Ruixue Hou1, Shelley A Cole2, Mariaelisa Graff3, Karin Haack2, Sandra Laston4, Anthony G Comuzzie5, Nitesh R Mehta6, Kathleen Ryan7, Diana L Cousminer8, Babette S Zemel9, Struan F A Grant10, Braxton D Mitchell7, Roman J Shypailo6, Margaret L Gourlay11, Kari E North3, Nancy F Butte6, V Saroja Voruganti12. 1. Department of Nutrition and Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC, USA. 2. Population Health Program, Texas Biomedical Research Institute, San Antonio, TX, USA. 3. Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 4. South Texas Diabetes and Obesity Institute and Department of Human Genetics, University of Texas the Rio Grande Valley, Brownsville, TX, USA. 5. The Obesity Society, Silver Spring, MD, USA. 6. Department of Pediatrics and USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA. 7. Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.; Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, USA. 8. Division of Human Genetics, Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, USA; Department of Genetics, University of Pennsylvania, USA. 9. Division of GI, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, University of Pennsylvania, Philadelphia, USA. 10. Division of Human Genetics, Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, USA; Department of Pediatrics, University of Pennsylvania, Philadelphia, USA; Department of Genetics, University of Pennsylvania, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA, USA. 11. Department of Family Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 12. Department of Nutrition and Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC, USA. Electronic address: saroja@unc.edu.
Abstract
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.
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.
Authors: Augustine Kong; Daniel F Gudbjartsson; Jesus Sainz; Gudrun M Jonsdottir; Sigurjon A Gudjonsson; Bjorgvin Richardsson; Sigrun Sigurdardottir; John Barnard; Bjorn Hallbeck; Gisli Masson; Adam Shlien; Stefan T Palsson; Michael L Frigge; Thorgeir E Thorgeirsson; Jeffrey R Gulcher; Kari Stefansson Journal: Nat Genet Date: 2002-06-10 Impact factor: 38.330
Authors: Eva Riveira-Munoz; Olivier Devuyst; Hendrica Belge; Nikola Jeck; Laurence Strompf; Rosa Vargas-Poussou; Xavier Jeunemaître; Anne Blanchard; Nine V Knoers; Martin Konrad; Karin Dahan Journal: Nephrol Dial Transplant Date: 2008-05-09 Impact factor: 5.992
Authors: Mark I McCarthy; Gonçalo R Abecasis; Lon R Cardon; David B Goldstein; Julian Little; John P A Ioannidis; Joel N Hirschhorn Journal: Nat Rev Genet Date: 2008-05 Impact factor: 53.242
Authors: Elizabeth A Streeten; Daniel J McBride; Toni I Pollin; Kathy Ryan; Jay Shapiro; Sandy Ott; Braxton D Mitchell; Alan R Shuldiner; Jeffery R O'Connell Journal: J Bone Miner Res Date: 2006-09 Impact factor: 6.741
Authors: Stuart H Ralston; Nick Galwey; Ian MacKay; Omar M E Albagha; Lon Cardon; Juliet E Compston; Cyrus Cooper; Emma Duncan; Richard Keen; Bente Langdahl; Alastair McLellan; Jeffrey O'Riordan; Huibert A Pols; David M Reid; Andre G Uitterlinden; John Wass; Simon T Bennett Journal: Hum Mol Genet Date: 2005-03-03 Impact factor: 6.150
Authors: Leonard Buckbinder; David T Crawford; Hong Qi; Hua Zhu Ke; Lisa M Olson; Kelly R Long; Peter C Bonnette; Amy P Baumann; John E Hambor; William A Grasser; Lydia C Pan; Thomas A Owen; Michael J Luzzio; Catherine A Hulford; David F Gebhard; Vishwas M Paralkar; Hollis A Simmons; John C Kath; W Gregory Roberts; Steven L Smock; Angel Guzman-Perez; Thomas A Brown; Mei Li Journal: Proc Natl Acad Sci U S A Date: 2007-05-30 Impact factor: 11.205
Authors: Jonathan A Mitchell; Alessandra Chesi; Diana L Cousminer; Shana E McCormack; Heidi J Kalkwarf; Joan M Lappe; Vicente Gilsanz; Sharon E Oberfield; John A Shepherd; Andrea Kelly; Babette S Zemel; Struan Fa Grant Journal: J Bone Miner Res Date: 2018-03-30 Impact factor: 6.741
Authors: Sergey A Krupenko; Shelley A Cole; Ruixue Hou; Karin Haack; Sandra Laston; Nitesh R Mehta; Anthony G Comuzzie; Nancy F Butte; V Saroja Voruganti Journal: Am J Clin Nutr Date: 2022-08-04 Impact factor: 8.472
Authors: Ruixue Hou; Shelley A Cole; Mariaelisa Graff; Yujie Wang; Karin Haack; Sandra Laston; Nitesh R Mehta; Roman J Shypailo; Margaret L Gourlay; Anthony G Comuzzie; Kari E North; Nancy F Butte; Venkata Saroja Voruganti Journal: BMC Pediatr Date: 2021-02-15 Impact factor: 2.125
Authors: S Ghatan; A Costantini; R Li; C De Bruin; N M Appelman-Dijkstra; E M Winter; L Oei; Carolina Medina-Gomez Journal: Curr Osteoporos Rep Date: 2021-05-04 Impact factor: 5.096