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1. Altered expression of glutamate signaling, growth factor, and glia genes in the locus coeruleus of patients with major depression

Author: Bernard, R, Kerman, IA, Thompson, RC, Jones, EG, Bunney, WE, Barchas, JD, Schatzberg, AF, Myers, RM, Akil, H, and Watson, SJ
Subjects: Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Psychology, Pharmacology and Pharmaceutical Sciences, Genetics, Depression, Neurosciences, Brain Disorders, Biotechnology, Serious Mental Illness, Mental Health, 2.1 Biological and endogenous factors, Aetiology, Adolescent, Adult, Aged, Depressive Disorder, Major, Female, Gene Expression Profiling, Gene Expression Regulation, Glutamate Plasma Membrane Transport Proteins, Glutamic Acid, Humans, Intercellular Signaling Peptides and Proteins, Locus Coeruleus, Male, Microdissection, Middle Aged, Models, Biological, Nerve Tissue Proteins, Neuroglia, Oligonucleotide Array Sequence Analysis, RNA, Messenger, Signal Transduction, Young Adult, laser-capture microdissection, human, monoamine, norepinephrine, post mortem, microarray, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract: Several studies have proposed that brain glutamate signaling abnormalities and glial pathology have a role in the etiology of major depressive disorder (MDD). These conclusions were primarily drawn from post-mortem studies in which forebrain brain regions were examined. The locus coeruleus (LC) is the primary source of extensive noradrenergic innervation of the forebrain and as such exerts a powerful regulatory role over cognitive and affective functions, which are dysregulated in MDD. Furthermore, altered noradrenergic neurotransmission is associated with depressive symptoms and is thought to have a role in the pathophysiology of MDD. In the present study we used laser-capture microdissection (LCM) to selectively harvest LC tissue from post-mortem brains of MDD patients, patients with bipolar disorder (BPD) and from psychiatrically normal subjects. Using microarray technology we examined global patterns of gene expression. Differential mRNA expression of select candidate genes was then interrogated using quantitative real-time PCR (qPCR) and in situ hybridization (ISH). Our findings reveal multiple signaling pathway alterations in the LC of MDD but not BPD subjects. These include glutamate signaling genes, SLC1A2, SLC1A3 and GLUL, growth factor genes FGFR3 and TrkB, and several genes exclusively expressed in astroglia. Our data extend previous findings of altered glutamate, astroglial and growth factor functions in MDD for the first time to the brainstem. These findings indicate that such alterations: (1) are unique to MDD and distinguishable from BPD, and (2) affect multiple brain regions, suggesting a whole-brain dysregulation of such functions.
Published: 2011

2. Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders

Author: Andlauer, TFM, Guzman-Parra, J, Streit, F, Strohmaier, J, González, MJ, Gil Flores, S, Cabaleiro Fabeiro, FJ, del Río Noriega, F, Perez, FP, Haro González, J, Orozco Diaz, G, de Diego-Otero, Y, Moreno-Küstner, B, Auburger, G, Degenhardt, F, Heilmann-Heimbach, S, Herms, S, Hoffmann, P, Frank, J, Foo, JC, Treutlein, J, Witt, SH, Cichon, S, Kogevinas, M, Stahl, EA, Breen, G, Forstner, AJ, McQuillin, A, Ripke, S, Trubetskoy, V, Mattheisen, M, Wang, Y, Coleman, JRI, Gaspar, HA, de Leeuw, CA, Steinberg, S, Pavlides, JMW, Trzaskowski, M, Pers, TH, Holmans, PA, Abbott, L, Agerbo, E, Akil, H, Albani, D, Alliey-Rodriguez, N, Als, TD, Anjorin, A, Antilla, V, Awasthi, S, Badner, JA, Bækvad-Hansen, M, Barchas, JD, Bass, N, Bauer, M, Belliveau, R, Bergen, SE, Pedersen, CB, Bøen, E, Boks, M, Boocock, J, Budde, M, Bunney, W, Burmeister, M, Bybjerg-Grauholm, J, Byerley, W, Casas, M, Cerrato, F, Cervantes, P, Chambert, K, Charney, AW, Chen, D, Churchhouse, C, Clarke, TK, Coryell, W, Craig, DW, Cruceanu, C, Czerski, PM, Dale, AM, de Jong, S, Del-Favero, J, DePaulo, JR, Djurovic, S, Dobbyn, AL, Dumont, A, Elvsåshagen, T, Escott-Price, V, Fan, CC, Fischer, SB, Flickinger, M, Foroud, TM, Forty, L, Fraser, C, Freimer, NB, Frisén, L, Gade, K, Gage, D, Garnham, J, Giambartolomei, C, Andlauer, TFM, Guzman-Parra, J, Streit, F, Strohmaier, J, González, MJ, Gil Flores, S, Cabaleiro Fabeiro, FJ, del Río Noriega, F, Perez, FP, Haro González, J, Orozco Diaz, G, de Diego-Otero, Y, Moreno-Küstner, B, Auburger, G, Degenhardt, F, Heilmann-Heimbach, S, Herms, S, Hoffmann, P, Frank, J, Foo, JC, Treutlein, J, Witt, SH, Cichon, S, Kogevinas, M, Stahl, EA, Breen, G, Forstner, AJ, McQuillin, A, Ripke, S, Trubetskoy, V, Mattheisen, M, Wang, Y, Coleman, JRI, Gaspar, HA, de Leeuw, CA, Steinberg, S, Pavlides, JMW, Trzaskowski, M, Pers, TH, Holmans, PA, Abbott, L, Agerbo, E, Akil, H, Albani, D, Alliey-Rodriguez, N, Als, TD, Anjorin, A, Antilla, V, Awasthi, S, Badner, JA, Bækvad-Hansen, M, Barchas, JD, Bass, N, Bauer, M, Belliveau, R, Bergen, SE, Pedersen, CB, Bøen, E, Boks, M, Boocock, J, Budde, M, Bunney, W, Burmeister, M, Bybjerg-Grauholm, J, Byerley, W, Casas, M, Cerrato, F, Cervantes, P, Chambert, K, Charney, AW, Chen, D, Churchhouse, C, Clarke, TK, Coryell, W, Craig, DW, Cruceanu, C, Czerski, PM, Dale, AM, de Jong, S, Del-Favero, J, DePaulo, JR, Djurovic, S, Dobbyn, AL, Dumont, A, Elvsåshagen, T, Escott-Price, V, Fan, CC, Fischer, SB, Flickinger, M, Foroud, TM, Forty, L, Fraser, C, Freimer, NB, Frisén, L, Gade, K, Gage, D, Garnham, J, and Giambartolomei, C
Abstract: Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development.
Published: 2021

3. Genome-wide association study identifies 30 loci associated with bipolar disorder

Author: Stahl, EA, Breen, G, Forstner, AJ, McQuillin, A, Ripke, S, Trubetskoy, V, Mattheisen, M, Wang, Y, Coleman, JRI, Gaspar, HA, de Leeuw, CA, Steinberg, S, Pavlides, JMW, Trzaskowski, M, Byrne, EM, Pers, TH, Holmans, PA, Richards, AL, Abbott, L, Agerbo, E, Akil, H, Albani, D, Alliey-Rodriguez, N, Als, TD, Anjorin, A, Antilla, V, Awasthi, S, Badner, JA, Bækvad-Hansen, M, Barchas, JD, Bass, N, Bauer, M, Belliveau, R, Bergen, SE, Pedersen, CB, Bøen, E, Boks, MP, Boocock, J, Budde, M, Bunney, W, Burmeister, M, Bybjerg-Grauholm, J, Byerley, W, Casas, M, Cerrato, F, Cervantes, P, Chambert, K, Charney, AW, Chen, D, Churchhouse, C, Clarke, TK, Coryell, W, Craig, DW, Cruceanu, C, Curtis, D, Czerski, PM, Dale, AM, de Jong, S, Degenhardt, F, Del-Favero, J, DePaulo, JR, Djurovic, S, Dobbyn, AL, Dumont, A, Elvsåshagen, T, Escott-Price, V, Fan, CC, Fischer, SB, Flickinger, M, Foroud, TM, Forty, L, Frank, J, Fraser, C, Freimer, NB, Frisén, L, Gade, K, Gage, D, Garnham, J, Giambartolomei, C, Pedersen, MG, Goldstein, J, Gordon, SD, Gordon-Smith, K, Green, EK, Green, MJ, Greenwood, TA, Grove, J, Guan, W, Guzman-Parra, J, Hamshere, ML, Hautzinger, M, Heilbronner, U, Herms, S, Hipolito, M, Hoffmann, P, Holland, D, Huckins, L, Jamain, S, Johnson, JS, Juréus, A, Stahl, EA, Breen, G, Forstner, AJ, McQuillin, A, Ripke, S, Trubetskoy, V, Mattheisen, M, Wang, Y, Coleman, JRI, Gaspar, HA, de Leeuw, CA, Steinberg, S, Pavlides, JMW, Trzaskowski, M, Byrne, EM, Pers, TH, Holmans, PA, Richards, AL, Abbott, L, Agerbo, E, Akil, H, Albani, D, Alliey-Rodriguez, N, Als, TD, Anjorin, A, Antilla, V, Awasthi, S, Badner, JA, Bækvad-Hansen, M, Barchas, JD, Bass, N, Bauer, M, Belliveau, R, Bergen, SE, Pedersen, CB, Bøen, E, Boks, MP, Boocock, J, Budde, M, Bunney, W, Burmeister, M, Bybjerg-Grauholm, J, Byerley, W, Casas, M, Cerrato, F, Cervantes, P, Chambert, K, Charney, AW, Chen, D, Churchhouse, C, Clarke, TK, Coryell, W, Craig, DW, Cruceanu, C, Curtis, D, Czerski, PM, Dale, AM, de Jong, S, Degenhardt, F, Del-Favero, J, DePaulo, JR, Djurovic, S, Dobbyn, AL, Dumont, A, Elvsåshagen, T, Escott-Price, V, Fan, CC, Fischer, SB, Flickinger, M, Foroud, TM, Forty, L, Frank, J, Fraser, C, Freimer, NB, Frisén, L, Gade, K, Gage, D, Garnham, J, Giambartolomei, C, Pedersen, MG, Goldstein, J, Gordon, SD, Gordon-Smith, K, Green, EK, Green, MJ, Greenwood, TA, Grove, J, Guan, W, Guzman-Parra, J, Hamshere, ML, Hautzinger, M, Heilbronner, U, Herms, S, Hipolito, M, Hoffmann, P, Holland, D, Huckins, L, Jamain, S, Johnson, JS, and Juréus, A
Abstract: Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10 −4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10 −8 ) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.
Published: 2019

4. Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

Author: Ruderfer, DM, Ripke, S, McQuillin, A, Boocock, J, Stahl, EA, Pavlides, JMW, Mullins, N, Charney, AW, Ori, APS, Loohuis, LMO, Domenici, E, Di Florio, A, Papiol, S, Kalman, JL, Trubetskoy, V, Adolfsson, R, Agartz, I, Agerbo, E, Akil, H, Albani, D, Albus, M, Alda, M, Alexander, M, Alliey-Rodriguez, N, Als, TD, Amin, F, Anjorin, A, Arranz, MJ, Awasthi, S, Bacanu, SA, Badner, JA, Baekvad-Hansen, M, Bakker, S, Band, G, Barchas, JD, Barroso, I, Bass, N, Bauer, M, Baune, BT, Begemann, M, Bellenguez, C, Belliveau, RA, Bellivier, F, Bender, S, Bene, J, Bergen, SE, Berrettini, WH, Bevilacqua, E, Biernacka, JM, Bigdeli, TB, Black, DW, Blackburn, H, Blackwell, JM, Blackwood, DHR, Pedersen, CB, Boehnke, M, Boks, M, Borglum, AD, Bramon, E, Breen, G, Brown, MA, Bruggeman, R, Buccola, NG, Buckner, RL, Budde, M, Bulik-Sullivan, B, Bumpstead, SJ, Bunney, W, Burmeister, M, Buxbaum, JD, Bybjerg-Grauholm, J, Byerley, W, Cahn, W, Cai, G, Cairns, MJ, Campion, D, Cantor, RM, Carr, VJ, Carrera, N, Casas, JP, Casas, M, Catts, SV, Cervantes, P, Chambert, KD, Chan, RCK, Chen, EYH, Chen, RYL, Cheng, W, Cheung, EFC, Chong, SA, Clarke, TK, Cloninger, CR, Cohen, D, Cohen, N, Coleman, JRI, Collier, DA, Cormican, P, Coryell, W, Craddock, N, Craig, DW, Ruderfer, DM, Ripke, S, McQuillin, A, Boocock, J, Stahl, EA, Pavlides, JMW, Mullins, N, Charney, AW, Ori, APS, Loohuis, LMO, Domenici, E, Di Florio, A, Papiol, S, Kalman, JL, Trubetskoy, V, Adolfsson, R, Agartz, I, Agerbo, E, Akil, H, Albani, D, Albus, M, Alda, M, Alexander, M, Alliey-Rodriguez, N, Als, TD, Amin, F, Anjorin, A, Arranz, MJ, Awasthi, S, Bacanu, SA, Badner, JA, Baekvad-Hansen, M, Bakker, S, Band, G, Barchas, JD, Barroso, I, Bass, N, Bauer, M, Baune, BT, Begemann, M, Bellenguez, C, Belliveau, RA, Bellivier, F, Bender, S, Bene, J, Bergen, SE, Berrettini, WH, Bevilacqua, E, Biernacka, JM, Bigdeli, TB, Black, DW, Blackburn, H, Blackwell, JM, Blackwood, DHR, Pedersen, CB, Boehnke, M, Boks, M, Borglum, AD, Bramon, E, Breen, G, Brown, MA, Bruggeman, R, Buccola, NG, Buckner, RL, Budde, M, Bulik-Sullivan, B, Bumpstead, SJ, Bunney, W, Burmeister, M, Buxbaum, JD, Bybjerg-Grauholm, J, Byerley, W, Cahn, W, Cai, G, Cairns, MJ, Campion, D, Cantor, RM, Carr, VJ, Carrera, N, Casas, JP, Casas, M, Catts, SV, Cervantes, P, Chambert, KD, Chan, RCK, Chen, EYH, Chen, RYL, Cheng, W, Cheung, EFC, Chong, SA, Clarke, TK, Cloninger, CR, Cohen, D, Cohen, N, Coleman, JRI, Collier, DA, Cormican, P, Coryell, W, Craddock, N, and Craig, DW
Abstract: Schizophrenia and bipolar disorder are two distinct diagnoses that share symptomology. Understanding the genetic factors contributing to the shared and disorder-specific symptoms will be crucial for improving diagnosis and treatment. In genetic data consisting of 53,555 cases (20,129 bipolar disorder [BD], 33,426 schizophrenia [SCZ]) and 54,065 controls, we identified 114 genome-wide significant loci implicating synaptic and neuronal pathways shared between disorders. Comparing SCZ to BD (23,585 SCZ, 15,270 BD) identified four genomic regions including one with disorder-independent causal variants and potassium ion response genes as contributing to differences in biology between the disorders. Polygenic risk score (PRS) analyses identified several significant correlations within case-only phenotypes including SCZ PRS with psychotic features and age of onset in BD. For the first time, we discover specific loci that distinguish between BD and SCZ and identify polygenic components underlying multiple symptom dimensions. These results point to the utility of genetics to inform symptomology and potential treatment. Genetic analysis of multiple bipolar disorder and schizophrenia cohorts reveals loci and polygenic risk scores that differentiate the clinical symptoms of these two highly correlated disorders.
Published: 2018

5. Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder

Author: de Jong, S, Abdalla Diniz, MJ, Saloma, A, Gadelha, A, Santoro, ML, Ota, VK, Noto, C, Curtis, C, Newhouse, SJ, Patel, H, Hall, LS, O'Reilly, PF, Belangero, S, Bressan, RA, Breen, G, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Blackwood, DHR, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Coleman, JR, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, C, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, Mcgrath, P, Mcguffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shyn, S, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, D, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, McIntosh, AM, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Borglum, AD, Sullivan, PF, Meier, S, Strauss, J, Xu, W, Vincent, JB, Matthews, K, Ferreira, M, O'Dushlaine, C, Purcell, S, Raychaudhuri, S, Ruderfer, DM, Sklar, P, Scott, LJ, Flickinger, M, Burmeister, M, Li, J, Guan, W, Absher, D, Thompson, RC, Meng, FG, Schatzberg, AF, Bunney, WE, Barchas, JD, Watson, SJ, Myers, RM, Akil, H, Boehnke, M, Chambert, K, Moran, J, Scolnick, E, Djurovic, S, Melle, I, Morken, G, Corvin, A, Anjorin, A, Kandaswamy, R, Lawrence, J, McLean, AW, Pickard, BS, Bergen, SE, Nimgaonkar, V, Landen, M, Schalling, M, Osby, U, Backlund, L, Frisen, L, Langstrom, N, Stahl, E, Dobbyn, A, Jamain, S, Etain, B, Bellivier, F, Leber, M, Maaser, A, Fischer, SB, Reinbold, CS, Kittel-Schneider, S, Fullerton, JM, Oruc, L, Para, JG, Mayoral, F, Rivas, F, Czerski, PM, Kammerer-Ciernioch, J, Vedder, H, Borrmann-Hassenbach, M, Pfennig, A, Brennan, P, McKay, JD, Kogevinas, M, Schwarz, M, Schofield, PR, Muehleisen, TW, Schumacher, J, Bauer, M, Wright, A, Mitchell, PB, Hautzinger, M, Kelsoe, JR, Greenwood, TA, Nievergelt, CM, Shilling, PD, Smith, EN, Bloss, CS, Edenberg, HJ, Koller, DL, Gershon, ES, Liu, C, Badner, JA, Scheftner, WA, Lawson, WB, Nwulia, EA, Hipolito, M, Coryell, W, Rice, J, Byerley, W, McMahon, FJ, Lohoff, FW, Zandi, PP, Mahon, PB, McInnis, MG, Zollner, S, Zhang, P, Szelinger, S, St Clair, D, Caesar, S, Gordon-Smith, K, Fraser, C, Green, EK, Grozeva, D, Hamshere, ML, Kirov, G, Nikolov, I, Collier, DA, Elkin, A, Williamson, R, Young, AH, Ferrier, IN, Milanova, V, Alda, M, Cervantes, P, Cruceanu, C, Rouleau, GA, Turecki, G, Paciga, S, Winslow, AR, Grigoroiu-Serbanescu, M, Ophoff, R, Adolfsson, R, Adolfsson, AN, Del-Favero, J, Pato, C, Biernacka, JM, Frye, MA, Morris, D, Schork, NJ, Reif, A, Lissowska, J, Hauser, J, Szeszenia-Dabrowska, N, McGhee, K, Quinn, E, Moskvina, V, Holmans, PA, Farmer, A, Kennedy, JL, Andreassen, OA, Mattingsdal, M, Bass, NJ, Gurling, H, McQuillin, A, Breuer, R, Hultman, C, Lichtenstein, P, Huckins, LM, Leboyer, M, Lathrop, M, Nurnberger, J, Steffens, M, Foroud, TM, Berrettini, WH, Craig, DW, Shi, J, de Jong, S, Abdalla Diniz, MJ, Saloma, A, Gadelha, A, Santoro, ML, Ota, VK, Noto, C, Curtis, C, Newhouse, SJ, Patel, H, Hall, LS, O'Reilly, PF, Belangero, S, Bressan, RA, Breen, G, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Blackwood, DHR, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Coleman, JR, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, C, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, Mcgrath, P, Mcguffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shyn, S, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, D, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, McIntosh, AM, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Borglum, AD, Sullivan, PF, Meier, S, Strauss, J, Xu, W, Vincent, JB, Matthews, K, Ferreira, M, O'Dushlaine, C, Purcell, S, Raychaudhuri, S, Ruderfer, DM, Sklar, P, Scott, LJ, Flickinger, M, Burmeister, M, Li, J, Guan, W, Absher, D, Thompson, RC, Meng, FG, Schatzberg, AF, Bunney, WE, Barchas, JD, Watson, SJ, Myers, RM, Akil, H, Boehnke, M, Chambert, K, Moran, J, Scolnick, E, Djurovic, S, Melle, I, Morken, G, Corvin, A, Anjorin, A, Kandaswamy, R, Lawrence, J, McLean, AW, Pickard, BS, Bergen, SE, Nimgaonkar, V, Landen, M, Schalling, M, Osby, U, Backlund, L, Frisen, L, Langstrom, N, Stahl, E, Dobbyn, A, Jamain, S, Etain, B, Bellivier, F, Leber, M, Maaser, A, Fischer, SB, Reinbold, CS, Kittel-Schneider, S, Fullerton, JM, Oruc, L, Para, JG, Mayoral, F, Rivas, F, Czerski, PM, Kammerer-Ciernioch, J, Vedder, H, Borrmann-Hassenbach, M, Pfennig, A, Brennan, P, McKay, JD, Kogevinas, M, Schwarz, M, Schofield, PR, Muehleisen, TW, Schumacher, J, Bauer, M, Wright, A, Mitchell, PB, Hautzinger, M, Kelsoe, JR, Greenwood, TA, Nievergelt, CM, Shilling, PD, Smith, EN, Bloss, CS, Edenberg, HJ, Koller, DL, Gershon, ES, Liu, C, Badner, JA, Scheftner, WA, Lawson, WB, Nwulia, EA, Hipolito, M, Coryell, W, Rice, J, Byerley, W, McMahon, FJ, Lohoff, FW, Zandi, PP, Mahon, PB, McInnis, MG, Zollner, S, Zhang, P, Szelinger, S, St Clair, D, Caesar, S, Gordon-Smith, K, Fraser, C, Green, EK, Grozeva, D, Hamshere, ML, Kirov, G, Nikolov, I, Collier, DA, Elkin, A, Williamson, R, Young, AH, Ferrier, IN, Milanova, V, Alda, M, Cervantes, P, Cruceanu, C, Rouleau, GA, Turecki, G, Paciga, S, Winslow, AR, Grigoroiu-Serbanescu, M, Ophoff, R, Adolfsson, R, Adolfsson, AN, Del-Favero, J, Pato, C, Biernacka, JM, Frye, MA, Morris, D, Schork, NJ, Reif, A, Lissowska, J, Hauser, J, Szeszenia-Dabrowska, N, McGhee, K, Quinn, E, Moskvina, V, Holmans, PA, Farmer, A, Kennedy, JL, Andreassen, OA, Mattingsdal, M, Bass, NJ, Gurling, H, McQuillin, A, Breuer, R, Hultman, C, Lichtenstein, P, Huckins, LM, Leboyer, M, Lathrop, M, Nurnberger, J, Steffens, M, Foroud, TM, Berrettini, WH, Craig, DW, and Shi, J
Abstract: Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.
Published: 2018

6. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

Author: O’dushlaine, C, Rossin, L, Lee, PH, Duncan, L, Parikshak, NN, Newhouse, S, Ripke, S, Neale, BM, Purcell, SM, Posthuma, D, Nurnberger, JI, Lee, SH, Faraone, SV, Perlis, RH, Mowry, BJ, Thapar, A, Goddard, ME, Witte, JS, Absher, D, Agartz, I, Akil, H, Amin, F, Andreassen, OA, Anjorin, A, Anney, R, Anttila, V, Arking, DE, Asherson, P, Azevedo, MH, Backlund, L, Badner, JA, Bailey, AJ, Banaschewski, T, Barchas, JD, Barnes, MR, Barrett, TB, Bass, N, Battaglia, A, Bauer, M, Bayés, M, Bellivier, F, Bergen, SE, Berrettini, W, Betancur, C, Bettecken, T, Biederman, J, Binder, EB, Black, DW, Blackwood, DHR, Bloss, CS, Boehnke, M, Boomsma, DI, Breuer, R, Bruggeman, R, Cormican, P, Buccola, NG, Buitelaar, JK, Bunney, WE, Buxbaum, JD, Byerley, WF, Byrne, EM, Caesar, S, Cahn, W, Cantor, RM, Casas, M, Chakravarti, A, Chambert, K, Choudhury, K, and Cichon, S
Abstract: © 2015 Nature America, Inc. All rights reserved. Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders.
Published: 2015
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7. Mitochondrial Mutations in Subjects with Psychiatric Disorders

Author: Sequeira, A, Rollins, B, Magnan, C, Oven, Mannis, Baldi, P, Myers, RM, Barchas, JD, Schatzberg, AF, Watson, SJ, Akil, H, Bunney, WE, Vawter, MP, Sequeira, A, Rollins, B, Magnan, C, Oven, Mannis, Baldi, P, Myers, RM, Barchas, JD, Schatzberg, AF, Watson, SJ, Akil, H, Bunney, WE, and Vawter, MP
Abstract: A considerable body of evidence supports the role of mitochondrial dysfunction in psychiatric disorders and mitochondrial DNA (mtDNA) mutations are known to alter brain energy metabolism, neurotransmission, and cause neurodegenerative disorders. Genetic studies focusing on common nuclear genome variants associated with these disorders have produced genome wide significant results but those studies have not directly studied mtDNA variants. The purpose of this study is to investigate, using next generation sequencing, the involvement of mtDNA variation in bipolar disorder, schizophrenia, major depressive disorder, and methamphetamine use. MtDNA extracted from multiple brain regions and blood were sequenced (121 mtDNA samples with an average of 8,800x coverage) and compared to an electronic database containing 26,850 mtDNA genomes. We confirmed novel and rare variants, and confirmed next generation sequencing error hotspots by traditional sequencing and genotyping methods. We observed a significant increase of non-synonymous mutations found in individuals with schizophrenia. Novel and rare non-synonymous mutations were found in psychiatric cases in mtDNA genes: ND6, ATP6, CYTB, and ND2. We also observed mtDNA heteroplasmy in brain at a locus previously associated with schizophrenia (T16519C). Large differences in heteroplasmy levels across brain regions within subjects suggest that somatic mutations accumulate differentially in brain regions. Finally, multiplasmy, a heteroplasmic measure of repeat length, was observed in brain from selective cases at a higher frequency than controls. These results offer support for increased rates of mtDNA substitutions in schizophrenia shown in our prior results. The variable levels of heteroplasmic/multiplasmic somatic mutations that occur in brain may be indicators of genetic instability in mtDNA.
Published: 2015

8. Identification of pathways for bipolar disorder: A meta-analysis

Author: Nurnberger, JI, Koller, DL, Jung, J, Edenberg, HJ, Foroud, T, Guella, I, Vawter, MP, Kelsoe, JR, Sklar, P, Ripke, S, Scott, LJ, Andreassen, OA, Cichon, S, Craddock, N, Rietschel, M, Blackwood, D, Corvin, A, Flickinger, M, Guan, W, Mattingsdal, M, McQuillin, A, Kwan, P, Wienker, TF, Daly, M, Dudbridge, F, Holmans, PA, Lin, D, Burmeister, M, Greenwood, TA, Hamshere, ML, Muglia, P, Smith, EN, Zandi, PP, Nievergelt, CM, McKinney, R, Shilling, PD, Schork, NJ, Bloss, CS, Gershon, ES, Liu, C, Badner, JA, Scheftner, WA, Lawson, WB, Nwulia, EA, Hipolito, M, Coryell, W, Rice, J, Byerley, W, McMahon, FJ, Schulze, TG, Berrettini, W, Lohoff, FW, Potash, JB, Mahon, PB, McInnis, MG, Zollner, S, Zhang, P, Craig, DW, Szelinger, S, Barrett, TB, Breuer, R, Meier, S, Strohmaier, J, Witt, SH, Tozzi, F, Farmer, A, McGuffin, P, Strauss, J, Xu, W, Kennedy, JL, Vincent, JB, Matthews, K, Day, R, Ferreira, MA, O'Dushlaine, C, Perlis, R, Raychaudhuri, S, Ruderfer, D, Lee, PH, Smoller, JW, Li, J, Absher, D, Bunney, WE, Barchas, JD, Schatzberg, AF, Jones, EG, Meng, F, Thompson, RC, Watson, SJ, Myers, RM, Akil, H, Boehnke, M, Chambert, K, Moran, J, Scolnick, EM, Djurovic, S, Melle, I, Morken, G, Gill, M, Morris, D, Nurnberger, JI, Koller, DL, Jung, J, Edenberg, HJ, Foroud, T, Guella, I, Vawter, MP, Kelsoe, JR, Sklar, P, Ripke, S, Scott, LJ, Andreassen, OA, Cichon, S, Craddock, N, Rietschel, M, Blackwood, D, Corvin, A, Flickinger, M, Guan, W, Mattingsdal, M, McQuillin, A, Kwan, P, Wienker, TF, Daly, M, Dudbridge, F, Holmans, PA, Lin, D, Burmeister, M, Greenwood, TA, Hamshere, ML, Muglia, P, Smith, EN, Zandi, PP, Nievergelt, CM, McKinney, R, Shilling, PD, Schork, NJ, Bloss, CS, Gershon, ES, Liu, C, Badner, JA, Scheftner, WA, Lawson, WB, Nwulia, EA, Hipolito, M, Coryell, W, Rice, J, Byerley, W, McMahon, FJ, Schulze, TG, Berrettini, W, Lohoff, FW, Potash, JB, Mahon, PB, McInnis, MG, Zollner, S, Zhang, P, Craig, DW, Szelinger, S, Barrett, TB, Breuer, R, Meier, S, Strohmaier, J, Witt, SH, Tozzi, F, Farmer, A, McGuffin, P, Strauss, J, Xu, W, Kennedy, JL, Vincent, JB, Matthews, K, Day, R, Ferreira, MA, O'Dushlaine, C, Perlis, R, Raychaudhuri, S, Ruderfer, D, Lee, PH, Smoller, JW, Li, J, Absher, D, Bunney, WE, Barchas, JD, Schatzberg, AF, Jones, EG, Meng, F, Thompson, RC, Watson, SJ, Myers, RM, Akil, H, Boehnke, M, Chambert, K, Moran, J, Scolnick, EM, Djurovic, S, Melle, I, Morken, G, Gill, M, and Morris, D
Abstract: IMPORTANCE Genome-wide investigations provide systematic information regarding the neurobiology of psychiatric disorders. OBJECTIVE To identify biological pathways that contribute to risk for bipolar disorder (BP) using genes with consistent evidence for association in multiple genome-wide association studies (GWAS). DATA SOURCES Four independent data sets with individual genome-wide data available in July 2011 along with all data sets contributed to the Psychiatric Genomics Consortium Bipolar Group by May 2012. A prior meta-analysis was used as a source for brain gene expression data. STUDY SELECTION The 4 published GWAS were included in the initial sample. All independent BP data sets providing genome-wide data in the Psychiatric Genomics Consortium were included as a replication sample. DATA EXTRACTION AND SYNTHESIS We identified 966 genes that contained 2 or more variants associated with BP at P < .05 in 3 of 4 GWAS data sets (n = 12 127 [5253 cases, 6874 controls]). Simulations using 10 000 replicates of these data sets corrected for gene size and allowed the calculation of an empirical P value for each gene; empirically significant genes were entered into a pathway analysis. Each of these pathways was then tested in the replication sample (n = 8396 [3507 cases, 4889 controls]) using gene set enrichment analysis for single-nucleotide polymorphisms. The 226 genes were also compared with results from ameta-analysis of gene expression in the dorsolateral prefrontal cortex. MAIN OUTCOMES AND MEASURES Empirically significant genes and biological pathways. RESULTS Among 966 genes, 226 were empirically significant (P < .05). Seventeen pathways were overrepresented in analyses of the initial data set. Six of the 17 pathways were associated with BP in both the initial and replication samples: corticotropin-releasing hormone signaling, cardiac β-adrenergic signaling, phospholipase C signaling, glutamate receptor signaling, endothelin 1 signaling, and cardiac hypertrophy
Published: 2014

9. G protein-linked signaling pathways in bipolar and major depressive disorders.

Author: Tomita, H, Ziegler, ME, Kim, HB, Evans, SJ, Choudary, PV, Li, JZ, Meng, F, Dai, M, Myers, RM, Neal, CR, Speed, TP, Barchas, JD, Schatzberg, AF, Watson, SJ, Akil, H, Jones, EG, Bunney, WE, Vawter, MP, Tomita, H, Ziegler, ME, Kim, HB, Evans, SJ, Choudary, PV, Li, JZ, Meng, F, Dai, M, Myers, RM, Neal, CR, Speed, TP, Barchas, JD, Schatzberg, AF, Watson, SJ, Akil, H, Jones, EG, Bunney, WE, and Vawter, MP
Abstract: The G-protein linked signaling system (GPLS) comprises a large number of G-proteins, G protein-coupled receptors (GPCRs), GPCR ligands, and downstream effector molecules. G-proteins interact with both GPCRs and downstream effectors such as cyclic adenosine monophosphate (cAMP), phosphatidylinositols, and ion channels. The GPLS is implicated in the pathophysiology and pharmacology of both major depressive disorder (MDD) and bipolar disorder (BPD). This study evaluated whether GPLS is altered at the transcript level. The gene expression in the dorsolateral prefrontal (DLPFC) and anterior cingulate (ACC) were compared from MDD, BPD, and control subjects using Affymetrix Gene Chips and real time quantitative PCR. High quality brain tissue was used in the study to control for confounding effects of agonal events, tissue pH, RNA integrity, gender, and age. GPLS signaling transcripts were altered especially in the ACC of BPD and MDD subjects. Transcript levels of molecules which repress cAMP activity were increased in BPD and decreased in MDD. Two orphan GPCRs, GPRC5B and GPR37, showed significantly decreased expression levels in MDD, and significantly increased expression levels in BPD. Our results suggest opposite changes in BPD and MDD in the GPLS, "activated" cAMP signaling activity in BPD and "blunted" cAMP signaling activity in MDD. GPRC5B and GPR37 both appear to have behavioral effects, and are also candidate genes for neurodegenerative disorders. In the context of the opposite changes observed in BPD and MDD, these GPCRs warrant further study of their brain effects.
Published: 2013

10. Modulation of activity of the striatal dopaminergic system during the hibernation cycle

Author: Kilduff, TS, primary, Bowersox, SS, additional, Faull, KF, additional, Zeller-DeAmicis, L, additional, Radeke, CM, additional, Ciaranello, RD, additional, Heller, HC, additional, Barchas, JD, additional, and Dement, WC, additional
Published: 1987
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11. Co-localization and characterization of immunoreactive peptides derived from two opioid precursors in guinea pig adrenal glands

Author: Evans, CJ, primary, Erdelyi, E, additional, Hunter, J, additional, and Barchas, JD, additional
Published: 1985
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12. Regional distribution of dynorphin and neo-endorphin peptides in rat brain, spinal cord, and pituitary

Author: Cone, RI, primary, Weber, E, additional, Barchas, JD, additional, and Goldstein, A, additional
Published: 1983
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13. Isolation and characterization of an endogenous C-terminal fragment of the alpha-neo-endorphin/dynorphin precursor from bovine caudate nucleus

Author: Evans, CJ, primary, Barchas, JD, additional, Esch, FS, additional, Bohlen, P, additional, and Weber, E, additional
Published: 1985
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14. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

Author: Anita Thapar, Lena Backlund, Lindsey Kent, Walter J. Muir, A. Jeremy Willsey, Sandra K. Loo, Michael Boehnke, Christa Lese Martin, Ania Korszun, Guiomar Oliveira, Veronica J. Vieland, Stephen W. Scherer, René S. Kahn, Darina Czamara, Jeremy R. Parr, Michael E. Goddard, Willem A. Nolen, Josep Antoni Ramos-Quiroga, Stephen Sanders, Karola Rehnstroem, Nelson B. Freimer, Erin N. Smith, Ann Olincy, Ingrid Melle, Myrna M. Weissman, James A. Knowles, William Byerley, Aravinda Chakravarti, Shaun Purcell, Jens Treutlein, Sebastian Zoellner, Hakon Hakonarson, Susanne Lucae, Markus M. Noethen, Ian B. Hickie, Marion Friedl, Srinivasa Thirumalai, Stephen Newhouse, Joseph Piven, Andrew M. McIntosh, Cathryn M. Lewis, Srdjan Djurovic, Francis J. McMahon, Ayman H. Fanous, Bernie Devlin, Steven A. McCarroll, Alan F. Schatzberg, Peter Szatmari, Marta Ribasés, C. Robert Cloninger, Brenda W.J.H. Penninx, Gerard van Grootheest, Phil Lee, Richard Anney, Elaine K. Green, Geraldine Dawson, Joseph A. Sergeant, Digby Quested, Magdalena Gross, Jack D. Barchas, Nicholas G. Martin, Timothy W. Yu, Jouke-Jan Hottenga, Mark Lathrop, Federica Tozzi, Martin Hautzinger, Alysa E. Doyle, Cinnamon S. Bloss, Sandra Meier, Louise Gailagher, David A. Collier, Farooq Amin, Michael C. Neale, Martin Schalling, Lieuwe de Haan, Bru Cormand, Falk W. Lohoff, Jennifer Crosbie, Howard J. Edenberg, Aarno Palotie, Johannes H. Smit, Robert Freedman, Katherine Gordon-Smith, Michele L. Pergadia, Enda M. Byrne, Hans-Christoph Steinhausen, Benjamin M. Neale, Anjali K. Henders, Michele T. Pato, Manuel Mattheisen, Urban Ösby, Edward M. Scolnick, Evaristus A. Nwulia, Fritz Poustka, Gonneke Willemsen, Andrew C. Heath, David St. Cair, Emma M. Quinn, I. Nicol Ferrier, John R. Kelsoe, Vanessa Hus, Andrew McQuillin, John P. Rice, William M. McMahon, Joseph Biederman, Danyu Lin, Wolfgang Maier, Frans G. Zitman, Josephine Elia, Nicholas J. Schork, Stéphane Jamain, Lizzy Rossin, Jubao Duan, Ingrid Agartz, Devin Absher, Jordan W. Smoller, Matthew W. State, Richard M. Myers, Shrikant Mane, Carlos N. Pato, William E. Bunney, Marian L. Hamshere, Manfred Uhr, Nicholas John Craddock, Astrid M. Vicente, Tobias Banaschewski, David Curtis, Anne Farmer, Scott D. Gordon, Anna K. Kaehler, Eric M. Morrow, Marcella Rietschel, Patrik K. E. Magnusson, Klaus-Peter Lesch, Rebecca McKinney, Jana Strohmaier, Thomas F. Wienker, Pablo V. Gejman, Douglas Blackwood, Maria Helena Pinto de Azevedo, Tiffany A. Greenwood, Don H. Linszen, Daniel L. Koller, Richard Bruggeman, Vinay Puri, Naomi R. Wray, Stanley J. Watson, Elena Maestrini, Valentina Moskvina, Frank Dudbridge, Danielle Posthuma, Edward G. Jones, Lambertus Klei, Sarah E. Bergen, Fan Meng, Steven P. Hamilton, Guy A. Rouleau, Pierandrea Muglia, Mikael Landén, Stephanie H. Witt, Laramie E. Duncan, Stanley Zammit, Judith A. Badner, Florian Holsboer, Eco J. C. de Geus, Daniel Moreno-De-Luca, Benjamin S. Pickard, Gunnar Morken, Michael Conlon O'Donovan, Michael Steffens, Kathryn Roeder, Dorret I. Boomsma, Paul D. Shilling, Stephan Ripke, Nigel Williams, Jeremy M. Silverman, David Craig, Mark J. Daly, Michael Bauer, Detelina Grozeva, Markus J. Schwarz, Peter Holmans, Hugh Gurling, T. Scott Stroup, Aribert Rothenberger, Gary Donohoe, Eric Fombonne, Joseph D. Buxbaum, Matthew Flicldnger, Bryan J. Mowry, Thomas Hansen, Ina Giegling, Grant W. Montgomery, Caroline M. Nievergelt, Susan L. Smalley, Jung-Ying Tzeng, David H. Ledbetter, Christopher A. Walsh, Gerard D. Schellenberg, Sarah E. Medland, Robert D. Oades, James B. Potash, Dan E. Arking, Johannes Schumacher, Michael Gill, James J. McGough, Jennifer L. Moran, Donald W. Black, Sian Caesar, Neelroop N. Parikshak, Ian W. Craig, Sabine M. Klauck, Wade H. Berrettini, T. Foroud, Peter P. Zandi, Inez Myin-Germeys, Marcus Ising, Sven Cichon, Alexandre A. Todorov, Mònica Bayés, Thomas Werge, Susan L. Slager, Stanley I. Shyn, Jim van Os, Derek W. Morris, Douglas M. Ruderfer, Thomas W. Muehleisen, Matthew C. Keller, Susmita Datta, Ian Jones, John B. Vincent, James L. Kennedy, Anthony P. Monaco, Jianxin Shi, Dale R. Nyholt, Bruno Etain, Christine Fraser, Paul Cormican, Miguel Casas, Radhika Kandaswamy, Gerome Breen, Stephen V. Faraone, Jonna Kuntsi, Thomas Bettecken, Witte J.G. Hoogendijk, Nancy G. Buccola, Franziska Degenhardt, Lyudmila Georgieva, Marion Leboyer, Alan R. Sanders, John Strauss, Dan Rujescu, Russell Schachar, Helena Medeiros, Lisa Jones, Peter M. Visscher, Lauren A. Weiss, René Breuer, John I. Nurnberger, Andreas Reif, Phoenix Kwan, Vihra Milanova, Chunyu Liu, Martin A. Kohli, Donald J. MacIntyre, Nicholas Bass, Khalid Choudhury, Edwin H. Cook, Catherine Lord, Andrew D. Paterson, Jobst Meyer, Richard P. Ebstein, Zhaoming Zhao, Niklas Laengstroem, Thomas G. Schulze, Peter Propping, Wei Xu, Robert C. Thompson, Kimberly Chambert, Jonathan Pimm, Ivan Nikolov, Pamela A. F. Madden, Kevin A. McGhee, Jacob Lawrence, Jan K. Buitelaar, Andres Ingason, Christine M. Freitag, Robert Krasucki, Wiepke Cahn, Rita M. Cantor, Christina M. Hultman, Melvin G. McInnis, Catalina Betancur, Eftichia Duketis, Michael T. Murtha, Thomas H. Wassink, Philip Asherson, John S. Witte, Elaine Kenny, Edmund J.S. Sonuga-Barke, Lydia Krabbendam, Line Olsen, Agatino Battaglia, Laura J. Scott, Annette M. Hartmann, Yunjung Kim, Richard O. Day, Edwin J. C. G. van den Oord, Ole A. Andreassen, Herbert Roeyers, Michael John Owen, Colm O'Dushlaine, Peng Zhang, Morten Mattingsdal, Michael L. Cuccaro, Margaret A. Pericak-Vance, Joachim Hallmayer, Jun Li, Pamela B. Mahon, Elisabeth B. Binder, William A. Scheftner, Daniel H. Geschwind, Christel M. Middeldorp, Josef Frank, Keith Matthews, Jennifer K. Lowe, Paul Lichtenstein, Verneri Anttila, Pamela Sklar, Szabocls Szelinger, Roel A. Ophoff, Peter McGuffin, Stefan Herms, Bettina Konte, George Kirov, Hilary Coon, Maria Hipolito, Louise Frisén, Kenneth S. Kendler, Frank Bellivier, James S. Sutdiffe, Jeffrey A. Lieberman, Todd Lencz, Susanne Hoefels, Alan W. McLean, Barbara Franke, Huda Akil, Soumya Raychaudhuri, Ellen M. Wijsman, Vishwajit L. Nimgaonkar, Roy H. Perlis, Patrick J. McGrath, Susan L. Santangelo, William Coryell, Henrik B. Rasmussen, Weihua Guan, William Lawson, Elliot S. Gershon, Sean Ennis, Aiden Corvin, Allan H. Young, Thomas B. Barrett, Jonathan L. Haines, Douglas F. Levinson, Ana Miranda, Anil K. Malhotra, S. Hong Lee, Stan F. Nelson, Anthony J. Bailey, Patrick F. Sullivan, Dorothy E. Grice, Lefkos T. Middleton, Bertram Mueller-Myhsok, Michael R. 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Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Human genetics, Psychiatry, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, Child and Adolescent Psychiatry / Psychology, Epidemiology, Gastroenterology & Hepatology, Hematology, University of St Andrews. School of Medicine, University of St Andrews. Institute of Behavioural and Neural Sciences, Psychiatrie & Neuropsychologie, MUMC+: MA Psychiatrie (3), MUMC+: Hersen en Zenuw Centrum (3), RS: MHeNs - R2 - Mental Health, ANS - Amsterdam Neuroscience, Adult Psychiatry, Child Psychiatry, Universitat de Barcelona, Perceptual and Cognitive Neuroscience (PCN), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Complex Trait Genetics, Biological Psychology, Educational Neuroscience, Clinical Neuropsychology, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, LEARN! - Social cognition and learning, LEARN! - Brain, learning and development, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), O'Dushlaine, Colm, Rossin, Lizzy, Lee, Phil H, Duncan, Laramie, Lee, S Hong, Breen, Gerome, International Inflammatory Bowel Disease Genetics Consortium (IIBDGC), Network and Pathway Analysis Subgroup of the Psychiatric Genomics Consortium, and Myin-Germeys, Inez
Subjects: Netherlands Twin Register (NTR), Statistical methods, Autism, Medizin, LOCI, Genome-wide association study, heritability, Genome-wide association studies, Histones, Genètica mèdica, 0302 clinical medicine, Histone methylation, Databases, Genetic, 2.1 Biological and endogenous factors, Psychology, GWAS, Aetiology, Psychiatric genetics, R2C, bipolar disorder, Psychiatry, 0303 health sciences, Disorders, Loci, Depression, General Neuroscience, Mental Disorders, Medical genetics, METHYLATION, Brain, 3rd-DAS, Serious Mental Illness, Psychiatric Disorders, 3. Good health, Histone, Mental Health, Schizophrenia, Mental Disorder, Cognitive Sciences, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Promoters, BDC, BURDEN, RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry, Human, Signal Transduction, medicine.medical_specialty, DISORDERS, Genomics, Network and Pathway Analysis Subgroup of Psychiatric Genomics Consortium, Burden, Biology, Methylation, Article, Biological pathway, PROMOTERS, 03 medical and health sciences, Databases, Genetic, medicine, Genetics, Humans, Genetic Predisposition to Disease, histone methylation, Bipolar disorder, Psiquiatria, AUTISM, 030304 developmental biology, Genetic association, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Neurology & Neurosurgery, Neuroscience (all), Human Genome, Neurosciences, medicine.disease, Brain Disorders, Good Health and Well Being, DE-NOVO MUTATIONS, Perturbações do Desenvolvimento Infantil e Saúde Mental, RC0321, Genome-wide Association Studies, De-novo mutations, major depression, Neuroscience, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: G.B. and S.N. acknowledge funding support for this work from the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. P.H.L. is supported by US National Institute of Mental Health (NIMH) grant K99MH101367. Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders. Postprint
Published: 2015
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15. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs

Author: Laura J. Scott, Bernie Devlin, Steven A. McCarroll, James S. Sutcliffe, Stefan Herms, Yunjung Kim, Richard O. Day, Thomas F. Wienker, Frank Dudbridge, I. Nicol Ferrier, Bettina Konte, Marta Ribasés, C. Robert Cloninger, Brenda W.J.H. Penninx, Detelina Grozeva, Herbert Roeyers, Peter Holmans, Colm O'Dushlaine, Scott D. Gordon, Sarah E. Bergen, Fan Meng, Morten Mattingsdal, Hugh Gurling, Ina Giegling, Gerard van Grootheest, Ania Korszun, Markus J. Schwarz, George Kirov, Sebastian Zöllner, Kenneth S. Kendler, Nicholas G. Martin, Michael Conlon O'Donovan, Michael C. Neale, Jim van Os, Aravinda Chakravarti, Timothy W. Yu, Mikael Landén, Inez Myin-Germeys, Markus M. Nöthen, Kathryn Roeder, James B. Potash, Alan W. McLean, Louise Gallagher, Anna K. Kähler, Thomas Bettecken, Nigel Williams, Frank Bellivier, Joseph D. Buxbaum, Derek W. Morris, Susan L. Smalley, Jung-Ying Tzeng, Martin Schalling, Douglas M. Ruderfer, Caroline M. Nievergelt, T. Scott Stroup, David H. Ledbetter, Jennifer Crosbie, Anita Thapar, Barbara Franke, Jeffrey A. Lieberman, Huda Akil, Miguel Casas, Daniel H. Geschwind, Paul Cormican, Bertram Müller-Myhsok, Lyudmila Georgieva, Robert Krasucki, Martin Hautzinger, Alysa E. Doyle, Cinnamon S. Bloss, Gerard D. Schellenberg, Todd Lencz, Melvin G. McInnis, Catalina Betancur, Josep Antoni Ramos-Quiroga, Stephen Sanders, Eftichia Duketis, Don H. Linszen, Matthew W. State, Richard M. Myers, Soumya Raychaudhuri, Lizzy Rossin, Howard J. Edenberg, Michael E. Goddard, S. Hong Lee, Elisabeth B. Binder, Pablo V. Gejman, William A. Scheftner, Wolfgang Maier, Judith A. Badner, Christel M. Middeldorp, Maria Helena Pinto de Azevedo, Johannes H. Smit, Willem A. Nolen, Lieuwe de Haan, Gonneke Willemsen, Keith Matthews, Ellen M. Wijsman, Jennifer K. Lowe, Rebecca McKinney, Magdalena Gross, Dorothy E. Grice, James A. Knowles, Andrew C. Heath, Jana Strohmaier, Vishwajit L. Nimgaonkar, William Byerley, William E. Bunney, Dan E. Arking, Andrew McQuillin, William M. McMahon, Manuel Mattheisen, Hans-Christoph Steinhausen, Joseph Biederman, Guy A. Rouleau, James J. McGough, Sian Caesar, Edward M. Scolnick, Lefkos T. Middleton, Jack D. Barchas, Ian B. Hickie, Danyu Lin, Patrik K. E. Magnusson, Douglas Blackwood, Francis J. McMahon, Ingrid Agartz, Elena Maestrini, Marian L. Hamshere, Lindsey Kent, Walter J. Muir, Stephan Ripke, Lydia Krabbendam, Christine Fraser, Maria Hipolito, Louise Frisén, Eric Fombonne, Emma M. Quinn, Michael Bauer, Richard P. Ebstein, Michael Steffens, Jordan W. Smoller, Stanley J. Watson, Michael Boehnke, Philip Asherson, Agatino Battaglia, Elliot S. Gershon, Russell Schachar, Marcus Ising, Peng Zhang, Margaret A. Pericak-Vance, Joachim Hallmayer, Sean Ennis, Radhika Kandaswamy, René S. Kahn, Susanne Hoefels, Thomas W. Mühleisen, Pamela Sklar, Paul Lichtenstein, Verneri Anttila, Michael L. Cuccaro, Florian Holsboer, René Breuer, Eric M. Morrow, Vinay Puri, Naomi R. Wray, Szabocls Szelinger, Sabine M. Klauck, John B. Vincent, Shrikant Mane, Aribert Rothenberger, Marion Friedl, Ian Jones, Khalid Choudhury, Michael R. Barnes, Adebayo Anjorin, Edwin H. Cook, William Lawson, Allan H. Young, Lambertus Klei, Bryan J. Mowry, Johannes Schumacher, Michael Gill, James L. Kennedy, Marcella Rietschel, Aiden Corvin, Henrik B. Rasmussen, Susmita Datta, Kimberly Chambert, Daniel Moreno-De-Luca, Benjamin S. Pickard, Stan F. Nelson, Veronica J. Vieland, Stephen W. Scherer, Peter M. Visscher, John Strauss, Andreas Reif, Andrew D. Paterson, Ann Olincy, Phoenix Kwan, Anthony J. Bailey, Patrick F. Sullivan, Pierandrea Muglia, Gunnar Morken, Susanne Lucae, Ayman H. Fanous, Jacob Lawrence, Donald J. MacIntyre, Nancy G. Buccola, Rita M. Cantor, Christina M. Hultman, Weihua Guan, Anthony P. Monaco, Jouke-Jan Hottenga, Elaine Kenny, Jianxin Shi, Dale R. Nyholt, Kevin A. McGhee, Falk W. Lohoff, Jonna Kuntsi, Niklas Långström, John I. Nurnberger, Nelson B. Freimer, Erin N. Smith, John P. Rice, Michael T. Murtha, Thomas H. Wassink, Alexandre A. Todorov, Edmund J.S. Sonuga-Barke, Dan Rujescu, Roy H. Perlis, John S. Witte, Christopher A. Walsh, Matthew C. Keller, Pamela B. Mahon, Patrick J. McGrath, Susan L. Santangelo, Annette M. Hartmann, Ole A. Andreassen, Tatiana Foroud, Shaun Purcell, Josef Frank, Douglas F. Levinson, William Coryell, Ana Miranda, Alan F. Schatzberg, Peter Szatmari, Jun Li, Gerome Breen, Stephen V. Faraone, Anil K. Malhotra, Helena Medeiros, Martin A. Kohli, Nicholas Bass, Catherine Lord, Peter Propping, Wei Xu, Federica Tozzi, Ivan Nikolov, Jan K. Buitelaar, Thomas G. Schulze, Katherine Gordon-Smith, Michele L. Pergadia, Fritz Poustka, Valentina Moskvina, David Curtis, Tobias Banaschewski, Devin Absher, Danielle Posthuma, Stanley Zammit, Gary Donohoe, Ingrid Melle, Karola Rehnström, Thomas Hansen, Myrna M. Weissman, Stanley I. Shyn, Hakon Hakonarson, Christa Lese Martin, Digby Quested, Darina Czamara, Jeremy R. Parr, Pamela A. F. Madden, Jens Treutlein, Aarno Palotie, Robert Freedman, Sandra Meier, Bru Cormand, Nicholas J. Schork, Michele T. Pato, John R. Kelsoe, Vanessa Hus, Frans G. Zitman, Josephine Elia, David St Clair, Roel A. Ophoff, Peter McGuffin, Jonathan Pimm, Jonathan L. Haines, Wiepke Cahn, Matthew Flickinger, Steven P. Hamilton, Michael John Owen, Paul D. Shilling, Jeremy M. Silverman, David Craig, Mark J. Daly, Sarah E. Medland, Robert D. Oades, Marion Leboyer, Alan R. Sanders, Vihra Milanova, Chunyu Liu, Jobst Meyer, Dorret I. Boomsma, Evaristus A. Nwulia, Thomas B. Barrett, Jennifer L. Moran, Donald W. Black, Mònica Bayés, Witte J.G. Hoogendijk, Franziska Degenhardt, Benjamin M. Neale, Daniel L. Koller, Carlos N. Pato, Nicholas John Craddock, Richard Bruggeman, Enda M. Byrne, Edward G. Jones, Eco J. C. de Geus, Stéphane Jamain, Jubao Duan, Anne Farmer, Astrid M. Vicente, Grant W. Montgomery, Thomas Werge, Cathryn M. Lewis, Srdjan Djurovic, Phil Lee, Richard Anney, Elaine K. Green, Wade H. Berrettini, Peter P. Zandi, Susan L. Slager, Stephanie H. Witt, Ian W. Craig, Lisa Jones, Sven Cichon, Bruno Etain, Mark Lathrop, Hilary Coon, Robert C. Thompson, Lena Backlund, A. Jeremy Willsey, Andres Ingason, Christine M. Freitag, Sandra K. Loo, Guiomar Oliveira, Line Olsen, Edwin J. C. G. van den Oord, Geraldine Dawson, Joseph A. Sergeant, David A. Collier, Farooq Amin, Srinivasa Thirumalai, Manfred Uhr, Joseph Piven, Andrew M. McIntosh, Anjali K. Henders, Urban Ösby, Klaus-Peter Lesch, Tiffany A. Greenwood, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Perceptual and Cognitive Neuroscience (PCN), Lee, S Hong, Ripke, Stephan, Neale, Benjamin M, Faraone, Stephen V, Wray, Naomi R, Cross-Disorder Group of the Psychiatric Genomics Consortium, International Inflammatory Bowel Disease Genetics Consortium (IIBDGC), Queensland Brain Institute, University of Queensland [Brisbane], Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], SUNY Upstate Medical University, State University of New York (SUNY), Mount Sinai School of Medicine, Department of Psychiatry-Icahn School of Medicine at Mount Sinai [New York] (MSSM), Psychiatric and Neurodevelopmental Genetics Unit, Queensland Centre for Mental Health Research, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council (MRC)-School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff], New South Wales Department of Primary Industries (NSW DPI), Faculty of Land and Food Resources, University of Melbourne, HudsonAlpha Institute for Biotechnology [Huntsville, AL], Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Diakonhjemmet Hospital, University of Michigan [Ann Arbor], University of Michigan System, Molecular and Behavioral Neuroscience Institute (MBNI), University of Michigan System-University of Michigan System, Emory University [Atlanta, GA], Oslo University Hospital [Oslo], University College of London [London] (UCL), Trinity College Dublin, Johns Hopkins University School of Medicine [Baltimore], MRC Social Genetic Developmental and Psychiatry Centre, Institute of Psychiatry, King's College London, University of Coimbra [Portugal] (UC), Karolinska Institutet [Stockholm], University of Chicago, University of British Columbia (UBC), Department of Child and Adolescent Psychiatry and Psychotherapy [Mannheim], Universität Heidelberg [Heidelberg] = Heidelberg University, Weill Medical College of Cornell University [New York], GlaxoSmithKline, Glaxo Smith Kline, Portland Veterans Administration Medical Center, Windeyer Institute for Medical Sciences, IRCCS Fondazione Stella Maris [Pisa], University Hospital Carl Gustav Carus [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Centro Nacional de Analisis Genomico [Barcelona] (CNAG), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - 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Georg-August-Universität Göttingen, Yale University School of Medicine, Georg-August-University [Göttingen], ANS - Amsterdam Neuroscience, Adult Psychiatry, Child Psychiatry, Psychiatry, Human genetics, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, Lee SH, Ripke S, Neale BM, Faraone SV, Purcell SM, Perlis RH, Mowry BJ, Thapar A, Goddard ME, Witte JS, Absher D, Agartz I, Akil H, Amin F, Andreassen OA, Anjorin A, Anney R, Anttila V, Arking DE, Asherson P, Azevedo MH, Backlund L, Badner JA, Bailey AJ, Banaschewski T, Barchas JD, Barnes MR, Barrett TB, Bass N, Battaglia A, Bauer M, Bayés M, Bellivier F, Bergen SE, Berrettini W, Betancur C, Bettecken T, Biederman J, Binder EB, Black DW, Blackwood DH, Bloss CS, Boehnke M, Boomsma DI, Breen G, Breuer R, Bruggeman R, Cormican P, Buccola NG, Buitelaar JK, Bunney WE, Buxbaum JD, Byerley WF, Byrne EM, Caesar S, Cahn W, Cantor RM, Casas M, Chakravarti A, Chambert K, Choudhury K, Cichon S, Cloninger CR, Collier DA, Cook EH, Coon H, Cormand B, Corvin A, Coryell WH, Craig DW, Craig IW, Crosbie J, Cuccaro ML, Curtis D, Czamara D, Datta S, Dawson G, Day R, De Geus EJ, Degenhardt F, Djurovic S, Donohoe GJ, Doyle AE, Duan J, Dudbridge F, Duketis E, Ebstein RP, Edenberg HJ, Elia J, Ennis S, Etain B, Fanous A, Farmer AE, Ferrier IN, Flickinger M, Fombonne E, Foroud T, Frank J, Franke B, Fraser C, Freedman R, Freimer NB, Freitag CM, Friedl M, Frisén L, Gallagher L, Gejman PV, Georgieva L, Gershon ES, Geschwind DH, Giegling I, Gill M, Gordon SD, Gordon-Smith K, Green EK, Greenwood TA, Grice DE, Gross M, Grozeva D, Guan W, Gurling H, De Haan L, Haines JL, Hakonarson H, Hallmayer J, Hamilton SP, Hamshere ML, Hansen TF, Hartmann AM, Hautzinger M, Heath AC, Henders AK, Herms S, Hickie IB, Hipolito M, Hoefels S, Holmans PA, Holsboer F, Hoogendijk WJ, Hottenga JJ, Hultman CM, Hus V, Ingason A, Ising M, Jamain S, Jones EG, Jones I, Jones L, Tzeng JY, Kähler AK, Kahn RS, Kandaswamy R, Keller MC, Kennedy JL, Kenny E, Kent L, Kim Y, Kirov GK, Klauck SM, Klei L, Knowles JA, Kohli MA, Koller DL, Konte B, Korszun A, Krabbendam L, Krasucki R, Kuntsi J, Kwan P, Landén M, Långström N, Lathrop M, Lawrence J, Lawson WB, Leboyer M, Ledbetter DH, Lee PH, Lencz T, Lesch KP, Levinson DF, Lewis CM, Li J, Lichtenstein P, Lieberman JA, Lin DY, Linszen DH, Liu C, Lohoff FW, Loo SK, Lord C, Lowe JK, Lucae S, MacIntyre DJ, Madden PA, Maestrini E, Magnusson PK, Mahon PB, Maier W, Malhotra AK, Mane SM, Martin CL, Martin NG, Mattheisen M, Matthews K, Mattingsdal M, McCarroll SA, McGhee KA, McGough JJ, McGrath PJ, McGuffin P, McInnis MG, McIntosh A, McKinney R, McLean AW, McMahon FJ, McMahon WM, McQuillin A, Medeiros H, Medland SE, Meier S, Melle I, Meng F, Meyer J, Middeldorp CM, Middleton L, Milanova V, Miranda A, Monaco AP, Montgomery GW, Moran JL, Moreno-De-Luca D, Morken G, Morris DW, Morrow EM, Moskvina V, Muglia P, Mühleisen TW, Muir WJ, Müller-Myhsok B, Murtha M, Myers RM, Myin-Germeys I, Neale MC, Nelson SF, Nievergelt CM, Nikolov I, Nimgaonkar V, Nolen WA, Nöthen MM, Nurnberger JI, Nwulia EA, Nyholt DR, O'Dushlaine C, Oades RD, Olincy A, Oliveira G, Olsen L, Ophoff RA, Osby U, Owen MJ, Palotie A, Parr JR, Paterson AD, Pato CN, Pato MT, Penninx BW, Pergadia ML, Pericak-Vance MA, Pickard BS, Pimm J, Piven J, Posthuma D, Potash JB, Poustka F, Propping P, Puri V, Quested DJ, Quinn EM, Ramos-Quiroga JA, Rasmussen HB, Raychaudhuri S, Rehnström K, Reif A, Ribasés M, Rice JP, Rietschel M, Roeder K, Roeyers H, Rossin L, Rothenberger A, Rouleau G, Ruderfer D, Rujescu D, Sanders AR, Sanders SJ, Santangelo SL, Sergeant JA, Schachar R, Schalling M, Schatzberg AF, Scheftner WA, Schellenberg GD, Scherer SW, Schork NJ, Schulze TG, Schumacher J, Schwarz M, Scolnick E, Scott LJ, Shi J, Shilling PD, Shyn SI, Silverman JM, Slager SL, Smalley SL, Smit JH, Smith EN, Sonuga-Barke EJ, St Clair D, State M, Steffens M, Steinhausen HC, Strauss JS, Strohmaier J, Stroup TS, Sutcliffe JS, Szatmari P, Szelinger S, Thirumalai S, Thompson RC, Todorov AA, Tozzi F, Treutlein J, Uhr M, van den Oord EJ, Van Grootheest G, Van Os J, Vicente AM, Vieland VJ, Vincent JB, Visscher PM, Walsh CA, Wassink TH, Watson SJ, Weissman MM, Werge T, Wienker TF, Wijsman EM, Willemsen G, Williams N, Willsey AJ, Witt SH, Xu W, Young AH, Yu TW, Zammit S, Zandi PP, Zhang P, Zitman FG, Zöllner S, Devlin B, Kelsoe JR, Sklar P, Daly MJ, O'Donovan MC, Craddock N, Sullivan PF, Smoller JW, Kendler KS, Wray NR, Cardiff University-Medical Research Council (MRC), HudsonAlpha Institute for Biotechnology, The Institute of Psychiatry-King‘s College London, Cornell University-Weill Medical College of Cornell University [New York], Stanford University Medical School, Technische Universität Dresden (TUD)-University Hospital Carl Gustav Carus, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, McGill University-Montreal Children's Hospital, Universidade Federal do Rio de Janeiro [Rio de Janeiro] (UFRJ), Stanford University School of Medicine [Stanford], Stanford University [Stanford], Eberhard Karls Universität Tübingen, Friedrich Alexander University [Erlangen-Nürnberg], Università di Bologna [Bologna] (UNIBO), University of Toronto-The Hospital for Sick Children-Department of Molecular Genetics-McLaughlin Centre, Washington University School of Medicine, Ghent University [Belgium] (UGENT), University of Goettingen, CHUM Research Center, Psychiatry and Behavioral Science, Stanford University School of Medicine [CA, USA], Aalborg Psychiatric Hospital, Aarhus University Hospital, Washington University in St Louis, Instituto Nacional de Saude Dr Ricardo Jorge, Oades, Robert D., Guellaen, Georges, Medical Oncology, Epidemiology, Child and Adolescent Psychiatry / Psychology, and Hematology
Subjects: Netherlands Twin Register (NTR), Medizin, Inheritance Patterns, Social Sciences, AUTISM SPECTRUM DISORDERS, nosology, heritability, COMMON SNPS, 0302 clinical medicine, Crohn Disease, SCHIZOPHRENIA, Child, Psychiatric genetics, Genetics & Heredity, MAJOR DEPRESSIVE DISORDER, RISK, 0303 health sciences, ATTENTION-DEFICIT/HYPERACTIVITY DISORDER, 120 000 Neuronal Coherence, Mental Disorders, Variants, BIPOLAR DISORDER, ASSOCIATION, Genomic disorders and inherited multi-system disorders [DCN PAC - Perception action and control IGMD 3], Psychiatric Disorders, CROHNS-DISEASE, 3. Good health, Schizophrenia, genetic association study, Medical genetics, Major depressive disorder, SNPs, Adult, medicine.medical_specialty, genetic etiology, medical genetics, DEFICIT HYPERACTIVITY DISORDER, Biology, Polymorphism, Single Nucleotide, behavioral disciplines and activities, Article, Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3], Heritability, Genetic Heterogeneity, 03 medical and health sciences, Prevalence of mental disorders, mental disorders, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics, medicine, ddc:61, Humans, Attention deficit hyperactivity disorder, Genetic Predisposition to Disease, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, DCN PAC - Perception action and control NCEBP 9 - Mental health, ddc:610, Medizinische Fakultät » Universitätsklinikum Essen » LVR-Klinikum Essen » Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, Bipolar disorder, Psychiatry, 030304 developmental biology, Depressive Disorder, Major, Genome, Human, Genetic heterogeneity, medicine.disease, schizophrenia, Attention Deficit Disorder with Hyperactivity, Child Development Disorders, Pervasive, Perturbações do Desenvolvimento Infantil e Saúde Mental, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: AM Vicente - Cross-Disorder Group of the Psychiatric Genomics Consortium Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
Published: 2013
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16. Neurotransmission-related gene expression in the frontal pole is altered in subjects with bipolar disorder and schizophrenia.

Author: Medina AM, Hagenauer MH, Krolewski DM, Hughes E, Forrester LCT, Walsh DM, Waselus M, Richardson E, Turner CA, Sequeira PA, Cartagena PM, Thompson RC, Vawter MP, Bunney BG, Myers RM, Barchas JD, Lee FS, Schatzberg AF, Bunney WE, Akil H, and Watson SJ Jr
Subjects: Humans, Adolescent, Frontal Lobe metabolism, Gene Expression, Synaptic Transmission genetics, Bipolar Disorder genetics, Bipolar Disorder metabolism, Schizophrenia metabolism
Abstract: The frontal pole (Brodmann area 10, BA10) is the largest cytoarchitectonic region of the human cortex, performing complex integrative functions. BA10 undergoes intensive adolescent grey matter pruning prior to the age of onset for bipolar disorder (BP) and schizophrenia (SCHIZ), and its dysfunction is likely to underly aspects of their shared symptomology. In this study, we investigated the role of BA10 neurotransmission-related gene expression in BP and SCHIZ. We performed qPCR to measure the expression of 115 neurotransmission-related targets in control, BP, and SCHIZ postmortem samples (n = 72). We chose this method for its high sensitivity to detect low-level expression. We then strengthened our findings by performing a meta-analysis of publicly released BA10 microarray data (n = 101) and identified sources of convergence with our qPCR results. To improve interpretation, we leveraged the unusually large database of clinical metadata accompanying our samples to explore the relationship between BA10 gene expression, therapeutics, substances of abuse, and symptom profiles, and validated these findings with publicly available datasets. Using these convergent sources of evidence, we identified 20 neurotransmission-related genes that were differentially expressed in BP and SCHIZ in BA10. These results included a large diagnosis-related decrease in two important therapeutic targets with low levels of expression, HTR2B and DRD4, as well as other findings related to dopaminergic, GABAergic and astrocytic function. We also observed that therapeutics may produce a differential expression that opposes diagnosis effects. In contrast, substances of abuse showed similar effects on BA10 gene expression as BP and SCHIZ, potentially amplifying diagnosis-related dysregulation., (© 2023. The Author(s).)
Published: 2023
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17. Large Common Mitochondrial DNA Deletions Are Associated with a Mitochondrial SNP T14798C Near the 3' Breakpoints.

Author: Hjelm BE, Ramiro C, Rollins BL, Omidsalar AA, Gerke DS, Das SC, Sequeira A, Morgan L, Schatzberg AF, Barchas JD, Lee FS, Myers RM, Watson SJ, Akil H, Bunney WE, and Vawter MP
Abstract: Introduction: Large somatic deletions of mitochondrial DNA (mtDNA) accumulate with aging in metabolically active tissues such as the brain. We have cataloged the breakpoints and frequencies of large mtDNA deletions in the human brain., Methods: We quantified 112 high-frequency mtDNA somatic deletions across four human brain regions with the Splice-Break2 pipeline. In addition, we utilized PLINK/Seq to test the association of mitochondrial genotypes with the abundance of these high-frequency mtDNA deletions. A conservative p value threshold of 5E-08 was used to find the significant loci., Results: One mtDNA SNP (T14798C) was significantly associated with mtDNA deletions in two brain regions, the dorsolateral prefrontal cortex (DLPFC) and the superior temporal gyrus. Since the DLPFC showed the most robust association between T14798C and two deletion breakpoints (7816-14807 and 5462-14807), this association was tested in the DLPFC of a replication sample and validated the first results. Incorporating the C allele at 14,798 bp increased the perfect/imperfect length of the repeat at the 3' breakpoint of the two associated deletions., Conclusion: This is the first study to identify the association of mtDNA SNP with large mtDNA deletions in the human brain. The T14798C allele located in the MT-CYB gene is a common polymorphism that occurs in several mitochondrial haplogroups. We hypothesize that the T14798C association with two deletions occurs by extending the repeat length around the 3' deletion breakpoints. This simple mechanism suggests that mtDNA SNPs can affect the mitochondrial genome structure, especially in brain where high levels of reactive oxygen species lead to deletion accumulation with aging., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.)
Published: 2023
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18. Mitochondria DNA copy number, mitochondria DNA total somatic deletions, Complex I activity, synapse number, and synaptic mitochondria number are altered in schizophrenia and bipolar disorder.

Author: Das SC, Hjelm BE, Rollins BL, Sequeira A, Morgan L, Omidsalar AA, Schatzberg AF, Barchas JD, Lee FS, Myers RM, Watson SJ, Akil H, Bunney WE, and Vawter MP
Subjects: DNA Copy Number Variations, DNA, Mitochondrial genetics, Female, Humans, Mitochondria genetics, Mitochondria metabolism, Synapses metabolism, Bipolar Disorder metabolism, Schizophrenia metabolism
Abstract: Mitochondrial dysfunction is a neurobiological phenomenon implicated in the pathophysiology of schizophrenia and bipolar disorder that can synergistically affect synaptic neurotransmission. We hypothesized that schizophrenia and bipolar disorder share molecular alterations at the mitochondrial and synaptic levels. Mitochondria DNA (mtDNA) copy number (CN), mtDNA common deletion (CD), mtDNA total deletion, complex I activity, synapse number, and synaptic mitochondria number were studied in the postmortem human dorsolateral prefrontal cortex (DLPFC), superior temporal gyrus (STG), primary visual cortex (V1), and nucleus accumbens (NAc) of controls (CON), and subjects with schizophrenia (SZ), and bipolar disorder (BD). The results showed (i) the mtDNA CN is significantly higher in DLPFC of both SZ and BD, decreased in the STG of BD, and unaltered in V1 and NAc of both SZ and BD; (ii) the mtDNA CD is significantly higher in DLPFC of BD while unaltered in STG, V1, and NAc of both SZ and BD; (iii) The total deletion burden is significantly higher in DLPFC in both SZ and BD while unaltered in STG, V1, and NAc of SZ and BD; (iv) Complex I activity is significantly lower in DLPFC of both SZ and BD, which is driven by the presence of medications, with no alteration in STG, V1, and NAc. In addition, complex I protein concentration, by ELISA, was decreased across three cortical regions of SZ and BD subjects; (v) The number of synapses is decreased in DLPFC of both SZ and BD, while the synaptic mitochondria number was significantly lower in female SZ and female BD compared to female controls. Overall, these findings will pave the way to understand better the pathophysiology of schizophrenia and bipolar disorder for therapeutic interventions., (© 2022. The Author(s).)
Published: 2022
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19. Rare coding variants in ten genes confer substantial risk for schizophrenia.

Author: Singh T, Poterba T, Curtis D, Akil H, Al Eissa M, Barchas JD, Bass N, Bigdeli TB, Breen G, Bromet EJ, Buckley PF, Bunney WE, Bybjerg-Grauholm J, Byerley WF, Chapman SB, Chen WJ, Churchhouse C, Craddock N, Cusick CM, DeLisi L, Dodge S, Escamilla MA, Eskelinen S, Fanous AH, Faraone SV, Fiorentino A, Francioli L, Gabriel SB, Gage D, Gagliano Taliun SA, Ganna A, Genovese G, Glahn DC, Grove J, Hall MH, Hämäläinen E, Heyne HO, Holi M, Hougaard DM, Howrigan DP, Huang H, Hwu HG, Kahn RS, Kang HM, Karczewski KJ, Kirov G, Knowles JA, Lee FS, Lehrer DS, Lescai F, Malaspina D, Marder SR, McCarroll SA, McIntosh AM, Medeiros H, Milani L, Morley CP, Morris DW, Mortensen PB, Myers RM, Nordentoft M, O'Brien NL, Olivares AM, Ongur D, Ouwehand WH, Palmer DS, Paunio T, Quested D, Rapaport MH, Rees E, Rollins B, Satterstrom FK, Schatzberg A, Scolnick E, Scott LJ, Sharp SI, Sklar P, Smoller JW, Sobell JL, Solomonson M, Stahl EA, Stevens CR, Suvisaari J, Tiao G, Watson SJ, Watts NA, Blackwood DH, Børglum AD, Cohen BM, Corvin AP, Esko T, Freimer NB, Glatt SJ, Hultman CM, McQuillin A, Palotie A, Pato CN, Pato MT, Pulver AE, St Clair D, Tsuang MT, Vawter MP, Walters JT, Werge TM, Ophoff RA, Sullivan PF, Owen MJ, Boehnke M, O'Donovan MC, Neale BM, and Daly MJ
Subjects: Case-Control Studies, Exome, Genetic Predisposition to Disease genetics, Humans, Receptors, N-Methyl-D-Aspartate genetics, Mutation, Neurodevelopmental Disorders genetics, Schizophrenia genetics
Abstract: Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3-50, P < 2.14 × 10 -6 ) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-D-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders 1 , epilepsy and severe neurodevelopmental disorders 2 , although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk 3 , suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Published: 2022
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20. Electrophysiological evaluation of extracellular spermine and alkaline pH on synaptic human GABA A receptors.

Author: Limon A, Delbruck E, Yassine A, Pandya D, Myers RM, Barchas JD, Lee F, Schatzberg, Watson SJ, Akil H, Bunney WE, Vawter MP, and Sequeira A
Subjects: Humans, Hydrogen-Ion Concentration, Neurons drug effects, Neurons metabolism, Oocytes drug effects, Oocytes metabolism, Prefrontal Cortex metabolism, Synapses metabolism, Synaptic Membranes metabolism, Prefrontal Cortex drug effects, Receptors, GABA-A metabolism, Spermine pharmacology, Synapses drug effects, Synaptic Membranes drug effects
Abstract: Polyamines have fundamental roles in brain homeostasis as key modulators of cellular excitability. Several studies have suggested alterations in polyamine metabolism in stress related disorders, suicide, depression, and neurodegeneration, making the pharmacological modulation of polyamines a highly appealing therapeutic strategy. Polyamines are small aliphatic molecules that can modulate cationic channels involved in neuronal excitability. Previous indirect evidence has suggested that polyamines can modulate anionic GABA A receptors (GABA A Rs), which mediate inhibitory signaling and provide a direct route to reduce hyperexcitability. Here, we attempted to characterize the effect that spermine, the polyamine with the strongest reported effect on GABA A Rs, has on human postmortem native GABA A Rs. We microtransplanted human synaptic membranes from the dorsolateral prefrontal cortex of four cases with no history of mental or neurological disorders, and directly recorded spermine effects on ionic GABA A Rs responses on microtransplanted oocytes. We show that in human synapses, inhibition of GABA A Rs by spermine was better explained by alkalization of the extracellular solution. Additionally, spermine had no effect on the potentiation of GABA-currents by diazepam, indicating that even if diazepam binding is enhanced by spermine, it does not translate to changes in functional activity. Our results clearly demonstrate that while extracellular spermine does not have direct effects on human native synaptic GABA A Rs, spermine-mediated shifts of pH inhibit GABA A Rs. Potential spermine-mediated increase of pH in synapses in vivo may therefore participate in increased neuronal activity observed during physiological and pathological states, and during metabolic alterations that increase the release of spermine to the extracellular milieu.
Published: 2019
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21. Splice-Break: exploiting an RNA-seq splice junction algorithm to discover mitochondrial DNA deletion breakpoints and analyses of psychiatric disorders.

Author: Hjelm BE, Rollins B, Morgan L, Sequeira A, Mamdani F, Pereira F, Damas J, Webb MG, Weber MD, Schatzberg AF, Barchas JD, Lee FS, Akil H, Watson SJ, Myers RM, Chao EC, Kimonis V, Thompson PM, Bunney WE, and Vawter MP
Subjects: Algorithms, Base Sequence, Brain metabolism, Brain pathology, DNA Breaks, DNA, Mitochondrial chemistry, Depressive Disorder, Major blood, Female, Humans, Male, Polymerase Chain Reaction, Computational Biology methods, DNA, Mitochondrial genetics, Depressive Disorder, Major genetics, RNA Splice Sites genetics, Sequence Analysis, RNA methods, Sequence Deletion
Abstract: Deletions in the 16.6 kb mitochondrial genome have been implicated in numerous disorders that often display muscular and/or neurological symptoms due to the high-energy demands of these tissues. We describe a catalogue of 4489 putative mitochondrial DNA (mtDNA) deletions, including their frequency and relative read rate, using a combinatorial approach of mitochondria-targeted PCR, next-generation sequencing, bioinformatics, post-hoc filtering, annotation, and validation steps. Our bioinformatics pipeline uses MapSplice, an RNA-seq splice junction detection algorithm, to detect and quantify mtDNA deletion breakpoints rather than mRNA splices. Analyses of 93 samples from postmortem brain and blood found (i) the 4977 bp 'common deletion' was neither the most frequent deletion nor the most abundant; (ii) brain contained significantly more deletions than blood; (iii) many high frequency deletions were previously reported in MitoBreak, suggesting they are present at low levels in metabolically active tissues and are not exclusive to individuals with diagnosed mitochondrial pathologies; (iv) many individual deletions (and cumulative metrics) had significant and positive correlations with age and (v) the highest deletion burdens were observed in major depressive disorder brain, at levels greater than Kearns-Sayre Syndrome muscle. Collectively, these data suggest the Splice-Break pipeline can detect and quantify mtDNA deletions at a high level of resolution., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Published: 2019
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22. Inference of cell type content from human brain transcriptomic datasets illuminates the effects of age, manner of death, dissection, and psychiatric diagnosis.

Author: Hagenauer MH, Schulmann A, Li JZ, Vawter MP, Walsh DM, Thompson RC, Turner CA, Bunney WE, Myers RM, Barchas JD, Schatzberg AF, Watson SJ, and Akil H
Subjects: Age Factors, Animals, Female, Gene Ontology, Humans, Male, Mental Disorders diagnosis, Mental Disorders mortality, Mice, Oligonucleotide Array Sequence Analysis, Brain metabolism, Brain pathology, Gene Expression Profiling, Mental Disorders genetics, Mental Disorders pathology
Abstract: Psychiatric illness is unlikely to arise from pathology occurring uniformly across all cell types in affected brain regions. Despite this, transcriptomic analyses of the human brain have typically been conducted using macro-dissected tissue due to the difficulty of performing single-cell type analyses with donated post-mortem brains. To address this issue statistically, we compiled a database of several thousand transcripts that were specifically-enriched in one of 10 primary cortical cell types in previous publications. Using this database, we predicted the relative cell type content for 833 human cortical samples using microarray or RNA-Seq data from the Pritzker Consortium (GSE92538) or publicly-available databases (GSE53987, GSE21935, GSE21138, CommonMind Consortium). These predictions were generated by averaging normalized expression levels across transcripts specific to each cell type using our R-package BrainInABlender (validated and publicly-released on github). Using this method, we found that the principal components of variation in the datasets strongly correlated with the predicted neuronal/glial content of the samples. This variability was not simply due to dissection-the relative balance of brain cell types appeared to be influenced by a variety of demographic, pre- and post-mortem variables. Prolonged hypoxia around the time of death predicted increased astrocytic and endothelial gene expression, illustrating vascular upregulation. Aging was associated with decreased neuronal gene expression. Red blood cell gene expression was reduced in individuals who died following systemic blood loss. Subjects with Major Depressive Disorder had decreased astrocytic gene expression, mirroring previous morphometric observations. Subjects with Schizophrenia had reduced red blood cell gene expression, resembling the hypofrontality detected in fMRI experiments. Finally, in datasets containing samples with especially variable cell content, we found that controlling for predicted sample cell content while evaluating differential expression improved the detection of previously-identified psychiatric effects. We conclude that accounting for cell type can greatly improve the interpretability of transcriptomic data., Competing Interests: The authors are members of the Pritzker Neuropsychiatric Disorders Research Consortium, which is supported by Pritzker Neuropsychiatric Disorders Research Fund, LLC. A shared intellectual property agreement exists between the academic and philanthropic entities of the consortium. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The authors have declared that no competing interests exist.
Published: 2018
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23. Mitochondrial Complex I Deficiency in Schizophrenia and Bipolar Disorder and Medication Influence.

Author: Rollins BL, Morgan L, Hjelm BE, Sequeira A, Schatzberg AF, Barchas JD, Lee FS, Myers RM, Watson SJ, Akil H, Potkin SG, Bunney WE, and Vawter MP
Abstract: Subjects with schizophrenia (SZ) and bipolar disorder (BD) show decreased protein and transcript levels for mitochondrial complex I. In vitro results suggest antipsychotic and antidepressant drugs may be responsible. We measured complex I activity in BD, SZ, and controls and presence of antipsychotic and antidepressant medications, mitochondrial DNA (mtDNA) copy number, and the mtDNA "common deletion" in the brain. Complex I activity in the prefrontal cortex was decreased by 45% in SZ compared to controls ( p = 0.02), while no significant difference was found in BD. Complex I activity was significantly decreased ( p = 0.01) in pooled cases (SZ and BD) that had detectable psychotropic medications and drugs compared to pooled cases with no detectable levels. Subjects with age at onset in their teens and psychotropic medications showed decreased ( p < 0.05) complex I activity compared to subjects with an adult age at onset. Both SZ and BD groups displayed significant increases ( p < 0.05) in mtDNA copy number compared to controls; however, common deletion burden was not altered. Complex I deficiency is found in SZ brain tissue, and psychotropic medications may play a role in mitochondrial dysfunction. Studies of medication-free first-episode psychosis patients are needed to elucidate whether mitochondrial pathophysiology occurs independent of medication effects.
Published: 2018
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24. Post-mortem molecular profiling of three psychiatric disorders.

Author: Ramaker RC, Bowling KM, Lasseigne BN, Hagenauer MH, Hardigan AA, Davis NS, Gertz J, Cartagena PM, Walsh DM, Vawter MP, Jones EG, Schatzberg AF, Barchas JD, Watson SJ, Bunney BG, Akil H, Bunney WE, Li JZ, Cooper SJ, and Myers RM
Subjects: Autopsy, Bipolar Disorder metabolism, Chromatin Immunoprecipitation, Depressive Disorder, Major metabolism, Early Growth Response Protein 1 metabolism, Female, Humans, Male, Metabolomics, Schizophrenia metabolism, Sequence Analysis, RNA, Bipolar Disorder genetics, Brain metabolism, Depressive Disorder, Major genetics, Schizophrenia genetics, Transcriptome
Abstract: Background: Psychiatric disorders are multigenic diseases with complex etiology that contribute significantly to human morbidity and mortality. Although clinically distinct, several disorders share many symptoms, suggesting common underlying molecular changes exist that may implicate important regulators of pathogenesis and provide new therapeutic targets., Methods: We performed RNA sequencing on tissue from the anterior cingulate cortex, dorsolateral prefrontal cortex, and nucleus accumbens from three groups of 24 patients each diagnosed with schizophrenia, bipolar disorder, or major depressive disorder, and from 24 control subjects. We identified differentially expressed genes and validated the results in an independent cohort. Anterior cingulate cortex samples were also subjected to metabolomic analysis. ChIP-seq data were used to characterize binding of the transcription factor EGR1., Results: We compared molecular signatures across the three brain regions and disorders in the transcriptomes of post-mortem human brain samples. The most significant disease-related differences were in the anterior cingulate cortex of schizophrenia samples compared to controls. Transcriptional changes were assessed in an independent cohort, revealing the transcription factor EGR1 as significantly down-regulated in both cohorts and as a potential regulator of broader transcription changes observed in schizophrenia patients. Additionally, broad down-regulation of genes specific to neurons and concordant up-regulation of genes specific to astrocytes was observed in schizophrenia and bipolar disorder patients relative to controls. Metabolomic profiling identified disruption of GABA levels in schizophrenia patients., Conclusions: We provide a comprehensive post-mortem transcriptome profile of three psychiatric disorders across three brain regions. We highlight a high-confidence set of independently validated genes differentially expressed between schizophrenia and control patients in the anterior cingulate cortex and integrate transcriptional changes with untargeted metabolite profiling.
Published: 2017
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25. Variable telomere length across post-mortem human brain regions and specific reduction in the hippocampus of major depressive disorder.

Author: Mamdani F, Rollins B, Morgan L, Myers RM, Barchas JD, Schatzberg AF, Watson SJ, Akil H, Potkin SG, Bunney WE, Vawter MP, and Sequeira PA
Published: 2016
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26. Quantitative Trait Locus and Brain Expression of HLA-DPA1 Offers Evidence of Shared Immune Alterations in Psychiatric Disorders.

Author: Morgan LZ, Rollins B, Sequeira A, Byerley W, DeLisi LE, Schatzberg AF, Barchas JD, Myers RM, Watson SJ, Akil H, Bunney WE Jr, and Vawter MP
Abstract: Genome-wide association studies of schizophrenia encompassing the major histocompatibility locus (MHC) were highly significant following genome-wide correction. This broad region implicates many genes including the MHC complex class II. Within this interval we examined the expression of two MHC II genes (HLA-DPA1 and HLA-DRB1) in brain from individual subjects with schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and controls by differential gene expression methods. A third MHC II mRNA, CD74, was studied outside of the MHC II locus, as it interacts within the same immune complex. Exon microarrays were performed in anterior cingulate cortex (ACC) in BD compared to controls, and both HLA-DPA1 and CD74 were decreased in expression in BD. The expression of HLA-DPA1 and CD74 were both reduced in hippocampus, amygdala, and dorsolateral prefrontal cortex regions in SZ and BD compared to controls by specific qPCR assay. We found several novel HLA-DPA1 mRNA variants spanning HLA-DPA1 exons 2-3-4 as suggested by exon microarrays. The intronic rs9277341 SNP was a significant cis expression quantitative trait locus (eQTL) that was associated with the total expression of HLA-DPA1 in five brain regions. A biomarker study of MHC II mRNAs was conducted in SZ, BD, MDD, and control lymphoblastic cell lines (LCL) by qPCR assay of 87 subjects. There was significantly decreased expression of HLA-DPA1 and CD74 in BD, and trends for reductions in SZ in LCLs. The discovery of multiple splicing variants in brain for HLA-DPA1 is important as the HLA-DPA1 gene is highly conserved, there are no reported splicing variants, and the functions in brain are unknown. Future work on the function and localization of MHC Class II proteins in brain will help to understand the role of alterations in neuropsychiatric disorders. The HLA-DPA1 eQTL is located within a large linkage disequilibrium block that has an irrefutable association with schizophrenia. Future tests in a larger cohort are needed to determine the significance of this eQTL association with schizophrenia. Our findings support the long-held hypothesis that alterations in immune function are associated with the pathophysiology of psychiatric disorders.
Published: 2016
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27. Fibroblast growth factor 9 is a novel modulator of negative affect.

Author: Aurbach EL, Inui EG, Turner CA, Hagenauer MH, Prater KE, Li JZ, Absher D, Shah N, Blandino P Jr, Bunney WE, Myers RM, Barchas JD, Schatzberg AF, Watson SJ Jr, and Akil H
Subjects: Adult, Aged, Aged, 80 and over, Animals, Anxiety complications, Anxiety metabolism, Avoidance Learning drug effects, Case-Control Studies, Demography, Dentate Gyrus drug effects, Dentate Gyrus metabolism, Depressive Disorder, Major complications, Depressive Disorder, Major metabolism, Female, Fibroblast Growth Factor 9 administration & dosage, Fibroblast Growth Factor 9 genetics, Fibroblast Growth Factor 9 pharmacology, Gene Expression Regulation drug effects, Gene Knockdown Techniques, Humans, Lentivirus metabolism, Male, Microinjections, Middle Aged, Postmortem Changes, RNA, Small Interfering metabolism, Rats, Rats, Sprague-Dawley, Receptor, Fibroblast Growth Factor, Type 1 metabolism, Stress, Psychological complications, Stress, Psychological genetics, Young Adult, Affect drug effects, Fibroblast Growth Factor 9 metabolism
Abstract: Both gene expression profiling in postmortem human brain and studies using animal models have implicated the fibroblast growth factor (FGF) family in affect regulation and suggest a potential role in the pathophysiology of major depressive disorder (MDD). FGF2, the most widely characterized family member, is down-regulated in the depressed brain and plays a protective role in rodent models of affective disorders. By contrast, using three microarray analyses followed by quantitative RT-PCR confirmation, we show that FGF9 expression is up-regulated in the hippocampus of individuals with MDD, and that FGF9 expression is inversely related to the expression of FGF2. Because little is known about FGF9's function in emotion regulation, we used animal models to shed light on its potential role in affective function. We found that chronic social defeat stress, an animal model recapitulating some aspects of MDD, leads to a significant increase in hippocampal FGF9 expression, paralleling the elevations seen in postmortem human brain tissue. Chronic intracerebroventricular administration of FGF9 increased both anxiety- and depression-like behaviors. In contrast, knocking down FGF9 expression in the dentate gyrus of the hippocampus using a lentiviral vector produced a decrease in FGF9 expression and ameliorated anxiety-like behavior. Collectively, these results suggest that high levels of hippocampal FGF9 play an important role in the development or expression of mood and anxiety disorders. We propose that the relative levels of FGF9 in relation to other members of the FGF family may prove key to understanding vulnerability or resilience in affective disorders.
Published: 2015
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28. Variable telomere length across post-mortem human brain regions and specific reduction in the hippocampus of major depressive disorder.

Author: Mamdani F, Rollins B, Morgan L, Myers RM, Barchas JD, Schatzberg AF, Watson SJ, Akil H, Potkin SG, Bunney WE, Vawter MP, and Sequeira PA
Subjects: Analysis of Variance, Brain pathology, Cadaver, Dissection, Female, Genetic Techniques, Humans, Male, Middle Aged, Polymerase Chain Reaction, Depressive Disorder, Major genetics, Depressive Disorder, Major pathology, Hippocampus pathology, Telomere genetics, Telomere pathology
Abstract: Stress can be a predisposing factor to psychiatric disorders and has been associated with decreased neurogenesis and reduced hippocampal volume especially in depression. Similarly, in white blood cells chronic psychological stress has been associated with telomere shortening and with mood disorders and schizophrenia (SZ). However, in previous post-mortem brain studies from occipital cortex and cerebellum, no difference in telomere length was observed in depression. We hypothesized that in psychiatric disorders, stress-driven accelerated cellular aging can be observed in brain regions particularly sensitive to stress. Telomere length was measured by quantitative-PCR in five brain regions (dorsolateral prefrontal cortex, hippocampus (HIPP), amygdala, nucleus accumbens and substantia nigra (SN)) in major depressive disorder (MDD), bipolar disorder, SZ and normal control subjects (N = 40, 10 subjects per group). We observed significant differences in telomere length across brain regions suggesting variable levels of cell aging, with SN and HIPP having the longest telomeres and the dorsolateral prefrontal cortex the shortest. A significant decrease (P < 0.02) in telomere length was observed specifically in the HIPP of MDD subjects even after controlling for age. In the HIPP of MDD subjects, several genes involved in neuroprotection and in stress response (FKBP5, CRH) showed altered levels of mRNA. Our results suggest the presence of hippocampal stress-mediated accelerated cellular aging in depression. Further studies are needed to investigate the cellular specificity of these findings.
Published: 2015
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29. Mitochondrial mutations in subjects with psychiatric disorders.

Author: Sequeira A, Rollins B, Magnan C, van Oven M, Baldi P, Myers RM, Barchas JD, Schatzberg AF, Watson SJ, Akil H, Bunney WE, and Vawter MP
Subjects: Adult, Case-Control Studies, DNA Mutational Analysis, Electrophoresis, Agar Gel, Female, Genetic Loci, Humans, Male, Mental Disorders blood, Middle Aged, Molecular Sequence Data, Prefrontal Cortex pathology, DNA, Mitochondrial genetics, Mental Disorders genetics, Mutation genetics
Abstract: A considerable body of evidence supports the role of mitochondrial dysfunction in psychiatric disorders and mitochondrial DNA (mtDNA) mutations are known to alter brain energy metabolism, neurotransmission, and cause neurodegenerative disorders. Genetic studies focusing on common nuclear genome variants associated with these disorders have produced genome wide significant results but those studies have not directly studied mtDNA variants. The purpose of this study is to investigate, using next generation sequencing, the involvement of mtDNA variation in bipolar disorder, schizophrenia, major depressive disorder, and methamphetamine use. MtDNA extracted from multiple brain regions and blood were sequenced (121 mtDNA samples with an average of 8,800x coverage) and compared to an electronic database containing 26,850 mtDNA genomes. We confirmed novel and rare variants, and confirmed next generation sequencing error hotspots by traditional sequencing and genotyping methods. We observed a significant increase of non-synonymous mutations found in individuals with schizophrenia. Novel and rare non-synonymous mutations were found in psychiatric cases in mtDNA genes: ND6, ATP6, CYTB, and ND2. We also observed mtDNA heteroplasmy in brain at a locus previously associated with schizophrenia (T16519C). Large differences in heteroplasmy levels across brain regions within subjects suggest that somatic mutations accumulate differentially in brain regions. Finally, multiplasmy, a heteroplasmic measure of repeat length, was observed in brain from selective cases at a higher frequency than controls. These results offer support for increased rates of mtDNA substitutions in schizophrenia shown in our prior results. The variable levels of heteroplasmic/multiplasmic somatic mutations that occur in brain may be indicators of genetic instability in mtDNA.
Published: 2015
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30. Circadian dysregulation of clock genes: clues to rapid treatments in major depressive disorder.

Author: Bunney BG, Li JZ, Walsh DM, Stein R, Vawter MP, Cartagena P, Barchas JD, Schatzberg AF, Myers RM, Watson SJ, Akil H, and Bunney WE
Subjects: Animals, Excitatory Amino Acid Antagonists therapeutic use, Gyrus Cinguli metabolism, Humans, Ketamine therapeutic use, Sleep Deprivation, Antidepressive Agents therapeutic use, CLOCK Proteins genetics, Chronobiology Disorders complications, Chronobiology Disorders genetics, Depressive Disorder, Major etiology, Depressive Disorder, Major genetics, Depressive Disorder, Major therapy
Abstract: Conventional antidepressants require 2-8 weeks for a full clinical response. In contrast, two rapidly acting antidepressant interventions, low-dose ketamine and sleep deprivation (SD) therapy, act within hours to robustly decrease depressive symptoms in a subgroup of major depressive disorder (MDD) patients. Evidence that MDD may be a circadian-related illness is based, in part, on a large set of clinical data showing that diurnal rhythmicity (sleep, temperature, mood and hormone secretion) is altered during depressive episodes. In a microarray study, we observed widespread changes in cyclic gene expression in six regions of postmortem brain tissue of depressed patients matched with controls for time-of-death (TOD). We screened 12 000 transcripts and observed that the core clock genes, essential for controlling virtually all rhythms in the body, showed robust 24-h sinusoidal expression patterns in six brain regions in control subjects. In MDD patients matched for TOD with controls, the expression patterns of the clock genes in brain were significantly dysregulated. Some of the most robust changes were seen in anterior cingulate (ACC). These findings suggest that in addition to structural abnormalities, lesion studies, and the large body of functional brain imaging studies reporting increased activation in the ACC of depressed patients who respond to a wide range of therapies, there may be a circadian dysregulation in clock gene expression in a subgroup of MDDs. Here, we review human, animal and neuronal cell culture data suggesting that both low-dose ketamine and SD can modulate circadian rhythms. We hypothesize that the rapid antidepressant actions of ketamine and SD may act, in part, to reset abnormal clock genes in MDD to restore and stabilize circadian rhythmicity. Conversely, clinical relapse may reflect a desynchronization of the clock, indicative of a reactivation of abnormal clock gene function. Future work could involve identifying specific small molecules capable of resetting and stabilizing clock genes to evaluate if they can rapidly relieve symptoms and sustain improvement.
Published: 2015
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31. Altered choroid plexus gene expression in major depressive disorder.

Author: Turner CA, Thompson RC, Bunney WE, Schatzberg AF, Barchas JD, Myers RM, Akil H, and Watson SJ
Abstract: Given the emergent interest in biomarkers for mood disorders, we assessed gene expression in the choroid plexus (CP), the region that produces cerebrospinal fluid (CSF), in individuals with major depressive disorder (MDD). Genes that are expressed in the CP can be secreted into the CSF and may be potential biomarker candidates. Given that we have previously shown that fibroblast growth factor family members are differentially expressed in post-mortem brain of subjects with MDD and the CP is a known source of growth factors in the brain, we posed the question whether growth factor dysregulation would be found in the CP of subjects with MDD. We performed laser capture microscopy of the CP at the level of the hippocampus in subjects with MDD and psychiatrically normal controls. We then extracted, amplified, labeled, and hybridized the cRNA to Illumina BeadChips to assess gene expression. In controls, the most highly abundant known transcript was transthyretin. Moreover, half of the 14 most highly expressed transcripts in controls encode ribosomal proteins. Using BeadStudio software, we identified 169 transcripts differentially expressed (p < 0.05) between control and MDD samples. Using pathway analysis we noted that the top network altered in subjects with MDD included multiple members of the transforming growth factor-beta (TGFβ) pathway. Quantitative real-time PCR (qRT-PCR) confirmed downregulation of several transcripts that interact with the extracellular matrix in subjects with MDD. These results suggest that there may be an altered cytoskeleton in the CP in MDD subjects that may lead to a disrupted blood-CSF-brain barrier.
Published: 2014
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32. G protein-linked signaling pathways in bipolar and major depressive disorders.

Author: Tomita H, Ziegler ME, Kim HB, Evans SJ, Choudary PV, Li JZ, Meng F, Dai M, Myers RM, Neal CR, Speed TP, Barchas JD, Schatzberg AF, Watson SJ, Akil H, Jones EG, Bunney WE, and Vawter MP
Abstract: The G-protein linked signaling system (GPLS) comprises a large number of G-proteins, G protein-coupled receptors (GPCRs), GPCR ligands, and downstream effector molecules. G-proteins interact with both GPCRs and downstream effectors such as cyclic adenosine monophosphate (cAMP), phosphatidylinositols, and ion channels. The GPLS is implicated in the pathophysiology and pharmacology of both major depressive disorder (MDD) and bipolar disorder (BPD). This study evaluated whether GPLS is altered at the transcript level. The gene expression in the dorsolateral prefrontal (DLPFC) and anterior cingulate (ACC) were compared from MDD, BPD, and control subjects using Affymetrix Gene Chips and real time quantitative PCR. High quality brain tissue was used in the study to control for confounding effects of agonal events, tissue pH, RNA integrity, gender, and age. GPLS signaling transcripts were altered especially in the ACC of BPD and MDD subjects. Transcript levels of molecules which repress cAMP activity were increased in BPD and decreased in MDD. Two orphan GPCRs, GPRC5B and GPR37, showed significantly decreased expression levels in MDD, and significantly increased expression levels in BPD. Our results suggest opposite changes in BPD and MDD in the GPLS, "activated" cAMP signaling activity in BPD and "blunted" cAMP signaling activity in MDD. GPRC5B and GPR37 both appear to have behavioral effects, and are also candidate genes for neurodegenerative disorders. In the context of the opposite changes observed in BPD and MDD, these GPCRs warrant further study of their brain effects.
Published: 2013
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33. Circadian patterns of gene expression in the human brain and disruption in major depressive disorder.

Author: Li JZ, Bunney BG, Meng F, Hagenauer MH, Walsh DM, Vawter MP, Evans SJ, Choudary PV, Cartagena P, Barchas JD, Schatzberg AF, Jones EG, Myers RM, Watson SJ Jr, Akil H, and Bunney WE
Subjects: ARNTL Transcription Factors, Adult, Aged, Autopsy, Basic Helix-Loop-Helix Transcription Factors genetics, Circadian Clocks genetics, Female, Homeodomain Proteins genetics, Humans, Male, Middle Aged, Nuclear Receptor Subfamily 1, Group D, Member 1 genetics, Oligonucleotide Array Sequence Analysis, Period Circadian Proteins genetics, Brain metabolism, Circadian Rhythm genetics, Depressive Disorder, Major genetics, Gene Expression Profiling
Abstract: A cardinal symptom of major depressive disorder (MDD) is the disruption of circadian patterns. However, to date, there is no direct evidence of circadian clock dysregulation in the brains of patients who have MDD. Circadian rhythmicity of gene expression has been observed in animals and peripheral human tissues, but its presence and variability in the human brain were difficult to characterize. Here, we applied time-of-death analysis to gene expression data from high-quality postmortem brains, examining 24-h cyclic patterns in six cortical and limbic regions of 55 subjects with no history of psychiatric or neurological illnesses ("controls") and 34 patients with MDD. Our dataset covered ~12,000 transcripts in the dorsolateral prefrontal cortex, anterior cingulate cortex, hippocampus, amygdala, nucleus accumbens, and cerebellum. Several hundred transcripts in each region showed 24-h cyclic patterns in controls, and >100 transcripts exhibited consistent rhythmicity and phase synchrony across regions. Among the top-ranked rhythmic genes were the canonical clock genes BMAL1(ARNTL), PER1-2-3, NR1D1(REV-ERBa), DBP, BHLHE40 (DEC1), and BHLHE41(DEC2). The phasing of known circadian genes was consistent with data derived from other diurnal mammals. Cyclic patterns were much weaker in the brains of patients with MDD due to shifted peak timing and potentially disrupted phase relationships between individual circadian genes. This transcriptome-wide analysis of the human brain demonstrates a rhythmic rise and fall of gene expression in regions outside of the suprachiasmatic nucleus in control subjects. The description of its breakdown in MDD suggests potentially important molecular targets for treatment of mood disorders.
Published: 2013
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34. Evidence for transcriptional factor dysregulation in the dorsal raphe nucleus of patients with major depressive disorder.

Author: Kerman IA, Bernard R, Bunney WE, Jones EG, Schatzberg AF, Myers RM, Barchas JD, Akil H, Watson SJ, and Thompson RC
Abstract: Extensive evidence implicates dysfunction in serotonin (5-HT) signaling in the etiology of major depressive disorder (MDD). Dorsal raphe nucleus (DR) is a major source of serotonin in the brain, and previous studies have reported within it alterations in 5-HT-related gene expression, protein levels, receptor binding, and morphological organization in mood disorders. In the present study, we utilized in situ hybridization-guided laser capture microdissection to harvest tissue samples from the middle-caudal subregion of the human DR post-mortem from MDD patients and from psychiatrically normal comparison subjects. Extracted RNA was prepared for gene expression profiling, and subsequent confirmation of select targets with quantitative real-time PCR. Our data indicate expression changes in functional gene families that regulate: (1) cellular stress and energy balance, (2) intracellular signaling and transcriptional regulation, and (3) cell proliferation and connectivity. The greatest changes in expression were observed among transcriptional regulators, including downregulation in the expression of TOB1, EGR1, and NR4A2 and their downstream targets. Previous studies have implicated these gene products in the regulation of functional domains impacted by MDD, including cognitive function, affective regulation, and emotional memory formation. These observations indicate altered function of several transcriptional regulators and their downstream targets, which may lead to the dysregulation of multiple cellular functions that contribute to the pathophysiology of MDD. Future studies will require single cell analyses in the DR to determine potential impact of these changes on its cellular functions and related circuits.
Published: 2012
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35. Genome-wide association and meta-analysis of bipolar disorder in individuals of European ancestry.

Author: Scott LJ, Muglia P, Kong XQ, Guan W, Flickinger M, Upmanyu R, Tozzi F, Li JZ, Burmeister M, Absher D, Thompson RC, Francks C, Meng F, Antoniades A, Southwick AM, Schatzberg AF, Bunney WE, Barchas JD, Jones EG, Day R, Matthews K, McGuffin P, Strauss JS, Kennedy JL, Middleton L, Roses AD, Watson SJ, Vincent JB, Myers RM, Farmer AE, Akil H, Burns DK, and Boehnke M
Subjects: Europe, Genome-Wide Association Study, Humans, Bipolar Disorder genetics, Chromosomes, Human, Pair 1 genetics, Chromosomes, Human, Pair 3 genetics, Chromosomes, Human, Pair 5 genetics, Genome, Human
Abstract: Bipolar disorder (BP) is a disabling and often life-threatening disorder that affects approximately 1% of the population worldwide. To identify genetic variants that increase the risk of BP, we genotyped on the Illumina HumanHap550 Beadchip 2,076 bipolar cases and 1,676 controls of European ancestry from the National Institute of Mental Health Human Genetics Initiative Repository, and the Prechter Repository and samples collected in London, Toronto, and Dundee. We imputed SNP genotypes and tested for SNP-BP association in each sample and then performed meta-analysis across samples. The strongest association P value for this 2-study meta-analysis was 2.4 x 10(-6). We next imputed SNP genotypes and tested for SNP-BP association based on the publicly available Affymetrix 500K genotype data from the Wellcome Trust Case Control Consortium for 1,868 BP cases and a reference set of 12,831 individuals. A 3-study meta-analysis of 3,683 nonoverlapping cases and 14,507 extended controls on >2.3 M genotyped and imputed SNPs resulted in 3 chromosomal regions with association P approximately 10(-7): 1p31.1 (no known genes), 3p21 (>25 known genes), and 5q15 (MCTP1). The most strongly associated nonsynonymous SNP rs1042779 (OR = 1.19, P = 1.8 x 10(-7)) is in the ITIH1 gene on chromosome 3, with other strongly associated nonsynonymous SNPs in GNL3, NEK4, and ITIH3. Thus, these chromosomal regions harbor genes implicated in cell cycle, neurogenesis, neuroplasticity, and neurosignaling. In addition, we replicated the reported ANK3 association results for SNP rs10994336 in the nonoverlapping GSK sample (OR = 1.37, P = 0.042). Although these results are promising, analysis of additional samples will be required to confirm that variant(s) in these regions influence BP risk.
Published: 2009
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36. Aaron Lerner: perspectives and lessons learned from the melatonin days.

Author: Barchas JD
Subjects: Connecticut, History, 20th Century, History, 21st Century, Humans, Research history, Dermatology history, Melatonin physiology
Published: 2007
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37. Amplified RNA synthesized from limited quantities of heterogeneous cDNA.

Author: Van Gelder RN, von Zastrow ME, Yool A, Dement WC, Barchas JD, and Eberwine JH
Subjects: Actins genetics, Animals, Base Sequence, Blotting, Northern, Blotting, Southern, GTP-Binding Proteins genetics, Genetic Techniques, Molecular Sequence Data, Oligonucleotide Probes, RNA biosynthesis, RNA, Messenger genetics, Rats, Transcription, Genetic, Cerebellum metabolism, DNA genetics, RNA genetics
Abstract: The heterogeneity of neural gene expression and the spatially limited expression of many low-abundance messenger RNAs in the brain has made cloning and analysis of such messages difficult. To generate amounts of nucleic acids sufficient for use in standard cloning strategies, we have devised a method for producing amplified heterogeneous populations of RNA from limited quantities of cDNA. Whole cerebellar RNA was primed with a synthetic oligonucleotide containing the T7 RNA polymerase promoter sequence 5' to a polythymidylate region. After second-strand cDNA synthesis, T7 RNA polymerase was used to generate amplified antisense RNA (aRNA). Up to 80-fold molar amplification has been achieved from nanogram quantities of cDNA. The amplified material is similar in size distribution to the parent cDNA and shows sequence heterogeneity as assessed by Southern and Northern blot analysis. Specific messages for moderate-abundance mRNAs for actin and guanine nucleotide-binding protein (G-protein) alpha subunits have been detected in the amplified material. By using in situ transcription to generate cDNA, sequences for cyclophilin have been detected in aRNA derived from single cerebellar tissue sections. cDNA derived from a single cerebellar Purkinje cell also has been amplified and yields material that hybridizes to cognate whole RNA and mRNA but not to Escherichia coli RNA.
Published: 1990
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38. Long-term stress-induced analgesia and activation of the opiate system.

Author: Grau JW, Hyson RL, Maier SF, Madden J 4th, and Barchas JD
Subjects: Analgesia, Animals, Electroshock, Endorphins antagonists & inhibitors, Naltrexone pharmacology, Rats, Tail, Time Factors, Endorphins physiology, Pain physiopathology, Stress, Physiological physiopathology
Published: 1981
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39. Immunoreactive dynorphin-(1-8) and corticotropin- releasing factor in subpopulation of hypothalamic neurons.

Author: Roth KA, Weber E, Barchas JD, Chang D, and Chang JK
Subjects: Animals, Corticotropin-Releasing Hormone immunology, Dynorphins, Endorphins immunology, Fluorescent Antibody Technique, Hypothalamus cytology, Neurons metabolism, Paraventricular Hypothalamic Nucleus metabolism, Peptide Fragments metabolism, Rats, Corticotropin-Releasing Hormone metabolism, Endorphins metabolism, Hypothalamus metabolism
Abstract: Immunoreactive corticotropin-releasing factor (CRF) and dynorphin-(I-8) were visualized in rat hypothalamus by immunohistofluorescence with specific antibodies. In brains from colchicine-treated, adrenalectomized rats, neuronal perikarya with immunoreactive CRF were observed in the paraventricular nucleus of the hypothalamus. The CRF occurred together with the dynorphin-(1-8). However, the CRF immunoreactivity occurred only in a subpopulation of the dynorphin-(1-8) immunoreactive cells. These findings suggest that there may be a functional interrelationship of CRF with dynorphin-related opioid peptides and provide further evidence that neurons may contain more than one bioactive substance.
Published: 1983
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40. Effects of naloxone on schizophrenia: reduction in hallucinations in a subpopulation of subjects.

Author: Watson SJ, Berger PA, Akil H, Mills MJ, and Barchas JD
Subjects: Adult, Chronic Disease, Clinical Trials as Topic, Dose-Response Relationship, Drug, Double-Blind Method, Endorphins physiology, Humans, Male, Naloxone administration & dosage, Schizophrenia physiopathology, Schizophrenia, Paranoid drug therapy, Time Factors, Hallucinations drug therapy, Naloxone therapeutic use, Schizophrenia drug therapy
Abstract: Endogenous opiate-like peptides (endorphins) are putative neuroregulators located throughout the mammalian brainstem. There is some evidence for their role in pain, stress, and affect. We report that the opiate antagonist, naloxone, alters some schizophrenic symptoms. In a double-blind, cross-over study, naloxone produced decreases in auditory hallucinations in some schizophrenic patients. This finding supports the hypothesis that the endorphins may play a roll in modulating hallucinations in a highly selected subgroup of chronically hallucinating schizophrenic patients.
Published: 1978
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41. Appearance of beta-endorphin-like immunoreactivity in human ventricular cerebrospinal fluid upon analgesic electrical stimulation.

Author: Akil H, Richardson DE, Barchas JD, and Li CH
Subjects: Analgesia, Electric Stimulation, Endorphins immunology, Humans, Male, Radioimmunoassay, Thalamus metabolism, Brain metabolism, Endorphins cerebrospinal fluid
Abstract: beta-Endorphin-like immunoreactivity in human ventricular cerebrospinal fluid was measured with a specific radioimmunoassay. The subjects were undergoing a surgical procedure for relief of chronic intractable pain. This procedure involved the focal stimulation of a medial thalamic site adjacent to the wall of the third ventricle. Samples were collected before and during the analgesic stimulation. No beta-endorphin-like immunoreactivity could be detected prior to stimulation, suggesting that baseline levels are below 25 fmol/ml of cerebrospinal fluid. Electrical stimulation led to substantial increases (13- to 20-fold) in immunoreactive material in every subject. These results suggest that beta-endorphin-like material can be released into the ventricular system and may contribute to the pain blockade that results from periventricular stimulation.
Published: 1978
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42. Immunohistochemical distribution of alpha-neo-endorphin/dynorphin neuronal systems in rat brain: evidence for colocalization.

Author: Weber E, Roth KA, and Barchas JD
Subjects: Animals, Antibody Specificity, Colchicine pharmacology, Dynorphins, Endorphins immunology, Fluorescent Antibody Technique, Nerve Endings metabolism, Neurons metabolism, Rats, Brain metabolism, Endorphins metabolism, Protein Precursors metabolism
Abstract: alpha-Neo-endorphin and dynorphin immunoreactivities in rat brain were visualized by double antibody immunofluorescence of frozen sections. Antibodies were used that were specific for their respective antigens. The pattern of neuronal immunostaining produced by alpha-neo-endorphin and dynorphin antisera in adjacent serial sections was completely superimposible. No areas were found in which alpha-neo-endorphin or dynorphin immunoreactivities existed alone. The following brain regions contained alpha-neo-endorphin/dynorphin-immunoreactive fibers and terminals: the median forebrain bundle, the internal capsule, the substantia nigra, the hypothalamus, the nucleus accumbens, the hippocampus, and the medulla oblongata. A few fibers were seen in the cerebral cortex and in the corpus striatum. In many regions, this neuronal fiber system seems to overlap the neuronal system previously described to contain [Met]-/[Leu]enkephalin-immunoreactive material. In brains from colchicine-treated animals, numerous alpha-neo-endorphin/dynorphin-immunoreactive neuronal cell bodies were seen in the supraoptic, retrochiasmatic supraoptic, paraventricular, and magnocellular accessory nuclei of the hypothalamus. It is concluded that alpha-neo-endorphin-like and dynorphin-like immunoreactivities are part of the same neuronal system.
Published: 1982
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43. Predominance of the amino-terminal octapeptide fragment of dynorphin in rat brain regions.

Author: Weber E, Evans CJ, and Barchas JD
Subjects: Amino Acid Sequence, Animals, Antibody Specificity, Corpus Striatum metabolism, Dynorphins, Endorphins immunology, Hypothalamus metabolism, Peptide Fragments metabolism, Protein Precursors metabolism, Radioimmunoassay, Rats, Brain metabolism, Endorphins metabolism
Published: 1982
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44. Peptide neuroregulators: the opioid system as a model.

Author: Barchas JD, Evans C, Elliott GR, and Berger PA
Subjects: Animals, Depression drug therapy, Endorphins metabolism, Endorphins therapeutic use, Humans, Melanocyte-Stimulating Hormones physiology, Melatonin physiology, Mental Disorders etiology, Mental Disorders physiopathology, Models, Biological, Naloxone therapeutic use, Schizophrenia drug therapy, beta-Endorphin, Endorphins physiology, Nerve Tissue Proteins physiology, Nervous System Physiological Phenomena
Abstract: Aaron Lerner's work provides a stunning set of examples of substances that help to transmit information in the brain and body. His characterization of alpha-MSH and melatonin and his sparking of interest in the further discovery of previously unknown substances have been of inestimable value for the field of neurobiology. Efforts such as those that Lerner undertook so successfully in the field of investigative dermatology now constitute a major research thrust in the field of behavioral neurochemistry and are directly related to advances in psychiatry and neurology. This review considers aspects of research on the neuropeptides, with particular attention to the endogenous opioid (morphine-like) peptides that are active on neural tissue. Neuropeptide research can be categorized broadly as efforts to discover and characterize new families and classes of active agents, investigations of their genetic and molecular processing, and studies of their relationships to behavior in animals and human beings. This review selectively considers some key research questions and strategies that arise from such research.
Published: 1985

45. Metorphamide: isolation, structure, and biologic activity of an amidated opioid octapeptide from bovine brain.

Author: Weber E, Esch FS, Böhlen P, Paterson S, Corbett AD, McKnight AT, Kosterlitz HW, Barchas JD, and Evans CJ
Subjects: Amino Acid Sequence, Animals, Binding, Competitive, Biological Assay, Brain metabolism, Carboxypeptidases, Carboxypeptidases A, Cattle, Chromatography, High Pressure Liquid methods, Enkephalin, Methionine isolation & purification, Enkephalin, Methionine pharmacology, Guinea Pigs, Male, Mice, Muscle Contraction drug effects, Myenteric Plexus drug effects, Rabbits, Rats, Receptors, Opioid metabolism, Structure-Activity Relationship, Vas Deferens drug effects, Caudate Nucleus analysis, Enkephalin, Methionine analogs & derivatives
Abstract: Acid acetone extracts of caudate nucleus from bovine brain were found to contain an amidated opioid octapeptide with the following structure: Tyr-Gly-Gly-Phe-Met-Arg-Arg-Val-NH2. The peptide has been named metorphamide. Bovine metorphamide appears to be derived by proteolytic cleavage from proenkephalin, the common precursor to [Met5]enkephalin and [Leu5]enkephalin. The cleavage within the precursor giving rise to the carboxyl terminus of metorphamide occurs at a single arginine residue and is followed by transformation of a carboxyl-terminal glycine into an amide group. Metorphamide was detected in bovine caudate nucleus extracts by radioimmunoassay, and it was purified to homogeneity by gel filtration and reversed-phase high performance liquid chromatography. Amino acid composition analysis and automated Edman degradation in the gas-phase sequencer confirmed the postulated amino acid sequence. Carboxyl-terminal amidation of bovine metorphamide was shown by stability to carboxypeptidase A digestion and full crossreactivity in a radioimmunoassay that required the carboxyl-terminal amide as part of the recognition site. A synthetic replicate of metorphamide as well as several synthetic analogs were tested for opioid activity in several bioassays and binding assays, and metorphamide was found to have a high mu-binding activity. Metorphamide is the only known naturally occurring opioid peptide that has a high mu-binding activity. The kappa-binding activity is approximately equal to 50% that of the mu-binding activity, but delta-binding activity is negligible.
Published: 1983
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46. Novel peptide neuronal system in rat brain and pituitary.

Author: Weber E, Evans CJ, Samuelsson SJ, and Barchas JD
Subjects: Animals, Axons analysis, FMRFamide, Fluorescent Antibody Technique, Organ Specificity, Radioimmunoassay, Rats, Brain Chemistry, Nerve Tissue Proteins analysis, Neurons analysis, Pituitary Gland analysis, Spinal Cord analysis
Abstract: Immunohistofluorescence studies of the rat central nervous system with antibodies to Phe-Met-Arg-Phe-NH2 (molluskan cardioexcitatory peptide) revealed a widespread neuronal system in the brain, spinal cord, and posterior pituitary. Immunoreactive axons and cell bodies were mainly located in cortical, limbic, and hypothalamic areas. Immunostaining of serial sections of the brain and pituitary showed that the Phe-Met-Arg-Phe-NH2 immunoreactive neurons were different from neurons labeled by antibodies to either Met-enkephalin or the putative Met-enkephalin precursor Tyr-Gly-Gly-Phe-Met-Arg-Phe, which is structurally related to Phe-Met-Arg-Phe-NH2. Control staining by antiserum absorption and radioimmunoassay indicated that the antibodies that caused the specific immunofluorescence recognized peptides with an amidated Arg-Phe sequence at the carboxyl terminus.
Published: 1981
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47. Tryptoline formation by a preparation from brain with 5-methyltetrahydrofolic acid and tryptamine.

Author: Wyatt RJ, Erdelyi E, DoAmaral JR, Elliott GR, Renson J, and Barchas JD
Subjects: Carbolines, Humans, Hydrogen-Ion Concentration, Kinetics, Methylation, Piperidines metabolism, Structure-Activity Relationship, Brain enzymology, Indoles metabolism, Tetrahydrofolates metabolism, Tissue Extracts, Tryptamines metabolism
Abstract: An enzymatic preparation from human brain converts tryptamine to tryptoline (9H-1,2,3,4-tetrahydropyrido[3,4-b]indole) in the presence of 5-methyltetrahydrofolic acid. Similarly, N-methyltryptamine and 5-hydroxytryptamine yield 1-methyltryptoline and 5-hydroxytryptoline, respectively. Neither in vitro nor in vivo formation of these compounds by human tissues has been described.
Published: 1975
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48. Constitutively expressed rat mRNA encoding a 70-kilodalton heat-shock-like protein.

Author: O'Malley K, Mauron A, Barchas JD, and Kedes L
Subjects: Animals, Base Sequence, Cell Line, DNA genetics, Drosophila melanogaster genetics, Gene Expression Regulation, Heat-Shock Proteins biosynthesis, Humans, Mice, Nucleic Acid Hybridization, Rats, Species Specificity, Tissue Distribution, Heat-Shock Proteins genetics, RNA, Messenger genetics
Abstract: A nearly full-length cDNA clone isolated from the rat pheochromocytoma cell line, PC12, revealed extensive nucleotide sequence similarity between the rat cDNA and the Drosophila melanogaster hsp70 gene. The rat recombinant clone encodes a 71,000-dalton protein that is 70% identical with the dipteran hsp70 protein. Remarkably, a truncated segment of this cDNA clone was originally isolated by immunoreactivity with antisera raised to catecholamine-synthesizing enzymes, suggesting that this heat shock protein and these catecholamine enzymes shared antigenic determinants. The rat hsp70-related mRNA is responsible for the production of a constitutive hsp70 protein, because it is present in abundant amounts in various tissues at normal growth temperatures and is only minimally induced by hyperthermia. The rat hsp70-related sequence is part of a multigene family that extends across species to mice and humans.
Published: 1985
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49. The concentrations of amine metabolites in cerebrospinal fluid from normal and narcoleptic dogs [proceedings].

Author: Barchas JD, Dement WC, Faull K, Foutz AS, and Holman RB
Subjects: 3,4-Dihydroxyphenylacetic Acid cerebrospinal fluid, Animals, Dogs, Homovanillic Acid cerebrospinal fluid, Humans, Hydroxyindoleacetic Acid cerebrospinal fluid, Methoxyhydroxyphenylglycol cerebrospinal fluid, Probenecid pharmacology, Narcolepsy cerebrospinal fluid
Published: 1979

50. A national plan for schizophrenia research: panel recommendations. Research resources.

Author: Barchas JD, Hadley SW, Detre T, Endicott J, Glover R, King R, Meltzer HY, Sackeim H, Strauss JS, and Wahl P
Subjects: Humans, National Institute of Mental Health (U.S.), Research, Risk Factors, Schizophrenia genetics, United States, Schizophrenia etiology, Schizophrenic Psychology
Published: 1988
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