BMD Loci Contribute to Ethnic and Developmental Differences in Skeletal Fragility across Populations: Assessment of Evolutionary Selection Pressures.

Carolina Medina-Gómez,Heidi J Kalkwarf,Denise H.M Heppe,Alessandra Chesi,Babette S Zemel,Oscar Lao,Joan M Lappe,Vicente Gilsanz,Sharon E Oberfield,Fernando Rivadeneira,Vincent W.V Jaddoe,Manfred Kayser,Struan F.A Grant,Andrea Kelly,Albert Hofman,André G Uitterlinden,Jia-Lian Yin,John A Shepherd

doi:10.1093/molbev/msv170

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.

Highlights

Enormous progress in mapping complex traits has been achieved in the last decade with thousands of loci identified by the implementation of genome-wide association studies (GWAS) (Visscher et al 2012)
To characterize pediatric ethnic differences in Bone mineral density (BMD), we selected a sample of 3,994 children of multiethnic background taking part in the Generation R Study (Jaddoe et al 2012), who had GWAS data and dual-energy X-ray absorptiometry (DXA) measurements
In line with the previous test, we evaluated the population-specific departure of the BMD genetic score (BMD-GS) score from its expected genomic value and determined that the proportion of variance attributable to the categorization into Sub-Saharan African and non-Sub-Saharan African populations, was significantly higher (P = 0.011) for the original BMD-GS than that observed in 100,000 GS sets of 61 single nucleotide polymorphisms (SNPs) randomly sampled from the genome

Summary

Introduction

Enormous progress in mapping complex traits has been achieved in the last decade with thousands of loci identified by the implementation of genome-wide association studies (GWAS) (Visscher et al 2012). Variants at these loci each make modest contributions, collectively, the effect of large sets of variants increase significantly the amount of explained trait variance. These discoveries have enabled studying how selective pressures influence the genetic architecture of complex traits across populations.

Methods

Results

Conclusion