ABO and LINC00339 as shared causal genes between endometriosis, endometriosis subtypes and epithelial ovarian cancer: a genome-wide association study

We analyzed genome-wide association study (GWAS) data to explore the shared genetic structure and causality association of EM and EM subtypes with EOC. Linkage disequilibrium score regression (LDSC) was used to assess genetic correlations, while pleiotropy and enrichment were evaluated through the pleiotropic analysis under composite null hypothesis (PLACO), the multi-marker analysis of genoMic annotation (MAGMA), the Functional Mapping and Annotation of Genetic Associations (FUMA) and colocalization analyses. Mendelian randomization (MR) was applied to assess causal relationships. The positive genetic associations of EM, adenomyosis (AM), ovarian endometriosis (OE), pelvic peritoneal endometriosis (PPE) and unspecified/other endometriosis (UOE) with EOC were identified, while no correlations of deep endometriosis (DE), fallopian tube endometriosis (FTE), intestinal endometriosis (IE) and endometriosis of the rectovaginal septum and vagina (ERSV) with EOC were found. PLACO and FUMA analysis identified 6 independent genomic risk loci for EM and EOC (EM-EOC), 2 for AM and EOC (AM-EOC), 5 for OE and EOC (OE-EOC), 6 for PPE and EOC (PPE-EOC), and 2 for UOE and EOC (UOE-EOC), 2 of which had strong evidence of colocalization (ABO and LINC00339). Additionally, PLACO and MAGMA analyses revealed that pleiotropic genes associated with EM-EOC, OE-EOC, PPE-EOC, and UOE-EOC were particularly enriched in ovarian tissues. Meanwhile, pleiotropic genes linked to OE-EOC were also specifically enriched in fallopian tubes. Pathway analysis determined the key role of the proteoglycans in cancer and pathways in cancer for EM-EOC, OE-EOC, and PPE-EOC. Finally, the MR analysis demonstrated that EM and EM subtypes causally increase the risk of EOC, while no evidence supported reverse causation.本研究通过分析全基因组关联研究（Genome-Wide Association Study, GWAS）数据，旨在探讨子宫内膜异位症（Endometriosis, EM）及其亚型与上皮性卵巢癌（EOC）的共有遗传结构及因果关联。本研究采用连锁不平衡得分回归（Linkage Disequilibrium Score Regression, LDSC）评估遗传相关性，并通过复合零假设下的多效性分析（Pleiotropic Analysis Under Composite Null Hypothesis, PLACO）、基因组注释多标记分析（Multi-Marker Analysis of Genomic Annotation, MAGMA）、遗传关联功能定位与注释（Functional Mapping and Annotation of Genetic Associations, FUMA）以及共定位分析来评估多效性与富集特征；同时采用孟德尔随机化（Mendelian Randomization, MR）分析因果关联关系。 本研究确认了EM、子宫腺肌症（Adenomyosis, AM）、卵巢型子宫内膜异位症（Ovarian Endometriosis, OE）、盆腔腹膜型子宫内膜异位症（Pelvic Peritoneal Endometriosis, PPE）以及未特指型/其他型子宫内膜异位症（Unspecified/Other Endometriosis, UOE）与EOC存在正向遗传关联；而深部浸润型子宫内膜异位症（Deep Endometriosis, DE）、输卵管型子宫内膜异位症（Fallopian Tube Endometriosis, FTE）、肠道型子宫内膜异位症（Intestinal Endometriosis, IE）以及直肠阴道隔及阴道型子宫内膜异位症（Endometriosis of the Rectovaginal Septum and Vagina, ERSV）与EOC未发现显著相关性。 通过PLACO与FUMA分析，本研究共鉴定出EM与EOC（EM-EOC）相关的6个独立基因组风险位点、AM与EOC（AM-EOC）相关的2个、OE与EOC（OE-EOC）相关的5个、PPE与EOC（PPE-EOC）相关的6个以及UOE与EOC（UOE-EOC）相关的2个；其中2个位点（ABO与LINC00339）具有较强的共定位证据。此外，PLACO与MAGMA分析显示，与EM-EOC、OE-EOC、PPE-EOC以及UOE-EOC相关的多效性基因在卵巢组织中呈现显著富集；与此同时，与OE-EOC相关的多效性基因在输卵管组织中也呈现特异性富集。通路分析结果表明，蛋白聚糖与癌症通路在EM-EOC、OE-EOC以及PPE-EOC的发病机制中发挥关键作用。最后，孟德尔随机化分析证实，EM及其亚型可因果性升高EOC的发病风险，未发现反向因果关联的证据。