Linkage, association, and the genetic analysis of bone mineral density andrelated phenotypes - An overview for clinicians

Most medical genetic studies seek to answer one of two questions: What gene s are important in determining disease risk? and What alleles of a candidat e 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 th e essential features of meiosis, crossing over, and allele detection. Secon d, mapping strategies are described and illustrated. Third, this article co nsiders studies of the association between alleles of specific candidate ge nes and bone phenotypes. Linkage without association and association withou t linkage are both possible. Fourth, the ability of studies using inbred mi ce to establish both linkage and association is explained. Fifth, the trans mission disequilibrium test is proposed as a superior design for investigat ing the association of alleles with bone phenotypes. Sixth and last, a syst ematic approach to reading medical genetic studies critically is developed. Common shortcomings in published articles include insufficient evidence fo r candidate choice, confusion between functionally significant alleles and markers, and failure to distinguish between identity by descent and identit y by state.