Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata
Eeva Sliz, Jaakko Tyrmi, Nilüfer Rahmioğlu, Krina T. Zondervan, Christian M. Becker, FinnGen, Aarno Palotie, Mark J. Daly, Bridget Riley-Gills, Howard J. Jacob, Dirk S. Paul, Athena Matakidou, Adam Platt, Heiko Runz, Sally John, George Okafo, Nathan Lawless, Heli Salminen‐Mankonen, Robert M. Plenge, Joseph Maranville, Mark I. McCarthy, Margaret G. Ehm, Kirsi Auro, Simonne Longerich, Caroline S. Fox, Anders Mälarstig, K. Klinger, Clément Chatelain, Matthias Gossel, Karol Estrada, Robert Graham, Robert Yang, Chris O ́Donnell, Tomi P. Mäkelä, Jaakko Kaprio, Petri Virolainen, Antti Hakanen, Terhi Kilpi, Markus Perola, Jukka Partanen, Anne Pitkäranta, Taneli Raivio, Raisa Serpi, Tarja Laitinen, Veli‐Matti Kosma, Jari A. Laukkanen, Marco Hautalahti, Outi Tuovila, Raimo Pakkanen, Jeffrey F. Waring, Bridget Riley‐Gillis, Fedik Rahimov, Ioanna Tachmazidou, Chia‐Yen Chen, Zhihao Ding, Marc Jung, Shameek Biswas, Rion Pendergrass, David Pulford, Neha Raghavan, Adriana Huertas‐Vázquez, Jae-Hoon Sul, Xinli Hu, Åsa K. Hedman, Manuel A. Rivas, Dawn Waterworth, Nicole Renaud, Ma ́en Obeidat, Samuli Ripatti, Johanna Schleutker, Mikko Arvas, Olli Carpén, Reetta Hinttala, Arto Mannermaa, Katriina Aalto‐Setälä, Mika Kähönen, Johanna Mäkelä, Reetta Kälviäinen, Valtteri Julkunen, Hilkka Soininen, Anne M. Remes, Mikko Hiltunen, Jukka Peltola, Minna Raivio, Pentti Tienari, Juha O. Rinne, Roosa Kallionpää, Juulia Partanen, Ali Abbasi, Adam Ziemann, Nizar Smaoui, Anne Lehtonen, Susan Eaton, Sanni Lahdenperä, Natalie Bowers, Edmond Teng, Fanli Xu, Laura Addis, John D. Eicher, Qingqin S. Li
Abstract
Uterine leiomyomata (UL) are the most common tumours of the female genital tract and the primary cause of surgical removal of the uterus. Genetic factors contribute to UL susceptibility. To add understanding to the heritable genetic risk factors, we conduct a genome-wide association study (GWAS) of UL in up to 426,558 European women from FinnGen and a previous UL meta-GWAS. In addition to the 50 known UL loci, we identify 22 loci that have not been associated with UL in prior studies. UL-associated loci harbour genes enriched for development, growth, and cellular senescence. Of particular interest are the smooth muscle cell differentiation and proliferation-regulating genes functioning on the myocardin-cyclin dependent kinase inhibitor 1 A pathway. Our results further suggest that genetic predisposition to increased fat-free mass may be causally related to higher UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings add to the understanding of the genetic pathways underlying UL, which may aid in developing novel therapeutics.