Genome-wide scans of three independent sets of 90 Irish multiplex schizophrenia families and follow-up of selected regions in all families provides evidence for multiple susceptibility genes

Abstract

From our linkage study of Irish families with a high density of schizophrenia, we have previously reported evidence for susceptibility genes in regions 5q21–31, 6p24–21, 8p22–21, and 10p15–p11. In this report, we describe the cumulative results from independent genome scans of three a priori random subsets of 90 families each, and from multipoint analysis of all 270 families in ten regions. Of these ten regions, three (13q32, 18p11–q11, and 18q22–23) did not generate scores above the empirical baseline pairwise scan results, and one (6q13–26) generated a weak signal. Six other regions produced more positive pairwise and multipoint results. They showed the following maximum multipoint H-LOD (heterogeneity LOD) and NPL scores: 2p14–13: 0.89 (P = 0.06) and 2.08 (P = 0.02), 4q24–32: 1.84 (P = 0.007) and 1.67 (P = 0.03), 5q21–31: 2.88 (P= 0.0007), and 2.65 (P = 0.002), 6p25–24: 2.13 (P = 0.005) and 3.59 (P = 0.0005), 6p23: 2.42 (P = 0.001) and 3.07 (P = 0.001), 8p22–21: 1.57 (P = 0.01) and 2.56 (P = 0.005), 10p15–11: 2.04 (P = 0.005) and 1.78 (P = 0.03). The degree of ‘internal replication’ across subsets differed, with 5q, 6p, and 8p being most consistent and 2p and 10p being least consistent. On 6p, the data suggested the presence of two susceptibility genes, in 6p25–24 and 6p23–22. Very few families were positive on more than one region, and little correlation between regions was evident, suggesting substantial locus heterogeneity. The levels of statistical significance were modest, as expected from loci contributing to complex traits. However, our internal replications, when considered along with the positive results obtained in multiple other samples, suggests that most of these six regions are likely to contain genes that influence liability to schizophrenia.