Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21-q22

Abstract

Schizophrenia is a complex disorder, and there is substantial evidence supporting a genetic etiology. Despite this, prior attempts to localize susceptibility loci have produced predominantly suggestive findings. A genome-wide scan for schizophrenia susceptibility loci in 22 extended families with high rates of schizophrenia provided highly significant evidence of linkage to chromosome 1 (1q21-q22), with a maximum heterogeneity logarithm of the likelihood of linkage (lod) score of 6.50. This linkage result should provide sufficient power to allow the positional cloning of the underlying susceptibility gene.

Fig. 1

Two-point lod scores for the genome-wide scan. Affected and unaffected individuals in 22 families segregating schizophrenia were genotyped at 381 marker loci throughout the genome. Maximum two-point lod scores under the narrow definition (18) and the assumption of genetic heterogeneity are plotted as a function of marker location in centimorgans for both recessive and dominant models of inheritance. Chromosome number is designated at the top of the plot.

Fig. 2

Multipoint lod scores for the schizophrenia susceptibility locus relative to markers in the 1q21-q23 region. Parametric four-point lod scores were calculated with the narrow defi-nition (18) and the markers D1S1653, D1S1679, and D1S1677 under the recessive model of inheritance. The results are plotted as a function of distance from D1S1653 under the assumption of homogeneity (100% of families linked) and heterogeneity (75% of families linked). In both cases, the maximum lod scores were located within the 12-cM interval between the markers D1S1653 and D1S1679, rising from a value of 5.89 (P < 0.0002) under homogeneity to 6.50 (P < 0.0002) under heterogeneity.