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 language | English |
|---|---|
| Article number | e0144531 |
| Journal | PLoS ONE |
| Volume | 10 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - 1 Dec 2015 |
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Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci. / Reppe, Sjur; Wang, Yunpeng; Thompson, Wesley K.; McEvoy, Linda K.; Schork, Andrew J.; Zuber, Verena; LeBlanc, Marissa; Bettella, Francesco; Mills, Ian G.; Desikan, Rahul S.; Djurovic, Srdjan; Gautvik, Kaare M.; Dale, Anders M.; Andreassen, Ole A.; Estrada, Karol; Styrkarsdottir, Unnur; Evangelou, Evangelos; Hsu, Yi Hsiang; Duncan, Emma L.; Ntzani, Evangelia E.; Oei, Ling; Albagha, Omar M.E.; Amin, Najaf; Kemp, John P.; Koller, Daniel L.; Li, Guo; Liu, Ching Ti; Minster, Ryan L.; Moayyeri, Alireza; Vandenput, Liesbeth; Willner, Dana; Xiao, Su Mei; Yerges-Armstrong, Laura M.; Zheng, Hou Feng; Alonso, Nerea; Eriksson, Joel; Kammerer, Candace M.; Kaptoge, Stephen K.; Leo, Paul J.; Thorleifsson, Gudmar; Wilson, Scott G.; Wilson, James F.; Aalto, Ville; Alen, Markku; Aragaki, Aaron K.; Aspelund, Thor; Center, Jacqueline R.; Dailiana, Zoe; Duggan, David J.; Garcia, Melissa; Garcia-Giralt, Natàlia; Giroux, Sylvie; Hallmans, Göran; Hocking, Lynne J.; Husted, Lise Bjerre; Jameson, Karen A.; Khusainova, Rita; Kim, Ghi Su; Kooperberg, Charles; Koromila, Theodora; Kruk, Marcin; Laaksonen, Marika; Lacroix, Andrea Z.; Lee, Seung Hun; Leung, Ping C.; Lewis, Joshua R.; Masi, Laura; Mencej-Bedrac, Simona; Nguyen, Tuan V.; Nogues, Xavier; Patel, Millan S.; Prezelj, Janez; Rose, Lynda M.; Scollen, Serena; Siggeirsdottir, Kristin; Smith, Albert V.; Svensson, Olle; Trompet, Stella; Trummer, Olivia; Van Schoor, Natasja M.; Woo, Jean; Zhu, Kun; Balcells, Susana; Brandi, Maria Luisa; Buckley, Brendan M.; Cheng, Sulin; Christiansen, Claus; Cooper, Cyrus; Dedoussis, George; Ford, Ian; Frost, Morten; Goltzman, David; González-Macías, Jesús; Kähönen, Mika; Karlsson, Magnus; Khusnutdinova, Elza; Koh, Jung Min; Kollia, Panagoula; Langdahl, Bente Lomholt; Leslie, William D.; Lips, Paul; Ljunggren, Östen; Lorenc, Roman S.; Marc, Janja; Mellström, Dan; Obermayer-Pietsch, Barbara; Olmos, José M.; Pettersson-Kymmer, Ulrika; Reid, David M.; Riancho, José A.; Ridker, Paul M.; Rousseau, François; Slagboom, P. Eline; Tang, Nelson L.S.; Urreizti, Roser; Van Hul, Wim; Viikari, Jorma; Zarrabeitia, María T.; Aulchenko, Yurii S.; Castano-Betancourt, Martha; Grundberg, Elin; Herrera, Lizbeth; Ingvarsson, Thorvaldur; Johannsdottir, Hrefna; Kwan, Tony; Li, Rui; Luben, Robert; Medina-Gómez, Carolina; Palsson, Stefan Th; Rotter, Jerome I.; Sigurdsson, Gunnar; Van Meurs, Joyce B.J.; Verlaan, Dominique; Williams, Frances M.K.; Wood, Andrew R.; Zhou, Yanhua; Pastinen, Tomi; Raychaudhuri, Soumya; Cauley, Jane A.; Chasman, Daniel I.; Clark, Graeme R.; Cummings, Steven R.; Danoy, Patrick; Dennison, Elaine M.; Eastell, Richard; Eisman, John A.; Gudnason, Vilmundur; Hofman, Albert; Jackson, Rebecca D.; Jones, Graeme; Jukema, J. Wouter; Khaw, Kay Tee; Lehtimäki, Terho; Liu, Yongmei; Lorentzon, Mattias; McCloskey, Eugene; Mitchell, Braxton D.; Nandakumar, Kannabiran; Nicholson, Geoffrey C.; Oostra, Ben A.; Peacock, Munro; Pols, Huibert A.P.; Prince, Richard L.; Raitakari, Olli; Reid, Ian R.; Robbins, John; Sambrook, Philip N.; Sham, Pak Chung; Shuldiner, Alan R.; Tylavsky, Frances A.; Van Duijn, Cornelia M.; Wareham, Nick J.; Cupples, L. Adrienne; Econs, Michael J.; Evans, David M.; Harris, Tamara B.; Kung, Annie Wai Chee; Psaty, Bruce M.; Reeve, Jonathan; Spector, Timothy D.; Streeten, Elizabeth A.; Zillikens, M. Carola; Thorsteinsdottir, Unnur; Ohlsson, Claes; Karasik, David; Richards, J. Brent; Brown, Matthew A.; Stefansson, Kari; Uitterlinden, André G.; Ralston, Stuart H.; Ioannidis, John P.A.; Kiel, Douglas P.; Rivadeneira, Fernando; GEFOS Consortium.
In: PLoS ONE, Vol. 10, No. 12, e0144531, 01.12.2015.Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci
AU - Reppe, Sjur
AU - Wang, Yunpeng
AU - Thompson, Wesley K.
AU - McEvoy, Linda K.
AU - Schork, Andrew J.
AU - Zuber, Verena
AU - LeBlanc, Marissa
AU - Bettella, Francesco
AU - Mills, Ian G.
AU - Desikan, Rahul S.
AU - Djurovic, Srdjan
AU - Gautvik, Kaare M.
AU - Dale, Anders M.
AU - Andreassen, Ole A.
AU - Estrada, Karol
AU - Styrkarsdottir, Unnur
AU - Evangelou, Evangelos
AU - Hsu, Yi Hsiang
AU - Duncan, Emma L.
AU - Ntzani, Evangelia E.
AU - Oei, Ling
AU - Albagha, Omar M.E.
AU - Amin, Najaf
AU - Kemp, John P.
AU - Koller, Daniel L.
AU - Li, Guo
AU - Liu, Ching Ti
AU - Minster, Ryan L.
AU - Moayyeri, Alireza
AU - Vandenput, Liesbeth
AU - Willner, Dana
AU - Xiao, Su Mei
AU - Yerges-Armstrong, Laura M.
AU - Zheng, Hou Feng
AU - Alonso, Nerea
AU - Eriksson, Joel
AU - Kammerer, Candace M.
AU - Kaptoge, Stephen K.
AU - Leo, Paul J.
AU - Thorleifsson, Gudmar
AU - Wilson, Scott G.
AU - Wilson, James F.
AU - Aalto, Ville
AU - Alen, Markku
AU - Aragaki, Aaron K.
AU - Aspelund, Thor
AU - Center, Jacqueline R.
AU - Dailiana, Zoe
AU - Duggan, David J.
AU - Garcia, Melissa
AU - Garcia-Giralt, Natàlia
AU - Giroux, Sylvie
AU - Hallmans, Göran
AU - Hocking, Lynne J.
AU - Husted, Lise Bjerre
AU - Jameson, Karen A.
AU - Khusainova, Rita
AU - Kim, Ghi Su
AU - Kooperberg, Charles
AU - Koromila, Theodora
AU - Kruk, Marcin
AU - Laaksonen, Marika
AU - Lacroix, Andrea Z.
AU - Lee, Seung Hun
AU - Leung, Ping C.
AU - Lewis, Joshua R.
AU - Masi, Laura
AU - Mencej-Bedrac, Simona
AU - Nguyen, Tuan V.
AU - Nogues, Xavier
AU - Patel, Millan S.
AU - Prezelj, Janez
AU - Rose, Lynda M.
AU - Scollen, Serena
AU - Siggeirsdottir, Kristin
AU - Smith, Albert V.
AU - Svensson, Olle
AU - Trompet, Stella
AU - Trummer, Olivia
AU - Van Schoor, Natasja M.
AU - Woo, Jean
AU - Zhu, Kun
AU - Balcells, Susana
AU - Brandi, Maria Luisa
AU - Buckley, Brendan M.
AU - Cheng, Sulin
AU - Christiansen, Claus
AU - Cooper, Cyrus
AU - Dedoussis, George
AU - Ford, Ian
AU - Frost, Morten
AU - Goltzman, David
AU - González-Macías, Jesús
AU - Kähönen, Mika
AU - Karlsson, Magnus
AU - Khusnutdinova, Elza
AU - Koh, Jung Min
AU - Kollia, Panagoula
AU - Langdahl, Bente Lomholt
AU - Leslie, William D.
AU - Lips, Paul
AU - Ljunggren, Östen
AU - Lorenc, Roman S.
AU - Marc, Janja
AU - Mellström, Dan
AU - Obermayer-Pietsch, Barbara
AU - Olmos, José M.
AU - Pettersson-Kymmer, Ulrika
AU - Reid, David M.
AU - Riancho, José A.
AU - Ridker, Paul M.
AU - Rousseau, François
AU - Slagboom, P. Eline
AU - Tang, Nelson L.S.
AU - Urreizti, Roser
AU - Van Hul, Wim
AU - Viikari, Jorma
AU - Zarrabeitia, María T.
AU - Aulchenko, Yurii S.
AU - Castano-Betancourt, Martha
AU - Grundberg, Elin
AU - Herrera, Lizbeth
AU - Ingvarsson, Thorvaldur
AU - Johannsdottir, Hrefna
AU - Kwan, Tony
AU - Li, Rui
AU - Luben, Robert
AU - Medina-Gómez, Carolina
AU - Palsson, Stefan Th
AU - Rotter, Jerome I.
AU - Sigurdsson, Gunnar
AU - Van Meurs, Joyce B.J.
AU - Verlaan, Dominique
AU - Williams, Frances M.K.
AU - Wood, Andrew R.
AU - Zhou, Yanhua
AU - Pastinen, Tomi
AU - Raychaudhuri, Soumya
AU - Cauley, Jane A.
AU - Chasman, Daniel I.
AU - Clark, Graeme R.
AU - Cummings, Steven R.
AU - Danoy, Patrick
AU - Dennison, Elaine M.
AU - Eastell, Richard
AU - Eisman, John A.
AU - Gudnason, Vilmundur
AU - Hofman, Albert
AU - Jackson, Rebecca D.
AU - Jones, Graeme
AU - Jukema, J. Wouter
AU - Khaw, Kay Tee
AU - Lehtimäki, Terho
AU - Liu, Yongmei
AU - Lorentzon, Mattias
AU - McCloskey, Eugene
AU - Mitchell, Braxton D.
AU - Nandakumar, Kannabiran
AU - Nicholson, Geoffrey C.
AU - Oostra, Ben A.
AU - Peacock, Munro
AU - Pols, Huibert A.P.
AU - Prince, Richard L.
AU - Raitakari, Olli
AU - Reid, Ian R.
AU - Robbins, John
AU - Sambrook, Philip N.
AU - Sham, Pak Chung
AU - Shuldiner, Alan R.
AU - Tylavsky, Frances A.
AU - Van Duijn, Cornelia M.
AU - Wareham, Nick J.
AU - Cupples, L. Adrienne
AU - Econs, Michael J.
AU - Evans, David M.
AU - Harris, Tamara B.
AU - Kung, Annie Wai Chee
AU - Psaty, Bruce M.
AU - Reeve, Jonathan
AU - Spector, Timothy D.
AU - Streeten, Elizabeth A.
AU - Zillikens, M. Carola
AU - Thorsteinsdottir, Unnur
AU - Ohlsson, Claes
AU - Karasik, David
AU - Richards, J. Brent
AU - Brown, Matthew A.
AU - Stefansson, Kari
AU - Uitterlinden, André G.
AU - Ralston, Stuart H.
AU - Ioannidis, John P.A.
AU - Kiel, Douglas P.
AU - Rivadeneira, Fernando
AU - GEFOS Consortium
PY - 2015/12/1
Y1 - 2015/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84958012773&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0144531
DO - 10.1371/journal.pone.0144531
M3 - Article
C2 - 26695485
AN - SCOPUS:84958012773
VL - 10
JO - PLoS ONE
JF - PLoS ONE
SN - 1932-6203
IS - 12
M1 - e0144531
ER -