Linkage disequilibrium mapping of complex traits using SNP and microsatellite markers

Abstract

Linkage analysis of the major psychoses, schizophrenia and bipolar affective disorder, is providing increasing evidence in support of several genetic loci. Some of including chromo-somes 13q and 22q, appear to be shared between the two diagnoses. Linkage disequilibrium mapping, using simple sequence repeat markers and SNPs, followed by the analysis of positional candidate genes, is the most likely route by which susceptibility alleles at loci such as these will be found. However little is known about linkage disequilibrium relationships between different classes of genetic markers and between ethnic groups. We demonstrate that substantial differences exist in allele frequencies for both SNP and microsatellite markers between subjects of Chinese and European origin, which has significant implications for LD mapping. Analysis of about 30 SNPs in brain-expressed candidate genes reveals that about half of those polymorphic in UK populations are monomorphic in the Chinese, and many of the remainder differ significantly in allele frequency. Likewise although almost all of over 100 microsatellites tested are polymorphic in both populations, allele frequencies differ substantially for most, with common alleles present in one population often being infrequent or absent in the other. Using the high/low activity phenotype at the COMT locus (chromosome 22q11) as a phenotype, we have modeled the linkage disequilibrium mapping process with both SNPs and microsatellites. We demonstrate the linkage disequilibrium relationships between markers in this region, the advantages of each marker type, and provide information on the sample size and power required for LD mapping. We also present methods for LD mapping using familial transmission of haplotypes with the program TRANSMIT.