Strong association between polymorphisms in ANKH locus and skeletal size traits

Loss of bone strength is the main determinant of bone fragility. Bone strength is directly dependent on bone size (BS). A substantial portion of BS variation is attributable to genetic effects. However, the list of genes and allelic variants involved in the determination of BS variation is far from being complete. Polymorphisms in the ANKH gene have been shown to be associated with radiographic hand BS-related phenotypes. The present study examined the possible association of the ANKH gene with skeletal size and shape in order to test the universality of the ANKH effect on BS traits. Our sample consisted of a total of 212 ethnically homogeneous nuclear families (743 individuals) of European origin. Each individual was measured for body height, weight, and several other anthropometrical measurements, and genotyped for nine polymorphic markers (the average heterozygosity level was 0.4). We observed significant associations with practically all the anthropometrical phenotypes studied. More specifically, we found associations with body weight and height, limb length (P ≤ 0.001; promoter region). After adjustment for body height, we demonstrated the substantial association increase for biacromial breadth (P=0.0012; some 140 kb downstream from ANKH) and vertebral column length (P = 0.0008; exons 2-7 region). The majority of the observed associations persisted even after correction for multiple testing. For the first time the reliable evidence in support of universality of ANKH gene polymorphisms effect on bone size was provided.