title: A trans-ethnic genome-wide association study identifies gender-specific loci influencing pediatric aBMD and BMC at the distal radius.
abstract: Childhood fractures are common, with the forearm being the most common site. Genome-wide association studies (GWAS) have identified more than 60 loci associated with bone mineral density (BMD) in adults but less is known about genetic influences specific to bone in childhood. To identify novel genetic factors that influence pediatric bone strength at a common site for childhood fractures, we performed a sex-stratified trans-ethnic genome-wide association study of areal BMD (aBMD) and bone mineral content (BMC) Z-scores measured by dual energy X-ray absorptiometry at the one-third distal radius, in a cohort of 1399 children without clinical abnormalities in bone health. We tested signals with P < 5 × 10(-6) for replication in an independent, same-age cohort of 486 Caucasian children. Two loci yielded a genome-wide significant combined P-value: rs7797976 within CPED1 in females [P = 2.4 × 10(-11), β =- 0.30 standard deviations (SD) per T allele; aBMD-Z] and rs7035284 at 9p21.3 in males (P = 1.2 × 10(-8), β = 0.28 SD per G allele; BMC-Z). Signals at the CPED1-WNT16-FAM3C locus have been previously associated with BMD at other skeletal sites in adults and children. Our result at the distal radius underscores the importance of this locus at multiple skeletal sites. The 9p21.3 locus is within a gene desert, with the nearest gene flanking each side being MIR31HG and MTAP, neither of which has been implicated in BMD or BMC previously. These findings suggest that genetic determinants of childhood bone accretion at the radius, a skeletal site that is primarily cortical bone, exist and also differ by sex.
authors.affiliation: Division of Human Genetics, chesia@email.chop.edu.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Chesi
authors.affiliation: Department of Biostatistics and Epidemiology, Perelman School of Medicine and.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Mitchell
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: Center for Applied Genomics.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Bradfield
authors.affiliation: Division of Endocrinology, Department of Medicine, Creighton University, Omaha, NB, USA.
authors.forename: Joan M
authors.initials: JM
authors.lastname: Lappe
authors.affiliation: Division of Human Genetics, Division of Endocrinology and, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Shana E
authors.initials: SE
authors.lastname: McCormack
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 and.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Oberfield
authors.affiliation: Division of Human Genetics, Center for Applied Genomics, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
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 Gastroenterology, Hepatology and Nutrition, 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 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, Center for Applied Genomics, Division of Endocrinology and, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Struan F A
authors.initials: SF
authors.lastname: Grant
mesh_terms: D000293:Adolescent; D015519:Bone Density / Q000235:genetics*; D001851:Bone Diseases, Metabolic / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D010024:Osteoporosis / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D011884:Radius; D012737:Sex Factors