Genetic variants affecting bone mineral density and bone mineral content at multiple skeletal site in Hispanic children

Authors: HOU, RUIXUE - University Of North Carolina; COLE, SHELLY - Texas Biomedical Institute; GRAFF, MARIAELISA - University Of North Carolina; HAACK, KAREN - Texas Biomedical Institute; LASTON, SANDRA - University Of Texas Rio Grande Valley; COMUZZIE, ANTHONY - The Obesity Society; MEHTA, NITESH - Children'S Nutrition Research Center (CNRC); RYAN, KATHLEEN - University Of Maryland School Of Medicine; COUSMINER, DIANA - University Of Pennsylvania; ZEMEL, BABETTE - University Of Pennsylvania; GRANT, STRUAN F - University Of Pennsylvania; MITCHELL, BRAXTON - University Of Maryland School Of Medicine; SHYPAILO, ROMAN - Children'S Nutrition Research Center (CNRC); GOURLAY, MARGARET - University Of North Carolina; NORTH, KARI - University Of North Carolina; BUTTE, NANCY - Children'S Nutrition Research Center (CNRC); VORUGANTI, V. SAROJA - University Of North Carolina

Submitted to: Bone
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/22/2019
Publication Date: 11/29/2019
Citation: Hou, R., Cole, S.A., Graff, M., Haack, K., Laston, S., Comuzzie, A.G., Mehta, N.R., Ryan, K., Cousminer, D.L., Zemel, B.S., Grant, S.A., Mitchell, B.D., Shypailo, R.J., Gourlay, M.L., North, K.E., Butte, N.F., Voruganti, V. 2020. Genetic variants affecting bone mineral density and bone mineral content at multiple skeletal site in Hispanic children. Bone. 132:115175. https://doi.org/10.1016/j.bone.2019.115175.
DOI: https://doi.org/10.1016/j.bone.2019.115175

Interpretive Summary: Osteoporosis, a major public health threat for millions of people in the U.S., is more common in Mexican Americans compared to other ethnicities. However, factors related to bone health are not well studied in Hispanics, especially in children. Genetic factors play a role in bone health, but most genetic studies have been done in adults. We wanted to look at genetic factors associated with bone mineral content (BMC) and bone mineral density (BMD) that we measured by dual-energy x-ray absorptiometry (DXA). The data came from a family-based study – Viva La Familia Study (VFS) – that included 1030 Hispanic children from 4-19 years of age. DNA obtained from blood samples was processed to identify various genetic markers. We also measured body weight, height, and BMI. We analyzed the genetic data to identify chromosomal locations affecting variations in bone, and to estimate heritability. We also included age, sex, BMI, and sexual maturity levels in models identifying gene locations associated with bone characteristics. We found that heritability was significant for all skeletal sites, such as spine, pelvis, and total body. We identified several novel genetic locations associated with BMC and BMD. This will lead to a better understanding of bone genetics and help us understand the biological mechanisms behind bone variations.

Technical Abstract: Osteoporosis is a major public health burden with significant economic costs. However, the correlates of bone health in Hispanic children are understudied. We aimed to identify genetic variants associated with bone mineral density (BMD) and bone mineral content (BMC) at multiple skeletal sites in Hispanic children. We conducted a cross-sectional genome-wide linkage analysis, genome-wide and exome-wide association analysis of BMD and BMC. The Viva La Familia Study is a family-based cohort with a total of 1030 Hispanic children (4–19 years old at baseline) conducted in Houston, TX. BMD and BMC were measured by Dual-energy X-ray absorptiometry. Significant heritability were observed for BMC and BMD at multiple skeletal sites ranging between 44 and 68% (P < 2.8 x 10-9). Significant evidence for linkage was found for BMD of pelvis and left leg on chromosome 7p14, lumbar spine on 20q13 and left rib on 6p21, and BMC of pelvis on chromosome 20q12 and total body on 14q22-23 (logarithm of odds score > 3). We found genome-wide significant association between BMC of right arm and rs762920 at PVALB (P = 4.6 x 10-8), and between pelvis BMD and rs7000615 at PTK2B (P = 7.4 x 10-8). Exome-wide association analysis revealed novel association of variants at MEGF10 and ABRAXAS2 with left arm and lumber spine BMC, respectively (P < 9 x 10-7). We identified novel loci associated with BMC and BMD in Hispanic children, with strongest evidence for PTK2B. These findings provide better understanding of bone genetics and shed light on biological mechanisms underlying BMD and BMC variation.