A multi-level investigation of the genetic relationship between endometriosis and ovarian cancer histotypes.
A multi-level investigation of the genetic relationship between endometriosis and ovarian cancer histotypes.
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DOI：
10.1016/j.xcrm.2022.100542
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发表时间：
2022-03-15
期刊：
影响因子：
--
通讯作者：
Kar SP
中科院分区：
文献类型：
--
作者：
Mortlock S;Corona RI;Kho PF;Pharoah P;Seo JH;Freedman ML;Gayther SA;Siedhoff MT;Rogers PAW;Leuchter R;Walsh CS;Cass I;Karlan BY;Rimel BJ;Ovarian Cancer Association Consortium, International Endometriosis Genetics Consortium;Montgomery GW;Lawrenson K;Kar SP
子宫内膜异位症与上皮性卵巢癌（EOC）的风险增加有关。利用来自大型子宫内膜异位症和EOC全基因组关联荟萃分析的数据，我们估计了遗传相关性，评估了子宫内膜异位症遗传易感性与EOC组织型之间的因果关系，并确定了共同的易感基因座。我们估计子宫内膜异位症与透明细胞癌（rg = 0.71）、类卵巢癌（rg = 0.48）和高级别浆液性卵巢癌（rg = 0.19）之间存在显著的遗传相关性（rg），孟德尔随机化分析支持这种相关性。双变量荟萃分析确定了28个与子宫内膜异位症和EOC相关的位点，其中19个位点有共同的潜在相关信号。共同风险的差异表明不同的潜在途径可能有助于子宫内膜异位症和不同组织型之间的关系。使用相关组织/细胞的转录组和表观基因组谱的功能注释突出了几个靶基因。这种全面的分析揭示了子宫内膜异位症和EOC组织型之间深刻的遗传重叠，对于理解疾病的生物学机制具有重要的基因组靶点。子宫内膜异位症与CCOC、ENOC和HGSOC遗传相关子宫内膜异位症的遗传易感性赋予这些EOC组织型的风险子宫内膜异位症和EOC风险位点遗传关联的深刻共定位功能注释突出了阐明遗传联系的共同靶基因Mortlock et al.使用遗传相关性、孟德尔随机化、双变量GWAS、共定位和功能基因组分析，报告了子宫内膜异位症和上皮性卵巢癌（EOCs）之间的强遗传关系。结果增加了我们对交叉疾病发病机制的理解，并产生了多效性靶点，以促进潜在的预防性药物干预和靶向EOC筛查。
Endometriosis is associated with increased risk of epithelial ovarian cancers (EOCs). Using data from large endometriosis and EOC genome-wide association meta-analyses, we estimate the genetic correlation and evaluate the causal relationship between genetic liability to endometriosis and EOC histotypes, and identify shared susceptibility loci. We estimate a significant genetic correlation (rg) between endometriosis and clear cell (rg = 0.71), endometrioid (rg = 0.48), and high-grade serous (rg = 0.19) ovarian cancer, associations supported by Mendelian randomization analyses. Bivariate meta-analysis identified 28 loci associated with both endometriosis and EOC, including 19 with evidence for a shared underlying association signal. Differences in the shared risk suggest different underlying pathways may contribute to the relationship between endometriosis and the different histotypes. Functional annotation using transcriptomic and epigenomic profiles of relevant tissues/cells highlights several target genes. This comprehensive analysis reveals profound genetic overlap between endometriosis and EOC histotypes with valuable genomic targets for understanding the biological mechanisms linking the diseases. Endometriosis is genetically correlated with CCOC, ENOC, and HGSOC Genetic liability to endometriosis confers risk of these EOC histotypes Profound colocalization of genetic associations at endometriosis and EOC risk loci Functional annotation highlights shared target genes elucidating the genetic link Mortlock et al. report a strong genetic relationship between endometriosis and epithelial ovarian cancers (EOCs) using genetic correlation, Mendelian randomization, bivariate GWAS, colocalization, and functional genomic analyses. Results increase our understanding of cross-disorder pathogenesis and yield pleiotropic targets to facilitate potential preventive pharmacological intervention and targeted EOC screening.
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遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
7.3
作者：
Cochrane, Dawn R.;Tessier-Cloutier, Basile;Huntsman, David G.
通讯作者：
Huntsman, David G.
影响因子：
2.1
作者：
Bowden J;Davey Smith G;Haycock PC;Burgess S
通讯作者：
Burgess S
评估上皮性卵巢癌组织学亚型的遗传结构。
影响因子：
5.3
作者：
Cuellar-Partida G;Lu Y;Dixon SC;Australian Ovarian Cancer Study;Fasching PA;Hein A;Burghaus S;Beckmann MW;Lambrechts D;Van Nieuwenhuysen E;Vergote I;Vanderstichele A;Doherty JA;Rossing MA;Chang-Claude J;Rudolph A;Wang-Gohrke S;Goodman MT;Bogdanova N;Dörk T;Dürst M;Hillemanns P;Runnebaum IB;Antonenkova N;Butzow R;Leminen A;Nevanlinna H;Pelttari LM;Edwards RP;Kelley JL;Modugno F;Moysich KB;Ness RB;Cannioto R;Høgdall E;Høgdall C;Jensen A;Giles GG;Bruinsma F;Kjaer SK;Hildebrandt MA;Liang D;Lu KH;Wu X;Bisogna M;Dao F;Levine DA;Cramer DW;Terry KL;Tworoger SS;Stampfer M;Missmer S;Bjorge L;Salvesen HB;Kopperud RK;Bischof K;Aben KK;Kiemeney LA;Massuger LF;Brooks-Wilson A;Olson SH;McGuire V;Rothstein JH;Sieh W;Whittemore AS;Cook LS;Le ND;Blake Gilks C;Gronwald J;Jakubowska A;Lubiński J;Kluz T;Song H;Tyrer JP;Wentzensen N;Brinton L;Trabert B;Lissowska J;McLaughlin JR;Narod SA;Phelan C;Anton-Culver H;Ziogas A;Eccles D;Campbell I;Gayther SA;Gentry-Maharaj A;Menon U;Ramus SJ;Wu AH;Dansonka-Mieszkowska A;Kupryjanczyk J;Timorek A;Szafron L;Cunningham JM;Fridley BL;Winham SJ;Bandera EV;Poole EM;Morgan TK;Goode EL;Schildkraut JM;Pearce CL;Berchuck A;Pharoah PD;Webb PM;Chenevix-Trench G;Risch HA;MacGregor S
通讯作者：
MacGregor S
影响因子：
4.6
作者：
Bakshi A;Zhu Z;Vinkhuyzen AA;Hill WD;McRae AF;Visscher PM;Yang J
通讯作者：
Yang J