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.

References:

Bock RD, Kolakowski D. Further evidence of sex-linked major-gene influence on human spatial visualizing ability. Am J Hum Genet. 1973 Jan;25(1):1-14. Abstract

Crespi B. Genomic imprinting in the development and evolution of psychotic spectrum conditions. Biol Rev Camb Philos Soc. 2008 Nov;83(4):441-93. Abstract

Deary IJ, Johnson W, Houlihan LM. Genetic foundations of human intelligence. Hum Genet. 2009 Jul;126(1):215-32. Abstract

DeLisi LE, Maurizio AM, Svetina C, Ardekani B, Szulc K, Nierenberg J, Leonard J, Harvey PD. Klinefelter's syndrome (XXY) as a genetic model for psychotic disorders. Am J Med Genet B Neuropsychiatr Genet. 2005 May 5;135B(1):15-23. Abstract

Goldstein JM, Cherkerzian S, Seidman LJ, Petryshen TL, Fitzmaurice G, Tsuang MT, Buka SL. Sex-specific rates of transmission of psychosis in the New England high-risk family study. Schizophr Res. 2011 May;128(1-3):150-5. Abstract

Harlap S, Perrin MC, Deutsch L, Kleinhaus K, Fennig S, Nahon D, Teitelbaum A, Friedlander Y, Malaspina D. Schizophrenia and birthplace of paternal and maternal grandfather in the Jerusalem perinatal cohort prospective study. Schizophr Res. 2009 Jun;111(1-3):23-31. Abstract

Jones JR, Skinner C, Friez MJ, Schwartz CE, Stevenson RE. Hypothesis: dysregulation of methylation of brain-expressed genes on the X chromosome and autism spectrum disorders. Am J Med Genet A. 2008 Sep 1;146A(17):2213-20. Abstract

Loat CS, Haworth CM, Plomin R, Craig IW. A model incorporating potential skewed X-inactivation in MZ girls suggests that X-linked QTLs exist for several social behaviours including autism spectrum disorder. Ann Hum Genet. 2008 Nov;72(Pt 6):742-51. Abstract

Perrin M, Harlap S, Kleinhaus K, Lichtenberg P, Manor O, Draiman B, Fennig S, Malaspina D. Older paternal age strongly increases the morbidity for schizophrenia in sisters of affected females. Am J Med Genet B Neuropsychiatr Genet. 2010 Oct 5;153B(7):1329-35. Abstract

Pidsley R, Dempster EL, Mill J. Brain weight in males is correlated with DNA methylation at IGF2. Mol Psychiatry. 2010 Sep;15(9):880-1. Abstract

Rosa A, Picchioni MM, Kalidindi S, Loat CS, Knight J, Toulopoulou T, Vonk R, van der Schot AC, Nolen W, Kahn RS, McGuffin P, Murray RM, Craig IW. Differential methylation of the X-chromosome is a possible source of discordance for bipolar disorder female monozygotic twins. Am J Med Genet B Neuropsychiatr Genet. 2008 Jun 5;147B(4):459-62. Abstract

van Rijn S, Aleman A, Swaab H, Kahn R. Klinefelter's syndrome (karyotype 47,XXY) and schizophrenia-spectrum pathology. Br J Psychiatry. 2006 Nov;189:459-60. Abstract

Walker JT, Krasnoff AG, Peaco D. Visual spatial perception in adolescents and their parents: the X-linked recessive hypothesis. Behav Genet. 1981 Jul;11(4):403-13. Abstract

Wittig MA. Sex-differences in intellectual-functioning - how much of a difference do genes make. Sex Roles 1976 2(1):63-74.

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