Evidence for linkage to psychosis and cerebral asymmetry (relative hand skill) on the X chromosome

Abstract

The hypothesis that psychosis arises as a part of the genetic diversity associated with the evolution of language generates the prediction that illness will be linked to a gene determining cerebral asymmetry, which, from the evidence of sex chromosome aneuploidies, is present in homologous form on the X and Y chromosomes. We investigated evidence of linkage to markers on the X chromosome in 1) 178 families multiply affected with schizophrenia or schizoaffective disorder with a series of 16 markers spanning the centromere (study 1), and 2) 180 pairs of left-handed brothers with 14 markers spanning the whole chromosome (study 2). In study 1, excess allele-sharing was observed in brother-brother pairs (but not brother-sister or a small sample of sister-sister pairs) over a region of approximately 20 cM, with a maximum LOD score of 1.5 at DXS991. In study 2, an association between allele-sharing and degree of left-handedness was observed extending over approximately 60 cM, with a maximum lod score of 2.8 at DXS990 (approximately 20 cM from DXS991). Within the overlap of allele-sharing is located a block in Xq21 that transposed to the Y chromosome in recent hominid evolution and is now represented as two segments on Yp. In one of two XX males with psychosis we found that the breakpoint on the Y is located within the distal region of homology to the block in Xq21. These findings are consistent with the hypothesis that an X-Y homologous determinant of cerebral asymmetry carries the variation that contributes to the predisposition to psychotic illness.

Parametric and nonparametric genome scan analyses for human handedness

“…26 Very recently this QTL was confirmed 27 in a subset of left-handed male brothers from a previously collected sample cohort. 25 However, we found no evidence of this QTL in this genome scan. Given the amount of power present in our sample cohort, the characteristics of Klar's model, the NPL results and the robustness of two-point analysis against model misspecification, we can assume that if the monogenic models were correct, it would have been possible to detect this single locus.…”

“…24,25 Association analysis between allele sharing of markers on the X-chromosome and a reduction of hand skill variance in left-handed brothers resulted in an LOD score of 2.8 for marker DXS990. 25 In this genome scan, no positive LOD scores were obtained for DXS990, thereby providing no evidence for the presence of a locus on the X-chromosome.…”

Identification and phylogenetic analysis of long terminal repeat elements of the human ehdogenous retrovims K family (HEW‐K) from a human brain cDNA library

“…The retroviral sequence derived from a cDNA library from postmorte brain tissue of an individual with psychosis in a genomic region (Xq21.3). The Xq21.3 region has been tentatively linked to schizophrenia and schizoaffective disorder by Laval et al (1998). We identified two retroposons, HS307 and HS408, on human Xq21.…”

Isolation and phytogeny of SINE‐R retroposons derived from human endogenous retrovirus HERV‐K family in schizophrenia

“…According to the retrovirus hypothesis, recently proliferated retroviral elements in the human genome after separation of the human and chimpanzee could be implicated with the psychotic diseases (Crow, 1984). In the previous study, we identified two retroposons (HS307 and HS408) and four HERV-K LTRs (K-X7-3, K-X10-5, K-X13-1, and K-X13-2) in human Xq21.3 region by PCR approach using YAC clone panel (Kim et al, 1999b;Kim and Crow, 2001), as the Xq21.3 region has been known to be putativefy linked to psychosis (Laval et al, 1998).…”