Association between bone mineral density and candidate genes in different ethnic populations and its implications

The objectives of this study were (1). to identify the ethnic population in which bone mineral density (BMD) has been reported to be associated with polymorphisms of candidate genes in the literature; (2). to estimate the maximal distances between candidate genes and BMD-affecting loci, and (3). to explore the implications of phenotype-genotype association found in different ethnic populations. MEDLINE was searched for association between polymorphisms of candidate genes and BMD. The distances between marker and BMD-affecting loci were estimated with Lewontin's D'. Polymorphisms at 25 candidate loci have been reported to be associated with BMD. Eight of them are associated with BMD in both Caucasians and Asians, one with BMD in Caucasians with an allele frequency as high as 0.22, which is 0 in Asians, one with BMD in the three major ethnic populations (including Africans) and 15 with BMD in one ethnic population (not investigated in a second ethnic population yet). The maximal distance between BMD-affecting genes and marker loci was 230 (range 196-275) kb when an association is found in Caucasians and Asians. The association between vitamin D receptor gene polymorphisms and BMD is found in the three major ethnic populations, and the maximal marker-mutant distance is 79 (50-95) kb. It was concluded that most mutations affecting BMD are very old and are common in two or three major ethnic populations, which implies that these BMD-affecting loci are very close to, and are likely to be within, the candidate genes. Phenotype-genotype associations found in East Asians are unlikely to be due to admixture with Caucasians.