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

The X chromosome has long been an intriguing site for harboring genes that have importance in brain development and function. It has received the most attention for having specific genes underlying the X-linked inherited intellectual disabilities, but has also been associated with schizophrenia in a number of early studies. An X chromosome hypothesis for a genetic predisposition for schizophrenia initially came from the X chromosome anomaly population data showing an excess of schizophrenia in Klinefelter's (XXY) males and triple X (XXX) females. Crow and colleagues later expanded the X chromosome hypothesis to include the possibility of a locus on the Y chromosome and, specifically, genes on X that escaped inactivation and are X-Y homologous loci. Some new information about possible risk loci on these chromosomes has come from the current large genetic consortia genome-wide association studies, suggesting that perhaps this hypothesis needs to be revisited for some schizophrenias. The following commentary reviews the early and more recent literature supporting or refuting this dormant hypothesis and emphasizes the possible candidate genes still of interest that could be explored in further studies.