, Adams, M, Awasthi, S, Ganda, M, Hafferty, JD, Hishimoto, A, Kim, M, Okazaki, S, Otsuka, I, Ripke, S, Ware, EB, Bergen, AW, Berrettini, WH, Bohus, M, Brandt, H, Chang, X, Chen, WJ, Chen, H-C, Crawford, S, Crow, S, DiBlasi, E, Duriez, P, Fernandez-Aranda, F, Fichter, MM, Gallinger, S, Glatt, SJ, Gorwood, P, Guo, Y, Hakonarson, H, Halmi, KA, Hwu, H-G, Jain, S, Jamain, S, Jimenez-Murcia, S, Johnson, C, Kaplan, AS, Kaye, WH, Keel, PK, Kennedy, JL, Klump, KL, Li, D, Liao, S-C, Lieb, K, Lilenfeld, L, Liu, C-M, Magistretti, PJ, Marshall, CR, Mitchell, JE, Monson, ET, Myers, RM, Pinto, D, Powers, A, Ramoz, N, Roepke, S, Rozanov, V, Scherer, SW, Schmahl, C, Sokolowski, M, Strober, M, Thornton, LM, Treasure, J, Tsuang, MT, Witt, SH, Woodside, DB, Yilmaz, Z, Zillich, L, Adolfsson, R, Agartz, I, Air, TM, Alda, M, Alfredsson, L, Andreassen, OA, Anjorin, A, Appadurai, V, Artigas, MS, Van der Auwera, S, Azevedo, MH, Bass, N, Bau, CHD, Baune, BT, Bellivier, F, Berger, K, Biernacka, JM, Bigdeli, TB, Binder, EB, Boehnke, M, Boks, MP, Bosch, R, Braff, DL, Bryant, R, Budde, M, Byrne, EM, Cahn, W, Casas, M, Castelao, E, Cervilla, JA, Chaumette, B, Cichon, S, Corvin, A, Craddock, N, Craig, D, Degenhardt, F, Djurovic, S, Edenberg, HJ, Fanous, AH, Foo, JC, Forstner, AJ, Frye, M, Fullerton, JM, Gatt, JM, Gejman, P, Giegling, I, Grabe, HJ, Green, MJ, Grevet, EH, Grigoroiu-Serbanescu, M, Gutierrez, B, Guzman-Parra, J, Hamilton, SP, Hamshere, ML, Hartmann, A, Hauser, J, Heilmann-Heimbach, S, Hoffmann, P, Ising, M, Jones, I, Jones, LA, Jonsson, L, Kahn, RS, Kelsoe, JR, Kendler, KS, Kloiber, S, Koenen, KC, Kogevinas, M, Konte, B, Krebs, M-O, Lander, M, Lawrence, J, Leboyer, M, Lee, PH, Levinson, DF, Liao, C, Lissowska, J, Lucae, S, Mayoral, F, McElroy, SL, McGrath, P, McGuffin, P, McQuillin, A, Medland, SE, Mehta, D, Melle, I, Milaneschi, Y, Mitchell, PB, Molina, E, Morken, G, Mortensen, PB, Mueller-Myhsok, B, Nievergelt, C, Nimgaonkar, V, Noethen, MM, O'Donovan, MC, Ophoff, RA, Owen, MJ, Pato, C, Pato, MT, Penninx, BWJH, Pimm, J, Pistis, G, Potash, JB, Power, RA, Preisig, M, Quested, D, Ramos-Quiroga, JA, Reif, A, Ribases, M, Richarte, V, Rietschel, M, Rivera, M, Roberts, A, Roberts, G, Rouleau, GA, Rovaris, DL, Rujescu, D, Sanchez-Mora, C, Sanders, AR, Schofield, PR, Schulze, TG, Scott, LJ, Serretti, A, Shi, J, Shyn, S, Sirignano, L, Sklar, P, Smeland, OB, Smoller, JW, Sonuga-Barke, EJS, Spalletta, G, Strauss, JS, Swiatkowska, B, Trzaskowski, M, Turecki, G, Vilar-Ribo, L, Vincent, JB, Voelzke, H, Walters, JTR, Weickert, CS, Weickert, TW, Weissman, MM, Williams, LM, Wray, NR, Zai, CC, Ashley-Koch, AE, Beckham, JC, Hauser, ER, Hauser, MA, Kimbrel, NA, Lindquist, JH, McMahon, B, Oslin, DW, Qin, X, Agerbo, E, Borglum, AD, Breen, G, Erlangsen, A, Esko, T, Gelernter, J, Hougaard, DM, Kessler, RC, Kranzler, HR, Li, QS, Martin, NG, McIntosh, AM, Mors, O, Nordentoft, M, Olsen, CM, Porteous, D, Ursano, RJ, Wasserman, D, Werge, T, Whiteman, DC, Bulik, CM, Coon, H, Demontis, D, Docherty, AR, Kuo, P-H, Lewis, CM, Mann, JJ, Renteria, ME, Smith, DJ, Stahl, EA, Stein, MB, Streit, F, Willour, V, and Ruderfer, DM

Abstract

BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.

Published
2022

8. 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
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18. Polygenic risk for schizophrenia and neurocognitive performance in patients with schizophrenia

Author

Wang, S.-H., primary, Hsiao, P.-C., additional, Yeh, L.-L., additional, Liu, C.-M., additional, Liu, C.-C., additional, Hwang, T.-J., additional, Hsieh, M. H., additional, Chien, Y.-L., additional, Lin, Y.-T., additional, Chandler, S. D., additional, Faraone, S. V., additional, Laird, N., additional, Neale, B., additional, McCarroll, S. A., additional, Glatt, S. J., additional, Tsuang, M. T., additional, Hwu, H.-G., additional, and Chen, W. J., additional

Published
2017
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19. Aberrant expression of microRNAs as biomarker for schizophrenia: from acute state to partial remission, and from peripheral blood to cortical tissue

Author

Lai, C-Y, Lee, S-Y, Scarr, E, Yu, Y-H, Lin, Y-T, Liu, C-M, Hwang, T-J, Hsieh, MH, Liu, C-C, Chien, Y-L, Udawela, M, Gibbons, AS, Everall, IP, Hwu, H-G, Dean, B, Chen, WJ, Lai, C-Y, Lee, S-Y, Scarr, E, Yu, Y-H, Lin, Y-T, Liu, C-M, Hwang, T-J, Hsieh, MH, Liu, C-C, Chien, Y-L, Udawela, M, Gibbons, AS, Everall, IP, Hwu, H-G, Dean, B, and Chen, WJ

Abstract

Based on our previous finding of a seven-miRNA (hsa-miR-34a, miR-449a, miR-564, miR-432, miR-548d, miR-572 and miR-652) signature as a potential biomarker for schizophrenia, this study aimed to examine if hospitalization could affect expressions of these miRNAs. We compared their expression levels between acute state and partial remission state in people with schizophrenia (n=48) using quantitative PCR method. Further, to examine whether the blood and brain show similar expression patterns, the expressions of two miRNAs (hsa-miR-34a and hsa-miR-548d) were examined in the postmortem brain tissue of people with schizophrenia (n=25) and controls (n=27). The expression level of the seven miRNAs did not alter after ~2 months of hospitalization with significant improvement in clinical symptoms, suggesting the miRNAs could be traits rather than state-dependent markers. The aberrant expression seen in the blood of hsa-miR-34a and hsa-miR-548d were not present in the brain samples, but this does not discount the possibility that the peripheral miRNAs could be clinically useful biomarkers for schizophrenia. Unexpectedly, we found an age-dependent increase in hsa-miR-34a expressions in human cortical (Brodmann area 46 (BA46)) but not subcortical region (caudate putamen). The correlation between hsa-miR-34a expression level in BA46 and age was much stronger in the controls than in the cases, and the corresponding correlation in the blood was only seen in the cases. The association between the miRNA dysregulations, the disease predisposition and aging warrants further investigation. Taken together, this study provides further insight on the candidate peripheral miRNAs as stable biomarkers for the diagnostics of schizophrenia.

Published
2016

20. Aberrant expression of microRNAs as biomarker for schizophrenia: from acute state to partial remission, and from peripheral blood to cortical tissue

Author

Lai, C-Y, primary, Lee, S-Y, additional, Scarr, E, additional, Yu, Y-H, additional, Lin, Y-T, additional, Liu, C-M, additional, Hwang, T-J, additional, Hsieh, M H, additional, Liu, C-C, additional, Chien, Y-L, additional, Udawela, M, additional, Gibbons, A S, additional, Everall, I P, additional, Hwu, H-G, additional, Dean, B, additional, and Chen, W J, additional

Published
2016
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21. A splicing-regulatory polymorphism in DRD2 disrupts ZRANB2 binding, impairs cognitive functioning and increases risk for schizophrenia in six Han Chinese samples

Author

Cohen, O S, Weickert, T W, Hess, J L, Paish, L M, Mccoy, S Y, Rothmond, D A, Galletly, Cherrie, Liu, D, Weinberg, D D, Huang, Xu-Feng, Xu, Q, Shen, Y, Zhang, D, Yue, W, Yan, J, Wang, L F, Lu, T, He, Lin, Shi, Yishan, Xu, M, Che, Ronglin, Tang, Wei, Chen, C-H, Chang, W-H, Hwu, H-G, Liu, C-M, Liu, Y-L, Wen, C-C, Fann, Cs-J, Chang, C-C, Kanazawa, T, Middleton, F A, Duncan, T M, Faraone, S V, Shannon Weickert, Cynthia, Tsuang, M T, Glatt, S, Cohen, O S, Weickert, T W, Hess, J L, Paish, L M, Mccoy, S Y, Rothmond, D A, Galletly, Cherrie, Liu, D, Weinberg, D D, Huang, Xu-Feng, Xu, Q, Shen, Y, Zhang, D, Yue, W, Yan, J, Wang, L F, Lu, T, He, Lin, Shi, Yishan, Xu, M, Che, Ronglin, Tang, Wei, Chen, C-H, Chang, W-H, Hwu, H-G, Liu, C-M, Liu, Y-L, Wen, C-C, Fann, Cs-J, Chang, C-C, Kanazawa, T, Middleton, F A, Duncan, T M, Faraone, S V, Shannon Weickert, Cynthia, Tsuang, M T, and Glatt, S

Abstract

The rs1076560 polymorphism of DRD2 (encoding dopamine receptor D2) is associated with alternative splicing and cognitive functioning; however, a mechanistic relationship to schizophrenia has not been shown. Here, we demonstrate that rs1076560(T) imparts a small but reliable risk for schizophrenia in a sample of 616 affected families and five independent replication samples totaling 4017 affected and 4704 unaffected individuals (odds ratio=1.1; P=0.004). rs1076560(T) was associated with impaired verbal fluency and comprehension in schizophrenia but improved performance among healthy comparison subjects. rs1076560(T) also associated with lower D2 short isoform expression in postmortem brain. rs1076560(T) disrupted a binding site for the splicing factor ZRANB2, diminished binding affinity between DRD2 pre-mRNA and ZRANB2 and abolished the ability of ZRANB2 to modulate short:long isoform-expression ratios of DRD2 minigenes in cell culture. Collectively, this work implicates rs1076560(T) as one possible risk factor for schizophrenia in the Han Chinese population, and suggests molecular mechanisms by which it may exert such influence.

Published
2015

22. Analysis of exome sequence in 604 trios for recessive genotypes in schizophrenia

Author

University of Helsinki, Institute for Molecular Medicine Finland (FIMM), Rees, E., Kirov, G., Walters, J. T., Richards, A. L., Howrigan, D., Kavanagh, D. H., Pocklington, A. J., Fromer, M., Ruderfer, D. M., Georgieva, L., Carrera, N., Gormley, P., Palta, P., Williams, H., Dwyer, S., Johnson, J. S., Roussos, P., Barker, D. D., Banks, E., Milanova, V., Rose, S. A., Chambert, K., Mahajan, M., Scolnick, E. M., Moran, J. L., Tsuang, M. T., Glatt, S. J., Chen, W. J., Hwu, H-G, Neale, B. M., Palotie, A., Sklar, P., Purcell, S. M., McCarroll, S. A., Holmans, P., Owen, M. J., O'Donovan, M. C., Taiwanese Trios Exome Sequencing C, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), Rees, E., Kirov, G., Walters, J. T., Richards, A. L., Howrigan, D., Kavanagh, D. H., Pocklington, A. J., Fromer, M., Ruderfer, D. M., Georgieva, L., Carrera, N., Gormley, P., Palta, P., Williams, H., Dwyer, S., Johnson, J. S., Roussos, P., Barker, D. D., Banks, E., Milanova, V., Rose, S. A., Chambert, K., Mahajan, M., Scolnick, E. M., Moran, J. L., Tsuang, M. T., Glatt, S. J., Chen, W. J., Hwu, H-G, Neale, B. M., Palotie, A., Sklar, P., Purcell, S. M., McCarroll, S. A., Holmans, P., Owen, M. J., O'Donovan, M. C., and Taiwanese Trios Exome Sequencing C

Abstract

Genetic associations involving both rare and common alleles have been reported for schizophrenia but there have been no systematic scans for rare recessive genotypes using fully phased trio data. Here, we use exome sequencing in 604 schizophrenia proband-parent trios to investigate the role of recessive (homozygous or compound heterozygous) nonsynonymous genotypes in the disorder. The burden of recessive genotypes was not significantly increased in probands at either a genome-wide level or in any individual gene after adjustment for multiple testing. At a system level, probands had an excess of nonsynonymous compound heterozygous genotypes (minor allele frequency, MAF

Published
2015

23. A splicing-regulatory polymorphism in DRD2 disrupts ZRANB2 binding, impairs cognitive functioning and increases risk for schizophrenia in six Han Chinese samples

Author

Cohen, O S, primary, Weickert, T W, additional, Hess, J L, additional, Paish, L M, additional, McCoy, S Y, additional, Rothmond, D A, additional, Galletly, C, additional, Liu, D, additional, Weinberg, D D, additional, Huang, X-F, additional, Xu, Q, additional, Shen, Y, additional, Zhang, D, additional, Yue, W, additional, Yan, J, additional, Wang, L, additional, Lu, T, additional, He, L, additional, Shi, Y, additional, Xu, M, additional, Che, R, additional, Tang, W, additional, Chen, C-H, additional, Chang, W-H, additional, Hwu, H-G, additional, Liu, C-M, additional, Liu, Y-L, additional, Wen, C-C, additional, Fann, C S-J, additional, Chang, C-C, additional, Kanazawa, T, additional, Middleton, F A, additional, Duncan, T M, additional, Faraone, S V, additional, Weickert, C S, additional, Tsuang, M T, additional, and Glatt, S J, additional

Published
2015
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31. Violence

Author

Langlois, L. E., primary, Shannon, H. S., additional, Griffith, L., additional, Haines, T., additional, Cortina, L. M., additional, Geldart, S., additional, Chen, W-C., additional, Chiu, H-J., additional, Hwu, H-G., additional, Wang, J-D., additional, Myers, D. J. M., additional, De Raeve, L., additional, Jansen, N. W. H., additional, van den Brandt, P. A., additional, Vasse, R. M., additional, Kant, I., additional, Kling, R., additional, Yassi, A., additional, Lovato, C., additional, Smailes, E., additional, and Koehoorn, M., additional

Published
2007
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33. Association evidence of schizophrenia with distal genomic region of NOTCH4 in Taiwanese families

Author

Liu, C.‐M., primary, Liu, Y.‐L., additional, Fann, C. S‐J., additional, Chen, W. J., additional, Yang, W.‐C., additional, Ouyang, W.‐C., additional, Chen, C.‐Y., additional, Jou, Y.‐S., additional, Hsieh, M.‐H., additional, Liu, S.‐K., additional, Hwang, T.‐J., additional, Faraone, S. V., additional, Tsuang, M. T., additional, and Hwu, H.‐G., additional

Published
2006
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35. A splicing-regulatory polymorphism in DRD2disrupts ZRANB2 binding, impairs cognitive functioning and increases risk for schizophrenia in six Han Chinese samples

Author

Cohen, O S, Weickert, T W, Hess, J L, Paish, L M, McCoy, S Y, Rothmond, D A, Galletly, C, Liu, D, Weinberg, D D, Huang, X-F, Xu, Q, Shen, Y, Zhang, D, Yue, W, Yan, J, Wang, L, Lu, T, He, L, Shi, Y, Xu, M, Che, R, Tang, W, Chen, C-H, Chang, W-H, Hwu, H-G, Liu, C-M, Liu, Y-L, Wen, C-C, Fann, C S-J, Chang, C-C, Kanazawa, T, Middleton, F A, Duncan, T M, Faraone, S V, Weickert, C S, Tsuang, M T, and Glatt, S J

Abstract

The rs1076560 polymorphism of DRD2(encoding dopamine receptor D2) is associated with alternative splicing and cognitive functioning; however, a mechanistic relationship to schizophrenia has not been shown. Here, we demonstrate that rs1076560(T) imparts a small but reliable risk for schizophrenia in a sample of 616 affected families and five independent replication samples totaling 4017 affected and 4704 unaffected individuals (odds ratio=1.1; P=0.004). rs1076560(T) was associated with impaired verbal fluency and comprehension in schizophrenia but improved performance among healthy comparison subjects. rs1076560(T) also associated with lower D2 short isoform expression in postmortembrain. rs1076560(T) disrupted a binding site for the splicing factor ZRANB2, diminished binding affinity between DRD2pre-mRNA and ZRANB2 and abolished the ability of ZRANB2 to modulate short:long isoform-expression ratios of DRD2minigenes in cell culture. Collectively, this work implicates rs1076560(T) as one possible risk factor for schizophrenia in the Han Chinese population, and suggests molecular mechanisms by which it may exert such influence.

Published
2016
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38. Progress in the search for schizophrenia susceptibility genes

Author

Moises, H.W., primary, Yang, L., additional, Kristbjarnarson, H., additional, Byerley, W., additional, Macciardi, F., additional, Arolt, V., additional, Blackwood, D., additional, Aschauer, H.N., additional, Hwu, H.-G., additional, Weissenbach, J., additional, Schwinger, E., additional, Gottesman, I.I., additional, Wetterberg, L., additional, and Helgason, T., additional

Published
1996
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40. An international two–stage genome–wide search for schizophrenia susceptibility genes

Author

Moises, H.W., primary, Yang, L., additional, Kristbjarnarson, H., additional, Wiese, C., additional, Byerley, W., additional, Macciardi, F., additional, Arolt, V., additional, Blackwood, D., additional, Liu, X., additional, Sjögren, B., additional, Aschauer, H.N., additional, Hwu, H.-G., additional, Jang, K., additional, Livesley, W.J., additional, Kennedy, J.L., additional, Zoega, T., additional, Ivarsson, O., additional, Bui, M.-T., additional, Yu, M.-H., additional, Havsteen, B., additional, Commenges, D., additional, Weissenbach, J., additional, Schwinger, E., additional, Gottesman, I.I., additional, Pakstis, A.J., additional, Wetterberg, L., additional, Kidd, K.K., additional, and Helgason, T., additional

Published
1995
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41. Risperidone and Olanzapine versus Another First Generation Antipsychotic in Patients with Schizophrenia Inadequately Responsive to First Generation Antipsychotics.

Author

Chen, J.- J., Chan, H.- Y., Chen, C.- H., Gau, S. S.- F., and Hwu, H.- G.

Subjects
PEOPLE with schizophrenia, RISPERIDONE, OLANZAPINE, ANTIPSYCHOTIC agents, WEIGHT gain
Abstract

Objective: This study compares the efficacy of risperidone and olanzapine to that of first-generation antipsychotics (FGAs) in patients with schizophrenia, who failed to show a response to initial trials of FGAs. Method: This study was an 8-week treatment, randomized, rater-blind, active-control study with 3 treatment arms. 48 patients, who showed inadequate response to 1 FGA, were enrolled and randomized into risperidone, olanzapine, or FGA (haloperidol or trifl uoperazine) groups. They were blindly assessed with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression Scale-Severity, and the Extrapyramidal Symptom Rating Scale (ESRS) at baseline and biweekly. Results: All 3 groups demonstrated a significant decrease in the PANSS total, positive, and general scores from baseline to endpoint (p-values range from 0.003 to 0.021). There were no significant differences among the 3 groups in score changes. The olanzapine group had significant score reductions than the risperidone and FGAs groups in terms of the ESRS subjective total score and did not experience a significant increase in the dose of anticholinergics. The FGA group demonstrated that extrapyramidal syndrome (EPS) worsened under an increased dosage of anti-EPS drugs. Olanzapine was associated with significant body weight gain (2.69 ± 4.0 kg, p = 0.026), but there were no significant group differences on weight gain. Conclusions: Haloperidol or trifluoperazine demonstrated similar efficacy as risperidone or olanzapine for patients with schizophrenia who had failed their first trial with a FGA. Related double-blind, fixed dose studies with a larger sample size are needed to confirm the results of our study. [ABSTRACT FROM AUTHOR]

Published
2012
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42. A randomised controlled study of risperidone and olanzapine for schizophrenic patients with neuroleptic-induced acute dystonia or parkinsonism.

Author

Chan, H. Y., Chang, C. J., Chiang, S. C., Chen, J. J., Chen, C. H., Sun, H. J., Hwu, H. G., and Lai, M. S.

Subjects
EXTRAPYRAMIDAL disorders, RISPERIDONE, OLANZAPINE, PEOPLE with schizophrenia, ANTIPSYCHOTIC agents, SCHIZOPHRENIA, PARKINSON'S disease
Abstract

The objective of this study was to compare the effects of risperidone and olanzapine in schizophrenic patients with intolerant extrapyramidal side effects (EPS) on first generation antipsychotics. We conducted an 8-week, rater-blinded, flexible dose study. Seventy patients with schizophrenia, who met the DSM-IV research criteria of having neuroleptic-induced acute dystonia or parkinsonism, were randomly assigned to risperidone or olanzapine group. The primary outcome was a comparison of the incidence of concomitant anticholinergic drugs usage between the groups to manage their acute dystonia and parkinsonism. The average doses of risperidone and olanzapine from baseline to study end point were 1.8-3.5 mg/day and 7.7-11.7 mg/day, respectively. There were no significant differences in demographic data, severity of EPS or psychotic symptoms between the groups at baseline assessment. Patients taking risperidone had significantly higher incidence of using anticholinergic drugs to manage acute dystonia or parkinsonism overall during the study (OR = 5.17, 95%CI = 1.49-17.88, P = 0.013). There was no significant between-group difference in the changing of rating scales of EPS and psychotic symptoms. The results of our study favour olanzapine as a better choice in schizophrenic patients with intolerant EPS. Double-blinded, fixed dose and different ethnical study for EPS-intolerant schizophrenic patients is needed to confirm the results of our study. [ABSTRACT FROM AUTHOR]

Published
2010
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