GWLS became feasible in the 1980s with genomewide “maps” (7) of hundreds of DNA sequence variations (markers). Linkage analysis (reviewed in (15)), of families with multiple ill members, exploits within-family correlations between illness and the alternative sequences (alleles) of the markers that are closest to the disease-related gene(s). Linkage studies led to the discovery of (mostly rare dominant or recessive) mutations for more than 1,600 diseases (Online Mendelian Inheritance in Man, http://www.ncbi.nlm.nih.gov/Omim/mimstats.html). They have been less successful for complex (multifactorial/multigenic) disorders. In psychiatric linkage studies (catalogued at https://slep.unc.edu), small samples of pedigrees were initially studied in the hope of discovering simpler genetic mechanisms that would provide clues to pathophysiology. Then, larger studies (hundreds of families) searched for genes with smaller effects. There are diverse opinions about these studies’ past success and future prospects. Statistically significant linkages have been reported but have been difficult to replicate, presumably because linkage is much less powerful when risk variants have small effects and there is heterogeneity in the underlying genetic factors in different families. Meta-analyses have supported linkage for some disorders. (16-18)
