Bipolar disorder (BD) is a common mood disorder characterized by recurrent episodes of mania and depression. Both genetic and environmental factors have been implicated in BD etiology, but the biological underpinnings remain elusive. Recently, genome-wide association studies (GWAS) of neuropsychiatric disorders have identified a risk locus for BD containing the SYNE1 gene, a large gene encoding multiple proteins. The BD association signal spans, almost exclusively, the part of SYNE1 encoding CPG2, a brain-specific protein localized to excitatory postsynaptic sites, where it regulates glutamate receptor internalization. Here we show that CPG2 protein levels are significantly decreased in postmortem brain tissue from BD patients, as compared to control subjects, as well as schizophrenia and depression patients. We identify genetic variants within the postmortem brains that map to the CPG2 promoter region, and show that they negatively affect gene expression. We also identify missense single nucleotide polymorphisms (SNPs) in CPG2 coding regions that affect CPG2 expression, localization, and synaptic function. Our findings link genetic variation in the CPG2 region of SYNE1 with a mechanism for glutamatergic synapse dysfunction that could underlie susceptibility to BD in some individuals. Few GWAS hits in human genetics for neuropsychiatric disorders to date have afforded such mechanistic clues. Further, the potential for genetic distinction of susceptibility to BD from other neuropsychiatric disorders with overlapping clinical traits holds promise for improved diagnostics and treatment of this devastating illness.
Subscribe to Journal
Get full journal access for 1 year
only $62.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Merikangas KR, Akiskal HS, Angst J, Greenberg PE, Hirschfeld RM, Petukhova M, et al. Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch Gen Psychiatry. 2007;64:543–52.
Crump C, Sundquist K, Winkleby MA, Sundquist J. Comorbidities and mortality in bipolar disorder: a Swedish national cohort study. JAMA Psychiatry. 2013;70:931–9.
Jamison KR. Suicide and bipolar disorder. J Clin Psychiatry. 2000;61:47–51.
Bavamian S, Mellios N, Lalonde J, Fass DM, Wang J, Sheridan SD, et al. Noncoding RNAs connect genetic risk factors to the neurodevelopmental basis of bipolar disorder. Mol Psychiatry. 2015;20:548.
Bavamian S, Mellios N, Lalonde J, Fass DM, Wang J, Sheridan SD, et al. Dysregulation of miR-34a links neuronal development to genetic risk factors for bipolar disorder. Mol Psychiatry. 2015;20:573–84.
Jablensky A. Psychiatric classifications: validity and utility. World Psychiatry. 2016;15:26–31.
Schretlen DJ, Cascella NG, Meyer SM, Kingery LR, Testa SM, Munro CA, et al. Neuropsychological functioning in bipolar disorder and schizophrenia. Biol Psychiatry. 2007;62:179–86.
Scott J, Leboyer M. Consequences of delayed diagnosis of bipolar disorders. Encephale. 2011;37:S173–175.
Strakowski SM, Adler CM, Almeida J, Altshuler LL, Blumberg HP, Chang KD, et al. The functional neuroanatomy of bipolar disorder: a consensus model. Bipolar Disord. 2012;14:313–25.
Delvecchio G, Fossati P, Boyer P, Brambilla P, Falkai P, Gruber O, et al. Common and distinct neural correlates of emotional processing in Bipolar Disorder and Major Depressive Disorder: a voxel-based meta-analysis of functional magnetic resonance imaging studies. Eur Neuropsychopharmacol. 2012;22:100–13.
Delvecchio G, Sugranyes G, Frangou S. Evidence of diagnostic specificity in the neural correlates of facial affect processing in bipolar disorder and schizophrenia: a meta-analysis of functional imaging studies. Psychol Med. 2013;43:553–69.
Linden DE. The challenges and promise of neuroimaging in psychiatry. Neuron. 2012;73:8–22.
Craddock N, Sklar P. Genetics of bipolar disorder. Lancet. 2013;381:1654–62.
McGuffin P, Rijsdijk F, Andrew M, Sham P, Katz R, Cardno A. The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Arch Gen Psychiatry. 2003;60:497–502.
Kieseppä T, Partonen T, Haukka J, Kaprio J, Lönnqvist J. High concordance of bipolar I disorder in a nationwide sample of twins. Am J Psychiatry. 2004;161:1814–21.
Edvardsen J, Torgersen S, Røysamb E, Lygren S, Skre I, Onstad S, et al. Heritability of bipolar spectrum disorders. Unity or heterogeneity?. J Affect Disord. 2008;106:229–40.
Craddock N, Sklar P. Genetics of bipolar disorder: successful start to a long journey. Trends Genet. 2009;25:99–105.
O’Donovan MC, Owen MJ. The implications of the shared genetics of psychiatric disorders. Nat Med. 2016;22:1214–9.
Lee SH, Ripke S, Neale BM, Faraone SV, Purcell SM, Perlis RH, et al. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet. 2013;45:984–94.
Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC, Sullivan PF, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460:748–52.
Gandal MJ, Haney JR, Parikshak NN, Leppa V, Ramaswami G, Hartl C, et al. Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science. 2018;359:693–7.
Lichtenstein P, Yip BH, Björk C, Pawitan Y, Cannon TD, Sullivan PF, et al. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet. 2009;373:234–9.
Consortium C-DGotPG. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet. 2013;381:1371–9.
Ferreira MA, O’Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L, et al. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet. 2008;40:1056–8.
Psychiatric GCBDWG.. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet. 2011;43:977–83.
Green EK, Grozeva D, Forty L, Gordon-Smith K, Russell E, Farmer A, et al. Association at SYNE1 in both bipolar disorder and recurrent major depression. Mol Psychiatry. 2013;18:614–7.
Green EK, Hamshere M, Forty L, Gordon-Smith K, Fraser C, Russell E, et al. Replication of bipolar disorder susceptibility alleles and identification of two novel genome-wide significant associations in a new bipolar disorder case-control sample. Mol Psychiatry. 2013;18:1302–7.
Hou L, Bergen SE, Akula N, Song J, Hultman CM, Landén M, et al. Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder. Hum Mol Genet. 2016;25:3383–94.
Heyes S, Pratt WS, Rees E, Dahimene S, Ferron L, Owen MJ, et al. Genetic disruption of voltage-gated calcium channels in psychiatric and neurological disorders. Prog Neurobiol. 2015;134:36–54.
Iqbal Z, Vandeweyer G, van der Voet M, Waryah AM, Zahoor MY, Besseling JA, et al. Homozygous and heterozygous disruptions of ANK3: at the crossroads of neurodevelopmental and psychiatric disorders. Hum Mol Genet. 2013;22:1960–70.
Forstner AJ, Hecker J, Hofmann A, Maaser A, Reinbold CS, Mühleisen TW, et al. Identification of shared risk loci and pathways for bipolar disorder and schizophrenia. PLoS ONE. 2017;12:e0171595.
Cross-Disorder Group of the Psychiatric Genomics C. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet. 2013;381:1371–9.
Xu W, Cohen-Woods S, Chen Q, Noor A, Knight J, Hosang G, et al. Genome-wide association study of bipolar disorder in Canadian and UK populations corroborates disease loci including SYNE1 and CSMD1. BMC Med Genet. 2014;15:2.
Sanacora G, Zarate CA, Krystal JH, Manji HK. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov. 2008;7:426–37.
Nurnberger JI Jr., Koller DL, Jung J, Edenberg HJ, Foroud T, Guella I, et al. Identification of pathways for bipolar disorder: a meta-analysis. JAMA Psychiatry. 2014;71:657–64.
Machado-Vieira R, Ibrahim L, Henter ID, Zarate CA. Novel glutamatergic agents for major depressive disorder and bipolar disorder. Pharmacol Biochem Behav. 2012;100:678–87.
Perlis RH, Smoller JW, Ferreira MA, McQuillin A, Bass N, Lawrence J, et al. A genomewide association study of response to lithium for prevention of recurrence in bipolar disorder. Am J Psychiatry. 2009;166:718–25.
Scarr E, Pavey G, Sundram S, MacKinnon A, Dean B. Decreased hippocampal NMDA, but not kainate or AMPA receptors in bipolar disorder. Bipolar Disord. 2003;5:257–64.
McCullumsmith RE, Kristiansen LV, Beneyto M, Scarr E, Dean B, Meador-Woodruff JH. Decreased NR1, NR2A, and SAP102 transcript expression in the hippocampus in bipolar disorder. Brain Res. 2007;1127:108–18.
Nudmamud-Thanoi S, Reynolds GP. The NR1 subunit of the glutamate/NMDA receptor in the superior temporal cortex in schizophrenia and affective disorders. Neurosci Lett. 2004;372:173–7.
Meador-Woodruff JH, Hogg AJ Jr, Smith RE. Striatal ionotropic glutamate receptor expression in schizophrenia, bipolar disorder, and major depressive disorder. Brain Res Bull. 2001;5:631–40.
Beneyto M, Meador-Woodruff JH. Lamina-specific abnormalities of AMPA receptor trafficking and signaling molecule transcripts in the prefrontal cortex in schizophrenia. Synapse. 2006;60:585–98.
Loebrich S, Rathje M, Hager E, Ataman B, Harmin DA, Greenberg ME, et al. Genomic mapping and cellular expression of human CPG2 transcripts in the SYNE1 gene. Mol Cell Neurosci. 2016;71:46–55.
Puckelwartz MJ, Kessler E, Zhang Y, Hodzic D, Randles KN, Morris G, et al. Disruption of nesprin-1 produces an Emery Dreifuss muscular dystrophy-like phenotype in mice. Hum Mol Genet. 2009;18:607–20.
Zhang Q, Bethmann C, Worth NF, Davies JD, Wasner C, Feuer A, et al. Nesprin-1 and -2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity. Hum Mol Genet. 2007;16:2816–33.
Nedivi E, Hevroni D, Naot D, Israeli D, Citri Y. Numerous candidate plasticity-related genes revealed by differential cDNA cloning. Nature. 1993;363:718–22.
Cottrell JR, Borok E, Horvath TL, Nedivi E. CPG2: a brain- and synapse-specific protein that regulates the endocytosis of glutamate receptors. Neuron. 2004;44:677–90.
Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25:1754–60.
Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009;25:2078–9.
Li H. A statistical framework for SNP calling, mutation discovery, association mapping and population genetical parameter estimation from sequencing data. Bioinformatics. 2011;27:2987–93.
Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38:e164.
Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, Heravi-Moussavi A, et al. Integrative analysis of 111 reference human epigenomes. Nature. 2015;518:317–30.
Rathje M, Fang H, Bachman JL, Anggono V, Gether U, Huganir RL, et al. AMPA receptor pHluorin-GluA2 reports NMDA receptor-induced intracellular acidification in hippocampal neurons. Proc Natl Acad Sci USA. 2013;110:14426–31.
Fujino T, Lee WC, Nedivi E. Regulation of cpg15 by signaling pathways that mediate synaptic plasticity. Mol Cell Neurosci. 2003;24:538–54.
Savitz JB, Price JL, Drevets WC. Neuropathological and neuromorphometric abnormalities in bipolar disorder: view from the medial prefrontal cortical network. Neurosci Biobehav Rev. 2014;42:132–47.
Selvaraj S, Arnone D, Job D, Stanfield A, Farrow TF, Nugent AC, et al. Grey matter differences in bipolar disorder: a meta-analysis of voxel-based morphometry studies. Bipolar Disord. 2012;14:135–45.
Arnone D, Cavanagh J, Gerber D, Lawrie SM, Ebmeier KP, McIntosh AM. Magnetic resonance imaging studies in bipolar disorder and schizophrenia: meta-analysis. Br J Psychiatry. 2009;195:194–201.
Eker C, Simsek F, Yılmazer EE, Kitis O, Cinar C, Eker OD, et al. Brain regions associated with risk and resistance for bipolar I disorder: a voxel-based MRI study of patients with bipolar disorder and their healthy siblings. Bipolar Disord. 2014;16:249–61.
Morris RW, Sparks A, Mitchell PB, Weickert CS, Green MJ. Lack of cortico-limbic coupling in bipolar disorder and schizophrenia during emotion regulation. Transl Psychiatry. 2012;2:e90.
Shepherd JD, Bear MF. New views of Arc, a master regulator of synaptic plasticity. Nat Neurosci. 2011;14:279–84.
Ikeda M, Takahashi A, Kamatani Y, Okahisa Y, Kunugi H, Mori N, et al. A genome-wide association study identifies two novel susceptibility loci and trans population polygenicity associated with bipolar disorder. Mol Psychiatry. 2018;23:639–47.
Smith EN, Koller DL, Panganiban C, Szelinger S, Zhang P, Badner JA, et al. Genome-wide association of bipolar disorder suggests an enrichment of replicable associations in regions near genes. PLoS Genet. 2011;7:e1002134.
Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, et al. Finding the missing heritability of complex diseases. Nature. 2009;461:747–53.
Bomba L, Walter K, Soranzo N. The impact of rare and low-frequency genetic variants in common disease. Genome Biol. 2017;18:77.
Loebrich S, Djukic B, Tong ZJ, Cottrell JR, Turrigiano GG, Nedivi E. Regulation of glutamate receptor internalization by the spine cytoskeleton is mediated by its PKA-dependent association with CPG2. Proc Natl Acad Sci USA. 2013;110:E4548–4556.
McCarroll SA, Hyman SE. Progress in the genetics of polygenic brain disorders: significant new challenges for neurobiology. Neuron. 2013;80:578–87.
Consortium SWGotPG. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–7.
Richards AL, Jones L, Moskvina V, Kirov G, Gejman PV, Levinson DF, et al. Schizophrenia susceptibility alleles are enriched for alleles that affect gene expression in adult human brain. Mol Psychiatry. 2012;17:193–201.
Nicolae DL, Gamazon E, Zhang W, Duan S, Dolan ME, Cox NJ. Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS. PLoS Genet. 2010;6:e1000888.
Maurano MT, Humbert R, Rynes E, Thurman RE, Haugen E, Wang H, et al. Systematic localization of common disease-associated variation in regulatory DNA. Science. 2012;337:1190–5.
Heintzman ND, Hon GC, Hawkins RD, Kheradpour P, Stark A, Harp LF, et al. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature. 2009;459:108–12.
Sharp SI, Lange J, Kandaswamy R, Daher M, Anjorin A, Bass NJ, et al. Identification of rare nonsynonymous variants in SYNE1/CPG2 in bipolar affective disorder. Psychiatr Genet. 2017;27:81–88.
Loebrich S, Nedivi E. The function of activity-regulated genes in the nervous system. Physiol Rev. 2009;89:1079–103.
Human postmortem brain tissue samples were generously provided by the Stanley Medical Research Institute neuropathology collection, Massachusetts Alzheimer’s Disease Research Center (funding source: P50 AG005134) and NIH Neurobiobank with contributions from Harvard Brain Tissue Resource Center, Mount Sinai NIH Brain & Tissue Repository and University of Maryland Brain & Tissue Bank. We acknowledge Picower Institute for Learning and Memory Staff Bioinformatician, Fan Gao, for invaluable help with bioinformatics and statistical analyses. Furthermore, we acknowledge Drs. Jeffrey Cottrell and Dennis Lal at the Stanley Center for Psychiatric Research, and our colleagues in the Nedivi Laboratory for valuable input and editing of the manuscript. The work was funded by the Jeffry M. and Barbara Picower Foundation (E.N.), The Gail Steel Fund (E.N.), the Carlsberg Foundation (M.R.), Lundbeck Foundation (M.R.), and the Danish Council for Independent Research (M.R.).
Conflict of interest
The authors declare that they have no conflict of interest.
About this article
Cite this article
Rathje, M., Waxman, H., Benoit, M. et al. Genetic variants in the bipolar disorder risk locus SYNE1 that affect CPG2 expression and protein function. Mol Psychiatry (2019). https://doi.org/10.1038/s41380-018-0314-z
Frontiers in Neurology (2020)
Integrated Analysis of microRNA and mRNA Expression Profiles: An Attempt to Disentangle the Complex Interaction Network in Attention Deficit Hyperactivity Disorder
Brain Sciences (2019)