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PLoS One. 2015 Dec 22;10(12):e0144531. doi: 10.1371/journal.pone.0144531. eCollection 2015.

Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci.

Author information

1
Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.
2
Lovisenberg Diakonale Hospital, Oslo, Norway.
3
Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
4
NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
5
Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
6
Department of Psychiatry, University of California San Diego, La Jolla, California, United States of America.
7
Department of Neurosciences, University of California San Diego, La Jolla, California, United States of America.
8
Multimodal Imaging Laboratory, University of California San Diego, La Jolla, California, United States of America.
9
Department of Radiology, University of California San Diego, La Jolla, California, United States of America.
10
Cognitive Sciences Graduate Program, University of California San Diego, La Jolla, California, United States of America.
11
Department of Clinical Molecular Biology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
12
Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, University of Oslo, Oslo, Norway.
13
Prostate Cancer Research Group, Centre for Molecular Medicine Norway (NCMM), University of Oslo and Oslo University Hospital, Oslo, Norway.

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.

PMID:
26695485
PMCID:
PMC4687843
DOI:
10.1371/journal.pone.0144531
[Indexed for MEDLINE]
Free PMC Article

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