In this study we are unable to

In this study we are unable to estimate the contribution of environmental factors to schizophrenia risk. We interpret the overall higher risk in MZ twins (in all our results) as indication of the importance of genetic factors according to the classical twin model (Boomsma et al., 2002). Furthermore, one assumption in the classical twin model is the “Equal Environment Assumption”, i.e. that DZ twins share their environment to the same extend as MZ twins (Rijsdijk and Sham, 2002). This has been subject to debate, and if MZ twins do share a more equal environment than DZ twins, then the impact of genetic factors on illness risk can be overestimated. The observation of significant genetic effects does not insinuate that the environmental risks are less important because schizophrenia is a complex disorder with a heterogeneous clinical presentation (Owen et al., 2016). Indeed it HZ-1157 is influenced by both genetic and several environmental risk factors and the complex interaction between them (Davis et al., 2016). We showed that the almost identical genetic background in MZ twins compared with the average genetic identity of 50% in DZ twins is reflected in higher concordance with respect to time at illness onset within pairs, i.e. in MZ twins the observed time span between the assignments of the diagnoses is shorter than in DZ twins (Fig. 2). To our knowledge, the association of a shared genetic background and timing of illness onset in twins has not been demonstrated previously. A study of genetic influence on subtypes of schizophrenia, such as age at onset, did not show a simple genetic architecture in relation to early illness onset (Bergen et al., 2014), but our results indicate the importance of genetic effects in the pattern of illness onset in twin pairs. The Kaplan Meier curve in Fig. 2a and b does not stratify between the outcome and possible competing risks. Accordingly, the absolute figures on the Y-axis must be taken with reservation. The most important competing risk in this study is occurrence of death before having a possible diagnosis of schizophrenia spectrum. In this study, we can assume that censoring and competing risks will be the same for MZ and DZ twins, thus we expect the result of a greater proximity of schizophrenia spectrum disorders in MZ twins compared to DZ twins, to be governed by genetic effects rather than competing risks. The Kaplan-Meier curves illustrating schizophrenia and schizophrenia spectrum are similar (Fig. 2a and b). This indicates that the timing of illness onset does not seem to differ when comparing a narrow illness definition to the broader including the schizophrenia spectrum. Also the HR estimated in Tables 1–3 does not indicate profound differences in the two diagnostic outcomes. In general, our results support that the genetic susceptibility covers a broad phenotypic outcome in the full spectrum of schizophrenia. Previous studies have also confirmed the importance of a broad approach when estimating the risk of severe mental illness in relatives (Mortensen et al., 2010; Rasic et al., 2014). General strengths and limitations: The present sample consists of twin pairs from a comprehensive, nationwide register and is as such less liable to ascertainment bias. Removing twin pairs with UZ from the estimates might introduce a selection bias, but since the degree of shared genetic material is unknown in UZ twins, it is not possible to study genetic importance in risk of early illness onset. As a national register, the Danish Psychiatric Central Research Register is highly representative of patients with schizophrenia in Denmark since only a minimal number of patients are treated privately (Mors et al., 2011). Furthermore, a recent study demonstrated a high validity of the register diagnosis in schizophrenia consolidating the validity and consistency of the register diagnosis (Uggerby et al., 2013). Despite the comprehensive register data undiagnosed cases could exist. Additionally, the register-based data does not provide specific information on the twin pairs, thereby we are unable to include knowledge on environmental parameters of interest, such as whether twin pairs were reared together, or information on e.g. the importance of the prodromal phase, which could be relevant when addressing illness risk. In general, there may be a twin diagnosis bias in which there is a higher probability for the second twin to come to the attention of clinicians and thus be diagnosed, which could partly explain the increased risk of schizophrenia in the second twin. It is also possible that clinicians may be more attentive towards families presenting with an early onset case. The use of a Danish twin sample may limit the generalizability of our findings. In general it is assumed that twins are representative for the general population (Rijsdijk and Sham, 2002).