Identification of Major Risk Alleles for Schizophrenia in Consanguineous Families

Schizophrenia is a severely disabling mental illness that changes people's thought processes and the way they perceive the world around them. It is a common yet poorly understood condition which the World Health Organisation rates as equivalent to heart disease and cancer put together in terms of the disability it causes. It often persists throughout adult life, resulting in substantial costs to society, because patients remain unemployed and require ongoing care. Currently available medicines at best treat only some symptoms, don't work at all in around 30% of patients and are often associated with severe side-effects. In part, this is because we know so little about the root causes.

However, we do know that much of the risk of developing schizophrenia is carried in our genes. By identifying the genetic defects involved, we can begin to piece together the complex jigsaw of genetic and environmental effects that combine to cause schizophrenia. Considerable effort has therefore been put into the identification of the genes involved. The approach used by most researchers so far, looking for an increase in the burden of small changes in genes in large groups of unrelated patients, has delivered only limited successes. Some hints of involvement for a handful of genes have been found, but these have generally not been confirmed by all the groups who have looked, so there remains much controversy and confusion around our genetic understanding of schizophrenia.

We propose to use a much simpler method, namely looking at families in which several individuals have schizophrenia and determining what they have inherited in common that might have caused their illness. This approach presumes that, in at least some families, the disease is caused mainly by one gene defect which has a devastating effect on those who carry it. Other researchers have suggested that this approach will not work because schizophrenia is too complex, with the disease in any one person resulting from many genetic defects, each with only a small effect, combining with stresses in the environment to cause the disease. We suggest that previous searches for such "simple" schizophrenia families may have failed in the past because they were looking in the wrong population. We have looked in families from the Pakistani community of West Yorkshire, most of whom are the children of settlers who came to Bradford in the 1950s. This community is therefore likely to harbour a smaller range of mutations, but may have individual mutations with higher frequency, making them easier to find. Furthermore the Pakistani community of Bradford has a high level of marriage between cousins (consanguinity), which makes such mutations more likely to come together in children of related parents who carry the same mutation.

We have already tried this approach in one family and it has worked spectacularly well, giving us strong evidence of the presence and location of a mutation on human chromosome 13 which, when an individual inherits two copies, is alone sufficient to cause schizophrenia. Others had already suggested the existence of such a gene but tentatively, and with only vague and differing suggestions as to its location. Our findings reveal the first compelling evidence for a "simple" genetic form of schizophrenia, and should now make it relatively easy for us to find the gene involved. We therefore seek funding, first to identify the actual gene and mutation, and then to repeat this search in more consanguineous Pakistani families, many of which we have already recruited or are recruiting, in order to locate and identify more genes mutated in schizophrenia. By studying these families we should be able to unequivocally track down at least some of the proteins involved and from that knowledge work out exactly what is going wrong. This will highlight pathways and processes that can then be targets for the development of novel therapies.

Schizophrenia is a common yet poorly understood chronic mental illness. Ranked by the WHO as equivalent to heart disease and cancer together in disability terms, it often persists throughout adult life, resulting in a substantial burden on families and cost to society. Currently available treatments treat only positive (hallucinations, delusions, thought disorder) and not negative (decreased motivation, emotional blunting) symptoms or cognitive deficits, are ineffective in up to 30% of patients and have unacceptable side-effects. There is therefore a clear need for new and better therapies, for which a better understanding of the aetiological basis is an essential prerequisite.
Family studies suggest a significant genetic contribution. Identifying the genes involved will offer valuable insights into the pathways affected, and will help dissect environmental contributions. However, the GWAS approach used by most psychiatric geneticists to date has delivered only limited successes and there remains much controversy around our genetic understanding of schizophrenia. We propose instead to use autozygosity mapping in multiplex Pakistani families. The Pakistani community of West Yorkshire is both highly consanguineous, increasing the frequency of all recessive disease, and endogamous, potentially reducing genetic complexity. This approach presumes that, in at least some families, the disease is caused by a single recessive mutation with high penetrance. Others have suggested this approach will not work because schizophrenia is too complex. However, our initial findings show that in one family this approach has worked spectacularly well, proving the existence of a locus on chromosome 13q and revealing the first documented case of "Mendelian" schizophrenia. We now seek funding to identify the gene and mutation on 13q, then to repeat the process in further consanguineous Pakistani families to locate and identify more genes mutated in schizophrenia.

In this proposal, we set out research to identify at least one recessive susceptibility allele of major effect in schizophrenia. There will be clinical applications in genetic counselling, genetic testing, and further research to target existing treatments more effectively and develop new ones. Identifying the genes involved, regardless of risk size, will also increase our general understanding of the biological basis of schizophrenia, again contributing to the development of more effective and safer treatments, or prevention approaches. Our proposal focuses on consanguineous families that have multiple members affected by schizophrenia, in particular, a large family of Pakistani ethnicity living in West Yorkshire that was recruited to this study by AC and TM and whose affected members have been treated by TM over 10 years. By studying these families, we aim to identify proteins which, when mutated, cause schizophrenia, and then confirm their involvement in schizophrenia through molecular analyses. This will not only highlight pathways and processes that can then be targets for the development of novel therapies, but will also offer important clinical applications in genetic counselling and testing. As such, the impact of our research is aimed squarely at patients and their healthcare providers. While claims linking genetic findings with clinical benefits can sometimes appear tenuous or extremely long-term, we believe that our family-based approach takes a step beyond primary genetic findings into the realm of genetic counselling and presymptomatic intervention.

The immediate beneficiaries of our research will be the families involved. The Pakistani community has a custom of arranged marriages within the community and often between first cousins. Once an allele is unequivocally proven to cause schizophrenia, additional family members can be offered informed genetic counselling via Yorkshire Regional Genetics service and in certain cases, with family consent, it may also be possible to investigate the potential benefits of presymptomatic intervention with cognitive behavioural therapy and other behavioural interventions. Other researchers interested in the genetic basis of schizophrenia will also benefit from our research, since they may be able to use our genetic findings to identify risk variants of the same gene in different populations. Indeed, we have already agreed a collaboration with Prof. Linda Brzustowicz (Rutgers University, USA) and Prof. Anne Bassett (CAMH, Canada) to screen Canadian familial cases of schizophrenia linked to 13q for mutations in the gene affected in the Yorkshire family. The identification of risk alleles may also identify novel targets for pharmaceutical interventions. As such, our research will be of interest to the pharmaceutical industry.

In England alone, that represents over 2.5 million potential beneficiaries, requiring £5.5 billion in direct health/support service costs and affecting the national economy through the £11 billion per annum in lost earnings due to illness. The award of this grant would contribute to a pool of resources and expertise and build up critical research mass at Leeds. Aside from the funded posts, we would expect degree project, PhD students, post-docs, visiting researchers and industrial contacts to be exposed to the techniques and to apply them in academic and industrial settings. Traditional academic research outputs will be supplemented through the applicants' commitment to contribute to the general public's understanding and perception of scientific research in general and this work in particular. This will be achieved through local public engagement events, online resources and dissemination through media outlets. We will provide the public, as tax-paying stakeholders in, and potential direct or indirect beneficiaries of, medical research access to relevant research dividends and their current and future implications.