Sex-specific rates of transmission of psychosis in the New England high-risk family study

Abstract

Recent molecular genetic studies have demonstrated X-chromosome abnormalities in the transmission of psychosis, a finding that may contribute to understanding sex differences in the disorder. Using our family high risk paradigm, we tested the hypothesis that there are sex-specific patterns of transmission of psychosis and whether there is specificity comparing nonaffective- with affective-type psychoses. We identified 159 parents with psychoses (schizophrenia psychosis spectrum disorders (SPS, n = 59) and affective (AP, n = 100)) and 114 comparable, healthy control parents. 203 high risk (HR) and 147 control offspring were diagnostically assessed (185 females; 165 males). We compared the proportion of male:female offspring with psychoses by affected parent sex and the consistency for SPS compared to AP parents, and tested (using exact logistic regression) whether the male:female ratio for affected offspring differed significantly between affected mothers and affected fathers. Risk of psychosis in offspring was a function of the sex of the parent and offspring. Among ill mothers, 18.8% of their male offspring developed psychosis compared with 9.5% of their daughters. In contrast, among ill fathers, 3.1% of their male offspring developed psychosis compared with 15.2% of their daughters. The male:female ratio for affected offspring differed significantly (p < 0.05) between affected mothers and fathers. Similar patterns held for SPS and AP. Results demonstrated sex-specific transmission of psychosis regardless of psychosis-type and suggest X-linked inheritance. This has important implications for molecular genetic studies of psychoses underscoring the impact of one's gender on gene–brain–behavior phenotypes of SCZ.

Introduction

Relative risk estimate for schizophrenia in first-degree relatives of persons with schizophrenia (SCZ) is ~ 10% (Gottesman, 1994), with a high schizophrenia (SCZ) heritability estimate of 80–85% (Cardno and Gottesman, 2000). Recent genomic studies have implicated a small number of SCZ susceptibility genes, including major histocompatibility complex (MHC) locus (Stefansson et al., 2009, Shi et al., 2009) and copy number variations (Sebat et al., 2009, Bassett et al., 2010) although not consistently (Craddock et al., 2010), and suggest that small effect genes act in aggregate to account for ≥ one-third of SCZ liability (International Schizophrenia Consortium et al., 2009).

It was generally accepted that elevated risk among relatives did not vary by proband's gender. This was challenged by our group and others demonstrating that the risk was associated with proband or relative gender (Bellodi et al., 1986, Pulver et al., 1990, Goldstein et al., 1990). Another line of thinking hypothesized that a gene for psychosis was located on the sex chromosomes (DeLisi and Crow, 1989), based in part on the high rates of psychosis and schizophrenia traits in individuals with X chromosome anomalies (Boks et al., 2007, DeLisi et al., 2005, van Rijn et al., 2006, Roser and Kawohl, 2008). However, linkage studies investigating X chromosome reported weak evidence on Xp11, Xq21, and Xq26 (Paterson, 1999), and a consensus review report on X chromosome (Paterson, 1999) and a large sibling pair cohort study (DeLisi et al., 2000) reported overall negative evidence for X linkage with SCZ. Thus investigators have been less likely to pursue this hypothesis even though there has been recent molecular genetic evidence that there may be an X-chromosome contribution to understanding schizophrenia (Philibert et al., 2007, Carrera et al., 2009, Wei and Hemmings, 2006, Crow, 2008). Reasons for discrepancies across studies include: false-positive results, small sample sizes with insufficient statistical power to identify a locus, genetic and clinical heterogeneity of samples, and statistical methods unable to take into account the complexity of gene–gene or gene–environment transmission (Szatmari et al., 1998, Porteous et al., 2003, Alaerts and Del-Favero, 2009, Bearden et al., 2004).

Thus, in a recently completed high-risk (HR) study, we tested the hypothesis that there are sex differences in the risk for psychoses among adult offspring of parents with psychoses. Specifically, if there was evidence of X chromosome transmission, we predicted that fathers with psychoses would be more likely to produce daughters with psychoses than sons, given that fathers do not transmit an X chromosome to sons, and mothers with psychoses would be more likely to give birth to affected sons than daughters, given that only mothers transmit the X chromosome to sons. Given the previous literature, we further predicted that this sex-specific pattern would be consistent for schizophrenia spectrum psychotic disorders and for affective psychoses (e.g., bipolar disorder with psychosis).