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

Hou, Ruixue; Cole, Shelley A.; Graff, Mariaelisa; Haack, Karin; Laston, Sandra; Comuzzie, Anthony G.; Mehta, Nitesh R.; Ryan, Kathleen; Cousminer, Diana L.; Zemel, Babette S.; Grant, Struan F. A.; Mitchell, Braxton D.; Shypailo, Roman J.; Gourlay, Margaret L.; North, Kari E.; Butte, Nancy F.; Voruganti, V. Saroja

Affiliations

¹Department of Nutrition and Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC, USA

²Population Health Program, Texas Biomedical Research Institute, San Antonio, TX, USA

³Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

⁴South Texas Diabetes and Obesity Institute and Department of Human Genetics, University of Texas the Rio Grande Valley, Brownsville, TX, USA

⁵The Obesity Society, Silver Spring, MD, USA

⁶Department of Pediatrics and USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA

⁷Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

⁸Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, USA

⁹Division of Human Genetics, Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, USA

¹⁰Department of Genetics, University of Pennsylvania, USA

¹¹Division of GI, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, USA

¹²Department of Pediatrics, University of Pennsylvania, Philadelphia, USA

¹³Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

¹⁴Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA, USA

¹⁵Department of Family Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Abstract and keywords

Context: Osteoporosis is a major public health burden with significant economic costs. However, the correlates of bone health in Hispanic children are understudied.

Objective: We aimed to identify genetic variants associated with bone mineral density (BMD) and bone mineral content (BMC) at multiple skeletal sites in Hispanic children.

Methods: 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.

Results: Significant heritability were observed for BMC and BMD at multiple skeletal sites ranging between 44 and 68% (P < 2.8 × 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 × 10⁻⁸), and between pelvis BMD and rs7000615 at PTK2B (P = 7.4 × 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 × 10⁻⁷).

Conclusions: 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.

Keywords: Bone; Genetic variants; Hispanic; Children; Osteoporosis

Links

DOI: 10.1016/j.bone.2019.115175

PubMed: 31790847

WoS: 000510529200001

History

Received: 2019-06-27

Revised: 2019-11-22

Accepted: 2019-11-22

Online: 2019-11-29

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Cited By (1)

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2020	Zhang H, Zhang Y, Terajima M, Romanowicz G, Liu Y, Omi M, Bigelow E, Joiner DM, Waldorff EI, Zhu P, Raghavan M, Lynch M, Kamiya N, Zhang R, Jepsen KJ, Goldstein S, Morris MD, Yamauchi M, Kohn DH, Mishina Y. Loss of BMP signaling mediated by BMPR1A in osteoblasts leads to differential bone phenotypes in mice depending on anatomical location of the bones. Bone. August 2020;137:115402.