Relevance of the genes for bone mass variation to susceptibility to osteoporotic fractures and its implications to gene search for complex human diseases.
We investigate the relevance of the genetic determination of bone mineral density (BMD) variation to that of differential risk to osteoporotic fractures (OF). The high heritability (h(2)) of BMD and the significant phenotypic correlations between high BMD and low risk to OF are well known. Little is reported on h(2) for OF. Extensive molecular genetic studies aimed at uncovering genes for differential risks to OF have focussed on BMD as a surrogate phenotype. However, the relevance of the genetic determination of BMD to that of OF is unknown. This relevance can be characterized by genetic correlation between BMD and OF. For 50 Caucasian pedigrees, we estimated that h(2) at the hip is 0.65 (P < 0.0001) for BMD and 0.53 (P < 0.05) for OF; however, the genetic correlation between BMD and OF is nonsignificant (P > 0.45) and less than 1% of additive genetic variance is shared between them. Hence, most genes found important for BMD may not be relevant to OF at the hip. The phenotypic correlation between high BMD and low risk to OF at the hip (approximately -0.30) is largely due to an environmental correlation (rho(E) = -0.73, P < 0.0001). The search for genes for OF should start with a significant h(2) for OF and should include risk factors (besides BMD) that are genetically correlated with OF. All genes found important for various risk factors must be tested for their relevance to OF. Ideally, employing OF per se as a direct phenotype for gene hunting and testing can ensure the importance and direct relevance of the genes found for the risk of OF. This study may have significant implications for the common practice of gene search for complex diseases through underlying risk factors (usually quantitative traits).
Deng
Hong-Wen
HW
Osteoporosis Research Center, Creighton University, 601 N. 30th St. Suite 6787, Omaha, NE 68131, USA. deng@creighton.edu
Mahaney
Michael C
MC
Williams
Jeff T
JT
Li
Jing
J
Conway
Theresa
T
Davies
K Michael
KM
Li
Jin-Long
JL
Deng
Hongyi
H
Recker
Robert R
RR
D000328:Adult; D015519:Bone Density / Q000235:genetics*; D016009:Chi-Square Distribution; D005260:Female; D005598:Fractures, Spontaneous / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D016013:Likelihood Functions; D008297:Male; D010024:Osteoporosis / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D012307:Risk Factors; D011795:Surveys and Questionnaires; D044465:White People / Q000235:genetics