Skip to main content

Advertisement

SpringerLink
Log in

Significance of an altered lncRNA landscape in schizophrenia and cognition: clues from a case–control association study

  • Original Paper
  • Published:
European Archives of Psychiatry and Clinical Neuroscience Aims and scope Submit manuscript

Abstract

Genetic etiology of schizophrenia is poorly understood despite large genome-wide association data. Long non-coding RNAs (lncRNAs) with a probable regulatory role are emerging as important players in neuro-psychiatric disorders including schizophrenia. Prioritising important lncRNAs and analyses of their holistic interaction with their target genes may provide insights into disease biology/etiology. Of the 3843 lncRNA SNPs reported in schizophrenia GWASs extracted using lincSNP 2.0, we prioritised n = 247 based on association strength, minor allele frequency and regulatory potential and mapped them to lncRNAs. lncRNAs were then prioritised based on their expression in brain using lncRBase, epigenetic role using 3D SNP and functional relevance to schizophrenia etiology. 18 SNPs were finally tested for association with schizophrenia (n = 930) and its endophenotypes—tardive dyskinesia (n = 176) and cognition (n = 565) using a case–control approach. Associated SNPs were characterised by ChIP seq, eQTL, and transcription factor binding site (TFBS) data using FeatSNP. Of the eight SNPs significantly associated, rs2072806 in lncRNA hsaLB_IO39983 with regulatory effect on BTN3A2 was associated with schizophrenia (p = 0.006); rs2710323 in hsaLB_IO_2331 with role in dysregulation of ITIH1 with tardive dyskinesia (p < 0.05); and four SNPs with significant cognition score reduction (p < 0.05) in cases. Two of these with two additional variants in eQTL were observed among controls (p < 0.05), acting likely as enhancer SNPs and/or altering TFBS of eQTL mapped downstream genes. This study highlights important lncRNAs in schizophrenia and provides a proof of concept of novel interactions of lncRNAs with protein-coding genes to elicit alterations in immune/inflammatory pathways of schizophrenia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data availability

The authors confirm that all the data supporting the findings of this study are available within the article and its supplementary materials.

References

  1. H L (2008) Clinical handbook of schizophrenia. In: Mueser KT JD, editor. New York, Guilford Press, pp 3–12

  2. Beck AT, Rector NA, Stolar N GP (2009) H. New York, New York, Guilford Press, pp 30–61

  3. Sumiyoshi T, Stockmeier CA, Overholser JC, Dilley GE, Meltzer HY (1996) Serotonin1A receptors are increased in postmortem prefrontal cortex in schizophrenia. Brain Res 708(1–2):209–214

    Article  PubMed  CAS  Google Scholar 

  4. Wible CG, Anderson J, Shenton ME, Kricun A, Hirayasu Y, Tanaka S et al (2001) Prefrontal cortex, negative symptoms, and schizophrenia: an MRI study. Psychiatry Res Neuroimaging 108(2):65–78

    Article  CAS  Google Scholar 

  5. Brisch R, Saniotis A, Wolf R, Bielau H, Bernstein HG, Steiner J et al (2014) The role of dopamine in schizophrenia from a neurobiological and evolutionary perspective: Old fashioned, but still in vogue. Front Psychiatry 5:110

    PubMed Central  Google Scholar 

  6. Howes OD, Kapur S (2009) The dopamine hypothesis of schizophrenia: Version III—the final common pathway. Schizophr Bull 35:549–562

    Article  PubMed  PubMed Central  Google Scholar 

  7. Sullivan PF, Kendler KS, Neale MC (2003) Schizophrenia as a complex trait. Arch Gen Psychiatry 60(12):1187

    Article  PubMed  Google Scholar 

  8. Lichtenstein P, Yip BH, Björk C, Pawitan Y, Cannon TD, Sullivan PF et al (2009) Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. The Lancet 373(9659):234–239

    Article  CAS  Google Scholar 

  9. Yue WH, Wang HF, Sun LD, Tang FL, Liu ZH, Zhang HX et al (2011) Genome-wide association study identifies a susceptibility locus for schizophrenia in Han Chinese at 11p11.2. Nat Genet 43(12):1228–31

    Article  PubMed  CAS  Google Scholar 

  10. Ripke S, Sanders AR, Kendler KS, Levinson DF, Sklar P, Holmans PA et al (2011) Genome-wide association study identifies five new schizophrenia loci. Nat Genet 43(10):969–978

    Article  CAS  Google Scholar 

  11. Zhang F, Lupski JR (2015) Non-coding genetic variants in human disease. Hum Mol Genet 24(R1):R102–R110

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Ponting CP, Oliver PL, Reik W (2009) Evolution and functions of long noncoding RNAs. Cell 136(4):629–641

    Article  PubMed  CAS  Google Scholar 

  13. Ørom UA, Derrien T, Beringer M, Gumireddy K, Gardini A, Bussotti G et al (2010) Long noncoding RNAs with enhancer-like function in human cells. Cell 143(1):46–58

    Article  PubMed  PubMed Central  Google Scholar 

  14. Schor IE, Bussotti G, Maleš M, Forneris M, Viales RR, Enright AJ et al (2018) Non-coding RNA expression, function, and variation during drosophila embryogenesis. Curr Biol 28(22):3547-3561.e9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Kopp F (2019) Molecular functions and biological roles of long non-coding RNAs in human physiology and disease. J Gene Med. https://doi.org/10.1002/jgm.3104

    Article  PubMed  Google Scholar 

  16. Li CY, Li X, Liu Z, Ni W, Zhang X, Hazi W et al (2019) Identification and characterization of long non-coding RNA in prenatal and postnatal skeletal muscle of sheep. Genomics 111(2):133–141

    Article  PubMed  CAS  Google Scholar 

  17. Leone S, Santoro R (2016) Challenges in the analysis of long noncoding RNA functionality. FEBS Lett 590:2342–53

    Article  PubMed  CAS  Google Scholar 

  18. da Sacco L, Baldassarre A, Masotti A (2012) Bioinformatics tools and novel challenges in long non-coding RNAs (lncRNAs) functional analysis. Int J Mol Sci 13:97–114

    Article  PubMed  Google Scholar 

  19. Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H et al (2012) The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res 22(9):1775–1789

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Mercer TR, Dinger ME, Sunkin SM, Mehler MF, Mattick JS (2008) Specific expression of long noncoding RNAs in the mouse brain. Proc Natl Acad Sci 105(2):716–721

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Lin N, Chang KY, Li Z, Gates K, Rana ZA, Dang J et al (2014) An evolutionarily conserved long noncoding RNA TUNA controls pluripotency and neural lineage commitment. Mol Cell 53(6):1005–1019

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Ng SY, Johnson R, Stanton LW (2012) Human long non-coding RNAs promote pluripotency and neuronal differentiation by association with chromatin modifiers and transcription factors. EMBO J 31(3):522–533

    Article  PubMed  CAS  Google Scholar 

  23. Ng SY, Bogu GK, Soh BS, Stanton LW (2013) The long noncoding RNA RMST interacts with SOX2 to regulate neurogenesis. Mol Cell 51(3):349–359

    Article  PubMed  CAS  Google Scholar 

  24. Rapicavoli NA, Poth EM, Blackshaw S (2010) The long noncoding RNA RNCR2 directs mouse retinal cell specification. BMC Dev Biol 10(1):49. https://doi.org/10.1186/1471-213X-10-49

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Merelo V, Durand D, Lescallette AR, Vrana KE, Hong LE, Faghihi MA et al (2015) Associating schizophrenia, long non-coding RNAs and neurostructural dynamics. Front Mol Neurosci 8:57

    Article  PubMed  PubMed Central  Google Scholar 

  26. Liu Y, Chang X, Hahn CG, Gur RE, Sleiman PAM, Hakonarson H (2018) Non-coding RNA dysregulation in the amygdala region of schizophrenia patients contributes to the pathogenesis of the disease. Transl Psychiatry 8(1):1–10

    Article  Google Scholar 

  27. Jin G, Sun J, Isaacs SD, Wiley KE, Kim ST, Chu LW et al (2011) Human polymorphisms at long non-coding RNAs (lncRNAs) and association with prostate cancer risk. Carcinogenesis 32(11):1655–1659

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Qi J, Du L, Deng J, Qin Y, Su G, Hou S et al (2019) Replication of genome-wide association analysis identifies new susceptibility loci at long noncoding RNA regions for Vogt-Koyanagi-Harada disease. Invest Ophthalmol Vis Sci 60(14):4820–9

    Article  PubMed  CAS  Google Scholar 

  29. Yuen O, Caligiuri MP, Williams R, Dickson RA (1996) Tardive dyskinesia and positive and negative symptoms of schizophrenia. A study using instrumental measures. Br J Psychiatry 168(6):702–8

    Article  PubMed  CAS  Google Scholar 

  30. Telfer S, Shivashankar S, Krishnadas R, McCreadie RG, Kirkpatrick B (2011) Tardive dyskinesia and deficit schizophrenia. Acta Psychiatr Scand 124(5):357–362. https://doi.org/10.1111/j.1600-0447.2011.01751.x

    Article  PubMed  CAS  Google Scholar 

  31. Waddington JL, Youssef HA, Dolphin C, Kinsella A (1987) Cognitive dysfunction, negative symptoms, and tardive dyskinesia in schizophrenia. Their association in relation to topography of involuntary movements and criterion of their abnormality. Arch Gen Psychiatry 44(10):907–12

    Article  PubMed  CAS  Google Scholar 

  32. Dickinson D, Harvey PD (2009) Systemic hypotheses for generalized cognitive deficits in schizophrenia: a new take on an old problem. Schizophr Bull 35(2):403–414

    Article  PubMed  Google Scholar 

  33. Kalkstein S, Hurford I, Gur RC (2010) Neurocognition in schizophrenia. Curr Top Behav Neurosci. 4:373–90

    Article  PubMed  Google Scholar 

  34. Millan M (2008) Animal and translational models for CNS drug discovery. Elsevier, Amsterdam

    Google Scholar 

  35. Li M, Chen C, Zhang W, Gao R, Wang Q, Chen H et al (2019) Identification of the potential key long non-coding RNAs in aged mice with postoperative cognitive dysfunction. Front Aging Neurosci 11(JUL):181. https://doi.org/10.3389/fnagi.2019.00181/full

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Taft R, Mattick J (2003) Increasing biological complexity is positively correlated with the relative genome-wide expansion of non-protein-coding DNA sequences. Genome Biol 5(1):1–24. https://doi.org/10.1186/gb-2003-5-1-p1

    Article  Google Scholar 

  37. Deshpande SN, Mathur MN, Das SK, Bhatia T, Sharma S, Nimgaonkar VL (1998) A Hindi version of the diagnostic interview for genetic studies. Schizophr Bull 24(3):489–493

    Article  PubMed  CAS  Google Scholar 

  38. Nurnberger JI, Blehar MC, Kaufmann CA, York-Cooler C, Simpson SG, Harkavy-Friedman J et al (1994) Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. Arch Gen Psychiatry 51(11):849–59 (discussion 863-4)

    Article  PubMed  Google Scholar 

  39. Tiwari AK, Deshpande SN, Rao AR, Bhatia T, Lerer B, Nimgaonkar VL et al (2005) Genetic susceptibility to tardive dyskinesia in chronic schizophrenia subjects: III. Lack of association of CYP3A4 and CYP2D6 gene polymorphisms. Schizophr Res 75(1):21–6

    Article  PubMed  Google Scholar 

  40. Tiwari AK, Deshpande SN, Lerer B, Nimgaonkar VL, Thelma BK (2007) Genetic susceptibility to Tardive Dyskinesia in chronic schizophrenia subjects: V. Association of CYP1A2 1545 C>T polymorphism. Pharmacogenomics J 7(5):305–11

    Article  PubMed  CAS  Google Scholar 

  41. Bhatia T, Agarwal A, Shah G, Wood J, Richard J, Gur RE et al (2012) Adjunctive cognitive remediation for schizophrenia using yoga: an open, non-randomised trial. Acta Neuropsychiatr 24(02):91–100

    Article  PubMed  Google Scholar 

  42. Kukshal P, Bhatia T, Bhagwat AM, Gur RE, Gur RC, Deshpande SN et al (2013) Association study of Neuregulin-1 gene polymorphisms in a north Indian schizophrenia sample. Schizophr Res 144(1–3):24–30

    Article  PubMed  PubMed Central  Google Scholar 

  43. Ning S, Yue M, Wang P, Liu Y, Zhi H, Zhang Y et al (2017) LincSNP 2.0: an updated database for linking disease-associated SNPs to human long non-coding RNAs and their TFBSs. Nucleic Acids Res 45(D1):D74-8

    Article  PubMed  CAS  Google Scholar 

  44. Boyle AP, Hong EL, Hariharan M, Cheng Y, Schaub MA, Kasowski M et al (2012) Annotation of functional variation in personal genomes using RegulomeDB. Genome Res 22(9):1790–1797

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Chakraborty S, Deb A, Maji RK, Saha S, Ghosh Z (2014) LncRBase: an enriched resource for lncRNA information. Rogozin IB, editor. PLoS ONE. 9(9):e108010. https://doi.org/10.1371/journal.pone.0108010

  46. Lu Y, Quan C, Chen H, Bo X, Zhang C (2017) 3DSNP: a database for linking human noncoding SNPs to their three-dimensional interacting genes. Nucleic Acids Res 45(D1):D643–D649. https://doi.org/10.1093/nar/gkw1022

    Article  PubMed  CAS  Google Scholar 

  47. Gauderman WJ (2002) Sample size requirements for association studies of gene-gene interaction. Am J Epidemiol 155(5):478–484. https://doi.org/10.1093/aje/155.5.478

    Article  PubMed  Google Scholar 

  48. Gauderman WJ (2002) Sample size requirements for matched case-control studies of gene-environment interaction. Stat Med 21(1):35–50

    Article  PubMed  Google Scholar 

  49. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D et al (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81(3):559–575

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Applied Regression 3E. https://socialsciences.mcmaster.ca/jfox/Books/Companion/. Accessed 9 Feb 2022

  51. Ma C, Madden P, Gontarz P, Wang T, Zhang B (2019) FeatSNP: an interactive database for brain-specific epigenetic annotation of human SNPs. Front Genet 10:262. https://doi.org/10.3389/fgene.2019.00262/full

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Roadmap Epigenomics Consortium, Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A et al (2015) Integrative analysis of 111 reference human epigenomes. Nature 518(7539):317–30

    Article  PubMed Central  Google Scholar 

  53. Ardlie KG, DeLuca DS, Segrè AV, Sullivan TJ, Young TR, Gelfand ET et al (2015) The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science (1979) 348(6235):648–60. https://doi.org/10.1126/science.1262110

    Article  CAS  Google Scholar 

  54. Rietveld CA, Esko T, Davies G, Pers TH, Turley P, Benyamin B et al (2014) Common genetic variants associated with cognitive performance identified using the proxy-phenotype method. Proc Natl Acad Sci USA 111(38):13790–13794

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Lee JJ, Wedow R, Okbay A, Kong E, Maghzian O, Zacher M et al (2018) Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 11 million individuals. Nat Genet 50(8):1112–21

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Benyamin B, Pourcain B, Davis OS, Davies G, Hansell NK, Brion MJ et al (2014) Childhood intelligence is heritable, highly polygenic and associated with FNBP1L. Mol Psychiatry 19(2):253–258

    Article  PubMed  CAS  Google Scholar 

  57. Davies G, Lam M, Harris SE, Trampush JW, Luciano M, Hill WD et al (2018) Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. Nat Commun 9(1):2098

    Article  PubMed  PubMed Central  Google Scholar 

  58. Davies G, Marioni RE, Liewald DC, Hill WD, Hagenaars SP, Harris SE et al (2016) Genome-wide association study of cognitive functions and educational attainment in UK Biobank (N=112 151). Mol Psychiatry 21(6):758–767

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Luciano M, Hagenaars SP, Davies G, Hill WD, Clarke TK, Shirali M et al (2017) Association analysis in over 329,000 individuals identifies 116 independent variants influencing neuroticism. Nat Genet 50(1):6–11

    Article  PubMed  PubMed Central  Google Scholar 

  60. McGuire JL, Hammond JH, Yates SD, Chen D, Haroutunian V, Meador-Woodruff JH et al (2014) Altered serine/threonine kinase activity in schizophrenia. Brain Res 1568:42

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. McArthur S, Cristante E, Paterno M, Christian H, Roncaroli F, Gillies GE et al (2010) Annexin A1: a central player in the anti-inflammatory and neuroprotective role of microglia. J Immunol 185(10):6317

    Article  PubMed  CAS  Google Scholar 

  62. You JE, Jung SH, Kim PH (2021) The effect of Annexin A1 as a potential new therapeutic target on neuronal damage by activated microglia. Mol Cells 44(4):195

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Zou J, Huang GF, Xia Q, Li X, Shi J, Sun N (2022) Electroacupuncture promotes microglial M2 polarization in ischemic stroke via annexin A1. Acupunct Med 40(3):258–67. https://doi.org/10.1177/09645284211057570

    Article  PubMed  Google Scholar 

  64. Andrade A, Brennecke A, Mallat S, Brown J, Gomez-Rivadeneira J, Czepiel N et al (2019) Genetic associations between voltage-gated calcium channels and psychiatric disorders. Int J Mol Sci 20(14):3537

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Soldatov N (2015) CACNB2: an emerging pharmacological target for hypertension, heart failure, arrhythmia and mental disorders. Curr Mol Pharmacol 8(1):32–42

    Article  PubMed  CAS  Google Scholar 

  66. He K, Wang Q, Chen J, Li T, Li Z, Li W et al (2014) ITIH family genes confer risk to schizophrenia and major depressive disorder in the Han Chinese population. Prog Neuropsychopharmacol Biol Psychiatry 3(51):34–38

    Article  Google Scholar 

  67. Miyake Y, Tanaka K, Arakawa M (2018) ITIH3 and ITIH4 polymorphisms and depressive symptoms during pregnancy in Japan: the Kyushu Okinawa Maternal and Child Health Study. J Neural Transm (Vienna) 125(10):1503–1509

    Article  PubMed  CAS  Google Scholar 

  68. Brandl EJ, Lett TA, Chowdhury NI, Tiwari AK, Bakanidze G, Meltzer HY et al (2016) The role of the ITIH3 rs2535629 variant in antipsychotic response. Schizophr Res 176(2–3):131–135

    Article  PubMed  CAS  Google Scholar 

  69. Swanwick CC, Shapiro ME, Vicini S, Wenthold RJ (2010) Flotillin-1 promotes formation of glutamatergic synapses in hippocampal neurons. Dev Neurobiol 70(13):875–883. https://doi.org/10.1002/dneu.20828

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Wu Y, Bi R, Zeng C, Ma C, Sun C, Li J et al (2019) Identification of the primate-specific gene BTN3A2 as an additional schizophrenia risk gene in the MHC loci. EBioMedicine 44:530

    Article  PubMed  PubMed Central  Google Scholar 

  71. Afrache H, Gouret P, Ainouche S, Pontarotti P, Olive D (2012) The butyrophilin (BTN) gene family: from milk fat to the regulation of the immune response. Immunogenetics 64(11):781–794

    Article  PubMed  CAS  Google Scholar 

  72. Lin Y, Zhou H, Li S (2022) BTN3A2 expression is connected with favorable prognosis and high infiltrating immune in lung adenocarcinoma. Front Genet 13:1

    Article  CAS  Google Scholar 

  73. Cai P, Lu Z, Wu J, Qin X, Wang Z, Zhang Z et al (2020) BTN3A2 serves as a prognostic marker and favors immune infiltration in triple-negative breast cancer. J Cell Biochem 121(3):2643–2654. https://doi.org/10.1002/jcb.29485

    Article  PubMed  CAS  Google Scholar 

  74. Boukouaci W, Lajnef M, Richard JR, Wu CL, Bouassida J, Rafik I et al (2021) HLA-E circulating and genetic determinants in schizophrenia and bipolar disorder. Sci Rep 11(1):1–10

    Article  Google Scholar 

  75. Festenstein H, Murray R (1983) A family study of HLA antigens and other genetic markers in schizophrenia. Psychol Med 13(1):31–43. https://www.cambridge.org/core/journals/psychological-medicine/article/abs/family-study-of-hla-antigens-and-other-genetic-markers-in-schizophrenia/8CB9864961A90EBB3FE035218CDA4F85. Accessed 10 Mar 2023

  76. Sayeh A, Ben Cheikh C, Mardessi A, Mrad M, Nsiri B, Oumaya A et al (2017) HLA DRB1*03 as a possible common etiology of schizophrenia, Graves’ disease, and type 2 diabetes. Ann Gen Psychiatry 16(1):1–4. https://doi.org/10.1186/s12991-017-0128-4

    Article  Google Scholar 

  77. McGuffin P, Power RA (2013) Schizophrenia as a human leukocyte antigen-associated disease revisited. Am J Psychiatry 170(8):821–823. https://doi.org/10.1176/appi.ajp.2013.13030336

    Article  PubMed  Google Scholar 

  78. Wright P, Nimgaonkar VL, Donaldson PT, Murray RM (2001) Schizophrenia and HLA: a review. Schizophr Res 47(1):1–12

    Article  PubMed  CAS  Google Scholar 

  79. Crowe RR, Thompson JS, Flink R, Weinberger B (1979) HLA antigens and schizophrenia. Arch Gen Psychiatry 36(2):231–233

    Article  PubMed  CAS  Google Scholar 

  80. Sayeh A, Cheikh CB, Mrad M, Lakhal N, Gritli N, Galelli S et al (2014) Association of HLA-DR/DQ polymorphisms with schizophrenia in Tunisian patients. Ann Saudi Med 34(6):503

    Article  PubMed  PubMed Central  Google Scholar 

  81. Ibrahim EC, Guillemot V, Comte M, Tenenhaus A, Zendjidjian XY, Cancel A et al (2017) Modeling a linkage between blood transcriptional expression and activity in brain regions to infer the phenotype of schizophrenia patients. npj Schizophrenia 3(1):1–10

    Article  CAS  Google Scholar 

  82. Sidibé H, Dubinski A, Vande VC (2021) The multi-functional RNA-binding protein G3BP1 and its potential implication in neurodegenerative disease. J Neurochem 157(4):944

    Article  PubMed  PubMed Central  Google Scholar 

  83. Ohi K, Sumiyoshi C, Fujino H, Yasuda Y, Yamamori H, Fujimoto M et al (2018) Genetic overlap between general cognitive function and schizophrenia: a review of cognitive GWASs. Int J Mol Sci 19(12):3822

    Article  PubMed  PubMed Central  Google Scholar 

  84. Heckman PRA, Van Duinen MA, Bollen EPP, Nishi A, Wennogle LP, Blokland A et al (2016) Phosphodiesterase inhibition and regulation of dopaminergic frontal and striatal functioning: clinical implications. Int J Neuropsychopharmacol 19(10):1–16

    Article  CAS  Google Scholar 

  85. Kelly MP, Brandon NJ (2009) Differential function of phosphodiesterase families in the brain: gaining insights through the use of genetically modified animals. Prog Brain Res 179(C):67–73

    Article  PubMed  CAS  Google Scholar 

  86. Warnica W, Merico D, Costain G, Alfred SE, Wei J, Marshall CR et al (2015) Copy number variable microRNAs in schizophrenia and their neurodevelopmental gene targets. Biol Psychiatry 77(2):158

    Article  PubMed  CAS  Google Scholar 

  87. Han C, Cui K, Bi X, Wang L, Sun M, Yang L et al (2019) Association between polymorphism of the NEDD4 gene and cognitive dysfunction of schizophrenia patients in Chinese Han population. BMC Psychiatry. 19(1):405

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Bi X, Cui K, Han C, Sun M, Wang L, Yang L et al (2015) Association of NEDD4 gene polymorphisms with schizophrenia and its clinical characteristics in Chinese Han population. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 32(3):385–390

    PubMed  CAS  Google Scholar 

  89. Lin A, Hou Q, Jarzylo L, Amato S, Gilbert J, Shang F et al (2011) Nedd4-mediated AMPA receptor ubiquitination regulates receptor turnover and trafficking. J Neurochem 119(1):27–39

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Lord MS, Melrose J, Day AJ, Whitelock JM (2020) The inter-α-trypsin inhibitor family: versatile molecules in biology and pathology. J Histochem Cytochem 68(12):907–927

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Glatt SJ, Stone WS, Nossova N, Liew CC, Seidman LJ, Tsuang MT (2011) Similarities and differences in peripheral blood gene expression signatures of individuals with schizophrenia and their first-degree biological relatives. Am J Med Genet B Neuropsychiatr Genet 156(8):869

    Article  PubMed Central  CAS  Google Scholar 

  92. Ma L, Semick SA, Chen Q, Li C, Tao R, Price AJ et al (2019) Schizophrenia risk variants influence multiple classes of transcripts of sorting nexin 19 (SNX19). Mol Psychiatry. https://doi.org/10.1038/s41380-018-0293-0

    Article  PubMed  PubMed Central  Google Scholar 

  93. Mahadevan J, Pathak AK, Vemula A, Nadella RK, Viswanath B, Jain S et al (2021) Analysis of whole exome sequencing in severe mental illness hints at selection of brain development and immune related genes. Sci Rep 11(1):1–10

    Article  Google Scholar 

  94. Mladinov M, Sedmak G, Fuller HR, Babić Leko M, Mayer D, Kirincich J et al (2016) Gene expression profiling of the dorsolateral and orbital prefrontal cortex in schizophrenia. Transl Neurosci 7(1):139–150. https://doi.org/10.1515/tnsci-2016-0021/html

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Li M, Huang L, Grigoroiu-Serbanescu M, Bergen SE, Landén M, Hultman CM et al (2016) Convergent lines of evidence support LRP8 as a susceptibility gene for psychosis. Mol Neurobiol 53(10):6608–6619

    Article  PubMed  CAS  Google Scholar 

  96. Xiao X, Yu H, Li J, Wang L, Li L, Chang H et al (2020) Further evidence for the association between LRP8 and schizophrenia. Schizophr Res 215:499–505

    Article  PubMed  Google Scholar 

  97. Huang Y, Todd N, Thathiah A (2017) The role of GPCRs in neurodegenerative diseases: avenues for therapeutic intervention. Curr Opin Pharmacol 32:96–110

    Article  PubMed  CAS  Google Scholar 

  98. Girgenti MJ, Nisenbaum LK, Bymaster F, Terwilliger R, Duman RS, Newton SS (2010) Antipsychotic induced gene regulation in multiple brain regions. J Neurochem 113(1):175

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Zheng F, Yan H, Liu B, Yue W, Fan L, Liao J et al (2017) ALDH2 Glu504Lys confers susceptibility to schizophrenia and impacts hippocampal-prefrontal functional connectivity. Cereb Cortex 27(3):2034–2040

    PubMed  Google Scholar 

  100. Mcmahon JJ, Shi L, Silver DL (2014) Generation of a Magoh conditional allele in mice. Genesis 52(8):752

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Shi J, Levinson DF, Duan J, Sanders AR, Zheng Y, Péer I et al (2009) Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 460(7256):753–7

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Smith IA, Knezevic BR, Ammann JU, Rhodes DA, Aw D, Palmer DB et al (2010) BTN1A1, the mammary gland butyrophilin, and BTN2A2 are both inhibitors of T cell activation. J Immunol 184(7):3514–3525

    Article  PubMed  CAS  Google Scholar 

  103. Sarter K, Leimgruber E, Gobet F, Agrawal V, Dunand-Sauthier I, Barras E et al (2016) Btn2a2, a T cell immunomodulatory molecule coregulated with MHC class II genes. J Exp Med 213(2):177–187

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Messal N, Mamessier E, Sylvain A, Celis-Gutierrez J, Thibult ML, Chetaille B et al (2011) Differential role for CD277 as a co-regulator of the immune signal in T and NK cells. Eur J Immunol 41(12):3443–3454. https://doi.org/10.1002/eji.201141404

    Article  PubMed  CAS  Google Scholar 

  105. Harly C, Guillaume Y, Nedellec S, Peigne CM, Monkkonen H, Monkkonen J et al (2012) Key implication of CD277/butyrophilin-3 (BTN3A) in cellular stress sensing by a major human T-cell subset. Blood 120(11):2269–2279

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Pape K, Tamouza R, Leboyer M, Zipp F (2019) Immunoneuropsychiatry—novel perspectives on brain disorders. Nat Rev Neurol 15(6):317–328

    Article  PubMed  Google Scholar 

  107. Debnath M (2015) Adaptive immunity in schizophrenia: functional implications of T cells in the etiology, course and treatment. J Neuroimmune Pharmacol 10(4):610–619

    Article  PubMed  Google Scholar 

  108. van Kesteren CFMG, Gremmels H, de Witte LD, Hol EM, van Gool AR, Falkai PG et al (2017) Immune involvement in the pathogenesis of schizophrenia: a meta-analysis on postmortem brain studies. Transl Psychiatry 7(3):e1075

    Article  PubMed  PubMed Central  Google Scholar 

  109. Müller N, Schwarz MJ (2010) Immune system and schizophrenia. Curr Immunol Rev 6(3):213–220

    Article  PubMed  PubMed Central  Google Scholar 

  110. Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J (2009) Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 29(13):3974–3980

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Wang J, Hodes GE, Zhang H, Zhang S, Zhao W, Golden SA et al (2018) Epigenetic modulation of inflammation and synaptic plasticity promotes resilience against stress in mice. Nat Commun 9(1):477

    Article  PubMed  PubMed Central  Google Scholar 

  112. Ellwardt E, Pramanik G, Luchtman D, Novkovic T, Jubal ER, Vogt J et al (2018) Maladaptive cortical hyperactivity upon recovery from experimental autoimmune encephalomyelitis. Nat Neurosci 21(10):1392–1403

    Article  PubMed  CAS  Google Scholar 

  113. Jeppesen R, Benros ME (2019) Autoimmune diseases and psychotic disorders. Front Psychiatry 10:131

    Article  PubMed  PubMed Central  Google Scholar 

  114. Knight JG (1984) Is schizophrenia an autoimmune disease? A review. Methods Find Exp Clin Pharmacol 6(7):395–403

    PubMed  CAS  Google Scholar 

  115. Mokhtari R, Lachman HM (2016) The Major Histocompatibility Complex (MHC) in schizophrenia: a review. J Clin Cell Immunol 7(6):479

    Article  PubMed  PubMed Central  Google Scholar 

  116. Brown AS (2006) Prenatal infection as a risk factor for schizophrenia. Schizophr Bull 32(2):200

    Article  PubMed  PubMed Central  Google Scholar 

  117. Radjavi A, Smirnov I, Kipnis J (2014) Brain antigen-reactive CD4+ T cells are sufficient to support learning behavior in mice with limited T cell repertoire. Brain Behav Immun 35:58–63

    Article  PubMed  CAS  Google Scholar 

  118. Craddock RM, Lockstone HE, Rider DA, Wayland MT, Harris LJW, McKenna PJ et al (2007) Altered T-cell function in schizophrenia: a cellular model to investigate molecular disease mechanisms. PLoS ONE 2(8):e692

    Article  PubMed  PubMed Central  Google Scholar 

  119. Riedel M, Spellmann I, Schwarz M, Strassnig M, Sikorski C, Moller H et al (2007) Decreased T cellular immune response in schizophrenic patients. J Psychiatr Res 41(1–2):3–7

    Article  PubMed  Google Scholar 

  120. Rajan TM, Bharadwaj B, Rajkumar RP, Adole PS (2018) Frequency and correlates of tardive dyskinesia in Indian patients with type I bipolar disorder. Asian J Psychiatr 32:92–98

    Article  PubMed  Google Scholar 

  121. Nemeth E, Ganz T (2009) The role of hepcidin in iron metabolism. Acta Haematol 122(2–3):78–86

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. D’Angelo G (2013) Role of hepcidin in the pathophysiology and diagnosis of anemia. Blood Res 48(1):10–15

    Article  PubMed  PubMed Central  Google Scholar 

  123. Tseng SCG (2016) HC-HA/PTX3 purified from amniotic membrane as novel regenerative matrix: insight into relationship between inflammation and regeneration. Investig Opthalmol Vis Sci. 57(5):ORSFh1

    Article  CAS  Google Scholar 

  124. Lutgens E, Lievens D, Beckers L, Wijnands E, Soehnlein O, Zernecke A et al (2010) Deficient CD40-TRAF6 signaling in leukocytes prevents atherosclerosis by skewing the immune response toward an antiinflammatory profile. J Exp Med 207(2):391–404

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Woollard KJ, Geissmann F (2010) Monocytes in atherosclerosis: subsets and functions. Nat Rev Cardiol 7(2):77–86

    Article  PubMed  PubMed Central  Google Scholar 

  126. He H, Li W, Chen SY, Zhang S, Chen YT, Hayashida Y et al (2008) Suppression of activation and induction of apoptosis in RAW2647 cells by amniotic membrane extract. Investig Opthalmol Vis Sci 49(10):4468

    Article  Google Scholar 

  127. McFadden EJ, Hargrove AE (2016) Biochemical methods to investigate lncRNA and the influence of lncRNA: protein complexes on chromatin. Biochemistry 55(11):1615–1630

    Article  PubMed  CAS  Google Scholar 

  128. He H, Zhang S, Tighe S, Son J, Tseng SCG (2013) Immobilized heavy chain-hyaluronic acid polarizes lipopolysaccharide-activated macrophages toward M2 phenotype. J Biol Chem 288(36):25792–25803

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Aderem A, Underhill DM (1999) Mechanisms of phagocytosis in macrophages. Annu Rev Immunol 17(1):593–623. https://doi.org/10.1146/annurev.immunol.17.1.593

    Article  PubMed  CAS  Google Scholar 

  130. Underhill DM, Goodridge HS (2012) Information processing during phagocytosis. Nat Rev Immunol 12(7):492–502

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Murray PJ, Wynn TA (2011) Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 11(11):723–737

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Torihashi S, Ho M, Kawakubo Y, Komatsu K, Nagai M, Hirayama Y et al (2015) Acute and temporal expression of tumor necrosis factor (TNF)-α-stimulated Gene 6 Product, TSG6, in mesenchymal stem cells creates microenvironments required for their successful transplantation into muscle tissue. J Biol Chem 290(37):22771–22781

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Bowie CR, Harvey PD (2006) Cognitive deficits and functional outcome in schizophrenia. Neuropsychiatr Dis Treat 2(4):531–536

    Article  PubMed  PubMed Central  Google Scholar 

  134. Zhang H, Wang Y, Hu Y, Zhu Y, Zhang T, Wang J et al (2019) Meta-analysis of cognitive function in Chinese first-episode schizophrenia: MATRICS Consensus Cognitive Battery (MCCB) profile of impairment. Gen Psychiatr 32(3):e100043

    Article  PubMed  PubMed Central  Google Scholar 

  135. Bilder RM, Goldman RS, Robinson D, Reiter G, Bell L, Bates JA et al (2000) Neuropsychology of first-episode schizophrenia: initial characterization and clinical correlates. Am J Psychiatry 157(4):549–559

    Article  PubMed  CAS  Google Scholar 

  136. Saykin AJ, Shtasel DL, Gur RE, Kester DB, Mozley LH, Stafiniak P et al (1994) Neuropsychological deficits in neuroleptic naive patients with first-episode schizophrenia. Arch Gen Psychiatry 51(2):124

    Article  PubMed  CAS  Google Scholar 

  137. Rund BR (1998) A review of longitudinal studies of cognitive functions in schizophrenia patients. Schizophr Bull 24(3):425–435

    Article  PubMed  CAS  Google Scholar 

  138. Cornblatt BA, Erlenmeyer-Kimling L (1985) Global attentional deviance as a marker of risk for schizophrenia: specificity and predictive validity. J Abnorm Psychol 94(4):470–486

    Article  PubMed  CAS  Google Scholar 

  139. Davidson M, Reichenberg A, Rabinowitz J, Weiser M, Kaplan Z, Mark M (1999) Behavioral and intellectual markers for schizophrenia in apparently healthy male adolescents. Am J Psychiatry 156(9):1328–1335

    Article  PubMed  CAS  Google Scholar 

  140. Trampush JW, Yang MLZ, Yu J, Knowles E, Davies G, Liewald DC et al (2017) GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium. Mol Psychiatry 22(3):336–45

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Lencz T, Consortium C (2017) Gwas meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from The Cogent Consortium. Eur Neuropsychopharmacol 27:S493

    Article  Google Scholar 

Download references

Acknowledgements

We are thankful to the trained and dedicated staff at Dr. RML hospital for the study sample collection and Mrs. Anjali Dabral for DNA isolation at the University of Delhi South Campus. Computational facilities provided by Central Instrumentation Facility, University of Delhi South Campus, Department of Science and Technology, New Delhi, for FIST and DU-DST PURSE programmes to the Department of Genetics, UDSC, are gratefully acknowledged. Senior Research Fellowship (2019-6722/SCR-BMS) from Indian Council of Medical Research, New Delhi to A.M; J.C Bose fellowship (#SR/S2/JCB44/2011 & 2016) from Science and Engineering Research Board, New Delhi to B.K.T.

Author information

Authors and Affiliations

  1. Department of Genetics, University of Delhi South Campus, Benito Juarez Marg, New Delhi, 110021, India

    Anirban Mukhopadhyay & B. K. Thelma

  2. Department of Psychiatry, Postgraduate Institute of Medical Education and Research-Dr. Ram Manohar Lohia Hospital, New Delhi, India

    Smita N. Deshpande & Triptish Bhatia

Authors
  1. Anirban Mukhopadhyay
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Smita N. Deshpande
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Triptish Bhatia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B. K. Thelma
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AM and BKT designed the study and SND diagnosed and recruited the study samples; AM performed all data analysis. TB contributed to sample recruitment and phenotype data documentation; AM and BKT wrote the first draft of manuscript. All authors contributed to and have approved the final manuscript.

Corresponding author

Correspondence to B. K. Thelma.

Ethics declarations

Conflict of interest

The authors have declared that there no conflicts of interest in relation to the subject of this study.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 411 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mukhopadhyay, A., Deshpande, S.N., Bhatia, T. et al. Significance of an altered lncRNA landscape in schizophrenia and cognition: clues from a case–control association study. Eur Arch Psychiatry Clin Neurosci 273, 1677–1691 (2023). https://doi.org/10.1007/s00406-023-01596-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00406-023-01596-9

Keywords

Search

Navigation