Site and gender specificity of inheritance of bone mineral density.
Differences in genetic control of BMD by skeletal sites and genders were examined by complex segregation analysis in 816 members of 147 families with probands with extreme low BMD. Spine BMD correlated more strongly in male-male comparisons and hip BMD in female-female comparisons, consistent with gender- and site-specificity of BMD heritability.


BACKGROUND
Evidence from studies in animals and humans suggests that the genetic control of bone mineral density (BMD) may differ at different skeletal sites and between genders. This question has important implications for the design and interpretation of genetic studies of osteoporosis.


METHODS
We examined the genetic profile of 147 families with 816 individuals recruited through probands with extreme low BMD (T-score < -2.5, Z-score < -2.0). Complex segregation analysis was performed using the Pedigree Analysis Package. BMD was measured by DXA at both lumbar spine (L1-L4) and femoral neck.


RESULTS
Complex segregation analysis excluded purely monogenic and environmental models of segregation of lumbar spine and femoral neck BMD in these families. Pure polygenic models were excluded at the lumbar spine when menopausal status was considered as a covariate, but not at the femoral neck. Mendelian models with a residual polygenic component were not excluded. These models were consistent with the presence of a rare Mendelian genotype of prevalence 3-19%, causing high BMD at the hip and spine in these families, with additional polygenic effects. Total heritability range at the lumbar spine was 61-67% and at the femoral neck was 44-67%. Significant differences in correlation of femoral neck and lumbar spine BMD were observed between male and female relative pairs, with male-male comparisons exhibiting stronger lumbar spine BMD correlation than femoral neck, and female-female comparisons having greater femoral neck BMD correlation than lumbar spine. These findings remained true for parent-offspring correlations when menopausal status was taken into account. The recurrence risk ratio for siblings of probands of a Z-score < -2.0 was 5.4 at the lumbar spine and 5.9 at the femoral neck.


CONCLUSIONS
These findings support gender- and site-specificity of the inheritance of BMD. These results should be considered in the design and interpretation of genetic studies of osteoporosis.
Duncan
Emma L
EL
Metabolic Bone Unit, Nuffield Orthopaedic Centre, Oxford, United Kingdom.
Cardon
Lon R
LR
Sinsheimer
Janet S
JS
Wass
John A H
JA
Brown
Matthew A
MA
D015519:Bone Density / Q000235:genetics*; D005190:Family; D005260:Female; D005272:Femur Neck; D006801:Humans; D008159:Lumbar Vertebrae; D008297:Male; D008593:Menopause / Q000502:physiology; D012307:Risk Factors; D012727:Sex Characteristics