Endocrine Abstracts (2002) 3 OC1

All in the family: Site and gender specificity of the genetic control of bone mineral density

EL Duncan1,2, L Cardon2, JAH Wass1 & MA Brown2

1Department of Endocrinology and Metabolism, Nuffield Orthopaedic Centre, Oxford, UK; 2Wellcome Trust Centre for Human Genetics, Oxford, UK.

Bone mineral density (BMD) is a highly heritable trait. We sought to investigate site and gender specificity of BMD inheritance in general pedigrees.

Probands with primary osteoporosis and low BMD relative to an age- and sex- matched cohort (z-score <-2.0 at either lumbar spine (LS) or femoral neck (FN)) were identified from the Nuffield Orthopaedic Centre (Oxford UK) (45 male, 102 female). All available first- and second-degree relatives were recruited. A total of 147 pedigrees comprising 743 individuals were analysed.

Siblings of probands recruited through low BMD at FN had significantly lower BMD at FN than did siblings of probands with low BMD only at LS (z-scores -1.33 vs. -0.61, p=0.00005), suggesting site specificity of BMD.

Using Pedigree Analysis Package (PAP) (1), and correcting for ascertainment bias, it was noted that all male-male correlations of BMD were greater at LS than at FN, whilst all female-female correlations were greater at FN than at LS. Further, male-male correlations were higher at LS that were female-female correlations, whilst at FN female-female correlations were greater than male-male correlations. As examples, mother-daughter correlation at FN was significantly greater than both father-son correlation (0.225 vs. 0.660, p=0.0035) and father-daughter correlation (0.225 vs. 0.100, p=0.02). Father-son correlation was significantly higher at LS than at FN (0.261 vs. 0.0660, p=0.014).

Using PAP (1), heritability of BMD at LS was 0.484 and at FN was 0.482 with covariates of height and weight. Using SOLAR (2), heritability of BMD at LS was 0.639 and at FN was 0.432, with BMI as covariate.

These data strongly suggest that there is significant site and gender specific genetic control of BMD, which has major implications for the design and interpretation of gene-mapping projects.

1. Hasstedt SJ (1993) Genet Epidemiol 10(3): 145-58.

2. Almasy, L., Blangero, J. (1998)

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