EMPIRICAL GENOMEWIDE SIGNIFICANCE LEVELS ESTABLISHED BY WHOLE GENOME SIMULATIONS

The advent of high-resolution genetic maps and semiautomated genotypin g technology has opened the way for genome screening in genetically co mplex traits. Many such screens an now under way, or completed, most u sing multipoint nonparametric linkage analysis of affected sibling pai rs. This type of linkage analysis uses all the available genotype info rmation to calculate the maximum lod score (MLS) value at each point i n the genome, and thereby generates MLS profiles along each chromosome . Any positive MLS values indicate potential linkage, but the peaks in these profiles, which may be referred to as ''hits,'' identify the mo st likely locations of disease susceptibility genes. However, such ana lysis presents serious problems of multiple testing, and the assessmen t of the statistical significance of hits has become a contentious iss ue [Lander and Kruglyak (1995) Nat Genet 11:241-247; Curtis (1996) Nat Genet 12:356-357; Witte et al. (1996) Nat Genet 12:355-356]. Having r ecently completed a genome screen in multiple sclerosis, we decided to investigate the statistical properties of our study by simulation. We report here in detail the results of this simulation study. Our main conclusion is that, for the particular set of families and markers use d in our screen, an MLS of 3.2 carries a genome-wide significance of 5 % (that is, there is a 5% probability of observing at least one false hit, above this threshold in a complete genome screen). This value is closer to the familiar limit of 3.0, originally suggested by Morton [1 955; Am J Hum Genet 7:277-318] than to the more stringent limit of 4.0 recently proposed by Lander and Kruglyak [1995; Nat Genet 11:241-247] . This is somewhat reassuring, in view of the very large sample sizes that would be necessary to achieve adequate power to detect linkage at the more stringent threshold. (C) 1997 Wiley-Liss, Inc.