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 | |
| State | Published - 1 Dec 2015 |
| Externally published | Yes |
Bibliographical note
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.
Funding
This work was supported by the Research Council of Norway [grant number 183782/V50 to OAA]; the South East Norway Health Authority [grant number 2010-074 to OAA and 52009/8029 to KMG]; the National Institutes of Health [grant number T32 EB005970 to RSD, RC2DA029475 and R01HD061414 to AJS]; the Robert J. Glushko and Pamela Samuelson Graduate Fellowship to AJS; the 6th EU framework program [grant number LSHM-CT- 2003-502941 to KMG and SR]; and Oslo University Hospital, Ullevaal [grant number 52009/8029 to KMG]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors would like to thank the genome-wide association study consortia for access to summary statistics data. Andreassen and Dale had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Membership of the GEFOS Consortium of Erasmus MC University Medical Center, Rotterdam, Netherlands: GEFOS lead author: Fernando Rivadeneira ([email protected]).
| Funders | Funder number |
|---|---|
| Erasmus MC University | |
| Oslo University Hospital | |
| South East Norway Health Authority | 2010-074, 52009/8029 |
| National Institutes of Health | LSHM-CT- 2003-502941, T32 EB005970, RC2DA029475 |
| National Institute of Child Health and Human Development | R01HD061414 |
| Obstetric Anaesthetists' Association | |
| the Research Council of Norway | 183782/V50 |
