Identification of Major Risk Alleles for Schizophrenia in Consanguineous Families

近亲家庭中精神分裂症主要风险等位基因的鉴定

• 批准号: MR/J004391/1
• 负责人: Steven Clapcote
• 金额: $ 41.98万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ004391%2F1
• 关键词: Identification; Major; Risk; Alleles; Schizophrenia

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.

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。这是一种常见但知之甚少的疾病，世界卫生组织认为，就其导致的残疾而言，它相当于心脏病和癌症。它往往在整个成年生活中持续存在，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。部分原因是我们对根本原因知之甚少。然而，我们确实知道，患精神分裂症的大部分风险都存在于我们的基因中。通过识别相关的遗传缺陷，我们可以开始拼凑出遗传和环境效应的复杂拼图，这些效应联合收割机共同导致精神分裂症。因此，在鉴定所涉及的基因方面已经投入了相当大的努力。到目前为止，大多数研究人员使用的方法，在大量无关患者中寻找基因微小变化的负担增加，只取得了有限的成功。我们已经发现了一些与少数基因有关的线索，但这些线索通常还没有得到所有研究小组的证实，因此我们对精神分裂症的遗传理解仍然存在很多争议和混乱。我们建议使用一种简单得多的方法，即观察几个患有精神分裂症的家庭，确定他们共同遗传了什么，可能导致他们的疾病。这种方法假定，至少在某些家庭中，这种疾病主要是由一种基因缺陷引起的，这种缺陷对携带这种缺陷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基因缺陷引起的，每一个基因缺陷的影响都很小，再加上环境中的压力导致疾病。我们认为，以前的搜索这样的“简单”的精神分裂症家庭在过去可能已经失败，因为他们在错误的人口。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，这个社区可能含有较小范围的突变，但可能具有更高频率的个体突变，使其更容易被发现。此外，布拉德福德的巴基斯坦社区有很高的表兄弟之间的婚姻我们已经在一个家庭中尝试了这种方法，效果非常好，给了我们强有力的证据，证明人类13号染色体上存在一个突变，当一个人继承了两个拷贝，就足以导致精神分裂症。其他人已经提出了这样一个基因的存在，但只是试探性的，而且对于它的位置只有模糊和不同的建议。我们的发现揭示了精神分裂症的“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地找到相关基因。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血缘家庭中重复这一搜索，其中许多我们已经招募或正在招募，以便定位和确定精神分裂症中更多的突变基因。通过研究这些家族，我们应该能够明确地追踪至少一些相关的蛋白质，并根据这些知识准确地找出问题所在。这将突出途径和过程，然后可以成为新疗法开发的目标。

项目成果

A Recessively Inherited Risk Locus on Chromosome 13q22-31 Conferring Susceptibility to Schizophrenia.

• DOI: 10.1093/schbul/sbaa161
• 发表时间: 2021-04-29
• 期刊: Schizophrenia bulletin
• 影响因子: 6.6
• 作者: Mahmood T;El-Asrag ME;Poulter JA;Cardno AG;Tomlinson A;Ahmed S;Al-Amri A;Nazari J;Neill J;Chamali RS;Kiwan N;Ghuloum S;Alhaj HA;Randerson Moor J;Khan S;Al-Amin H;Johnson CA;Woodruff P;Wilkinson ID;Ali M;Clapcote SJ;Inglehearn CF
• 通讯作者: Inglehearn CF

In memory of Professor Iain Wilkinson: cognitive and neuroimaging endophenotypes in a consanguineous schizophrenia multiplex family.

• DOI: 10.1017/s0033291721005250
• 发表时间: 2023-05
• 期刊: PSYCHOLOGICAL MEDICINE
• 影响因子: 6.9
• 作者: Wilkinson, Iain D.;Mahmood, Tariq;Yasmin, Sophia Faye;Tomlinson, Anneka;Nazari, Jamshid;Alhaj, Hamid;el Din, Soumaya Nasser;Neill, Joanna;Pandit, Chhaya;Ashraf, Shahzad;Cardno, Alastair G.;Clapcote, Steven J.;Inglehearn, Chris F.;Woodruff, Peter W.
• 通讯作者: Woodruff, Peter W.

891 - Consanguinity multiplex and schizophrenia - the royal road to genes of major effect

891 - 血缘多重性和精神分裂症 - 通向重大效应基因的康庄大道

• DOI: 10.1016/s0924-9338(13)76056-5
• 发表时间: 2013
• 期刊: European Psychiatry
• 影响因子: 7.8
• 作者: Mahmood T

LHFPL5 mutation: A rare cause of non-syndromic autosomal recessive hearing loss

• DOI: 10.1016/j.ejmg.2018.11.026
• 发表时间: 2019-12-01
• 期刊: EUROPEAN JOURNAL OF MEDICAL GENETICS
• 影响因子: 1.9
• 作者: Al-Amri, Ahmed H.;Al Saegh, Abeer;Ali, Manir
• 通讯作者: Ali, Manir