Estimation of the genetic correlation among human cancers and identification of pleiotropic cancer loci

人类癌症之间遗传相关性的估计和多效性癌症位点的鉴定

• 批准号: MR/K014781/1
• 负责人: Albert Tenesa
• 金额: $ 51.21万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 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%2FK014781%2F1
• 关键词: Estimation; genetic; correlation; among; human

Over the last twenty-five years or so geneticists have been trying to identify those genes that when mutated increase the risk of developing disease. Some of these diseases are rare in the population and in many cases the main gene that increases risk has been identified. Other diseases are common in the population and scientists call them 'common diseases'. These include, among others, most cancers, diabetes and heart disease. Understanding the genetics of common diseases is tricky because they are likely to be caused by the aggregate effect of thousands of mutations in the genome, each increasing risk by very little. Technological developments after the completion of the Human Genome Project have allowed the possibility of trying to identify the regions of the genome that make some people more prone to develop common diseases than others. The strategy has worked to some extend and has identified large numbers of regions for different diseases. Despite that success we know that the identified loci cannot explain all the recurrent risk of disease that we observe within families. There are numerous reasons why the current approach has had limited success. One of them is that the statistical methods applied are not able to model the structure of the genome properly. For instance, there could be multiple mutations on the same region whose combined effect makes one more prone to disease. At the moment the statistical methods applied only investigate one mutation at a time. We will develop more complex statistical methods to solve this problem. Another limitation of the current strategy is that scientists study one disease at a time. This is quite unsatisfactory because we know that some people tend to have multiple diseases either simultaneously or at different times. For example, being overweight increases one risk of developing cancer and this could be because the same genes that increase susceptibility to being overweight increase the chances of having cancer. We believe that by taking a more general approach and modelling two or more diseases simultaneously we could be more successful in identifying those furtive genomic regions that current methods cannot locate. We propose to develop methodology that can do that.To make our research more useful we will also apply our methods to different cancers. Different cancers often develop within families and there is a good chance that this is because susceptibility genes are shared among cancers. However, we know very little about this. We wish to learn more because this could be used for predicting cancer risk more accurately or to find new uses for available drugs (i.e. use drugs developed to treat one cancer to treat another one).

在过去25年左右的时间里，遗传学家们一直在努力识别那些突变后会增加患病风险的基因。其中一些疾病在人群中很罕见，在许多情况下，已经确定了增加风险的主要基因。其他疾病在人群中很常见，科学家称它们为“常见病”。其中包括大多数癌症、糖尿病和心脏病。了解常见疾病的遗传学是很棘手的，因为它们很可能是由基因组中数千个突变的综合效应引起的，每一个突变增加的风险都很小。人类基因组计划完成后的技术发展使人们有可能尝试确定基因组的哪些区域使一些人比其他人更容易患上常见疾病。该战略在一定程度上发挥了作用，并确定了不同疾病的大量区域。尽管取得了成功，但我们知道，已确定的基因座并不能解释我们在家庭中观察到的所有疾病复发风险。目前的方法之所以收效甚微，原因有很多。其中之一是所应用的统计方法不能正确地模拟基因组的结构。例如，同一区域可能存在多个突变，其综合影响使一个人更容易患病。目前应用的统计方法一次只调查一个突变。我们将开发更复杂的统计方法来解决这个问题。当前策略的另一个限制是，科学家只能一次研究一种疾病。这是非常不令人满意的，因为我们知道有些人往往同时或在不同时间患有多种疾病。例如，超重会增加患癌症的风险，这可能是因为增加超重易感性的基因也会增加患癌症的几率。我们相信，通过采用一种更普遍的方法，同时对两种或两种以上的疾病进行建模，我们可以更成功地识别出目前方法无法定位的那些隐秘的基因组区域。我们建议开发能够做到这一点的方法。为了使我们的研究更有用，我们还将把我们的方法应用于不同的癌症。不同的癌症通常在家族中发生，这很有可能是因为癌症的易感基因是共享的。然而，我们对此所知甚少。我们希望了解更多，因为这可以用来更准确地预测癌症风险，或者找到现有药物的新用途（即使用为治疗一种癌症而开发的药物来治疗另一种癌症）。

项目成果

Variation at 2q35 (PNKD and TMBIM1) influences colorectal cancer risk and identifies a pleiotropic effect with inflammatory bowel disease.

2q35（PNKD和TMBIM1）的变化影响结直肠癌的风险，并鉴定出与炎症性肠病的多效效应。

• DOI: 10.1093/hmg/ddw087
• 发表时间: 2016-06-01
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Orlando G;Law PJ;Palin K;Tuupanen S;Gylfe A;Hänninen UA;Cajuso T;Tanskanen T;Kondelin J;Kaasinen E;Sarin AP;Kaprio J;Eriksson JG;Rissanen H;Knekt P;Pukkala E;Jousilahti P;Salomaa V;Ripatti S;Palotie A;Järvinen H;Renkonen-Sinisalo L;Lepistö A;Böhm J;Mecklin JP;Al-Tassan NA;Palles C;Martin L;Barclay E;Tenesa A;Farrington S;Timofeeva MN;Meyer BF;Wakil SM;Campbell H;Smith CG;Idziaszczyk S;Maughan TS;Kaplan R;Kerr R;Kerr D;Buchanan DD;Win AK;Hopper J;Jenkins M;Lindor NM;Newcomb PA;Gallinger S;Conti D;Schumacher F;Casey G;Taipale J;Cheadle JP;Dunlop MG;Tomlinson IP;Aaltonen LA;Houlston RS
• 通讯作者: Houlston RS

Genome-wide association study and meta-analysis in Northern European populations replicate multiple colorectal cancer risk loci.

• DOI: 10.1002/ijc.31076
• 发表时间: 2018-02-01
• 期刊: International journal of cancer
• 影响因子: 6.4
• 作者: Tanskanen T;van den Berg L;Välimäki N;Aavikko M;Ness-Jensen E;Hveem K;Wettergren Y;Bexe Lindskog E;Tõnisson N;Metspalu A;Silander K;Orlando G;Law PJ;Tuupanen S;Gylfe AE;Hänninen UA;Cajuso T;Kondelin J;Sarin AP;Pukkala E;Jousilahti P;Salomaa V;Ripatti S;Palotie A;Järvinen H;Renkonen-Sinisalo L;Lepistö A;Böhm J;Mecklin JP;Al-Tassan NA;Palles C;Martin L;Barclay E;Tenesa A;Farrington SM;Timofeeva MN;Meyer BF;Wakil SM;Campbell H;Smith CG;Idziaszczyk S;Maughan TS;Kaplan R;Kerr R;Kerr D;Buchanan DD;Win AK;Hopper J;Jenkins MA;Newcomb PA;Gallinger S;Conti D;Schumacher FR;Casey G;Cheadle JP;Dunlop MG;Tomlinson IP;Houlston RS;Palin K;Aaltonen LA
• 通讯作者: Aaltonen LA

Improved Genetic Profiling of Anthropometric Traits Using a Big Data Approach.

• DOI: 10.1371/journal.pone.0166755
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Canela-Xandri O;Rawlik K;Woolliams JA;Tenesa A
• 通讯作者: Tenesa A

Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1.

• DOI: 10.1038/srep17369
• 发表时间: 2015-12-01
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Cheng TH;Thompson D;Painter J;O'Mara T;Gorman M;Martin L;Palles C;Jones A;Buchanan DD;Win AK;Hopper J;Jenkins M;Lindor NM;Newcomb PA;Gallinger S;Conti D;Schumacher F;Casey G;Giles GG;Pharoah P;Peto J;Cox A;Swerdlow A;Couch F;Cunningham JM;Goode EL;Winham SJ;Lambrechts D;Fasching P;Burwinkel B;Brenner H;Brauch H;Chang-Claude J;Salvesen HB;Kristensen V;Darabi H;Li J;Liu T;Lindblom A;Hall P;de Polanco ME;Sans M;Carracedo A;Castellvi-Bel S;Rojas-Martinez A;Aguiar Jnr S;Teixeira MR;Dunning AM;Dennis J;Otton G;Proietto T;Holliday E;Attia J;Ashton K;Scott RJ;McEvoy M;Dowdy SC;Fridley BL;Werner HM;Trovik J;Njolstad TS;Tham E;Mints M;Runnebaum I;Hillemanns P;Dörk T;Amant F;Schrauwen S;Hein A;Beckmann MW;Ekici A;Czene K;Meindl A;Bolla MK;Michailidou K;Tyrer JP;Wang Q;Ahmed S;Healey CS;Shah M;Annibali D;Depreeuw J;Al-Tassan NA;Harris R;Meyer BF;Whiffin N;Hosking FJ;Kinnersley B;Farrington SM;Timofeeva M;Tenesa A;Campbell H;Haile RW;Hodgson S;Carvajal-Carmona L;Cheadle JP;Easton D;Dunlop M;Houlston R;Spurdle A;Tomlinson I
• 通讯作者: Tomlinson I

The autosomal genetic control of sexually dimorphic traits in humans is largely the same across the sexes

人类性别二态性特征的常染色体遗传控制在性别上基本相同

• DOI: 10.1186/s13059-016-1035-8
• 发表时间: 2016
• 期刊: Genome Biology
• 影响因子: 12.3
• 作者: Kassam I