Failure to establish linkage on the X chromosome in 301 families with schizophrenia or schizoaffective disorder

The hypothesis that a gene for susceptibility to psychosis (specifically in the X-Y homologous class) is located on the sex chromosomes has been propo sed. Such a gene would account for the excess of sex chromosome anomalous m ales and females in populations of patients with psychosis, a tendency towa rds concordance by sex within families, and sex differences associated with psychosis and its underlying brain pathology. In earlier studies we observ ed small positive LOD scores in Xp11, and in a more recent and larger cohor t of 178 sibling pairs, a peak multipoint nonparametric LOD score of 1.55 a t the locus DXS8032 in Xq21. The present study with a new set of markers ex tended the cohort to 301 ill sibling pairs and their parents. Despite the i ncrease in sample size, the LOD score did not increase. A peak NPL of 1.55 was observed at the locus DXS1068 in proximal Xp, a region remote from the previous report. Separating families into those who were more likely to hav e X chromosome inheritance (maternal with no male to male transmission) did not yield stronger findings. In spite of the evidence that psychosis is re lated to a sex-dependent dimension of cerebral asymmetry, it is concluded t hat no consistent linkage of schizophrenia to the X chromosome can be demon strated. In the context of the general failure of replication of linkage in psychosis, the possibility that the genetic predisposition to psychosis Is contributed to by epigenetic modification rather than variations in the nu cleotide sequence has to be considered. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:335-341, 2000. (C) 2000 Wiley-Liss, Inc.