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.
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.|Lovisenberg Diakonale Hospital, Oslo, Norway.|Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Sjur
authors.initials: S
authors.lastname: Reppe
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.|Department of Psychiatry, University of California San Diego, La Jolla, California, United States of America.|Department of Neurosciences, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Wesley K
authors.initials: WK
authors.lastname: Thompson
authors.affiliation: Multimodal Imaging Laboratory, University of California San Diego, La Jolla, California, United States of America.|Department of Radiology, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Linda K
authors.initials: LK
authors.lastname: McEvoy
authors.affiliation: Multimodal Imaging Laboratory, University of California San Diego, La Jolla, California, United States of America.|Cognitive Sciences Graduate Program, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Schork
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors.forename: Verena
authors.initials: V
authors.lastname: Zuber
authors.affiliation: Department of Clinical Molecular Biology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, University of Oslo, Oslo, Norway.
authors.forename: Marissa
authors.initials: M
authors.lastname: LeBlanc
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bettella
authors.affiliation: Prostate Cancer Research Group, Centre for Molecular Medicine Norway (NCMM), University of Oslo and Oslo University Hospital, Oslo, Norway.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Mills
authors.affiliation: Multimodal Imaging Laboratory, University of California San Diego, La Jolla, California, United States of America.|Department of Radiology, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Rahul S
authors.initials: RS
authors.lastname: Desikan
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors.forename: Srdjan
authors.initials: S
authors.lastname: Djurovic
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.|Lovisenberg Diakonale Hospital, Oslo, Norway.|Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Kaare M
authors.initials: KM
authors.lastname: Gautvik
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, California, United States of America.|Department of Neurosciences, University of California San Diego, La Jolla, California, United States of America.|Multimodal Imaging Laboratory, University of California San Diego, La Jolla, California, United States of America.|Department of Radiology, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Anders M
authors.initials: AM
authors.lastname: Dale
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.|Department of Psychiatry, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Ole A
authors.initials: OA
authors.lastname: Andreassen
mesh_terms: D015519:Bone Density; D002318:Cardiovascular Diseases / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D053263:Gene Regulatory Networks; D056426:Genetic Loci; D058685:Genetic Pleiotropy; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D049629:Waist-Hip Ratio