Transcriptional risk scores link GWAS to eQTLs and predict complications in Crohn's disease.
Transcriptional risk scores link GWAS to eQTLs and predict complications in Crohn's disease.
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DOI：
10.1038/ng.3936
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发表时间：
2017-10
期刊：
影响因子：
30.8
通讯作者：
Gibson G
中科院分区：
文献类型：
--
作者：
Marigorta UM;Denson LA;Hyams JS;Mondal K;Prince J;Walters TD;Griffiths A;Noe JD;Crandall WV;Rosh JR;Mack DR;Kellermayer R;Heyman MB;Baker SS;Stephens MC;Baldassano RN;Markowitz JF;Kim MO;Dubinsky MC;Cho J;Aronow BJ;Kugathasan S;Gibson G
基因表达谱可用于揭示通过全基因组关联研究（GWAS）鉴定的基因座对病理学的贡献机制。鉴于大多数GWAS命中是在推定的调控区和转录丰度是生理上更接近感兴趣的表型，我们假设，风险等位基因相关的基因表达的总和，即转录风险评分（TRS），应该提供准确的估计疾病的风险。我们将概要水平的GWAS和表达数量性状基因座（eQTL）数据与来自RISK研究的RNA-seq数据整合，RISK研究是儿科克罗恩病的初始队列。我们表明，基于与炎症性肠病（IBD）相关的变异体调控的基因的TRS不仅在区分克罗恩病与健康样本方面优于遗传风险评分（GRS），而且还有助于识别及时进展为复杂疾病的患者。我们对eQTL效应的分析可以用来区分与疾病相关的基因是通过促进还是保护，从而将统计学关联与生物学机制联系起来。TRS方法构成了个性化医疗的潜在策略，增强了静态基因型风险评估的推断。
Gene expression profiling can be used to uncover the mechanisms by which loci identified through genome-wide association studies (GWAS) contribute to pathology,. Given that most GWAS hits are in putative regulatory regions and transcript abundance is physiologically closer to the phenotype of interest, we hypothesized that summation of risk-allele-associated gene expression, namely a transcriptional risk score (TRS), should provide accurate estimates of disease risk. We integrate summary-level GWAS and expression quantitative trait locus (eQTL) data with RNA-seq data from the RISK study, an inception cohort of pediatric Crohn's disease,. We show that TRSs based on genes regulated by variants linked to inflammatory bowel disease (IBD) not only outperform genetic risk scores (GRSs) in distinguishing Crohn's disease from healthy samples, but also serve to identify patients who in time will progress to complicated disease. Our dissection of eQTL effects may be used to distinguish genes whose association with disease is through promotion versus protection, thereby linking statistical association to biological mechanism. The TRS approach constitutes a potential strategy for personalized medicine that enhances inference from static genotypic risk assessment.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
克罗恩病和溃疡性结肠炎表型的遗传决定因素：遗传关联研究。
DOI：
10.1016/s0140-6736(15)00465-1
发表时间：
2016-01-09
期刊：
Lancet (London, England)
影响因子：
--
作者：
Cleynen I;Boucher G;Jostins L;Schumm LP;Zeissig S;Ahmad T;Andersen V;Andrews JM;Annese V;Brand S;Brant SR;Cho JH;Daly MJ;Dubinsky M;Duerr RH;Ferguson LR;Franke A;Gearry RB;Goyette P;Hakonarson H;Halfvarson J;Hov JR;Huang H;Kennedy NA;Kupcinskas L;Lawrance IC;Lee JC;Satsangi J;Schreiber S;Théâtre E;van der Meulen-de Jong AE;Weersma RK;Wilson DC;International Inflammatory Bowel Disease Genetics Consortium;Parkes M;Vermeire S;Rioux JD;Mansfield J;Silverberg MS;Radford-Smith G;McGovern DP;Barrett JC;Lees CW
通讯作者：
Lees CW
影响因子：
32.4
作者：
Nabekura, Tsukasa;Kanaya, Minoru;Shibuya, Akira;Fu, Guo;Gascoigne, Nicholas R. J.;Lanier, Lewis L.
通讯作者：
Lanier, Lewis L.
影响因子：
3.6
作者：
Di Narzo AF;Peters LA;Argmann C;Stojmirovic A;Perrigoue J;Li K;Telesco S;Kidd B;Walker J;Dudley J;Cho J;Schadt EE;Kasarskis A;Curran M;Dobrin R;Hao K
通讯作者：
Hao K
影响因子：
5.8
作者：
Mecham, Brigham H.;Nelson, Peter S.;Storey, John D.
通讯作者：
Storey, John D.