Genetic brain disorders affect the development and function of the brain. While there are many genetic disorders recorded in medical science, inherited disorders which affect the brain and its functioning are of special concern, with respect to the delicate nature of the brain area and the severe complications resulting from such disorders. Many people with genetic brain disorders fail to produce enough of certain proteins that influence brain development and function. These brain disorders can cause serious problems that affect the nervous system (NIH).
Genetics has transformed our understanding of mechanisms mediating brain disorders. Some genetic brain disorders are due to random gene mutations or mutations caused by environmental exposure. Other disorders are inherited, which means that a mutated gene or group of genes is passed down through a family. Still other disorders are due to a combination of genetic changes and other outside factors (NIH). Some examples of genetic brain disorders include autism or bipolar diseases.
Tremendous progresses have been brought in terms of accurate molecular diagnoses and knowledge of the genes and pathways that are involved in a large number of brain disorders. New methods and analytical approaches, including "next-generation" sequencing technologies, are bringing deeper insights into the subtle complexities of the genetic architecture that determines the risks for these disorders. As we now seek to translate these discoveries back to clinical applications, a major challenge for the field will be in bridging the gap between genes and biology (Zoghbi et al., 2010).
There is a need to put more emphasis on research into the causes and developmental pathways of brain disorders, so that better drugs and better psychological treatments can be developed as well as allowing for empirically based treatment (Gustavsson et al., 2011). Brain disorders are still largely mysterious, which is mainly why there has been so little advance in their medical treatment in the past 60 years or so. Nonetheless, recent studies of mouse models of genetic forms of neuropsychiatric disorders suggest that many of the behavioral and physiological abnormalities reflect reversible functional defects in the adult brain, rather than irreversible structural defects (Ehninger et al., 2008). There is now a pressing need to discover what these functional neurobiological defects are.
Far more research is also needed because brain disorders are an enormous burden to society, in terms of both human suffering and economic cost: they are responsible for more than 40% of all years lived with disability in North America and Europe (Hyman, 2008). Twin data suggest that more than 40% of the societal burden of brain disorders is likely to be genetically mediated (Uhl et al., 2004).
With growing predictive capabilities on the one hand but cure still an elusive goal, the ethical challenges for people and society are enormous. Currently, our research projects focus on the ethical issues raised by the genetics of autism and bipolar disorders and by the genetic research in this field. See our research projects and below for more information.
What is the genetics of autism?
A large number of studies have confirmed that genetic factors play an important role in autism (Geschwind, 2011 ; Muhle et al., 2004). Studies in twins show concordance rates in monozygotic (MZ) twins of 70-90 % whereas dizygotic (DZ) twin concordance is 0 to 10% (Shao et al., 2003). Familial aggregation studies show that the relative risk for developing autism in first-degree relatives of autism subjects is 3 to 7%. The recurrence risk of autism in second- and third-degree relatives of autism subjects decreases very sharply (0.18% and 0.12% respectively). Such a huge difference between monozygotic and dizygotic concordance can only be explained by a high rate of new mutations, or polygenic inheritance, where the effects of multiple risk genes acting additively or multiplicatively result in disease. In the few genes identified in autism and Rett Syndrome (a closely related disorder) new mutations have been found to be responsible for the vast majority of cases.
Genome-wide genetic linkage studies have been conducted in autism kindreds and association studies have been used to test specific etiological hypotheses in autism. Mutations have been found. Other studies have shown in vitro that the frame shifting and the missense mutations described in humans alter the formation of pre-synaptic terminals (Chih et al., 2004 ; Comoletti et al., 2004). These findings support the hypothesis that autism is caused by synaptic malfunctions.
See our research project(s) in this field (coming soon).
What is the genetics of bipolar disorder?
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, P.I. of this research project, et al.) 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 resequenced 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.
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): 54-6; discussion W1-3.
Chih B, Afridi SK, Clark L, Scheiffele P. Disorder-associated mutations lead to functional inactivation of neuroligins. Hum Mol Genet. 2004; 13: 1471-7.
Comoletti D, De Jaco A, Jennings LL, Flynn RE, Gaietta G, Tsigelny I, Ellisman MH, Taylor P. The Arg451Cys-neuroligin-3 mutation associated with autism reveals a defect in protein processing. J Neurosci. 2004 ; 24: 4889-93.
Ehninger D, Li W, Fox K, Stryker MP, Silva AJ. Reversing neurodevelopmental disorders in adults. Neuron 2008 Dec 26; 60(6): 950-60.
Gustavsson A, Svensson M, Jacobi F, et al. Cost of disorders of the brain in Europe 2010. Eur Neuropsychopharmacol. 2011 Oct; 21(10): 718-79.
Hyman SE. A glimmer of light for neuropsychiatric disorders. Nature 2008; 455(7215): 890–93.
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.
Muhle R, Trentacoste SV, Rapin I. The genetics of autism. Pediatrics 2004 May; 113(5): e472-86.
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.?
Uhl GR, Grow RW. The burden of complex genetics in brain disorders. Arch Gen Psychiatry 2004 Mar; 61(3): 223-9.
Shao Y, Cuccaro ML, Hauser ER, et al. Fine mapping of autistic disorder to chromosome 15q11-q13 by use of phenotypic subtypes. Am J Hum Genet. 2003 Mar; 72(3): 539-48.
Zoghbi HY, Warren ST. Neurogenetics: advancing the "next-generation" of brain research. Neuron 2010 Oct 21; 68(2): 165-73.
See also National Human Genome Institute. Learning about autism. Online: http://www.genome.gov/25522099 (Accessed January 9, 2012).
Publication Inclusion and Exclusion in Nutrigenetics Clinical Research: Ethical and Scientific Challenges
An article by Hurlimann T, Stenne R, Menuz V and Godard B published in the Journal of Nutrigenetics and Nutrigenomics 2011; 4(6). Online first. There are compelling reasons to ensure the participation of ethnic minorities and... Read more
An article by Hurlimann T, Stenne R, Menuz V and Godard B published in the Journal of Nutrigenetics and Nutrigenomics 2011; 4(6). Online first. There are compelling reasons to ensure the participation of ethnic minorities and populations of all ages worldwide in nutrigenetics clinical research. If findings in such research are valid for some individuals, groups, or communities, and not for others, then ethical questions of justice – and not only issues of methodology and external validity – arise. This paper aims to examine inclusion in nutrigenetics clinical research and its scientific and ethical challenges. For more information, click here.
Publication Is Human Enhancement also a Personal Matter?
An article by Vincent Menuz, Thierry Hurlimann and Béatrice Godard, published in Science and engineering ethics, online first (2011) DOI:Read more
An article by Vincent Menuz, Thierry Hurlimann and Béatrice Godard, published in Science and engineering ethics, online first (2011) DOI:10.1007/s11948-011-9294-y. This paper proposes a timely and much needed examination of the various definitions of human enhancement found in the literature and proposes a definition of human enhancement that focuses on individual perceptions. While acknowledging that a definition that mainly depends on personal and subjective individual perceptions raises many challenges, the authors suggest that a comprehensive approach to define human enhancement could constitute a useful premise to appropriately address the complexity of the ethical and social issues it generates. For a full abstract and paper, click here.
