Complex trait locus linkage mapping in atherosclerosis: time to take a step back before moving forward?

E ver since the initial proposal to use polymorphic DNA markers to map genetic diseases,1 linkage analysis (also called “positional cloning”) has been used successfully to find the gene defects for hundreds of monogenic Mendelian traits.2 Because monogenic diseases can serve as important models for understanding pathogenesis, especially if they point to novel biochemical and physiological pathways, linkage analysis has revolutionized biomedicine. A prime example of the success of linkage analysis in atherosclerosis was the discovery that ABCA1 was the causative gene for Tangier disease,3 which has created an exciting and thriving new subfield of research. The notable success in localizing the molecular defects in monogenic disorders follows from the simple disease pathogenesis model: a single mutated disease gene is necessary and sufficient to cause the observed trait. A recent search of the Online Mendelian Inheritance in Man (OMIM) human genetic disease database roughly quantifies the extent of this success: by entering the keywords “linkage analysis” AND “autosomal,” 900 individual entries were returned. And this likely underestimates the number of monogenic diseases for which the molecular genetic basis was solved by linkage analysis.