Advertisement

Der Nervenarzt

, Volume 88, Issue 7, pp 755–759 | Cite as

Genetische Grundlagen der bipolaren Störung

  • M. Budde
  • A. J. Forstner
  • K. Adorjan
  • S. K. Schaupp
  • M. M. Nöthen
  • T. G. SchulzeEmail author
Leitthema

Zusammenfassung

Die bipolare Störung (BD) ist multifaktoriell verursacht, zur Entstehung tragen sowohl genetische als auch Umweltfaktoren bei. Der Durchbruch bei der Identifizierung der verantwortlichen Gene gelang mit genomweiten Assoziationsstudien (GWAS), in denen erstmals replizierbare genetische Risikovarianten für die BD gefunden wurden. Neben den durch die GWAS identifizierten häufigen genetischen Varianten mit kleinen Effekten werden auch seltene Varianten mit höherer Penetranz zur Krankheitsentstehung beitragen. So gibt es erste Hinweise darauf, dass genomische Kopienzahlvarianten mit der Entstehung der BD assoziiert sind, ihr Beitrag zur Krankheitsentstehung ist aber geringer als bei der Schizophrenie oder dem Autismus. Die wenigen bisher bei der BD durchgeführten großflächigen Sequenzierungsstudien deuten auf eine Anreicherung seltener Varianten in zuvor mit der BD assoziierten Stoffwechselwegen und Genen hin. Im Bereich der Pharmakogenetik konnte mit einer großen internationalen GWAS erstmals ein Gen identifiziert werden, welches das individuell unterschiedliche Ansprechen auf Lithium beeinflusst. Die bisher beschriebenen Risikovarianten erklären allerdings einen zu geringen Anteil der phänotypischen Varianz, als dass sie derzeit für eine individuelle Prädiktion des Erkrankungsrisikos, des Krankheitsverlaufs oder des Ansprechens auf Medikamente genutzt werden könnten. Die genetische Forschung wird in Zukunft weitere BD-assoziierte Gene identifizieren und damit das Wissen um die biologischen Grundlagen der BD entscheidend erweitern. Die genetischen Kenntnisse werden u. a. helfen, ätiologische Subgruppen sowie diagnoseübergreifende Krankheitsmechanismen zu identifizieren.

Schlüsselwörter

Seltene genetische Varianten Häufige genetische Varianten Erkrankungsrisiko Lithium Pharmakogenetik 

Genetics of bipolar disorder

Abstract

Bipolar disorder (BD) has a multifactorial etiology. Its development is influenced by genetic as well as environmental factors. Large genome-wide association studies (GWAS), in which genetic risk allelic variants for the disorder could be replicated for the first time, marked the breakthrough in the identification of the responsible risk genes. In addition to these common genetic variants with moderate effects identified by GWAS, rare variants with a higher penetrance are expected to play a role in disease development. The results of recent studies suggest that copy number variants might contribute to BD development, although to a lesser extent than in other psychiatric disorders, such as schizophrenia or autism. Results from the initial next generation sequencing studies indicate an enrichment of rare variants in pathways and genes that were previously found to be associated with BD. In the field of pharmacogenetics, a risk gene that influences the individual variance in the response to lithium treatment was identified for the first time in a recent large international GWAS. Currently the reported risk alleles do not sufficiently explain the phenotypic variance to be used for individual prediction of disease risk, disease course or response to medication. Future genetic research will provide important insights into the biological basis of BD by the identification of additional genes associated with BD. This knowledge of genetics will help identify potential etiological subgroups as well as cross-diagnostic disease mechanisms.

Keywords

Rare genetic variants Common genetic variants Genetic predisposition to disease Lithium Pharmacogenetics 

Notes

Einhaltung ethischer Richtlinien

Interessenkonflikt

M. Budde, A.J. Forstner, K. Adorjan und S.K. Schaupp geben an, dass kein Interessenkonflikt besteht. M.M. Nöthen und T.G. Schulze erhalten Drittmittel von der Deutschen Forschungsgemeinschaft (DFG; FOR2107, NO246/10–1; SCHU 1603/5–1, SCHU 1603/7–1) und dem Bundesministerium für Bildung und Forschung (BMBF; 01ZX1314A, 01ZX1314K, 01ZX1314D, 01EE1404H). M.M. Nöthen ist Mitglied des DFG-geförderten Exzellenzclusters ImmunoSensation. T.G. Schulze wird von der Dr. Lisa Oehler-Stiftung (Kassel) unterstützt.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

Literatur

  1. 1.
    Ament SA, Szelinger S, Glusman G et al (2015) Rare variants in neuronal excitability genes influence risk for bipolar disorder. Proc Natl Acad Sci USA 112:3576–3581CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Baum AE, Akula N, Cabanero M et al (2008) A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder. Mol Psychiatry 13:197–207CrossRefPubMedGoogle Scholar
  3. 3.
    Bienvenu OJ, Davydow DS, Kendler KS (2011) Psychiatric ‘diseases’ versus behavioral disorders and degree of genetic influence. Psychol Med 41:33–40CrossRefPubMedGoogle Scholar
  4. 4.
    Budde M, Degner D, Brockmöller J et al (2017) Pharmacogenomic aspects of bipolar disorder: an update. Eur Neuropsychopharmacol. doi: 10.1016/j.euroneuro.2017.02.001 PubMedGoogle Scholar
  5. 5.
    Charney AW, Ruderfer DM, Stahl EA et al (2017) Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder. Transl Psychiatry 7:e993CrossRefPubMedGoogle Scholar
  6. 6.
    Chen DT, Jiang X, Akula N et al (2013) Genome-wide association study meta-analysis of European and Asian-ancestry samples identifies three novel loci associated with bipolar disorder. Mol Psychiatry 18:195–205CrossRefPubMedGoogle Scholar
  7. 7.
    Chen YC, Carter H, Parla J et al (2013) A hybrid likelihood model for sequence-based disease association studies. PLOS Genet 9:e1003224CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Chen CH, Lee CS, Lee MT et al (2014) Variant GADL1 and response to lithium therapy in bipolar I disorder. N Engl J Med 370:119–128CrossRefPubMedGoogle Scholar
  9. 9.
    Cichon S, Mühleisen TW, Degenhardt FA et al (2011) Genome-wide association study identifies genetic variation in neurocan as a susceptibility factor for bipolar disorder. Am J Hum Genet 88:372–381CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium, Psychosis Endophenotypes International Consortium (2017) Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat Genet 49:27–35Google Scholar
  11. 11.
    Consortium on Lithium Genetics, Hou L, Heilbronner U et al (2014) Variant GADL1 and response to lithium in bipolar I disorder. N Engl J Med 370:1857–1859Google Scholar
  12. 12.
    Craddock N, Sklar P (2013) Genetics of bipolar disorder. Lancet 381:1654–1662CrossRefPubMedGoogle Scholar
  13. 13.
    Cross-Disorder Group of the Psychiatric Genomics Consortium, Lee SH, Ripke S et al (2013) Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet 45:984–994CrossRefPubMedCentralGoogle Scholar
  14. 14.
    Cruceanu C, Ambalavanan A, Spiegelman D et al (2013) Family-based exome-sequencing approach identifies rare susceptibility variants for lithium-responsive bipolar disorder. Genome 56:634–640CrossRefPubMedGoogle Scholar
  15. 15.
    Ferrari AJ, Stockings E, Khoo JP et al (2016) The prevalence and burden of bipolar disorder: findings from the Global Burden of Disease Study 2013. Bipolar Disord 18:440–450CrossRefPubMedGoogle Scholar
  16. 16.
    Ferreira MA, O’Donovan MC, Meng YA et al (2008) Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 40:1056–1058CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Fiorentino A, O’Brien NL, Locke DP et al (2014) Analysis of ANK3 and CACNA1C variants identified in bipolar disorder whole genome sequence data. Bipolar Disord 16:583–591CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Forstner AJ, Hofmann A, Maaser A et al (2015) Genome-wide analysis implicates microRNAs and their target genes in the development of bipolar disorder. Transl Psychiatry 5:e678CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Forstner AJ, Hecker J, Hofmann A et al (2017) Identification of shared risk loci and pathways for bipolar disorder and schizophrenia. PLOS ONE 12(2):e0171595CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Geoffroy PA, Bellivier F, Leboyer M et al (2014) Can the response to mood stabilizers be predicted in bipolar disorder? Front Biosci (Elite Ed) 6:120–138CrossRefGoogle Scholar
  21. 21.
    Georgi B, Craig D, Kember RL et al (2014) Genomic view of bipolar disorder revealed by whole genome sequencing in a genetic isolate. PLOS Genet 10:e1004229CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Goes FS (2016) Genetics of bipolar disorder: recent update and future directions. Psychiatr Clin North Am 39:139–155CrossRefPubMedGoogle Scholar
  23. 23.
    Goes FS, Pirooznia M, Parla JS et al (2016) Exome sequencing of familial bipolar disorder. JAMA Psychiatry 73:590–597CrossRefPubMedGoogle Scholar
  24. 24.
    Gratten J, Wray NR, Keller MC et al (2014) Large-scale genomics unveils the genetic architecture of psychiatric disorders. Nat Neurosci 17:782–790CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Green EK, Grozeva D, Forty L et al (2013) Association at SYNE1 in both bipolar disorder and recurrent major depression. Mol Psychiatry 18:614–617CrossRefPubMedGoogle Scholar
  26. 26.
    Green EK, Hamshere M, Forty L et al (2013) 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 18:1302–1307CrossRefPubMedGoogle Scholar
  27. 27.
    Green EK, Rees E, Walters JT et al (2016) Copy number variation in bipolar disorder. Mol Psychiatry 21:89–93CrossRefPubMedGoogle Scholar
  28. 28.
    Grozeva D, Kirov G, Conrad DF et al (2013) Reduced burden of very large and rare CNVs in bipolar affective disorder. Bipolar Disord 15:893–898CrossRefPubMedGoogle Scholar
  29. 29.
    Hou L, Bergen SE, Akula N et al (2016) Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder. Hum Mol Genet 25:3383–3394CrossRefPubMedGoogle Scholar
  30. 30.
    Hou L, Heilbronner U, Degenhardt F et al (2016) Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study. Lancet 387:1085–1093CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Kataoka M, Matoba N, Sawada T et al (2016) Exome sequencing for bipolar disorder points to roles of de novo loss-of-function and protein-altering mutations. Mol Psychiatry 21:885–893CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Kato T (2015) Whole genome/exome sequencing in mood and psychotic disorders. Psychiatry Clin Neurosci 69:65–76CrossRefPubMedGoogle Scholar
  33. 33.
    Kerner B, Rao AR, Christensen B et al (2013) Rare genomic variants link bipolar disorder with anxiety disorders to CREB-regulated intracellular signaling pathways. Front Psychiatry 4:154CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Lupski JR, Belmont JW, Boerwinkle E et al (2011) Clan genomics and the complex architecture of human disease. Cell 147:32–43CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Malhotra D, Sebat J (2012) CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell 148:1223–1241CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Malhotra D, Mccarthy S, Michaelson JJ et al (2011) High frequencies of de novo CNVs in bipolar disorder and schizophrenia. Neuron 72:951–963CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Merikangas KR, Jin R, He JP et al (2011) Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry 68:241–251CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Mühleisen TW, Leber M, Schulze TG et al (2014) Genome-wide association study reveals two new risk loci for bipolar disorder. Nat Commun 5:3339CrossRefPubMedGoogle Scholar
  39. 39.
    Nurnberger JI Jr., Koller DL, Jung J et al (2014) Identification of pathways for bipolar disorder: a meta-analysis. JAMA Psychiatry 71:657–664CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Perlis RH, Smoller JW, Ferreira MA et al (2009) A genomewide association study of response to lithium for prevention of recurrence in bipolar disorder. Am J Psychiatry 166:718–725CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Priebe L, Degenhardt FA, Herms S et al (2012) Genome-wide survey implicates the influence of copy number variants (CNVs) in the development of early-onset bipolar disorder. Mol Psychiatry 17:421–432CrossRefPubMedGoogle Scholar
  42. 42.
    Psychiatric GWAS Consortium Bipolar Disorder Working Group (2011) Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet 43:977–983CrossRefGoogle Scholar
  43. 43.
    Psychiatric GWAS Consortium Bipolar Disorder Working Group (2015) Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways. Nat Neurosci 18:199–209CrossRefGoogle Scholar
  44. 44.
    Ruderfer DM, Fanous AH, Ripke S et al (2014) Polygenic dissection of diagnosis and clinical dimensions of bipolar disorder and schizophrenia. Mol Psychiatry 19:1017–1024CrossRefPubMedGoogle Scholar
  45. 45.
    Squassina A, Manchia M, Borg J et al (2011) Evidence for association of an ACCN1 gene variant with response to lithium treatment in Sardinian patients with bipolar disorder. Pharmacogenomics 12:1559–1569CrossRefPubMedGoogle Scholar
  46. 46.
    Strauss KA, Markx S, Georgi B et al (2014) A population-based study of KCNH7 p.Arg394His and bipolar spectrum disorder. Hum Mol Genet 23:6395–6406CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Zhang D, Cheng L, Qian Y et al (2009) Singleton deletions throughout the genome increase risk of bipolar disorder. Mol Psychiatry 14:376–380CrossRefPubMedGoogle Scholar

Copyright information

© Springer Medizin Verlag GmbH 2017

Authors and Affiliations

  • M. Budde
    • 1
  • A. J. Forstner
    • 2
    • 3
    • 4
    • 5
    • 6
  • K. Adorjan
    • 1
    • 7
  • S. K. Schaupp
    • 1
    • 8
  • M. M. Nöthen
    • 2
    • 3
  • T. G. Schulze
    • 1
    Email author
  1. 1.Institut für Psychiatrische Phänomik und Genomik (IPPG)Klinikum der Universität MünchenMünchenDeutschland
  2. 2.Institut für HumangenetikUniversitätsklinikum BonnBonnDeutschland
  3. 3.Department of Genomics, Life & Brain CenterUniversität BonnBonnDeutschland
  4. 4.Universitäre Psychiatrische Kliniken (UPK)Universität BaselBaselSchweiz
  5. 5.Human Genomics Research Group, Departement BiomedizinUniversität BaselBaselSchweiz
  6. 6.Institut für medizinische Genetik und PathologieUniversitätsspital BaselBaselSchweiz
  7. 7.Klinik für Psychiatrie und PsychotherapieKlinikum der Universität MünchenMünchenDeutschland
  8. 8.Klinik für Psychiatrie, Psychotherapie und PsychosomatikBezirkskrankenhaus AugsburgAugsburgDeutschland

Personalised recommendations