title: Genetic Risk Scores Implicated in Adult Bone Fragility Associate With Pediatric Bone Density.
abstract: Using adult identified bone mineral density (BMD) loci, we calculated genetic risk scores (GRS) to determine if they were associated with changes in BMD during childhood. Longitudinal data from the Bone Mineral Density in Childhood Study were analyzed (N = 798, 54% female, all European ancestry). Participants had up to 6 annual dual energy X-ray scans, from which areal BMD (aBMD) Z-scores for the spine, total hip, and femoral neck were estimated, as well as total body less head bone mineral content (TBLH-BMC) Z-scores. Sixty-three single-nucleotide polymorphisms (SNPs) were genotyped, and the percentage of BMD-lowering alleles carried was calculated (overall adult GRS). Subtype GRS that include SNPs associated with fracture risk, pediatric BMD, WNT signaling, RANK-RANKL-OPG, and mesenchymal stem cell differentiation were also calculated. Linear mixed effects models were used to test associations between each GRS and bone Z-scores, and if any association differed by sex and/or chronological age. The overall adult, fracture, and WNT signaling GRS were associated with lower Z-scores (eg, spine aBMD Z-score: βadult  = -0.04, p = 3.4 × 10(-7) ; βfracture = -0.02, p = 8.9 × 10(-6) ; βWNT  = -0.01, p = 3.9 × 10(-4) ). The overall adult GRS was more strongly associated with lower Z-scores in females (p-interaction ≤ 0.05 for all sites). The fracture GRS was more strongly associated with lower Z-scores with increasing age (p-interaction ≤ 0.05 for all sites). The WNT GRS associations remained consistent for both sexes and all ages (p-interaction > 0.05 for all sites). The RANK-RANKL-OPG GRS was more strongly associated in females with increasing age (p-interaction < 0.05 for all sites). The mesenchymal stem cell GRS was associated with lower total hip and femoral neck Z-scores, in both boys and girls, across all ages. No associations were observed between the pediatric GRS and bone Z-scores. In conclusion, adult identified BMD loci associated with BMD and BMC in the pediatric setting, especially in females and in loci involved in fracture risk and WNT signaling.
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Mitchell
authors.affiliation: Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Chesi
authors.affiliation: Biostatistics and Data Management Core, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Okan
authors.initials: O
authors.lastname: Elci
authors.affiliation: Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Shana E
authors.initials: SE
authors.lastname: McCormack
authors.affiliation: Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Sani M
authors.initials: SM
authors.lastname: Roy
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Heidi J
authors.initials: HJ
authors.lastname: Kalkwarf
authors.affiliation: Division of Endocrinology, Department of Medicine, Creighton University, Omaha, NE, USA.
authors.forename: Joan M
authors.initials: JM
authors.lastname: Lappe
authors.affiliation: Department of Radiology, Children's Hospital Los Angeles, Los Angeles, CA, USA.
authors.forename: Vicente
authors.initials: V
authors.lastname: Gilsanz
authors.affiliation: Division of Pediatric Endocrinology, Diabetes, and Metabolism, Department of Pediatrics, Columbia University Medical Center, New York, NY, USA.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Oberfield
authors.affiliation: Department of Radiology, University of California San Francisco, San Francisco, CA, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Shepherd
authors.affiliation: Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Kelly
authors.affiliation: Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Struan Fa
authors.initials: SF
authors.lastname: Grant
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Babette S
authors.initials: BS
authors.lastname: Zemel
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D015519:Bone Density / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D002648:Child; D005260:Female; D005500:Follow-Up Studies; D050723:Fractures, Bone / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics / Q000378:metabolism; D018570:Risk Assessment; D012307:Risk Factors; D012737:Sex Factors
chemical_list: D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human
keywords: CHILDHOOD; DXA; GENERAL POPULATION STUDIES; GENETIC RESEARCH; PUBERTY