Evidence for major pleiotropic effects on bone size variation from a principal component analysis of 451 Caucasian families.

Aim: To identify pleiotropic quantitative trait loci (QTL) influencing bone size (BS) at different skeletal sites in Caucasians.

Methods: In a sample containing 3899 Caucasians from 451 pedigrees, 410 microsatellite markers spaced approximately 8.9 cM apart across the human genome were genotyped. Phenotypical and genetic correlations of BS at lumbar spine, hip (femoral neck, trochanter, and intertrochanter regions), and wrist (ultradistal, mid-distal, and one-third distal sites) were determined using bivariate quantitative genetic analysis. A principal component analysis (PCA) was performed to obtain principal component (PC) factors that were then subjected to variance components linkage analysis to identify regions linked to the PC.

Results: Genetic correlations of BS at different skeletal sites ranged from 0.40 to 0.79 (P<0.001). The PCA yielded a PC named PCtotal, which explained up to 76% of the total (co)variation of all the BS at the 7 skeletal sites for the whole sample. We identified a QTL influencing the BS of multiple skeletal sites on chromosome 7 at 140 cM [logarithm of odds (LOD)=2.85] in the overall sample. Sex-specific evidence for linkage was observed on chromosome 11 at 53 cM (LOD =2.82) in the male-only data subset.

Conclusion: Our study identified several genomic regions that may have pleiotropic effects on different skeletal sites. These regions may contain genes that play a critical role in overall bone development and osteoporosis at multiple skeletal sites, hence are biologically and clinically important.