X marks the missing heritability?
Discovering sources of the “missing” heritability for mental disorders such as schizophrenia remains one of the most important issues in contemporary psychiatry. A new paper by Goldstein et al. (2011) in Schizophrenia Research provides a novel clue. Their study of high-risk families demonstrates strongly, significantly sex-specific transmission of psychosis. For mothers with psychosis, 18.8 percent (12 of 64) of their sons developed psychosis, compared to 9.5 percent (7 of 74) of their daughters. Fathers with psychosis showed the opposite pattern: 3.1 percent (1 of 32) of their sons developed psychosis, compared to 15.2 percent (5 of 33) of their daughters (P < 0.05 comparing affected son to daughter ratio between mothers and fathers). Goldstein et al. (2011) note that these findings can be explained by two simple processes: 1) X-linked inheritance, in that fathers pass their X chromosome only to daughters, while mothers pass an X to both son and daughter, and 2) reduced penetrance of the effect in females compared to males.
These results are extraordinary for their apparent magnitude: if such X-linked effects generalize to other populations, then a substantial proportion of the “missing” heritability for psychosis resides on the X chromosome. For a start, comparable sex-specific inheritance results were also reported in Perrin et al. (2010, Figures 1 and 2) for schizophrenia (see also Harlap et al., 2009). But how can such an inference hold if GWAS and candidate-gene studies fail to show any concentration for risk of schizophrenia on the X? One possible explanation noted by the authors is X-linked epigenetic variation, such as effects of variable methylation or X inactivation, affecting brain phenotypes and psychiatric conditions. For example, variable DNA methylation of IGF2 (at 11p15.5) is highly correlated with brain weight in males (Pidsley et al., 2010), and discordance in X inactivation patterns was higher in female bipolar twins discordant for bipolar disorder (though not for schizophrenia) than in those concordant for the disorder (Rosa et al., 2008). X-linked epigenetic effects may also help to explain findings such as: 1) a concentration of intellectual disability genes on the X, coupled with a lack of evidence from linkage or genetic association studies for X-linked genes underlying measures of intelligence (Deary et al., 2009); 2) early studies showing X-linked inheritance patterns of visual-spatial abilities (Bock and Kolakowski 1973; Wittig 1976; Walker et al., 1981) and measures of IQ (Lehrke, 1997, page 134) that have not been followed up by modern behavioral geneticists; and 3) high rates of schizophrenia in Klinefelter syndrome (usually XXY) and XXX females (DeLisi et al., 2005; van Rijn et al., 2006; Crespi, 2008). Dysregulated methylation of brain-expressed, X-linked genes has also been postulated as a contributing factor in the etiology of autism, based on convergent, albeit indirect, evidence (Jones et al., 2008; see also Loat et al., 2008).
Do heritable epigenetic marks on the X contribute to schizophrenia risk? Methylation of the X chromosome in relation to psychiatric conditions has yet to be studied, but now appears even more worthy of attention.
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