Consistent with prior literature, this study found elevated rates of psychosis among offspring of affected parents generally comparable for males and females, when parent gender was not taken into consideration. However, we also demonstrated a sex-specific pattern of transmission when parent gender and offspring gender were considered. The rate of psychosis among sons of mothers with psychosis was substantially higher (18.8%) than among the daughters of these women (9.5%). In contrast, the rate of psychosis in daughters was higher when the father was affected (15.2%) compared with that among the sons of these fathers (3.1%). Findings demonstrated a significant difference in the male:female ratio of ill offspring among ill mothers versus ill fathers. Similar patterns were observed when analyses were restricted to SPS or AP, suggesting non-specificity of the sex-dependent risk for type of psychosis, although we had insufficient power to fully test this formally. In addition, inclusion of non-psychotic spectrum disorders attenuated the sex-specific transmission pattern, suggesting specificity of the sex-dependent effect for risk of psychosis and not spectrum disorders per se.
This observed pattern of transmission is, in part, suggestive of X-linked inheritance. As XY males receive their Y chromosomes from fathers, a psychosis risk variant on the X chromosome would never be transmitted from affected fathers to sons. In our sample, only one son of a father with psychosis developed the disease, resulting in prevalence similar to control parent rates and to baseline occurrence of psychosis in the general population. In contrast, an X-linked risk variant would be transmitted from affected XX mothers to 50% of sons on average, assuming each maternal X chromosome has equal chance of transmission. As the psychosis rate in sons of affected mothers was ~19% instead of 50%, the putative X-linked risk variant appears to have reduced penetrance, most likely due to other genetic, epigenetic, and environmental factors contributing to the development of psychosis.
The approximately 2:1 ratio of the risk of psychosis in daughters of affected fathers versus mothers also suggests X-linked inheritance, since an X-linked risk variant would be transmitted from affected XY fathers to all daughters, but to only 50% of daughters of affected mothers (i.e., our data showed: 15.2% versus 9.5% psychosis in daughters of fathers versus mothers with psychosis; ). However, the risk of psychosis in daughters of affected fathers was lower than the expected 100% if the putative risk variant was sufficient for the development of psychosis or a 50% rate if it acted in a recessive manner. This suggests reduced penetrance or multifactorial effects, or X inactivation of the risk chromosome may decrease susceptibility in females, which was previously suggested for psychosis (Crow, 2007
) and bipolar disorder (Rosa et al., 2008
). Lower penetrance in females compared to males was indicated by the lower proportion of psychosis in daughters compared to sons of affected mothers (9.5% versus 18.8%). Since both sexes have an equal chance of receiving the putative mutant X chromosome from affected mothers, the disparity in psychosis risk suggests sex-dependent disease penetrance.
Our findings seem to suggest that an X-linked variant with a relatively large effect influences risk of psychosis. However, linkage and association studies have not identified a large-effect gene on the X chromosome, thus studies may have been underpowered due to incomplete penetrance, small sample sizes, insufficient numbers of affected parents, or allelic heterogeneity. Alternatively, the relevant variation may be epigenetic and thereby undetectable by conventional linkage and association analyses. Epigenetic regulation is gaining increasing attention as an important factor in the etiology of psychosis (Pidsley and Mill, 2011
An alternative explanation for the observed findings could conceivably be due to differential attrition related to both parent and offspring gender. For example, the low prevalence of psychosis among male offspring of affected fathers might have occurred due to a high level of attrition of affected offspring of this type. However, participation rates according to parent and offspring gender were generally quite uniform, ranging from 70% to 90%, with no evidence of a pattern of higher attrition due to gender of the parent or offspring.
The primary limitation of this study is the small sample size when separated by sex of parent and offspring. Thus, it is possible that the observed rates of psychosis are indicative of sex-dependent transmission, and specifically X-linked inheritance, by chance. However, while these findings clearly require replication, we had an a priori hypothesis (and thus we were not “fishing” for significant findings), and the results show a sex-specific pattern that is consistent even though we had low power to reach significance in some of the tests. The 1945 study of a large sample of familial pairs by Penrose(Penrose, 1991
) suggested increased frequency of psychosis in mother-son pairs compared with father-son pairs, although mother-son transmission was only higher in affective psychoses and not in schizophrenia. However, the early definitions of “schizophrenia” and “affective” categories were very heterogeneous compared with current criteria, thus most likely contributing to differences between our findings and those of Penrose when applied to schizophrenia per se. In fact, when examined by psychosis in general, their findings were consistent with ours.
Recent molecular genetic studies have further implicated X chromosome loci in the risk for psychosis and schizophrenia, specifically. For example, male-specific association with SCZ has been reported for haplotypes of the MAOB gene on Xp11.23 (Carrera et al., 2009
), and association between a MAOB polymorphism and psychotic disorders (Bergen et al., 2009
). Furthermore, the SYP/CACNA1F locus in the Xp11 region (Wei and Hemmings, 2006
), the GPR50 gene at Xq28 (Thomson et al., 2005
), and the HOPA gene at Xq13 (Philibert et al., 2001
; Sandhu et al., 2003
; Philibert et al., 2007
) have been associated with schizophrenia or psychosis in general. In addition, the protocadherin 11 X-linked (PCDH11X) gene has been proposed in the etiology of psychosis (Crow, 2008
). Further, the distal long arm (q) of the X chromosome has been linked to schizophrenia spectrum diagnoses in females with Fragile X syndrome (Reiss et al., 1988
), juvenile-onset mood disorders (Wigg et al., 2009
), bipolar and related affective disorders, such as schizoaffective bipolar disorder (Del Zompo et al., 1984
; Zandi et al., 2003
; Mendlewicz et al., 1980
; Baron et al., 1987
), suggesting that polymorphisms in this region of the X chromosome may be associated with psychosis in general rather than specific to schizophrenia. Interestingly, rare variants in microRNA genes, which negatively regulate gene expression, located on the X chromosome were implicated in SCZ risk (Feng et al., 2009
). Of possible further relevance to our data is the finding that a missense mutation in the Xq28 gene methyl-CpG binding-protein 2 (MECP2), which epigenetically regulates transcription via binding methylated DNA, is responsible for PPM-X syndrome, a male-specific X-linked mental retardation syndrome with psychosis, pyramidal signs, and macro-orchidism (Klauck et al., 2002
). These recent molecular genetic studies are consistent with the findings in our high risk study that the X-chromosome is implicated in the development of psychosis and may contribute to understanding sex differences in schizophrenia.
In fact, partial or full X chromosome monosomies in Turner’s syndrome (Ross et al., 2000
; Murphy et al., 1997
; Haberecht et al., 2001
) have been associated with cognitive deficits, such as memory, spatial working memory, language ability, and attention, functions in which sex differences in schizophrenia have been reported (Goldstein et al., 1998
). Further, structural brain abnormalities and brain activity deficits in hippocampus, amygdala, orbitofrontal cortex, have also been reported in Turner’s syndrome (e.g., (Murphy et al., 1997
; Haberecht et al., 2001
; Molko et al., 2004
)), i.e., brain regions that are “normally sexually dimorphic” (Goldstein et al., 2001
; Ross et al., 2000
), and for which we and others have previously demonstrated sex differences in brain volumes in schizophrenia (Goldstein et al., 2002
; Gur et al., 2004
; Elsabagh et al., 2009
; Abbs et al., 2010
- resubmitted). In addition, sex chromosome dosage related to cerebral asymmetry in Turner’s and Kleinfelter’s syndromes suggesting relevance to the genetic basis of psychosis (Rezaie et al., 2009
)). Furthermore, Weickert and colleagues (Weickert et al., 2009
) reported specific genes on the sex chromosomes that influenced the development of prefrontal cortex in a sex-specific manner, a key brain region contributing to schizophrenia pathology. These findings thus provide some evidence that sex-specific transmission of psychosis related to the sex chromosomes has functional relevance for understanding sex differences in the neurobiology of schizophrenia and potentially other psychoses.
Future work in our high risk study includes molecular genetic work in these families. One of the advantages of this high risk study is that offspring were followed from the maternal pregnancy and offspring birth until age 48 years and includes prenatal stored sera. Therefore, we have a unique opportunity to investigate genetic variation in the context of potential prenatal environmental insults and childhood developmental pathways, thus contributing to understanding potential gene-environment interactions in explaining sex differences in psychoses.