TY - JOUR
T1 - Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci
AU - GEFOS Consortium
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 - Van Schoor, Natasja M.
AU - Lips, Paul
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 - https://doi.org/10.1371/journal.pone.0144531
DO - https://doi.org/10.1371/journal.pone.0144531
M3 - Article
C2 - 26695485
SN - 1932-6203
VL - 10
JO - PLOS ONE
JF - PLOS ONE
IS - 12
M1 - e0144531
ER -