Type A and Type B polygenic disorders

We have argued elsewhere that the genetic aetiology of most major psychiatric disorders is most likely to be polygenic and multifactorial (Reference Farmer and OwenFarmer & Owen, 1996). Along with other common illnesses such as coronary artery disease, hypertension and diabetes, polygenic mental disorders can be divided into two main types. In the first (Type A), a few rare families have forms of the disorder showing simple Mendelian patterns of transmission that are due to the inheritance of single genetic mutations which are sufficient to cause disease. Such sub-forms are tractable to molecular genetic approaches, and the identification of disease genes can provide important pointers to the aetiology and pathophysiology of more common, polygenic varieties of the disorder. Recent success in finding genes for autosomal dominant, early-onset forms of Alzheimer's disease has opened up new avenues of research into the neurobiology of common forms of the disorder (Reference Goate, Chartier-Harlin and MullanGoate et al, 1991).

The majority of major mental illnesses, however, are more likely to be Type B disorders, in which rare Mendelian sub-forms are not found. Hence the detection of genes, which for Type B disorders will have small effect, is more difficult and requires analysis of much larger samples, using a combination of allele sharing linkage methods and allelic association studies (Reference Owen and CraddockOwen & Craddock, 1996). To date, a number of replicated chromosomal regions of interest have been found for some mental disorders, and some genes of quite small effect have been identified, but much work is still required (Reference Williams, McGuffin and NothenWilliams et al, 1997). It has been pointed out (Reference DeLisi and CrowDeLisi & Crow, 1999) that there have been many claims of linkage but little replication across studies. There has also been a lack of agreement between systematic genome searches on any one locus for a phenotype — for example, whether the positive linkage is associated with schizophrenia or bipolar disorder.

In those with Type B and in the majority of those with Type A disorders, disease probably reflects the action of a number of genes, which combine together in an additive and/or multiplicative fashion to give a vulnerability to develop the disorder when other non-genetic risk factors are also present. Such genes are termed susceptibility genes and individually their presence does not mean that the carrier will inevitably develop the illness (Reference McGuffin, Owen and O'DonovanMcGuffin et al, 1994). In fact, in many instances the predictive value of tests for such genes will be low, as is exemplified by apolipoprotein E testing for late-onset Alzheimer's disease (Reference Relkin, Tanzi and BreitnerRelkin et al, 1996). Indeed, even when all susceptibility genes for a given disorder have been identified, it will still not be possible to predict the development of disease with certainty until the relevant environmental risk factors have also been identified and the nature of the various interactions understood (Reference Owen and McGuffinOwen & McGuffin, 1997).

The Nuffield Council on Bioethics Report

For this reason, the Nuffield Council report (Nuffield Council on Bioethics, 1998) concluded that genetic tests would not be useful for diagnosing mental disorder with complex causes either prenatally or in population screening. One of the report's main recommendations was that genetic testing for susceptibility genes which offer low predictive or diagnostic certainty should be discouraged unless there are clear medical benefits. This and other aspects of the report are worth considering in an international context as well as in the context of human genetics generally.

Funding for ethics research

In 1988, the Noble laureate James Watson, then Director of the National Institutes of Health Genetic Research Program, stated that he would allocate 3% of the genetic research budget for research into the ethical, legal and social implications of genetic research (Reference WatsonWatson, 1997). The budget for such research then increased annually, and by 1996 had reached US$7 000 000. Elsewhere, funding has been less generous, but a national bioethics committee has existed in France since 1983 (Reference ButlerButler, 1997), and a similar body was more recently established in Germany (Reference AbbottAbbott, 1997). The areas that are of most practical relevance are: those relating to informed consent; in the USA the Institutional Review Boards that assess the ethical issues associated with individual research applications (equivalent to local ethics committees in the UK); the role of the individual, their families and confidentiality; and commercial interests in genetic research (Reference MeslinMeslin, 1997).

Informed consent

As in other types of research, participants in genetic research need to understand the likely benefits, foreseeable risks and alternatives to participation. Little physical harm is likely. The usual requirements are the completion of various standardised interviews and psychometric tests, and providing a sample of DNA. For this, even a blood test can often be avoided, because DNA can now be obtained from buccal mucosa cells swabbed or washed from the inside of the cheek.

However, the main ethical concern is that of non-physical harm. Research subjects may fail to understand the difference between testing that is done as part of clinical treatment or diagnosis and that being done for research. Relatives may believe that in agreeing to participate that they will learn more about their own risk for developing a disorder. As we have already outlined, the presence of susceptibility genes does not alone confer the certainty that a disorder will develop, and individual risk assessment is currently not possible. Consent forms must therefore make this explicit, and state that the only benefits will be those of furthering scientific and medical knowledge.

The Nuffield Council on Bioethics Report (1998) also asserts that freely given informed consent guidelines are required for the establishment and maintenance of genetic registers (as a safeguard against new eugenic pressures). The report comments that individuals with mental disorders have capacity (as legally defined) to give informed and genuine consent to participate in research, unless it can be shown otherwise. This emphasises the point that, for the most part, those with mental disorders are not any different in their capacity to understand and agree to participate in research from those with other medical illnesses.

Ethics committees

The scrutiny of all research proposals involving human subjects by an ethics committee is accepted in most industrialised countries. The guiding principles are those included in the Nuremberg Code (Reference Faraone, Gottesman and TsuangFaraone et al, 1997), which states that research subjects should give voluntary consent, and not be subjected to suffering, and that the research will lead to “fruitful results for the good of society, unprocurable by other methods or means of study”. Hence, the code implies that to be considered ethical, the research must also be scientifically sound. In our view, one of the particular problems for local committees in a rapidly advancing field such as genetics is their competence to judge the scientific merits of the proposal. Where a new technological advance or a novel methodological approach is being employed, the committee may have to seek an external opinion; but where research has already been peer reviewed by a funding body, further detailed scrutiny of the scientific merit of the proposal is probably unnecessary.

A second problem relating to the fact that ethics committees are locally based is that genetic research now requires very large samples that may need to be derived from wide geographical areas. Researchers may therefore have to apply to several ethics committees for approval. The situation can arise in which a study given ethical approval in one district is refused it in the adjacent district. To overcome this problem (which also applies to other areas such as clinical trials) the Medical Research Council and other funding bodies in the UK are establishing mechanisms of review by ethics committees with a wider geographical brief.

The role of individuals, their families and confidentiality

Genetic research often requires information from non-affected family members who need to be approached regarding their participation. How this approach is made has caused some differences of opinion between ethics committees. Clearly, relatives should not be approached if the index subject refuses permission. However, when permission has been given, should the relatives be approached directly by the research team or only via the proband? If the research team is only allowed to contact the relatives through the proband, it can make the research much more difficult, time-consuming and expensive.

Another ethical issue relating to the inclusion of non-affected family members in genetic research is that the family's perception of the illness may be changed by their involvement in the study. For example, family members may not be aware that an illness is partly caused by faulty genes until the approach to participate in the research is made. There is also the issue of confidentiality: some patients would not wish their relatives to know that they have a mental illness. Family members also sometimes reveal symptoms to a researcher that they have not revealed to anyone else. In such cases the confidentiality of the respondent must be strictly preserved.

Commercialisation of products

Commercial interest in genetic material has rapidly increased recently. Genes such as the cystic fibrosis gene and the breast cancer 1 gene have been patented in the USA, where the law allows this. A patent has also been granted to the discoverers of one of the mutations in the amyloid precursor protein gene associated with early-onset Alzheimer's disease (Reference Goate, Chartier-Harlin and MullanGoate et al, 1991). There are two main ethical issues relating to such patenting. The first is whether it is ethical to patent a naturally occurring, biological compound that is not an invention. Although it can be argued that as much time and research effort goes into discovering a DNA sequence as into an invention, the question then arises as to who should receive resulting profits — just the researcher, or also the individuals who provided the DNA.

The issue of ownership of DNA is especially pertinent to a number of ethnic groups and geographically isolated communities who have been approached to provide DNA because they may be genetically informative (see, e.g., ‘Aborigines fear gene study may threaten rights’ — Sydney Morning Herald, 24 July 1997). In Iceland the government has recently passed legislation allowing a commercial company, deCODE Genetics, access to all medical and genealogical material as well as stored DNA samples for the whole population of the country (approximately 270 000 individuals) (Reference Gulcher and StefanssonGulcher & Stefansson, 1998; Reference BergerBerger, 1999). From a genetic perspective Iceland is particularly attractive because the population is relatively homogeneous and mainly descended from a small number of founders who arrived a little over 1000 years ago. This makes it a much better hunting ground for genes associated with common diseases than countries with older, more genetically intermixed populations. There has been much criticism about such an enterprise, both within Iceland and abroad. Much of this criticism has centred on concerns regarding invasion of privacy, but there has also been a sort of ‘gut reaction’ by some to the notion that a commercial enterprise can effectively stage a takeover of an entire nation's DNA. Against this, the parliament of Iceland — a country with limited natural resources — has taken a hard-nosed commercial decision, which it believes will bring financial benefits to its people. In the longer term, deCODE and its major backer, a pharmaceutical giant, aim to identify genes that can inform the search for targets for novel drug development. Undoubtedly, profit is an important motive, but it is difficult to argue that discovery of better, more specific treatments for common disorders is disreputable.