The XY gene hypothesis of psychosis: Origins and current status

Abstract

Sex differences in psychosis and their interaction with laterality (systematic departures from 50:50 left-right symmetry across the antero-posterior neural axis) are reviewed in the context of the X-Y gene hypothesis. Aspects of laterality (handedness/cerebral asymmetry/the torque) predict (1) verbal and non-verbal ability in childhood and across adult life and (2) anatomical, physiological, and linguistic variation relating to psychosis. Neuropsychological and MRI evidence from individuals with sex chromosome aneuploidies indicates that laterality is associated with an X-Y homologous gene pair. Within each mammalian species the complement of such X-Y gene pairs reflects their potential to account for taxon-specific sexual dimorphisms. As a consequence of the mechanism of meiotic suppression of unpaired chromosomes <MSUC> such X-Y gene pairs generate epigenetic variation around a species defining motif that is carried to the zygote with potential to initiate embryonic gene expression in XX or XY format. The Protocadherin11XY (PCDH11XY) gene pair in Xq21.3/Yp11.2 in probable coordination with a gene or genes within PAR2 (the second pseudo-autosomal region) is the prime candidate in relation to cerebral asymmetry and psychosis in Homo sapiens. The lately-described pattern of sequence variation associated with psychosis on the autosomes may reflect a component of the human genome's adjustment to selective pressures generated by the sexually dimorphic mate recognition system. © 2013 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by John Wiley and Sons, Ltd.

Mixed-footedness is a more relevant predictor of schizotypy than mixed-handedness

“…With regard to (1), two further things have to be noted: (i) sex effects were in opposite direction for the different factors of schizotypy (more positive symptoms among women, but more negative and disorganized symptoms among men); (ii) men were at the same time more likely to be mixedfooted than women, i.e., over-and-above a direct main effect of sex, men were at an additional risk of schizotypal traits, because of their overall higher propensity of being mixed-footed, compared to women. This pattern appears consistent with the hypothesis of a common epigenetic origin of cerebral lateralization and of psychosis-relevant traits (Crow, 2013). Clearly, more research is needed here.…”

“…There is evidence for a dimensional continuum between schizotypy and schizophrenia (van Os et al, 2010;Giakoumaki, 2012;Linscott and van Os, 2013;Nelson et al, 2013), meaning that there is a phenomenological and temporal continuity between schizotypy and psychotic disorder (Linscott and van Os, 2013). Whereas the genetic bases of schizotypy and schizophrenia are still inconclusive (Crow, 2013;Nelson et al, 2013), the onset of psychotic syndromes is likely triggered by gene-environment interactions (van Os et al, 2010).…”

“…Handedness is indicative of language lateralization in the brain (Szaflarski et al, 2002(Szaflarski et al, , 2006) and may thus be considered an observable manifestation of cerebral lateralization. Ample evidence suggests abnormalities with regard to cerebral lateralization in schizophrenia, indicating that deficits in lateralization may play an important causal role (Crow, 2013). In a broader context, mixed-handedness was also reported a risk factor for neurodevelopmental disorders in children (Rodriguez et al, 2010) and there is evidence that it is associated with prenatal exposure to maternal distress (Glover et al, 2004) and neurodevelopmental instability (Rodriguez and Waldenström, 2008) that is also relevant for schizophrenia (Golembo-Smith et al, 2012).…”

The Sex Chromosome Hypothesis of Schizophrenia: Alive, Dead, or Forgotten? A Commentary and Review

“…The combination of these 2 lines of evidence led DeLisi and Crow in a series of papers in the 1980s and 1990s to postulate that a gene for schizophrenia must exist on the sex chromosomes, not just on X but also on Y [3,[14][15][16][17]. Since the illness was transmitted to females and males from both mothers and fathers and, thus, did not follow the typical X-linked pattern of inheritance, the hypothesis led to emphasizing the regions of homology between both X and Y and also loci where recombination between X and Y chromosomes is known to occur [3,14] (reviewed in [18]). The hypothesis was further supported by the observations that many genes expressed in the brain responsible for cognitive development are derived from the X chromosome and that approximately 50% of all intellectual disabilities have a defect in a gene on the X chromosome as its underlying basis (reviewed in [19,20]).…”

Epigenetic approaches for bipolar disorder drug discovery

“…An enormous amount of work has been put into finding the genetic mutations and polymorphisms underlying BD using genetic mapping studies, comprising mainly linkage and association studies. However, to date, no genetic mutation or polymorphism predisposing to the pathogenesis of BD has been definitively identified [4]. It has also been suggested that epigenetic mechanisms of gene expression could be involved in the inheritance of BD [5,6].…”