Simulation studies of detection of a complex disease in a partially isolated population

Simulation studies were undertaken with POPGEN, a new population simulation program, to explore strategies for detecting loci underlying rare and comm on disorders in a small population that has been partially isolated for 10 generations. Haplotype-sharing analysis (HSA) and non-parametric linkage an alysis (NPL) were applied to the simulated haplotype and pedigree data for 100 eases, 100 controls, and an average of 28 multiplex pedigrees from case s' families, for a 2-5 cM map of markers. When identity by descent (IBD) st atus was known (using unique founder marker allele designations assigned du ring simulation), a linkage disequilibrium (LD) signal. could be detected u nder disease-generating models predicting relative risk to sibs of 11.8 (hi gh-RR) or 2.67 (mod-RR), Detection was more difficult when marker alleles w ere down-coded to resemble microsatellites (heterozygosities 0.75-0.80). Fa lse-positive peaks on non-disease chromosomes were uncommon. NPL analysis w as more powerful than HSA at this marker density using down-coded alleles a nd assuming availability of all affected relatives. LD mapping of common di sorders is likely to require denser maps of highly polymorphic markers to a pproximate full IBD information. LD and linkage mapping provide independent information, and strategies that combine these two methods could be useful in studies of small isolated populations. Am. J. Med. Genet. (Neuropsychia tr. Genet.) 105:65-70, 2001. (C) 2001 Wiley-Liss, Inc.