title: Genetics of Bone Mass in Childhood and Adolescence: Effects of Sex and Maturation Interactions.
abstract: We aimed to determine if adult bone mineral density (BMD) susceptibility loci were associated with pediatric bone mass and density, and if sex and pubertal stage influenced any association. We analyzed prospective areal BMD (aBMD) and bone mineral content (BMC) data from the Bone Mineral Density in Childhood Study (n = 603, European ancestry, 54% female). Linear mixed models were used to assess if 77 single-nucleotide polymorphisms (SNPs) near known adult BMD susceptibility loci interacted with sex and pubertal stage to influence the aBMD/BMC; adjusting for age, BMI, physical activity, and dietary calcium. The strongest main association was observed between an SNP near C7orf58 and distal radius aBMD. However, this association had a significant sex • SNP interaction, revealing a significant association only in females (b = -0.32, p = 1.8 × 10(-6)). Furthermore, the C12orf23 locus had significant interactions with both sex and pubertal stage, revealing associations in females during Tanner stage I for total hip aBMD (b = 0.24, p = 0.001) and femoral neck aBMD (b = 0.27, p = 3.0 × 10(-5)). In contrast, the sex • SNP interactions for loci near LRP5 and WNT16 uncovered associations that were only in males for total body less head BMC (b = 0.22, p = 4.4 × 10(-4)) and distal radius aBMD (b = 0.27, p = 0.001), respectively. Furthermore, the LRP5 locus interacted with both sex and pubertal stage, demonstrating associations that were exclusively in males during Tanner V for total hip aBMD (b = 0.29, p = 0.003). In total, significant sex • SNP interactions were found at 15 loci; pubertal stage • SNP interactions at 23 loci and 19 loci interacted with both sex and pubertal stage. In conclusion, variants originally associated with adult BMD influence bone mass in children of European ancestry, highlighting the fact that many of these loci operate early in life. However, the direction and magnitude of associations for a large number of SNPs only became evident when accounting for sex and maturation.
authors.affiliation: Department of Biostatistics and Epidemiology, 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.
authors.forename: Shana E
authors.initials: SE
authors.lastname: McCormack
authors.affiliation: Division of General and Community Pediatrics, 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.
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 Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Babette S
authors.initials: BS
authors.lastname: Zemel
authors.affiliation: Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.|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.
authors.forename: Struan F A
authors.initials: SF
authors.lastname: Grant
mesh_terms: D000293:Adolescent; D000328:Adult; D015519:Bone Density / Q000235:genetics*; D001846:Bone Development; D001842:Bone and Bones / Q000502:physiology*; D002136:Calcium, Dietary; D002648:Child; D002675:Child, Preschool; D003720:Densitometry; D005260:Female; D050723:Fractures, Bone / Q000473:pathology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011627:Puberty / Q000502:physiology*; D012737:Sex Factors; D014481:United States; D055815:Young Adult
chemical_list: D002136:Calcium, Dietary; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5
keywords: CHILDHOOD; DXA; GENERAL POPULATION STUDIES; GENETIC RESEARCH; PUBERTY