Genetic overlap analysis of endometriosis and asthma identifies shared loci implicating sex hormones and thyroid signalling pathways

Emmanuel O Adewuyi, D Mehta, Divya Mehta, Yadav Sapkota, International Endogene Consortium (IEC), Kosuke Yoshihara, 23andMe Research Team, Mette Nyegaard, Valgerður Steinthórsdóttir, Andrew P. Morris, Amelie Fassbender, Nilüfer Rahmioğlu, Immaculata De Vivo, Julie E. Buring, Futao Zhang, Todd L. Edwards, Sarah Jones, O Dorien, Daniëlle Peterse, Kathryn M. Rexrode, Paul M. Ridker, Andrew J. Schork, Stuart MacGregor, Nicholas G. Martin, Christian M. Becker, Sosuke Adachi, Takayuki Enomoto, Atsushi Takahashi, Yoichiro Kamatani, Koichi Matsuda, Michiaki Kubo, Guðmar Þorleifsson, Reynir Tómas Geirsson, Unnur Þorsteinsdóttir, Leanne Wallace, Jian Yang, Digna R. Velez Edwards, Siew‐Kee Low, Krina T. Zondervan, Stacey A. Missmer, Thomas D'Hooghe, Thomas D’Hooghe, Kāri Stefánsson, Joyce Y. Tung, Grant W. Montgomery, Daniel I. Chasman, Michelle Agee, Babak Alipanahi, Adam Auton, Robert K. Bell, Katarzyna Bryc, Sarah L. Elson, Pierre Fontanillas, Nicholas A. Furlotte, Karen E. Huber, Aaron Kleinman, Nadia K. Litterman, Matthew H. McIntyre, Joanna L. Mountain, Elizabeth S. Noblin, Carrie A. M. Northover, Steven J. Pitts, J. Fah Sathirapongsasuti, Olga V. Sazonova, Janie F. Shelton, Suyash Shringarpure, Chao Tian, Vladimir Vacic, Catherine H. Wilson, Dale R. Nyholt
Human Reproduction · 2021 · vol. 37(2) , pp. 366–383 · doi:10.1093/humrep/deab254 · PMID:35472084 · PMC8804329 · W4213179251
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This study found a significant, non-causal genetic association between endometriosis and asthma, identifying shared susceptibility loci and implicating sex hormone and thyroid signaling pathways.

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Abstract

STUDY QUESTION: Is there a shared genetic or causal association of endometriosis with asthma or what biological mechanisms may underlie their potential relationships? SUMMARY ANSWER: 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. WHAT IS KNOWN ALREADY: 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. MAIN RESULTS AND THE ROLE OF CHANCE: 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. LARGE SCALE DATA: 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. WIDER IMPLICATIONS OF THE FINDINGS: 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.

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Condition tags

endometriosis

MeSH descriptors

Asthma Asthma Asthma Asthma Asthma Asthma Asthma Asthma Asthma Asthma Asthma Asthma Asthma Asthma Asthma Asthma Endometriosis Endometriosis Endometriosis Endometriosis

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