Queensland University of Technology, Faculty of Health, School of Biomedical Sciences, Centre for Genomics and Personalised Health, Brisbane, Queensland, Australia.
Centre for Precision Health, School of Medical and Health Sciences, Edith Cowan University, Perth, Australia.
Hum Reprod. 2022 Jan 28;37(2):366-383. doi: 10.1093/humrep/deab254.
Is there a shared genetic or causal association of endometriosis with asthma or what biological mechanisms may underlie their potential relationships?
Our results confirm a significant but non-causal association of endometriosis with asthma implicating shared genetic susceptibility and biological pathways in the mechanisms of the disorders, and potentially, their co-occurrence.
Some observational studies have reported a pattern of co-occurring relationship between endometriosis and asthma; however, there is conflicting evidence and the aetiology, as well as the underlying mechanisms of the relationship, remain unclear.
STUDY DESIGN, SIZE, DURATION: We applied multiple statistical genetic approaches in the analysis of well-powered, genome-wide association study (GWAS) summary data to comprehensively assess the relationship of endometriosis with asthma. Endometriosis GWAS from the International Endogene Consortium (IEC, 17 054 cases and 191 858 controls) and asthma GWAS from the United Kingdom Biobank (UKB, 26 332 cases and 375 505 controls) were analysed. Additional asthma data from the Trans-National Asthma Genetic Consortium (TAGC, 19 954 cases and 107 715 controls) were utilized for replication testing.
PARTICIPANTS/MATERIALS, SETTING, METHODS: We assessed single-nucleotide polymorphism (SNP)-level genetic overlap and correlation between endometriosis and asthma using SNP effect concordance analysis (SECA) and linkage disequilibrium score regression analysis (LDSC) methods, respectively. GWAS meta-analysis, colocalization (GWAS-PW), gene-based and pathway-based functional enrichment analysis methods were applied, respectively, to identify SNP loci, genomic regions, genes and biological pathways shared by endometriosis and asthma. Potential causal associations between endometriosis and asthma were assessed using Mendelian randomization (MR) methods.
SECA revealed significant concordance of SNP risk effects across the IEC endometriosis and the UKB asthma GWAS. Also, LDSC analysis found a positive and significant genetic correlation (rG = 0.16, P = 2.01 × 10-6) between the two traits. GWAS meta-analysis of the IEC endometriosis and UKB asthma GWAS identified 14 genome-wide significant (Pmeta-analysis < 5.0 × 10-8) independent loci, five of which are putatively novel. Three of these loci were consistently replicated using TAGC asthma GWAS and reinforced in colocalization and gene-based analyses. Additional shared genomic regions were identified in the colocalization analysis. MR found no evidence of a significant causal association between endometriosis and asthma. However, combining gene-based association results across the GWAS for endometriosis and asthma, we identified 17 shared genes with a genome-wide significant Fisher's combined P-value (FCPgene) <2.73 × 10-6. Additional analyses (independent gene-based analysis) replicated evidence of gene-level genetic overlap between endometriosis and asthma. Biological mechanisms including 'thyroid hormone signalling', 'abnormality of immune system physiology', 'androgen biosynthetic process' and 'brain-derived neurotrophic factor signalling pathway', among others, were significantly enriched for endometriosis and asthma in a pathway-based analysis.
The GWAS for endometriosis data were sourced from the International Endogen Consortium (IEC) and can be accessed by contacting the consortium. The GWAS data for asthma are freely available online at Lee Lab (https://www.leelabsg.org/resources) and from the Trans-National Asthma Genetic Consortium (TAGC).
LIMITATIONS, REASONS FOR CAUTION: Given we analysed GWAS datasets from mainly European populations, our results may not be generalizable to other ancestries.
This study provides novel insights into mechanisms underpinning endometriosis and asthma, and potentially their observed relationship. Findings support a co-occurring relationship of endometriosis with asthma largely due to shared genetic components. Agents targeting 'selective androgen receptor modulators' may be therapeutically relevant in both disorders. Moreover, SNPs, loci, genes and biological pathways identified in our study provide potential targets for further investigation in endometriosis and asthma.
STUDY FUNDING/COMPETING INTEREST(S): National Health and Medical Research Council (NHMRC) of Australia (241,944, 339,462, 389,927, 389,875, 389,891, 389,892, 389,938, 443,036, 442,915, 442,981, 496,610, 496,739, 552,485, 552,498, 1,026,033 and 1,050,208), Wellcome Trust (awards 076113 and 085475) and the Lundbeck Foundation (R102-A9118 and R155-2014-1724). All researchers had full independence from the funders. Authors do not have any conflict of interest.
子宫内膜异位症与哮喘是否存在共同的遗传或因果关联，或者潜在的关联可能涉及哪些生物学机制？
我们的研究结果证实了子宫内膜异位症与哮喘之间存在显著但非因果关联，这表明这两种疾病存在共同的遗传易感性和生物学途径，也可能存在共病的情况。
一些观察性研究报告了子宫内膜异位症和哮喘之间存在共病关系的模式；然而，证据存在矛盾，其发病机制以及潜在的关联机制仍不清楚。
研究设计、规模和持续时间：我们应用了多种统计遗传方法，对经过充分验证的、全基因组关联研究（GWAS）汇总数据进行分析，全面评估了子宫内膜异位症与哮喘之间的关系。国际内胚层研究协会（IEC）的子宫内膜异位症 GWAS（17054 例病例和 191858 例对照）和英国生物银行（UKB）的哮喘 GWAS（26332 例病例和 375505 例对照）被分析。来自 Trans-National Asthma Genetic Consortium（TAGC）的额外哮喘数据（19954 例病例和 107715 例对照）被用于复制测试。
参与者/材料、设置、方法：我们使用 SNP 效应一致性分析（SECA）和连锁不平衡得分回归分析（LDSC）方法分别评估了子宫内膜异位症和哮喘之间的 SNP 水平遗传重叠和相关性。我们应用 GWAS 荟萃分析、共定位（GWAS-PW）、基因和途径功能富集分析方法，分别鉴定了子宫内膜异位症和哮喘共有的 SNP 位点、基因组区域、基因和生物学途径。使用孟德尔随机化（MR）方法评估了子宫内膜异位症和哮喘之间的潜在因果关系。
SECA 显示 IEC 子宫内膜异位症和 UKB 哮喘 GWAS 中 SNP 风险效应具有显著的一致性。此外，LDSC 分析发现这两种特征之间存在正相关且具有统计学意义（rG=0.16，P=2.01×10-6）。对 IEC 子宫内膜异位症和 UKB 哮喘 GWAS 的荟萃分析确定了 14 个全基因组显著（Pmeta-analysis < 5.0×10-8）的独立位点，其中 5 个可能是新的。其中 3 个通过 TAGC 哮喘 GWAS 进行了一致的复制，并在共定位和基因基础分析中得到了加强。在共定位分析中还确定了其他共享的基因组区域。MR 未发现子宫内膜异位症和哮喘之间存在显著的因果关系。然而，我们结合了 GWAS 对子宫内膜异位症和哮喘的基因关联结果，确定了 17 个具有全基因组显著 Fisher 联合 P 值（FCPgene）<2.73×10-6的共享基因。额外的分析（独立的基因关联分析）复制了子宫内膜异位症和哮喘之间基因水平遗传重叠的证据。在途径分析中，甲状腺激素信号转导、免疫系统生理学异常、雄激素生物合成过程和脑源性神经营养因子信号通路等生物学机制显著富集了子宫内膜异位症和哮喘。
子宫内膜异位症的 GWAS 数据来自国际内胚层研究协会（IEC），可以通过联系该协会获取。哮喘的 GWAS 数据可在 Lee 实验室（https://www.leelabsg.org/resources）和 Trans-National Asthma Genetic Consortium（TAGC）上免费获取。
局限性、谨慎的原因：鉴于我们分析了主要来自欧洲人群的 GWAS 数据集，因此我们的结果可能不适用于其他种族。
本研究为子宫内膜异位症和哮喘的潜在发病机制提供了新的见解，并可能为这两种疾病的发病机制提供了新的见解。研究结果支持子宫内膜异位症与哮喘之间存在共病关系，这主要是由于共同的遗传成分。靶向“选择性雄激素受体调节剂”的药物可能对这两种疾病都具有治疗意义。此外，我们研究中鉴定的 SNP、基因座、基因和生物学途径为子宫内膜异位症和哮喘提供了潜在的治疗靶点。
研究资金/利益冲突：澳大利亚国家卫生和医学研究委员会（NHMRC）（241944、339462、389927、389875、389891、389892、389938、443036、442915、442981、496610、496739、552485、552498、1026033 和 1050208）、威康信托（奖项 076113 和 085475）和隆德基金会（R102-A9118 和 R155-2014-1724）。所有研究人员都完全独立于资助者。作者没有任何利益冲突。
