| Stress and osteoporotic fractures are much more common in females than males. Bone size (BS) is an important risk factor for osteoporotic fractures. To explore sex-specific quantitative trait loci (QTL) influencing BS variation, we performed genomewide linkage analyses of BS in males and females separately. BS at three skeletal sites (spine, total hip and forearm) was measured using dual-energy X-ray absorptiometry (DXA) scanners. Since BS at different skeletal sites is highly correlated, we extracted a principal component based on BS measurements at the three skeletal sites and used it as new "composite phenotype" of BS for linkage analyses. A total of 3,899 Caucasians (including 1736 male and 2520 female subjects) from 451 pedigrees were genotyped with 410 microsatellite markers. We detected a QTL influencing the composite phenotype of BS in the females (logarithm of odds [LOD] = 3.03) on chromosome 8 at 164 cM but not in the males (LOD = 0.02, P for gene-by-sex interaction = 0.046). In addition, linkage to the composite phenotype of BS was detected in the males on chromosomes 5 at 130cM (LOD = 2.97) but not in the females (LOD = 0.00, P for gene-by-sex interaction = 0.022). Our study identified chromosomal regions that may contain QTLs contributing to sex dimorphism of BS and possibly the differential incidences of osteoporotic fracture in the two genders. It also demonstrated the importance of considering gene-by-sex interaction in the search for BS related genes.Both body mass index (BMI) is commonly used to predict morbidity and morality from obesity-related diseases and disclose genetic variants that increase an individual's risk for obesity and its complications. Adult human height is an important physical index to reflect skeletal growth and development. Converging evidences from epidemiology, genetics, and cell molecular studies suggest that skeletal growth and obesity are closely related. To identify the common genetic factors shared between BMI and height, we performed the first bivariate genomewide association study in search for genes underlying co-variation of BMI and height, scanning～500,000 SNPs in 597 unrelated homogeneous Chinese. We identified two SNPs rs11150978, 10kb upstream of ZNF236 (zinc finger protein 236) gene and rs17077512, 15kb upstream of FRK(fyn-related kinase) gene, which were bivariately associated with both BMI-height, achieved bivariate association p values of 6.26×10-6 and 5.88×10-6 , respectively. The subjects of homozygous rs11150978 GG have lower BMI (1.2 kg/m2) and higher height (2.6 cm) than those of homozygous AA, however, the subjects of the heterozygous GA have higher BMI (2.1 kg/m2) than those of homozygous GG. The subjects of homozygous rs17077512 AA have higher BMI (2 kg/m2) and higher height (1.5 cm) than those of heterozygous AC. ZNF236 was a newly identified genes with no known functions on skeletal growth and obesity. However the zinc finger protein families, to which the gene belongs, play very important roles in a variety of processes associated with skeletal growth and obesity. FRK gene functions during G1 and S phase of the cell cycle and suppress growth. It also plays a role in theβ-cell proliferation and death and obesity linked type 2 diabetes. Together with our findings, these evidences support that FRK and ZNF236 may be two novel genes underlying co-variation of human stature and BMI in Chinese.
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