title: BMD Loci Contribute to Ethnic and Developmental Differences in Skeletal Fragility across Populations: Assessment of Evolutionary Selection Pressures.
abstract: Bone mineral density (BMD) is a highly heritable trait used both for the diagnosis of osteoporosis in adults and to assess bone health in children. Ethnic differences in BMD have been documented, with markedly higher levels in individuals of African descent, which partially explain disparity in osteoporosis risk across populations. To date, 63 independent genetic variants have been associated with BMD in adults of Northern-European ancestry. Here, we demonstrate that at least 61 of these variants are predictive of BMD early in life by studying their compound effect within two multiethnic pediatric cohorts. Furthermore, we show that within these cohorts and across populations worldwide the frequency of those alleles associated with increased BMD is systematically elevated in individuals of Sub-Saharan African ancestry. The amount of differentiation in the BMD genetic scores among Sub-Saharan and non-Sub-Saharan populations together with neutrality tests, suggest that these allelic differences are compatible with the hypothesis of selective pressures acting on the genetic determinants of BMD. These findings constitute an explorative contribution to the role of selection on ethnic BMD differences and likely a new example of polygenic adaptation acting on a human trait.
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands The Generation R Study Group, Erasmus University Medical Center, Rotterdam, The Netherlands Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Carolina
authors.initials: C
authors.lastname: Medina-Gómez
authors.affiliation: Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Chesi
authors.affiliation: The Generation R Study Group, Erasmus University Medical Center, Rotterdam, The Netherlands Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands Department of Pediatrics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Denise H M
authors.initials: DH
authors.lastname: Heppe
authors.affiliation: Division of GI, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania.
authors.forename: Babette S
authors.initials: BS
authors.lastname: Zemel
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands The Generation R Study Group, Erasmus University Medical Center, Rotterdam, The Netherlands Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Jia-Lian
authors.initials: JL
authors.lastname: Yin
authors.affiliation: Division of General and Community Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
authors.forename: Heidi J
authors.initials: HJ
authors.lastname: Kalkwarf
authors.affiliation: The Generation R Study Group, Erasmus University Medical Center, Rotterdam, The Netherlands Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Division of Endocrinology, Creighton University, Omaha, NE.
authors.forename: Joan M
authors.initials: JM
authors.lastname: Lappe
authors.affiliation: Division of GI, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Kelly
authors.affiliation: Department of Genetic Identification, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Manfred
authors.initials: M
authors.lastname: Kayser
authors.affiliation: Division of Pediatric Endocrinology, Diabetes, and Metabolism, Department of Pediatrics, Columbia University Medical Center, New York, NY.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Oberfield
authors.affiliation: Department of Radiology, Children's Hospital Los Angeles, Los Angeles, CA.
authors.forename: Vicente
authors.initials: V
authors.lastname: Gilsanz
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands The Generation R Study Group, Erasmus University Medical Center, Rotterdam, The Netherlands Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco.
authors.forename: John A
authors.initials: JA
authors.lastname: Shepherd
authors.affiliation: The Generation R Study Group, Erasmus University Medical Center, Rotterdam, The Netherlands Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands Department of Pediatrics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Vincent W V
authors.initials: VW
authors.lastname: Jaddoe
authors.affiliation: Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA.
authors.forename: Struan F A
authors.initials: SF
authors.lastname: Grant
authors.affiliation: Department of Genetic Identification, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Oscar
authors.initials: O
authors.lastname: Lao
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands The Generation R Study Group, Erasmus University Medical Center, Rotterdam, The Netherlands Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands f.rivadeneira@erasmusmc.nl.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
mesh_terms: D000328:Adult; D000483:Alleles; D044466:Asian People / Q000235:genetics; D005075:Biological Evolution; D044383:Black People / Q000235:genetics; D015519:Bone Density / Q000235:genetics*; D002648:Child; D019143:Evolution, Molecular; D005260:Female; D056726:Genetic Association Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D010024:Osteoporosis / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D044469:Racial Groups / Q000235:genetics*; D012641:Selection, Genetic; D044465:White People / Q000235:genetics
keywords: adaptation; bone mineral density; ethnic differences; genome-wide association studies; polygenic; selective pressures