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Biomarkers in first-degree relatives of patients with bipolar disorder: what can they tell us?

The study of subjects at increased risk of bipolar disorder (BD), such as first-degree relatives of patients, is a highly relevant and informative approach for investigation of the mechanisms involved in BD risk and onset. Because biological siblings of patients with BD, for example, share part of their genetic background with the latter, they are likely to present at least a subset of genetic markers of BD susceptibility. Although the reported heritability of BD is extremely high (70-80%), recent studies have suggested that its multifactorial molecular genetics is determined by several common and rare genetic variants, each with very small penetrance.11. Goes FS. Genetics of bipolar disorder: recent update and future directions. Psychiatr Clin North Am. 2016;39:139-55. Whether these risk markers will lead to onset of illness in susceptible subjects is likely determined by a combination of numerous factors, particularly environmental exposures.

The study by Nery et al.22. Nery FG, Gigante AD, Amaral JA, Fernandes FB, Berutti M, Almeida KM, et al. Serum BDNF levels in unaffected first-degree relatives of patients with bipolar disorder. Rev Bras Psiquiatr. 2016;38:197-200. recently published in Revista Brasileira de Psiquiatria was the first to examine peripheral brain-derived neurotrophic factor (BDNF) levels in unaffected siblings of patients with BD. Their ultimate goal was to investigate whether abnormal expression of this neurotrophin might represent an endophenotype of illness, i.e., a quantitative trait that is intermediate between the disease phenotype and its underlying biological process.33. Bearden CE, Freimer NB. Endophenotypes for psychiatric disorders: ready for primetime? Trends Genet. 2006;22:306-13. Despite their negative results, the study makes use of a clinically well-characterized sample and provides evidence that, contrary to the initial hypothesis, a high genetic risk is not accompanied by altered peripheral BDNF levels in unaffected siblings of patients with BD. This finding was recently replicated in another population of high-risk siblings.44. Vasconcelos-Moreno MP, Fries GR, Gubert C, dos Santos BT, Fijtman A, Sartori J, et al. Telomere length, oxidative stress, inflammation and BDNF levels in siblings of patients with bipolar disorder: implications for accelerated cellular aging. Int J Neuropsychopharmacol. 2017;20:445-54.

The concept and investigation of endophenotypes has emerged as a strategy to overcome methodological difficulties inherent to the classical investigation of complex heterogeneous disorders, such as BD. The traditional definition of endophenotypes states that: i) they should be associated with the illness in the population; ii) they should be heritable and state-independent (i.e., detectable regardless of whether the illness is active); iii) they should co-segregate within families; and iv) they should be detectable in unaffected relatives of patients at a higher rate than in the general population.33. Bearden CE, Freimer NB. Endophenotypes for psychiatric disorders: ready for primetime? Trends Genet. 2006;22:306-13. Because of this, first-degree relatives represent an invaluable population for endophenotype research. In addition, endophenotype-oriented studies of psychiatric disorders are particularly supported by the Research Domains Criteria (RDoC), which has been recently proposed by the National Institute of Mental Health as an alternative to current research approaches.

Finally, the study of first-degree relatives also provides an ideal framework for analysis of the risk/resilience diathesis, considering that their genetic background has been shown to lead to a 10- to 20-fold increased risk of developing BD compared with relatives of healthy individuals. Longitudinal assessments of these individuals through the ages of peak risk of illness onset (15-24 and 45-54 years55. Kroon JS, Wohlfarth TD, Dieleman J, Sutterland AL, Storosum JG, Denys D, et al. Incidence rates and risk factors of bipolar disorder in the general population: a population-based cohort study. Bipolar Disord. 2013;15:306-13.) are particularly warranted, and should not only allow identification of biomarkers and/or environmental factors associated with resilience to BD, but can also provide predictive measures or pinpoint the most relevant prodromal symptoms for those that will ultimately develop a full-blown psychiatric diagnosis.

Acknowledgments

The Translational Psychiatry Program (USA) is funded by the Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth). Laboratório de Neurociências (Brazil) is one of the centers of the National Institute for Molecular Medicine (INCT-MM) and one of the members of Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC). Its research is supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; JQ), Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina (FAPESC; JQ), Instituto Cérebro e Mente (JQ), and Universidade do Extremo Sul Catarinense (UNESC; JQ). JQ is a 1A CNPq Research Fellow.

References

  • 1
    Goes FS. Genetics of bipolar disorder: recent update and future directions. Psychiatr Clin North Am. 2016;39:139-55.
  • 2
    Nery FG, Gigante AD, Amaral JA, Fernandes FB, Berutti M, Almeida KM, et al. Serum BDNF levels in unaffected first-degree relatives of patients with bipolar disorder. Rev Bras Psiquiatr. 2016;38:197-200.
  • 3
    Bearden CE, Freimer NB. Endophenotypes for psychiatric disorders: ready for primetime? Trends Genet. 2006;22:306-13.
  • 4
    Vasconcelos-Moreno MP, Fries GR, Gubert C, dos Santos BT, Fijtman A, Sartori J, et al. Telomere length, oxidative stress, inflammation and BDNF levels in siblings of patients with bipolar disorder: implications for accelerated cellular aging. Int J Neuropsychopharmacol. 2017;20:445-54.
  • 5
    Kroon JS, Wohlfarth TD, Dieleman J, Sutterland AL, Storosum JG, Denys D, et al. Incidence rates and risk factors of bipolar disorder in the general population: a population-based cohort study. Bipolar Disord. 2013;15:306-13.

Publication Dates

  • Publication in this collection
    Sept 2017

History

  • Received
    15 Apr 2017
  • Accepted
    17 Apr 2017
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