Fig displays the distribution of age at onset among all

Fig. 1 displays the distribution of age at onset among all twins affected with schizophrenia and schizophrenia spectrum. We observed that the age range is wider for the schizophrenia spectrum compared to schizophrenia and that spectrum disorders appear to have a slightly earlier onset than the narrow illness definition. The risk of developing schizophrenia in the second twin is 4.7 times higher if the first twin has an early onset of schizophrenia, Table 2a; Hazard ratio (HR)=4.7, 95% CI=(2.05–10.1). The risk is 4.4 times higher in schizophrenia spectrum (HR=4.39, 95% CI=(2.56–7.52)). When adding a correction for sex in the second twin no significant change in the effect of zygosity and age at onset was observed for the risk of either schizophrenia or schizophrenia spectrum (Table 2b). The risk of both illness categories was slightly higher in women than in men but not significant (Table 2b). In addition an interaction term between sex in the second twin and age at onset was added to the model. It has no effect on the risk of schizophrenia spectrum disorder but did reduce the main effect of age at onset on risk of schizophrenia (Table 2c). A putative link between sex in the second twin and onset of schizophrenia (but not schizophrenia spectrum) is also seen when female and male twins are analyzed separately. We observed that the effect of early onset in the first twin on risk of disease in the second twin is markedly larger in females than in males. The effect is significant but there is uncertainty about the size of the effect because of wide confidence intervals (Females: HR=8·66, CI=(2.65–28.33)) (Table 3). One pair was excluded because the twins were diagnosed on the same day, hence the final analyses included a sample of N=447 and N=787 pairs for analysis in schizophrenia and schizophrenia spectrum respectively. The total follow-up time in co-twins was 18,385.36 and 32,382.19years for schizophrenia and schizophrenia spectrum respectively; this corresponds to 41.13 and 41.14years per co-twin. Dividing the age at onset in the first diagnosed twin into four intervals; i.e. <18, [18–22), [22–30) and [30, onwards) shows that co-twins within the first three intervals (<18, [18–22), [22–30)) all have an increased risk of schizophrenia (Table 4). In fact, having a diagnosed co-twin with onset below 18years increases the risk of illness 7 times ([1.3–39]), likewise onset from 18 to 22years increases the risk off illness 9 times ([2.8–30.9]). Results were similar for schizophrenia spectrum with a significantly increased risk of schizophrenia spectrum in the co-twin with lower age at onset of the diagnosed twin. Upon dividing the sample into four age intervals, the sample size was smaller and it HZ-1157 was not possible to apply the same analysis strategy (with gender specific analysis and interaction terms) as in Table 2. Kaplan-Meier curves documented a closer proximity in time of diagnoses among MZ twins than DZ twins following both the onset of schizophrenia and schizophrenia spectrum disorder in the co-twin (Fig. 2a; Chi2=15.12, P<0.001, Fig. 2b; Chi2=16.55, P<0.001).
Discussion Our main finding indicates, law of the minimum early illness onset can be perceived as a clinical marker for increased genetic vulnerability. This is in line with a study showing that increased family illness load predicted an earlier age at illness onset (Goldberg et al., 2011) and a Swedish register-based study investigating age-specific risk of illness with the highest risk found in the youngest age groups (Li et al., 2007). In our study the risk seemed more prominent in females, suggesting that early onset in females is caused by a higher genetic burden. This is consistent with females in general having a lower risk of developing schizophrenia than males (Pedersen et al., 2014) and thereby may require a stronger genetic contribution to affect the predisposition to illness. Sex difference was not apparent for the broader illness category. The association of increased familial aggregation of schizophrenia with a younger age at onset was also described in a meta-analysis (Esterberg et al., 2010).This applied to both sexes; however but without familial aggregation males had a significantly earlier onset. The results further underline the importance of genetic factors to affect early illness onset in females, whereas an early onset for the male sex to a larger extent could be influenced by other risk factors, such as environmental risks. This is supported by evidence from a study showing that early onset cases are more likely to be males that have experienced obstetric complications and had a history of drug abuse and low academic performance (Liu et al., 2013), and from a study in male patients where accumulated environmental risks significantly lowered age at illness onset (Stepniak et al., 2014). In conclusion, these findings indicate that female sex may modify the association with early onset of schizophrenia and increase risk and supports a role for sex-specific genetic interactions. All though the findings are significant, a specific limitation is the low number of cases (concordant pairs) when dividing the dataset into both illness onset before and after age 22 and sex. Other studies support differences in illness presentation between males and females regarding premorbid adjustment and symptom severity but not to illness course (Goldberg et al., 2011; Drake et al., 2016). However, there is contradictory evidence for a specific genetic association to sex differences in schizophrenia (Hänninen et al., 2007; Yuan et al., 2013; Bergen et al., 2014; Chow et al., 2016). When dividing the age at onset in four intervals we were able to examine the possible presence of a more stepwise increase of risk rather than the dichotomous cut in before and after age 22. Here we found an increasing risk of illness in the second twin with decreasing age at onset in the first diagnosed twin (Table 4). In general the confidence intervals are rather wide, which reflect a small number of cases in each age group, especially when studying the narrow illness definition (Table 1). In the schizophrenia spectrum category where more cases are included, all results are significant and have smaller confidence intervals.