Multiple GWAS-Implicated Adult Height Loci Operate in the Context of Pediatric Bone Mineral Density and Content Determination

Presentation Number: LB-OR01-5
Date of Presentation: March 5th, 2015

Kevin J Basile*1, Alessandra Chesi2, Jonathan A. Mitchell3, Shana E. McCormack2, Sani M. Roy2, Heidi J. Kalkwarf4, Joan M. Lappe5, Vicente Gilsanz6, Sharon E Oberfield7, John A. Shepherd8, Andrea Kelly2, Babette S. Zemel2 and Struan F.A. Grant9
1Children's Hospital of Philadelphia, Philadelphia, PA, 2The Children's Hospital of Philadelphia, Philadelphia, PA, 3University of Pennsylvania, 4Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 5Creighton University, Omaha, NE, 6Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, 7Columbia University College of Physicians and Surgeons, New York, NY, 8University of California San Francisco, San Francisco, CA, 9The Children's Hospital of Philadelphia, Philadelphia

Abstract

Background: Height is a complex trait influenced by environmental and genetic factors operating in a number of biological pathways, including those related to hormone activity and bone accretion. The most recent meta-analysis of genome-wide association studies of adult height identified 697 variants corresponding to 423 distinct genomic loci, which collectively account for up to one-fifth of this trait’s heritability. However, the physiological route by which these genetic variants influence an individual’s overall height is not known.

 

Objective/Methods: Stature reflects skeletal size, which is achieved by bone mineral accretion during childhood growth. Thus, we investigated the effects of genetic variants known to associate with adult height on pediatric bone mineral content and density. We leveraged a prospective observational study of 691 participants of European ancestry enrolled in the Bone Mineral Density in Childhood Study (52% female), then sought further support from an additional cohort of 472 Caucasian subjects (51% female). Bone mineral content (BMC) and areal bone mineral density (aBMD) of the radius, hip, spine and total body (to estimate head and whole body BMC/aBMD) were assessed by dual energy X-ray absorptiometry (DXA) and expressed as age and sex-specific Z-scores. We further tested bone Z-scores adjusted for height-for-age Z-score to account for known effects of size on DXA outcomes. DNA was extracted from blood/saliva and genotyped using high-throughput technology. Genotyping of subjects was performed at the Children’s Hospital of Philadelphia using the Illumina Infinium™ II OMNI Express plus Exome BeadChip technology.

 

Results: Three of the loci previously linked to adult height yielded Bonferroni-corrected significance for association with pediatric bone accretion at specific skeletal sites. These loci were rs3750972 at TPCN2 for head aBMD in males (P = 5.48x10-5; ß = 0.241), rs6952113 at C7orf58 (also known as CPED1) for both BMC and aBMD at the distal radius in females (P = 1.63x10-5; ß = -0.250 and P = 6.30x10-8; ß = -0.317, respectively), and rs2781373 at MAX with aBMD at the distal radius in females (P = 3.22x10-5; ß = 0.243). These loci did not show any degree of significant association with height Z-score, nor did height adjustment of BMC/aBMD outcomes dramatically alter the significance of association of these loci to their respective skeletal phenotypes. Additionally, 19 other adult height loci demonstrated at least a nominally significant, directionally consistent association in both the discovery and replication cohorts for a variety of other skeletal phenotypes.

 

Conclusions: These results indicate that at least some of the genetic variants associated with adult height may be exerting their influence via alterations in pediatric bone accretion. Additionally, our data have implicated TPCN2 and MAX as novel pediatric bone density loci.

 

Nothing to Disclose: KJB, AC, JAM, SEM, SMR, HJK, JML, VG, SEO, JAS, AK, BSZ, SFAG