Identification of Major Risk Alleles for Schizophrenia in Consanguineous Families

精神分裂症是一种严重致残的精神疾病，它会改变人们的思维过程和感知周围世界的方式。这是一种常见但却鲜为人知的疾病，世界卫生组织（World Health organization）认为，就其导致的残疾而言，它相当于心脏病和癌症之和。它往往持续整个成年生活，给社会带来巨大的成本，因为患者仍然失业，需要持续的护理。目前可用的药物最多只能治疗一些症状，对大约30%的患者根本不起作用，而且往往伴有严重的副作用。在某种程度上，这是因为我们对根本原因知之甚少。然而，我们确实知道，患精神分裂症的风险很大程度上是由我们的基因携带的。通过识别相关的遗传缺陷，我们可以开始拼凑出导致精神分裂症的遗传和环境影响的复杂拼图。因此，在鉴定相关基因方面已经付出了相当大的努力。到目前为止，大多数研究人员使用的方法是在一大群不相关的患者中寻找基因微小变化带来的负担增加，但只取得了有限的成功。已经发现了一些与少数基因有关的线索，但这些线索通常并没有得到所有研究小组的证实，因此，围绕我们对精神分裂症的遗传理解，仍然存在许多争议和困惑。我们建议使用一种更简单的方法，即观察有几个人患有精神分裂症的家庭，并确定他们有哪些共同的遗传因素可能导致他们的疾病。这种方法假定，至少在一些家庭中，这种疾病主要是由一种基因缺陷引起的，这种基因缺陷对携带这种基因的人有毁灭性的影响。其他研究人员认为这种方法行不通，因为精神分裂症太复杂了，任何一个人的疾病都是由许多遗传缺陷引起的，每个遗传缺陷只有很小的影响，再加上环境中的压力导致疾病。我们认为，以前对这种“简单的”精神分裂症家族的研究可能失败了，因为他们在错误的人群中寻找。我们调查了来自西约克郡巴基斯坦社区的家庭，他们中的大多数人都是20世纪50年代来到布拉德福德的定居者的孩子。因此，这个群体可能拥有较小范围的突变，但可能具有更高频率的个体突变，使它们更容易被发现。此外，布拉德福德的巴基斯坦社区表亲之间的婚姻水平很高，这使得这种突变更有可能在携带相同突变的相关父母的孩子身上发生。我们已经在一个家庭中尝试了这种方法，效果非常好，为我们提供了强有力的证据，证明人类13号染色体上存在一种突变，当一个人遗传了两个拷贝时，这种突变就足以导致精神分裂症。其他人已经试探性地提出了这样一种基因的存在，而且对它的位置只给出了模糊和不同的建议。我们的发现揭示了精神分裂症“简单”遗传形式的第一个令人信服的证据，现在应该使我们相对容易找到相关基因。因此，我们寻求资金，首先确定实际的基因和突变，然后在更多的巴基斯坦近亲家庭中重复这种搜索，其中许多我们已经招募或正在招募，以便定位和确定更多的精神分裂症突变基因。通过研究这些家族，我们应该能够明确地追踪到至少一些相关的蛋白质，并从这些知识中找出到底是哪里出了问题。这将突出可以作为新疗法开发目标的途径和过程。

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.