The genetics of bipolar disorder

Abstract

Bipolar disorder (BD) is one of the most heritable mental illnesses, but the elucidation of its genetic basis has proven to be a very challenging endeavor. Genome-Wide Association Studies (GWAS) have transformed our understanding of BD, providing the first reproducible evidence of specific genetic markers and a highly polygenic architecture that overlaps with that of schizophrenia, major depression, and other disorders. Individual GWAS markers appear to confer little risk, but common variants together account for about 25% of the heritability of BD. A few higher-risk associations have also been identified, such as a rare copy number variant on chromosome 16p11.2. Large scale next-generation sequencing studies are actively searching for other alleles that confer substantial risk. As our understanding of the genetics of BD improves, there is growing optimism that some clear biological pathways will emerge, providing a basis for future studies aimed at molecular diagnosis and novel therapeutics.

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References

  1. 1.

    Merikangas KR, Jin R, He J-P, Kessler RC, Lee S, Sampson NA, et al. Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry. 2011;68:241–51.

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    Oxford University Press. Manic-Depressive illness: bipolar disorders and recurrent depression. 2nd ed. Oxford, New York: Oxford University Press; 2007.

  3. 3.

    McMahon FJ, Stine OC, Chase GA, Meyers DA, Simpson SG, DePaulo JRJ. Influence of clinical subtype, sex, and lineality on age at onset of major affective disorder in a family sample. Am J Psychiatry. 1994;151:210–5.

    CAS  PubMed  Google Scholar 

  4. 4.

    Perlis RH, Ostacher MJ, Goldberg JF, Miklowitz DJ, Friedman E, Calabrese J, et al. Transition to mania during treatment of bipolar depression. Neuropsychopharmacol. 2010;35:2545–52.

    Google Scholar 

  5. 5.

    Simon NM, Otto MW, Wisniewski SR, Fossey M, Sagduyu K, Frank E, et al. Anxiety disorder comorbidity in bipolar disorder patients: data from the first 500 participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry. 2004;161:2222–9.

    PubMed  Google Scholar 

  6. 6.

    Deckersbach T, Peters AT, Sylvia L, Urdahl A, Magalhaes PVS, Otto MW, et al. Do comorbid anxiety disorders moderate the effects of psychotherapy for bipolar disorder? Results from STEP-BD. Am J Psychiatry. 2014;171:178–86.

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Merikangas KR, Mehta RL, Molnar BE, Walters EE, Swendsen JD, Aguilar-Gaziola S, et al. Comorbidity of substance use disorders with mood and anxiety disorders: results of the International Consortium in Psychiatric Epidemiology. Addict Behav. 1998;23:893–907.

    CAS  PubMed  Google Scholar 

  8. 8.

    Kessler RC, Crum RM, Warner LA, Nelson CB, Schulenberg J, Anthony JC. Lifetime co-occurrence of DSM-III-R alcohol abuse and dependence with other psychiatric disorders in the National Comorbidity Survey. Arch Gen Psychiatry. 1997;54:313–21.

    CAS  PubMed  Google Scholar 

  9. 9.

    Reich T, Clayton PJ, Winokur G. Family history studies: V. The genetics of mania. Am J Psychiatry. 1969;125:1358–69.

    CAS  PubMed  Google Scholar 

  10. 10.

    Strober M. Relevance of early age-of-onset in genetic studies of bipolar affective disorder. J Am Acad Child Adolesc Psychiatry. 1992;31:606–10.

    CAS  PubMed  Google Scholar 

  11. 11.

    Goes FS, Zandi PP, Miao K, McMahon FJ, Steele J, Willour VL, et al. Mood-incongruent psychotic features in bipolar disorder: familial aggregation and suggestive linkage to 2p11-q14 and 13q21-33. Am J Psychiatry. 2007;164:236–47.

    PubMed  Google Scholar 

  12. 12.

    Potash JB, Chiu Y-F, MacKinnon DF, Miller EB, Simpson SG, McMahon FJ, et al. Familial aggregation of psychotic symptoms in a replication set of 69 bipolar disorder pedigrees. Am J Med Genet Part B. 2003;116B:90–7.

    PubMed  Google Scholar 

  13. 13.

    Fisfalen ME, Schulze TG, DePaulo JRJ, DeGroot LJ, Badner JA, McMahon FJ. Familial variation in episode frequency in bipolar affective disorder. Am J Psychiatry. 2005;162:1266–72.

    PubMed  Google Scholar 

  14. 14.

    Kassem L, Lopez V, Hedeker D, Steele J, Zandi P, McMahon FJ. Familiality of polarity at illness onset in bipolar affective disorder. Am J Psychiatry. 2006;163:1754–9.

    PubMed  Google Scholar 

  15. 15.

    Schulze TG, Hedeker D, Zandi P, Rietschel M, McMahon FJ. What is familial about familial bipolar disorder? Resemblance among relatives across a broad spectrum of phenotypic characteristics. Arch Gen Psychiatry. 2006;63:1368–76.

    PubMed  Google Scholar 

  16. 16.

    Coryell W, Kriener A, Butcher B, Nurnberger J, McMahon F, Berrettini W, et al. Risk factors for suicide in bipolar I disorder in two prospectively studied cohorts. J Affect Disord. 2016;190:1–5.

    PubMed  Google Scholar 

  17. 17.

    Cipriani A, Hawton K, Stockton S, Geddes JR. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ. 2013;346:f3646. https://doi.org/10.1136/bmj.f3646.

    PubMed  Google Scholar 

  18. 18.

    Willour VL, Zandi PP, Badner JA, Steele J, Miao K, Lopez V, et al. Attempted suicide in bipolar disorder pedigrees: evidence for linkage to 2p12. Biol Psychiatry. 2007;61:725–7.

    CAS  PubMed  Google Scholar 

  19. 19.

    Song J, Sjölander A, Joas E, Bergen SE, Runeson B, Larsson H, et al. Suicidal behavior during lithium and valproate treatment: a within-individual 8-year prospective study of 50,000 patients with bipolar disorder. Am J Psychiatry. 2017;174:795–802.

    PubMed  Google Scholar 

  20. 20.

    Cipriani A, Pretty H, Hawton K, Geddes JR. Lithium in the prevention of suicidal behavior and all-cause mortality in patients with mood disorders: a systematic review of randomized trials. Am J Psychiatry. 2005;162:1805–19.

    PubMed  Google Scholar 

  21. 21.

    Pompili M, Gonda X, Serafini G, Innamorati M, Sher L, Amore M, et al. Epidemiology of suicide in bipolar disorders: a systematic review of the literature. Bipolar Disord. 2013;15:457–90.

    PubMed  Google Scholar 

  22. 22.

    Potash JB, Kane HS, Chiu YF, Simpson SG, MacKinnon DF, McInnis MG, et al. Attempted suicide and alcoholism in bipolar disorder: clinical and familial relationships. Am J Psychiatry. 2000;157:2048–50.

    CAS  PubMed  Google Scholar 

  23. 23.

    Egeland JA, Sussex JN. Suicide and family loading for affective disorders. J Am Med Assoc. 1985;254:915–8.

    CAS  Google Scholar 

  24. 24.

    Grof P, Muller-Oerlinghausen B. A critical appraisal of lithium’s efficacy and effectiveness: the last 60 years. Bipolar Disord. 2009;11(Suppl 2):10–9.

    CAS  PubMed  Google Scholar 

  25. 25.

    Smith KA, Cipriani A. Lithium and suicide in mood disorders: updated meta-review of the scientific literature. Bipolar Disord. 2017. https://doi.org/10.1111/bdi.12543.

    CAS  PubMed  Google Scholar 

  26. 26.

    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. 2017;22:1223. https://doi.org/10.1038/mp.2016.246.

    CAS  PubMed  Google Scholar 

  27. 27.

    Hou L, Heilbronner U, Degenhardt F, Adli M, Akiyama K, Akula N, et al. Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study. Lancet. 2016;387:1085–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Chen C-H, Lee C-S, Lee M-TM, Ouyang W-C, Chen C-C, Chong M-Y, et al. Variant GADL1 and response to lithium therapy in bipolar I disorder. N. Engl J Med. 2014;370:119–28.

    CAS  PubMed  Google Scholar 

  29. 29.

    Hou L, Heilbronner U, Rietschel M, Kato T, Kuo P-H, McMahon FJ, et al. Variant GADL1 and response to lithium in bipolar I disorder. N. Engl J Med. 2014;370:1857–9.

    PubMed  PubMed Central  Google Scholar 

  30. 30.

    Wang JL, Shamah SM, Sun AX, Waldman ID, Haggarty SJ, Perlis RH. Label-free, live optical imaging of reprogrammed bipolar disorder patient-derived cells reveals a functional correlate of lithium responsiveness. Transl Psychiatry. 2014;4:e428. https://doi.org/10.1038/tp.2014.72.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Liang M-H, Wendland JR, Chuang D-M. Lithium inhibits Smad3/4 transactivation via increased CREB activity induced by enhanced PKA and AKT signaling. Mol Cell Neurosci. 2008;37:440–53.

    CAS  PubMed  Google Scholar 

  32. 32.

    Ferensztajn-Rochowiak E, Tarnowski M, Samochowiec J, Michalak M, Ratajczak MZ, Rybakowski JK. Increased mRNA expression of peripheral glial cell markers in bipolar disorder: the effect of long-term lithium treatment. Eur Neuropsychopharmacol. 2016;26:1516–21.

    CAS  PubMed  Google Scholar 

  33. 33.

    Smoller JW, Finn CT. Family, twin, and adoption studies of bipolar disorder. Am J Med Genet. 2003;123C:48–58.

    Google Scholar 

  34. 34.

    Rice J, Cloninger CR, Reich T. Multifactorial inheritance with cultural transmission and assortative mating. I. Description and basic properties of the unitary models. Am J Hum Genet. 1978;30:618–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Merikangas KR, Spiker DG. Assortative mating among in-patients with primary affective disorder. Psychol Med. 1982;12:753–64.

    CAS  PubMed  Google Scholar 

  36. 36.

    Merikangas KR. Assortative mating for psychiatric disorders and psychological traits. Arch Gen Psychiatry. 1982;39:1173–80.

    CAS  PubMed  Google Scholar 

  37. 37.

    Mathews CA, Reus VI. Assortative mating in the affective disorders: a systematic review and meta-analysis. Compr Psychiatry. 2001;42:257–62.

    CAS  PubMed  Google Scholar 

  38. 38.

    Baron M, Mendlewicz J, Gruen R, Asnis L, Fieve RR. Assortative mating in affective disorders. J Affect Disord. 1981;3:167–71.

    CAS  PubMed  Google Scholar 

  39. 39.

    Maes HHM, Neale MC, Kendler KS, Hewitt JK, Silberg JL, Foley DL, et al. Assortative mating for major psychiatric diagnoses in two population-based samples. Psychol Med. 1998;28:1389–401.

    CAS  PubMed  Google Scholar 

  40. 40.

    Merikangas KR. Divorce and assortative mating among depressed patients. Am J Psychiatry. 1984;141:74–76.

    CAS  PubMed  Google Scholar 

  41. 41.

    Dunner DL, Fleiss JL, Addonizio G, Fieve RR. Assortative mating in primary affective disorder. Biol Psychiatry. 1976;11:43–51.

    CAS  PubMed  Google Scholar 

  42. 42.

    Krueger RF, Moffitt TE, Caspi A, Bleske A, Silva PA. Assortative mating for antisocial behavior: developmental and methodological implications. Behav Genet. 1998;28:173–86.

    CAS  PubMed  Google Scholar 

  43. 43.

    Gershon ES, Dunner DL, Sturt L, Goodwin FK. Assortative mating in the affective disorders. Biol Psychiatry. 1973;1:63–74.

  44. 44.

    Stulp G, Simons MJP, Grasman S, Pollet TV. Assortative mating for human height: a meta-analysis. Am J Hum Biol Off J Hum Biol Counc. 2017;29:1–10.

    PubMed Central  Google Scholar 

  45. 45.

    Montiglio P-O, Wey TW, Chang AT, Fogarty S, Sih A. Multiple mating reveals complex patterns of assortative mating by personality and body size. J Anim Ecol. 2016;85:125–35.

    PubMed  Google Scholar 

  46. 46.

    Smieja M, Stolarski M. Assortative mating for emotional intelligence. Curr Psychol. 2018;37:180–7.

    PubMed  Google Scholar 

  47. 47.

    Krzyzanowska M, Mascie-Taylor CGN. Educational and social class assortative mating in fertile British couples. Ann Hum Biol. 2014;41:561–7.

    PubMed  Google Scholar 

  48. 48.

    McInnis MG, McMahon FJ, Chase GA, Simpson SG, Ross CA, DePaulo JRJ. Anticipation in bipolar affective disorder. Am J Hum Genet. 1993;53:385–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    de Jong S, Diniz MJA, Saloma A, Gadelha A, Santoro ML, Ota VK, et al. Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder. Commun Biol. 2018;1:163. https://doi.org/10.1038/s42003-018-0155-y.

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    Peyrot WJ, Robinson MR, Penninx BWJH, Wray NR. Exploring boundaries for the genetic consequences of assortative mating for psychiatric traits. JAMA Psychiatry. 2016;73:1189–95.

    PubMed  Google Scholar 

  51. 51.

    Grover D, Verma R, Goes FS, Mahon PLB, Gershon ES, McMahon FJ, et al. Family-based association of YWHAH in psychotic bipolar disorder. Am J Med Genet Part B. 2009;150B:977–83.

    CAS  PubMed  Google Scholar 

  52. 52.

    McInnis MG, Breschel TS, Margolis RL, Chellis J, MacKinnon DF, McMahon FJ, et al. Family-based association analysis of the hSKCa3 potassium channel gene in bipolar disorder. Mol Psychiatry. 1999;4:217–9.

    CAS  PubMed  Google Scholar 

  53. 53.

    Prathikanti S, McMahon FJ. Genome scans for susceptibility genes in bipolar affective disorder. Ann Med. 2001;33:257–62.

    CAS  PubMed  Google Scholar 

  54. 54.

    Judy JT, Seifuddin F, Mahon PB, Huo Y, Goes FS, Jancic D, et al. Association study of serotonin pathway genes in attempted suicide. Am J Med Genet Part B. 2012;159B:112–9.

    PubMed  Google Scholar 

  55. 55.

    Risch N, Merikangas K. The future of genetic studies of complex human diseases. Science. 1996;273:1516–7.

    CAS  PubMed  Google Scholar 

  56. 56.

    Kraft JB, Peters EJ, Slager SL, Jenkins GD, Reinalda MS, McGrath PJ, et al. Analysis of association between the serotonin transporter and antidepressant response in a large clinical sample. Biol Psychiatry. 2007;61:734–42.

    CAS  PubMed  Google Scholar 

  57. 57.

    Allen NC, Bagade S, McQueen MB, Ioannidis JPA, Kavvoura FK, Khoury MJ, et al. Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nat Genet. 2008;40:827–34.

    CAS  PubMed  Google Scholar 

  58. 58.

    Gatt JM, Burton KLO, Williams LM, Schofield PR. Specific and common genes implicated across major mental disorders: a review of meta-analysis studies. J Psychiatr Res. 2015;60:1–13.

    PubMed  Google Scholar 

  59. 59.

    Hu X-Z, Rush AJ, Charney D, Wilson AF, Sorant AJM, Papanicolaou GJ, et al. Association between a functional serotonin transporter promoter polymorphism and citalopram treatment in adult outpatients with major depression. Arch Gen Psychiatry. 2007;64:783–92.

    CAS  PubMed  Google Scholar 

  60. 60.

    Schulze TG, Ohlraun S, Czerski PM, Schumacher J, Kassem L, Deschner M, et al. Genotype-phenotype studies in bipolar disorder showing association between the DAOA/G30 locus and persecutory delusions: a first step toward a molecular genetic classification of psychiatric phenotypes. Am J Psychiatry. 2005;162:2101–8.

    PubMed  Google Scholar 

  61. 61.

    Maheshwari M, Shi J, Badner JA, Skol A, Willour VL, Muzny DM, et al. Common and rare variants of DAOA in bipolar disorder. Am J Med Genet Part B. 2009;150B:960–6.

    CAS  PubMed  Google Scholar 

  62. 62.

    Detera-Wadleigh SD, Liu C, Maheshwari M, Cardona I, Corona W, Akula N, et al. Sequence variation in DOCK9 and heterogeneity in bipolar disorder. Psychiatr Genet. 2007;17:274–86.

    PubMed  Google Scholar 

  63. 63.

    Dreimuller N, Schlicht KF, Wagner S, Peetz D, Borysenko L, Hiemke C, et al. Early reactions of brain-derived neurotrophic factor in plasma (pBDNF) and outcome to acute antidepressant treatment in patients with Major Depression. Neuropharmacology. 2012;62:264–9.

    PubMed  Google Scholar 

  64. 64.

    Laje G, Perlis RH, Rush AJ, McMahon FJ. Pharmacogenetics studies in STAR*D: strengths, limitations, and results. Psychiatr Serv Wash DC. 2009;60:1446–57.

    Google Scholar 

  65. 65.

    Liu L, Foroud T, Xuei X, Berrettini W, Byerley W, Coryell W, et al. Evidence of association between brain-derived neurotrophic factor gene and bipolar disorder. Psychiatr Genet. 2008;18:267–74.

    PubMed  PubMed Central  Google Scholar 

  66. 66.

    Boulle F, Van den Hove DLA, Jakob SB, Rutten BP, Hamon M, Van Os J, et al. Epigenetic regulation of the BDNF gene: implications for psychiatric disorders. Mol Psychiatry. 2012;17:584–96.

    CAS  PubMed  Google Scholar 

  67. 67.

    Domschke K, Lawford B, Laje G, Berger K, Young R, Morris P, et al. Brain-derived neurotrophic factor (BDNF) gene: no major impact on antidepressant treatment response. Int J Neuropsychopharmacol. 2010;13:93–101.

    PubMed  Google Scholar 

  68. 68.

    Gao Y, Galante M, El-Mallakh J, Nurnberger JIJ, Delamere NA, Lei Z, et al. BDNF expression in lymphoblastoid cell lines carrying BDNF SNPs associated with bipolar disorder. Psychiatr Genet. 2012;22:253–5.

    CAS  PubMed  Google Scholar 

  69. 69.

    Duncan LE, Hutchison KE, Carey G, Craighead WE. Variation in brain-derived neurotrophic factor (BDNF) gene is associated with symptoms of depression. J Affect Disord. 2009;115:215–9.

    CAS  PubMed  Google Scholar 

  70. 70.

    Lopez JP, Mamdani F, Labonte B, Beaulieu MM, Yang JP, Berlim MT, et al. Epigenetic regulation of BDNF expression according to antidepressant response. Mol Psychiatry. 2013;18:398–9.

    CAS  PubMed  Google Scholar 

  71. 71.

    Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A, et al. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447:661–78.

    CAS  Google Scholar 

  72. 72.

    Smith EN, Bloss CS, Badner JA, Barrett T, Belmonte PL, Berrettini W, et al. Genome-wide association study of bipolar disorder in European American and African American individuals. Mol Psychiatry. 2009;14:755–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    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;40:1056–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Group PGCBDW. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet. 2011;43:977–83.

    Google Scholar 

  75. 75.

    Ikeda M, Takahashi A, Kamatani Y, Okahisa Y, Kunugi H, Mori N, et al. A genome-wide association study identifies two novel susceptibility loci and trans population polygenicity associated with bipolar disorder. Mol Psychiatry. 2018;23:639–47.

    PubMed  PubMed Central  Google Scholar 

  76. 76.

    Chen DT, Jiang X, Akula N, Shugart YY, Wendland JR, Steele CJM, et al. Genome-wide association study meta-analysis of European and Asian-ancestry samples identifies three novel loci associated with bipolar disorder. Mol Psychiatry. 2013;18:195–205.

    CAS  PubMed  Google Scholar 

  77. 77.

    Muhleisen TW, Leber M, Schulze TG, Strohmaier J, Degenhardt F, Treutlein J, et al. Genome-wide association study reveals two new risk loci for bipolar disorder. Nat Commun. 2014;5:3339. https://doi.org/10.1038/ncomms4339.

    PubMed  Google Scholar 

  78. 78.

    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. https://doi.org/10.1093/hmg/ddw181.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Baum AE, Akula N, Cabanero M, Cardona I, Corona W, Klemens B, et al. A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder. Mol Psychiatry. 2008;13:197–207.

    PubMed  PubMed Central  Google Scholar 

  80. 80.

    Xu W, Cohen-Woods S, Chen Q, Noor A, Knight J, Hosang G, et al. Genome-wide association study of bipolar disorder in Canadian and UK populations corroborates disease loci including SYNE1 and CSMD1. BMC Med Genet. 2014;15:2. https://doi.org/10.1186/1471-2350-15-2.

    PubMed  PubMed Central  Google Scholar 

  81. 81.

    Smith EN, Koller DL, Panganiban C, Szelinger S, Zhang P, Badner JA, et al. Genome-wide association of bipolar disorder suggests an enrichment of replicable associations in regions near genes. PLoS Genet. 2011;7:e1002134. https://doi.org/10.1371/journal.pgen.1002134.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Bergen SE, O’dushlaine CT, Ripke S, Lee PH, Ruderfer DM, Akterin S, et al. Genome-wide association study in a Swedish population yields support for greater CNV and MHC involvement in schizophrenia compared with bipolar disorder. Mol Psychiatry. 2012;17:880–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Kuo PH, Chuang LC, Liu JR, Liu CM, Huang MC, Lin SK, et al. Identification of novel loci for bipolar I disorder in a multi-stage genome-wide association study. Prog Neuropsychopharmacol Biol Psychiatry. 2014;51:58–64.

    CAS  PubMed  Google Scholar 

  84. 84.

    Ruderfer DM, Ripke S, McQuillin A, Boocock J, Stahl EA, Pavlides JMW, et al. Genomic dissection of bipolar disorder and schizophrenia, including 28 subphenotypes. Cell. 2018;173:1705–15.e16.

    CAS  PubMed Central  Google Scholar 

  85. 85.

    Kao C-F, Chen H-W, Chen H-C, Yang J-H, Huang M-C, Chiu Y-H, et al. Identification of susceptible loci and enriched pathways for bipolar ii disorder using genome-wide association studies. Int J Neuropsychopharmacol. 2016. https://doi.org/10.1093/ijnp/pyw064.

    PubMed  PubMed Central  Google Scholar 

  86. 86.

    Witt SH, Streit F, Jungkunz M, Frank J, Awasthi S, Reinbold CS, et al. Genome-wide association study of borderline personality disorder reveals genetic overlap with bipolar disorder, major depression and schizophrenia. Transl Psychiatry. 2017;7:e1155. https://doi.org/10.1038/tp.2017.115.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Huckins L, Dobbyn A, McFadden W, Wang W, Ruderfer D, Hoffman G, et al. Transcriptomic imputation of bipolar disorder and bipolar subtypes reveals 29 novel associated genes. BioRxiv. 2017:222786. https://doi.org/10.1101/222786.

  89. 89.

    Akula N, Marenco S, Johnson K, Feng N, Cross J, England B, et al. Deep transcriptome sequencing of subgenual anterior cingulate cortex reveals disorder-specific expression changes in major psychiatric disorders. BioRxiv. 2019:598649. https://doi.org/10.1101/598649.

  90. 90.

    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;20:931–40.

    PubMed  PubMed Central  Google Scholar 

  91. 91.

    Rueckert EH, Barker D, Ruderfer D, Bergen SE, O’Dushlaine C, Luce CJ, et al. Cis-acting regulation of brain-specific ANK3 gene expression by a genetic variant associated with bipolar disorder. Mol Psychiatry. 2013;18:922–9.

    CAS  PubMed  Google Scholar 

  92. 92.

    Belmonte Mahon P, Pirooznia M, Goes FS, Seifuddin F, Steele J, Lee PH, et al. Genome-wide association analysis of age at onset and psychotic symptoms in bipolar disorder. Am J Med Genet Part B Neuropsychiatr Genet. 2011;156B:370–8.

    Google Scholar 

  93. 93.

    Durak O, de Anda FC, Singh KK, Leussis MP, Petryshen TL, Sklar P, et al. Ankyrin-G regulates neurogenesis and Wnt signaling by altering the subcellular localization of beta-catenin. Mol Psychiatry. 2014. https://doi.org/10.1038/mp.2014.42.

    PubMed  PubMed Central  Google Scholar 

  94. 94.

    Lippard ETC, Jensen KP, Wang F, Johnston JAY, Spencer L, Pittman B, et al. Effect of ANK3 variation on gray and white matter in bipolar disorder. Mol Psychiatry. 2017;22:1345–51.

    PubMed  PubMed Central  Google Scholar 

  95. 95.

    Schulze TG, Detera-Wadleigh SD, Akula N, Gupta A, Kassem L, Steele J, et al. Two variants in Ankyrin 3 (ANK3) are independent genetic risk factors for bipolar disorder. Mol Psychiatry. 2009;14:487–91.

    CAS  PubMed  Google Scholar 

  96. 96.

    Lim CH, Zain SM, Reynolds GP, Zain MA, Roffeei SN, Zainal NZ, et al. Genetic association of LMAN2L gene in schizophrenia and bipolar disorder and its interaction with ANK3 gene polymorphism. Prog Neuropsychopharmacol Biol Psychiatry. 2014;54:157–62.

    CAS  PubMed  Google Scholar 

  97. 97.

    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;10:1024–32.

    PubMed  PubMed Central  Google Scholar 

  98. 98.

    Yamankurt G, Wu HC, McCarthy M, Cunha SR. Exon organization and novel alternative splicing of Ank3 in mouse heart. PLoS ONE 2015;10:e012817. https://doi.org/10.1371/journal.pone.0128177.

    PubMed  PubMed Central  Google Scholar 

  99. 99.

    Zhu S, Cordner ZA, Xiong J, Chiu C-T, 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 USA. 2017;114:10479–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    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;14:252–60.

    CAS  PubMed  Google Scholar 

  101. 101.

    Cross Disorder Group of the Psychiatric Genomics Consortium. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet. 2013;381:1371–9.

    PubMed Central  Google Scholar 

  102. 102.

    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;68:801–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    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;19:890–4.

    CAS  PubMed  Google Scholar 

  104. 104.

    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;24:613–24.

    CAS  PubMed  Google Scholar 

  105. 105.

    Ruderfer DM, Fanous AH, Ripke S, McQuillin A, Amdur RL, Consortium SWG of PG. et al. Polygenic dissection of diagnosis and clinical dimensions of bipolar disorder and schizophrenia. Mol Psychiatry. 2014;19:1017–24.

    CAS  PubMed  Google Scholar 

  106. 106.

    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;54:2031–44.

    CAS  PubMed  Google Scholar 

  107. 107.

    Gandal MJ, Zhang P, Hadjimichael E, Walker RL, Chen C, Liu S, et al. Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder. Science. 2018;362:eaat8127. https://doi.org/10.1126/science.aat8127.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC, Sullivan PF, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460:748–52.

    CAS  PubMed  Google Scholar 

  109. 109.

    Schulze TG, Akula N, Breuer R, Steele J, Nalls MA, Singleton AB, et al. Molecular genetic overlap in bipolar disorder, schizophrenia, and major depressive disorder. World J Biol Psychiatry. 2014;15:200–8.

    PubMed  Google Scholar 

  110. 110.

    Kirov G, Rees E, Walters JT, Escott-Price V, Georgieva L, Richards AL, et al. The penetrance of copy number variations for schizophrenia and developmental delay. Biol Psychiatry. 2014;75:378–85.

    CAS  PubMed  Google Scholar 

  111. 111.

    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;99:540–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, Moreno-De-Luca D, et al. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron. 2011;70:863–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Williams NM, Zaharieva I, Martin A, Langley K, Mantripragada K, Fossdal R, et al. Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis. Lancet. 2010;376:1401–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    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;5:573–80.

    PubMed  PubMed Central  Google Scholar 

  115. 115.

    Gilissen C, Hehir-Kwa JY, Thung DT, van de Vorst M, van Bon BW, Willemsen MH, et al. Genome sequencing identifies major causes of severe intellectual disability. Nature. 2014;511:344–7.

    CAS  PubMed  Google Scholar 

  116. 116.

    Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R, et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature. 2010;466:368–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Rippey C, Walsh T, Gulsuner S, Brodsky M, Nord AS, Gasperini M, et al. Formation of chimeric genes by copy-number variation as a mutational mechanism in schizophrenia. Am J Hum Genet. 2013;93:697–710.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Szatkiewicz JP, O’Dushlaine C, Chen G, Chambert K, Moran JL, Neale BM, et al. Copy number variation in schizophrenia in Sweden. Mol Psychiatry. 2014;19:762–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119.

    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. https://doi.org/10.1186/s41065-016-0025-x.

    PubMed  PubMed Central  Google Scholar 

  120. 120.

    Bassett AS, Marshall CR, Lionel AC, Chow EW, Scherer SW. Copy number variations and risk for schizophrenia in 22q11.2 deletion syndrome. Hum Mol Genet. 2008;17:4045–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Gulsuner S, McClellan JM. Copy number variation in schizophrenia. Neuropsychopharmacol. 2015;40:252–4.

    CAS  Google Scholar 

  122. 122.

    Ingason A, Rujescu D, Cichon S, Sigurdsson E, Sigmundsson T, Pietilainen OPH, et al. Copy number variations of chromosome 16p13.1 region associated with schizophrenia. Mol Psychiatry. 2011;16:17–25.

    PubMed  PubMed Central  Google Scholar 

  123. 123.

    Ahn K, An SS, Shugart YY, Rapoport JL. Common polygenic variation and risk for childhood-onset schizophrenia. Mol Psychiatry. 2016;21:94–6.

    PubMed  Google Scholar 

  124. 124.

    Grozeva D, Kirov G, Ivanov D, Jones IR, Jones L, Green EK, et al. Rare copy number variants: a point of rarity in genetic risk for bipolar disorder and schizophrenia. Arch Gen Psychiatry. 2010;67:318–27.

    PubMed  PubMed Central  Google Scholar 

  125. 125.

    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;41:1223–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    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;72:951–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Green EK, Rees E, Walters JTR, Smith KG, Forty L, Grozeva D, et al. Copy number variation in bipolar disorder. Mol Psychiatry. 2015;21:2189–93.

    Google Scholar 

  128. 128.

    Kirov G. CNVs in neuropsychiatric disorders. Hum Mol Genet. 2015;24:R45–9.

    CAS  PubMed  Google Scholar 

  129. 129.

    Zufferey F, Sherr EH, Beckmann ND, Hanson E, Maillard AM, Hippolyte L, et al. A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders. J Med Genet. 2012;49:660–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Guha S, Rees E, Darvasi A, Ivanov D, Ikeda M, Bergen SE, et al. Implication of a rare deletion at distal 16p11.2 in schizophrenia. JAMA Psychiatry. 2013;70:253–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Charney AW, Stahl EA, Green EK, Chen C-Y, Moran JL, Chambert K, et al. Contribution of rare copy number variants to bipolar disorder risk is limited to schizoaffective cases. Biol Psychiatry. 2019;86:110–9.

    CAS  PubMed  Google Scholar 

  132. 132.

    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. https://doi.org/10.1038/ng.3247.

    CAS  PubMed  Google Scholar 

  133. 133.

    Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38:e164. https://doi.org/10.1093/nar/gkq603.

    PubMed  PubMed Central  Google Scholar 

  134. 134.

    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 USA. 2014;111:E455–64.

    CAS  PubMed  Google Scholar 

  135. 135.

    Ament SA, Szelinger S, Glusman G, Ashworth J, Hou L, Akula N, et al. Rare variants in neuronal excitability genes influence risk for bipolar disorder. Proc Natl Acad Sci USA. 2015;112:3576–81.

    CAS  PubMed  Google Scholar 

  136. 136.

    Goes FS, Pirooznia M, Parla JS, Kramer M, Ghiban E, Mavruk S, et al. Exome sequencing of familial bipolar disorder. JAMA Psychiatry 2016;73:590–7.

    PubMed  PubMed Central  Google Scholar 

  137. 137.

    Kataoka M, Matoba N, Sawada T, Kazuno A-A, Ishiwata M, Fujii K, et al. Exome sequencing for bipolar disorder points to roles of de novo loss-of-function and protein-altering mutations. Mol Psychiatry. 2016;21:885–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    Georgi B, Craig D, Kember RL, Liu W, Lindquist I, Nasser S, et al. Genomic view of bipolar disorder revealed by whole genome sequencing in a genetic isolate. PLoS Genet. 2014;10:e1004229. https://doi.org/10.1371/journal.pgen.1004229.

    PubMed  PubMed Central  Google Scholar 

  139. 139.

    Hou L, Faraci G, Chen DT, Kassem L, Schulze TG, Shugart YY, et al. Amish revisited: next-generation sequencing studies of psychiatric disorders among the Plain people. Trends Genet. 2013;29:412–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Hou L, Kember RL, Roach JC, O’Connell JR, Craig DW, Bucan M, et al. A population-specific reference panel empowers genetic studies of Anabaptist populations. Sci Rep. 2017;7:6079. https://doi.org/10.1038/s41598-017-05445-3.

  141. 141.

    Akula N, Barb J, Jiang X, Wendland JR, Choi KH, Sen SK, et al. RNA-sequencing of the brain transcriptome implicates dysregulation of neuroplasticity, circadian rhythms and GTPase binding in bipolar disorder. Mol Psychiatry. 2014;19:1179–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Pacifico R, Davis RL. Transcriptome sequencing implicates dorsal striatum-specific gene network, immune response and energy metabolism pathways in bipolar disorder. Mol Psychiatry. 2017;22:441–9.

    CAS  PubMed  Google Scholar 

  143. 143.

    Akula N, Wendland JR, Choi KH, McMahon FJ. An integrative genomic study implicates the postsynaptic density in the pathogenesis of bipolar disorder. Neuropsychopharmacology. 2016;41:886–95.

    CAS  PubMed  Google Scholar 

  144. 144.

    Li YI, Geijn B, van de, Raj A, Knowles DA, Petti AA, Golan D, et al. RNA splicing is a primary link between genetic variation and disease. Science. 2016;352:600–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Pandey A, Davis NA, White BC, Pajewski NM, Savitz J, Drevets WC, et al. Epistasis network centrality analysis yields pathway replication across two GWAS cohorts for bipolar disorder. Transl Psychiatry. 2012;2:e154. https://doi.org/10.1038/tp.2012.80.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146.

    Chang S, Wang J, Zhang K, Wang J. Pathway-based analysis for genome-wide association study data of bipolar disorder provides new insights for genetic study. Protein Cell. 2015;6:912–5.

    PubMed  PubMed Central  Google Scholar 

  147. 147.

    Zandi PP, Belmonte PL, Willour VL, Goes FS, Badner JA, Simpson SG, et al. Association study of Wnt signaling pathway genes in bipolar disorder. Arch Gen Psychiatry. 2008;65:785–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148.

    Berridge MJ. Calcium signaling and psychiatric disease: bipolar disorder and schizophrenia. Cell Tissue Res. 2014;357:477–92.

    CAS  PubMed  Google Scholar 

  149. 149.

    Nurnberger JIJ, Koller DL, Jung J, Edenberg HJ, Foroud T, Guella I, et al. Identification of pathways for bipolar disorder: a meta-analysis. JAMA Psychiatry. 2014;71:657–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150.

    Patel SD, Le-Niculescu H, Koller DL, Green SD, Lahiri DK, McMahon FJ, et al. Coming to grips with complex disorders: genetic risk prediction in bipolar disorder using panels of genes identified through convergent functional genomics. Am J Med Genet Part B. 2010;153B:850–77.

    CAS  PubMed  Google Scholar 

  151. 151.

    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. https://doi.org/10.1038/tp.2014.12.

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152.

    de Groot MWGDM, Dingemans MML, Rus KH, de Groot A, RHS Westerink. Characterization of calcium responses and electrical activity in differentiating mouse neural progenitor cells in vitro. Toxicol Sci J Soc Toxicol. 2014;137:428–35.

    Google Scholar 

  153. 153.

    Yoshimizu T, Pan JQ, Mungenast AE, Madison JM, Su S, Ketterman J, et al. Functional implications of a psychiatric risk variant within CACNA1C in induced human neurons. Mol Psychiatry. 2014;20:162–9.

    PubMed  PubMed Central  Google Scholar 

  154. 154.

    Schlecker C, Boehmerle W, Jeromin A, DeGray B, Varshney A, Sharma Y, et al. Neuronal calcium sensor-1 enhancement of InsP3 receptor activity is inhibited by therapeutic levels of lithium. J Clin Investig. 2006;116:1668–74.

    CAS  PubMed  Google Scholar 

  155. 155.

    Krane-Gartiser K, Steinan MK, Langsrud K, Vestvik V, Sand T, Fasmer OB, et al. Mood and motor activity in euthymic bipolar disorder with sleep disturbance. J Affect Disord. 2016;202:23–31.

    PubMed  Google Scholar 

  156. 156.

    Ng TH, Chung K-F, Ho FY-Y, Yeung W-F, Yung K-P, Lam T-H. Sleep–wake disturbance in interepisode bipolar disorder and high-risk individuals: a systematic review and meta-analysis. Sleep Med Rev. 2015;20:46–58.

    PubMed  Google Scholar 

  157. 157.

    Pagani L, Clair PAS, Teshiba TM, Fears SC, Araya C, Araya X, et al. Genetic contributions to circadian activity rhythm and sleep pattern phenotypes in pedigrees segregating for severe bipolar disorder. Proc Natl Acad Sci USA. 2016;113:E754–61.

    CAS  PubMed  Google Scholar 

  158. 158.

    Castro J, Zanini M, Gonçalves B, da SB, Coelho FMS, Bressan R, et al. Circadian rest–activity rhythm in individuals at risk for psychosis and bipolar disorder. Schizophr Res. 2015;168:50–5.

    PubMed  Google Scholar 

  159. 159.

    Geoffroy PA, Etain B, Lajnef M, Zerdazi E-H, 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;15:660–8.

    CAS  PubMed  Google Scholar 

  160. 160.

    Shi J, Wittke-Thompson JK, Badner JA, Hattori E, Potash JB, Willour VL, et al. Clock genes may influence bipolar disorder susceptibility and dysfunctional circadian rhythm. Am J Med Genet Part B Neuropsychiatr Genet. 2008;147B:1047–55.

    CAS  Google Scholar 

  161. 161.

    Mancuso M, Orsucci D, Ienco EC, Pini E, Choub A, Siciliano G. Psychiatric involvement in adult patients with mitochondrial disease. Neurol Sci. 2013;34:71–4.

    PubMed  Google Scholar 

  162. 162.

    Kasahara T, Ishiwata M, Kakiuchi C, Fuke S, Iwata N, Ozaki N, et al. Enrichment of deleterious variants of mitochondrial DNA polymerase gene (POLG1) in bipolar disorder. Psychiatry Clin Neurosci. 2017;71:518–29.

    CAS  PubMed  Google Scholar 

  163. 163.

    Mertens J, Wang Q-W, Kim Y, Yu DX, Pham S, Yang B, et al. Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature. 2015;527:95–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164.

    Sequeira A, Martin MV, Rollins B, Moon EA, Bunney WE, Macciardi F, et al. Mitochondrial mutations and polymorphisms in psychiatric disorders. Front Genet. 2012;3:103. https://doi.org/10.3389/fgene.2012.00103.

    PubMed  PubMed Central  Google Scholar 

  165. 165.

    Craddock N, Jones I. Genetics of bipolar disorder. J Med Genet. 1999;36:585–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166.

    Zuk O, Hechter E, Sunyaev SR, Lander ES. The mystery of missing heritability: genetic interactions create phantom heritability. Proc Natl Acad Sci USA. 2012;109:1193–8.

    CAS  PubMed  Google Scholar 

  167. 167.

    Visscher PM, Hill WG, Wray NR. Heritability in the genomics era—concepts and misconceptions. Nat Rev Genet. 2008;9:255–66.

    CAS  PubMed  Google Scholar 

  168. 168.

    Song J, Bergen SE, Kuja-Halkola R, Larsson H, Landén M, Lichtenstein P. Bipolar disorder and its relation to major psychiatric disorders: a family-based study in the Swedish population. Bipolar Disord. 2014;17:184–93.

    PubMed  Google Scholar 

  169. 169.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  170. 170.

    Stahl E, Forstner A, McQuillin A, Ripke S, Bipolar Disorder Working Group of the Psychiatric Genetics Consortium, Ophoff R. et al. Genomewide association study identifies 30 loci associated with bipolar disorder. Nat Genet. 2019;51:793–803.

    CAS  PubMed  PubMed Central  Google Scholar 

  171. 171.

    Girirajan S, Rosenfeld JA, Cooper GM, Antonacci F, Siswara P, Itsara A, et al. A recurrent 16p12. 1 microdeletion supports a two-hit model for severe developmental delay. Nat Genet. 2010;42:203–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  172. 172.

    McGue M, Gottesman II, Rao DC. The transmission of schizophrenia under a multifactorial threshold model. Am J Hum Genet. 1983;35:1161–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173.

    Feder A, Nestler EJ, Charney DS. Psychobiology and molecular genetics of resilience. Nat Rev Neurosci. 2009;10:446–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174.

    McGrath LM, Cornelis MC, Lee PH, Robinson EB, Duncan LE, Barnett JH, et al. Genetic predictors of risk and resilience in psychiatric disorders: a cross-disorder genome-wide association study of functional impairment in major depressive disorder, bipolar disorder, and schizophrenia. Am J Med Genet Part B. 2013;162B:779–88.

    PubMed  Google Scholar 

  175. 175.

    Boyle EA, Li YI, Pritchard JK. An expanded view of complex traits: from polygenic to omnigenic. Cell. 2017;169:1177–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 176.

    Hosang GM, Fisher HL, Cohen-Woods S, McGuffin P, Farmer AE. Stressful life events and catechol-O-methyl-transferase (COMT) gene in bipolar disorder. Depress Anxiety. 2017;34:419–26.

    CAS  PubMed  Google Scholar 

  177. 177.

    Oliveira J, Etain B, Lajnef M, Hamdani N, Bennabi M, Bengoufa D, et al. Combined effect of TLR2 gene polymorphism and early life stress on the age at onset of bipolar disorders. PloS ONE. 2015;10:e0119702. https://doi.org/10.1371/journal.pone.0119702.

    PubMed  PubMed Central  Google Scholar 

  178. 178.

    Hosang GM, Uher R, Keers R, Cohen-Woods S, Craig I, Korszun A, et al. Stressful life events and the brain-derived neurotrophic factor gene in bipolar disorder. J Affect Disord. 2010;125:345–9.

    CAS  PubMed  Google Scholar 

  179. 179.

    Miller S, Hallmayer J, Wang PW, Hill SJ, Johnson SL, Ketter TA. Brain-derived neurotrophic factor val66met genotype and early life stress effects upon bipolar course. J Psychiatr Res. 2013;47:252–8.

    PubMed  Google Scholar 

  180. 180.

    Zeni CP, Mwangi B, Cao B, Hasan KM, Walss-Bass C, Zunta-Soares G, et al. Interaction between BDNF rs6265 Met allele and low family cohesion is associated with smaller left hippocampal volume in pediatric bipolar disorder. J Affect Disord. 2016;189:94–7.

    CAS  PubMed  Google Scholar 

  181. 181.

    Bulik-Sullivan B, Finucane HK, Anttila V, Gusev A, Day FR, Loh P-R, et al. An atlas of genetic correlations across human diseases and traits. Nat Genet. 2015;47:1236–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  182. 182.

    Middeldorp CM, de Moor MH, McGrath LM, Gordon SD, Blackwood DH, Costa PT, et al. The genetic association between personality and major depression or bipolar disorder. A polygenic score analysis using genome-wide association data. Transl Psychiatry. 2011;1:e50. https://doi.org/10.1038/tp.2011.45.

    PubMed  PubMed Central  Google Scholar 

  183. 183.

    Huang J, Perlis RH, Lee PH, Rush AJ, Fava M, Sachs GS, et al. Cross-disorder genomewide analysis of schizophrenia, bipolar disorder, and depression. Am J Psychiatry. 2010;167:1254–63.

    PubMed  Google Scholar 

  184. 184.

    Weber H, Kittel-Schneider S, Gessner A, Domschke K, Neuner M, Jacob CP, et al. Cross-disorder analysis of bipolar risk genes: further evidence of DGKH as a risk gene for bipolar disorder, but also unipolar depression and adult ADHD. Neuropsychopharmacology. 2011;36:2076–85.

    PubMed  PubMed Central  Google Scholar 

  185. 185.

    O’Brien HE, Hannon E, Hill MJ, Toste CC, Robertson MJ, Morgan JE, et al. Expression quantitative trait loci in the developing human brain and their enrichment in neuropsychiatric disorders. Genome Biol. 2018;19:194. https://doi.org/10.1186/s13059-018-1567-1.

    PubMed  PubMed Central  Google Scholar 

  186. 186.

    Power RA, Steinberg S, Bjornsdottir G, Rietveld CA, Abdellaoui A, Nivard MM, et al. Polygenic risk scores for schizophrenia and bipolar disorder predict creativity. Nat Neurosci. 2015;18:953–5.

    CAS  PubMed  Google Scholar 

  187. 187.

    Kyaga S, Lichtenstein P, Boman M, Landén M. Bipolar disorder and leadership–a total population study. Acta Psychiatr Scand. 2015;131:111–9.

    CAS  PubMed  Google Scholar 

  188. 188.

    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;21:1290–7.

    CAS  PubMed  Google Scholar 

  189. 189.

    Anghelescu I, Dettling M. Variant GADL1 and response to lithium in bipolar I disorder. N Engl J Med. 2014;370.

  190. 190.

    Ikeda M, Kondo K, Iwata N. Variant GADL1 and response to lithium in bipolar I disorder. N. Engl J Med. 2014;370:1856–7.

    PubMed  Google Scholar 

  191. 191.

    Lee CS, Cheng AT. Variant GADL1 and response to lithium in bipolar I disorder. N Engl J Med. 2014;370:1859–60.

    CAS  PubMed  Google Scholar 

  192. 192.

    Chung W-H, Hung S-I, Hong H-S, Hsih M-S, Yang L-C, Ho H-C, et al. Medical genetics: a marker for Stevens–Johnson syndrome. Nature. 2004;428:486.

    CAS  PubMed  Google Scholar 

  193. 193.

    McCormack M, Alfirevic A, Bourgeois S, Farrell JJ, Kasperavičiūtė D, Carrington M, et al. HLA-A* 3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med. 2011;364:1134–43.

    CAS  PubMed  Google Scholar 

  194. 194.

    Li X, Yu K, Mei S, Huo J, Wang J, Zhu Y, et al. HLA-B*1502 increases the risk of phenytoin or lamotrigine induced stevens-johnson syndrome/toxic epidermal necrolysis: evidence from a meta-analysis of nine case-control studies. Drug Res Stuttg. 2014. https://doi.org/10.1055/s-0034-1375684. 28 May 2014.

    Article  PubMed  Google Scholar 

  195. 195.

    Amstutz U, Shear NH, Rieder MJ, Hwang S, Fung V, Nakamura H, et al. Recommendations for HLA-B*15:02 and HLA-A*31:01 genetic testing to reduce the risk of carbamazepine-induced hypersensitivity reactions. Epilepsia. 2014;55:496–506.

    CAS  PubMed  Google Scholar 

  196. 196.

    Charney AW, Ruderfer DM, Stahl EA, Moran JL, Chambert K, Belliveau RA, et al. Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder. Transl Psychiatry. 2017;7:e993. https://doi.org/10.1038/tp.2016.242.

    CAS  PubMed  PubMed Central  Google Scholar 

  197. 197.

    Allardyce J, Leonenko G, Hamshere M, Pardinas A, 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.

    PubMed  Google Scholar 

  198. 198.

    Mathew I, Gardin TM, Tandon N, Eack S, Francis AN, Seidman LJ, et al. Medial temporal lobe structures and hippocampal subfields in psychotic disorders: findings from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study. JAMA Psychiatry. 2014;71:769–77.

    PubMed  Google Scholar 

  199. 199.

    Emsell L, Leemans A, Langan C, Van Hecke W, Barker GJ, McCarthy P, et al. Limbic and callosal white matter changes in euthymic bipolar I disorder: an advanced diffusion magnetic resonance imaging tractography study. Biol Psychiatry. 2013;73:194–201.

    PubMed  Google Scholar 

  200. 200.

    Liu X, Akula N, Skup M, Brotman MA, Leibenluft E, McMahon FJ. A genome-wide association study of amygdala activation in youths with and without bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2010;49:33–41.

    Google Scholar 

  201. 201.

    Meda SA, Ruano G, Windemuth A, O’Neil K, Berwise C, Dunn SM, et al. Multivariate analysis reveals genetic associations of the resting default mode network in psychotic bipolar disorder and schizophrenia. Proc Natl Acad Sci USA. 2014;111:E2066–75.

    CAS  PubMed  Google Scholar 

  202. 202.

    Fears SC, Service SK, Kremeyer B, Araya C, Araya X, Bejarano J, et al. Multisystem component phenotypes of bipolar disorder for genetic investigations of extended pedigrees. JAMA Psychiatry. 2014;71:375–87.

    PubMed  PubMed Central  Google Scholar 

  203. 203.

    Cardenas SA, Kassem L, Brotman MA, Leibenluft E, McMahon FJ. Neurocognitive functioning in euthymic patients with bipolar disorder and unaffected relatives: a review of the literature. Neurosci Biobehav Rev. 2016;69:193–215.

    PubMed  PubMed Central  Google Scholar 

  204. 204.

    Glahn DC, Winkler AM, Kochunov P, Almasy L, Duggirala R, Carless MA, et al. Genetic control over the resting brain. Proc Natl Acad Sci USA. 2010;107:1223–8.

    CAS  PubMed  Google Scholar 

  205. 205.

    Tamminga CA, Pearlson GD, Stan AD, Gibbons RD, Padmanabhan J, Keshavan M, et al. Strategies for advancing disease definition using biomarkers and genetics: the bipolar and schizophrenia network for intermediate phenotypes. Biol Psychiatry Cogn Neurosci Neuroimaging. 2017;2:20–7.

    Google Scholar 

  206. 206.

    Muffat J, Li Y, Jaenisch R. CNS disease models with human pluripotent stem cells in the CRISPR age. Curr Opin Cell Biol. 2016;43:96–103.

    CAS  PubMed  Google Scholar 

  207. 207.

    O’Shea KS, McInnis MG. Induced pluripotent stem cell (iPSC) models of bipolar disorder. Neuropsychopharmacol Publ Am Coll Neuropsychopharmacol. 2015;40:248–9.

    Google Scholar 

  208. 208.

    O’shea KS, McInnis MG. Neurodevelopmental origins of bipolar disorder: iPSC models. Mol Cell Neurosci. 2016;73:63–83.

    PubMed  Google Scholar 

  209. 209.

    Stern S, Santos R, Marchetto MC, Mendes APD, Rouleau GA, Biesmans S, et al. Neurons derived from patients with bipolar disorder divide into intrinsically different sub-populations of neurons, predicting the patients’ responsiveness to lithium. Mol Psychiatry. 2017. https://doi.org/10.1038/mp.2016.260.

    PubMed  PubMed Central  Google Scholar 

  210. 210.

    Schulze TG, McMahon FJ. Defining the phenotype in human genetic studies: forward genetics and reverse phenotyping. Hum Hered. 2004;58:131–8.

    PubMed  Google Scholar 

  211. 211.

    Stessman HA, Bernier R, Eichler EE. A genotype-first approach to defining the subtypes of a complex disease. Cell. 2014;156:872–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  212. 212.

    Raznahan A. Genetics-first approaches in biological psychiatry. Biol Psychiatry. 2018;84:234–5.

    PubMed  Google Scholar 

  213. 213.

    Geschwind DH, State MW. Gene hunting in autism spectrum disorder: on the path to precision medicine. Lancet Neurol. 2015;14:1109–20.

    PubMed  PubMed Central  Google Scholar 

  214. 214.

    Stefansson H, Meyer-Lindenberg A, Steinberg S, Magnusdottir B, Morgen K, Arnarsdottir S, et al. CNVs conferring risk of autism or schizophrenia affect cognition in controls. Nature. 2014;505:361–6.

    CAS  PubMed  Google Scholar 

  215. 215.

    Raznahan A, Cutter W, Lalonde F, Robertson D, Daly E, Conway GS, et al. Cortical anatomy in human X monosomy. NeuroImage. 2010;49:2915–23.

    PubMed  Google Scholar 

  216. 216.

    Hoeffding LK, Trabjerg BB, Olsen L, Mazin W, Sparsø T, Vangkilde A, et al. Risk of psychiatric disorders among individuals with the 22q11. 2 deletion or duplication: a Danish nationwide, register-based study. JAMA Psychiatry. 2017;74:282–90.

    PubMed  Google Scholar 

  217. 217.

    Gur R, Yi J, Tang S, Calkins M, Moore T, Schmitt J, et al. Psychosis risk in 22q11. 2 deletion syndrome: findings from the Philadelphia sample. Eur Neuropsychopharmacol. 2017;27:S480.

    Google Scholar 

  218. 218.

    Sahoo T, Theisen A, Rosenfeld JA, Lamb AN, Ravnan JB, Schultz RA, et al. Copy number variants of schizophrenia susceptibility loci are associated with a spectrum of speech and developmental delays and behavior problems. Genet Med. 2011;13:868–80.

    PubMed  PubMed Central  Google Scholar 

  219. 219.

    D’Angelo D, Lebon S, Chen Q, Martin-Brevet S, Snyder LG, Hippolyte L, et al. Defining the effect of the 16p11.2 duplication on cognition, behavior, and medical comorbidities. JAMA Psychiatry. 2016;73:20–30.

    PubMed  PubMed Central  Google Scholar 

  220. 220.

    Tobe BTD, Brandel MG, Nye JS, Snyder EY. Implications and limitations of cellular reprogramming for psychiatric drug development. Exp Mol Med. 2013;45:e59. https://doi.org/10.1038/emm.2013.124.

    PubMed  PubMed Central  Google Scholar 

  221. 221.

    Schadt EE, Buchanan S, Brennand KJ, Merchant KM. Evolving toward a human-cell based and multiscale approach to drug discovery for CNS disorders. Front Pharmacol. 2014;5:252. https://doi.org/10.3389/fphar.2014.00252.

    PubMed  PubMed Central  Google Scholar 

  222. 222.

    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;19:1392–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  223. 223.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  224. 224.

    Zhang Y, Qi G, Park J-H, Chatterjee N. Estimation of complex effect-size distributions using summary-level statistics from genome-wide association studies across 32 complex traits. Nat Genet. 2018;50:1318–26.

    CAS  PubMed  Google Scholar 

  225. 225.

    Tan RYY, Markus HS. Genetics and genomics of stroke. In: Kumar D, Elliott P, editors. Cardiovascular genetics and genomics. Principles and clinical practice, pp 695–722. Cham: Springer International Publishing; 2018.

    Google Scholar 

  226. 226.

    McMahon FJ, Akula N, Schulze TG, Muglia P, Tozzi F, Detera-Wadleigh SD, et al. Meta-analysis of genome-wide association data identifies a risk locus for major mood disorders on 3p21.1. Nat Genet. 2010;42:128–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  227. 227.

    Wang K-S, Liu X-F, Aragam N. A genome-wide meta-analysis identifies novel loci associated with schizophrenia and bipolar disorder. Schizophr Res. 2010;124:192–9.

    PubMed  Google Scholar 

  228. 228.

    Fabbri C, Serretti A. Pharmacogenetics of major depressive disorder: top genes and pathways toward clinical applications. Curr Psychiatry Rep. 2015;17:1–11.

    CAS  Google Scholar 

  229. 229.

    Green EK, Grozeva D, Forty L, Gordon-Smith K, Russell E, Farmer A, et al. Association at SYNE1 in both bipolar disorder and recurrent major depression. Mol Psychiatry. 2013;18:614–7.

    CAS  PubMed  Google Scholar 

  230. 230.

    Kerner B, Lambert CG, Muthen BO. Genome-wide association study in bipolar patients stratified by co-morbidity. PLoS ONE. 2011;6:e28477. https://doi.org/10.1371/journal.pone.0028477.

    CAS  PubMed  PubMed Central  Google Scholar 

  231. 231.

    Jiang Y, Zhang H. Propensity score-based nonparametric test revealing genetic variants underlying bipolar disorder. Genet Epidemiol. 2011;35:125–32.

    PubMed  PubMed Central  Google Scholar 

  232. 232.

    Cichon S, Mühleisen TW, Degenhardt FA, Mattheisen M, Miró X, Strohmaier J, et al. Genome-wide association study identifies genetic variation in neurocan as a susceptibility factor for bipolar disorder. Am J Hum Genet. 2011;88:372–81.

    CAS  PubMed  PubMed Central  Google Scholar 

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This study was supported by the Intramural Research Program of the NIMH.

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Gordovez, F.J.A., McMahon, F.J. The genetics of bipolar disorder. Mol Psychiatry 25, 544–559 (2020). https://doi.org/10.1038/s41380-019-0634-7

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