A Genomewide Association Study Identifies Two Sex-Specific Loci, at SPTB and IZUMO3, Influencing Pediatric Bone Mineral Density at Multiple Skeletal Sites.
Failure to achieve optimal bone mineral accretion during childhood and adolescence results in subsequent suboptimal peak bone mass, contributing to osteoporosis risk later in life. To identify novel genetic factors that influence pediatric bone mass at discrete skeletal sites, we performed a sex-stratified genomewide association study of areal bone mineral density (BMD) measured by dual-energy X-ray absorptiometry at the 1/3 distal radius, spine, total hip, and femoral neck in a cohort of 933 healthy European American children. We took forward signals with p < 5 × 10-5and minor allele frequency (MAF) >5% into an independent cohort of 486 European American children in search of replication. In doing so, we identified five loci that achieved genome wide significance in the combined cohorts (nearest genes: CPED1, IZUMO3, RBFOX1, SPBT, and TBPL2), of which the last four were novel and two were sex-specific (SPTB in females and IZUMO3 in males), with all of them yielding associations that were particularly strong at a specific skeletal site. Annotation of potential regulatory function, expression quantitative trait loci (eQTL) effects and pathway analyses identified several potential target genes at these associated loci. This study highlights the importance of sex-stratified analyses at discrete skeletal sites during the critical period of bone accrual, and identifies novel loci for further functional follow-up to pinpoint key genes and better understand the regulation of bone development in children. © 2017 American Society for Bone and Mineral Research.
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Alessandra
A
Chesi
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.
Jonathan A
JA
Mitchell
Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Heidi J
HJ
Kalkwarf
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Jonathan P
JP
Bradfield
Division of Endocrinology, Department of Medicine, Creighton University, Omaha, NE, USA.
Joan M
JM
Lappe
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.
Diana L
DL
Cousminer
Division of Endocrinology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Sani M
SM
Roy
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Division of Endocrinology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Shana E
SE
McCormack
Department of Radiology, Children's Hospital Los Angeles, Los Angeles, CA, USA.
Vicente
V
Gilsanz
Division of Pediatric Endocrinology, Diabetes, and Metabolism, Department of Pediatrics, Columbia University Medical Center, New York, NY, USA.
Sharon E
SE
Oberfield
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Hakon
H
Hakonarson
Department of Radiology, University of California San Francisco, San Francisco, CA, USA.
John A
JA
Shepherd
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Division of Endocrinology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Andrea
A
Kelly
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.
Babette S
BS
Zemel
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Division of Endocrinology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Struan Fa
SF
Grant
D000293:Adolescent; D015519:Bone Density / Q000235:genetics*; D001842:Bone and Bones / Q000502:physiology*; D002648:Child; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D058977:Molecular Sequence Annotation; D040641:Quantitative Trait Loci / Q000235:genetics*; D012727:Sex Characteristics; D013049:Spectrin / Q000235:genetics*; D055815:Young Adult
C000626581:IZUMO3 protein, human; D007136:Immunoglobulins; D008565:Membrane Proteins; C000626580:SPTB protein, human; D013049:Spectrin
ANALYSIS/QUANTITATION OF BONE; DXA ANALYSIS; GENETIC RESEARCH; HUMAN ASSOCIATION STUDIES