The aim of this multigenerational, multiplex family study of schizophrenia was to construct genetically homogeneous and uncorrelated schizotypal personality disorder genetic factor scales, estimate heritabilities of the genetic factor scales, and calculate genetic correlations between the genetic factor scales and schizophrenia, major depressive disorder (MDD), and substance dependence. The findings can be summarized as follows and are discussed below:
- Six uncorrelated, schizotypal personality disorder genetic factors were identified, accounting for 87% of the variance in all SIS scales.
- All schizotypal personality disorder genetic factor scales were significantly heritable. Thus, the difference among individuals on a particular factor scale was importantly caused by genetic effects.
- Two of the genetically distinct schizotypal personality disorder factor scales, Eccentric Behavior and Unusual Beliefs, were significantly negatively genetically correlated with schizophrenia.
- None of the six schizotypal personality disorder genetic factor scales were significantly genetically correlated with MDD or substance dependence.
Schizotypy Genetic Factors
To date, factor analyses of schizotypal personality disorder symptoms among relatives of schizophrenia patients have been exclusively “phenotypic” in nature. Phenotypic factors reflect both genetic and environmental covariance and thus confound the effects of genes and environment on symptoms of schizotypal personality disorder. This study is the first to examine the genetic factor structure of schizotypy in an attempt to disentangle genetic and environmental effects. This exploratory factor analysis suggested that six genetic factors best accounted for the genetic covariance among SIS scales, a solution similar to the five traits of “borderline schizophrenia” originally proposed by Kety and colleagues (Copenhagen Adoption Study; Kety, Rosenthal, Wender, & Schulsinger, 1968
All six genetic factors were significantly heritable and genetically uncorrelated with each other, and thus appear to reflect six distinct, latent genetic variables. The modest heritabilities obtained for the schizotypy genetic factors (h2
mean = 0.45, range: 0.25 to 0.58) and the individual SIS scales (h2
mean = 0.47, range: 0.18 to 0.74) are consistent with previous heritability estimates for schizotypal personality disorder in relatives of schizophrenia patients (estimated at 0.61; Torgersen et al., 2000
). This suggests that on average, approximately half the variance of schizotypy traits can be attributed to genetic effects, although this percentage varies considerably across traits, ranging from approximately 20% to over 70%. Given that schizophrenia has an estimated heritability of approximately 0.80 (Cardno et al., 1999
), but is not itself apparently associated with one or a few genes of large effect, it is clear that high heritability does not necessarily indicate utility in identifying schizophrenia “risk” genes (Pogue-Geile & Yokley, 2010
). Alternatively, if less than 50% of a trait’s variance is attributable to genetic effects, but that genetic variance is correlated with the effects of only one or a small number of “risk” genes, such traits could be useful in detecting genetic associations.
Schizotypy Genetic Factor Scales and Genetic Correlation with Schizophrenia
Two genetic factor scales, Eccentric Behavior and Unusual Beliefs, were significantly negatively genetically correlated with schizophrenia. These results suggest that during the interview, close relatives of schizophrenia probands reported fewer atypical beliefs, superstitions, and feelings of being scrutinized in public, and were observed by the interviewer to display less unconventional thinking, odd social behavior, and hostility, compared to more distant relatives. The negative direction of the significant genetic correlations for the Eccentric Behavior and Unusual Beliefs factor scales was not predicted. In an effort to understand these unexpected findings, several possible explanations were considered.
First, it certainly may be that the significant negative correlations we observed were simply a result of chance. A Bonferroni correction suggests assuming a significance threshold of .008 for the six SIS genetic factors. Utilizing these guidelines, all six genetic factors would remain significantly heritable. However, none of the genetic correlations with schizophrenia would remain significant; therefore, Bonferroni corrected results would indicate no genetic association between schizotypal personality disorder symptoms and schizophrenia. Although Bonferroni correction is conservative, it is possible that these significant negative genetic correlations with schizophrenia are due to chance. Similarly, it may be that these unexpected negative genetic correlations with schizophrenia are spurious given that the interviewers were not blind to participant group status. However, most hypotheses of rater bias effects would predict inflated positive genetic correlations with schizophrenia, not negative.
It is also possible that first-degree relatives from multiplex families may be somehow different on measures of schizotypy compared to first-degree relatives from simplex families, perhaps due to differences in expression of risk genes or environmental experiences. As such, the negative genetic correlations between schizotypal symptoms and schizophrenia in the current multiplex sample may be valid, but could differ from findings in simplex families. Recent evidence suggests a similar phenotypic factor structure of schizotypal personality disorder symptoms in multiplex and simplex families, however (Lien, et al., 2010
A final potential explanation for the negative genetic correlations observed for Eccentric Behavior and Unusual Beliefs is that during the interview, closer relatives were especially likely to underreport unusual ideas, beliefs, and behavior. As familial relatedness to schizophrenia probands decreased, bias against reporting unusual thoughts and behavior in turn became increasingly rare. This situation would produce a negative familial correlation between the more “unusual” or “positive” symptoms of schizotypy (e.g., magical thinking) and schizophrenia in the current study.
The notion of response bias against “positive” or psychotic-like symptoms in relatives of schizophrenia patients was first suggested more than two decades ago by Katsanis, Iacono and Beiser (1990)
and Clementz, Grove, Katsanis, and Iacono (1991)
. Both reports indicated that first-degree relatives scored lower (endorsed less pathology) than controls on the Perceptual Aberration Scale (Chapman, Chapman, & Raulin, 1978
), despite scoring higher (greater pathology) than controls on the Social and Physical Anhedonia scales (Chapman, Chapman, & Raulin, 1976
). Since that time, several studies have reported similar findings using the Chapman Scales as well as questionnaire and interview measures of schizotypal personality disorder (Huxley et al., 1993
). For example, Appels et al., (2004)
reported that parents of schizophrenia patients endorsed significantly fewer unusual experiences and beliefs compared to controls on the Schizotypal Personality Questionnaire (SPQ; Raine, 1991
). In fact, in our recent review of schizotypy in relatives, results of available studies published between 1991 and 2009 supported a medium to large effect of social-interpersonal symptoms among first-degree relatives compared to controls (mean d = 0.67), but only a small effect of cognitive-perceptual symptoms (mean d = 0.37) (Tarbox & Pogue-Geile, 2011
Models of reporting bias
The results of the current study and others suggest two possible models of reporting bias in relatives of schizophrenia patients. First, a response bias among relatives could occur due to increased “exposure” to the schizophrenia proband and reluctance to endorse positive schizotypal symptoms associated with their relative’s illness. In this situation, biased responding among close relatives could be entirely due to shared environmental effects rather than schizotypal suspiciousness associated with genetic liability to schizophrenia. This hypothesis implies that in family studies, closer degree relatives will show lower self-reported positive symptoms than more distant relatives due to their increased exposure to a proband. This will be detected as a negative “genetic” correlation with schizophrenia because in family studies like the current one genetic and shared environmental similarity are confounded. In addition, under this model it could also be hypothesized that these self-report ratings should be uncorrelated with observer-rated pathology within relatives. This is predicted because the observer ratings arise primarily due to relatives’ own pathology, whereas the self-report bias comes from a different (presumably uncorrelated) source – degree of exposure to the proband.
A second, but not mutually exclusive model is that increased genetic liability to schizophrenia does elevate schizotypy symptoms, including suspiciousness, leading to heightened guardedness and underreporting among close relatives irrespective of their experience with the schizophrenia proband. In this case, some relatives may adopt a reporting stance of broad symptom minimization that includes both positive and negative schizotypy. As above, this scenario would predict that closer relatives to a schizophrenia proband would show lower self-report symptoms compared to more distant relatives due to genetic effects on suspiciousness. However, this second model could also be hypothesized to predict a negative correlation between self-report positive symptom ratings and observed pathology within relatives because those individual relatives observed to be most pathological would also tend to be most suspicious and thus under-report symptoms.
The construction of the SIS provides an opportunity to further examine these models of response bias. The SIS instrument consists of two types of scales, those rated based on the participant’s self-report responses to interview questions and those rated after the interview based on the interviewer’s observation of the participant. Post-hoc examination of genetic correlations between the individual SIS scales and schizophrenia (provided in ) show first, that the observer-rated SIS scales were on average positively genetically correlated with schizophrenia (Rg
: mean = 0.19; range = −0.04 to 0.47), with only one of seven (14%) showing a negative genetic correlation. Furthermore, among the observer ratings, “Guardedness” showed the strongest positive genetic correlation with schizophrenia (Rg
= 0.47). Of note, performance on a computerized neurocognitive battery, which also is less likely to be influenced by response bias, was positively genetically correlated with schizophrenia in this multiplex sample such that first-degree relatives showed greater cognitive impairments than less closely related family members (Gur, et al., 2007
; Yokley et al., in press
). These findings support an association between genetic relatedness to schizophrenia and observed pathology among relatives.
Genetic Correlations of SIS Scales and Schizophrenia
Second, in contrast to observation ratings, self-report SIS scales had a mean genetic correlation with schizophrenia of Rg
= −0.02 (range: −0.35 to 0.25), and 50% (7 of 14) of the scales were negatively genetically correlated with schizophrenia. The three self-report scales most strongly negatively correlated with schizophrenia were (Rg
): Ideas of Reference: Watched (−0.35), Magical Thinking (−0.30), and Illusions (−0.23) (all involving psychotic-like phenomena), whereas the strongest positive genetic correlations were for Social Isolation (0.25), Sexual Anhedonia (0.18), and Anger to Perceived Slights (0.18). This suggests that underreporting may be primarily restricted to positive schizotypy symptoms, rather than a generalized minimization of pathology. Other studies also suggest that relatives of schizophrenia patients do not appear to demonstrate generalized defensive underreporting as measured by the K scale on the Minnesota Multiphasic Personality Inventory (MMPI). The K scale is a sensitive measure of underreporting developed to adjust scores on MMPI clinical scales that may have been spuriously minimized by defensive response bias (Greene, 1980
). Two studies found that relatives scored higher than controls on the K scale, but the differences were small and probably not significant (MacCrimmon, Cleghorn, Asarnow, & Steffy, 1980
; Moldin, Gottesman, Erlenmeyer-Kimling, & Cornblatt, 1990
). In another study, MMPI K-scale items were interspersed within the Schizotypal Personality Questionnaire (SPQ; Raine, 1991
) and relatives scored significantly lower (less-defensive) than controls (although curiously both groups scored higher than “normal” suggesting perhaps something unusual about the control group or measurement instrument (Calkins, Curtis, Grove, & Iacono, 2004
). These observations also support underreporting of specific psychosis-like pathology in relatives, but not necessarily due to a generalized defensiveness such as that measured by the K scale.
Third, correlations within relatives between the three self-report SIS scales most negatively genetically correlated with schizophrenia (all positive schizotypy symptoms - Ideas of Reference: Watched, Magical Thinking, and Illusions) and the seven observer-rated SIS scales are also informative. Ideas of Reference: Watched showed small, but significant positive correlations with all observer ratings (r: mean = 0.16; range = 0.09 to 0.20) and correlations for Magical Thinking were also in the positive direction with five reaching significance (r: mean = 0.11; range = 0.03 to 0.16), whereas the Illusions scale was not correlated with any observer ratings (r: mean = 0.02; range = −0.07 to 0.06). As such, self-reported positive schizotypy symptoms were either modestly positively correlated, or uncorrelated with ratings of observed pathology within relatives. This lack of negative within-person correlations between self-report and observer ratings is not consistent with the second model of bias (underreporting due to genetically influenced suspiciousness). Instead, these correlations are somewhat, although not unambiguously, more supportive of the first model of bias based on relatives’ exposure to probands, which predicts self-report and observer ratings to be uncorrelated.
Although the results of these post-hoc analyses, along with previous reports, may be somewhat more consistent with the first “exposure” model of reporting bias described above, which suggests that reluctance to endorse positive schizotypy symptoms is affected by shared environmental experience with a relative with schizophrenia, the most definitive evidence needed to distinguish between these two models of bias is information from adoptive and reared apart biological relatives, which unfortunately is not available in the current study. Without adoption data we cannot know for certain if the observed negative familial correlations reflect genetically influenced suspiciousness or reluctance to endorse psychotic-like experiences due to shared environmental knowledge.
There are a few adoption studies that provide relevant data, although they do not decisively resolve this issue. Comparisons between adoptive relatives of schizophrenia adoptees and non-schizophrenia control adoptees have found that adoptive mothers of schizophrenia probands are less guarded compared to adoptive mothers of controls (Rimmer et al., 1979
; Wender, Rosenthal, & Kety, 1968
). These findings are inconsistent with the model that bias is an effect of shared environmental exposure to a proband, although perhaps adoptive parent knowledge that they are genetically unrelated to the proband served to reduce parent guardedness. Important data from reared apart biological relatives of schizophrenia probands are available from Ingraham’s report from the Danish adoption studies. These data indicate that suspicion, flat affect, and withdrawal were the only schizotypal symptoms significantly increased among reared apart biological relatives of schizophrenia adoptees compared to controls, whereas positive psychotic-like symptoms were not significantly increased (Ingraham, 1995
). However, it is unclear if these data support genetic effects on bias, because the statistical analysis was one-tailed and thus appropriately did not indicate whether biological relatives reported significantly decreased positive psychotic-like symptoms (which would suggest underreporting due to genetic effects), or simply reported no significant differences from controls.
Schizotypy Genetic Factor Scales and Genetic Correlation with MDD and Substance Dependence
In contrast to schizophrenia, none of the six genetic factor scales were significantly genetically correlated with either MDD or substance dependence. The possible exception is Paranoid Fears, which may share a proportion of genetic effects with liability to substance dependence. The low genetic correlations of these factor scales with MDD and substance dependence in this sample support a degree of specificity to schizophrenia, or to positive symptoms in particular. Of course, replication in general population samples of MDD and substance dependence probands and their relatives is necessary to clarify generalizability, but inflation of results due to schizophrenia risk genes seems unlikely as these diagnoses were not genetically correlated with schizophrenia in this sample.
Large multiply affected families represent a minority of families of schizophrenia patients, thus comparisons between our results and those obtained from simplex family studies may not be straightforward. Given that the MDD and substance dependence “probands” in the current study were also relatives of schizophrenia patients, generalizability of these results also should remain tentative until they can be replicated in a general population sample of individuals with these diagnoses. In addition, the family design of this study prevented the separate examination of effects that were due to genes and those that were due to shared environmental effects. As in the case of twin studies, this family study presumes no correlation between genetic effects and shared environmental effects. However, as noted above, without adoptive relatives in the current study, we cannot know for sure if the observed negative “genetic” correlations reflect guardedness due to genetic effects or due to shared environmental experience.