Skip to main content
SpringerLink
Log in

Progress and Implications from Genetic Studies of Bipolar Disorder

  • Review
  • Published:
Neuroscience Bulletin Aims and scope Submit manuscript

Abstract

With the advancements in gene sequencing technologies, including genome-wide association studies, polygenetic risk scores, and high-throughput sequencing, there has been a tremendous advantage in mapping a detailed blueprint for the genetic model of bipolar disorder (BD). To date, intriguing genetic clues have been identified to explain the development of BD, as well as the genetic association that might be applied for the development of susceptibility prediction and pharmacogenetic intervention. Risk genes of BD, such as CACNA1C, ANK3, TRANK1, and CLOCK, have been found to be involved in various pathophysiological processes correlated with BD. Although the specific roles of these genes have yet to be determined, genetic research on BD will help improve the prevention, therapeutics, and prognosis in clinical practice. The latest preclinical and clinical studies, and reviews of the genetics of BD, are analyzed in this review, aiming to summarize the progress in this intriguing field and to provide perspectives for individualized, precise, and effective clinical practice.

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

References

  1. Vigo D, Thornicroft G, Atun R. Estimating the true global burden of mental illness. Lancet Psychiatry 2016, 3: 171–178.

    Article  PubMed  Google Scholar 

  2. Passos IC, Mwangi B, Vieta E, Berk M, Kapczinski F. Areas of controversy in neuroprogression in bipolar disorder. Acta Psychiatr Scand 2016, 134: 91–103.

    Article  CAS  PubMed  Google Scholar 

  3. Liu YC, Tseng HH, Chang YH, Chang HH, Yang YK, Chen PS. The social cognitive ability in Han Chinese euthymic patients with bipolar I and bipolar II disorder. J Formos Med Assoc 2020: S0929–S6646(20)30472–1.

  4. Merikangas KR, Jin R, He JP, Kessler RC, Lee S, Sampson NA. Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry 2011, 68: 241–251.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Merikangas KR, Akiskal HS, Angst J, Greenberg PE, Hirschfeld RMA, Petukhova M, et al. Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch Gen Psychiatry 2007, 64: 543–552.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Juruena MF, Jelen LA, Young AH, Cleare AJ. New pharmacological interventions in bipolar disorder. Curr Top Behav Neurosci 2021, 48: 303–324.

    Article  CAS  PubMed  Google Scholar 

  7. Wang WYS, Barratt BJ, Clayton DG, Todd JA. Genome-wide association studies: Theoretical and practical concerns. Nat Rev Genet 2005, 6: 109–118.

    Article  CAS  PubMed  Google Scholar 

  8. Badner JA, Koller D, Foroud T, Edenberg H, Nurnberger JI Jr, Zandi PP, et al. Genome-wide linkage analysis of 972 bipolar pedigrees using single-nucleotide polymorphisms. Mol Psychiatry 2012, 17: 818–826.

    Article  CAS  PubMed  Google Scholar 

  9. Ruzicka WB, Subburaju S, Benes FM. Circuit- and diagnosis-specific DNA methylation changes at γ-aminobutyric acid-related genes in postmortem human Hippocampus in schizophrenia and bipolar disorder. JAMA Psychiatry 2015, 72: 541–551.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Cruceanu C, Tan PPC, Rogic S, Lopez JP, Torres-Platas SG, Gigek CO, et al. Transcriptome sequencing of the anterior cingulate in bipolar disorder: Dysregulation of G protein-coupled receptors. Am J Psychiatry 2015, 172: 1131–1140.

    Article  PubMed  Google Scholar 

  11. McCarthy SE, Makarov V, Kirov G, Addington AM, McClellan J, Yoon S, et al. Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet 2009, 41: 1223–1227.

  12. Kasahara T, Kato T. What can mitochondrial DNA analysis tell us about mood disorders? Biol Psychiatry 2018, 83: 731–738.

    Article  CAS  PubMed  Google Scholar 

  13. Souery D, Rivelli SK, Mendlewicz J. Molecular genetic and family studies in affective disorders: State of the art. J Affect Disord 2001, 62: 45–55.

    Article  CAS  PubMed  Google Scholar 

  14. Sul JH, Service SK, Huang AY, Ramensky V, Hwang SG, Teshiba TM, et al. Contribution of common and rare variants to bipolar disorder susceptibility in extended pedigrees from population isolates. Transl Psychiatry 2020, 10: 74.

  15. Muntané G, Farré X, Bosch E, Martorell L, Navarro A, Vilella E. The shared genetic architecture of schizophrenia, bipolar disorder and lifespan. Hum Genet 2021, 140: 441–455.

    Article  PubMed  Google Scholar 

  16. Sullivan PF, Magnusson C, Reichenberg A, Boman M, Dalman C, Davidson M, et al. Family history of schizophrenia and bipolar disorder as risk factors for autism. Arch Gen Psychiatry 2012, 69: 1099–1103.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Kendler KS, Ohlsson H, Sundquist J, Sundquist K. An extended Swedish national adoption study of bipolar disorder illness and cross-generational familial association with schizophrenia and major depression. JAMA Psychiatry 2020, 77: 814–822.

    Article  PubMed  Google Scholar 

  18. Craddock N, Jones I. Genetics of bipolar disorder. J Med Genet 1999, 36: 585–594.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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.

    Article  PubMed  Google Scholar 

  20. 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: 1814–1821.

    Article  PubMed  Google Scholar 

  21. Toma C, Shaw AD, Overs BJ, Mitchell PB, Schofield PR, Cooper AA, et al. De novo gene variants and familial bipolar disorder. JAMA Netw Open 2020, 3: e203382.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Rasic D, Hajek T, Alda M, Uher R. Risk of mental illness in offspring of parents with schizophrenia, bipolar disorder, and major depressive disorder: A meta-analysis of family high-risk studies. Schizophr Bull 2014, 40: 28–38.

    Article  PubMed  Google Scholar 

  23. Köhler-Forsberg O, Sylvia LG, Ruberto VL, Kuperberg M, Shannon AP, Fung V, et al. Familial severe psychiatric history in bipolar disorder and correlation with disease severity and treatment response. J Affect Disord 2020, 273: 131–137.

    Article  PubMed  Google Scholar 

  24. Stapp EK, Mendelson T, Merikangas KR, Wilcox HC. Parental bipolar disorder, family environment, and offspring psychiatric disorders: A systematic review. J Affect Disord 2020, 268: 69–81.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Yang J, Yang J, Goddard ME, Visscher PM. GCTA: A tool for genome-wide complex trait analysis. Am J Hum Genet 2011, 88: 76–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Stahl EA, Breen G, Forstner AJ, McQuillin A, Ripke S, Trubetskoy V, et al. Genome-wide association study identifies 30 loci associated with bipolar disorder. Nat Genet 2019, 51: 793–803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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: 3383–3394.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bienvenu OJ, Davydow DS, Kendler KS. Psychiatric ‘diseases’ versus behavioral disorders and degree of genetic influence. Psychol Med 2011, 41: 33–40.

    Article  CAS  PubMed  Google Scholar 

  29. Bertelsen A, Harvald B, Hauge M. A Danish twin study of manic-depressive disorders. Br J Psychiatry 1977, 130: 330–351.

    Article  CAS  PubMed  Google Scholar 

  30. Gordovez FJA, McMahon FJ. The genetics of bipolar disorder. Mol Psychiatry 2020, 25: 544–559.

    Article  PubMed  Google Scholar 

  31. McInnes LA, Escamilla MA, Service SK, Reus VI, Leon P, Silva S, et al. A complete genome screen for genes predisposing to severe bipolar disorder in two Costa Rican pedigrees. Proc Natl Acad Sci U S A 1996, 93: 13060–13065.

  32. Schulze TG, McMahon FJ. Genetic linkage and association studies in bipolar affective disorder: A time for optimism. Am J Med Genet C Semin Med Genet 2003, 123C: 36–47.

    Article  PubMed  Google Scholar 

  33. Escamilla MA, Zavala JM. Genetics of bipolar disorder. Dialogues Clin Neurosci 2008, 10: 141–152.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Craddock N, Sklar P. Genetics of bipolar disorder: Successful start to a long journey. Trends Genet 2009, 25: 99–105.

    Article  CAS  PubMed  Google Scholar 

  35. Detera-Wadleigh SD, Liu CY, Maheshwari M, Cardona I, Corona W, Akula N, et al. Sequence variation in DOCK9 and heterogeneity in bipolar disorder. Psychiatr Genet 2007, 17: 274–286.

    Article  PubMed  Google Scholar 

  36. McInnes LA, Service SK, Reus VI, Barnes G, Charlat O, Jawahar S, et al. Fine-scale mapping of a locus for severe bipolar mood disorder on chromosome 18p11.3 in the Costa Rican population. Proc Natl Acad Sci U S A 2001, 98: 11485–11490.

  37. Lee BD, Walss-Bass C, Thompson PM, Dassori A, Montero PA, Medina R, et al. Malic enzyme 2 and susceptibility to psychosis and mania. Psychiatry Res 2007, 150: 1–11.

    Article  CAS  PubMed  Google Scholar 

  38. Ohnishi T, Yamada K, Ohba H, Iwayama Y, Toyota T, Hattori E, et al. A promoter haplotype of the inositol monophosphatase 2 gene (IMPA2) at 18p11.2 confers a possible risk for bipolar disorder by enhancing transcription. Neuropsychopharmacology 2007, 32: 1727–1737.

  39. Washizuka S, Kametani M, Sasaki T, Tochigi M, Umekage T, Kohda K, et al. Association of mitochondrial complex I subunit gene NDUFV2 at 18p11 with schizophrenia in the Japanese population. Am J Med Genet B Neuropsychiatr Genet 2006, 141B: 301–304.

    Article  CAS  PubMed  Google Scholar 

  40. Weller AE, Dahl JP, Lohoff FW, Ferraro TN, Berrettini WH. Analysis of variations in the NAPG gene on chromosome 18p11 in bipolar disorder. Psychiatr Genet 2006, 16: 3–8.

    Article  PubMed  Google Scholar 

  41. Barrett TB, Hauger RL, Kennedy JL, Sadovnick AD, Remick RA, Keck PE, et al. Evidence that a single nucleotide polymorphism in the promoter of the G protein receptor kinase 3 gene is associated with bipolar disorder. Mol Psychiatry 2003, 8: 546–557.

    Article  CAS  PubMed  Google Scholar 

  42. Shen W, Wang QW, Liu YN, Marchetto MC, Linker S, Lu SY, et al. Synaptotagmin-7 is a key factor for bipolar-like behavioral abnormalities in mice. Proc Natl Acad Sci U S A 2020, 117: 4392–4399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Seifuddin F, Mahon PB, Judy J, Pirooznia M, Jancic D, Taylor J, et al. Meta-analysis of genetic association studies on bipolar disorder. American J Med Genetics Pt B 2012, 159B: 508–518.

    Article  Google Scholar 

  44. Bulik-Sullivan BK, Loh PR, Finucane HK, Ripke S, Yang J, Schizophrenia Working Group of the Psychiatric Genomics Consortium, et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat Genet 2015, 47: 291–295.

  45. Lee JJ, McGue M, Iacono WG, Chow CC. The accuracy of LD Score regression as an estimator of confounding and genetic correlations in genome-wide association studies. Genet Epidemiol 2018, 42: 783–795.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Alam R, Abdolmaleky HM, Zhou JR. Microbiome, inflammation, epigenetic alterations, and mental diseases. Am J Med Genet B Neuropsychiatr Genet 2017, 174: 651–660.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Leussis MP, Berry-Scott EM, Saito M, Jhuang H, de Haan G, Alkan O, et al. The ANK3 bipolar disorder gene regulates psychiatric-related behaviors that are modulated by lithium and stress. Biol Psychiatry 2013, 73: 683–690.

    Article  CAS  PubMed  Google Scholar 

  48. Craddock N, Sklar P. Genetics of bipolar disorder. Lancet 2013, 381: 1654–1662.

    Article  CAS  PubMed  Google Scholar 

  49. Mullins N, Forstner AJ, O’Connell KS, Coombes B, Coleman JRI, Qiao Z, et al. Genome-wide association study of more than 40, 000 bipolar disorder cases provides new insights into the underlying biology. Nat Genet 2021, 53: 817–829.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Waszczuk MA, Jonas KG, Bornovalova M, Breen G, Bulik CM, Docherty AR, et al. Dimensional and transdiagnostic phenotypes in psychiatric genome-wide association studies. Mol Psychiatry 2023: 1–11.

  51. Bipolar Disorder and Schizophrenia Working Group of the Psychiatric Genomics Consortium. Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes. Cell 2018, 173: 1705–1715 e16.

  52. Akula N, Marenco S, Johnson K, Feng N, Zhu K, Schulmann A, et al. Deep transcriptome sequencing of subgenual anterior cingulate cortex reveals cross-diagnostic and diagnosis-specific RNA expression changes in major psychiatric disorders. Neuropsychopharmacology 2021, 46: 1364–1372.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wellcome Trust Case Control Consortium. Genome-wide association study of 14, 000 cases of seven common diseases and 3, 000 shared controls. Nature 2007, 447: 661–678.

    Article  Google Scholar 

  54. Geaghan MP, Reay WR, Cairns MJ. MicroRNA binding site variation is enriched in psychiatric disorders. Hum Mutat 2022, 43: 2153–2169.

    Article  CAS  PubMed  Google Scholar 

  55. Yamada Y, Matsumoto M, Iijima K, Sumiyoshi T. Specificity and continuity of schizophrenia and bipolar disorder: Relation to biomarkers. Curr Pharm Des 2020, 26: 191–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ferreira MAR, 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: 1056–1058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Psychiatric GWAS Consortium Bipolar Disorder Working Group. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet 2011, 43: 977–983.

    Article  Google Scholar 

  58. Moskvina V, Craddock N, Holmans P, Nikolov I, Pahwa JS, Green E, et al. Gene-wide analyses of genome-wide association data sets: Evidence for multiple common risk alleles for schizophrenia and bipolar disorder and for overlap in genetic risk. Mol Psychiatry 2009, 14: 252–260.

    Article  CAS  PubMed  Google Scholar 

  59. Smedler E, Abé C, Pålsson E, Ingvar M, Landén M. CACNA1C polymorphism and brain cortical structure in bipolar disorder. J Psychiatry Neurosci 2019, 45: 182–187.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Gershon ES, Grennan K, Busnello J, Badner JA, Ovsiew F, Memon S, et al. A rare mutation of CACNA1C in a patient with bipolar disorder, and decreased gene expression associated with a bipolar-associated common SNP of CACNA1C in brain. Mol Psychiatry 2014, 19: 890–894.

    Article  CAS  PubMed  Google Scholar 

  61. Hannon E, Lunnon K, Schalkwyk L, Mill J. Interindividual methylomic variation across blood, cortex, and cerebellum: Implications for epigenetic studies of neurological and neuropsychiatric phenotypes. Epigenetics 2015, 10: 1024–1032.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium. Genome-wide association study identifies five new schizophrenia loci. Nat Genet 2011, 43: 969–976.

  63. Zhu S, Cordner ZA, Xiong J, Chiu CT, Artola A, Zuo Y, et al. Genetic disruption of ankyrin-G in adult mouse forebrain causes cortical synapse alteration and behavior reminiscent of bipolar disorder. Proc Natl Acad Sci U S A 2017, 114: 10479–10484.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Dao DT, Mahon PB, Cai X, Kovacsics CE, Blackwell RA, Arad M, et al. Mood disorder susceptibility gene CACNA1C modifies mood-related behaviors in mice and interacts with sex to influence behavior in mice and diagnosis in humans. Biol Psychiatry 2010, 68: 801–810.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Jiang X, Detera-Wadleigh SD, Akula N, Mallon BS, Hou L, Xiao T, et al. Sodium valproate rescues expression of TRANK1 in iPSC-derived neural cells that carry a genetic variant associated with serious mental illness. Mol Psychiatry 2019, 24: 613–624.

    Article  CAS  PubMed  Google Scholar 

  66. Schiavone S, Mhillaj E, Neri M, Morgese MG, Tucci P, Bove M, et al. Early loss of blood-brain barrier integrity precedes NOX2 elevation in the prefrontal cortex of an animal model of psychosis. Mol Neurobiol 2017, 54: 2031–2044.

    Article  CAS  PubMed  Google Scholar 

  67. Almeida HS, Mitjans M, Arias B, Vieta E, Ríos J, Benabarre A. Genetic differences between bipolar disorder subtypes: A systematic review focused in bipolar disorder type II. Neurosci Biobehav Rev 2020, 118: 623–630.

    Article  CAS  PubMed  Google Scholar 

  68. Hayashi A, Le Gal K, Södersten K, Vizlin-Hodzic D, Ågren H, Funa K. Calcium-dependent intracellular signal pathways in primary cultured adipocytes and ANK3 gene variation in patients with bipolar disorder and healthy controls. Mol Psychiatry 2015, 20: 931–940.

    Article  CAS  PubMed  Google Scholar 

  69. de Groot MWGDM, Dingemans MML, Rus KH, de Groot A, Westerink RHS. Characterization of calcium responses and electrical activity in differentiating mouse neural progenitor cells in vitro. Toxicol Sci 2014, 137: 428–435.

  70. Chen HM, DeLong CJ, Bame M, Rajapakse I, Herron TJ, McInnis MG, et al. Transcripts involved in calcium signaling and telencephalic neuronal fate are altered in induced pluripotent stem cells from bipolar disorder patients. Transl Psychiatry 2014, 4: e375.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Geoffroy PA, Etain B, Lajnef M, Zerdazi EH, Brichant-Petitjean C, Heilbronner U, et al. Circadian genes and lithium response in bipolar disorders: Associations with PPARGC1A (PGC-1α) and RORA. Genes Brain Behav 2016, 15: 660–668.

    Article  CAS  PubMed  Google Scholar 

  72. Castro J, Zanini M, daS Gonçalves B, Coelho FM, Bressan R, Bittencourt L, et al. Circadian rest-activity rhythm in individuals at risk for psychosis and bipolar disorder. Schizophr Res 2015, 168: 50–55.

  73. Courtois E, Schmid M, Wajsbrot O, Barau C, Le Corvoisier P, Aouizerate B, et al. Contribution of common and rare damaging variants in familial forms of bipolar disorder and phenotypic outcome. Transl Psychiatry 2020, 10: 124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 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: 639–647.

    Article  CAS  PubMed  Google Scholar 

  75. Glaser C, Heinrich J, Koletzko B. Role of FADS1 and FADS2 polymorphisms in polyunsaturated fatty acid metabolism. Metabolism 2010, 59: 993–999.

    Article  CAS  PubMed  Google Scholar 

  76. Li HJ, Zhang C, Hui L, Zhou DS, Li Y, Zhang CY, et al. Novel risk loci associated with genetic risk for bipolar disorder among Han Chinese individuals: A genome-wide association study and meta-analysis. JAMA Psychiatry 2021, 78: 320–330.

    Article  PubMed  Google Scholar 

  77. Jian X, Chen J, Li Z, Fahira A, Shao W, Zhou J, et al. Common variants in FAN1, located in 15q13.3, confer risk for schizophrenia and bipolar disorder in Han Chinese. Prog Neuropsychopharmacol Biol Psychiatry 2020, 103: 109973.

  78. Baird DA, Liu JZ, Zheng J, Sieberts SK, Perumal T, Elsworth B, et al. Identifying drug targets for neurological and psychiatric disease via genetics and the brain transcriptome. PLoS Genet 2021, 17: e1009224.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014, 511: 421–427.

    Article  PubMed Central  Google Scholar 

  80. 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: 234–239.

    Article  CAS  PubMed  Google Scholar 

  81. Prata DP, Costa-Neves B, Cosme G, Vassos E. Unravelling the genetic basis of schizophrenia and bipolar disorder with GWAS: A systematic review. J Psychiatr Res 2019, 114: 178–207.

    Article  PubMed  Google Scholar 

  82. Coleman JRI, Gaspar HA, Bryois J, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Breen G. The genetics of the mood disorder spectrum: Genome-wide association analyses of more than 185, 000 cases and 439, 000 controls. Biol Psychiatry 2020, 88: 169–184.

  83. Consortium IS, Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009, 460: 748–752.

    Article  Google Scholar 

  84. Crawford K, Bracher-Smith M, Owen D, Kendall KM, Rees E, Pardiñas AF, et al. Medical consequences of pathogenic CNVs in adults: Analysis of the UK Biobank. J Med Genet 2019, 56: 131–138.

    Article  CAS  PubMed  Google Scholar 

  85. Leppa VM, Kravitz SN, Martin CL, Andrieux J, Le Caignec C, Martin-Coignard D, et al. Rare inherited and de novo CNVs reveal complex contributions to ASD risk in multiplex families. Am J Hum Genet 2016, 99: 540–554.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Olsen L, Sparsø T, Weinsheimer SM, Dos Santos MBQ, Mazin W, Rosengren A, et al. Prevalence of rearrangements in the 22q11.2 region and population-based risk of neuropsychiatric and developmental disorders in a Danish population: A case-cohort study. Lancet Psychiatry 2018, 5: 573–580.

  87. Ahn K, An SS, Shugart YY, Rapoport JL. Common polygenic variation and risk for childhood-onset schizophrenia. Mol Psychiatry 2016, 21: 94–96.

    Article  CAS  PubMed  Google Scholar 

  88. Yuan J, Hu J, Li Z, Zhang F, Zhou D, Jin C. A replication study of schizophrenia-related rare copy number variations in a Han Southern Chinese population. Hereditas 2017, 154: 2.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Malhotra D, McCarthy S, Michaelson JJ, Vacic V, Burdick KE, Yoon S, et al. High frequencies of de novo CNVs in bipolar disorder and schizophrenia. Neuron 2011, 72: 951–963.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Green EK, Rees E, Walters JR, Smith KG, Forty L, Grozeva D, et al. Copy number variation in bipolar disorder. Mol Psychiatry 2016, 21: 89–93.

    Article  CAS  PubMed  Google Scholar 

  91. Charney AW, Stahl EA, Green EK, Chen CY, Moran JL, Chambert K, et al. Contribution of rare copy number variants to bipolar disorder risk is limited to schizoaffective cases. Biol Psychiatry 2019, 86: 110–119.

    Article  CAS  PubMed  Google Scholar 

  92. O’Connell KS, Coombes BJ. Genetic contributions to bipolar disorder: Current status and future directions. Psychol Med 2021, 51: 2156–2167.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Wilcox HC, Fullerton JM, Glowinski AL, Benke K, Kamali M, Hulvershorn LA, et al. Traumatic stress interacts with bipolar disorder genetic risk to increase risk for suicide attempts. J Am Acad Child Adolesc Psychiatry 2017, 56: 1073–1080.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Mullins N, Bigdeli TB, Børglum AD, Coleman JRI, Demontis D, Mehta D, et al. GWAS of suicide attempt in psychiatric disorders and association with major depression polygenic risk scores. Am J Psychiatry 2019, 176: 651–660.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Lopes FL, Zhu K, Purves KL, Song C, Ahn K, Hou L, et al. Polygenic risk for anxiety influences anxiety comorbidity and suicidal behavior in bipolar disorder. Transl Psychiatry 2020, 10: 298.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Lewis KJS, Richards A, Karlsson R, Leonenko G, Jones SE, Jones HJ, et al. Comparison of genetic liability for sleep traits among individuals with bipolar disorder I or II and control participants. JAMA Psychiatry 2020, 77: 303.

    Article  PubMed  Google Scholar 

  97. Coombes BJ, Markota M, Mann JJ, Colby C, Stahl E, Talati A, et al. Dissecting clinical heterogeneity of bipolar disorder using multiple polygenic risk scores. Transl Psychiatry 2020, 10: 314.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Tondo L, Vázquez GH, Baldessarini RJ. Depression and Mania in bipolar disorder. Curr Neuropharmacol 2017, 15: 353–358.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Allardyce J, Leonenko G, Hamshere M, Pardiñas AF, Forty L, Knott S, et al. Association between schizophrenia-related polygenic liability and the occurrence and level of mood-incongruent psychotic symptoms in bipolar disorder. JAMA Psychiatry 2018, 75: 28–35.

    Article  PubMed  Google Scholar 

  100. Markota M, Coombes BJ, Larrabee BR, McElroy SL, Bond DJ, Veldic M, et al. Association of schizophrenia polygenic risk score with manic and depressive psychosis in bipolar disorder. Transl Psychiatry 2018, 8: 188.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Reginsson GW, Ingason A, Euesden J, Bjornsdottir G, Olafsson S, Sigurdsson E, et al. Polygenic risk scores for schizophrenia and bipolar disorder associate with addiction. Addict Biol 2018, 23: 485–492.

    Article  CAS  PubMed  Google Scholar 

  102. Zuk O, Schaffner SF, Samocha K, Do R, Hechter E, Kathiresan S, et al. Searching for missing heritability: Designing rare variant association studies. Proc Natl Acad Sci U S A 2014, 111: E455–E464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Gudbjartsson DF, Helgason H, Gudjonsson SA, Zink F, Oddson A, Gylfason A, et al. Large-scale whole-genome sequencing of the Icelandic population. Nat Genet 2015, 47: 435–444.

    Article  CAS  PubMed  Google Scholar 

  104. Pacifico R, Davis RL. Transcriptome sequencing implicates dorsal striatum-specific gene network, immune response and energy metabolism pathways in bipolar disorder. Mol Psychiatry 2017, 22: 441–449.

    Article  CAS  PubMed  Google Scholar 

  105. Akula N, Wendland JR, Choi KH, McMahon FJ. An integrative genomic study implicates the postsynaptic density in the pathogenesis of bipolar disorder. Neuropsychopharmacology 2016, 41: 886–895.

    Article  CAS  PubMed  Google Scholar 

  106. Truvé K, Parris TZ, Vizlin-Hodzic D, Salmela S, Berger E, Ågren H, et al. Identification of candidate genetic variants and altered protein expression in neural stem and mature neural cells support altered microtubule function to be an essential component in bipolar disorder. Transl Psychiatry 2020, 10: 390.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Wu LSH, Huang MC, Fann CSJ, Lane HY, Kuo CJ, Chiu WC, et al. Genome-wide association study of early-onset bipolar I disorder in the Han Taiwanese population. Transl Psychiatry 2021, 11: 301.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Forstner AJ, Fischer SB, Schenk LM, Strohmaier J, Maaser-Hecker A, Reinbold CS, et al. Whole-exome sequencing of 81 individuals from 27 multiply affected bipolar disorder families. Transl Psychiatry 2020, 10: 57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Goes FS, Pirooznia M, Tehan M, Zandi PP, McGrath J, Wolyniec P, et al. De novo variation in bipolar disorder. Mol Psychiatry 2021, 26: 4127–4136.

    Article  PubMed  Google Scholar 

  110. Toma C, Shaw AD, Allcock RJN, Heath A, Pierce KD, Mitchell PB, et al. An examination of multiple classes of rare variants in extended families with bipolar disorder. Transl Psychiatry 2018, 8: 65.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Ozer S, Ayhan Y, Uluşahin A. The utility of an endophenotype approach in overcoming the difficulties in bipolar and schizophrenia genetics. Turk Psikiyatri Derg 2004, 15: 125–137.

    PubMed  Google Scholar 

  112. Orsolini L, Fiorani M, Volpe U. Digital phenotyping in bipolar disorder: Which integration with clinical endophenotypes and biomarkers? Int J Mol Sci 2020, 21: 7684.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Peterson RE, Kuchenbaecker K, Walters RK, Chen CY, Popejoy AB, Periyasamy S, et al. Genome-wide association studies in ancestrally diverse populations: Opportunities, methods, pitfalls, and recommendations. Cell 2019, 179: 589–603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Guglielmo R, Miskowiak KW, Hasler G. Evaluating endophenotypes for bipolar disorder. Int J Bipolar Disord 2021, 9: 17.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Favre P, Pauling M, Stout J, Hozer F, Sarrazin S, Abé C, et al. Widespread white matter microstructural abnormalities in bipolar disorder: Evidence from mega- and meta-analyses across 3033 individuals. Neuropsychopharmacology 2019, 44: 2285–2293.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Shonibare DO, Patel R, Islam AH, Metcalfe AWS, Fiksenbaum L, Kennedy JL, et al. Preliminary study of structural magnetic resonance imaging phenotypes related to genetic variation in Interleukin-1β rs16944 in adolescents with Bipolar Disorder. J Psychiatr Res 2020, 122: 33–41.

    Article  PubMed  Google Scholar 

  117. Dickinson T, Becerra R, Coombes J. Executive functioning deficits among adults with Bipolar Disorder (types I and II): A systematic review and meta-analysis. J Affect Disord 2017, 218: 407–427.

    Article  PubMed  Google Scholar 

  118. Seidman LJ, Kremen WS, Koren D, Faraone SV, Goldstein JM, Tsuang MT. A comparative profile analysis of neuropsychological functioning in patients with schizophrenia and bipolar psychoses. Schizophr Res 2002, 53: 31–44.

    Article  PubMed  Google Scholar 

  119. Hasler G, Drevets WC, Gould TD, Gottesman II, Manji HK. Toward constructing an endophenotype strategy for bipolar disorders. Biol Psychiatry 2006, 60: 93–105.

    Article  PubMed  Google Scholar 

  120. Kaminsky Z, Tochigi M, Jia P, Pal M, Mill J, Kwan A, et al. A multi-tissue analysis identifies HLA complex group 9 gene methylation differences in bipolar disorder. Mol Psychiatry 2012, 17: 728–740.

    Article  CAS  PubMed  Google Scholar 

  121. Abdolmaleky HM, Smith CL, Faraone SV, Shafa R, Stone W, Glatt SJ, et al. Methylomics in psychiatry: Modulation of gene-environment interactions may be through DNA methylation. Am J Med Genet B Neuropsychiatr Genet 2004, 127B: 51–59.

    Article  PubMed  Google Scholar 

  122. Mattick JS, Makunin IV. Non-coding rna. Hum Mol Genet 2006, 15: R17–R29.

    Article  CAS  PubMed  Google Scholar 

  123. Fries GR, Lima CNC, Valvassori SS, Zunta-Soares G, Soares JC, Quevedo J. Preliminary investigation of peripheral extracellular vesicles’ microRNAs in bipolar disorder. J Affect Disord 2019, 255: 10–14.

    Article  CAS  PubMed  Google Scholar 

  124. Fries GR, Carvalho AF, Quevedo J. The miRNome of bipolar disorder. J Affect Disord 2018, 233: 110–116.

    Article  CAS  PubMed  Google Scholar 

  125. Sayad A, Taheri M, Omrani MD, Fallah H, Kholghi Oskooei V, Ghafouri-Fard S. Peripheral expression of long non-coding RNAs in bipolar patients. J Affect Disord 2019, 249: 169–174.

    Article  CAS  PubMed  Google Scholar 

  126. Gould TD, Chen G, Manji HK. In vivo evidence in the brain for lithium inhibition of glycogen synthase kinase-3. Neuropsychopharmacology 2004, 29: 32–38.

    Article  CAS  PubMed  Google Scholar 

  127. Michelon L, Meira-Lima I, Cordeiro Q, Miguita K, Breen G, Collier D, et al. Association study of the INPP1, 5HTT, BDNF, AP-2beta and GSK-3beta GENE variants and restrospectively scored response to lithium prophylaxis in bipolar disorder. Neurosci Lett 2006, 403: 288–293.

    Article  CAS  PubMed  Google Scholar 

  128. Iwahashi K, Nishizawa D, Narita S, Numajiri M, Murayama O, Yoshihara E, et al. Haplotype analysis of GSK-3β gene polymorphisms in bipolar disorder lithium responders and nonresponders. Clin Neuropharmacol 2014, 37: 108–110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Manchia M, Congiu D, Squassina A, Lampus S, Ardau R, Chillotti C, et al. No association between lithium full responders and the DRD1, DRD2, DRD3, DAT1, 5-HTTLPR and HTR2A genes in a Sardinian sample. Psychiatry Res 2009, 169: 164–166.

    Article  CAS  PubMed  Google Scholar 

  130. Haggarty SJ, Karmacharya R, Perlis RH. Advances toward precision medicine for bipolar disorder: Mechanisms & molecules. Mol Psychiatry 2021, 26: 168–185.

    Article  PubMed  Google Scholar 

  131. Emamian ES, Hall D, Birnbaum MJ, Karayiorgou M, Gogos JA. Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat Genet 2004, 36: 131–137.

    Article  CAS  PubMed  Google Scholar 

  132. Karege F, Perroud N, Schürhoff F, Méary A, Marillier G, Burkhardt S, et al. Association of AKT1 gene variants and protein expression in both schizophrenia and bipolar disorder. Genes Brain Behav 2010, 9: 503–511.

    Article  CAS  PubMed  Google Scholar 

  133. Millischer V, Matheson GJ, Martinsson L, Ek IR, Schalling M, Lavebratt C, et al. AKT1 and genetic vulnerability to bipolar disorder. Psychiatry Res 2020, 284: 112677.

    Article  CAS  PubMed  Google Scholar 

  134. Song J, Bergen SE, Di Florio A, Karlsson R, Charney A, Ruderfer DM, et al. Genome-wide association study identifies SESTD1 as a novel risk gene for lithium-responsive bipolar disorder. Mol Psychiatry 2016, 21: 1290–1297.

    Article  CAS  PubMed  Google Scholar 

  135. Stern S, Sarkar A, Stern T, Mei A, Mendes APD, Stern Y, et al. Mechanisms underlying the hyperexcitability of CA3 and dentate gyrus hippocampal neurons derived from patients with bipolar disorder. Biol Psychiatry 2020, 88: 139–149.

    Article  CAS  PubMed  Google Scholar 

  136. Santos R, Linker SB, Stern S, Mendes APD, Shokhirev MN, Erikson G, et al. Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients. Mol Psychiatry 2021, 26: 2440–2456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Cadigan KM, Waterman ML. TCF/LEFs and Wnt signaling in the nucleus. Cold Spring Harb Perspect Biol 2012, 4: a007906.

    Article  PubMed  PubMed Central  Google Scholar 

  138. Logan RW, Ozburn AR, Arey RN, Ketchesin KD, Winquist A, Crain A, et al. Valproate reverses mania-like behaviors in mice via preferential targeting of HDAC2. Mol Psychiatry 2021, 26: 4066–4084.

    Article  CAS  PubMed  Google Scholar 

  139. Machado-Vieira R, Ibrahim L, Zarate CA Jr. Histone deacetylases and mood disorders: Epigenetic programming in gene-environment interactions. CNS Neurosci Ther 2011, 17: 699–704.

    Article  CAS  PubMed  Google Scholar 

  140. Arent CO, Valvassori SS, Fries GR, Stertz L, Ferreira CL, Lopes-Borges J, et al. Neuroanatomical profile of antimaniac effects of histone deacetylases inhibitors. Mol Neurobiol 2011, 43: 207–214.

    Article  CAS  PubMed  Google Scholar 

  141. Leng Y, Liang MH, Ren M, Marinova Z, Leeds P, Chuang DM. Synergistic neuroprotective effects of lithium and valproic acid or other histone deacetylase inhibitors in neurons: Roles of glycogen synthase kinase-3 inhibition. J Neurosci 2008, 28: 2576–2588.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Schloesser RJ, Huang J, Klein PS, Manji HK. Cellular plasticity cascades in the pathophysiology and treatment of bipolar disorder. Neuropsychopharmacology 2008, 33: 110–133.

    Article  CAS  PubMed  Google Scholar 

  143. Kim B, Kim CY, Lee MJ, Joo YH. Preliminary evidence on the association between XBP1-116C/G polymorphism and response to prophylactic treatment with valproate in bipolar disorders. Psychiatry Res 2009, 168: 209–212.

    Article  CAS  PubMed  Google Scholar 

  144. Lee HY, Kim YK. Catechol-O-methyltransferase Val158Met polymorphism affects therapeutic response to mood stabilizer in symptomatic manic patients. Psychiatry Res 2010, 175: 63–66.

    Article  CAS  PubMed  Google Scholar 

  145. Perlis RH, Adams DH, Fijal B, Sutton VK, Farmen M, Breier A, et al. Genetic association study of treatment response with olanzapine/fluoxetine combination or lamotrigine in bipolar I depression. J Clin Psychiatry 2010, 71: 599–605.

    Article  CAS  PubMed  Google Scholar 

  146. Procopio DO, Saba LM, Walter H, Lesch O, Skala K, Schlaff G, et al. Genetic markers of comorbid depression and alcoholism in women. Alcohol Clin Exp Res 2013, 37: 896–904.

    Article  CAS  PubMed  Google Scholar 

  147. Fagiolini A, Forgione R, Maccari M, Cuomo A, Morana B, Dell’Osso MC, et al. Prevalence, chronicity, burden and borders of bipolar disorder. J Affect Disord 2013, 148: 161–169.

    Article  PubMed  Google Scholar 

  148. Wei YB, McCarthy M, Ren H, Carrillo-Roa T, Shekhtman T, DeModena A, et al. A functional variant in the serotonin receptor 7 gene (HTR7), rs7905446, is associated with good response to SSRIs in bipolar and unipolar depression. Mol Psychiatry 2020, 25: 1312–1322.

    Article  CAS  PubMed  Google Scholar 

  149. Melhuish Beaupre LM, Tiwari AK, Gonçalves VF, Lisoway AJ, Harripaul RS, Müller DJ, et al. Antidepressant-associated Mania in bipolar disorder: A review and meta-analysis of potential clinical and genetic risk factors. J Clin Psychopharmacol 2020, 40: 180–185.

    Article  PubMed  Google Scholar 

  150. Ho AMC, Coombes BJ, Nguyen TTL, Liu D, McElroy SL, Singh B, et al. Mood-stabilizing antiepileptic treatment response in bipolar disorder: A genome-wide association study. Clin Pharmacol Ther 2020, 108: 1233–1242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Burghardt KJ, Khoury AS, Msallaty Z, Yi Z, Seyoum B. Antipsychotic medications and DNA methylation in schizophrenia and bipolar disorder: A systematic review. Pharmacotherapy 2020, 40: 331–342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Breen G, Li Q, Roth BL, O’Donnell P, Didriksen M, Dolmetsch R, et al. Translating genome-wide association findings into new therapeutics for psychiatry. Nat Neurosci 2016, 19: 1392–1396.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Chatterjee N, Shi J, García-Closas M. Developing and evaluating polygenic risk prediction models for stratified disease prevention. Nat Rev Genet 2016, 17: 392–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Torkamani A, Wineinger NE, Topol EJ. The personal and clinical utility of polygenic risk scores. Nat Rev Genet 2018, 19: 581–590.

    Article  CAS  PubMed  Google Scholar 

  155. Martin AR, Kanai M, Kamatani Y, Okada Y, Neale BM, Daly MJ. Clinical use of current polygenic risk scores may exacerbate health disparities. Nat Genet 2019, 51: 584–591.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Engelbrecht HR, Dalvie S, Agenbag G, Stein DJ, Ramesar RS. Whole-exome sequencing in an Afrikaner family with bipolar disorder. J Affect Disord 2020, 276: 69–75.

    Article  CAS  PubMed  Google Scholar 

  157. Kaneva R, Milanova V, Angelicheva D, MacGregor S, Kostov C, Vladimirova R, et al. Bipolar disorder in the Bulgarian Gypsies: Genetic heterogeneity in a young founder population. Am J Med Genet B Neuropsychiatr Genet 2009, 150B: 191–201.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This review was supported by the Zhejiang Provincial Key Research and Development Program (2021C03107), the Leading Talent of Scientific and Technological Innovation “Ten Thousand Talents Program” of Zhejiang Province (2021R52016), the Innovation Team for Precision Diagnosis and Treatment of Major Brain Diseases (2020R01001), and the Research Project of Jinan Microecological Biomedicine Shandong Laboratory (JNL-2023001B).

Author information

Author notes

  1. Lingzhuo Kong and Yiqing Chen contributed equally to this review.

Authors and Affiliations

  1. Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China

    Lingzhuo Kong, Yiqing Chen, Yuting Shen, Danhua Zhang, Chen Wei, Jianbo Lai & Shaohua Hu

  2. The Key Laboratory of Mental Disorder Management in Zhejiang Province, Hangzhou, 310003, China

    Jianbo Lai & Shaohua Hu

  3. Brain Research Institute of Zhejiang University, Hangzhou, 310003, China

    Jianbo Lai & Shaohua Hu

  4. Zhejiang Engineering Center for Mathematical Mental Health, Hangzhou, 310003, China

    Jianbo Lai & Shaohua Hu

  5. Department of Neurobiology, NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brian Medicine, and MOE Frontier Science Center for Brain Science and Brain-machine Integration, Zhejiang University School of Medicine, Hangzhou, 310003, China

    Jianbo Lai & Shaohua Hu

Authors
  1. Lingzhuo Kong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yiqing Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuting Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Danhua Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chen Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jianbo Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shaohua Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jianbo Lai or Shaohua Hu.

Ethics declarations

Conflict of interest

We declare no competing interests.

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

Kong, L., Chen, Y., Shen, Y. et al. Progress and Implications from Genetic Studies of Bipolar Disorder. Neurosci. Bull. (2024). https://doi.org/10.1007/s12264-023-01169-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12264-023-01169-9

Keywords

Search

Navigation