Identifying genetic risk factors for osteoporosis.

Over the past decades epidemiological research of so-called "complex" diseases, i.e., common age-related disorders such as cancer, cardiovascular disease, diabetes, and osteoporosis, has identified anthropometric, behavioural, and serum parameters as risk factors. Recently, genetic polymorphisms have gained considerable interest, propelled by the Human Genome Project and its sequela that have identified most genes and uncovered a plethora of polymorphic variants, some of which embody the genetic risk factors. In all fields of complex disease genetics (including osteoporosis) progress in identifying these genetic factors has been hampered by often controversial results. Because of the small effect size for each individual risk polymorphism, this is mostly due to low statistical power and limitations of analytical methods. Genome-wide scanning approaches can be used to find the responsible genes. It is by now clear that linkage analysis is not suitable for this, but genome-wide association analysis has much better possibilities, as is illustrated by successful identification of risk alleles for several complex diseases. Candidate gene association analysis followed by replication and prospective multi-centred meta-analysis, is currently the best way forward to identify genetic markers for complex traits, such as osteoporosis. To accomplish this, we need large (global) collaborative studies using standardized methodology and definitions, to quantify by meta-analysis the subtle effects of the responsible gene variants.