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

Department of Medical Biochemistry
University of Oslo
Lovisenberg Diakonale Hospital
Institute of Basic Medical Sciences
Norwegian Centre for Mental Disorders Research (NORMENT)
Division of Mental Health and Addiction
University of California at San Diego
Multimodal Imaging Laboratory
Cognitive Sciences Graduate Program
Department of Clinical Molecular Biology
Oslo Centre for Biostatistics and Epidemiology
Prostate Cancer Research Group
Department of Clinical Biochemistry
Lovisenberg Deacon Hospital
Department of Internal Medicine
Erasmus University Rotterdam
Department of Epidemiology
Netherlands Genomics Initiative
deCODE Genetics
Department of Hygiene and Epidemiology
University of Ioannina
Institute for Aging Research
Department of Medicine
Harvard University
Human Genetics Group
University of Queensland
Department of Endocrinology
Royal Brisbane and Women's Hospital
University of Edinburgh
University of Bristol
Department of Medical and Molecular Genetics
Indiana University-Purdue University Indianapolis
Cardiovascular Health Research Unit
University of Washington
Department of Biostatistics
Boston University
Department of Human Genetics
University of Pittsburgh
Department of Public Health and Primary Care
University of Cambridge
Department of Twin Research and Genetic Epidemiology
King's College London
Centre for Bone and Arthritis Research
University of Gothenburg
Australian Centre for Ecogenomics
Department of Medicine
The University of Hong Kong
Research Centre of Heart
Division of Endocrinology, Diabetes, and Nutrition
University of Maryland, Baltimore
Department of Human Genetics
Sir Mortimer B. Davis-Jewish General Hospital
Rheumatic Diseases Unit
University of Western Australia
Department of Endocrinology and Diabetes
Sir Charles Gairdner Hospital
Centre for Population Health Sciences
Department of Clinical Physiology
University of Turku
Department of Medical Rehabilitation
University of Oulu
Division of Public Health Sciences
Fred Hutchinson Cancer Research Center
Icelandic Heart Association
University of Iceland
Osteoporosis and Bone Biology Program
Garvan Institute of Medical Research
Department of Medicine
University of New South Wales
Department of Endocrinology
St. Vincent's Hospital Sydney
Department of Orthopaedic Surgery
University of Thessaly
Translational Genomics Research Institute
Laboratory of Epidemiology
National Institutes of Health

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

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10.1371/journal.pone.0144531

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@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

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