Genetics of brain disorders: Research projects
Next-Generation Sequencing Approach to Identify Bipolar Disorder Genes: Ethical and Social Issues
Background
Bipolar Disorder (BD) is a mental disorder characterized by at least two episodes involving clinically significant disturbed mood, energy, and activity. Its prevalence ranges from 0.3% to 1.5% and BD has been ranked seventh among the worldwide causes of non-fatal disease burden. The annual direct and indirect socio-economic costs of BD are estimated at US$45 billion in the USA. Although little is known about the pathogenesis of BD, cumulative evidence suggests contributions from genetic and environmental factors. In spite of the strong genetic-epidemiological support for the role of genes in BD, molecular studies have by and large failed to identify specific genes because of phenotypic and genetic heterogeneity and disease complexity. Most researchers now agree that a more comprehensive approach is necessary.
The failure of genome-wide association studies (GWAS) in BD suggests that common variants in a small subset of genes are not the cause of the disease. Instead, some scientists (Guy Rouleau and colleagues, respectively P.I. and co-investigators in the Next-Generation Sequencing Approach to Identify... Read more
Background
Bipolar Disorder (BD) is a mental disorder characterized by at least two episodes involving clinically significant disturbed mood, energy, and activity. Its prevalence ranges from 0.3% to 1.5% and BD has been ranked seventh among the worldwide causes of non-fatal disease burden. The annual direct and indirect socio-economic costs of BD are estimated at US$45 billion in the USA. Although little is known about the pathogenesis of BD, cumulative evidence suggests contributions from genetic and environmental factors. In spite of the strong genetic-epidemiological support for the role of genes in BD, molecular studies have by and large failed to identify specific genes because of phenotypic and genetic heterogeneity and disease complexity. Most researchers now agree that a more comprehensive approach is necessary.
The failure of genome-wide association studies (GWAS) in BD suggests that common variants in a small subset of genes are not the cause of the disease. Instead, some scientists (Guy Rouleau and colleagues, respectively P.I. and co-investigators in the Next-Generation Sequencing Approach to Identify Bipolar Disorder Genes project) hypothesize that BD is caused by highly penetrant rare variants in a large number of different genes. Studies such as GWAS have relied on genotyping of common variants. However, very high-throughput next-generation sequencing (NGS) technologies have recently become available, allowing entire genomes to be re-sequenced in a matter of days, and providing a detailed snapshot of all variations in a single individual genome. These novel technologies will allow testing the hypothesis of whether rare variants play a role in BD.
Objectives
Our goal is to identify and analyze the ethical issues linked to the Next-Generation Sequencing Approach to Identify Bipolar Disorder Genes project.
Research Plan
Advances in scientific knowledge might affect inevitably the provision of research findings. Existing ethical issues are likely to become even more pressing as susceptibility genes and gene variants are identified for major mental disorders. It behooves researchers, health professionals, and ethics experts to consider how to use our growing scientific knowledge to best help research participants and patients in ways that anticipate and prevent, rather than respond to, ethical conflicts (Biesecker et al., 2003; Burke et al., 2008).
The purpose of our project is:
(A) To serve as an essential advisory group to the leadership of the research team on the Next-Generation Sequencing Approach to Identify Bipolar Disorder Genes project. Our general aims are:
(1) To identify ethical, social, and policy issues encountered in (1.1) Carrying out next-generation sequencing approach to identify bipolar disorder genes; (1.2) Applying that approach in practice;
(2) To identify options to address those issues linked to BD genetics and NGS approach.
In order to identify the issues, we participate in the research project leadership meetings, in an advisory capacity to help anticipate, identify and address ethical issues. During these meetings, our interaction with the research team leaders is to realize: (i) How can the ethics core best be of assistance and (ii) What do they anticipate will be the most important ethics, policy issues for their team?
(B) To design and conduct research to examine specific ethical, legal and policy issues related to the next-generation sequencing approach to identify bipolar disorder genes.
As a first step, some high-priority issues will be discussed between our advisory group and the research team. Many challenging ethical questions come with the scientific efforts to understand the complexity of bipolar disorder. Even if the concept of genetically based health care is intuitively appealing, potential harms are still associated to both whole genome sequencing (Kaye et al., 2010) and tests based on the genetic contributors to bipolar disorder (Burke et al., 2008; Peay et al., 2009). Moreover, given the important social and economic burden of bipolar disorder in our society and in world population, findings factors that could not only help better understand individual predisposition to this condition, but also better prevent potential harms (such as stigma, damaged self-esteem and anxiety) associated with risks of erroneous diagnosis and inappropriate therapy, will have an enormous social impact.
Outcomes
Acting as an essential advisory group to the leadership of the research team on the Next-Generation Sequencing Approach to Identify Bipolar Disorder Genes project will allow us to produce referrals to existing resources, “Issue briefs” on specific issues, education modules and manuscripts.
References
Biesecker BB, Peay HL. Ethical issues in psychiatric genetics research: points to consider. Psychopharmacology (Berl) 2003 Dec; 171(1): 27-35.
Burke W, Kuszler P, Starks H, Holland S, Press N. Translational genomics: seeking a shared vision of benefit. Am J Bioeth. 2008 Mar; 8(3): 54-56; discussion W1-3.
Kaye J, Boddington P, de Vries J, Hawkins N, Melham K. Ethical implications of the use of whole genome methods in medical research. Eur J Hum Genet. 2010 Apr; 18(4): 398-403.
Peay HL, Hooker GW, Kassem L, Biesecker BB. Family risk and related education and counseling needs: perceptions of adults with bipolar disorder and siblings of adults with bipolar disorder. Am J Med Genet A. 2009 Mar; 149A(3): 364-71.
Other useful references
Badner, J. A., D. Koller, et al. Genome-wide linkage analysis of 972 bipolar pedigrees using single-nucleotide polymorphisms. Mol Psychiatry 2011; eprint July 19: 1-9.
Day-Williams, A. G. and E. Zeggini. The effect of next-generation sequencing technology on complex trait research. Eur J Clin Invest. 2011; 41(5): 561-7.
Diamandis, E. P. Next-generation sequencing: a new revolution in molecular diagnostics? Clin Chem. 2009; 55(12): 2088-92.
Goes FS, R. M., Chen Y-C, Karchin R, Elhaik E, et al. Exonic DNA Sequencing of ERBB4 in Bipolar Disorder. PLoS ONE 2011; 6(5): 1-6.
Lehne, B., C. M. Lewis, et al. Exome localization of complex disease association signals. BMC Genomics 2011; 12: 92.
Li, C. Personalized medicine - the promised land: are we there yet? Clin Genet. 2011; 79(5): 403-12.
Majewski, J., J. Schwartzentruber, et al. What can exome sequencing do for you? J Med Genet. 2011; 48(9): 580-9.
McGuire, A. L., Caulfield, T. and Cho, M. K. Research ethics and the challenge of whole-genome sequencing. Nature Review Genetics 2008; 9: 152-156.
Oedegaard, K. J., T. A. Greenwood, et al. A genome-wide association study of bipolar disorder and comorbid migraine. Genes Brain Behav. 2010; 9(7): 673-80.
Smith, E. N., C. S. Bloss, et al. Genome-wide association study of bipolar disorder in European American and African American individuals. Mol Psychiatry 2009; 14(8): 755-763.
Raffan, E. and R. K. Semple. Next generation sequencing--implications for clinical practice. Br Med Bull. 2011; 99: 53-71.
Rotimi, C. N. and P. A. Marshall. Tailoring the process of informed consent in genetic and genomic research. Genome Med. 2010; 2(3): 20.
Sijmons, R. H., I. M. Van Langen, et al. A clinical perspective on ethical issues in genetic testing. Account Res. 2011; 18(3): 148-62.
Uhl, G. R., T. Dragon, et al. Molecular genetics of addiction and related heritable phenotypes: genome-wide association approaches identify "connectivity constellation" and drug target genes with pleiotropic effects. Ann N Y Acad Sci. 2008; 1141: 318-81.
For other and up-to-date references and useful materiel, please consult our section: “Related material” in our section “Genetics of brain disorders”.
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Date: From 2011 - ongoing
Research Team : Béatrice Godard, Iris Jaitovich Groisman, Ghislaine Mathieu
Funding: Genome Quebec
Contact:
Béatrice Godard
Considerations of providing individual results to participants in neurogenetic research: an ethical analysis
Research team: Béatrice Godard & Laurence Baret
Context: Neurogenetics studies are becoming increasingly prevalent, leading to a growing body of information on disease susceptibility with the potential to improve health care. Much of these data are characterized as exploratory (non-validated; no clinical utility). However, there is an international trend for research participants to be permitted access to their personal data if they so choose. Stakeholders are consequently confronting the issue of whether and how they should disclose individual results to research participants while maintaining the integrity and feasibility of genetic studies. But what are the attitudes and needs of research participants? There is a lack of empirical data on these attitudes and needs, and especially in the field of neurodevelopmental diseases.
Objectives: The study aims to get a benefit-to-risk assessment by balancing the potential positive vs negative consequences of disclosing individual results to research participants. To do so, the study investigates the attitudes and needs of parents of... Read more
Research team: Béatrice Godard & Laurence Baret
Context: Neurogenetics studies are becoming increasingly prevalent, leading to a growing body of information on disease susceptibility with the potential to improve health care. Much of these data are characterized as exploratory (non-validated; no clinical utility). However, there is an international trend for research participants to be permitted access to their personal data if they so choose. Stakeholders are consequently confronting the issue of whether and how they should disclose individual results to research participants while maintaining the integrity and feasibility of genetic studies. But what are the attitudes and needs of research participants? There is a lack of empirical data on these attitudes and needs, and especially in the field of neurodevelopmental diseases.
Objectives: The study aims to get a benefit-to-risk assessment by balancing the potential positive vs negative consequences of disclosing individual results to research participants. To do so, the study investigates the attitudes and needs of parents of children participating in a genetic study on autism. It also involves an analysis of (inter)national guidelines on the disclosure of individual results to research participants. Findings of these analyses might serve to develop an ethical framework to assist investigators providing study participants with the research results of neurogenetics studies.
Hypothesis: Providing individual genetic research results to participants is a key challenge. We expect to find major challenges in matters of return of result given both the high expectations surrounding genetic research and the vulnerable state of some patients/research participants.
References
Affleck, P. Is it ethical to deny genetic research participants individualised results? Journal of Medical Ethics 2009; 35: 209-13.
Bookman, E. B., Langehorne, A. A., Eckfeldt, J. H. et al. Reporting genetic results in research studies: Summary and recommendations of an NHLBI working group. American Journal of Medical Genetics 2006; Part A 140A: 1033-40.
Bredenoord, A. L., Kroes, H. Y., Cuppen, E. et al. Disclosure of individual genetic data to research participants: the debate reconsidered. Trends in Genetics 2010; 27: 41-7.
Clayton, E. W. & Ross, L. F. Implications of disclosing individual results of clinical research. JAMA 2006; 295: 37.
Dixon-Woods, M., Jackson, C., Windridge, K. C. et al. Receiving a summary of the results of a trial: qualitative study of participants' views. Qualitative study of participants' views. BMJ 2006; 332: 206-10.
Fabsitz, R. R., McGuire, M., Sharp, R. R. et al. Ethical and practical guidelines for reporting genetic research results to study participants. Updated guidelines from a national heart, lung, and blood institute working group. Circulation: Cardiovascular Genetics 2010; 3: 574-80.
Fernandez, C. V., Kodish, E. & Weijer, C. Informing study participants of research results: an ethical imperative. IRB: a Review of Human Subjects Research 2003; 25: 12-19.
Fernandez, C. V., Skedgel, C. & Weijer, C. Considerations and costs of disclosing study findings to research participants. Canadian Medical Association Journal 2004; 170: 1417-19.
Fernandez, C. V. Public expectations for return of results - Time to stop being paternalistic. The American Journal of Bioethics 2008; 8: 46-8.
Hayeems, R. Z., Miller, F. A., Li, L. et al. Not so simple: a quasi-experimental study of how researchers adjudicate genetic research results. Eur J Hum Genet 2011; 19(7): 740-7.
Knoppers, B. M., Joly, Y., Simard, J. et al. The emergence of an ethical duty to disclose genetic research results: international perspectives. Eur J Hum Genet 2006; 14: 1170-8.
Meltzer, L. A. Undesirable implications of disclosing individual genetic results to research participants. American Journal of Bioethics 2006; 6: 28-30.
McGuire, A. L., Caulfield, T. and Cho, M. K. Research ethics and the challenge of whole-genome sequencing. Nature Review Genetics 2008; 9: 152-156.
Miller, F., Christensen, R., Giacomini, M. et al. Duty to disclose what? Querying the putative obligation to return research results to participants. J Med Ethics 2008; 34: 210-3.
Miller, F., Giacomini, M., Ahern, C. et al. When research seems like clinical care: a qualitative study of the communication of individual cancer genetic research results. BMC Medical Ethics 2008; 9: 4.
Murphy, J., Scott, J., Kaufman, D. et al. Public expectations for return of results from large-cohort genetic research. American Journal of Bioethics 2009; 8: 36-43.
Ravitsky, V. & Wilfond, B. S. Disclosing individual genetic results to research participants. American Journal of Bioethics 2006; 6: 8-17.
Renegar, G., Webster, C., Stuerzebecher, S. et al. Returning genetic research results to individuals: Points to consider. Bioethics 2006; 20: 24-36.
Rothstein, M. A. Tiered Disclosure Options Promote the Autonomy and Well-Being of Research Subjects. The American Journal of Bioethics 2006; 6: 20.
Shalowitz, D. I. & Miller, F. G. Disclosing individual results of clinical research: implications of respect for participants. JAMA 2005; 294: 737-40.
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Publications
Baret, L., Godard, B. (2011) "Opinions and intentions of parents of an autistic child toward genetic research results: two typical profiles" Eur J Hum Genet. 19(11):1127-32. doi: 10.1038/ejhg.2011.106. Epub 2011 Jun 15.
Baret, L., Gauthier, J., Godard, B. "La communication des résultats d’une recherche aux personnes qui y ont participé: l’enfant pauvre de l’éthique de la recherche?" in Les actes de la 5e édition des journées d’étude des comités d’éthique de la recherche et de leurs partenaires. Ministère de la Santé et des Services Sociaux, Québec, 2010. Online: http://ethique.msss.gouv.qc.ca/site/download.php?a9d3b0048cbb2299407b6e2645747943 (Accessed March 2012)
Date: From 2006 to 2010
Research Team : Béatrice Godard
Funding: Genome Quebec
Contact:
Béatrice Godard
