Linkage, association, and the genetic analysis of bone mineral density and related phenotypes: an overview for clinicians.

Most medical genetic studies seek to answer one of two questions: What genes are important in determining disease risk? and What alleles of a candidate gene confer excess risk? This article seeks to provide physicians with a practical approach to assessing articles on genetic topics, using examples from bone mineral density and related areas. First, this article reviews the essential features of meiosis, crossing over, and allele detection. Second, mapping strategies are described and illustrated. Third, this article considers studies of the association between alleles of specific candidate genes and bone phenotypes. Linkage without association and association without linkage are both possible. Fourth, the ability of studies using inbred mice to establish both linkage and association is explained. Fifth, the transmission disequilibrium test is proposed as a superior design for investigating the association of alleles with bone phenotypes. Sixth and last, a systematic approach to reading medical genetic studies critically is developed. Common shortcomings in published articles include insufficient evidence for candidate choice, confusion between functionally significant alleles and markers, and failure to distinguish between identity by descent and identity by state.