Genomewide scans of complex human diseases: True linkage is hard to find

Many "complex" human diseases, which involve multiple genetic and environme ntal determinants, have increased in incidence during the past 2 decades. D uring the same time period, considerable effort and expense have been expen ded in whole-genome screens aimed at detection of genetic loci contributing to the susceptibility to complex human diseases. However, the success of p ositional cloning attempts based on whole-genome screens has been limited, and many of the fundamental questions relating to the genetic epidemiology of complex human disease remain unanswered. Both to review the success of t he positional cloning paradigm as applied to complex human disease and to i nvestigate the characteristics of the whole-genome scans undertaken to date , we created a database of 101 studies of complex human disease, which were found by a systematic Medline search (current as of December 2000). We com pared these studies, concerning 31 different human complex diseases, with r egard to design, methods, and results. The "significance" categorizations p roposed by Lander and Kruglyak were used as criteria for the "success" of a study. Most (66.3% [n=67]) of the studies did not show "significant" linka ge when the criteria of Lander and Kruglyak (1995) were used, and the resul ts of studies of the same disease were often inconsistent. Our analyses sug gest that no single study design consistently produces more-significant res ults. Multivariate analysis suggests that the only factors independently as sociated with increased study success are (a) an increase in the number of individuals studied and (b) study of a sample drawn from only one ethnic gr oup. Positional cloning based on whole-genome screens in complex human dise ase has proved more difficult than originally had been envisioned; detectio n of linkage and positional cloning of specific disease-susceptibility loci remains elusive.