Family, twin and adoption studies provide strong evidence that genetic factors play a major role in the etiology of schizophrenia. While evidence has begun to accumulate for replicated linkage for schizophrenia to several chromosomal regions, efforts to identify the location of susceptibility loci for schizophrenia have previously proven unsuccessful. This may in part be true because prior studies of linkage disequilibrium (LD) were small in size, utilized a case control vs. a family based method, were ethnically and clinically heterogeneous and were conducted in large out-bred populations where LD may exist over only very short genetic distances. One of the studies that has contributed to these advances is the Irish Study of High Density Schizophrenia Families (ISHDSF), the original phase of which ascertained and studied, in Ireland and Northern Ireland, 265 multiplex schizophrenia families containing 1,408 individuals with detailed clinical information and DNA. In this third and final submission of this competitive renewal, we seek support to critically extend the ISHDSF by collecting 500 proband-parent triads for family-based association studies. We will select triads with a positive family history of psychosis to reduce the rate of """"""""phenocopies"""""""", interview parents for their personal and family history of schizophrenia and schizophrenia spectrum illness so as to weight transmissions on the basis of the probability that they contain a susceptibility allele and sample all living and available relatives with schizophrenia or chronic schizoaffective disorder so as to weight, in those triad-families, those that are more likely to be segregating a susceptibility allele in a given chromosomal region. With support for the genotyping and statistical analysis of this new sample, we seek to address two critical questions: 1. Can we replicate, by means of linkage disequilibrium, previously obtained evidence for linkage in the 4 putative susceptibility regions found in the ISHDSF to date (6p24-22, 8p22-21, 5q21-31 and 10p15-p11) and new regions that may emerge as we complete our genome scan? 2. Can we, by applying dense marker maps to our triad sample, obtain fine localization of schizophrenia susceptibility loci in these and other potential candidate regions? High genetic and cultural homogeneity, large family size, low rates of drug abuse, high levels of linkage disequilibrium demonstrated over genetic distances of 0.5 to 1.0 centiMorgans and a cooperative, stable population make Ireland ideal for linkage disequilibrium studies of schizophrenia.
Showing the most recent 10 out of 148 publications
