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

GEFOS Consortium

doi:10.1371/journal.pone.0144531

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

GEFOS Consortium

University of Oslo
Lovisenberg Diakonale Hospital
University of California at San Diego
Lovisenberg Deacon Hospital
Erasmus University Rotterdam
Netherlands Genomics Initiative
deCODE Genetics
University of Ioannina
Institute for Aging Research
Harvard University
University of Queensland
Royal Brisbane and Women's Hospital
University of Edinburgh
University of Bristol
Indiana University-Purdue University Indianapolis
University of Washington
Boston University
University of Pittsburgh
University of Cambridge
King's College London
University of Gothenburg
The University of Hong Kong
University of Maryland, Baltimore
Sir Mortimer B. Davis-Jewish General Hospital
University of Western Australia
Sir Charles Gairdner Hospital
University of Turku
University of Oulu
Fred Hutchinson Cancer Research Center
Icelandic Heart Association
University of Iceland
Garvan Institute of Medical Research
University of New South Wales
St. Vincent's Hospital Sydney
University of Thessaly
Translational Genomics Research Institute
National Institutes of Health
Autonomous University of Barcelona
Hôpital du Saint-Sacrement
Umeå University
University of Aberdeen
Aarhus University
MRC Lifecourse Epidemiology Unit
Russian Academy of Sciences
Ufa University of Science and Technology
University of Ulsan
National and Kapodistrian University of Athens
Children's Memorial Health Institute
University of Helsinki
Chinese University of Hong Kong
University of Florence
University of Ljubljana
University of British Columbia
University Medical Center
Brigham and Women’s Hospital
Leiden University
Medical University of Graz
Vrije Universiteit (VU)
University of Barcelona
University College Cork
University of Jyväskylä
University of Eastern Finland
Center for Clinical and Basic Research A/S
Harokopio University
University of Glasgow
University of Southern Denmark
McGill University
Universidad de Cantabria
Hospital Universitario Marques de Valdecilla
Tampere University
Lund University
University of Manitoba
VU University Medical Center
Uppsala University
Université Laval
University of Antwerp
Wellcome Trust Sanger Institute
Akureyri Hospital
University of Akureyri
Cedars-Sinai Medical Center
Landspitali University Hospital
University of Exeter
Broad Institute
California Pacific Medical Center
University of Sheffield
Ohio State University
University of Tasmania
Durrer Center for Cardiovascular Research
Royal Netherlands Academy of Arts and Sciences
Wake Forest University
The University of Auckland
University of Davis
Kolling Institute of Medical Research
Department of Veterans Affairs
University of Tennessee Health Science Center
Medical Research Council
National Heart Lung and Blood Institute’s and Boston University’s Framingham Heart Study
Group Health Cooperative
Stanford University

Research output: Contribution to journal › Article › peer-review

16 Citations (Scopus)

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	https://doi.org/10.1371/journal.pone.0144531
Publication status	Published - 1 Dec 2015
Externally published	Yes

Access to Document

10.1371/journal.pone.0144531

Cite this

@article{ac029c91bca04290b251249d862305e3,

title = "Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci",

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.",

author = "\{GEFOS Consortium\} and Sjur Reppe and Yunpeng Wang and Thompson, \{Wesley K.\} and McEvoy, \{Linda K.\} and Schork, \{Andrew J.\} and Verena Zuber and Marissa LeBlanc and Francesco Bettella and Mills, \{Ian G.\} and Desikan, \{Rahul S.\} and Srdjan Djurovic and Gautvik, \{Kaare M.\} and Dale, \{Anders M.\} and Andreassen, \{Ole A.\} and Karol Estrada and Unnur Styrkarsdottir and Evangelos Evangelou and Hsu, \{Yi Hsiang\} and Duncan, \{Emma L.\} and Ntzani, \{Evangelia E.\} and Ling Oei and Albagha, \{Omar M.E.\} and Najaf Amin and Kemp, \{John P.\} and Koller, \{Daniel L.\} and Guo Li and Liu, \{Ching Ti\} and Minster, \{Ryan L.\} and Alireza Moayyeri and Liesbeth Vandenput and Dana Willner and Xiao, \{Su Mei\} and Yerges-Armstrong, \{Laura M.\} and Zheng, \{Hou Feng\} and Nerea Alonso and Joel Eriksson and Kammerer, \{Candace M.\} and Kaptoge, \{Stephen K.\} and Leo, \{Paul J.\} and Gudmar Thorleifsson and Wilson, \{Scott G.\} and Wilson, \{James F.\} and Ville Aalto and Markku Alen and Aragaki, \{Aaron K.\} and Thor Aspelund and Center, \{Jacqueline R.\} and Zoe Dailiana and Duggan, \{David J.\} and Melissa Garcia",

note = "Publisher Copyright: {\textcopyright} 2015 Reppe et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

year = "2015",

month = dec,

day = "1",

doi = "10.1371/journal.pone.0144531",

language = "English",

volume = "10",

journal = "PLoS ONE",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "12",

}

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 - Duggan, David J.

AU - Garcia, Melissa

N1 - Publisher Copyright: © 2015 Reppe et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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 - https://www.scopus.com/pages/publications/84958012773

U2 - 10.1371/journal.pone.0144531

DO - 10.1371/journal.pone.0144531

M3 - Article

C2 - 26695485

AN - SCOPUS:84958012773

SN - 1932-6203

VL - 10

JO - PLoS ONE

JF - PLoS ONE

IS - 12

M1 - e0144531

ER -

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

Abstract

Access to Document

Other files and links

Fingerprint

Cite this