Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Genetic substrates of bipolar disorder risk in Latino families

Molecular Psychiatry volume 28, pages 154–167 (2023)Cite this article

Subjects

Abstract

Genetic studies of bipolar disorder (BP) have been conducted in the Latin American population, to date, in several countries, including Mexico, the United States, Costa Rica, Colombia, and, to a lesser extent, Brazil. These studies focused primarily on linkage-based designs utilizing families with multiplex cases of BP. Significant BP loci were identified on Chromosomes 18, 5 and 8, and fine mapping suggested several genes of interest underlying these linkage peaks. More recently, studies in these same pedigrees yielded significant linkage loci for BP endophenotypes, including measures of activity, sleep cycles, and personality traits. Building from findings in other populations, candidate gene association analyses in Latinos from Mexican and Central American ancestry confirmed the role of several genes (including CACNA1C and ANK3) in conferring BP risk. Although GWAS, methylation, and deep sequencing studies have only begun in these populations, there is evidence that CNVs and rare SNPs both play a role in BP risk of these populations. Large segments of the Latino populations in the Americas remain largely unstudied regarding BP genetics, but evidence to date has shown that this type of research can be successfully conducted in these populations and that the genetic underpinnings of BP in these cohorts share at least some characteristics with risk genes identified in European and other populations.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Merikangas KR, Jin R, He JP, 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.

    Google Scholar 

  2. American Psychiatric Association. Bipolar and Related Disorders. Desk Reference to the Diagnostic Criteria from DSM-5 1000 Wilson Boulevard, Arlington, VA 22209-3901: American Psychiatric Association; 2013.p.169–76.

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

    Google Scholar 

  4. Cardno AG, Rijsdijk FV, Sham PC, Murray RM, McGuffin P. A twin study of genetic relationships between psychotic symptoms. Am J Psychiatry. 2002;159:539–45.

    Google Scholar 

  5. Gershon ES, Hamovit J, Guroff JJ, Dibble E, Leckman JF, Sceery W, et al. A family study of schizoaffective, bipolar I, bipolar II, unipolar, and normal control probands. Arch Gen Psychiatry. 1982;39:1157–67.

    CAS  Google Scholar 

  6. Andreasen NC, Rice J, Endicott J, Coryell W, Grove WM, Reich T. Familial rates of affective disorder. A report from the National Institute of Mental Health Collaborative Study. Arch Gen Psychiatry. 1987;44:461–9.

    CAS  Google Scholar 

  7. Dunayevich E, Keck PE Jr. Prevalence and description of psychotic features in bipolar mania. Curr Psychiatry Rep. 2000;2:286–90.

    CAS  Google Scholar 

  8. Worldometer. Population of Latin America and the Caribbean. 2022; Available at: worldometers.info. Accessed April 16, 2022.

  9. Campos-Sánchez R, Barrantes R, Silva S, Escamilla M, Ontiveros A, Nicolini H, et al. Genetic Structure Analysis of Three Hispanic Populations from Costa Rica, Mexico, and the Southwestern United States Using Y-Chromosome STR Markers and mtDNA Sequences. Hum Biol. 2006;78:551–63.

    Google Scholar 

  10. Little B. The Evolution and Genetics of Latin American Populations. Cambridge Studies in Biological and Evolutionary Anthropology, Volume 28. By Francisco M Salzano and, Maria Cátira Bortolini. Cambridge and New York: Cambridge University Press. $90.00. xvi + 512 p; ill.; author and subject indexes. ISBN: 0– 521–65275–8. 2002. Q Rev Biol. 2004;79:116–116.

    Google Scholar 

  11. Popejoy AB, Fullerton SM. Genomics is failing on diversity. Nature. 2016;538:161–4.

    CAS  Google Scholar 

  12. Gusella JF, Wexler NS, Conneally PM, Naylor SL, Anderson MA, Tanzi RE, et al. A polymorphic DNA marker genetically linked to Huntington’s disease. Nature. 1983;306:234–8.

    CAS  Google Scholar 

  13. Sofer T, Baier LJ, Browning SR, Thornton TA, Talavera GA, Wassertheil-Smoller S, et al. Admixture mapping in the Hispanic Community Health Study/Study of Latinos reveals regions of genetic associations with blood pressure traits. PLoS One. 2017;12:e0188400.

    Google Scholar 

  14. Glahn DC, Nimgaonkar VL, Raventós H, Contreras J, McIntosh AM, Thomson PA, et al. Rediscovering the value of families for psychiatric genetics research. Mol Psychiatry. 2019;24:523–35.

    Google Scholar 

  15. Escamilla MA. Population isolates: Their special value for locating genes for bipolar disorder: Population isolates and bipolar. Bipolar Disord. 2001;3:299–317.

    CAS  Google Scholar 

  16. Gonzalez S, Camarillo C, Rodriguez M, Ramirez M, Zavala J, Armas R, et al. A genome‐wide linkage scan of bipolar disorder in Latino families identifies susceptibility loci at 8q24 and 14q32. Am J Med Genet Part B, Neuropsychiatr Genet; Am J Med Genet B Neuropsychiatr Genet. 2014;165:479–91.

    CAS  Google Scholar 

  17. Bigdeli TB, Fanous AH, Li Y, Rajeevan N, Sayward F, Genovese G, et al. Genome-Wide Association Studies of Schizophrenia and Bipolar Disorder in a Diverse Cohort of US Veterans. Schizophrenia Bull. 2021;47:517–29.

    Google Scholar 

  18. Fonseca L, Sena BF, Crossley N, Lopez-Jaramillo C, Koenen K, Freimer NB, et al. Diversity matters: opportunities in the study of the genetics of psychotic disorders in low- and middle-income countries in Latin America. Braz J Psychiatry. Special article. 2020;0:1–7.

  19. Kim MS, Patel KP, Teng AK, Berens AJ, Lachance J. Genetic disease risks can be misestimated across global populations. Genome Biol. 2018;19:179–179.

    Google Scholar 

  20. Pato MT, Sobell JL, Medeiros H, Abbott C, Sklar BM, Buckley PF, et al. The genomic psychiatry cohort: partners in discovery. Am J Med Genet B Neuropsychiatr Genet. 2013;162B:306–12.

    Google Scholar 

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

    Google Scholar 

  22. Camarena B, Atkinson EG, Baker M, Becerra-Palars C, Chibnik LB, Escamilla-Orozco R, et al. Neuropsychiatric Genetics of Psychosis in the Mexican Population: A Genome-Wide Association Study Protocol for Schizophrenia, Schizoaffective, and Bipolar Disorder Patients and Controls. Complex Psychiatry 2021. https://doi.org/10.1159/000518926.

  23. Gottesman II, Gould TD. The endophenotype concept in psychiatry: Etymology and strategic intentions. Am J Psychiatry. 2003;160:636–45.

    Google Scholar 

  24. McInnes LA, Escamilla MA, Service SK, Reus V, 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 - PNAS. 1996;93:13060–5.

    CAS  Google Scholar 

  25. Freimer N, Reus V, Escamilla M, McInnes A, Spesny M, Leon P, et al. Genetic mapping using haplotype, association and linkage methods suggests a locus for severe bipolar disorder (BPI) at 18q22-q23. Nat Genet. 1996;12:436–41.

    CAS  Google Scholar 

  26. Garner C, McInnes LA, Service SK, Spesny M, Fournier E, Leon P, et al. Linkage analysis of a complex pedigree with severe bipolar disorder, using a Markov Chain Monte Carlo method. Am J Hum Genet. 2001;68:1061–4.

    CAS  Google Scholar 

  27. Herzberg I, Jasinska A, Carvajal L, Polanco G, Restrepo GJ, Lopez C, et al. Convergent linkage evidence from two Latin-American population isolates supports the presence of a susceptibility locus for bipolar disorder in 5q31 −34. Hum Mol Genet. 2006;15:3146–53.

    CAS  Google Scholar 

  28. Service S, Molina J, DeYoung J, Jawaheer D, Aldana I, Vu T, et al. Results of a SNP genome screen in a large Costa Rican pedigree segregating for severe bipolar disorder. Am J Med Genet Part B, Neuropsychiatr Genet; Am J Med Genet B Neuropsychiatr Genet. 2006;141B:367–73.

    Google Scholar 

  29. Hong KS, McInnes LA, Service SK, Song T, Lucas J, Silva S, et al. Genetic mapping using haplotype and model‐free linkage analysis supports previous evidence for a locus predisposing to severe bipolar disorder at 5q31‐33. Am J Med Genet Part B, Neuropsychiatr Genet; Am J Med Genet B Neuropsychiatr Genet. 2004;125B:83–86.

    Google Scholar 

  30. Escamilla MA, McInnes LA, Spesny M, Reus VI, Service SK, Shimayoshi N, et al. Assessing the Feasibility of Linkage Disequilibrium Methods for Mapping Complex Traits: An Initial Screen for Bipolar Disorder Loci on Chromosome 18. Am J Hum Genet. 1999;64:1670–8.

    CAS  Google Scholar 

  31. Escamilla MA, McInnes LA, Service SK, Spesny M, Reus VI, Molina J, et al. Genome screening for linkage disequilibrium in a Costa Rican sample of patients with bipolar‐I disorder: A follow‐up study on chromosome 18. Am J Med Genet. 2001;105:207–13.

    CAS  Google Scholar 

  32. Ophoff RA, Escamilla MA, Service SK, Spesny M, Meshi DB, Poon W, et al. Genomewide linkage disequilibrium mapping of severe bipolar disorder in a population isolate. Am J Hum Genet. 2002;71:565–74.

    CAS  Google Scholar 

  33. Walss-Bass C, Escamilla MA, Raventos H, Montero AP, Armas R, Dassori A, et al. Evidence of genetic overlap of schizophrenia and bipolar disorder: Linkage disequilibrium analysis of chromosome 18 in the Costa Rican population. Am J Med Genet B. 2005;139B:54–60.

    CAS  Google Scholar 

  34. Escamilla M, Lee BD, Ontiveros A, Raventos H, Nicolini H, Mendoza R, et al. The epsin 4 gene is associated with psychotic disorders in families of Latin American origin. Schizophr Res. 2008;106:253–7.

    Google Scholar 

  35. Jasinska AJ, Service S, Jawaheer D, DeYoung J, Levinson M, Zhang Z, et al. A narrow and highly significant linkage signal for severe bipolar disorder in the chromosome 5q33 region in Latin American pedigrees. American journal of medical genetics.Part B, Neuropsychiatric genetics. Am J Med Genet B Neuropsychiatr Genet. 2009;150B:998–1006.

    CAS  Google Scholar 

  36. Kremeyer B, García J, Müller H, Burley MW, Herzberg I, Parra MV, et al. Genome-Wide Linkage Scan of Bipolar Disorder in a Colombian Population Isolate Replicates Loci on Chromosomes 7p21–22, 1p31, 16p12 and 21q21–22 and Identifies a Novel Locus on Chromosome 12q. Hum Hered. 2010;70:255–68.

    CAS  Google Scholar 

  37. Gonzalez S, Villa E, Rodriguez M, Ramirez M, Zavala J, Armas R, et al. Fine‐mapping scan of bipolar disorder susceptibility loci in Latino pedigrees. Am J Med Genet Part B, Neuropsychiatr Genet; Am J Med Genet B Neuropsychiatr Genet. 2019;180:213–22.

    CAS  Google Scholar 

  38. Cai N, Revez JA, Adams MJ, Andlauer TFM, Breen G, Byrne EM, et al. Minimal phenotyping yields genome-wide association signals of low specificity for major depression. Nat Genet. 2020;52:437–47.

    CAS  Google Scholar 

  39. Gonzalez SD, Xu C, Ramirez ME, Zavala JM, Armas R, Contreras SA, et al. Family-based association of an ANK3 haplotype with bipolar disorder in Latino populations. Translational psychiatry. Transl Psychiatry. 2013;3:e265–e265.

    CAS  Google Scholar 

  40. Gonzalez SD, Xu C, Ramirez M, Zavala J, Armas R, Contreras SA, et al. Suggestive evidence for association between L‐type voltage‐gated calcium channel (CACNA1C) gene haplotypes and bipolar disorder in Latinos: a family‐ based association study. Bipolar Disord. 2013;15:206–14.

    CAS  Google Scholar 

  41. Gonzalez SD, Gupta J, Villa E, Mallawaarachchi I, Rodriguez M, Ramirez M, et al. Replication of genome‐wide association study (GWAS) susceptibility loci in a Latino bipolar disorder cohort. Bipolar Disord. 2016;18:520–7.

    CAS  Google Scholar 

  42. Walss‐Bass C, Raventos H, Montero AP, Armas R, Dassori A, Contreras S, et al. Association analyses of the neuregulin 1 gene with schizophrenia and manic psychosis in a Hispanic population. Acta Psychiatr Scand. 2006;113:314–21.

    Google Scholar 

  43. 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 USA 2001;98:11485–90.

    CAS  Google Scholar 

  44. Gonzalez R, Gonzalez S, Villa E, Ramirez M, Zavala J, Armas R, et al. Identification of circadian gene variants in bipolar disorder in Latino populations. J Affect Disord. 2015;186:367–75.

    CAS  Google Scholar 

  45. Cordeiro Q, Souza BR, Correa H, Guindalini C, Hutz MH, Vallada H, et al. A review of psychiatric genetics research in the Brazilian population. Rev brasileira de psiquiatria; Braz J Psychiatry. 2009;31:154–62.

    Google Scholar 

  46. Meira-Lima I, Pereira AC, Mota GFA, Krieger JE, Vallada H. Angiotensinogen and angiotensin converting enzyme gene polymorphisms and the risk of bipolar affective disorder in humans. Neurosci Lett. 2000;293:103–6.

    CAS  Google Scholar 

  47. Cordeiro Q, Talkowski ME, Chowdari KV, Wood J, Nimgaonkar V, Vallada H. Association and linkage analysis of RGS4 polymorphisms with schizophrenia and bipolar disorder in Brazil. Genes, brain and behavior. Genes Brain Behav. 2005;4:45–50.

    CAS  Google Scholar 

  48. Gordovez FJA, McMahon FJ. The genetics of bipolar disorder. Mol Psychiatry. 2020;25:544–59.

    Google Scholar 

  49. 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.

    Google Scholar 

  50. Vega-Sevey J, Martínez-Magaña JJ, Genis-Mendoza A, Escamilla M, Lanzagorta N, Tovilla-Zarate C, et al. Copy number variants in siblings of Mexican origin concordant for schizophrenia or bipolar disorder. Psychiatry Res. 2020;291:113018–113018.

    CAS  Google Scholar 

  51. Andlauer TFM, Guzman-Parra J, Streit F, Strohmaier J, González MJ, Gil Flores S, et al. Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders. Mol Psychiatry. 2019;26:1286–98.

    Google Scholar 

  52. Moore LD, Le T, Fan G. DNA methylation and its basic function. Neuropsychopharmacology. 2013;38:23–38.

    CAS  Google Scholar 

  53. Gunasekara CJ, Scott CA, Laritsky E, Baker MS, MacKay H, Duryea JD, et al. A genomic atlas of systemic interindividual epigenetic variation in humans. Genome Biol. 2019;20:105–105.

    Google Scholar 

  54. 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.

    Google Scholar 

  55. Li Y, Camarillo C, Xu J, Arana TB, Xiao Y, Zhao Z, et al. Genome-Wide Methylome Analyses Reveal Novel Epigenetic Regulation Patterns in Schizophrenia and Bipolar Disorder. Biomed Res Int. 2015;2015:201587–15.

    Google Scholar 

  56. Fries GR, Bauer IE, Scaini G, Wu M, Kazimi IF, Valvassori SS, et al. Accelerated epigenetic aging and mitochondrial DNA copy number in bipolar disorder. Transl Psychiatry; Transl Psychiatry. 2017;7:1283–10.

    Google Scholar 

  57. Glahn DC, Almasy L, Barguil M, Hare E, Peralta JM, Kent JW Jr, et al. Neurocognitive endophenotypes for bipolar disorder identified in multiplex multigenerational families. Arch Gen Psychiatry. 2010;67:168–77.

    Google Scholar 

  58. 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 (Chic, Ill); JAMA Psychiatry. 2014;71:375–87.

    Google Scholar 

  59. Fears SC, Schür R, Sjouwerman R, Service SK, Araya C, Araya X, et al. Brain structure-function associations in multi-generational families genetically enriched for bipolar disorder. Brain. 2015;138:2087–102.

    Google Scholar 

  60. Sandoval H, Soares JC, Mwangi B, Asonye S, Alvarado LA, Zavala J, et al. Confirmation of MRI anatomical measurements as endophenotypic markers for bipolar disorder in a new sample from the NIMH Genetics of Bipolar Disorder in Latino Populations study. Psychiatry Res Neuroimaging. 2015;247:34–41.

    Google Scholar 

  61. Knowles E, Meikle P, Huynh K, Goring H, Olvera R, Mathias S, et al. Serum Phosphatidylinositol as a Biomarker For Bipolar Disorder Liability. Eur Neuropsychopharmacol. 2017;27:S452–S453.

    Google Scholar 

  62. Pagani L, Patricia A, St. Clair, Teshiba TM, Service SK, Fears SC, 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–E761.

    CAS  Google Scholar 

  63. Lee BD, Gonzalez S, Villa E, Camarillo C, Rodriguez M, Yao Y, et al. A genome‐wide quantitative trait locus (QTL) linkage scan of NEO personality factors in Latino families segregating bipolar disorder. American journal of medical genetics.Part B, Neuropsychiatric genetics. Am J Med Genet B Neuropsychiatr Genet. 2017;174:683–90.

    CAS  Google Scholar 

  64. Vreeker A, Fears SC, Service SK, Pagani L, Takahashi JS, Araya C, et al. Genetic analysis of activity, brain and behavioral associations in extended families with heavy genetic loading for bipolar disorder. Psychol Med. 2021;51:494–502.

    Google Scholar 

  65. Fears SC, Service SK, Kremeyer B, Araya C, Araya X, Bejarano J, et al. Genome-wide mapping of brain phenotypes in extended pedigrees with strong genetic loading for bipolar disorder. Mol Psychiatry. 2021;26:5229–38.

  66. Carless MA, Glahn DC, Duggirala R, Moses EK, Göring H, Blangero J, et al. Impact of DISC1 variation on neuroanatomical and neurocognitive phenotypes. Mol Psychiatry. 2011;16:1096–104.

    CAS  Google Scholar 

  67. Carmiol N, Peralta JM, Almasy L, Contreras J, Pacheco A, Escamilla MA, et al. Shared genetic factors influence risk for bipolar disorder and alcohol use disorders. Eur Psychiat. 2013;29:282–7.

    Google Scholar 

  68. Knowles EEM, Carless MA, de Almeida MAA, Curran JE, McKay DR, Sprooten E, et al. Genome-wide significant localization for working and spatial memory: Identifying genes for psychosis using models of cognition. Am J Med Genet B. 2014;165B:84–95.

    Google Scholar 

  69. 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  Google Scholar 

  70. Pulit SL, Voight BF, de Bakker PIW. Multiethnic genetic association studies improve power for locus discovery. PLoS One; PLoS One. 2010;5:e12600–e12600.

    Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge the support of the Valley Baptist Legacy Fund (Harlingen, Texas), the UTRGV School of Medicine and the Texas Higher Education Coordinating Board for support of the authors related to this work.

Author information

Authors and Affiliations

  1. Departments of Psychiatry and Human Genetics, University of Texas Rio Grande Valley School of Medicine, Harlingen, TX, USA

    Michael Escamilla

  2. Department of Psychiatry and Behavioral Sciences, University of Minnesota Medical School, Minneapolis, MN, USA

    Camille Merhi

Authors
  1. Michael Escamilla
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Camille Merhi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ME and CM both participated in writing and compilation of information used in this article.

Corresponding author

Correspondence to Michael Escamilla.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Escamilla, M., Merhi, C. Genetic substrates of bipolar disorder risk in Latino families. Mol Psychiatry 28, 154–167 (2023). https://doi.org/10.1038/s41380-022-01705-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-022-01705-5

Search

Advanced search

Quick links