Genome-wide association analyses have recently been conducted in around 1500 ALSPAC children, and related to measures of skeletal phenotype as assessed by total body DXA scans obtained in the focus@9 clinic. One of the strongest associations was between polymorphisms in the osterix gene (a 'master gene' involved in regulating osteoblast differentiation) and bone mineral content, which were subsequently replicated in a further 3500 ALSPAC children. Another assoication observed in this genome-wide analysis was between two genetic variants in CTNNB1 and area-adjusted BMC, suggestive of an influence on cortical thickness. CTNNB1 encodes beta-catenin, which is also involved in regulating osteoblast differentiation, and has recently been found to interact with osterix (1). Also, based on analysis of the phenotype of mice with targeted gene deletion of beta catenin in osteocytes, beta catenin may play an important role in regulating cortical thickness (2).

As a next step, we now wish to genotype the remainder of the ALSPAC children for the two CTNNB1 genotypes in question, namely rs1798802 and rs4135385, with the aim of replicating the associations described above. This will be performed by Kbiosciences using existing DNA samples. As part of this project, we are also keen to examine associations between these genotypes and more direct measures of cortical thickness obtained from pQCT scans (results from these scans performed in the whole ALSPAC cohort at age 16 years will be available shortly). We are also keen to establish whether similar associations are evident in other chorts with GWAS and pQCT data (e.g. the GOOD cohort in Sweden comprising 1000 18 year old men, the Twins study).

1. Zhang C, Cho K, Huang Y, Lyons JP, Zhou X, Sinha K, McCrea PD, de Crombrugghe B 2008 Inhibition of Wnt signaling by the osteoblast-specific transcription factor Osterix. Proc Natl Acad Sci U S A 105(19):6936-41.

2. Kramer I, Halleux C, Brander-Weber P, Feng JQ, Boisclair J, Keller H, Kneissel M 2008 Osteocyte-specific ablation of canonical wnt signaling induces severe osteoporosis. J Bone Miner Res 23, Supplement 1:S12.