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Methodology for the identification of shared genetic aetiology between epidemiologically linked disorders

流行病学相关疾病之间共同遗传病因学的识别方法

基本信息

批准号：
MR/K021486/1
负责人：
Jennifer Asimit
金额：
$ 30.14万
依托单位：
Wellcome Sanger Institute
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2013
资助国家：
英国
起止时间：
2013 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FK021486%2F1
关键词：
Methodology identification shared genetic aetiology

项目摘要

Many common health disorders are frequently observed to co-occur in individuals. Hundreds of genetic disease association analyses have been completed, resulting in the identification of numerous genetic variants that are associated with a specific disease, such as type 2 diabetes, cancer, and osteoarthritis. The primary aim of the proposed research is to develop methodology to detect genetic variants that have an influence on susceptibility to two disorders, which are suspected of having shared genetic causes. The majority of existing approaches have focused on identifying genetic casual elements for a single trait, and only few of them jointly analyse linked disorders. There are many pairs of health disorders that have been identified as either frequently existing together, or having an inverse relationship, where the presence of one disorder tends to reduce the risk of another disease. Disease co-occurrence parings include type 2 diabetes with Crohn's disease, cancer, and psychiatric disorders, as well as osteoarthritis with body mass index (BMI) and height. It has been established that there is an inverse relationship between prostate cancer and type 2 diabetes. Moreover, a treatment for prostate cancer was found to increase the risk of diabetes and cardiovascular disease. This may be due to the roles of particular shared genetic variants. Thus, the development of non-adverse treatments for either of the two diseases may be assisted by the identification of gentic variants with such inverse effects on two diseases. This highlights, among others, the importance of identifying common genetic causes between linked diseases.Shared genetic causes for most of these disease pairings have been identified using simple separate analyses of each disease. One method is to compare the individual results from each analysis, and to choose common criteria for the identification of genetic disease associations. The overlap of the two sets of results is then examined. A caveat of this approach is that each analysis has a different level of how well it can detect associations, so that although an association may exist with both traits, it may only be detectable within one of the studies, and thus not found in the overlap analysis. Also, as with many other approaches, it does not take advantage of any known genetic information. Alternatively, associations with one disease may be searched for within the genes that have been recognized as associated with the other disease. However, this greatly reduces the search area.In developing methods to jointly analyse traits, the level of how well associations could be detected may be increased by taking into account known pieces of genetic and biological information, such as previously identified genetic variants, and the biological functions ascribed to them. Statistical analysis methods will be developed and tested for performance by generating various plausible datasets under an assortment of assumptions. The method with the best performance will then be applied to real datasets, such as type 2 diabetes with schizophrenia, waist-hip ratio with BMI, osteoarthritis with BMI, and osteoarthritis with migraine.

许多常见的健康障碍经常被观察到在个体中共同发生。已经完成了数百项遗传疾病关联分析，从而鉴定出与特定疾病（如2型糖尿病、癌症和骨关节炎）相关的许多遗传变异。拟议研究的主要目的是开发方法来检测对两种疾病易感性有影响的遗传变异，这两种疾病被怀疑具有共同的遗传原因。大多数现有的方法都集中在确定一个单一的性状的遗传因果因素，只有少数共同分析连锁疾病。有许多对健康障碍已被确定为经常一起存在，或具有相反的关系，其中一种障碍的存在往往会降低另一种疾病的风险。疾病共现配对包括2型糖尿病与克罗恩病、癌症和精神疾病，以及骨关节炎与体重指数（BMI）和身高。已经确定前列腺癌和2型糖尿病之间存在反比关系。此外，前列腺癌的治疗被发现会增加患糖尿病和心血管疾病的风险。这可能是由于特定的共享遗传变异的作用。因此，对这两种疾病中的任何一种的非不利治疗的开发可以通过鉴定对两种疾病具有这种相反作用的遗传变异来辅助。除其他外，这突出了确定连锁疾病之间共同遗传原因的重要性。通过对每种疾病进行简单的单独分析，已经确定了大多数这些疾病配对的共同遗传原因。一种方法是比较每个分析的个体结果，并选择共同的标准来识别遗传疾病的关联。然后检查两组结果的重叠。这种方法的一个警告是，每个分析都有不同的水平，它可以检测到的关联，因此，虽然可能存在的关联与两个性状，它可能只在其中一个研究中被检测到，因此没有发现在重叠分析。此外，与许多其他方法一样，它不利用任何已知的遗传信息。或者，可以在已经被识别为与另一种疾病相关的基因内搜索与一种疾病的关联。然而，这大大缩小了搜索范围，在开发联合分析性状的方法时，考虑到已知的遗传和生物信息，如以前确定的遗传变异及其生物功能，可能会提高检测相关性的程度。将开发统计分析方法，并通过在各种假设下生成各种合理数据集来测试性能。然后将具有最佳性能的方法应用于真实的数据集，例如2型糖尿病与精神分裂症，腰臀比与BMI，骨关节炎与BMI，以及骨关节炎与偏头痛。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A two-stage inter-rater approach for enrichment testing of variants associated with multiple traits.

DOI：
10.1038/ejhg.2016.171
发表时间：
2017-02
期刊：
European journal of human genetics : EJHG
影响因子：
0
作者：
Asimit JL;Payne F;Morris AP;Cordell HJ;Barroso I
通讯作者：
Barroso I

A two-stage inter-rater approach for enrichment testing of variants associated with multiple traits

用于对与多个性状相关的变异体进行富集测试的两阶段评估者间方法

DOI：
10.17863/cam.38732
发表时间：
2017
期刊：
影响因子：
0
作者：
Asimit J
通讯作者：
Asimit J

A Bayesian Approach to the Overlap Analysis of Epidemiologically Linked Traits.

DOI：
10.1002/gepi.21919
发表时间：
2015-12
期刊：
Genetic epidemiology
影响因子：
2.1
作者：
Asimit JL;Panoutsopoulou K;Wheeler E;Berndt SI;GIANT consortium, the arcOGEN consortium;Cordell HJ;Morris AP;Zeggini E;Barroso I
通讯作者：
Barroso I

Trans-ethnic study design approaches for fine-mapping.