Hostname: page-component-cd9895bd7-dzt6s Total loading time: 0 Render date: 2024-12-28T06:23:09.040Z Has data issue: false hasContentIssue false
  • English
  • Français

Whole blood transcriptome analysis in bipolar disorder reveals strong lithium effect

Published online by Cambridge University Press:  07 October 2019

Catharine E. Krebs Open the ORCID record for Catharine E. Krebs [Opens in a new window] ,
Anil P.S. Ori ,
Annabel Vreeker ,
Timothy Wu ,
Rita M. Cantor ,
Marco P. M. Boks ,
Rene S. Kahn ,
Loes M. Olde Loohuis  and
Roel A. Ophoff
Catharine E. Krebs
Affiliation:
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University California Los Angeles, Los Angeles, CA, USA Department of Human Genetics, University California Los Angeles, Los Angeles, CA, USA
Anil P.S. Ori
Affiliation:
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University California Los Angeles, Los Angeles, CA, USA
Annabel Vreeker
Affiliation:
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University California Los Angeles, Los Angeles, CA, USA Department of Medical Genetics, University Medical Center Utrecht, Utrecht, Netherlands
Timothy Wu
Affiliation:
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University California Los Angeles, Los Angeles, CA, USA
Rita M. Cantor
Affiliation:
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University California Los Angeles, Los Angeles, CA, USA Department of Human Genetics, University California Los Angeles, Los Angeles, CA, USA
Marco P. M. Boks
Affiliation:
Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands
Rene S. Kahn
Affiliation:
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Loes M. Olde Loohuis
Affiliation:
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University California Los Angeles, Los Angeles, CA, USA
Roel A. Ophoff*
Affiliation:
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University California Los Angeles, Los Angeles, CA, USA Department of Human Genetics, University California Los Angeles, Los Angeles, CA, USA Department of Psychiatry, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
*
Author for correspondence: Roel A. Ophoff, E-mail: ophoff@ucla.edu
Get access Rights & Permissions [Opens in a new window]

Abstract

Background

Bipolar disorder (BD) is a highly heritable mood disorder with complex genetic architecture and poorly understood etiology. Previous transcriptomic BD studies have had inconsistent findings due to issues such as small sample sizes and difficulty in adequately accounting for confounders like medication use.

Methods

We performed a differential expression analysis in a well-characterized BD case-control sample (Nsubjects = 480) by RNA sequencing of whole blood. We further performed co-expression network analysis, functional enrichment, and cell type decomposition, and integrated differentially expressed genes with genetic risk.

Results

While we observed widespread differential gene expression patterns between affected and unaffected individuals, these effects were largely linked to lithium treatment at the time of blood draw (FDR < 0.05, Ngenes = 976) rather than BD diagnosis itself (FDR < 0.05, Ngenes = 6). These lithium-associated genes were enriched for cell signaling and immune response functional annotations, among others, and were associated with neutrophil cell-type proportions, which were elevated in lithium users. Neither genes with altered expression in cases nor in lithium users were enriched for BD, schizophrenia, and depression genetic risk based on information from genome-wide association studies, nor was gene expression associated with polygenic risk scores for BD.

Conclusions

These findings suggest that BD is associated with minimal changes in whole blood gene expression independent of medication use but emphasize the importance of accounting for medication use and cell type heterogeneity in psychiatric transcriptomic studies. The results of this study add to mounting evidence of lithium's cell signaling and immune-related mechanisms.

Keywords

Bipolar disordergenome-wide disease risklithiumneutrophilstranscriptomewhole blood
Type
Original Articles
Information
Psychological Medicine , Volume 50 , Issue 15 , November 2020 , pp. 2575 - 2586
Check for updates
Copyright
Copyright © Cambridge University Press 2019

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Footnotes

*

Shared senior authorship.

References

Abramovic, L, Boks, MP, Vreeker, A, Bouter, DC, Kruiper, C, Verkooijen, S, Van Bergen, AH, Ophoff, RA, Kahn, RS and Van Haren, NE (2016) The association of antipsychotic medication and lithium with brain measures in patients with bipolar disorder. European Neuropsychopharmacology 26, 1741–1751.CrossRefGoogle ScholarPubMed
Abramovic, L, Boks, MPM, Vreeker, A, Verkooijen, S, Van Bergen, AH, Ophoff, RA, Kahn, RS and Van Haren, NEM (2018) White matter disruptions in patients with bipolar disorder. European Neuropsychopharmacology 28, 743–751.CrossRefGoogle ScholarPubMed
Akula, N, Barb, J, Jiang, X, Wendland, JR, Choi, KH, Sen, SK, Hou, L, Chen, DT, Laje, G, Johnson, K, Lipska, BK, Kleinman, JE, Corrada-Bravo, H, Detera-Wadleigh, S, Munson, PJ and Mcmahon, FJ (2014) RNA-sequencing of the brain transcriptome implicates dysregulation of neuroplasticity, circadian rhythms and GTPase binding in bipolar disorder. Molecular Psychiatry 19, 1179–1185.CrossRefGoogle ScholarPubMed
Alda, M (2015) Lithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics. Molecular Psychiatry 20, 661–670.CrossRefGoogle ScholarPubMed
Anand, A, Mcclintick, JN, Murrell, J, Karne, H, Nurnberger, JI and Edenberg, HJ (2016) Effects of lithium monotherapy for bipolar disorder on gene expression in peripheral lymphocytes. Molecular Neuropsychiatry 2, 115–123.CrossRefGoogle ScholarPubMed
Beech, RD, Leffert, JJ, Lin, A, Sylvia, LG, Umlauf, S, Mane, S, Zhao, H, Bowden, C, Calabrese, JR, Friedman, ES, Ketter, TA, Iosifescu, DV, Reilly-Harrington, NA, Ostacher, M, Thase, ME and Nierenberg, A (2014) Gene-expression differences in peripheral blood between lithium responders and non-responders in the Lithium Treatment-Moderate dose Use Study (LiTMUS). Pharmacogenomics Journal 14, 182–191.CrossRefGoogle Scholar
Breen, MS, White, CH, Shekhtman, T, Lin, K, Looney, D, Woelk, CH and Kelsoe, JR (2016) Lithium-responsive genes and gene networks in bipolar disorder patient-derived lymphoblastoid cell lines. Pharmacogenomics Journal 16, 446–453.CrossRefGoogle ScholarPubMed
Brown, KM and Tracy, DK (2013) Lithium: the pharmacodynamic actions of the amazing ion. Therapeutic Advances in Psychopharmacology 3, 163–176.CrossRefGoogle ScholarPubMed
Cai, C, Langfelder, P, Fuller, TF, Oldham, MC, Luo, R, Van Den Berg, LH, Ophoff, RA and Horvath, S (2010) Is human blood a good surrogate for brain tissue in transcriptional studies? BMC Genomics 11, 589.CrossRefGoogle Scholar
Choi, KH, Higgs, BW, Wendland, JR, Song, J, Mcmahon, FJ and Webster, MJ (2011) Gene expression and genetic variation data implicate PCLO in bipolar disorder. Biological Psychiatry 69, 353–359.CrossRefGoogle ScholarPubMed
Cipriani, A, Hawton, K, Stockton, S and Geddes, JR (2013) Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ 346, f3646.CrossRefGoogle ScholarPubMed
Cross-Disorder Group of the Psychiatric Genomics, C., 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, Bayes, 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, Frisen, 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, Kahler, 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, Landen, M, Langstrom, 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, Muhleisen, TW, Muir, WJ, Muller-Myhsok, B, Murtha, M, Myers, RM, Myin-Germeys, I, Neale, MC, Nelson, SF, Nievergelt, CM, Nikolov, I, Nimgaonkar, V, Nolen, WA, Nothen, 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, Rehnstrom, K, Reif, A, Ribases, 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, Zollner, S, Devlin, B, Kelsoe, JR, Sklar, P, Daly, MJ, O'Donovan, MC, Craddock, N, Sullivan, PF, Smoller, JW, Kendler, KS, Wray, NR, International Inflammatory Bowel Disease Genetics C (2013) Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nature Genetics 45, 984–994.Google ScholarPubMed
Cruceanu, C, Tan, PP, Rogic, S, Lopez, JP, Torres-Platas, SG, Gigek, CO, Alda, M, Rouleau, GA, Pavlidis, P and Turecki, G (2015) Transcriptome sequencing of the anterior cingulate in bipolar disorder: dysregulation of G protein-coupled receptors. American Journal of Psychiatry 172, 1131–1140.CrossRefGoogle ScholarPubMed
Da Huang, W, Sherman, BT and Lempicki, RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature Protocols 4, 44–57.CrossRefGoogle Scholar
De Leeuw, CA, Mooij, JM, Heskes, T and Posthuma, D (2015) MAGMA: generalized gene-set analysis of GWAS data. PLoS Computational Biology 11, e1004219.CrossRefGoogle ScholarPubMed
Eaton, WW, Martins, SS, Nestadt, G, Bienvenu, OJ, Clarke, D and Alexandre, P (2008) The burden of mental disorders. Epidemiologic Reviews 30, 1–14.CrossRefGoogle ScholarPubMed
Elashoff, M, Higgs, BW, Yolken, RH, Knable, MB, Weis, S, Webster, MJ, Barci, BM and Torrey, EF (2007) Meta-analysis of 12 genomic studies in bipolar disorder. Journal of Molecular Neuroscience 31, 221–243.Google ScholarPubMed
Fries, GR, Colpo, GD, Monroy-Jaramillo, N, Zhao, J, Zhao, Z, Arnold, JG, Bowden, CL and Walss-Bass, C (2017) Distinct lithium-induced gene expression effects in lymphoblastoid cell lines from patients with bipolar disorder. European Neuropsychopharmacology 27, 1110–1119.CrossRefGoogle ScholarPubMed
Fromer, M, Roussos, P, Sieberts, SK, Johnson, JS, Kavanagh, DH, Perumal, TM, Ruderfer, DM, Oh, EC, Topol, A, Shah, HR, Klei, LL, Kramer, R, Pinto, D, Gumus, ZH, Cicek, AE, Dang, KK, Browne, A, Lu, C, Xie, L, Readhead, B, Stahl, EA, Xiao, J, Parvizi, M, Hamamsy, T, Fullard, JF, Wang, YC, Mahajan, MC, Derry, JM, Dudley, JT, Hemby, SE, Logsdon, BA, Talbot, K, Raj, T, Bennett, DA, De Jager, PL, Zhu, J, Zhang, B, Sullivan, PF, Chess, A, Purcell, SM, Shinobu, LA, Mangravite, LM, Toyoshiba, H, Gur, RE, Hahn, CG, Lewis, DA, Haroutunian, V, Peters, MA, Lipska, BK, Buxbaum, JD, Schadt, EE, Hirai, K, Roeder, K, Brennand, KJ, Katsanis, N, Domenici, E, Devlin, B and Sklar, P (2016) Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nature Neuroscience 19, 1442–1453.CrossRefGoogle ScholarPubMed
Gandal, MJ, Haney, JR, Parikshak, NN, Leppa, V, Ramaswami, G, Hartl, C, Schork, AJ, Appadurai, V, Buil, A, Werge, TM, Liu, C, White, KP, Commonmind, C., Psych, E. C., I, P.-B. W. G., Horvath, S and Geschwind, DH (2018a) Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science 359, 693–697.CrossRefGoogle Scholar
Gandal, MJ, Zhang, P, Hadjimichael, E, Walker, RL, Chen, C, Liu, S, Won, H, Van Bakel, H, Varghese, M, Wang, Y, Shieh, AW, Haney, J, Parhami, S, Belmont, J, Kim, M, Moran Losada, P, Khan, Z, Mleczko, J, Xia, Y, Dai, R, Wang, D, Yang, YT, Xu, M, Fish, K, Hof, PR, Warrell, J, Fitzgerald, D, White, K, Jaffe, AE, Psych, EC, Peters, MA, Gerstein, M, Liu, C, Iakoucheva, LM, Pinto, D and Geschwind, DH (2018b) Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder. Science 362, eaat8127.CrossRefGoogle Scholar
Genomes Project, C., Auton, A, Brooks, LD, Durbin, RM, Garrison, EP, Kang, HM, Korbel, JO, Marchini, JL, Mccarthy, S, Mcvean, GA and Abecasis, GR (2015) A global reference for human genetic variation. Nature 526, 68–74.Google ScholarPubMed
Gitlin, M (2016) Lithium side effects and toxicity: prevalence and management strategies. International Journal of Bipolar Disorder 4, 27.CrossRefGoogle ScholarPubMed
Harvey, AG (2008) Sleep and circadian rhythms in bipolar disorder: seeking synchrony, harmony, and regulation. American Journal of Psychiatry 165, 820–829.CrossRefGoogle ScholarPubMed
Hess, JL, Tylee, DS, Barve, R, De Jong, S, Ophoff, RA, Kumarasinghe, N, Tooney, P, Schall, U, Gardiner, E, Beveridge, NJ, Scott, RJ, Yasawardene, S, Perera, A, Mendis, J, Carr, V, Kelly, B, Cairns, M, Neurobehavioural Genetics, U., Tsuang, MT and Glatt, SJ (2016) Transcriptome-wide mega-analyses reveal joint dysregulation of immunologic genes and transcription regulators in brain and blood in schizophrenia. Schizophrenia Research 176, 114–124.CrossRefGoogle Scholar
Hyde, CL, Nagle, MW, Tian, C, Chen, X, Paciga, SA, Wendland, JR, Tung, JY, Hinds, DA, Perlis, RH and Winslow, AR (2016) Identification of 15 genetic loci associated with risk of major depression in individuals of European descent. Nature Genetics 48, 1031–1036.CrossRefGoogle ScholarPubMed
Jansen, R, Penninx, BW, Madar, V, Xia, K, Milaneschi, Y, Hottenga, JJ, Hammerschlag, AR, Beekman, A, Van Der Wee, N, Smit, JH, Brooks, AI, Tischfield, J, Posthuma, D, Schoevers, R, Van Grootheest, G, Willemsen, G, De Geus, EJ, Boomsma, DI, Wright, FA, Zou, F, Sun, W and Sullivan, PF (2016) Gene expression in major depressive disorder. Molecular Psychiatry 21, 444.CrossRefGoogle ScholarPubMed
Jones, SE, Tyrrell, J, Wood, AR, Beaumont, RN, Ruth, KS, Tuke, MA, Yaghootkar, H, Hu, Y, Teder-Laving, M, Hayward, C, Roenneberg, T, Wilson, JF, Del Greco, F, Hicks, AA, Shin, C, Yun, CH, Lee, SK, Metspalu, A, Byrne, EM, Gehrman, PR, Tiemeier, H, Allebrandt, KV, Freathy, RM, Murray, A, Hinds, DA, Frayling, TM and Weedon, MN (2016) Genome-wide association analyses in 128 266 individuals identifies new morningness and sleep duration loci. PLoS Genetics 12, e1006125.CrossRefGoogle ScholarPubMed
Kast, RE (2008) How lithium treatment generates neutrophilia by enhancing phosphorylation of GSK-3, increasing HIF-1 levels and how this path is important during engraftment. Bone Marrow Transplantation 41, 23–26.CrossRefGoogle ScholarPubMed
Kim, D, Pertea, G, Trapnell, C, Pimentel, H, Kelley, R and Salzberg, SL (2013) Tophat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biology 14, R36.CrossRefGoogle ScholarPubMed
Kittel-Schneider, S, Hilscher, M, Scholz, CJ, Weber, H, Grunewald, L, Schwarz, R, Chiocchetti, AG and Reif, A (2017) Lithium-induced gene expression alterations in two peripheral cell models of bipolar disorder. World Journal of Biological Psychiatry 20, 462–475.CrossRefGoogle ScholarPubMed
Langfelder, P and Horvath, S (2008) WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics 9, 559.CrossRefGoogle Scholar
Law, CW, Chen, Y, Shi, W and Smyth, GK (2014) Voom: precision weights unlock linear model analysis tools for RNA-seq read counts. Genome Biology 15, R29.CrossRefGoogle ScholarPubMed
Luykx, JJ, Boks, MP, Terwindt, AP, Bakker, S, Kahn, RS and Ophoff, RA (2010) The involvement of GSK3beta in bipolar disorder: integrating evidence from multiple types of genetic studies. European Neuropsychopharmacology 20, 357–368.CrossRefGoogle ScholarPubMed
Luykx, JJ, Bakker, SC, Lentjes, E, Neeleman, M, Strengman, E, Mentink, L, Deyoung, J, De Jong, S, Sul, JH, Eskin, E, Van Eijk, K, Van Setten, J, Buizer-Voskamp, JE, Cantor, RM, Lu, A, Van Amerongen, M, Van Dongen, EP, Keijzers, P, Kappen, T, Borgdorff, P, Bruins, P, Derks, EM, Kahn, RS and Ophoff, RA (2014) Genome-wide association study of monoamine metabolite levels in human cerebrospinal fluid. Molecular Psychiatry 19, 228–234.CrossRefGoogle ScholarPubMed
Maddu, N and Raghavendra, PB (2015) Review of lithium effects on immune cells. Immunopharmacology and Immunotoxicology 37, 111–125.CrossRefGoogle ScholarPubMed
Madison, JM, Zhou, F, Nigam, A, Hussain, A, Barker, DD, Nehme, R, Van Der Ven, K, Hsu, J, Wolf, P, Fleishman, M, O'dushlaine, C, Rose, S, Chambert, K, Lau, FH, Ahfeldt, T, Rueckert, EH, Sheridan, SD, Fass, DM, Nemesh, J, Mullen, TE, Daheron, L, Mccarroll, S, Sklar, P, Perlis, RH and Haggarty, SJ (2015) Characterization of bipolar disorder patient-specific induced pluripotent stem cells from a family reveals neurodevelopmental and mRNA expression abnormalities. Molecular Psychiatry 20, 703–717.CrossRefGoogle ScholarPubMed
Malhi, GS, Gessler, D and Outhred, T (2017) The use of lithium for the treatment of bipolar disorder: recommendations from clinical practice guidelines. Journal of Affective Disorders 217, 266–280.CrossRefGoogle ScholarPubMed
Matigian, N, Windus, L, Smith, H, Filippich, C, Pantelis, C, Mcgrath, J, Mowry, B and Hayward, N (2007) Expression profiling in monozygotic twins discordant for bipolar disorder reveals dysregulation of the WNT signalling pathway. Molecular Psychiatry 12, 815–825.CrossRefGoogle ScholarPubMed
Mcguffin, P, Rijsdijk, F, Andrew, M, Sham, P, Katz, R and Cardno, A (2003) The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Archives of General Psychiatry 60, 497–502.CrossRefGoogle ScholarPubMed
Mertens, J, Wang, QW, Kim, Y, Yu, DX, Pham, S, Yang, B, Zheng, Y, Diffenderfer, KE, Zhang, J, Soltani, S, Eames, T, Schafer, ST, Boyer, L, Marchetto, MC, Nurnberger, JI, Calabrese, JR, Odegaard, KJ, Mccarthy, MJ, Zandi, PP, Alda, M, Nievergelt, CM, Pharmacogenomics of Bipolar Disorder, S., Mi, S, Brennand, KJ, Kelsoe, JR, Gage, FH and Yao, J (2015) Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature 527, 95–99.CrossRefGoogle ScholarPubMed
Mostafavi, S, Battle, A, Zhu, X, Potash, JB, Weissman, MM, Shi, J, Beckman, K, Haudenschild, C, Mccormick, C, Mei, R, Gameroff, MJ, Gindes, H, Adams, P, Goes, FS, Mondimore, FM, Mackinnon, DF, Notes, L, Schweizer, B, Furman, D, Montgomery, SB, Urban, AE, Koller, D and Levinson, DF (2014) Type I interferon signaling genes in recurrent major depression: increased expression detected by whole-blood RNA sequencing. Molecular Psychiatry 19, 1267–1274.CrossRefGoogle ScholarPubMed
Newman, AM, Liu, CL, Green, MR, Gentles, AJ, Feng, W, Xu, Y, Hoang, CD, Diehn, M and Alizadeh, AA (2015) Robust enumeration of cell subsets from tissue expression profiles. Nature Methods 12, 453–457.CrossRefGoogle ScholarPubMed
Pacifico, R and Davis, RL (2017) Transcriptome sequencing implicates dorsal striatum-specific gene network, immune response and energy metabolism pathways in bipolar disorder. Molecular Psychiatry 22, 441–449.CrossRefGoogle ScholarPubMed
Peterson, CB, Service, SK, Jasinska, AJ, Gao, F, Zelaya, I, Teshiba, TM, Bearden, CE, Cantor, RM, Reus, VI, Macaya, G, Lopez-Jaramillo, C, Bogomolov, M, Benjamini, Y, Eskin, E, Coppola, G, Freimer, NB and Sabatti, C (2016) Characterization of Expression Quantitative Trait Loci in Pedigrees from Colombia and Costa Rica Ascertained for Bipolar Disorder. PLoS Genetics 12, e1006046.CrossRefGoogle ScholarPubMed
Pickard, BS (2017) Genomics of lithium action and response. Neurotherapeutics 14, 582–587.CrossRefGoogle ScholarPubMed
Popova, T, Mennerich, D, Weith, A and Quast, K (2008) Effect of RNA quality on transcript intensity levels in microarray analysis of human post-mortem brain tissues. BMC Genomics 9, 91.CrossRefGoogle ScholarPubMed
Rosales, C, Demaurex, N, Lowell, CA and Uribe-Querol, E (2016) Neutrophils: their role in innate and adaptive immunity. Journal of Immunology Research 2016, 1469780.CrossRefGoogle ScholarPubMed
Rosenblat, JD and Mcintyre, RS (2017) Bipolar disorder and immune dysfunction: epidemiological findings, proposed pathophysiology and clinical implications. Brain Science 7, 144.CrossRefGoogle ScholarPubMed
Roux, M and Dosseto, A (2017) From direct to indirect lithium targets: a comprehensive review of omics data. Metallomics: Integrated Biometal Science 9, 1326–1351.CrossRefGoogle ScholarPubMed
Schizophrenia Working Group of the Psychiatric Genomics, C. (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427.CrossRefGoogle Scholar
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, Baekvad-Hansen, M, Barchas, JD, Bass, N, Bauer, M, Belliveau, R, Bergen, SE, Pedersen, CB, Boen, 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, Elvsashagen, T, Escott-Price, V, Fan, CC, Fischer, SB, Flickinger, M, Foroud, TM, Forty, L, Frank, J, Fraser, C, Freimer, NB, Frisen, 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, Jureus, A, Kandaswamy, R, Karlsson, R, Kennedy, JL, Kittel-Schneider, S, Knowles, JA, Kogevinas, M, Koller, AC, Kupka, R, Lavebratt, C, Lawrence, J, Lawson, WB, Leber, M, Lee, PH, Levy, SE, Li, JZ, Liu, C, Lucae, S, Maaser, A, MacIntyre, DJ, Mahon, PB, Maier, W, Martinsson, L, McCarroll, S, McGuffin, P, McInnis, MG, McKay, JD, Medeiros, H, Medland, SE, Meng, F, Milani, L, Montgomery, GW, Morris, DW, Muhleisen, TW, Mullins, N, Nguyen, H, Nievergelt, CM, Adolfsson, AN, Nwulia, EA, O'Donovan, C, Loohuis, LMO, Ori, APS, Oruc, L, Osby, U, Perlis, RH, Perry, A, Pfennig, A, Potash, JB, Purcell, SM, Regeer, EJ, Reif, A, Reinbold, CS, Rice, JP, Rivas, F, Rivera, M, Roussos, P, Ruderfer, DM, Ryu, E, Sanchez-Mora, C, Schatzberg, AF, Scheftner, WA, Schork, NJ, Shannon Weickert, C, Shehktman, T, Shilling, PD, Sigurdsson, E, Slaney, C, Smeland, OB, Sobell, JL, Soholm Hansen, C, Spijker, AT, St Clair, D, Steffens, M, Strauss, JS, Streit, F, Strohmaier, J, Szelinger, S, Thompson, RC, Thorgeirsson, TE, Treutlein, J, Vedder, H, Wang, W, Watson, SJ, Weickert, TW, Witt, SH, Xi, S, Xu, W, Young, AH, Zandi, P, Zhang, P, Zollner, S, e, QC, Consortium, B, Adolfsson, R, Agartz, I, Alda, M, Backlund, L, Baune, BT, Bellivier, F, Berrettini, WH, Biernacka, JM, Blackwood, DHR, Boehnke, M, Borglum, AD, Corvin, A, Craddock, N, Daly, MJ, Dannlowski, U, Esko, T, Etain, B, Frye, M, Fullerton, JM, Gershon, ES, Gill, M, Goes, F, Grigoroiu-Serbanescu, M, Hauser, J, Hougaard, DM, Hultman, CM, Jones, I, Jones, LA, Kahn, RS, Kirov, G, Landen, M, Leboyer, M, Lewis, CM, Li, QS, Lissowska, J, Martin, NG, Mayoral, F, McElroy, SL, McIntosh, AM, McMahon, FJ, Melle, I, Metspalu, A, Mitchell, PB, Morken, G, Mors, O, Mortensen, PB, Muller-Myhsok, B, Myers, RM, Neale, BM, Nimgaonkar, V, Nordentoft, M, Nothen, MM, O'Donovan, MC, Oedegaard, KJ, Owen, MJ, Paciga, SA, Pato, C, Pato, MT, Posthuma, D, Ramos-Quiroga, JA, Ribases, M, Rietschel, M, Rouleau, GA, Schalling, M, Schofield, PR, Schulze, TG, Serretti, A, Smoller, JW, Stefansson, H, Stefansson, K, Stordal, E, Sullivan, PF, Turecki, G, Vaaler, AE, Vieta, E, Vincent, JB, Werge, T, Nurnberger, JI, Wray, NR, Di Florio, A, Edenberg, HJ, Cichon, S, Ophoff, RA, Scott, LJ, Andreassen, OA, Kelsoe, J, Sklar, P, Bipolar Disorder Working Group of the Psychiatric Genomics C (2019) Genome-wide association study identifies 30 loci associated with bipolar disorder. Nature Genetics 51, 793–803.CrossRefGoogle ScholarPubMed
Van Eijk, KR, De Jong, S, Strengman, E, Buizer-Voskamp, JE, Kahn, RS, Boks, MP, Horvath, S and Ophoff, RA (2015) Identification of schizophrenia-associated loci by combining DNA methylation and gene expression data from whole blood. European Journal of Human Genetics 23, 1106–1110.CrossRefGoogle ScholarPubMed
Vizlin-Hodzic, D, Zhai, Q, Illes, S, Sodersten, K, Truve, K, Parris, TZ, Sobhan, PK, Salmela, S, Kosalai, ST, Kanduri, C, Strandberg, J, Seth, H, Bontell, TO, Hanse, E, Agren, H and Funa, K (2017) Early onset of inflammation during ontogeny of bipolar disorder: the NLRP2 inflammasome gene distinctly differentiates between patients and healthy controls in the transition between iPS cell and neural stem cell stages. Translational Psychiatry 7, e1010.CrossRefGoogle Scholar
Weissman, MM, Bland, RC, Canino, GJ, Faravelli, C, Greenwald, S, Hwu, HG, Joyce, PR, Karam, EG, Lee, CK, Lellouch, J, Lepine, JP, Newman, SC, Rubio-Stipec, M, Wells, JE, Wickramaratne, PJ, Wittchen, H and Yeh, EK (1996) Cross-national epidemiology of major depression and bipolar disorder. JAMA 276, 293–299.CrossRefGoogle ScholarPubMed
Witt, SH, Juraeva, D, Sticht, C, Strohmaier, J, Meier, S, Treutlein, J, Dukal, H, Frank, J, Lang, M, Deuschle, M, Schulze, TG, Degenhardt, F, Mattheisen, M, Brors, B, Cichon, S, Nothen, MM, Witt, CC and Rietschel, M (2014) Investigation of manic and euthymic episodes identifies state- and trait-specific gene expression and STAB1 as a new candidate gene for bipolar disorder. Translational Psychiatry 4, e426.CrossRefGoogle ScholarPubMed
Xiao, Y, Camarillo, C, Ping, Y, Arana, TB, Zhao, H, Thompson, PM, Xu, C, Su, BB, Fan, H, Ordonez, J, Wang, L, Mao, C, Zhang, Y, Cruz, D, Escamilla, MA, Li, X and Xu, C (2014) The DNA methylome and transcriptome of different brain regions in schizophrenia and bipolar disorder. PLoS One 9, e95875.CrossRefGoogle ScholarPubMed
Zhao, Z, Xu, J, Chen, J, Kim, S, Reimers, M, Bacanu, SA, Yu, H, Liu, C, Sun, J, Wang, Q, Jia, P, Xu, F, Zhang, Y, Kendler, KS, Peng, Z and Chen, X (2015) Transcriptome sequencing and genome-wide association analyses reveal lysosomal function and actin cytoskeleton remodeling in schizophrenia and bipolar disorder. Molecular Psychiatry 20, 563–572.CrossRefGoogle ScholarPubMed
Supplementary material: File

Krebs et al. supplementary material

Krebs et al. supplementary material 1

Download Krebs et al. supplementary material(File)
File 8.6 MB
Supplementary material: File

Krebs et al. supplementary material

Krebs et al. supplementary material 2

Download Krebs et al. supplementary material(File)
File 1.7 MB
Supplementary material: File

Krebs et al. supplementary material

Krebs et al. supplementary material 3

Download Krebs et al. supplementary material(File)
File 2 MB