ICCBH2013 Oral Communications Epidemiology (6 abstracts)
Role of bone-associated loci identified in GWAS meta-analyses in the context of longitudinal pediatric BMD in European Americans
Babette Zemel 1, , Heidi Kalkwarf 2 , Mingyao Li 3 , Sandra Deliard 1 , Celia Kim 1 , Liming Qu 3 , Rosetta Chiavacci 1 , Donna Paulhamus 1 , Joan Lappe 4 , Vicente Gilsanz 5 , Hakon Hakonarson 1, , Sharon Oberfield 6 , John Shepherd 7 , Ben Voight 1, , Andrea Kelly 1, & Struan Grant 1,
1Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; 2Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA; 3University of Pennsylvania, Philadelphia, Pennsylvania, USA; 4Creighton University, Omaha, Nebraska, USA; 5Children’s Hospital, Los Angeles, California, USA; 6Columbia University Medical Center, New York, New York, USA; 7University of California, San Francisco, California, USA.
Objective: With recent genome wide association studies (GWAS), ~70 loci have been robustly and reproducibly associated with adult bone density and/or osteoporosis. However, to date no systematic effort has investigated which of these loci operate early in life. We investigated whether these single nucleotide polymorphisms (SNPs) are associated with childhood areal bone mineral density (aBMD). In addition we determined if any of the associations were age dependent.
Methods: The Bone Mineral Density in Childhood Study (BMDCS) was a multi-center, multi-ethnic longitudinal study that enrolled ~2000 subjects, (ages 5–19). aBMD was measured annually (up to 7 years) using Hologic DXA devices. Scans were analyzed centrally and adjusted for inter-site differences and longitudinal drift. Additional measures included growth, puberty stage, and dietary intake and physical activity. Blood or saliva was collected at the final visit and genotyped on the Illumina Human OmniExpress BeadChip, involving in excess of 700 000 markers. Principal component analysis and self-report were used to restrict the cohort to subjects of European ancestry. Longitudinal mixed effects models were used to test for associations between spine BMD Z-score and all SNPs previously identified in adulthood, while accounting for sibships and multiple observations on the same subject. All models included adjustment for height and BMI Z-score, age, sex, puberty, calcium intake and physical activity. SNPs were included in the model as an additive trait. A SNP×age interaction term was also included to assess whether the associations changed relative to age. Significance was determined at a nominal P value of 0.05.
Results: The following GWAS-established adult bone density loci were associated with spine aBMD: LACTB2(+), GPATCH1(+), DHH(+), WLS(−), IDUA(+), LRP5(+), SPTBN1(+) and STARD3NL(+). In addition, significant SNP×age interactions were identified for: ARHGAP1, SP7, GPATCH1, JAG1, MEF2C, FOXL1, PKDCC, SMG6, C17orf53, C16orf38/CLCN7, CYLD, INSIG2, WNT16, CTNNB1, NTAN1, FAM9B, LRP4, SPTBN1, TNFRSF11B, FUBP3, KCNMA1, SOX9, KLHDC5/PTHLH and C6orf97/ESR1.
Conclusions: These findings suggest that multiple variants originally associated with adult bone density are in fact exerting their effects early on in life, and become increasingly expressed as children increase in age.
Support: R01 HD058886 and U54 RR024134.
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