Multi-trait genome-wide association study identifies a novel endometrial cancer risk locus that associates with testosterone levels.
Multi-trait genome-wide association study identifies a novel endometrial cancer risk locus that associates with testosterone levels.
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DOI：
10.1016/j.isci.2023.106590
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发表时间：
2023-05-19
期刊：
影响因子：
5.8
通讯作者：
O'Mara, Tracy A.
中科院分区：
文献类型：
--
作者：
Wang, Xuemin;Kho, Pik Fang;Ramachandran, Dhanya;Bafligil, Cemsel;Amant, Frederic;Goode, Ellen L.;Scott, Rodney J.;Tomlinson, Ian;Evans, D. Gareth;Crobie, Emma J.;Doerk, Thilo;Spurdle, Amanda B.;Clubb, Dylan M.;O'Mara, Tracy A.
为了检测新的子宫内膜癌风险变异，我们在多性状GWAS分析中利用了子宫内膜癌风险因素的信息。我们首先采用孟德尔随机化方法评估了确定的和可疑的子宫内膜癌危险因素与子宫内膜癌之间的因果关系。多变量分析后，5个独立的危险因素（腰围，睾酮水平，性激素结合球蛋白水平，初潮年龄，自然绝经年龄）被纳入多性状贝叶斯GWAS分析。我们确定了三个与子宫内膜癌风险相关的潜在新基因座，其中一个（7q22.1）在独立的子宫内膜癌GWAS数据集中复制，并且在荟萃分析中具有全基因组意义。该位点可能通过改变睾酮水平影响子宫内膜癌风险。与此一致，我们观察到子宫内膜癌风险信号和CYP 3A 7（一种参与睾酮代谢的基因）表达之间的共定位。因此，我们的研究结果表明，激素治疗的机会，以预防或治疗子宫内膜癌。通过多变量分析检测到5个独立的子宫内膜癌风险因素3个潜在的新的子宫内膜癌风险基因座通过多性状GWAS揭示子宫内膜癌GWAS复制组中新的7 q22. 1风险基因座的验证与CYP 3A 7表达和女性睾酮水平相关的7 q22. 1 GWAS变体生物信息学;系统生物学;癌症;基因组学
To detect novel endometrial cancer risk variants, we leveraged information from endometrial cancer risk factors in a multi-trait GWAS analysis. We first assessed causal relationships between established and suspected endometrial cancer risk factors, and endometrial cancer using Mendelian randomization. Following multivariable analysis, five independent risk factors (waist circumference, testosterone levels, sex hormone binding globulin levels, age at menarche, and age at natural menopause) were included in a multi-trait Bayesian GWAS analysis. We identified three potentially novel loci that associate with endometrial cancer risk, one of which (7q22.1) replicated in an independent endometrial cancer GWAS dataset and was genome-wide significant in a meta-analysis. This locus may affect endometrial cancer risk through altered testosterone levels. Consistent with this, we observed colocalization between the signals for endometrial cancer risk and expression of CYP3A7, a gene involved in testosterone metabolism. Thus, our findings suggest opportunities for hormone therapy to prevent or treat endometrial cancer. 5 independent endometrial cancer risk factors detected via multivariable analysis 3 potentially novel endometrial cancer risk loci revealed by multi-trait GWAS Validation of novel 7q22.1 risk locus in an endometrial cancer GWAS replication set GWAS variants at 7q22.1 linked to CYP3A7 expression and female testosterone levels Bioinformatics; Systems biology; Cancer; Genomics
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影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.
影响因子：
4.8
作者：
Crawford ED;Heidenreich A;Lawrentschuk N;Tombal B;Pompeo ACL;Mendoza-Valdes A;Miller K;Debruyne FMJ;Klotz L
通讯作者：
Klotz L
影响因子：
8.8
作者：
Larsson, Susanna C.;Lee, Wei-Hsuan;Allara, Elias
通讯作者：
Allara, Elias
模因套件：用于发现和搜索的工具。
影响因子：
14.9
作者：
Bailey TL;Boden M;Buske FA;Frith M;Grant CE;Clementi L;Ren J;Li WW;Noble WS
通讯作者：
Noble WS
影响因子：
30.8
作者：
Cheng TH;Thompson DJ;O'Mara TA;Painter JN;Glubb DM;Flach S;Lewis A;French JD;Freeman-Mills L;Church D;Gorman M;Martin L;National Study of Endometrial Cancer Genetics Group (NSECG);Hodgson S;Webb PM;Australian National Endometrial Cancer Study Group (ANECS);Attia J;Holliday EG;McEvoy M;Scott RJ;Henders AK;Martin NG;Montgomery GW;Nyholt DR;Ahmed S;Healey CS;Shah M;Dennis J;Fasching PA;Beckmann MW;Hein A;Ekici AB;Hall P;Czene K;Darabi H;Li J;Dörk T;Dürst M;Hillemanns P;Runnebaum I;Amant F;Schrauwen S;Zhao H;Lambrechts D;Depreeuw J;Dowdy SC;Goode EL;Fridley BL;Winham SJ;Njølstad TS;Salvesen HB;Trovik J;Werner HM;Ashton K;Otton G;Proietto T;Liu T;Mints M;Tham E;RENDOCAS;Consortium C;Jun Li M;Yip SH;Wang J;Bolla MK;Michailidou K;Wang Q;Tyrer JP;Dunlop M;Houlston R;Palles C;Hopper JL;AOCS Group;Peto J;Swerdlow AJ;Burwinkel B;Brenner H;Meindl A;Brauch H;Lindblom A;Chang-Claude J;Couch FJ;Giles GG;Kristensen VN;Cox A;Cunningham JM;Pharoah PDP;Dunning AM;Edwards SL;Easton DF;Tomlinson I;Spurdle AB
通讯作者：
Spurdle AB