Osteoporosis, a highly heritable disease, is characterized mainly by low bone-mineral
density (BMD), poor bone geometry, and/or osteoporotic fractures (OF). Copy-number
variation (CNV) has been shown to be associated with complex human diseases. The contribution
of CNV to osteoporosis has not been determined yet. We conducted case-control genome-wide
CNV analyses, using the Affymetrix 500K Array Set, in 700 elderly Chinese individuals
comprising 350 cases with homogeneous hip OF and 350 matched controls. We constructed
a genomic map containing 727 CNV regions in Chinese individuals. We found that CNV
4q13.2 was strongly associated with OF (p = 2.0 x 10(-4), Bonferroni-corrected p =
0.02, odds ratio = 1.73). Validation experiments using PCR and electrophoresis, as
well as real-time PCR, further identified a deletion variant of UGT2B17 in CNV 4q13.2.
Importantly, the association between CNV of UGT2B17 and OF was successfully replicated
in an independent Chinese sample containing 399 cases with hip OF and 400 controls.
We further examined this CNV's relevance to major risk factors for OF (i.e., hip BMD
and femoral-neck bone geometry) in both Chinese (689 subjects) and white (1000 subjects)
samples and found consistently significant results (p = 5.0 x 10(-4) -0.021). Because
UGT2B17 encodes an enzyme catabolizing steroid hormones, we measured the concentrations
of serum testosterone and estradiol for 236 young Chinese males and assessed their
UGT2B17 copy number. Subjects without UGT2B17 had significantly higher concentrations
of testosterone and estradiol. Our findings suggest the important contribution of
CNV of UGT2B17 to the pathogenesis of osteoporosis.