Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci

Sjur Reppe, Yunpeng Wang, Wesley K. Thompson, Linda K. McEvoy, Andrew J. Schork, Verena Zuber, Marissa LeBlanc, Francesco Bettella, Ian G. Mills, Rahul S. Desikan, Srdjan Djurovic, Kaare M. Gautvik, Anders M. Dale, Ole A. Andreassen, Karol Estrada, Unnur Styrkarsdottir, Evangelos Evangelou, Yi Hsiang Hsu, Emma L. Duncan, Evangelia E. NtzaniLing Oei, Omar M.E. Albagha, Najaf Amin, John P. Kemp, Daniel L. Koller, Guo Li, Ching Ti Liu, Ryan L. Minster, Alireza Moayyeri, Liesbeth Vandenput, Dana Willner, Su Mei Xiao, Laura M. Yerges-Armstrong, Hou Feng Zheng, Nerea Alonso, Joel Eriksson, Candace M. Kammerer, Stephen K. Kaptoge, Paul J. Leo, Gudmar Thorleifsson, Scott G. Wilson, James F. Wilson, Ville Aalto, Markku Alen, Aaron K. Aragaki, Thor Aspelund, Jacqueline R. Center, Zoe Dailiana, David J. Duggan, Melissa Garcia, Natàlia Garcia-Giralt, Sylvie Giroux, Göran Hallmans, Lynne J. Hocking, Lise Bjerre Husted, Karen A. Jameson, Rita Khusainova, Ghi Su Kim, Charles Kooperberg, Theodora Koromila, Marcin Kruk, Marika Laaksonen, Andrea Z. Lacroix, Seung Hun Lee, Ping C. Leung, Joshua R. Lewis, Laura Masi, Simona Mencej-Bedrac, Tuan V. Nguyen, Xavier Nogues, Millan S. Patel, Janez Prezelj, Lynda M. Rose, Serena Scollen, Kristin Siggeirsdottir, Albert V. Smith, Olle Svensson, Stella Trompet, Olivia Trummer, Natasja M. Van Schoor, Jean Woo, Kun Zhu, Susana Balcells, Maria Luisa Brandi, Brendan M. Buckley, Sulin Cheng, Claus Christiansen, Cyrus Cooper, George Dedoussis, Ian Ford, Morten Frost, David Goltzman, Jesús González-Macías, Mika Kähönen, Magnus Karlsson, Elza Khusnutdinova, Jung Min Koh, Panagoula Kollia, Bente Lomholt Langdahl, William D. Leslie, Paul Lips, Östen Ljunggren, Roman S. Lorenc, Janja Marc, Dan Mellström, Barbara Obermayer-Pietsch, José M. Olmos, Ulrika Pettersson-Kymmer, David M. Reid, José A. Riancho, Paul M. Ridker, François Rousseau, P. Eline Slagboom, Nelson L.S. Tang, Roser Urreizti, Wim Van Hul, Jorma Viikari, María T. Zarrabeitia, Yurii S. Aulchenko, Martha Castano-Betancourt, Elin Grundberg, Lizbeth Herrera, Thorvaldur Ingvarsson, Hrefna Johannsdottir, Tony Kwan, Rui Li, Robert Luben, Carolina Medina-Gómez, Stefan Th Palsson, Jerome I. Rotter, Gunnar Sigurdsson, Joyce B.J. Van Meurs, Dominique Verlaan, Frances M.K. Williams, Andrew R. Wood, Yanhua Zhou, Tomi Pastinen, Soumya Raychaudhuri, Jane A. Cauley, Daniel I. Chasman, Graeme R. Clark, Steven R. Cummings, Patrick Danoy, Elaine M. Dennison, Richard Eastell, John A. Eisman, Vilmundur Gudnason, Albert Hofman, Rebecca D. Jackson, Graeme Jones, J. Wouter Jukema, Kay Tee Khaw, Terho Lehtimäki, Yongmei Liu, Mattias Lorentzon, Eugene McCloskey, Braxton D. Mitchell, Kannabiran Nandakumar, Geoffrey C. Nicholson, Ben A. Oostra, Munro Peacock, Huibert A.P. Pols, Richard L. Prince, Olli Raitakari, Ian R. Reid, John Robbins, Philip N. Sambrook, Pak Chung Sham, Alan R. Shuldiner, Frances A. Tylavsky, Cornelia M. Van Duijn, Nick J. Wareham, L. Adrienne Cupples, Michael J. Econs, David M. Evans, Tamara B. Harris, Annie Wai Chee Kung, Bruce M. Psaty, Jonathan Reeve, Timothy D. Spector, Elizabeth A. Streeten, M. Carola Zillikens, Unnur Thorsteinsdottir, Claes Ohlsson, David Karasik, J. Brent Richards, Matthew A. Brown, Kari Stefansson, André G. Uitterlinden, Stuart H. Ralston, John P.A. Ioannidis, Douglas P. Kiel, Fernando Rivadeneira, GEFOS Consortium

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Abstract

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity.

Original languageEnglish
Article numbere0144531
JournalPLoS ONE
Volume10
Issue number12
DOIs
Publication statusPublished - 1 Dec 2015

Cite this

Reppe, S., Wang, Y., Thompson, W. K., McEvoy, L. K., Schork, A. J., Zuber, V., ... GEFOS Consortium (2015). Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci. PLoS ONE, 10(12), [e0144531]. https://doi.org/10.1371/journal.pone.0144531