Genomewide multipoint linkage analysis of seven extended Palauan pedigreeswith schizophrenia, by a Markov-chain Monte Carlo method

Palauans are an isolated population in Micronesia with lifetime prevalence of schizophrenia (SCZD) of 2%, compared to the world rate of similar to1%. The possible enrichment for SCZD genes, in conjunction with the potential f or reduced etiological heterogeneity and the opportunity to ascertain stati stically powerful extended pedigrees, makes Palauans a population of choice for the mapping of SCZD genes. We have used a Markov-chain Monte Carlo met hod to perform a genomewide multipoint analysis in seven extended pedigrees from Palau. Robust multipoint parametric and nonparametric linkage (NPL) a nalyses were performed under three nested diagnostic classifications-core, spectrum, and broad. We observed four regions of interest across the genome . Two of these regions-on chromosomes 2p13-14 (for which, under core diagno stic classification, NPL=65 and parametric LOD=4.8) and 13q12-22 (for which , under broad diagnostic classification, parametric LOD=3.6, and, under spe ctrum diagnostic classification, parametric LOD =3.5)-had evidence for link age with genomewide significance, after correction for multiple testing; wi th the current pedigree resource and genotyping, these regions are estimate d to be 4.3 cM and 19.75 cM in size, respectively. A third region, with int ermediate evidence for linkage, was identified on chromosome 5q22-qter (for which, under broad diagnostic classification, parametric LOD=2.5). The fou rth region of interest had only borderline suggestive evidence for linkage (on 3q24-28; for this region, under broad diagnostic classification, parame tric LOD=2.0). All regions exhibited evidence for genetic heterogeneity. Ou r findings provide significant evidence for susceptibility loci on chromoso mes 2p13-14 and 13q12-22 and support both a model of genetic heterogeneity and the utility of a broader set of diagnostic classifications in the popul ation from Palau.